CN1714084A - 嘧啶-2,4,6-三酮类金属蛋白酶抑制剂 - Google Patents
嘧啶-2,4,6-三酮类金属蛋白酶抑制剂 Download PDFInfo
- Publication number
- CN1714084A CN1714084A CNA018180841A CN01818084A CN1714084A CN 1714084 A CN1714084 A CN 1714084A CN A018180841 A CNA018180841 A CN A018180841A CN 01818084 A CN01818084 A CN 01818084A CN 1714084 A CN1714084 A CN 1714084A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- phenoxy
- group
- radical
- diseases
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 title abstract description 13
- 239000003475 metalloproteinase inhibitor Substances 0.000 title abstract description 5
- 238000000034 method Methods 0.000 claims abstract description 46
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 39
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 235
- -1 Alkyl radical Chemical class 0.000 claims description 224
- 125000001424 substituent group Chemical group 0.000 claims description 67
- 125000000217 alkyl group Chemical group 0.000 claims description 62
- 125000001072 heteroaryl group Chemical group 0.000 claims description 57
- 125000000623 heterocyclic group Chemical group 0.000 claims description 44
- 125000003545 alkoxy group Chemical group 0.000 claims description 41
- 229910052760 oxygen Inorganic materials 0.000 claims description 41
- 150000003839 salts Chemical class 0.000 claims description 41
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 38
- 229910052739 hydrogen Inorganic materials 0.000 claims description 37
- 239000001257 hydrogen Substances 0.000 claims description 37
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 35
- 239000001301 oxygen Substances 0.000 claims description 35
- 229910052736 halogen Inorganic materials 0.000 claims description 32
- 150000002367 halogens Chemical class 0.000 claims description 32
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 27
- 229910052801 chlorine Inorganic materials 0.000 claims description 27
- 229910052794 bromium Inorganic materials 0.000 claims description 26
- 201000010099 disease Diseases 0.000 claims description 26
- 150000005840 aryl radicals Chemical class 0.000 claims description 20
- 229910052731 fluorine Inorganic materials 0.000 claims description 20
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 19
- 239000000203 mixture Substances 0.000 claims description 18
- 125000004432 carbon atom Chemical group C* 0.000 claims description 17
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 17
- 241000124008 Mammalia Species 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 13
- 210000003169 central nervous system Anatomy 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 13
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 11
- 125000003342 alkenyl group Chemical group 0.000 claims description 10
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
- 238000006467 substitution reaction Methods 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- 125000005842 heteroatom Chemical group 0.000 claims description 7
- 208000018631 connective tissue disease Diseases 0.000 claims description 6
- 208000027866 inflammatory disease Diseases 0.000 claims description 6
- 208000017169 kidney disease Diseases 0.000 claims description 6
- 210000004185 liver Anatomy 0.000 claims description 6
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 5
- 208000022873 Ocular disease Diseases 0.000 claims description 5
- 208000019423 liver disease Diseases 0.000 claims description 5
- 208000030159 metabolic disease Diseases 0.000 claims description 5
- 230000009933 reproductive health Effects 0.000 claims description 5
- 208000023504 respiratory system disease Diseases 0.000 claims description 5
- 208000017520 skin disease Diseases 0.000 claims description 5
- 208000035473 Communicable disease Diseases 0.000 claims description 4
- 208000026935 allergic disease Diseases 0.000 claims description 4
- 208000026278 immune system disease Diseases 0.000 claims description 4
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 3
- 206010029098 Neoplasm skin Diseases 0.000 claims description 3
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 3
- 208000018556 stomach disease Diseases 0.000 claims description 3
- OXSYWPDJZMGUOT-UHFFFAOYSA-N 5-(2-ethoxyethyl)-5-[4-(4-pyrimidin-4-ylphenoxy)phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound C=1C=C(OC=2C=CC(=CC=2)C=2N=CN=CC=2)C=CC=1OC1(CCOCC)C(=O)NC(=O)NC1=O OXSYWPDJZMGUOT-UHFFFAOYSA-N 0.000 claims description 2
- VDBIMEBUTGEHGU-UHFFFAOYSA-N 5-(2-ethoxyethyl)-5-[4-[4-(1,3-oxazol-5-yl)phenoxy]phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound C=1C=C(OC=2C=CC(=CC=2)C=2OC=NC=2)C=CC=1OC1(CCOCC)C(=O)NC(=O)NC1=O VDBIMEBUTGEHGU-UHFFFAOYSA-N 0.000 claims description 2
- LNEQEABJJGGNEB-UHFFFAOYSA-N 5-(2-ethoxyethyl)-5-[4-[4-(1,3-thiazol-2-yl)phenoxy]phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound C=1C=C(OC=2C=CC(=CC=2)C=2SC=CN=2)C=CC=1OC1(CCOCC)C(=O)NC(=O)NC1=O LNEQEABJJGGNEB-UHFFFAOYSA-N 0.000 claims description 2
- PVQVZBZVLHMJTB-UHFFFAOYSA-N 5-(2-ethoxyethyl)-5-[4-[4-(1-methylpyrazol-3-yl)phenoxy]phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound C=1C=C(OC=2C=CC(=CC=2)C2=NN(C)C=C2)C=CC=1OC1(CCOCC)C(=O)NC(=O)NC1=O PVQVZBZVLHMJTB-UHFFFAOYSA-N 0.000 claims description 2
- YGKSLVOTSPIKIP-UHFFFAOYSA-N 5-(2-ethoxyethyl)-5-[4-[4-(1h-pyrazol-5-yl)phenoxy]phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound C=1C=C(OC=2C=CC(=CC=2)C2=NNC=C2)C=CC=1OC1(CCOCC)C(=O)NC(=O)NC1=O YGKSLVOTSPIKIP-UHFFFAOYSA-N 0.000 claims description 2
- LTARWDASSLDNCM-UHFFFAOYSA-N 5-(2-ethoxyethyl)-5-[4-[4-(2-methylpyrazol-3-yl)phenoxy]phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound C=1C=C(OC=2C=CC(=CC=2)C=2N(N=CC=2)C)C=CC=1OC1(CCOCC)C(=O)NC(=O)NC1=O LTARWDASSLDNCM-UHFFFAOYSA-N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims 2
- PKAJLIKKAVTDML-UHFFFAOYSA-N 5-(2-ethoxyethyl)-5-[4-[4-(2-methyl-1,3-thiazol-4-yl)phenoxy]phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound C=1C=C(OC=2C=CC(=CC=2)C=2N=C(C)SC=2)C=CC=1OC1(CCOCC)C(=O)NC(=O)NC1=O PKAJLIKKAVTDML-UHFFFAOYSA-N 0.000 claims 1
- 208000035475 disorder Diseases 0.000 abstract description 13
- 206010028980 Neoplasm Diseases 0.000 abstract description 6
- 206010061218 Inflammation Diseases 0.000 abstract description 3
- 230000004054 inflammatory process Effects 0.000 abstract description 3
- 201000011510 cancer Diseases 0.000 abstract 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 57
- 239000003112 inhibitor Substances 0.000 description 57
- 102000004190 Enzymes Human genes 0.000 description 47
- 108090000790 Enzymes Proteins 0.000 description 47
- 229940088598 enzyme Drugs 0.000 description 47
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 35
- 238000003556 assay Methods 0.000 description 34
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 33
- 239000002585 base Substances 0.000 description 29
- 239000000243 solution Substances 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 26
- 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 25
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- 230000005764 inhibitory process Effects 0.000 description 24
- 239000000460 chlorine Substances 0.000 description 23
- 108050005238 Collagenase 3 Proteins 0.000 description 22
- 102100027995 Collagenase 3 Human genes 0.000 description 22
- 239000002904 solvent Substances 0.000 description 22
- 239000000758 substrate Substances 0.000 description 22
- 102000029816 Collagenase Human genes 0.000 description 21
- 108060005980 Collagenase Proteins 0.000 description 21
- 239000003814 drug Substances 0.000 description 21
- 229960002424 collagenase Drugs 0.000 description 20
- 229940079593 drug Drugs 0.000 description 19
- 230000000694 effects Effects 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 102000002274 Matrix Metalloproteinases Human genes 0.000 description 17
- 108010000684 Matrix Metalloproteinases Proteins 0.000 description 17
- 238000004458 analytical method Methods 0.000 description 16
- 239000002253 acid Substances 0.000 description 15
- 229920001436 collagen Polymers 0.000 description 15
- 108010035532 Collagen Proteins 0.000 description 14
- 102000008186 Collagen Human genes 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- 238000002360 preparation method Methods 0.000 description 14
- MYRTYDVEIRVNKP-UHFFFAOYSA-N 1,2-Divinylbenzene Chemical compound C=CC1=CC=CC=C1C=C MYRTYDVEIRVNKP-UHFFFAOYSA-N 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 13
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 13
- 230000002401 inhibitory effect Effects 0.000 description 13
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 12
- 210000000845 cartilage Anatomy 0.000 description 12
- 238000010790 dilution Methods 0.000 description 12
- 239000012895 dilution Substances 0.000 description 12
- 125000000524 functional group Chemical group 0.000 description 12
- 102000004142 Trypsin Human genes 0.000 description 11
- 108090000631 Trypsin Proteins 0.000 description 11
- 239000012131 assay buffer Substances 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- 239000012588 trypsin Substances 0.000 description 11
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 230000006378 damage Effects 0.000 description 10
- 229940002612 prodrug Drugs 0.000 description 10
- 239000000651 prodrug Substances 0.000 description 10
- 210000001519 tissue Anatomy 0.000 description 10
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 102000005741 Metalloproteases Human genes 0.000 description 9
- 108010006035 Metalloproteases Proteins 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 210000001188 articular cartilage Anatomy 0.000 description 8
- 150000001721 carbon Chemical group 0.000 description 8
- 239000012312 sodium hydride Substances 0.000 description 8
- 229910000104 sodium hydride Inorganic materials 0.000 description 8
- PLIXOQYCVZTQMW-UHFFFAOYSA-N 4,4,5-trifluoro-5-[4,5,5-trifluoro-2,2-bis(trifluoromethyl)-1,3-dioxolan-4-yl]-2,2-bis(trifluoromethyl)-1,3-dioxolane Chemical compound O1C(C(F)(F)F)(C(F)(F)F)OC(F)(F)C1(F)C1(F)C(F)(F)OC(C(F)(F)F)(C(F)(F)F)O1 PLIXOQYCVZTQMW-UHFFFAOYSA-N 0.000 description 7
- IGRXBOAVFBJTER-UHFFFAOYSA-N 5-bromo-5-(2-ethoxyethyl)-1,3-diazinane-2,4,6-trione Chemical compound CCOCCC1(Br)C(=O)NC(=O)NC1=O IGRXBOAVFBJTER-UHFFFAOYSA-N 0.000 description 7
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 7
- 108010015302 Matrix metalloproteinase-9 Proteins 0.000 description 7
- 238000007466 Percutaneous biliary drainage Methods 0.000 description 7
- 229920001774 Perfluoroether Polymers 0.000 description 7
- 239000004793 Polystyrene Substances 0.000 description 7
- 239000007983 Tris buffer Substances 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 7
- 239000003054 catalyst Substances 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- 239000011159 matrix material Substances 0.000 description 7
- 125000004043 oxo group Chemical group O=* 0.000 description 7
- 229920002223 polystyrene Polymers 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- 230000035484 reaction time Effects 0.000 description 7
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 7
- 239000011550 stock solution Substances 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 6
- 102100030412 Matrix metalloproteinase-9 Human genes 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- 102100030416 Stromelysin-1 Human genes 0.000 description 6
- 239000002168 alkylating agent Substances 0.000 description 6
- 229940100198 alkylating agent Drugs 0.000 description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 125000001309 chloro group Chemical group Cl* 0.000 description 6
- 239000003085 diluting agent Substances 0.000 description 6
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 6
- 231100000252 nontoxic Toxicity 0.000 description 6
- 230000003000 nontoxic effect Effects 0.000 description 6
- 125000004076 pyridyl group Chemical group 0.000 description 6
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 6
- VKUYLANQOAKALN-UHFFFAOYSA-N 2-[benzyl-(4-methoxyphenyl)sulfonylamino]-n-hydroxy-4-methylpentanamide Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)N(C(CC(C)C)C(=O)NO)CC1=CC=CC=C1 VKUYLANQOAKALN-UHFFFAOYSA-N 0.000 description 5
- 102100026802 72 kDa type IV collagenase Human genes 0.000 description 5
- 241000283690 Bos taurus Species 0.000 description 5
- 102000013382 Gelatinases Human genes 0.000 description 5
- 108010026132 Gelatinases Proteins 0.000 description 5
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 5
- 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 5
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 5
- 102100027998 Macrophage metalloelastase Human genes 0.000 description 5
- 101710187853 Macrophage metalloelastase Proteins 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 101710108790 Stromelysin-1 Proteins 0.000 description 5
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 5
- 150000001298 alcohols Chemical class 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 230000015556 catabolic process Effects 0.000 description 5
- 150000001768 cations Chemical class 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 239000003636 conditioned culture medium Substances 0.000 description 5
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 5
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 5
- 230000005284 excitation Effects 0.000 description 5
- 229960002591 hydroxyproline Drugs 0.000 description 5
- 210000002184 nasal cartilage Anatomy 0.000 description 5
- 229910052763 palladium Inorganic materials 0.000 description 5
- 229940080818 propionamide Drugs 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 125000000714 pyrimidinyl group Chemical group 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 4
- 101710151806 72 kDa type IV collagenase Proteins 0.000 description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
- UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapentin Chemical compound OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 229940124761 MMP inhibitor Drugs 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- 229910019142 PO4 Inorganic materials 0.000 description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 239000005557 antagonist Substances 0.000 description 4
- 125000004104 aryloxy group Chemical group 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 210000001612 chondrocyte Anatomy 0.000 description 4
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 4
- 238000006731 degradation reaction Methods 0.000 description 4
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 125000001153 fluoro group Chemical group F* 0.000 description 4
- 150000002431 hydrogen Chemical class 0.000 description 4
- 229910052740 iodine Inorganic materials 0.000 description 4
- 238000005567 liquid scintillation counting Methods 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 201000008482 osteoarthritis Diseases 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 4
- 239000010452 phosphate Substances 0.000 description 4
- 239000002953 phosphate buffered saline Substances 0.000 description 4
- 239000002798 polar solvent Substances 0.000 description 4
- 125000003373 pyrazinyl group Chemical group 0.000 description 4
- 150000003431 steroids Chemical class 0.000 description 4
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 4
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 4
- 239000011592 zinc chloride Substances 0.000 description 4
- IEQAICDLOKRSRL-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-dodecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO IEQAICDLOKRSRL-UHFFFAOYSA-N 0.000 description 3
- KZKMAZVKJYDJJR-UHFFFAOYSA-N 2-[4-(4-methoxyphenoxy)phenyl]-1,3,4-oxadiazole Chemical compound C1=CC(OC)=CC=C1OC1=CC=C(C=2OC=NN=2)C=C1 KZKMAZVKJYDJJR-UHFFFAOYSA-N 0.000 description 3
- FVKFHMNJTHKMRX-UHFFFAOYSA-N 3,4,6,7,8,9-hexahydro-2H-pyrimido[1,2-a]pyrimidine Chemical compound C1CCN2CCCNC2=N1 FVKFHMNJTHKMRX-UHFFFAOYSA-N 0.000 description 3
- YZYKSWNRDDVRDL-UHFFFAOYSA-N 4-[4-(1,3,4-oxadiazol-2-yl)phenoxy]phenol Chemical compound C1=CC(O)=CC=C1OC1=CC=C(C=2OC=NN=2)C=C1 YZYKSWNRDDVRDL-UHFFFAOYSA-N 0.000 description 3
- QOPNRVDHKMBRSB-UHFFFAOYSA-N 5-(2-ethoxyethyl)-1,3-diazinane-2,4,6-trione Chemical compound CCOCCC1C(=O)NC(=O)NC1=O QOPNRVDHKMBRSB-UHFFFAOYSA-N 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 102000000503 Collagen Type II Human genes 0.000 description 3
- 108010041390 Collagen Type II Proteins 0.000 description 3
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 3
- 239000004971 Cross linker Substances 0.000 description 3
- 239000012981 Hank's balanced salt solution Substances 0.000 description 3
- 102000004877 Insulin Human genes 0.000 description 3
- 108090001061 Insulin Proteins 0.000 description 3
- 206010025323 Lymphomas Diseases 0.000 description 3
- 102100030417 Matrilysin Human genes 0.000 description 3
- 108090000855 Matrilysin Proteins 0.000 description 3
- 108010076557 Matrix Metalloproteinase 14 Proteins 0.000 description 3
- 102000000422 Matrix Metalloproteinase 3 Human genes 0.000 description 3
- 102100030216 Matrix metalloproteinase-14 Human genes 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- 108090000526 Papain Proteins 0.000 description 3
- 239000004365 Protease Substances 0.000 description 3
- 201000004681 Psoriasis Diseases 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 239000000443 aerosol Substances 0.000 description 3
- 239000000556 agonist Substances 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 3
- 150000008041 alkali metal carbonates Chemical class 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 206010003246 arthritis Diseases 0.000 description 3
- 208000010668 atopic eczema Diseases 0.000 description 3
- 150000001541 aziridines Chemical class 0.000 description 3
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 3
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 3
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 3
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 229960000590 celecoxib Drugs 0.000 description 3
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 230000011382 collagen catabolic process Effects 0.000 description 3
- 239000002442 collagenase inhibitor Substances 0.000 description 3
- 229940111134 coxibs Drugs 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- TXWOGHSRPAYOML-UHFFFAOYSA-N cyclobutanecarboxylic acid Chemical compound OC(=O)C1CCC1 TXWOGHSRPAYOML-UHFFFAOYSA-N 0.000 description 3
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 3
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 3
- 206010012601 diabetes mellitus Diseases 0.000 description 3
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 125000002541 furyl group Chemical group 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 229920002674 hyaluronan Polymers 0.000 description 3
- 150000002430 hydrocarbons Chemical group 0.000 description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 3
- 125000002883 imidazolyl group Chemical group 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 125000001041 indolyl group Chemical group 0.000 description 3
- 208000014674 injury Diseases 0.000 description 3
- 229940125396 insulin Drugs 0.000 description 3
- 229940047889 isobutyramide Drugs 0.000 description 3
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 3
- 125000001786 isothiazolyl group Chemical group 0.000 description 3
- 125000000842 isoxazolyl group Chemical group 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 208000002780 macular degeneration Diseases 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 210000001616 monocyte Anatomy 0.000 description 3
- 125000002757 morpholinyl group Chemical group 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 3
- 239000006186 oral dosage form Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 125000002971 oxazolyl group Chemical group 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 229940055729 papain Drugs 0.000 description 3
- 235000019834 papain Nutrition 0.000 description 3
- 230000001575 pathological effect Effects 0.000 description 3
- 125000004193 piperazinyl group Chemical group 0.000 description 3
- 125000003386 piperidinyl group Chemical group 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 3
- 125000003226 pyrazolyl group Chemical group 0.000 description 3
- 125000000168 pyrrolyl group Chemical group 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 229920005989 resin Polymers 0.000 description 3
- 239000011347 resin Substances 0.000 description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 210000002784 stomach Anatomy 0.000 description 3
- 108091007196 stromelysin Proteins 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 3
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 3
- 125000003831 tetrazolyl group Chemical group 0.000 description 3
- 125000000335 thiazolyl group Chemical group 0.000 description 3
- 125000001544 thienyl group Chemical group 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- POPHMOPNVVKGRW-UHFFFAOYSA-N 1,2,3,4,4a,5,6,7-octahydronaphthalene Chemical compound C1CCC2CCCCC2=C1 POPHMOPNVVKGRW-UHFFFAOYSA-N 0.000 description 2
- ZQXCQTAELHSNAT-UHFFFAOYSA-N 1-chloro-3-nitro-5-(trifluoromethyl)benzene Chemical compound [O-][N+](=O)C1=CC(Cl)=CC(C(F)(F)F)=C1 ZQXCQTAELHSNAT-UHFFFAOYSA-N 0.000 description 2
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 description 2
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 2
- ALKYHXVLJMQRLQ-UHFFFAOYSA-N 3-Hydroxy-2-naphthoate Chemical compound C1=CC=C2C=C(O)C(C(=O)O)=CC2=C1 ALKYHXVLJMQRLQ-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-M 3-carboxy-2,3-dihydroxypropanoate Chemical compound OC(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-M 0.000 description 2
- JTJXAGJXHRWKQU-UHFFFAOYSA-N 4-[4-(aminomethyl)phenoxy]phenol Chemical compound C1=CC(CN)=CC=C1OC1=CC=C(O)C=C1 JTJXAGJXHRWKQU-UHFFFAOYSA-N 0.000 description 2
- SUDQKNAYXMYUGX-UHFFFAOYSA-N 5-(2-ethoxyethyl)-5-[4-[4-(1,3,4-oxadiazol-2-yl)phenoxy]phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound C=1C=C(OC=2C=CC(=CC=2)C=2OC=NN=2)C=CC=1OC1(CCOCC)C(=O)NC(=O)NC1=O SUDQKNAYXMYUGX-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- 102100031172 C-C chemokine receptor type 1 Human genes 0.000 description 2
- 101710149814 C-C chemokine receptor type 1 Proteins 0.000 description 2
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-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
- 229940127291 Calcium channel antagonist Drugs 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical group [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 208000012895 Gastric disease Diseases 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 229920002683 Glycosaminoglycan Polymers 0.000 description 2
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 2
- 101150014058 MMP1 gene Proteins 0.000 description 2
- DBTDEFJAFBUGPP-UHFFFAOYSA-N Methanethial Chemical compound S=C DBTDEFJAFBUGPP-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 2
- 229910002651 NO3 Inorganic materials 0.000 description 2
- 102100030411 Neutrophil collagenase Human genes 0.000 description 2
- 101710118230 Neutrophil collagenase Proteins 0.000 description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 2
- 208000001132 Osteoporosis Diseases 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 208000017442 Retinal disease Diseases 0.000 description 2
- 206010038923 Retinopathy Diseases 0.000 description 2
- 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 2
- 229940124639 Selective inhibitor Drugs 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 208000006011 Stroke Diseases 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic anhydride Substances CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 206010064930 age-related macular degeneration Diseases 0.000 description 2
- 108010003059 aggrecanase Proteins 0.000 description 2
- 239000000783 alginic acid Substances 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 229960001126 alginic acid Drugs 0.000 description 2
- 150000004781 alginic acids Chemical class 0.000 description 2
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 2
- 150000008046 alkali metal hydrides Chemical class 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 125000005907 alkyl ester group Chemical group 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 230000000172 allergic effect Effects 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 125000000539 amino acid group Chemical group 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 208000007474 aortic aneurysm Diseases 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- KVVMXWRFYAGASO-UHFFFAOYSA-N azetidine-1-carboxylic acid Chemical compound OC(=O)N1CCC1 KVVMXWRFYAGASO-UHFFFAOYSA-N 0.000 description 2
- 150000007514 bases Chemical class 0.000 description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000001110 calcium chloride Substances 0.000 description 2
- 235000011148 calcium chloride Nutrition 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- 108700004333 collagenase 1 Proteins 0.000 description 2
- 239000011246 composite particle Substances 0.000 description 2
- 210000002808 connective tissue Anatomy 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- UURSXESKOOOTOV-UHFFFAOYSA-N dec-5-ene Chemical compound CCCCC=CCCCC UURSXESKOOOTOV-UHFFFAOYSA-N 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 229910052805 deuterium Inorganic materials 0.000 description 2
- 230000029087 digestion Effects 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 239000003136 dopamine receptor stimulating agent Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 150000002118 epoxides Chemical class 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 229960004945 etoricoxib Drugs 0.000 description 2
- MNJVRJDLRVPLFE-UHFFFAOYSA-N etoricoxib Chemical compound C1=NC(C)=CC=C1C1=NC=C(Cl)C=C1C1=CC=C(S(C)(=O)=O)C=C1 MNJVRJDLRVPLFE-UHFFFAOYSA-N 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 229960002870 gabapentin Drugs 0.000 description 2
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 229940050410 gluconate Drugs 0.000 description 2
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 2
- 229910052737 gold Inorganic materials 0.000 description 2
- 239000010931 gold Substances 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 2
- 238000000099 in vitro assay Methods 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 230000018276 interleukin-1 production Effects 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 125000005956 isoquinolyl group Chemical group 0.000 description 2
- 210000001503 joint Anatomy 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229960004844 lovastatin Drugs 0.000 description 2
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 2
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- CRGZYKWWYNQGEC-UHFFFAOYSA-N magnesium;methanolate Chemical compound [Mg+2].[O-]C.[O-]C CRGZYKWWYNQGEC-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000003771 matrix metalloproteinase inhibitor Substances 0.000 description 2
- 229940121386 matrix metalloproteinase inhibitor Drugs 0.000 description 2
- 210000004379 membrane Anatomy 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 229960000485 methotrexate Drugs 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- KJAOKBCFORQDGH-UHFFFAOYSA-N n-[[4-(4-hydroxyphenoxy)phenyl]methyl]propanamide Chemical compound C1=CC(CNC(=O)CC)=CC=C1OC1=CC=C(O)C=C1 KJAOKBCFORQDGH-UHFFFAOYSA-N 0.000 description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
- 239000007935 oral tablet Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 125000000962 organic group Chemical group 0.000 description 2
- 230000003349 osteoarthritic effect Effects 0.000 description 2
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 2
- 230000036407 pain Effects 0.000 description 2
- 208000033808 peripheral neuropathy Diseases 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 2
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 description 2
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 2
- 239000003880 polar aprotic solvent Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 125000002098 pyridazinyl group Chemical group 0.000 description 2
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 229960000371 rofecoxib Drugs 0.000 description 2
- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000012679 serum free medium Substances 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 2
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 125000005503 thioxanyl group Chemical group 0.000 description 2
- 150000003852 triazoles Chemical class 0.000 description 2
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 2
- 230000006433 tumor necrosis factor production Effects 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- 229960002004 valdecoxib Drugs 0.000 description 2
- LNPDTQAFDNKSHK-UHFFFAOYSA-N valdecoxib Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(N)(=O)=O)C=C1 LNPDTQAFDNKSHK-UHFFFAOYSA-N 0.000 description 2
- AGEBJYJJWHBPJT-UHFFFAOYSA-N $l^{1}-oxidanylsulfonylmethane Chemical compound CS([O])(=O)=O AGEBJYJJWHBPJT-UHFFFAOYSA-N 0.000 description 1
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 1
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 1
- XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 description 1
- FMCAFXHLMUOIGG-IWFBPKFRSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2r)-2-formamido-3-sulfanylpropanoyl]amino]-3-methylbutanoyl]amino]-3-(4-hydroxy-2,5-dimethylphenyl)propanoyl]amino]-4-methylsulfanylbutanoic acid Chemical compound O=CN[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCSC)C(O)=O)CC1=CC(C)=C(O)C=C1C FMCAFXHLMUOIGG-IWFBPKFRSA-N 0.000 description 1
- BIDNLKIUORFRQP-XYGFDPSESA-N (2s,4s)-4-cyclohexyl-1-[2-[[(1s)-2-methyl-1-propanoyloxypropoxy]-(4-phenylbutyl)phosphoryl]acetyl]pyrrolidine-2-carboxylic acid Chemical compound C([P@@](=O)(O[C@H](OC(=O)CC)C(C)C)CC(=O)N1[C@@H](C[C@H](C1)C1CCCCC1)C(O)=O)CCCC1=CC=CC=C1 BIDNLKIUORFRQP-XYGFDPSESA-N 0.000 description 1
- VOAAEKKFGLPLLU-UHFFFAOYSA-N (4-methoxyphenyl)boronic acid Chemical compound COC1=CC=C(B(O)O)C=C1 VOAAEKKFGLPLLU-UHFFFAOYSA-N 0.000 description 1
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- 229930182837 (R)-adrenaline Natural products 0.000 description 1
- NDAUXUAQIAJITI-LBPRGKRZSA-N (R)-salbutamol Chemical compound CC(C)(C)NC[C@H](O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-LBPRGKRZSA-N 0.000 description 1
- UKAUYVFTDYCKQA-UHFFFAOYSA-N -2-Amino-4-hydroxybutanoic acid Natural products OC(=O)C(N)CCO UKAUYVFTDYCKQA-UHFFFAOYSA-N 0.000 description 1
- 125000001766 1,2,4-oxadiazol-3-yl group Chemical group [H]C1=NC(*)=NO1 0.000 description 1
- 125000003626 1,2,4-triazol-1-yl group Chemical group [*]N1N=C([H])N=C1[H] 0.000 description 1
- 125000001305 1,2,4-triazol-3-yl group Chemical group [H]N1N=C([*])N=C1[H] 0.000 description 1
- DDMOUSALMHHKOS-UHFFFAOYSA-N 1,2-dichloro-1,1,2,2-tetrafluoroethane Chemical compound FC(F)(Cl)C(F)(F)Cl DDMOUSALMHHKOS-UHFFFAOYSA-N 0.000 description 1
- 125000004509 1,3,4-oxadiazol-2-yl group Chemical group O1C(=NN=C1)* 0.000 description 1
- 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 description 1
- DKYBVKMIZODYKL-UHFFFAOYSA-N 1,3-diazinane Chemical compound C1CNCNC1 DKYBVKMIZODYKL-UHFFFAOYSA-N 0.000 description 1
- JPRPJUMQRZTTED-UHFFFAOYSA-N 1,3-dioxolanyl Chemical group [CH]1OCCO1 JPRPJUMQRZTTED-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- XLHUBROMZOAQMV-UHFFFAOYSA-N 1,4-benzosemiquinone Chemical group [O]C1=CC=C(O)C=C1 XLHUBROMZOAQMV-UHFFFAOYSA-N 0.000 description 1
- FOZVXADQAHVUSV-UHFFFAOYSA-N 1-bromo-2-(2-bromoethoxy)ethane Chemical compound BrCCOCCBr FOZVXADQAHVUSV-UHFFFAOYSA-N 0.000 description 1
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 1
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 1
- MMGQBQAKOXSVRY-UHFFFAOYSA-M 2-(4-aminophenyl)acetate;mercury(1+) Chemical compound [Hg+].NC1=CC=C(CC([O-])=O)C=C1 MMGQBQAKOXSVRY-UHFFFAOYSA-M 0.000 description 1
- CSEWAUGPAQPMDC-UHFFFAOYSA-N 2-(4-aminophenyl)acetic acid Chemical compound NC1=CC=C(CC(O)=O)C=C1 CSEWAUGPAQPMDC-UHFFFAOYSA-N 0.000 description 1
- MSWZFWKMSRAUBD-GASJEMHNSA-N 2-amino-2-deoxy-D-galactopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O MSWZFWKMSRAUBD-GASJEMHNSA-N 0.000 description 1
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 description 1
- 125000001698 2H-pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- BRMWTNUJHUMWMS-UHFFFAOYSA-N 3-Methylhistidine Natural products CN1C=NC(CC(N)C(O)=O)=C1 BRMWTNUJHUMWMS-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
- 125000004364 3-pyrrolinyl group Chemical group [H]C1=C([H])C([H])([H])N(*)C1([H])[H] 0.000 description 1
- 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- WENOJMGPELLGMA-UHFFFAOYSA-N 4-(1,3,4-oxadiazol-2-yl)phenol Chemical compound C1=CC(O)=CC=C1C1=NN=CO1 WENOJMGPELLGMA-UHFFFAOYSA-N 0.000 description 1
- JBZOHIZDKWIRTD-UHFFFAOYSA-N 4-(4-hydroxyphenoxy)-n-methylbenzamide Chemical compound C1=CC(C(=O)NC)=CC=C1OC1=CC=C(O)C=C1 JBZOHIZDKWIRTD-UHFFFAOYSA-N 0.000 description 1
- KLXPCYHWTLAVLN-UHFFFAOYSA-N 4-(4-hydroxyphenoxy)benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1OC1=CC=C(O)C=C1 KLXPCYHWTLAVLN-UHFFFAOYSA-N 0.000 description 1
- 125000001826 4H-pyranyl group Chemical group O1C(=CCC=C1)* 0.000 description 1
- PJJGZPJJTHBVMX-UHFFFAOYSA-N 5,7-Dihydroxyisoflavone Chemical compound C=1C(O)=CC(O)=C(C2=O)C=1OC=C2C1=CC=CC=C1 PJJGZPJJTHBVMX-UHFFFAOYSA-N 0.000 description 1
- XGRGMVYYMIOGTE-UHFFFAOYSA-N 5-(2-ethoxyethyl)-5-[4-(3-phenylphenoxy)phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound C=1C=C(OC=2C=C(C=CC=2)C=2C=CC=CC=2)C=CC=1OC1(CCOCC)C(=O)NC(=O)NC1=O XGRGMVYYMIOGTE-UHFFFAOYSA-N 0.000 description 1
- TWFWAESOUBKZSN-UHFFFAOYSA-N 5-(2-ethoxyethyl)-5-[4-(4-imidazol-1-ylphenoxy)phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound C=1C=C(OC=2C=CC(=CC=2)N2C=NC=C2)C=CC=1OC1(CCOCC)C(=O)NC(=O)NC1=O TWFWAESOUBKZSN-UHFFFAOYSA-N 0.000 description 1
- SHISYUWYQPLRTA-UHFFFAOYSA-N 5-(2-ethoxyethyl)-5-[4-(4-methylsulfonylphenoxy)phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound C=1C=C(OC=2C=CC(=CC=2)S(C)(=O)=O)C=CC=1OC1(CCOCC)C(=O)NC(=O)NC1=O SHISYUWYQPLRTA-UHFFFAOYSA-N 0.000 description 1
- XXXIDXMAUYIGBL-UHFFFAOYSA-N 5-(2-ethoxyethyl)-5-[4-(4-phenylphenoxy)phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound C=1C=C(OC=2C=CC(=CC=2)C=2C=CC=CC=2)C=CC=1OC1(CCOCC)C(=O)NC(=O)NC1=O XXXIDXMAUYIGBL-UHFFFAOYSA-N 0.000 description 1
- JPWCZCVYTHLWLI-UHFFFAOYSA-N 5-(2-ethoxyethyl)-5-[4-(4-pyrazol-1-ylphenoxy)phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound C=1C=C(OC=2C=CC(=CC=2)N2N=CC=C2)C=CC=1OC1(CCOCC)C(=O)NC(=O)NC1=O JPWCZCVYTHLWLI-UHFFFAOYSA-N 0.000 description 1
- PVGPCZKMYDVTFZ-UHFFFAOYSA-N 5-(2-ethoxyethyl)-5-[4-(4-pyrrol-1-ylphenoxy)phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound C=1C=C(OC=2C=CC(=CC=2)N2C=CC=C2)C=CC=1OC1(CCOCC)C(=O)NC(=O)NC1=O PVGPCZKMYDVTFZ-UHFFFAOYSA-N 0.000 description 1
- DRFPYSCAHLBRCL-UHFFFAOYSA-N 5-(2-ethoxyethyl)-5-[4-[3-fluoro-4-(1,3,4-oxadiazol-2-yl)phenoxy]phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound C=1C=C(OC=2C=C(F)C(C=3OC=NN=3)=CC=2)C=CC=1OC1(CCOCC)C(=O)NC(=O)NC1=O DRFPYSCAHLBRCL-UHFFFAOYSA-N 0.000 description 1
- ZURFIPPOSARZIE-UHFFFAOYSA-N 5-(2-ethoxyethyl)-5-[4-[3-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound C=1C=C(OC=2C=C(F)C(C=3OC(C)=NN=3)=CC=2)C=CC=1OC1(CCOCC)C(=O)NC(=O)NC1=O ZURFIPPOSARZIE-UHFFFAOYSA-N 0.000 description 1
- ZMFWGEXRVOOMLZ-UHFFFAOYSA-N 5-(2-ethoxyethyl)-5-[4-[3-methyl-4-(1,3,4-oxadiazol-2-yl)phenoxy]phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound C=1C=C(OC=2C=C(C)C(C=3OC=NN=3)=CC=2)C=CC=1OC1(CCOCC)C(=O)NC(=O)NC1=O ZMFWGEXRVOOMLZ-UHFFFAOYSA-N 0.000 description 1
- ZNGKURNKMWJPGM-UHFFFAOYSA-N 5-(2-ethoxyethyl)-5-[4-[3-methyl-4-(1-methylpyrazol-4-yl)phenoxy]phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound C=1C=C(OC=2C=C(C)C(C3=CN(C)N=C3)=CC=2)C=CC=1OC1(CCOCC)C(=O)NC(=O)NC1=O ZNGKURNKMWJPGM-UHFFFAOYSA-N 0.000 description 1
- VZXWSXVCQFBUOG-UHFFFAOYSA-N 5-(2-ethoxyethyl)-5-[4-[3-methyl-4-(1h-pyrazol-4-yl)phenoxy]phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound C=1C=C(OC=2C=C(C)C(C3=CNN=C3)=CC=2)C=CC=1OC1(CCOCC)C(=O)NC(=O)NC1=O VZXWSXVCQFBUOG-UHFFFAOYSA-N 0.000 description 1
- HVJNEUQTXGOBFF-UHFFFAOYSA-N 5-(2-ethoxyethyl)-5-[4-[3-methyl-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound C=1C=C(OC=2C=C(C)C(C=3OC(C)=NN=3)=CC=2)C=CC=1OC1(CCOCC)C(=O)NC(=O)NC1=O HVJNEUQTXGOBFF-UHFFFAOYSA-N 0.000 description 1
- GAIPGMQAMYWSFY-UHFFFAOYSA-N 5-(2-ethoxyethyl)-5-[4-[4-(1,2,4-triazol-1-yl)phenoxy]phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound C=1C=C(OC=2C=CC(=CC=2)N2N=CN=C2)C=CC=1OC1(CCOCC)C(=O)NC(=O)NC1=O GAIPGMQAMYWSFY-UHFFFAOYSA-N 0.000 description 1
- OBWUVSIPPCXTGI-UHFFFAOYSA-N 5-(2-ethoxyethyl)-5-[4-[4-(1,2,4-triazol-4-yl)phenoxy]phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound C=1C=C(OC=2C=CC(=CC=2)N2C=NN=C2)C=CC=1OC1(CCOCC)C(=O)NC(=O)NC1=O OBWUVSIPPCXTGI-UHFFFAOYSA-N 0.000 description 1
- FZIMQXPGFWUSBX-UHFFFAOYSA-N 5-(2-ethoxyethyl)-5-[4-[4-(1,3-oxazol-4-yl)phenoxy]phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound C=1C=C(OC=2C=CC(=CC=2)C=2N=COC=2)C=CC=1OC1(CCOCC)C(=O)NC(=O)NC1=O FZIMQXPGFWUSBX-UHFFFAOYSA-N 0.000 description 1
- WAYBHGSGVUAFCF-UHFFFAOYSA-N 5-(2-ethoxyethyl)-5-[4-[4-(1,3-thiazol-4-yl)phenoxy]phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound C=1C=C(OC=2C=CC(=CC=2)C=2N=CSC=2)C=CC=1OC1(CCOCC)C(=O)NC(=O)NC1=O WAYBHGSGVUAFCF-UHFFFAOYSA-N 0.000 description 1
- JWTPNCCNGTXDIA-UHFFFAOYSA-N 5-(2-ethoxyethyl)-5-[4-[4-(1h-1,2,4-triazol-5-yl)phenoxy]phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound C=1C=C(OC=2C=CC(=CC=2)C=2NC=NN=2)C=CC=1OC1(CCOCC)C(=O)NC(=O)NC1=O JWTPNCCNGTXDIA-UHFFFAOYSA-N 0.000 description 1
- KYJIHFIQFFSFIR-UHFFFAOYSA-N 5-(2-ethoxyethyl)-5-[4-[4-(1h-pyrazol-4-yl)phenoxy]phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound C=1C=C(OC=2C=CC(=CC=2)C2=CNN=C2)C=CC=1OC1(CCOCC)C(=O)NC(=O)NC1=O KYJIHFIQFFSFIR-UHFFFAOYSA-N 0.000 description 1
- UBGNKBWIQKMTNG-UHFFFAOYSA-N 5-(2-ethoxyethyl)-5-[4-[4-(5-ethyl-1,3,4-oxadiazol-2-yl)phenoxy]phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound C=1C=C(OC=2C=CC(=CC=2)C=2OC(CC)=NN=2)C=CC=1OC1(CCOCC)C(=O)NC(=O)NC1=O UBGNKBWIQKMTNG-UHFFFAOYSA-N 0.000 description 1
- FNWRVBXWKRVHOK-UHFFFAOYSA-N 5-(2-ethoxyethyl)-5-[4-[4-(5-methyl-1,2-oxazol-3-yl)phenoxy]phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound C=1C=C(OC=2C=CC(=CC=2)C2=NOC(C)=C2)C=CC=1OC1(CCOCC)C(=O)NC(=O)NC1=O FNWRVBXWKRVHOK-UHFFFAOYSA-N 0.000 description 1
- RWMJTCFNRJUHQS-UHFFFAOYSA-N 5-(2-ethoxyethyl)-5-[4-[4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound C=1C=C(OC=2C=CC(=CC=2)C=2OC(C)=NN=2)C=CC=1OC1(CCOCC)C(=O)NC(=O)NC1=O RWMJTCFNRJUHQS-UHFFFAOYSA-N 0.000 description 1
- ATQKFMFBSKQKMT-UHFFFAOYSA-N 5-(2-ethoxyethyl)-5-[4-[4-(hydroxymethyl)phenoxy]phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound C=1C=C(OC=2C=CC(CO)=CC=2)C=CC=1OC1(CCOCC)C(=O)NC(=O)NC1=O ATQKFMFBSKQKMT-UHFFFAOYSA-N 0.000 description 1
- LXRVBLDEWRYZSO-UHFFFAOYSA-N 5-[(4-methyl-3-oxomorpholin-2-yl)methyl]-5-[4-[4-(1,3,4-oxadiazol-2-yl)phenoxy]phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound O=C1N(C)CCOC1CC1(OC=2C=CC(OC=3C=CC(=CC=3)C=3OC=NN=3)=CC=2)C(=O)NC(=O)NC1=O LXRVBLDEWRYZSO-UHFFFAOYSA-N 0.000 description 1
- OOBSJDFEZLSHPR-UHFFFAOYSA-N 5-[(4-methyl-5-oxomorpholin-2-yl)methyl]-5-[4-[4-(1,3,4-oxadiazol-2-yl)phenoxy]phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound O1CC(=O)N(C)CC1CC1(OC=2C=CC(OC=3C=CC(=CC=3)C=3OC=NN=3)=CC=2)C(=O)NC(=O)NC1=O OOBSJDFEZLSHPR-UHFFFAOYSA-N 0.000 description 1
- UKUAIKYIAWTSGA-UHFFFAOYSA-N 5-[4-(4-cyclohexylphenoxy)phenoxy]-5-(2-ethoxyethyl)-1,3-diazinane-2,4,6-trione Chemical compound C=1C=C(OC=2C=CC(=CC=2)C2CCCCC2)C=CC=1OC1(CCOCC)C(=O)NC(=O)NC1=O UKUAIKYIAWTSGA-UHFFFAOYSA-N 0.000 description 1
- YBXOUSVHTNKHDB-UHFFFAOYSA-N 5-[4-(4-cyclopentylphenoxy)phenoxy]-5-(2-ethoxyethyl)-1,3-diazinane-2,4,6-trione Chemical compound C=1C=C(OC=2C=CC(=CC=2)C2CCCC2)C=CC=1OC1(CCOCC)C(=O)NC(=O)NC1=O YBXOUSVHTNKHDB-UHFFFAOYSA-N 0.000 description 1
- IMORWUBERRPVSZ-UHFFFAOYSA-N 5-[4-[3-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]phenoxy]-5-(oxan-3-yl)-1,3-diazinane-2,4,6-trione Chemical compound O1C(C)=NN=C1C(C(=C1)F)=CC=C1OC(C=C1)=CC=C1OC1(C2COCCC2)C(=O)NC(=O)NC1=O IMORWUBERRPVSZ-UHFFFAOYSA-N 0.000 description 1
- DUTHFABWTHGZMO-UHFFFAOYSA-N 5-[4-[3-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]phenoxy]-5-(oxolan-2-ylmethyl)-1,3-diazinane-2,4,6-trione Chemical compound O1C(C)=NN=C1C(C(=C1)F)=CC=C1OC(C=C1)=CC=C1OC1(CC2OCCC2)C(=O)NC(=O)NC1=O DUTHFABWTHGZMO-UHFFFAOYSA-N 0.000 description 1
- OIZHRAPLTPQDTO-UHFFFAOYSA-N 5-[4-[3-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]phenoxy]-5-(oxolan-3-yl)-1,3-diazinane-2,4,6-trione Chemical compound O1C(C)=NN=C1C(C(=C1)F)=CC=C1OC(C=C1)=CC=C1OC1(C2COCC2)C(=O)NC(=O)NC1=O OIZHRAPLTPQDTO-UHFFFAOYSA-N 0.000 description 1
- SXAOTTXGDVCPPT-UHFFFAOYSA-N 5-[4-[3-methyl-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]phenoxy]-5-(oxolan-2-ylmethyl)-1,3-diazinane-2,4,6-trione Chemical compound O1C(C)=NN=C1C(C(=C1)C)=CC=C1OC(C=C1)=CC=C1OC1(CC2OCCC2)C(=O)NC(=O)NC1=O SXAOTTXGDVCPPT-UHFFFAOYSA-N 0.000 description 1
- VXUVJBNMIKPEMX-UHFFFAOYSA-N 5-[4-[4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]phenoxy]-5-(oxan-2-ylmethyl)-1,3-diazinane-2,4,6-trione Chemical compound O1C(C)=NN=C1C(C=C1)=CC=C1OC(C=C1)=CC=C1OC1(CC2OCCCC2)C(=O)NC(=O)NC1=O VXUVJBNMIKPEMX-UHFFFAOYSA-N 0.000 description 1
- SLSTWGCVGNVWSU-UHFFFAOYSA-N 5-[4-[4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]phenoxy]-5-(oxan-3-yl)-1,3-diazinane-2,4,6-trione Chemical compound O1C(C)=NN=C1C(C=C1)=CC=C1OC(C=C1)=CC=C1OC1(C2COCCC2)C(=O)NC(=O)NC1=O SLSTWGCVGNVWSU-UHFFFAOYSA-N 0.000 description 1
- JPBHMOZQQILPEP-UHFFFAOYSA-N 5-[4-[4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]phenoxy]-5-(oxolan-2-ylmethyl)-1,3-diazinane-2,4,6-trione Chemical compound O1C(C)=NN=C1C(C=C1)=CC=C1OC(C=C1)=CC=C1OC1(CC2OCCC2)C(=O)NC(=O)NC1=O JPBHMOZQQILPEP-UHFFFAOYSA-N 0.000 description 1
- JCJBJHRTGQQXTO-UHFFFAOYSA-N 5-[4-[4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]phenoxy]-5-(oxolan-3-yl)-1,3-diazinane-2,4,6-trione Chemical compound O1C(C)=NN=C1C(C=C1)=CC=C1OC(C=C1)=CC=C1OC1(C2COCC2)C(=O)NC(=O)NC1=O JCJBJHRTGQQXTO-UHFFFAOYSA-N 0.000 description 1
- CNSDEGZUPWKIPC-UHFFFAOYSA-N 5-[4-[4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]phenoxy]-5-(pyridin-2-ylmethyl)-1,3-diazinane-2,4,6-trione Chemical compound O1C(C)=NN=C1C(C=C1)=CC=C1OC(C=C1)=CC=C1OC1(CC=2N=CC=CC=2)C(=O)NC(=O)NC1=O CNSDEGZUPWKIPC-UHFFFAOYSA-N 0.000 description 1
- WCXUVNIKLKHEJC-UHFFFAOYSA-N 5-[4-[4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]phenoxy]-5-(pyridin-3-ylmethyl)-1,3-diazinane-2,4,6-trione Chemical compound O1C(C)=NN=C1C(C=C1)=CC=C1OC(C=C1)=CC=C1OC1(CC=2C=NC=CC=2)C(=O)NC(=O)NC1=O WCXUVNIKLKHEJC-UHFFFAOYSA-N 0.000 description 1
- NNCQCEIYYHQSDF-UHFFFAOYSA-N 5-[4-[4-(aminomethyl)phenoxy]phenoxy]-5-(2-ethoxyethyl)-1,3-diazinane-2,4,6-trione Chemical compound C=1C=C(OC=2C=CC(CN)=CC=2)C=CC=1OC1(CCOCC)C(=O)NC(=O)NC1=O NNCQCEIYYHQSDF-UHFFFAOYSA-N 0.000 description 1
- RIFPKTPRJKKVSR-UHFFFAOYSA-N 5-[4-[4-(aminomethyl)phenoxy]phenoxy]-5-cyclohexyl-1,3-diazinane-2,4,6-trione Chemical compound C1=CC(CN)=CC=C1OC(C=C1)=CC=C1OC1(C2CCCCC2)C(=O)NC(=O)NC1=O RIFPKTPRJKKVSR-UHFFFAOYSA-N 0.000 description 1
- CYJYESCPJUTLHW-UHFFFAOYSA-N 5-[4-[4-[5-(dimethylamino)-1,3,4-oxadiazol-2-yl]phenoxy]phenoxy]-5-(2-ethoxyethyl)-1,3-diazinane-2,4,6-trione Chemical compound C=1C=C(OC=2C=CC(=CC=2)C=2OC(=NN=2)N(C)C)C=CC=1OC1(CCOCC)C(=O)NC(=O)NC1=O CYJYESCPJUTLHW-UHFFFAOYSA-N 0.000 description 1
- GJCZEMSWAYKVRE-UHFFFAOYSA-N 5-[4-[6-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl]oxyphenoxy]-5-(oxolan-2-ylmethyl)-1,3-diazinane-2,4,6-trione Chemical compound O1C(C)=NN=C1C(N=C1)=CC=C1OC(C=C1)=CC=C1OC1(CC2OCCC2)C(=O)NC(=O)NC1=O GJCZEMSWAYKVRE-UHFFFAOYSA-N 0.000 description 1
- BAGBVIMRCUJVFQ-UHFFFAOYSA-N 5-cyclohexyl-5-[4-(3-phenylphenoxy)phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound O=C1NC(=O)NC(=O)C1(C1CCCCC1)OC(C=C1)=CC=C1OC1=CC=CC(C=2C=CC=CC=2)=C1 BAGBVIMRCUJVFQ-UHFFFAOYSA-N 0.000 description 1
- HXFUJUWEXUKZNL-UHFFFAOYSA-N 5-cyclohexyl-5-[4-(4-cyclohexylphenoxy)phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound O=C1NC(=O)NC(=O)C1(C1CCCCC1)OC(C=C1)=CC=C1OC1=CC=C(C2CCCCC2)C=C1 HXFUJUWEXUKZNL-UHFFFAOYSA-N 0.000 description 1
- WOKCWMXQJOATKL-UHFFFAOYSA-N 5-cyclohexyl-5-[4-(4-cyclopentylphenoxy)phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound O=C1NC(=O)NC(=O)C1(C1CCCCC1)OC(C=C1)=CC=C1OC1=CC=C(C2CCCC2)C=C1 WOKCWMXQJOATKL-UHFFFAOYSA-N 0.000 description 1
- HUNKLSOFLNAOOG-UHFFFAOYSA-N 5-cyclohexyl-5-[4-(4-fluoro-3-phenylphenoxy)phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound C1=C(C=2C=CC=CC=2)C(F)=CC=C1OC(C=C1)=CC=C1OC1(C2CCCCC2)C(=O)NC(=O)NC1=O HUNKLSOFLNAOOG-UHFFFAOYSA-N 0.000 description 1
- FGQCKEGZCRDTPI-UHFFFAOYSA-N 5-cyclohexyl-5-[4-(4-imidazol-1-ylphenoxy)phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound O=C1NC(=O)NC(=O)C1(C1CCCCC1)OC(C=C1)=CC=C1OC1=CC=C(N2C=NC=C2)C=C1 FGQCKEGZCRDTPI-UHFFFAOYSA-N 0.000 description 1
- GORHXXZUXFXSAP-UHFFFAOYSA-N 5-cyclohexyl-5-[4-(4-methylsulfonylphenoxy)phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound C1=CC(S(=O)(=O)C)=CC=C1OC(C=C1)=CC=C1OC1(C2CCCCC2)C(=O)NC(=O)NC1=O GORHXXZUXFXSAP-UHFFFAOYSA-N 0.000 description 1
- BUAFRSWZNIWDCM-UHFFFAOYSA-N 5-cyclohexyl-5-[4-(4-phenylphenoxy)phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound O=C1NC(=O)NC(=O)C1(C1CCCCC1)OC(C=C1)=CC=C1OC1=CC=C(C=2C=CC=CC=2)C=C1 BUAFRSWZNIWDCM-UHFFFAOYSA-N 0.000 description 1
- CJKGJHDOONDRQJ-UHFFFAOYSA-N 5-cyclohexyl-5-[4-(4-pyrazol-1-ylphenoxy)phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound O=C1NC(=O)NC(=O)C1(C1CCCCC1)OC(C=C1)=CC=C1OC1=CC=C(N2N=CC=C2)C=C1 CJKGJHDOONDRQJ-UHFFFAOYSA-N 0.000 description 1
- HDHFEPUXMRNHGU-UHFFFAOYSA-N 5-cyclohexyl-5-[4-(4-pyrrol-1-ylphenoxy)phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound O=C1NC(=O)NC(=O)C1(C1CCCCC1)OC(C=C1)=CC=C1OC1=CC=C(N2C=CC=C2)C=C1 HDHFEPUXMRNHGU-UHFFFAOYSA-N 0.000 description 1
- HNRHOSIBYNPGAK-UHFFFAOYSA-N 5-cyclohexyl-5-[4-[3-fluoro-4-(1,3,4-oxadiazol-2-yl)phenoxy]phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound C=1C=C(C=2OC=NN=2)C(F)=CC=1OC(C=C1)=CC=C1OC1(C2CCCCC2)C(=O)NC(=O)NC1=O HNRHOSIBYNPGAK-UHFFFAOYSA-N 0.000 description 1
- IBZLGAQTONBSKH-UHFFFAOYSA-N 5-cyclohexyl-5-[4-[3-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound O1C(C)=NN=C1C(C(=C1)F)=CC=C1OC(C=C1)=CC=C1OC1(C2CCCCC2)C(=O)NC(=O)NC1=O IBZLGAQTONBSKH-UHFFFAOYSA-N 0.000 description 1
- SEZNOPXMMIEXEN-UHFFFAOYSA-N 5-cyclohexyl-5-[4-[3-methyl-4-(1,3,4-oxadiazol-2-yl)phenoxy]phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound C=1C=C(C=2OC=NN=2)C(C)=CC=1OC(C=C1)=CC=C1OC1(C2CCCCC2)C(=O)NC(=O)NC1=O SEZNOPXMMIEXEN-UHFFFAOYSA-N 0.000 description 1
- ZBNLLHZQAVFUGG-UHFFFAOYSA-N 5-cyclohexyl-5-[4-[3-methyl-4-(1-methylpyrazol-4-yl)phenoxy]phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound C=1C=C(C2=CN(C)N=C2)C(C)=CC=1OC(C=C1)=CC=C1OC1(C2CCCCC2)C(=O)NC(=O)NC1=O ZBNLLHZQAVFUGG-UHFFFAOYSA-N 0.000 description 1
- LZLZMNJUJQUKAH-UHFFFAOYSA-N 5-cyclohexyl-5-[4-[3-methyl-4-(1h-pyrazol-4-yl)phenoxy]phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound C=1C=C(C2=CNN=C2)C(C)=CC=1OC(C=C1)=CC=C1OC1(C2CCCCC2)C(=O)NC(=O)NC1=O LZLZMNJUJQUKAH-UHFFFAOYSA-N 0.000 description 1
- BRRBJFXRCRHUPJ-UHFFFAOYSA-N 5-cyclohexyl-5-[4-[3-methyl-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound O1C(C)=NN=C1C(C(=C1)C)=CC=C1OC(C=C1)=CC=C1OC1(C2CCCCC2)C(=O)NC(=O)NC1=O BRRBJFXRCRHUPJ-UHFFFAOYSA-N 0.000 description 1
- XZTSZPNHGGAEIP-UHFFFAOYSA-N 5-cyclohexyl-5-[4-[4-(1,2,4-triazol-1-yl)phenoxy]phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound O=C1NC(=O)NC(=O)C1(C1CCCCC1)OC(C=C1)=CC=C1OC1=CC=C(N2N=CN=C2)C=C1 XZTSZPNHGGAEIP-UHFFFAOYSA-N 0.000 description 1
- QWWQDUIKVQFJKH-UHFFFAOYSA-N 5-cyclohexyl-5-[4-[4-(1,2,4-triazol-4-yl)phenoxy]phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound O=C1NC(=O)NC(=O)C1(C1CCCCC1)OC(C=C1)=CC=C1OC1=CC=C(N2C=NN=C2)C=C1 QWWQDUIKVQFJKH-UHFFFAOYSA-N 0.000 description 1
- HKQHPZKVBRFIJA-UHFFFAOYSA-N 5-cyclohexyl-5-[4-[4-(1,3,4-oxadiazol-2-yl)phenoxy]phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound O=C1NC(=O)NC(=O)C1(C1CCCCC1)OC(C=C1)=CC=C1OC1=CC=C(C=2OC=NN=2)C=C1 HKQHPZKVBRFIJA-UHFFFAOYSA-N 0.000 description 1
- UBJNRJXTIHQDPC-UHFFFAOYSA-N 5-cyclohexyl-5-[4-[4-(1,3-oxazol-4-yl)phenoxy]phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound O=C1NC(=O)NC(=O)C1(C1CCCCC1)OC(C=C1)=CC=C1OC1=CC=C(C=2N=COC=2)C=C1 UBJNRJXTIHQDPC-UHFFFAOYSA-N 0.000 description 1
- PGROHGDDAGPTRS-UHFFFAOYSA-N 5-cyclohexyl-5-[4-[4-(1,3-oxazol-5-yl)phenoxy]phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound O=C1NC(=O)NC(=O)C1(C1CCCCC1)OC(C=C1)=CC=C1OC1=CC=C(C=2OC=NC=2)C=C1 PGROHGDDAGPTRS-UHFFFAOYSA-N 0.000 description 1
- WKNJPSAWRCWTEC-UHFFFAOYSA-N 5-cyclohexyl-5-[4-[4-(1,3-thiazol-2-yl)phenoxy]phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound O=C1NC(=O)NC(=O)C1(C1CCCCC1)OC(C=C1)=CC=C1OC1=CC=C(C=2SC=CN=2)C=C1 WKNJPSAWRCWTEC-UHFFFAOYSA-N 0.000 description 1
- REERCPZLDNMBSP-UHFFFAOYSA-N 5-cyclohexyl-5-[4-[4-(1-methylpyrazol-3-yl)phenoxy]phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound CN1C=CC(C=2C=CC(OC=3C=CC(OC4(C5CCCCC5)C(NC(=O)NC4=O)=O)=CC=3)=CC=2)=N1 REERCPZLDNMBSP-UHFFFAOYSA-N 0.000 description 1
- DKDBCYXSTAHPLH-UHFFFAOYSA-N 5-cyclohexyl-5-[4-[4-(1h-1,2,4-triazol-5-yl)phenoxy]phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound O=C1NC(=O)NC(=O)C1(C1CCCCC1)OC(C=C1)=CC=C1OC1=CC=C(C=2NC=NN=2)C=C1 DKDBCYXSTAHPLH-UHFFFAOYSA-N 0.000 description 1
- ARPZNZMGNCBAHX-UHFFFAOYSA-N 5-cyclohexyl-5-[4-[4-(1h-pyrazol-4-yl)phenoxy]phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound O=C1NC(=O)NC(=O)C1(C1CCCCC1)OC(C=C1)=CC=C1OC1=CC=C(C2=CNN=C2)C=C1 ARPZNZMGNCBAHX-UHFFFAOYSA-N 0.000 description 1
- JASYENYVOUJWLU-UHFFFAOYSA-N 5-cyclohexyl-5-[4-[4-(1h-pyrazol-5-yl)phenoxy]phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound O=C1NC(=O)NC(=O)C1(C1CCCCC1)OC(C=C1)=CC=C1OC1=CC=C(C2=NNC=C2)C=C1 JASYENYVOUJWLU-UHFFFAOYSA-N 0.000 description 1
- SURXNWXDACHKRC-UHFFFAOYSA-N 5-cyclohexyl-5-[4-[4-(2-methyl-1,3-thiazol-4-yl)phenoxy]phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound S1C(C)=NC(C=2C=CC(OC=3C=CC(OC4(C5CCCCC5)C(NC(=O)NC4=O)=O)=CC=3)=CC=2)=C1 SURXNWXDACHKRC-UHFFFAOYSA-N 0.000 description 1
- OHFNBZFOBBDCJK-UHFFFAOYSA-N 5-cyclohexyl-5-[4-[4-(2-methylpyrazol-3-yl)phenoxy]phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound CN1N=CC=C1C(C=C1)=CC=C1OC(C=C1)=CC=C1OC1(C2CCCCC2)C(=O)NC(=O)NC1=O OHFNBZFOBBDCJK-UHFFFAOYSA-N 0.000 description 1
- UGUDABFJQGJZNZ-UHFFFAOYSA-N 5-cyclohexyl-5-[4-[4-(5-methyl-1,2-oxazol-3-yl)phenoxy]phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound O1C(C)=CC(C=2C=CC(OC=3C=CC(OC4(C5CCCCC5)C(NC(=O)NC4=O)=O)=CC=3)=CC=2)=N1 UGUDABFJQGJZNZ-UHFFFAOYSA-N 0.000 description 1
- HJJUOUPFZDHNPZ-UHFFFAOYSA-N 5-cyclohexyl-5-[4-[4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound O1C(C)=NN=C1C(C=C1)=CC=C1OC(C=C1)=CC=C1OC1(C2CCCCC2)C(=O)NC(=O)NC1=O HJJUOUPFZDHNPZ-UHFFFAOYSA-N 0.000 description 1
- RPCGHRXNXVHHIS-UHFFFAOYSA-N 5-cyclohexyl-5-[4-[4-(hydroxymethyl)phenoxy]phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound C1=CC(CO)=CC=C1OC(C=C1)=CC=C1OC1(C2CCCCC2)C(=O)NC(=O)NC1=O RPCGHRXNXVHHIS-UHFFFAOYSA-N 0.000 description 1
- INDDCOVGAQHVTR-UHFFFAOYSA-N 5-cyclohexyl-5-[4-[4-[5-(dimethylamino)-1,3,4-oxadiazol-2-yl]phenoxy]phenoxy]-1,3-diazinane-2,4,6-trione Chemical compound O1C(N(C)C)=NN=C1C(C=C1)=CC=C1OC(C=C1)=CC=C1OC1(C2CCCCC2)C(=O)NC(=O)NC1=O INDDCOVGAQHVTR-UHFFFAOYSA-N 0.000 description 1
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- 108091022885 ADAM Proteins 0.000 description 1
- 102000029791 ADAM Human genes 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 206010048998 Acute phase reaction Diseases 0.000 description 1
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 1
- 102100036601 Aggrecan core protein Human genes 0.000 description 1
- 108010067219 Aggrecans Proteins 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 102100028116 Amine oxidase [flavin-containing] B Human genes 0.000 description 1
- 244000144730 Amygdalus persica Species 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 208000003120 Angiofibroma Diseases 0.000 description 1
- 102400000068 Angiostatin Human genes 0.000 description 1
- 108010079709 Angiostatins Proteins 0.000 description 1
- 229940127398 Angiotensin 2 Receptor Antagonists Drugs 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 206010053555 Arthritis bacterial Diseases 0.000 description 1
- 206010003267 Arthritis reactive Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 1
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 1
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- KUVIULQEHSCUHY-XYWKZLDCSA-N Beclometasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)COC(=O)CC)(OC(=O)CC)[C@@]1(C)C[C@@H]2O KUVIULQEHSCUHY-XYWKZLDCSA-N 0.000 description 1
- 229940123208 Biguanide Drugs 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 229910000906 Bronze Inorganic materials 0.000 description 1
- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 description 1
- 239000002083 C09CA01 - Losartan Substances 0.000 description 1
- 239000002947 C09CA04 - Irbesartan Substances 0.000 description 1
- 206010006895 Cachexia Diseases 0.000 description 1
- 208000004434 Calcinosis Diseases 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 208000005145 Cerebral amyloid angiopathy Diseases 0.000 description 1
- ZKLPARSLTMPFCP-UHFFFAOYSA-N Cetirizine Chemical compound C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-UHFFFAOYSA-N 0.000 description 1
- 108091006146 Channels Proteins 0.000 description 1
- 206010008690 Chondrocalcinosis pyrophosphate Diseases 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 102000012422 Collagen Type I Human genes 0.000 description 1
- 108010022452 Collagen Type I Proteins 0.000 description 1
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- 206010011017 Corneal graft rejection Diseases 0.000 description 1
- 208000028006 Corneal injury Diseases 0.000 description 1
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 1
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 238000006969 Curtius rearrangement reaction Methods 0.000 description 1
- DSLZVSRJTYRBFB-LLEIAEIESA-N D-glucaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O DSLZVSRJTYRBFB-LLEIAEIESA-N 0.000 description 1
- VVNCNSJFMMFHPL-VKHMYHEASA-N D-penicillamine Chemical compound CC(C)(S)[C@@H](N)C(O)=O VVNCNSJFMMFHPL-VKHMYHEASA-N 0.000 description 1
- 208000016192 Demyelinating disease Diseases 0.000 description 1
- 101000783577 Dendroaspis angusticeps Thrombostatin Proteins 0.000 description 1
- 101000783578 Dendroaspis jamesoni kaimosae Dendroaspin Proteins 0.000 description 1
- 208000018035 Dental disease Diseases 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 206010012689 Diabetic retinopathy Diseases 0.000 description 1
- 206010056340 Diabetic ulcer Diseases 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 239000004338 Dichlorodifluoromethane Substances 0.000 description 1
- 240000001879 Digitalis lutea Species 0.000 description 1
- ZQZFYGIXNQKOAV-OCEACIFDSA-N Droloxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=C(O)C=CC=1)\C1=CC=C(OCCN(C)C)C=C1 ZQZFYGIXNQKOAV-OCEACIFDSA-N 0.000 description 1
- 206010013908 Dysfunctional uterine bleeding Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- 206010014561 Emphysema Diseases 0.000 description 1
- 108010061435 Enalapril Proteins 0.000 description 1
- 208000001976 Endocrine Gland Neoplasms Diseases 0.000 description 1
- 201000009273 Endometriosis Diseases 0.000 description 1
- 102400001047 Endostatin Human genes 0.000 description 1
- 108010079505 Endostatins Proteins 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- 206010014989 Epidermolysis bullosa Diseases 0.000 description 1
- 108010008165 Etanercept Proteins 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 208000022461 Glomerular disease Diseases 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 206010018691 Granuloma Diseases 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 206010019196 Head injury Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 239000004705 High-molecular-weight polyethylene Substances 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000768078 Homo sapiens Amine oxidase [flavin-containing] B Proteins 0.000 description 1
- 101000577887 Homo sapiens Collagenase 3 Proteins 0.000 description 1
- 101001002634 Homo sapiens Interleukin-1 alpha Proteins 0.000 description 1
- 101001011896 Homo sapiens Matrix metalloproteinase-19 Proteins 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- WOBHKFSMXKNTIM-UHFFFAOYSA-N Hydroxyethyl methacrylate Chemical compound CC(=C)C(=O)OCCO WOBHKFSMXKNTIM-UHFFFAOYSA-N 0.000 description 1
- LCWXJXMHJVIJFK-UHFFFAOYSA-N Hydroxylysine Natural products NCC(O)CC(N)CC(O)=O LCWXJXMHJVIJFK-UHFFFAOYSA-N 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 208000004575 Infectious Arthritis Diseases 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 102000051628 Interleukin-1 receptor antagonist Human genes 0.000 description 1
- 108700021006 Interleukin-1 receptor antagonist Proteins 0.000 description 1
- SHGAZHPCJJPHSC-NUEINMDLSA-N Isotretinoin Chemical compound OC(=O)C=C(C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-NUEINMDLSA-N 0.000 description 1
- 208000012659 Joint disease Diseases 0.000 description 1
- 208000003456 Juvenile Arthritis Diseases 0.000 description 1
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 description 1
- 201000002287 Keratoconus Diseases 0.000 description 1
- SNDPXSYFESPGGJ-BYPYZUCNSA-N L-2-aminopentanoic acid Chemical compound CCC[C@H](N)C(O)=O SNDPXSYFESPGGJ-BYPYZUCNSA-N 0.000 description 1
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 1
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 1
- 108010009384 L-Iditol 2-Dehydrogenase Proteins 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- RHGKLRLOHDJJDR-BYPYZUCNSA-N L-citrulline Chemical compound NC(=O)NCCC[C@H]([NH3+])C([O-])=O RHGKLRLOHDJJDR-BYPYZUCNSA-N 0.000 description 1
- UKAUYVFTDYCKQA-VKHMYHEASA-N L-homoserine Chemical compound OC(=O)[C@@H](N)CCO UKAUYVFTDYCKQA-VKHMYHEASA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- UCUNFLYVYCGDHP-BYPYZUCNSA-N L-methionine sulfone Chemical compound CS(=O)(=O)CC[C@H](N)C(O)=O UCUNFLYVYCGDHP-BYPYZUCNSA-N 0.000 description 1
- SNDPXSYFESPGGJ-UHFFFAOYSA-N L-norVal-OH Natural products CCCC(N)C(O)=O SNDPXSYFESPGGJ-UHFFFAOYSA-N 0.000 description 1
- 108010007859 Lisinopril Proteins 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- 206010052178 Lymphocytic lymphoma Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- 102000055008 Matrilin Proteins Human genes 0.000 description 1
- 108010072582 Matrilin Proteins Proteins 0.000 description 1
- 108010016165 Matrix Metalloproteinase 2 Proteins 0.000 description 1
- 108010016160 Matrix Metalloproteinase 3 Proteins 0.000 description 1
- 102100030201 Matrix metalloproteinase-15 Human genes 0.000 description 1
- 108090000560 Matrix metalloproteinase-15 Proteins 0.000 description 1
- 102100030200 Matrix metalloproteinase-16 Human genes 0.000 description 1
- 108090000561 Matrix metalloproteinase-16 Proteins 0.000 description 1
- 102100030219 Matrix metalloproteinase-17 Human genes 0.000 description 1
- 108090000585 Matrix metalloproteinase-17 Proteins 0.000 description 1
- 102100030218 Matrix metalloproteinase-19 Human genes 0.000 description 1
- 108090000587 Matrix metalloproteinase-19 Proteins 0.000 description 1
- 102000004055 Matrix metalloproteinase-19 Human genes 0.000 description 1
- 102100029693 Matrix metalloproteinase-20 Human genes 0.000 description 1
- 108090000609 Matrix metalloproteinase-20 Proteins 0.000 description 1
- 102000001776 Matrix metalloproteinase-9 Human genes 0.000 description 1
- 102000003843 Metalloendopeptidases Human genes 0.000 description 1
- 108090000131 Metalloendopeptidases Proteins 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 206010027514 Metrorrhagia Diseases 0.000 description 1
- BYBLEWFAAKGYCD-UHFFFAOYSA-N Miconazole Chemical compound ClC1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 BYBLEWFAAKGYCD-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 1
- 206010062207 Mycobacterial infection Diseases 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- JDHILDINMRGULE-LURJTMIESA-N N(pros)-methyl-L-histidine Chemical compound CN1C=NC=C1C[C@H](N)C(O)=O JDHILDINMRGULE-LURJTMIESA-N 0.000 description 1
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 1
- RHGKLRLOHDJJDR-UHFFFAOYSA-N Ndelta-carbamoyl-DL-ornithine Natural products OC(=O)C(N)CCCNC(N)=O RHGKLRLOHDJJDR-UHFFFAOYSA-N 0.000 description 1
- 206010029164 Nephrotic syndrome Diseases 0.000 description 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
- 102000006538 Nitric Oxide Synthase Type I Human genes 0.000 description 1
- 108010008858 Nitric Oxide Synthase Type I Proteins 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- 208000010191 Osteitis Deformans Diseases 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 208000027868 Paget disease Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 208000004210 Pressure Ulcer Diseases 0.000 description 1
- 208000024777 Prion disease Diseases 0.000 description 1
- 108010067787 Proteoglycans Proteins 0.000 description 1
- 102000016611 Proteoglycans Human genes 0.000 description 1
- 235000006040 Prunus persica var persica Nutrition 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical class C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 1
- 206010038933 Retinopathy of prematurity Diseases 0.000 description 1
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 description 1
- 206010039705 Scleritis Diseases 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- GIIZNNXWQWCKIB-UHFFFAOYSA-N Serevent Chemical compound C1=C(O)C(CO)=CC(C(O)CNCCCCCCOCCCCC=2C=CC=CC=2)=C1 GIIZNNXWQWCKIB-UHFFFAOYSA-N 0.000 description 1
- 244000000231 Sesamum indicum Species 0.000 description 1
- 208000021386 Sjogren Syndrome Diseases 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 229920002385 Sodium hyaluronate Polymers 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 102100026974 Sorbitol dehydrogenase Human genes 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 208000014151 Stomatognathic disease Diseases 0.000 description 1
- 102100028848 Stromelysin-2 Human genes 0.000 description 1
- 101710108792 Stromelysin-2 Proteins 0.000 description 1
- 102100028847 Stromelysin-3 Human genes 0.000 description 1
- 108050005271 Stromelysin-3 Proteins 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- 239000000150 Sympathomimetic Substances 0.000 description 1
- 108700012920 TNF Proteins 0.000 description 1
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 229940123464 Thiazolidinedione Drugs 0.000 description 1
- 229940122618 Trypsin inhibitor Drugs 0.000 description 1
- 101710162629 Trypsin inhibitor Proteins 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 108060008683 Tumor Necrosis Factor Receptor Proteins 0.000 description 1
- 102100040247 Tumor necrosis factor Human genes 0.000 description 1
- 206010064390 Tumour invasion Diseases 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 206010064996 Ulcerative keratitis Diseases 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 208000036866 Vitreoretinopathy Diseases 0.000 description 1
- 101001011890 Xenopus laevis Matrix metalloproteinase-18 Proteins 0.000 description 1
- YEEZWCHGZNKEEK-UHFFFAOYSA-N Zafirlukast Chemical compound COC1=CC(C(=O)NS(=O)(=O)C=2C(=CC=CC=2)C)=CC=C1CC(C1=C2)=CN(C)C1=CC=C2NC(=O)OC1CCCC1 YEEZWCHGZNKEEK-UHFFFAOYSA-N 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 229960000446 abciximab Drugs 0.000 description 1
- 208000002223 abdominal aortic aneurysm Diseases 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 206010000210 abortion Diseases 0.000 description 1
- 231100000176 abortion Toxicity 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 229960002632 acarbose Drugs 0.000 description 1
- XUFXOAAUWZOOIT-UHFFFAOYSA-N acarviostatin I01 Natural products OC1C(O)C(NC2C(C(O)C(O)C(CO)=C2)O)C(C)OC1OC(C(C1O)O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O XUFXOAAUWZOOIT-UHFFFAOYSA-N 0.000 description 1
- ZCHPKWUIAASXPV-UHFFFAOYSA-N acetic acid;methanol Chemical compound OC.CC(O)=O ZCHPKWUIAASXPV-UHFFFAOYSA-N 0.000 description 1
- 230000004658 acute-phase response Effects 0.000 description 1
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 1
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 239000003288 aldose reductase inhibitor Substances 0.000 description 1
- 229940090865 aldose reductase inhibitors used in diabetes Drugs 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 description 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 125000005233 alkylalcohol group Chemical group 0.000 description 1
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 description 1
- 229960000528 amlodipine Drugs 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 229940051880 analgesics and antipyretics pyrazolones Drugs 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 230000003872 anastomosis Effects 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 208000022531 anorexia Diseases 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000007131 anti Alzheimer effect Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 239000000043 antiallergic agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 239000003524 antilipemic agent Substances 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000000939 antiparkinson agent Substances 0.000 description 1
- 229940125688 antiparkinson agent Drugs 0.000 description 1
- 229940127218 antiplatelet drug Drugs 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000005129 aryl carbonyl group Chemical group 0.000 description 1
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- FZCSTZYAHCUGEM-UHFFFAOYSA-N aspergillomarasmine B Natural products OC(=O)CNC(C(O)=O)CNC(C(O)=O)CC(O)=O FZCSTZYAHCUGEM-UHFFFAOYSA-N 0.000 description 1
- 229960005370 atorvastatin Drugs 0.000 description 1
- WOIIIUDZSOLAIW-NSHDSACASA-N azapropazone Chemical compound C1=C(C)C=C2N3C(=O)[C@H](CC=C)C(=O)N3C(N(C)C)=NC2=C1 WOIIIUDZSOLAIW-NSHDSACASA-N 0.000 description 1
- 229960001671 azapropazone Drugs 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 description 1
- 229960004099 azithromycin Drugs 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 229950000210 beclometasone dipropionate Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004601 benzofurazanyl group Chemical group N1=C2C(=NO1)C(=CC=C2)* 0.000 description 1
- HAVZTGSQJIEKPI-UHFFFAOYSA-N benzothiadiazine Chemical compound C1=CC=C2C=NNSC2=C1 HAVZTGSQJIEKPI-UHFFFAOYSA-N 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- 229940000635 beta-alanine Drugs 0.000 description 1
- 150000004283 biguanides Chemical class 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000000133 brain stem Anatomy 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 239000010974 bronze Substances 0.000 description 1
- 229960004436 budesonide Drugs 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 229960003563 calcium carbonate Drugs 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 230000009400 cancer invasion Effects 0.000 description 1
- 229960000830 captopril Drugs 0.000 description 1
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 229960004424 carbon dioxide Drugs 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000003543 catechol methyltransferase inhibitor Substances 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 229920003174 cellulose-based polymer Polymers 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 229960003115 certolizumab pegol Drugs 0.000 description 1
- 210000003679 cervix uteri Anatomy 0.000 description 1
- 229960001803 cetirizine Drugs 0.000 description 1
- 229920001429 chelating resin Polymers 0.000 description 1
- 239000012320 chlorinating reagent Substances 0.000 description 1
- BFPSDSIWYFKGBC-UHFFFAOYSA-N chlorotrianisene Chemical compound C1=CC(OC)=CC=C1C(Cl)=C(C=1C=CC(OC)=CC=1)C1=CC=C(OC)C=C1 BFPSDSIWYFKGBC-UHFFFAOYSA-N 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 208000002849 chondrocalcinosis Diseases 0.000 description 1
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 description 1
- 208000019069 chronic childhood arthritis Diseases 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 229960002173 citrulline Drugs 0.000 description 1
- 235000013477 citrulline Nutrition 0.000 description 1
- 229960004022 clotrimazole Drugs 0.000 description 1
- VNFPBHJOKIVQEB-UHFFFAOYSA-N clotrimazole Chemical compound ClC1=CC=CC=C1C(N1C=NC=C1)(C=1C=CC=CC=1)C1=CC=CC=C1 VNFPBHJOKIVQEB-UHFFFAOYSA-N 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 230000019771 cognition Effects 0.000 description 1
- 239000000571 coke Substances 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 230000000112 colonic effect Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000003271 compound fluorescence assay Methods 0.000 description 1
- 208000010247 contact dermatitis Diseases 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 150000001879 copper Chemical class 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- KUNSUQLRTQLHQQ-UHFFFAOYSA-N copper tin Chemical compound [Cu].[Sn] KUNSUQLRTQLHQQ-UHFFFAOYSA-N 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 229960004544 cortisone Drugs 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000006547 cyclononyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 230000003412 degenerative effect Effects 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- YSMODUONRAFBET-UHFFFAOYSA-N delta-DL-hydroxylysine Natural products NCC(O)CCC(N)C(O)=O YSMODUONRAFBET-UHFFFAOYSA-N 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 229940000033 dermatological agent Drugs 0.000 description 1
- 239000003241 dermatological agent Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 1
- 229940042935 dichlorodifluoromethane Drugs 0.000 description 1
- 229940087091 dichlorotetrafluoroethane Drugs 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 1
- 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 description 1
- 125000005057 dihydrothienyl group Chemical group S1C(CC=C1)* 0.000 description 1
- 230000010339 dilation Effects 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- WJJMNDUMQPNECX-UHFFFAOYSA-N dipicolinic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=N1 WJJMNDUMQPNECX-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 229940052760 dopamine agonists Drugs 0.000 description 1
- 239000000221 dopamine uptake inhibitor Substances 0.000 description 1
- RUZYUOTYCVRMRZ-UHFFFAOYSA-N doxazosin Chemical compound C1OC2=CC=CC=C2OC1C(=O)N(CC1)CCN1C1=NC(N)=C(C=C(C(OC)=C2)OC)C2=N1 RUZYUOTYCVRMRZ-UHFFFAOYSA-N 0.000 description 1
- 229960001389 doxazosin Drugs 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 229950004203 droloxifene Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000012039 electrophile Substances 0.000 description 1
- 230000008451 emotion Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 229960000873 enalapril Drugs 0.000 description 1
- GBXSMTUPTTWBMN-XIRDDKMYSA-N enalapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 GBXSMTUPTTWBMN-XIRDDKMYSA-N 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940079360 enema for constipation Drugs 0.000 description 1
- 239000002662 enteric coated tablet Substances 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- 125000003700 epoxy group Chemical group 0.000 description 1
- YSMODUONRAFBET-UHNVWZDZSA-N erythro-5-hydroxy-L-lysine Chemical compound NC[C@H](O)CC[C@H](N)C(O)=O YSMODUONRAFBET-UHNVWZDZSA-N 0.000 description 1
- 229960000403 etanercept Drugs 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 210000002219 extraembryonic membrane Anatomy 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 208000024519 eye neoplasm Diseases 0.000 description 1
- 229940125753 fibrate Drugs 0.000 description 1
- 230000003176 fibrotic effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 1
- 229960004884 fluconazole Drugs 0.000 description 1
- 238000001506 fluorescence spectroscopy Methods 0.000 description 1
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 1
- 229960002714 fluticasone Drugs 0.000 description 1
- MGNNYOODZCAHBA-GQKYHHCASA-N fluticasone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(O)[C@@]2(C)C[C@@H]1O MGNNYOODZCAHBA-GQKYHHCASA-N 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229960002490 fosinopril Drugs 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- 125000003838 furazanyl group Chemical group 0.000 description 1
- 125000004612 furopyridinyl group Chemical group O1C(=CC2=C1C=CC=N2)* 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 208000007565 gingivitis Diseases 0.000 description 1
- 229960004580 glibenclamide Drugs 0.000 description 1
- ZJJXGWJIGJFDTL-UHFFFAOYSA-N glipizide Chemical compound C1=NC(C)=CN=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZJJXGWJIGJFDTL-UHFFFAOYSA-N 0.000 description 1
- 229960001381 glipizide Drugs 0.000 description 1
- 231100000852 glomerular disease Toxicity 0.000 description 1
- ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000003316 glycosidase inhibitor Substances 0.000 description 1
- 208000010758 granulomatous inflammation Diseases 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 201000011066 hemangioma Diseases 0.000 description 1
- 230000009033 hematopoietic malignancy Effects 0.000 description 1
- 230000000004 hemodynamic effect Effects 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 150000002390 heteroarenes Chemical class 0.000 description 1
- 125000005114 heteroarylalkoxy group Chemical group 0.000 description 1
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 1
- 125000005553 heteroaryloxy group Chemical group 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 125000004634 hexahydroazepinyl group Chemical group N1(CCCCCC1)* 0.000 description 1
- 229940018991 hyalgan Drugs 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- QJHBJHUKURJDLG-UHFFFAOYSA-N hydroxy-L-lysine Natural products NCCCCC(NO)C(O)=O QJHBJHUKURJDLG-UHFFFAOYSA-N 0.000 description 1
- XXSMGPRMXLTPCZ-UHFFFAOYSA-N hydroxychloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 XXSMGPRMXLTPCZ-UHFFFAOYSA-N 0.000 description 1
- 229960004171 hydroxychloroquine Drugs 0.000 description 1
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 description 1
- ZQDWXGKKHFNSQK-UHFFFAOYSA-N hydroxyzine Chemical compound C1CN(CCOCCO)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZQDWXGKKHFNSQK-UHFFFAOYSA-N 0.000 description 1
- 229960000930 hydroxyzine Drugs 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000005462 in vivo assay Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 229960000598 infliximab Drugs 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 1
- 201000006334 interstitial nephritis Diseases 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- OEXHQOGQTVQTAT-JRNQLAHRSA-N ipratropium Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)[N@@+]2(C)C(C)C)C(=O)C(CO)C1=CC=CC=C1 OEXHQOGQTVQTAT-JRNQLAHRSA-N 0.000 description 1
- 229960001888 ipratropium Drugs 0.000 description 1
- 229960002198 irbesartan Drugs 0.000 description 1
- YCPOHTHPUREGFM-UHFFFAOYSA-N irbesartan Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C=2[N]N=NN=2)C(CCCC)=NC21CCCC2 YCPOHTHPUREGFM-UHFFFAOYSA-N 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 229960005280 isotretinoin Drugs 0.000 description 1
- 125000003965 isoxazolidinyl group Chemical group 0.000 description 1
- 201000002215 juvenile rheumatoid arthritis Diseases 0.000 description 1
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 229940054136 kineret Drugs 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- 210000000867 larynx Anatomy 0.000 description 1
- VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 description 1
- 229960000681 leflunomide Drugs 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000003199 leukotriene receptor blocking agent Substances 0.000 description 1
- 229950008204 levosalbutamol Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 229960002394 lisinopril Drugs 0.000 description 1
- RLAWWYSOJDYHDC-BZSNNMDCSA-N lisinopril Chemical compound C([C@H](N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 RLAWWYSOJDYHDC-BZSNNMDCSA-N 0.000 description 1
- 229960003088 loratadine Drugs 0.000 description 1
- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 description 1
- 229960004773 losartan Drugs 0.000 description 1
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 230000002535 lyotropic effect Effects 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229910001425 magnesium ion Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 208000027202 mammary Paget disease Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229960003464 mefenamic acid Drugs 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000002175 menstrual effect Effects 0.000 description 1
- 125000005905 mesyloxy group Chemical group 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- 229960003105 metformin Drugs 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000005948 methanesulfonyloxy group Chemical group 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- AGJSNMGHAVDLRQ-IWFBPKFRSA-N methyl (2s)-2-[[(2s)-2-[[(2s)-2-[[(2r)-2-amino-3-sulfanylpropanoyl]amino]-3-methylbutanoyl]amino]-3-(4-hydroxy-2,3-dimethylphenyl)propanoyl]amino]-4-methylsulfanylbutanoate Chemical compound SC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCSC)C(=O)OC)CC1=CC=C(O)C(C)=C1C AGJSNMGHAVDLRQ-IWFBPKFRSA-N 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- IYETZZCWLLUHIJ-UHFFFAOYSA-N methyl-(1-phenylpropan-2-yl)-prop-2-ynylazanium;chloride Chemical compound Cl.C#CCN(C)C(C)CC1=CC=CC=C1 IYETZZCWLLUHIJ-UHFFFAOYSA-N 0.000 description 1
- 229960002509 miconazole Drugs 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 229960001664 mometasone Drugs 0.000 description 1
- QLIIKPVHVRXHRI-CXSFZGCWSA-N mometasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CCl)(O)[C@@]1(C)C[C@@H]2O QLIIKPVHVRXHRI-CXSFZGCWSA-N 0.000 description 1
- 210000005087 mononuclear cell Anatomy 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- 208000027531 mycobacterial infectious disease Diseases 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 208000001491 myopia Diseases 0.000 description 1
- 230000004379 myopia Effects 0.000 description 1
- GUAQVFRUPZBRJQ-UHFFFAOYSA-N n-(3-aminopropyl)-2-methylprop-2-enamide Chemical compound CC(=C)C(=O)NCCCN GUAQVFRUPZBRJQ-UHFFFAOYSA-N 0.000 description 1
- RPVADJLIFNQXCX-UHFFFAOYSA-N n-[[4-(5-hydroxypyridin-2-yl)oxyphenyl]methyl]acetamide Chemical compound C1=CC(CNC(=O)C)=CC=C1OC1=CC=C(O)C=N1 RPVADJLIFNQXCX-UHFFFAOYSA-N 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 201000003142 neovascular glaucoma Diseases 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 229960002715 nicotine Drugs 0.000 description 1
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 1
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 1
- 229960001597 nifedipine Drugs 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 239000000236 nitric oxide synthase inhibitor Substances 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 201000008106 ocular cancer Diseases 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000001451 organic peroxides Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 150000004866 oxadiazoles Chemical class 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 150000002916 oxazoles Chemical class 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 229960001639 penicillamine Drugs 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 210000003800 pharynx Anatomy 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 229960002895 phenylbutazone Drugs 0.000 description 1
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 229960005095 pioglitazone Drugs 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
- QQNAAOIGTOESQU-UHFFFAOYSA-N piperidine-2,4,6-trione Chemical class O=C1CC(=O)NC(=O)C1 QQNAAOIGTOESQU-UHFFFAOYSA-N 0.000 description 1
- 229960002702 piroxicam Drugs 0.000 description 1
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 1
- 229920001184 polypeptide Chemical group 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 108090000765 processed proteins & peptides Chemical group 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000006785 proliferative vitreoretinopathy Effects 0.000 description 1
- 150000004672 propanoic acids Chemical class 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 201000001474 proteinuria Diseases 0.000 description 1
- 230000001185 psoriatic effect Effects 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- JEXVQSWXXUJEMA-UHFFFAOYSA-N pyrazol-3-one Chemical class O=C1C=CN=N1 JEXVQSWXXUJEMA-UHFFFAOYSA-N 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- JSDRRTOADPPCHY-HSQYWUDLSA-N quinapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CC2=CC=CC=C2C1)C(O)=O)CC1=CC=CC=C1 JSDRRTOADPPCHY-HSQYWUDLSA-N 0.000 description 1
- 229960001455 quinapril Drugs 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 1
- RUOKEQAAGRXIBM-GFCCVEGCSA-N rasagiline Chemical compound C1=CC=C2[C@H](NCC#C)CCC2=C1 RUOKEQAAGRXIBM-GFCCVEGCSA-N 0.000 description 1
- 229960000245 rasagiline Drugs 0.000 description 1
- 208000002574 reactive arthritis Diseases 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000010410 reperfusion Effects 0.000 description 1
- 230000033458 reproduction Effects 0.000 description 1
- 229940124709 respiratory disease therapeutics Drugs 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- SVOOVMQUISJERI-UHFFFAOYSA-K rhodium(3+);triacetate Chemical compound [Rh+3].CC([O-])=O.CC([O-])=O.CC([O-])=O SVOOVMQUISJERI-UHFFFAOYSA-K 0.000 description 1
- 229960004586 rosiglitazone Drugs 0.000 description 1
- CSYSULGPHGCBQD-UHFFFAOYSA-N s-ethylisothiouronium diethylphosphate Chemical compound CCSC(N)=N.CCOP(O)(=O)OCC CSYSULGPHGCBQD-UHFFFAOYSA-N 0.000 description 1
- 229960002052 salbutamol Drugs 0.000 description 1
- 150000003873 salicylate salts Chemical class 0.000 description 1
- 229960004017 salmeterol Drugs 0.000 description 1
- 230000037390 scarring Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- MEZLKOACVSPNER-GFCCVEGCSA-N selegiline Chemical compound C#CCN(C)[C@H](C)CC1=CC=CC=C1 MEZLKOACVSPNER-GFCCVEGCSA-N 0.000 description 1
- 229960003946 selegiline Drugs 0.000 description 1
- 229960003678 selegiline hydrochloride Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 201000001223 septic arthritis Diseases 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- VGKDLMBJGBXTGI-SJCJKPOMSA-N sertraline Chemical compound C1([C@@H]2CC[C@@H](C3=CC=CC=C32)NC)=CC=C(Cl)C(Cl)=C1 VGKDLMBJGBXTGI-SJCJKPOMSA-N 0.000 description 1
- 229960002073 sertraline Drugs 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 229960002855 simvastatin Drugs 0.000 description 1
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 230000009759 skin aging Effects 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 229960001790 sodium citrate Drugs 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- 229940010747 sodium hyaluronate Drugs 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 208000020431 spinal cord injury Diseases 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid Chemical compound NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 229960000894 sulindac Drugs 0.000 description 1
- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000001975 sympathomimetic effect Effects 0.000 description 1
- 229940064707 sympathomimetics Drugs 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229940036220 synvisc Drugs 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229960001685 tacrine Drugs 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- VCKUSRYTPJJLNI-UHFFFAOYSA-N terazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1CCCO1 VCKUSRYTPJJLNI-UHFFFAOYSA-N 0.000 description 1
- 229960001693 terazosin Drugs 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 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
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 150000003557 thiazoles Chemical class 0.000 description 1
- 150000001467 thiazolidinediones Chemical class 0.000 description 1
- 125000003396 thiol group Chemical class [H]S* 0.000 description 1
- 125000004055 thiomethyl group Chemical group [H]SC([H])([H])* 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 230000007838 tissue remodeling Effects 0.000 description 1
- 230000006032 tissue transformation Effects 0.000 description 1
- MIQPIUSUKVNLNT-UHFFFAOYSA-N tolcapone Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC(O)=C(O)C([N+]([O-])=O)=C1 MIQPIUSUKVNLNT-UHFFFAOYSA-N 0.000 description 1
- 229960004603 tolcapone Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 239000006208 topical dosage form Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 229960005294 triamcinolone Drugs 0.000 description 1
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- 125000005455 trithianyl group Chemical group 0.000 description 1
- GXPHKUHSUJUWKP-UHFFFAOYSA-N troglitazone Chemical compound C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)COC(C=C1)=CC=C1CC1SC(=O)NC1=O GXPHKUHSUJUWKP-UHFFFAOYSA-N 0.000 description 1
- 229960001641 troglitazone Drugs 0.000 description 1
- GXPHKUHSUJUWKP-NTKDMRAZSA-N troglitazone Natural products C([C@@]1(OC=2C(C)=C(C(=C(C)C=2CC1)O)C)C)OC(C=C1)=CC=C1C[C@H]1SC(=O)NC1=O GXPHKUHSUJUWKP-NTKDMRAZSA-N 0.000 description 1
- 239000002753 trypsin inhibitor Substances 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 102000003298 tumor necrosis factor receptor Human genes 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000003021 water soluble solvent Substances 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
- 229960004764 zafirlukast Drugs 0.000 description 1
- MWLSOWXNZPKENC-SSDOTTSWSA-N zileuton Chemical compound C1=CC=C2SC([C@H](N(O)C(N)=O)C)=CC2=C1 MWLSOWXNZPKENC-SSDOTTSWSA-N 0.000 description 1
- 229960005332 zileuton Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/60—Three or more oxygen or sulfur atoms
- C07D239/62—Barbituric acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Pulmonology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pain & Pain Management (AREA)
- Ophthalmology & Optometry (AREA)
- Immunology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Cardiology (AREA)
- Rheumatology (AREA)
- Urology & Nephrology (AREA)
- Dermatology (AREA)
- Gastroenterology & Hepatology (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Dental Preparations (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明涉及式(I)的嘧啶-2,4,6-三酮类金属蛋白酶抑制剂,其中X,Y,A、B和R1如说明书中所定义;本发明还涉及药物组合物和治疗炎症、肿瘤和其它疾病的方法。
Description
发明领域
本发明涉及嘧啶-2,4,6-三酮类金属蛋白酶抑制剂,药物组合物以及治疗炎症、肿瘤及其他疾病的方法。
发明背景
本发明的化合物是含锌金属内肽酶,尤其是那些属于基质金属蛋白酶(也称MMP或matrixin)的抑制剂。
MMP酶亚家族,目前包含17个成员(MMP-1、MMP-2、MMP-3、MMP-7、MMP-8、MMP-9、MMP-10、MMP-11、MMP-12、MMP-13、MMP-14、MMP-15、MMP-16、MMP-17、MMP-18、MMP-19、MMP-20)。MMP类酶以在胞外基质蛋白的转化中发挥调节作用而出名,在如生殖、发育及分化等正常的生理过程中发挥重要作用。同时,MMP类酶也在很多病理状况下表达,通常发生异常的结缔组织转化。例如,研究已经证实对II型胶原质(软骨中主要胶原质形式)具有强降解活性的MMP-13,在骨关节炎软骨中高表达(Mitchell等,J.Clin.Invest.,1996,97,761)。其他的MMP(MMP-2、MMP-3、MMP-8、MMP-9、MMP-12)也在骨关节炎软骨中高表达,抑制其中的一些或所有MMP有望减缓或阻止如骨关节炎或风湿性关节炎等关节病中软骨的加速丢失。
已经认识到不同的病理状况有不同组合MMP的表达。因此,对特定MMP具有特异选择性的抑制剂也许有利于特定病理状态的治疗。
基质金属蛋白酶抑制剂在文献中已有报道。欧洲专利公报606,046(1994年7月13日公开)例举了异羟肟酸类MMP抑制剂;PCT公报WO 98/58925(1998年12月30日公开)报道几种吡啶-2,4,6三酮类MMP抑制剂;WO00/47565(2000年8月17日)报道了芳基取代嘧啶-2,4,6-三酮MMP抑制剂。美国非临时申请09/635156,2000年8月9日提交(要求享有1999年8月12日提交的美国临时申请60/148547的优先权)报道杂芳香取代嘧啶-2,4,6三酮类MMP抑制剂。美国临时申请,标题″螺-嘧啶-2,4,6-三酮金属蛋白酶抑制剂″,2000年10月26日提交,包括几种5-螺-嘧啶-2,4,6-三酮。巴比妥酸及其制备方法已为专业人员所熟悉,参见Goodman和Gilman,″Phamacological Basis of Thrapeutics,″345-382(Eighth Edition,McGrawHill,1990)。上述参考的文献及应用在此作为参考文献引入。
发明概要
本发明涉及下列结构式的化合物:
其中A为任选取代的(C6-C10)芳基或(C2-C10)杂芳基;
B为任选取代的(C6-C10)芳基,(C3-C8)环烷基,(C1-C10)杂芳香基,(C1-C10)杂环基,(C6-C10)芳基-(C1-C4)烷基,(C3-C8)环烷基-(C1-C4)烷基,(C1-C10)杂芳基-(C1-C4)烷基或(C1-C10)杂环基-(C1-C4)烷基;其中上述每个(C3-C8)环烷基或(C1-C10)杂环取代基可任选包含1-2个双键;
其中,A和B可以独立地由一种或两种取代基任选取代环上可另成键的碳原子,所述的取代基独立地为F,Cl,Br,CN,OH,(C1-C4)烷基,(C1-C4)全氟代烷基,(C1-C4)全氟代烷氧基,(C1-C4)烷氧基以及(C3-C8)环烷氧基;
X为O,>C=O,S,>SO2,S=O,>NR10,-CH2O-,-OCH2-,-CH2S-,-CH2(S=O)-,-CH2SO2-,-SCH2-,-SOCH2-,-SO2CH2-,-[N(R10)]CH2-,-CH2[N(R10)]-,-[N(R10)]SO2-,和-SO2[N(R10)]-;
Y为键,O,S,>C=O,>SO2,>S=O,>NR12,-CH2-,-CH2O-,-OCH2-,-CH2S-,-CH2(S=O)-,-CH2SO2-,-SCH2-,-(S=O)CH2-,-SO2CH2-,-[N(R12)]CH2-,-CH2[N(R12)]-,-CH2CH2-,-CH=CH-,-[N(R12)]-SO2-以及-SO2[N(R12)]-;
R1为氢,(R2)2n+1-(C)n-或(C3-C8)环烷基,其中(C3-C8)环烷基可以被一个或两个取代基任选取代,取代基独立地为卤原子,(C1-C4)烷基,(C1-C4)烯基,(C1-C4)炔基,R3,R3O-,全氟取代(C1-C4)烷氧基,R3-(C1-C4)烷基-O-,R3-(C=O)-O-,(R3)2N-(C=O)-O-,-NO2,(R3)2N-,R3-(C=O)-(NR4)-,R3-(SO2)-(NR4)-,R3O-(C=O)-(NR4)-,(R3)2-N-(C=O)-(NR4)-,R3-S-,R3-(S=O)-,R3-(SO2)-,(R3)2N-(SO2)-,-CN,R3-(C=O)-,R3-O-(C=O)-以及(R3)2N-(C=O)-;
N为1-10的整数;
每个R2独立地为卤素,R3-,(C1-C4)烯基,(C1-C4)炔基,R3-O-,全氟取代(C1-C4)烷氧基,R3-(C=O)-O-,(R3)2N-(C=O)-O-,-NO2,(R3)2N-,R3-(SO2)-(NR4)-,R3-(C=O)-(NR4)-,R3O-(C=O)-(NR4)-,(R3)2-N-(C=O)-(NR4)-,R3-S-,R3-(S=O)-,R3-(SO2)-,(R3)2N-(SO2)-,-CN,R3-(C=O)-,R3-O-(C=O)-以及(R3)2N-(C=O)-;其中至多三个已经提及的R2取代基不是氢,并且-(C)n-基团上的每一个碳原子可以与一个杂原子形成单键;其中任两个R2基团上的一个碳原子可以与碳原子成键,形成4-10元环;
每一个R3可以独立地为氢,(C1-C4)烷基,(C6-C10)芳基,(C3-C8)环氧基,(C1-C10)杂芳基以及(C1-C10)杂环基;其中R3中有成键能力的碳原子可以任选被取代,每个烷基部分有1~3个取代基,或每个环有1~3个取代基,取代基可以独立地为卤素,羟基,氨基,-CN,(C1-C4)烷基,(C1-C4)烷氧基,(C1-C4)烷NH-,[(C1-C4)烷基]2-N-,(C6-C10)芳基,(C3-C8)环烷基,(C1-C10)杂芳基和以及(C1-C10)杂环基;其中(C3-C8)环烷基和(C1-C10)杂环基可以任选地被氧代;(C1-C10)杂芳基及(C1-C10)杂环基中每环上可成键环氮原子可被1~2个取代基任选取代,取代基可以是(C1-C4)烷基,(C1-C4)烷基-(C=O)-,(C6-C10)芳基,(C3-C8)环烷基,(C1-C10)杂芳基及(C1-C10)杂环基;
其中R3基团可任选地与R4基团成键形成3-8元环;其中两个R4形成-个3-8元环;
R4独立地为氢和(C1-4)烷基;
G为R5-或R6-(CHR13)p-;其中G为B上可成键环碳原子的取代基,成键位置不在B与Y相连的邻位;
p为1-6的整数;
其中R5为R7-,R11-O-,R7-(C1-C4)烷基-O-,R8-(C=O)-O-,H2N(C=O)-O-,R8NH(C=O)-O-,(R8)2N(C=O)-O-,R8-S-,R8-(S=O)-,R8-(SO2)-,H2N-(SO2)-,R8-NH-(SO2)-,(R8)2N-(SO2)-,甲羧基,R8-(C=O)-,HO-(C=O)-,R8-O-(C=O)-,H2N-(C=O)-,R8NH-(C=O)-,(R8)2N-(C=O)-,-NO2,NH2,R8-NH-,(R8)2N-,H(C=O)-(NR9)-,R8-(C=O)-(NR9)-,H2N-(C=O)-(NR9)-,R8NH-(C=O)-(NR9),(R8)2N-(C=O)-(NR9)-,R8O-(C=O)-(NR9)-,R8-(SO2)-NH-及R8-(SO2)-(NR9)-;
R6为全氟代(C1-C4)烷基,(C1-C4)烯基,(C1-C4)炔基,R7,OH,R8-O-,R8-(C1-C4)烷基-O-,全氟代(C1-C4)烷氧基,R8-(C=O)-O-,H2N(C=O)-O-,R8-NH(C=O)-O-,(R8)2N(C=O)-O-,R8-S-,R8-(S=O)-,R8-(SO2)-,H2N-(SO2)-,R8NH-(SO2)-,(R8)2N-(SO2)-,甲羧基,-CN,R8-(C=O)-,HO-(C=O)-,R8-O-(C=O)-,H2N-(C=O)-,R8NH-(C=O)-,(R8)2N-(C=O)-,-NO2,NH2,R8-NH-,(R8)2N-,H(C=O)-(NR9)-,R8-(C=O)-(NR9)-,H2N-(C=O)-(NR9)-,R8NH-(C=O)-(NR9)-,(R8)2N-(C=O)-(NR9)-,R8O-(C=O)-(NR9)-,R8-(SO2)-NH-及R8-(SO2)-(NR9)-;
R7为(C6-C10)芳基,(C3-C8)环烷基,(C1-C10)杂芳基,(C1-C10)杂环基;其中(C6-C10)芳香基,(C3-C8)环烷基,(C1-C10)杂芳基,(C1-C10)杂环基部分每环中环上可成键碳原子可以任选被1-3个取代基取代,取代基独立地为F,Cl,Br,CN,OH,(C1-C4)烷基,(C1-C4)全氟代烷基,(C1-C4)全氟代烷氧基,(C1-C4)烷氧基,氨基,(C1-C4)烷基-NH-,[(C1-C4)烷基]2-N-及(C3-C8)环烷氧基;其中(C3-C8)环烷基及(C1-C10)杂环基部分可以任选地被氧代;其中(C1-C10)杂芳基及(C1-C10)杂环基部分环上成键氮原子可以被任选取代,每环上可以有1-2取代基,取代基独立地为(C1-C4)烷基,(C1-C4)烷基-(C=O)-;
R8为(C1-C4)烷基,(C6-C10)芳香基,(C3-C8)环烷基,(CI-C10)杂芳基,(C1-C10)杂环基;其中每个R8上可成键碳原子可任选被取代,每个烷基部分或环上可以有1-3个取代基,取代基独立地为F,Cl,Br,CN,OH,(C1-C4)烷基,(C1-C4)全氟代烷基,(C1-C4)全氟代烷氧基,(C1-C4)烷氧基,(C3-C8)环烷氧基;其中(C3-C8)环烷基及(C1-C10)杂环基可被任选氧代;其中(C1-C10)杂芳基,(C1-C10)杂环基部分环上成键氮原子也可以任选取代,每环上可以有1-2取代基,取代基为(C1-C4)烷基,(C1-C4)烷基-(C=O)-;其中这里提及的2个R8可以任选地与其连接的杂原子形成一个3-8元环;
R9独立地为氢和(C1-C4)烷基;R8与R9可以任选地与其连接的杂原子一起形成一个3-8元环;
R10独立地为氢和(C1-C4)烷基;
R11是(C6-C10)芳基,(C1-C10)杂芳基及(C1-C10)杂环基;其中(C6-C10)芳基,(C1-C10)杂芳基及(C1-C10)杂环基部分上环上可成键碳原子可任选被取代,每环可以有1~3个取代基,取代基独立地为F,Cl,Br,CN,OH,(C1-C4)烷基,(C1-C4)全氟代烷基,(C1-C4)全氟代烷氧基,(C1-C4)烷氧基以及(C3-C8)环烷氧基;其中(C1-C10)杂环基也可以任选被氧代;(C1-C10)杂芳基及(C1-C10)杂环基部分环上成键氮原子可以被任选取代,每环上可以有1-2取代基,取代基独立地为(C1-C4)烷基,(C1-C4)烷基-(C=O)-;
R12独立地为氢及(C1-C4)烷基;
R13独立地为氢及(C1-C4)烷基;R13也可以任选地与R6形成4-10元环;
或者上述化合物药用的盐。
本发明也涉及到式1所示化合物的药用加酸盐(酸加成盐)。用来制备本发明上述碱性化合物药用加酸盐的酸,是那些形成非毒性的盐,即包括药用可以接受的阴离子,如盐酸盐,氢溴酸盐,氢碘酸盐,硝酸盐,硫酸盐,硫酸氢盐,磷酸盐,酸式磷酸盐,乙酸盐,乳酸盐,柠檬酸盐,酸柠檬酸盐,酒石酸盐,酒石酸氢盐,琥珀酸盐,马来酸盐,延胡索酸盐,葡萄糖酸盐,糖二酸盐,苯甲酸盐,甲基磺酸盐,乙基磺酸盐,苯磺酸盐,对甲苯磺酸盐和pamoate[即,1,1’-亚甲基-双-(2-羟基-3萘甲酸盐)]。
本发明也包括式1化合物的加碱盐(碱加成盐)。用来制备本质上是酸性、式I化合物的药用碱盐的化学碱是那些与化合物形成无毒性加碱盐的试剂。这些无毒性加碱盐包括,但不仅限于那些来自那些药用的阳离子,如碱金属阳离子(如,钾和钠离子),碱土金属阳离子(如,钙、镁离子),铵离子或水溶性氨加成盐,如N-甲基葡糖胺-(meglumine),以及低级烷醇铵盐和其他有机胺的药用加碱盐。
官能团Y中的″键″,指Ar1与Z直接通过碳碳键连接形成pendent芳香基环,如联苯
“烷基”,除另有说明外,包括饱和的单价烃的基团,有直链,支链或环部分或及其组合。烷基可以地被合适的取代基任选取代;
″烯基″,除另有说明外,指含有至少一个烯键的有直链,支链或环部分或及其组合的碳氢基团;
″炔基″,除另有说明外,指含有至少一个碳碳叁键的直链,支链或环部分或及其组合的碳氢基团;
″烷氧基″,包含O-烷基,其中的″烷基″与上面定义一致。
″卤素″,除另有说明外,包括氟,氯,溴或碘,优选氟或氯。
″(C=O)″这里指羰基。与氮原子一起形成的官能团为酰氨。与氧原子一起形成的官能团为羧酸衍生物。
″芳基″,,除另有说明外,指从芳香烃移去1个或多个氢原子后的有机基团,如苯基,萘基-2,3-二氢化茚基或四氢萘基;其可被1-3个合适的取代基任选取代,取代基如氟,氯,氰基(CN),硝基,三氟甲基,(C1-C6)烷氧基,(C6-C10)芳香基氧,(C3-C8)环烷基氧,三氟甲氧基,二氟甲氧基或(C1-C6)烷基。
″环烷基″,除另有说明外,包括一个或两个碳环(如,环丙基,环丁基,环戊基,环己基,环庚基,环辛基,环壬基,环戊烯基,环己烯基,二环[2.2.1]庚基,二环[3.2.1]辛基以及二环[5.2.O]壬基等);其任选包括1-2双键,被1-3合适的取代基任选取代,取代基包括氟,氯,三氟甲基,(C1-C4)烷氧基,(C6-C10)芳基氧,三氟甲氧基,二氟甲氧基或(C1-C4)烷基,更优选的为氟,氯,甲基,乙基及甲氧基。
″杂芳基″,除另有说明外,包括从芳香杂环化合物移去1个或多个氢的有机基团,如苯并咪唑基,苯并呋喃基,苯并呋咱基,2H-1-苯并吡喃基,苯并噻二嗪,苯并噻嗪基,苯并噻唑基,苯并硫代苯基(benzothiophenyl),苯并噁唑基,苯并二氢吡喃基,肉啉基,呋咱基,呋喃并吡啶基,呋喃基,咪唑基,吲唑基,二氢吲哚基,中氮茚基,吲哚基,3H-吲哚基,异吲哚基,异喹啉基,异噻唑基,异噁唑基,1,5-二氮杂萘基,噁二唑基,噁唑基,2,3-二氮杂萘基,蝶啶基,嘌啉基,吡嗪基,哒嗪基,吡啶基,嘧啶基,吡唑基,吡咯基,喹唑啉基,喹啉基,喹喔啉基,四唑基,噻唑基,噻二唑基,噻吩基,三嗪基,和三唑基,其中(C1-C10)杂芳基任一个环上可成键碳原子可地被1~2个取代基任选取代,合适的取代基如F,Cl,Br,CN,OH,(C1-C4)烷基,(C1-C4)全氟代烷基,(C1-C4)全氟代烷氧基,(C1-C4)烷氧基,和(C3-C8)环烷氧基。从上述所列化合物得到的前述官能团,可能是C-连接或N-连接。如,从吡咯得到的官能团可以为吡咯-1-基(N-连接)或吡咯-3-基(C-连接)。
″杂环基″,除另有说明外,包括非芳香杂环化合物移去1甚至更多个氢原子或得到的有机官能团,如3-氮杂二环[3.1.0]己基,3-氮杂二环[4.1.0]-庚基,氮杂环丁烷基,二氢呋喃基,二氢吡喃基,二氢噻吩基,二氧杂环己基,1,3-二氧杂环戊基,1,4-二噻嗪基,六氢azepinyl,六氢嘧啶,咪唑烷基,咪唑啉基,异噁唑烷基,吗啉基,噁唑烷基,哌嗪基,哌啶基,2H-吡喃基,4H-吡喃基,吡唑烷基,吡唑啉基,吡咯烷基,2-吡咯啉基,3-吡咯啉基,喹嗪基,四氢呋喃基,四氢吡喃基,1,2,3,6-四氢吡啶基,四氢噻吩基,四氢硫代吡喃基,硫代吗啉基,噻噁烷基(thioxanyl),和三噻烷基(trithianyl)。从上述所列的化合物衍生得到的前述官能团,可能为C-连接或N-连接。如,官能团从哌啶得到的官能团可以是哌啶-1-基(N-连接)或哌啶-4-基(C-连接)。从上述所列的化合物衍生得到的前述官能团,可能的时候能被合适取代基任选取代,如氧代,F,Cl,Br,CN,OH,(C1-C4)烷基,(C1-C4)全氟取代烷基,(C1-C4)全氟取代烷氧基,(C1-C4)烷氧基,和(C3-C8)环烷基氧。
″合适的取代基″意指化学或药学上可接受的官能团,即,引入取代基不会使本发明化合物的抑制活性丧失。专业人员很容易选择出这些合适的取代基。合适取代基的例子包括但不限于,卤素,全氟取代烷基,全氟取代烷氧基,烷基,羟基,桥氧基(oxo),巯基,烷硫基,烷氧基,芳香基或杂芳香基,芳香基氧或杂芳香基氧,芳代脂烷基或杂芳代脂烷基,芳代脂烷氧基或杂芳代脂烷氧基,羰基,氨基,烷基及二烷基氨基,甲氨酰基,烷基羰基,烷氧基羰基,烷基氨基羰基,二烷基氨基羰基,芳香基羰基,芳香氧基羰基,烷基磺酰基,芳香基磺酰基及类似基团。
″可成键″指可以用另一种高级官能团取代氢。
″连接位置不在B环与Y连接位置的α-位″指与Y相连的桥头碳原子邻位的取代。如果B是苯基,那么确定的基团不能在邻位取代(即相对于苯基与Y的连接而言)。
式I中的一些化合物包含手性中心,因此存在不同的对映异构体式。本发明涉及式I所示的所有光学异构体,对映异构体,非对映异构体,立体异构体及其混合物。本发明的化合物也有不同互变异构体。本发明涉及式1所有的互变异构体。本领域的普通技术人员能意识到嘧啶-2,4,6-三酮母核在溶液中以互变异构体的混合物形式存在。固态及液态下,各互变异构体的比例取决于分子上不同的取代基以及用来纯化化合物所用的特定结晶技术。
本发明包括式I所示的化合物,其中更优选X为>C=O,更优选其中Y为键,氧,S,-CH2-,>SO2,-OCH2或-CH2O-,更优选Y为氧,-OCH2-或-CH2O-,最优选Y为氧。
本发明优选化合物包括那些化合物,其中X为氧,-OCH2-,-CH2O-,更优选X为氧;更优选Y为键,氧,S,-CH2-,>SO2,-OCH2-或-CH2O-,更优选Y为氧,-OCH2-或-CH2O-,最优选Y为氧。
本发明也包括式I代表的那些化合物,X为S,>SO2,>S=O,-SCH2-,-CH2S-,-(O=S)CH2-,-CH2(S=O)-,-CH2SO2-或-SO2CH2-,更优选Y为键,氧,S,-CH2-,>SO2,-OCH2-或-CH2O-,更优选Y为氧,-OCH2-或-CH2O-,最优选Y为氧。
本发明也包括式I代表的下列化合物,其中X为>NR10,-CH2N(R10)-或-N(R10)CH2-,更优选Y为键,氧,S,-CH2-,>SO2,-OCH2-或-CH2O-,更优选Y为氧,-OCH2-或-CH2O-,最优选Y为氧。
本发明也包括式I代表的下列化合物,其中X为-N(R10)SO2-或-SO2N(R10)-,更优选其中Y为键,氧,S,-CH2-,>SO2,-OCH2-或-CH2O-,更优选其中Y为氧,-OCH2-,最优选Y为氧。
其他优选化合物包括A为任选取代的苯基的化合物。
本发明也包括下列化合物,其中A为(C1-C10)杂芳香基;优选吡啶基,呋喃基,吡咯基,噻吩基,异噻唑基,咪唑基,苯并咪唑基,四唑基,吡嗪基,嘧啶基,喹啉基,异喹啉基,苯并呋喃基,异苯并呋喃基,苯并噻吩基,吡唑基,吲哚基,异吲哚基,嘌啉基,咔唑基,异噁唑基,噻唑基,噁唑基,苯并噻唑基或苯并噁唑基,更优选吡啶基,哒嗪基,吡嗪基,嘧啶基,最优选1-3合适的取代基任选取代的吡啶基,取代基如氟,氯,三氟甲基,(C1-C6)烷氧基,(C6-C10)芳香基氧,三氟甲氧基,二氟甲氧基或(C1-C6)烷基。
其他优选化合物包括B为任选取代苯基的化合物。
本发明也包括式I的代表化合物,其中B为(C1-C10)杂芳香基(C1-C4)烷基或(C1-C10)杂芳基,优选(C1-C10)杂芳基;其中(C1-C10)杂芳香基被1或多个取代基任选取代,优选0,1或2个取代基,取代基独立地为F,Cl,Br,-CN,OH,(C1-C4)烷基,(C1-C4)全氟代烷基,(C1-C4)全氟取代烷氧基,(C1-C4)烷氧基和(C3-C8)环烷氧基。
本发明也包括式I的代表化合物,其中B为-个(C1-C10)杂环基,如四氢呋喃基,四氢吡喃基,N-甲基-3-氮杂环丁基,哌嗪基,哌啶基,1,3-噁唑烷-4-酮-5-基,1,3-噁唑烷-2,4-二酮-5-基,4,5二氢-1,2-噁唑烷-3-酮-4-基,1,3-噻唑烷-4-酮-5-基,1,3-噻唑烷-2,4-二酮-5-基,1,3-咪唑烷-4-酮-5-基,1,3-咪唑烷-2,4-二酮-5-基,1,2-吡唑烷-3-酮-4-基,四氢-1,3-噁嗪-4-酮-5-基,四氢-1,3-噁嗪-2,4-二酮-5-基,吗啉基,吗啉-3-酮-2-基,吗啉-3,5-二酮-2-基,2,3-二氢-1,4-噁嗪-3-酮-2-基,四氢-1,3-噻嗪-4-酮-5-基,四氢-1,3-噻嗪-2,4-二酮-5-基,硫代吗啉基,硫代吗啉-3-酮-2-基,硫代吗啉-3,5-二酮-2-基,2,3-二氢-1,4-噻嗪-3-酮-2-基,六氢-1,2-二嗪-3-酮-4-基,4,5-二氢-2H-哒嗪-3-酮-4-基,六氢-1,3-二嗪-2,4-二酮-5-基,哌嗪-2-酮-3-基,哌嗪-2,6-二酮-3-基,四氢-1,3,4-噻二嗪-5-酮-6-基,5,6-二氢-1,3,4-噻二嗪-5-酮-6-基,1,3,4-噁二嗪-5-酮-6-基,5,6-二氢-1,2,4-噁二嗪-5-酮-6-基,四氢-1,2,4-噁二嗪-5-酮-6-基,1,2,4-三嗪-5-酮-6-基,四氢-1,2,4-噁二嗪-5-酮-6-基,5,6-二氢-1-2,4-噁二嗪-5-酮-6-基,1,2,4-噁二嗪-3,5-二酮-6-基,和1,2,4-三嗪-6-酮-5-基;优选四氢呋喃基,四氢吡喃基,N-甲基-3-氮杂丁烷基,哌嗪基,哌啶基,N-甲基哌啶基和吗啉基;更优选四氢呋喃基和四氢吡喃基;最优选四氢呋喃-2-基和四氢吡喃-2-基。普通技术人员会认识到详述中的编号方法为与标准命名法中以最重原子为起点一致。
本发明也包括式I的下列化合物,其中B为(C3-C10)环烷基,如环丙基,环丁基,环戊基,环己基或环庚基;优选环己基或环庚基。
本发明也包括式I的下列化合物,其中G为R5-,其中R5为H2N-(C=O)-,R8NH-(C=O)-,(R8)2N-(C=O)-,NH2,R8-NH-,(R8)2N-,R8-(C=O)-(NR9)-,H2N-(C=O)-(NR9)-,R8NH-(C=O)-(NR9)-,(R8)2N-(C=O)-(NR9)-,R8O-(C=O)-(NR9)-,R8-(SO2)-NH-,R8-(SO2)-(NR9)-R8-(SO2)-,和H2N-(SO2)-;优选H2N-(C=O)-,R8NH-(C=O)-,(R8)2N-(C=O)-,NH2,R8-NH-,(R8)2N-,和R8-(C=O)-(NR9)-,更优选R8为(C1-C4)烷基(优选甲基)。
本发明的其他优选化合物,其中G为R5,其中R5包括R8官能团,其中R8为(C1-C4)烷基或被任选取代的(C3-C8)环烷基,每个环上可成键环碳原子任选被1~3个取代基取代,取代基独立地为F,Cl,Br,CN,OH,(C1-C4)烷基,(C1-C4)全氟取代烷基,(C1-C4)全氟取代烷氧基,(C1-C4)烷氧基,(C3-C8)环烷基氧;优选(C1-C4)烷基和(C1-C4)烷氧基。
本发明优选的化合物包括那些化合物,其中G为R5-,其中R5-为H2N-(C=O)-,R8NH-(C=O)-,(R8)2N-(C=O)-或R8-(C=O)-(NR9)-。本发明更优选的化合物包括那些化合物,其中G为R5-,其中R5-为R8NH-(C=O)-或(R8)2N-(C=O)-。其中G为R5-、R5包括R8的最优选化合物为那些R8为甲基的化合物。
本发明最优选的化合物包括式I的那些化合物,其中G为R5-,其中R5为R7-或R7-(C1-C4)烷基-O-;其中R7优选为(C6-C10)芳香基,(C3-C10)环烷基或(C1-C10)杂芳香基;每个环上的可成键环碳原子可被1~3个取代基任选取代,取代基独立地为F,Cl,Br,CN,OH,(C1-C4)烷基,(C1-C4)全氟代烷基,(C1-C4)全氟烷氧基,(C1-C4)烷氧基,氨基,(C1-C4)烷基-NH-,[(C1-C4)烷基]2-N-和(C3-C8)环烷氧基。本发明更优选的化合物包括式I的那些化合物,其中G为R5-,其中R5为R7-,其中R7为(C1-C10)杂芳香基。
发明者感兴趣的其他化合物为那些化合物,其中G为R5-,其中R5为R7-,其中R7为(C6-C10)芳香基,更优选苯基。
本发明化合物,其中G为R5-,其中R5为R7-或R7-(C1-C4)烷基-O-;包括那些化合物,其中R7为(C1-C10)杂芳基,其选自吡啶基,呋喃基,吡咯基,噻吩基,异噻唑基,咪唑基,苯并咪唑基,四唑基,吡嗪基,嘧啶基,喹啉基,异喹啉基,苯并呋喃基,异苯并呋喃基,苯并噻吩基,吡唑基,吲哚基,异吲哚基,嘌啉基,咔唑基,异噁唑基,噻唑基,噁唑基,苯并噻唑基或苯并噁唑基,更优选吡啶基,嘧啶基,三唑,二唑,噁唑,噁二唑,吡咯或噻唑;其中每个(C1-C10)杂芳香基被1~3合适的取代基任选取代,如氟,氯,三氟甲基,(C1-C6)烷氧基,(C6-C10)芳香基氧,三氟甲氧基,二氟甲氧基和(C1-C6)烷基。
优选的(C1-C10)杂芳香基包括五元环杂芳香基,如三唑类,二唑类,噁唑类,噁二唑类,吡咯类和噻唑类;优选1,2,4-三唑-1-基,1,2,4-三唑-3-基,1,3,4-三唑-1-基,1,3-二唑-1-基,1,2-二唑-3-基,1,2-二唑-1-基,1,2-二唑-4-基,1,3-噁唑-4-基,1,3-噁唑-5-基,1,2-噁唑-5-基,1,2,4-噁二唑-3-基,1,3,4-噁二唑-2-基,吡咯-1-基,1,3-噻唑-4-基和1,3-噻唑-2-基;其被下列取代基任选取代:(C1-C4)烷基,氨基,(C1-4)烷基-NH-,[(C1-C4)烷基]2-N-,卤素或羟基,优选(C1-C4)烷基,更优选甲基。最优选(C1-C10)杂芳香基包括被(C1-C4)烷基任选取代的1,3,4-噁二唑基。
本发明包括式I的那些化合物,其中G为-R5,其中R5为R11-O-或R8-(C=O)-O-。发明者有兴趣包括的化合物,R5包括R11,其中R11为(C6-C10)芳香基或(C1-C10)杂芳香基,环上可成键碳原子可任选被1~3个取代基取代,取代基独立地为F,Cl,Br,CN,OH,(C1-C4)烷基,(C1-C4)全氟代烷基,(C1-C4)全氟代烷氧基,(C1-C4)烷氧基和(C3-C8)环烷氧基;优选CN,(C1-C4)烷基,氨基,(C1-C4)烷基-NH-和[(C1-C4)烷基]2-N-。
本发明也包括式I所示的其他化合物,其中G为R5-,其中R5为R8-O-(C=O)-或R8-(C=O)-。
本发明也包括式I所示的其他化合物,其中G为R5-,其中R5为R8-S-,R8-(S=O)-,R8-(SO2)-,R8-NH-(SO2)-或(R8)2N-(SO2)-。
本发明其它优选方案为式I所示的化合物,其中G为R6-(CHR13)p-,优选p为1~6的整数;下列化合物,其中R6为(C1-C4)烯基,(C1-C4)炔基,-CN,-NO2,OH,NH2,全氟取代(C1-C4)烷氧基,H2N-(SO2)-,H2N-(C=O)-,R8-NH-(C=O)-,(R8)2-(C=O)-和NH2-(C=O)-(NR9)-;优选其中R6为-CN,OH,NH2,H2N-(C=O)-或NH2-(C=O)-(NR9)-;最优选其中R6为H2N-(C=O)-或-CN。
本发明其他优选化合物包括式I所示的那些化合物,其中G为R6-(CHR13)p-,优选其中p为1-6的整数;下列化合物,其中R6为(C6-C10)芳香基,(C3-C8)环烷基,(C1-C10)杂芳香基和(C1-C10)杂环基。本发明更优选化合物是那些R6为(C1-C10)杂芳香基,任选地被0-3个取代基取代,取代基独立地为卤素或(C1-C4)烷基的化合物。
本发明其他优选化合物包括式I的那些化合物,其中G为R6-(CHR13)p-,优选p为1-6的整数;下列化合物,其中R6包括R8官能团,如R8-O-,R8-(C1-C4)烷基-O-,R8-NH-,(R8)2N-R8-S-,R8-(S=O)-,R8(SO2)-,R8-(SO2)-NH-,R8-(SO2)-(NR9)-,R8-NH-(SO2)-,(R8)2N-(SO2)-,H2N-(C=O)-(NR9)-,R8NH-(C=O)-(NR9)-,(R8)2N-(C=O)-(NR9)-,R8O-(C=O)-(NR9)-,R8-(C=O)-(NR9)-,R8-(C=O)-O-,R8-O-(C=O)-和R8-(C=O)-。本发明更优选的是那些化合物,其中R8为-(C1-C4)烷基或(C3-C6)环烷基,其被1-3个取代基任选地取代,取代基为卤素或(C1-C4)烷氧基。
本发明范围的其他化合物包括G为R6-(CHR13)p-,和R6包括R8官能团,其中R8为(C1-C10)杂芳香基,(C6-C10)芳香基或(C1-C10)杂环基的化合物,任一个环上可成键碳原子任选地被1-3个取代基取代,取代基可以为F,Cl,Br,CN,OH,(C1-C4)烷基,(C1-C4)全氟取代烷基,(C1-C4)全氟取代烷氧基,(C1-C4)烷氧基,和(C3-C8)环烷基氧;优选(C1-C4)烷基和(C1-C4)烷氧基。
最优选包括R8的-R6取代基为R8NH-(C=O)-(NR9)-,(R8)2NH-(C=O)-(NR 9 )-,R8O-(C=O)-(NR9)-和R8-(C=O)-(NR9)-,更优选其中R8为(C1-C4)烷基,更优选甲基。
本发明的其他化合物包括那些化合物,其中A与B上可以成键碳原子独立地被1-3取代基任选取代,取代基可以是F,Cl,Br,-CN,OH,(C1-C4)烷基,(C1-C4)全氟取代烷基,(C1-C4)全氟取代烷氧基,(C1-C4)烷氧基及(C3-C8)环烷氧基。
本发明包括式I代表其他的化合物,其中R1为(C3-C8)环烷基,其中,(C3-C8)环烷基可被1~2个取代基任选取代,取代基独立地为卤素,(C1-C4)烷基,(C1-C4)烯基,(C1-C4)炔基,R3-,R3-O-,全氟取代(C1-C4)烷氧基,R3-(C1-C4)烷基-O-,R3-(C=O)-O-,-NO2,(R3)2N-,R3-(C=O)-(NR4)-,R3-S-,R3-(S=O)-,R3-(SO2)-,R3-(SO2)-(NR4)-,R3-NH-(SO2)-,(R3)2N-(SO2)-,-CN,R3-(C=O)-,R3-O-(C=O)-和(R3)2N-(C=O)-。
本发明包括式I代表其他的化合物,其中R1为(R2)2n+1(C)n-,n为1-10的整数;每个R2独立地为卤素,R3-,(C1-C4)烯基,(C1-C4)炔基,R3-O-,全氟取代(C1-C4)烷氧基,R3-(C=O)-O-,(R3)2N-(C=O)-O-,-NO2,(R3)2N-,R3-(SO2)-NR4)-,R3-(C=O)-(NR4)-,R3O-(C=O)(NR4)-,(R3)2-N-(C=O)-(NR4)-,R3-S-,R3-(S=O)-,R3-(SO2)-,(R3)2N-(SO2)-,-CN,R3-(C=O)-,R3-O(C=O)-及(R3)2N-(C=O)-;其中不多于3个R2的取代基不是氢,-(C)n-上的任一个碳原子可仅包括一个与杂原子形成的键;每个R3独立地为氢,(C1-C4)烷基,(C6-C10)芳香基,(C3-C8)环烷基,(C1-C10)杂芳香基及(C1-C10)杂环基;其中每个R3可以被1-3个取代基任选地取代,取代基独立地为卤素,羟基,氨基,-CN,(C1-C4)烷基,(C1-C4)烷氧基,(C1-C4)烷基-NH-,[(C1-C4)烷基]2-N-(C6-C10)芳香基,(C3-C8)环烷基,(C1-C10)杂芳香基和(C1-C10)杂环基;其中R3可以任选地与R4形成3-8元环。
本发明还包括式I代表其他的化合物,其中R1为(R2)2n+1-(C)n-,n为1~10的整数;至少一个R2可以独立地为R3-,R3-O-,R3-(C=O)-O-,R3-S-,R3-(S=O)-,R3-(SO2)-,(R3)2N-,R3-(SO2)-(NR4)-,R3-NH-(SO2)-,(R3)2N-(SO2)-,R3-(C=O)-(NR4)-,R3-O-(C=O)-和R3-(C=O)-;每个R3独立地为氢和(C1-C4)烷基;其中每个R3(C1-C4)烷基部分可以被1~3个取代基任选取代,取代基独立地为卤素,羟基,氨基,-CN,(C1-C4)烷基,(C1-C4)烷氧基,(C1-C4)烷基-NH-,[(C1-C4)烷基]2-N-(C6-C10)芳香基,(C3-C8)环烷基,(C1-C10)杂芳香基和(C1-C10)杂环基;其中R3可以任选地与R4形成3-8元环。
本发明包括式I代表的其他化合物,其中R1为(R2)2n+1-(C)n-,n为1~10的整数;每个R2独立地为氢,卤素,(C1-C4)烷基,R3-和R3-O-。
本发明包括式I代表其他的化合物,其中n为1-3;每个R3独立地为氢和(C1-C4)烷基;其中每个R3(C1-C4)烷基部分可以被1-3个取代基任选取代,取代基独立地为卤素,羟基,氨基,-CN,(C1-C4)烷基,(C1-C4)烷氧基,(C1-C4)烷基-NH-,[(C1-C4)烷基]2-N-(C6-C10)芳香基,(C3-C8)环烷基,(C1-C10)杂芳香基和(C1-C10)杂环基。
本发明包括式I代表其他的化合物,其中n为1-3;每个R3独立地为氢和(C1-C4)烷基;其中至少一个R3(C1-C4)烷基被下列取代基取代:卤素,羟基,氨基,-CN,(C1-C4)烷基,(C1-C4)烷氧基,(C1-C4)烷基-NH-,[(C1-C4)烷基]2-N-(C6-C10)芳香基,(C3-C8)环烷基,(C1-C10)杂芳香基和(C1-C10)杂环基。
本发明包括式I代表其他的化合物,其中n为1;每个R3独立地为氢和(C1-C4)烷基;其中至少一个R3(C1-C4)烷基被(C1-C4)烷氧基,(C1-C4)烷基-NH-,或[(C1-C4)烷基]2-N-取代。
本发明包括式I代表其他的化合物,其中至少一个R3为(C6-C10)芳香基,(C3-C8)环烷基,(C1-C10)杂芳香基或(C1-C10)杂环基;其中每个R3可以被1~3个取代基任选取代,取代基为卤素,羟基,氨基,-CN,(C1-C4)烷基,(C1-C4)烷氧基,(C1-C4)烷基-NH-,[(C1-C4)烷基]2-N-(C6-C10)芳香基,(C3-C8)环烷基,(C1-C10)杂芳香基和(C1-C10)杂环基。
更优选R1为(C1-C4)烷氧基(C1-C4)烷基,最优选乙氧基乙基。
本发明更优选包括式I的化合物,其中X为氧,Y为键,氧,硫,-CH2-,>SO2,-OCH2-或-CH2O-;R1为(R2)2n+1-(C)n-,n为1;每个R2独立地为氢,(C1-C4)烷基;其中至少1个R3(C1-C4)烷基官能团为(C1-C4)烷氧基,(C1-C4)烷基-NH-或[(C1-C4)烷基]2-N-取代。
本发明最优选包括I化合物,其中X为氧;Y为氧;A和B为独立的任选取代苯基;G为任选取代的苯基,R1为(R2)2n+1-(C)n-,n为1;每个R2独立地为氢,(C1-C4)烷基,R3-及R3-O-,每个R3独立地为氢,(C1-C4)烷基;其中1个R3(C1-4)烷基官能团被(C1-C4)烷氧基取代。
本发明其他最优选包括式I化合物,其中X为氧;Y为氧;A和B为任选取代的苯基;G为任选取代的(C1-C10)杂芳香基,R1为(R2)2n+1-(C)n-,n为1;每个R2为独立地为氢,(C1-C4)烷基,R3-及R3-O-,每个R3独立地为氢和(C1-C4)烷基;其中1个R3(C1-C4)烷基被(C1-C4)烷氧基取代。
本发明更优选包括式I化合物,其中X为氧;Y为氧;A和B为任选取代的苯基;G为任选取代的(C3-C8)环烷基,R1为(R2)2n+1-(C)n-,n为1;每个R2独立地为氢,(C1-C4)烷基,R3-和R3-O-,每个R3独立地为氢和(C1-C4)烷基;其中一个R3(C1-C4)烷基被(C1-C4)烷氧基取代。
本发明最优选化合物,其中X为氧;Y为氧;A及B为任选取代的苯基;G为R6-(CHR9)p-,R1为(R2)2n+1-(C)n-,n为1;每个R2独立地为氢,(C1-C4)烷基,R3-和R3-O-,每个R3为独立地为氢和(C1-C4)烷基;其中1个R3(C1-C4)烷基被(C1-C4)烷氧基取代。
式I特别优选的化合物包括:
5-(2-乙氧乙基)-5-[4-(4-噻唑-2-基-苯氧)-苯氧]-嘧啶-2,4,6-三酮;
5-(2-乙氧乙基)-5-{4-[4-(2-甲基-2H-吡唑-3-基)-苯氧]-苯氧}-嘧啶-2,4,6-三酮;
5-(2-乙氧乙基)-5-{4-[4-(1-甲基-1H-吡唑-3-基)-苯氧]-苯氧}-嘧啶-2,4,6-三酮;
5-(4-{4-[5-(2-乙氧乙基)-2,4,6-三氧-六氢-嘧啶-5-基氧]-苯氧}苯基)-戊腈;
5-(2-乙氧乙基)-5-{4-[4-(2-甲基-噻唑-4-基)-苯基]-苯氧}-嘧啶-2,4,6-三酮;
5-(2-乙氧乙基)-5-{4-[4-(1H-吡唑-3-基)-苯氧]-苯氧}-嘧啶-2,4,6-三酮;
5-(2-乙氧乙基)-5-[4-(4-噁唑-5-基-苯氧)-苯氧]-嘧啶-2,4,6-三酮;及,
5-(2-乙氧乙基)-5-[4-(4-嘧啶-4-基-苯氧)-苯氧]-嘧啶-2,4,6-三酮;或药用盐类。
本发明其他的化合物包括:
5-[4-(联苯基-4-基氧)-苯氧]-5-(2-乙氧乙基)-嘧啶-2,4,6-三酮;
5-[4-(联苯基-3-基氧)-苯氧]-5-(2-乙氧乙基)-嘧啶-2,4,6-三酮;
N-(3-{4-[5-(2-乙氧乙基)-2,4,6-三氧-六氢-嘧啶-5-基氧]-苯氧基}-苯基)-乙酰胺;
5-(2-乙氧乙基)-5-[4-(4-[1,3,4]噁二唑-2-基-苯氧基)-苯氧基]-嘧啶-2,4,6-三酮;
5-(2-乙氧乙基)-5-[4-(4-[1,2,4]三唑-1-基-苯氧基)-苯氧基]-嘧啶-2,4,6-三酮;
5-[4-(4-氨甲基-苯氧基)-苯氧基]-5-(2-乙氧乙基)-嘧啶-2,4,6-三酮;
5-(2-乙氧乙基)-5-[4-(4-咪唑-1-基-苯氧基)-苯氧基]-嘧啶-2,4,6-三酮;
N-(4-{4-[5-(2-乙氧乙基)-2,4,6-三氧-六氢-嘧啶-5-基氧]-苯氧基}苄基)-乙酰胺;
4-{4-[5-(2-乙氧乙基)-2,4,6-三氧-六氢-嘧啶-5-基氧]-苯氧基}苯甲酰胺;
4’-{4-[5-(2-乙氧乙基)-2,4,6-三氧-六氢-嘧啶-5-基氧]-苯氧基}-联苯基-4-腈;
5-(2-乙氧乙基)-5-[4-(4-甲磺酰基-苯氧基)-苯氧基]-嘧啶-2,4,6-三酮;
4-{4-[5-(2-乙氧乙基)-2,4,6-三氧-六氢-嘧啶-5-基氧]-苯氧基}-N-甲基苯甲酰胺;
4-{4-[5-(2-乙氧乙基)-2,4,6-三氧-六氢-嘧啶-5-基氧]-苯氧基}-N,N二甲基-苯甲酰胺;
5-(2-乙氧乙基)-5-[4-(4-噁唑-4-基-苯氧基)-苯氧基]嘧啶-2,4,6-三酮;
5-{4-[4-(5-二甲基氨基-[1,3,4]噁二唑-2-基)-苯氧基]-苯氧基}-5-(2-乙氧乙基)-嘧啶-2,4,6-三酮;
5-(2-乙氧乙基)-5-[4-(4-吡咯-1-基-苯氧基)-苯氧基]-嘧啶-2,4,6-三酮;
5-(2-乙氧乙基)-5-{4-[4-(5-甲基-[1,3,4]噁二唑-2-基)-苯氧基]-苯氧基}-嘧啶-2,4,6-三酮;
5-(2-乙氧乙基)-5-{4-[4-(5-甲基-异噁唑-3-基)-苯氧基]-苯氧基}-嘧啶-2,4,6-三酮;
5-(2-乙氧乙基)-5-[4-(6-氟-联苯基-3-基氧)-苯基]-嘧啶-2,4,6-三酮;
2-(4-{4-[5-(2-乙氧乙基)-2,4,6-三氧-六氢-嘧啶-5-基氧]-苯氧基}苯基)-乙酰胺;
5-(2-乙氧乙基)-5-[4-(4-[1,2,4]三唑-4-基-苯氧基)-苯氧基]嘧啶-2,4,6-三酮;
5-[4-(4-环戊基-苯氧基)-苯氧基]-5-(2-乙氧乙基)-嘧啶-2,4,6-三酮;
5-[4-(4-环己基-苯氧基)-苯氧基]-5-(2-乙氧乙基)-嘧啶-2,4,6-三酮;
N-[2-(4-{4-[5-(2-乙氧乙基)-2,4,6-三氧-六氢-嘧啶-5-基氧]-苯氧基}苯基)-乙基]-乙酰胺;
5-(2-乙氧乙基)-5-{4-[4-(4H-[1,2,4]三唑-3-基)-苯氧基]-苯氧基}-嘧啶-2,4,6-三酮;
5-(2-乙氧乙基)-5-[4-(4-羟基甲基-苯氧基)-苯氧基]-嘧啶-2,4,6-三酮;
5-(2-乙氧乙基)-5-{4-[4-(5-乙基-[1,3,4]噁二唑-2-基)-苯氧基]-苯氧基}嘧啶-2,4,6-三酮;
N-(4-{4-[5-(2-乙氧乙基)-2,4,6-三氧-六氢-嘧啶-5-基氧]-苯氧基}苄基)-3-甲基-丁酰胺;
戊酸4-{4-[5-(2-乙氧乙基)-2,4,6-三氧-六氢-嘧啶-5-基氧]苯氧基}-苄基酰胺;
5-(2-乙氧乙基)-5-[4-(4-噻唑-4-基-苯氧基)-苯氧基]-嘧啶-2,4,6-三酮;
N-(4-{4-[5-(2-乙氧乙基)-2,4,6-三氧-六氢-嘧啶-5-基氧-苯氧基}苄基)-异丁酰胺;
N-(4-{4-[5-(2-乙氧乙基)-2,4,6-三氧-六氢-嘧啶-5-基氧]-苯氧基}苄基)-2-甲氧基-乙酰胺;
环丁烷羧酸4-{4-[5-(2-乙氧乙基)-2,4,6-三氧-六氢-嘧啶-5-基氧]-苯氧基}-苄基酰胺;
N-(4-{4-[5-(2-乙氧乙基)-2,4,6-三氧-六氢-嘧啶-5-基氧]-苯氧基}苄基)-2-甲基-丁酰胺;
N-(4-{4-[5-(2-乙氧乙基)-2,4,6-三氧-六氢-嘧啶-5-基氧]-苯氧基}苄基)-丙酰胺;
5-(2-乙氧乙基)-5-[4-(3-甲基-4-[1,3,4]噁二唑-2-基-苯氧基)-苯氧基]嘧啶-2,4,6-三酮;
5-(2-乙氧乙基)-5-{4-[3-甲基-4-(5-甲基-[1,3,4]噁二唑-2-基)-苯氧基]苯氧基}-嘧啶-2,4,6-三酮;
5-(2-乙氧乙基)-5-[4-(4-吡唑-1-基-苯氧基)-苯氧基]-嘧啶-2,4,6-三酮;
5-(2-乙氧乙基)-5-{4-[3-甲基-4-(1H-吡唑-4-基)-苯氧基]-苯氧基}-嘧啶-2,4,6-三酮;
5-(2-乙氧乙基)-5-{4-[3-甲基-4-(1-甲基-1H-吡唑-4-基)-苯氧基]-苯氧基}-嘧啶-2,4,6-三酮;
5-(2-乙氧乙基)-5-{4-[4-(1H-吡唑-4-基)-苯氧基]-苯氧基}-嘧啶-2,4,6-三酮;
1-(4-{4-[5-(2-乙氧乙基)-2,4,6-三氧-六氢-嘧啶-5-基氧]-苯氧基}苄基)-3-甲基-脲;
5-(2-乙氧乙基)-5-[4-(3-氟-4-[1,3,4]噁二唑-2-基-苯氧基)-苯氧基]嘧啶-2,4,6-三酮;
5-(2-乙氧乙基)-5-{4-[3-氟-4-(5-甲基-[1,3,4]噁二唑-2-基)-苯氧基]苯氧基}-嘧啶-2,4,6-三酮;
5-{4-[3-氟-4-(5-甲基-[1,3,4]噁二唑-2-基)-苯氧基]-苯氧基}-5-(四氢呋喃-3-基)-嘧啶-2,4,6-三酮;
5-(4-[3-氟-4-(5-甲基-[1,3,4]噁二唑-2-基)-苯氧基]-苯氧基}-5-(四氢吡喃-3-基)-嘧啶-2,4,6-三酮;
5-{4-[4-(5-甲基-[1,3,4]噁二唑-2-基)-苯氧基]-苯氧基}-5-(四氢-呋喃-3-基)嘧啶-2,4,6-三酮;
5-{4-[4-(5-甲基-[1,3,4]噁二唑-2-基)-苯氧基]苯氧基}-5-(四氢-吡喃-3-基)嘧啶-2,4,6-三酮;
5-{4-[4-(5-甲基-[1,3,4]噁二唑-2-基)-苯氧基]-苯氧基}-5-(四氢-吡喃-2基甲基)-嘧啶-2,4,6-三酮;
5-{4-[4-(5-甲基-[1,3,4]噁二唑-2-基)-苯氧基]-苯氧基}-5-(四氢-呋喃-2-基甲基)-嘧啶-2,4,6-三酮;
5-{4-[3-氟-4-(5-甲基-[1,3,4]噁二唑-2-基)-苯氧基]-苯氧基}-5-(四氢呋喃-2-基甲基)-嘧啶-2,4,6-三酮;
5-{4-[3-甲基-4-(5-甲基-[1,3,4]噁二唑-2-基)-苯氧基]-苯氧基}-5-(四氢-呋喃-2-基甲基)-嘧啶-2,4,6-三酮;
5-(4-甲基-5-氧代-吗啉-2-基甲基)-5-[4-(4-[1,3,4]噁二唑-2-基-苯氧基)苯氧基]-嘧啶-2,4,6-三酮;
5-(4-甲基-3-氧代-吗啉-2-基甲基)-5-[4-(4-[1,3,4]噁二唑-2-基-苯氧基)苯氧基]-嘧啶-2,4,6-三酮;
N-异丙基-2-{5-[4-(4-[1,3,4]噁二唑-2-基-苯氧基)-苯氧基]-2,4,6-三氧六氢-嘧啶-5-基}-乙酰胺;
N-(2-{5-[4-(4-[1,3,4]噁二唑-2-基-苯氧基)-苯氧基]-2,4,6-三氧-六氢嘧啶-5-基}-乙基)-异丁酰胺;
5-{4-[4-(5-甲基-[1,3,4]噁二唑-2-基)-苯氧基]-苯氧基}-5-吡啶-2-基甲基嘧啶-2,4,6-三酮;
5-{4-[4-(5-甲基-[1,3,4]噁二唑-2-基)-苯氧基]-苯氧基}-5-吡啶-3-基甲基-嘧啶-2,4,6-三酮;
5-{4-[4-(5-甲基-[1,3,4)噁二唑-2-基)-苯氧基]-苯氧基}-5-吡啶-4-基甲基-嘧啶-2,4,6-三酮;
5-{4-[6-(5-甲基-[1,3,4]噁二唑-2-基)-吡啶-3-基氧]-苯氧基}-5-(四氢-呋喃-2-基甲基)-嘧啶-2,4,6-三酮;
5-[4-(4-噁唑-2-基-苯氧基)-苯氧基-5-(四氢-呋喃-2-基甲基)-嘧啶-2,4,6-三酮;
5-{4-[4-(2-氧代-吡咯烷-1-基甲基)-苯氧基-苯氧基}-5-(四氢-呋喃-2-基甲基)-嘧啶-2,4,6-三酮;
环丁羧酸4-{4-[2,4,6-三氧-5-(四氢-呋喃-2-基甲基)六氢-嘧啶-5-基氧]-苯氧基}-苄基酰胺;
5-4-(4-吡唑-1-基甲基-苯氧基)-苯氧基-5-(四氢-呋喃-2-基甲基)-嘧啶-2,4,6-三酮;
(5-{4-[4-(5-甲基-[1,3,4]噁二唑-2-基)-苯氧基]-苯氧基}-2,4,6-三氧-六氢嘧啶-5-基)-乙酸;
(5-{4-[3-甲基-4-(5-甲基-[1,3,4]噁二唑-2-基)-苯氧基]-苯氧基}-2,4,6-三氧六氢-嘧啶-5-基)-乙酸;
(5-{4-[3-氟-4-(5-甲基-[1,3,4]噁二唑-2-基)-苯氧基]-苯氧基}-2,4,6-三氧六氢-嘧啶-5-基)-乙酸;
3-{5-[4-(5-([1,3,4]-噁二唑-2-基)-苯氧基)-苯氧基]-2,4,6-三氧-六氢嘧啶-5-基}-N,N-二甲基-丙酰胺;
5-[4-(联苯基-4-基氧)-苯氧基]-5-(环己基)-嘧啶-2,4,6-三酮;
5-[4-(联苯基-3-基氧)-苯氧基]-5-(环己基)-嘧啶-2,4,6-三酮;
N-(3-{4-[5-(环己基)-2,4,6-三氧-六氢-嘧啶-5-基氧]-苯氧基}-苯基)乙酰胺;
5-(环己基)-5-[4-(4-[1,3,4]噁二唑-2-基-苯氧基)-苯氧基]-嘧啶-2,4,6三酮;
5-(环己基)-5-[4-(4-[1,2,4]三唑-1-基-苯氧基)-苯氧基]-嘧啶-2,4,6-三酮;
5-[4-(4-氨基甲基-苯氧基)-苯氧基]-5-(环己基)-嘧啶-2,4,6-三酮;
5-(环己基)-5-[4-(4-咪唑-1-基-苯氧基)-苯氧基]-嘧啶-2,4,6-三酮;
N-(4-{4-[5-(环己基)-2,4,6-三氧-六氢-嘧啶-5-基氧]-苯氧基}-苄基)乙酰胺;
4-{4-[5-(环己基)-2,4,6-三氧-六氢-嘧啶-5-基氧]-苯氧基}-苯甲酰胺;
4’-14-[5-(环己基)-2,4,6-三氧-六氢-嘧啶-5-基氧]-苯氧基}-联苯基-4腈;
5-(环己基)-5-[4-(4-甲磺酰基-苯氧基)-苯氧基]-嘧啶-2,4,6-三酮;
4-{4-[5-(环己基)-2,4,6-三氧-六氢-嘧啶-5-基氧]-苯氧基}-N-甲基苯甲酰胺;
4-{4-[5-(环己基)-2,4,6-三氧-六氢-嘧啶-5-基氧]-苯氧基}-N,N-二甲基苯甲酰胺;
5-(环己基)-5-[4-(4-噁唑-5-基-苯氧基)-苯氧基]-嘧啶-2,4,6-三酮;
5-(环己基)-5-[4-(4-噁唑-4-基-苯氧基)-苯氧基]-嘧啶-2,4,6-三酮;
5-{4-[4-(5-二甲基氨基-[1,3,4]噁二唑-2-基)-苯氧基]-苯氧基}-5-(环己基)-嘧啶-2,4,6-三酮;
5-(环己基)-5-[4-(4-吡咯-1-基-苯氧基)-苯氧基]-嘧啶-2,4,6-三酮;
5-(环己基)-5-{4-[4-(5-甲基-[1,3,4]噁二唑-2-基)-苯氧基]-苯氧基}-嘧啶-2,4,6-三酮;
5-(环己基)-5-{4-[4-(5-甲基-异噁唑-3-基)-苯氧基]-苯氧基}-嘧啶-2,4,6三酮;
5-(环己基)-5-[4-(6-氟-联苯基-3-基氧)-苯氧基]-嘧啶-2,4,6-三酮;
2-(4-{4-[5-(环己基)-2,4,6-三氧-六氢-嘧啶-5-基氧]-苯氧基}-苯基)乙酰胺;
5-(环己基)-5-[4-(4-[1,2,4]三唑-4-基-苯氧基)-苯氧基]-嘧啶-2,4,6-三酮;
5-(环己基)-5-{4-[4-(1H-吡唑-3-基)-苯氧基]-苯氧基}-嘧啶-2,4,6-三酮;
5-(环己基)-5-{4-[4-(2-甲基-噻唑-4-基)-苯氧基]-苯氧基}-嘧啶-2,4,6三酮;
5-(4-{4-[5-(环己基)-2,4,6-三氧-六氢-嘧啶-5-基氧]-苯氧基}-苯基)-戊氰;
5-[4-(4-环戊基-苯氧基)-苯氧基]-5-(环己基)-嘧啶-2,4,6-三酮;
5-[4-(4-环己基-苯氧基)-苯氧基]-5-(环己基)-嘧啶-2,4,6-三酮;
N-[2-(4-{4-[5-(环己基)-2,4,6-三氧-六氢-嘧啶-5-基氧]-苯氧基}苯基)-乙基-乙酰胺;
5-(环己基)-5-{4-[4-(4H-[1,2,4]三唑-3-基)-苯氧基]-苯氧基}-嘧啶-2,4,6三酮;
5-(环己基)-5-{4-[4-(1-甲基-1H-吡唑-3-基)-苯氧基]-苯氧基}-嘧啶2,4,6-三酮;
5-(环己基)-5-{4-[4-(2-甲基-2H-吡唑-3-基)-苯氧基]-苯氧基}-嘧啶2,4,6-三酮;
5-(环己基)-5-[4-(4-羟基甲基-苯氧基)-苯氧基]-嘧啶-2,4,6-三酮;
5-(环己基)-5-{4-[4-(5-乙基-{1,3,4]噁二唑-2-基)-苯氧基]-苯氧基}-嘧啶-2,4,6-三酮;
N-(4-{4-[5-(环己基)-2,4,6-三氧-六氢-嘧啶-5-基氧]-苯氧基}-苄基)-3-甲基-丁酰胺;
戊酸4-{4-[5-(环己基)-2,4,6-三氧-六氢-嘧啶-5-基氧]苯氧基}-苄基酰胺;
5-(环己基)-5-{4-[4-(4-噻唑-4-基-苯氧基)-苯氧基]-嘧啶-2,4,6-三酮;
N-(4-{4-[5-(环己基)-2,4,6-三氧-六氢-嘧啶-5-基氧]-苯氧基}-苄基)-异丁酰胺;
N-(4-{4-[5-(环己基)-2,4,6-三氧-六氢-嘧啶-5-基氧]-苯氧基}-苄基)-2甲氧基-乙酰胺;
环丁烷羧酸4-{4-[5-(环己基)-2,4,6-三氧-六氢-嘧啶-5基氧]-苯氧基}-苄基酰胺;
N-(4-4-[5-(环己基)-2,4,6-三氧-六氢-嘧啶-5-基氧-苯氧基}-苄基)-2-甲基-丁酰胺;
N-(4-{4-[5-(环己基)-2,4,6-三氧-六氢-嘧啶-5-基氧]-苯氧}-苄基)丙酰胺;
5-(环己基)-5-[4-(4-噻唑-2-基-苯氧)-苯氧]-嘧啶-2,4,6-三酮;
5-(环己基1)-5-[4-(4-嘧啶-4-基-苯氧)-苯氧]-嘧啶-2,4,6-三酮;
5-(环己基)-5-[4-(3-甲基-4-[1,3,4]噁二唑-2-基-苯氧)-苯氧]-嘧啶-2,4,6-三酮;
5-(环己基)-5-{4-[3-甲基-4-(5-甲基-[1,3,4]噁二唑-2-基)-苯氧]-苯氧}-嘧啶-2,4,6-三酮;
5-(环己基)-5-[4-(4-吡唑-1-基-苯氧)-苯氧]-嘧啶-2,4,6-三酮;
5-(环己基)-5-{4-[3-甲基-4-(1H-吡唑-4-基)-苯氧]-苯氧}-嘧啶-2,4,6-三酮;
5-(环己基)-5-{4-[3-甲基-4-(1-甲基-1H-吡唑-4-基)-苯氧]-苯氧}嘧啶-2,4,6-三酮;
5-(环己基)-5-{4-[4-(1H-吡唑-4-基)-苯氧]-苯氧}-嘧啶-2,4,6-三酮;
1-(4-{4-[5-(环己基)-2,4,6-三氧-六氢-嘧啶-5-基氧]-苯氧}-苄基)-3-甲基-脲;
1-(4-{4-[5-(环己基)-2,4,6-三氧-六氢-嘧啶-5-基氧]-苯氧}-苄基)-3-丙基-脲;
氮杂环丁烷-1-羧酸4-{4-[5-(环己基)-2,4,6-三氧-六氢-嘧啶-5-基氧]-苯氧}-苄基酰胺;
5-(环己基)-5-{4-(3-氟-4-[1,3,4]噁二唑-2-基-苯氧)-苯氧}-嘧啶-2,4,6-三酮;
5-(环己基)-5-{4-[3-氟-4-(5-甲基-[1,3,4]噁二唑-2-基)-苯氧]-苯氧}-嘧啶-2,4,6-三酮;
1-(4-{4-[5-(2-乙氧乙基)-2,4,6-三氧-六氢-嘧啶-5-基氧]-苯氧}苄基)-3-丙基-脲;和
氮杂环丁烷-1-羧酸4-{4-[5-(2-乙氧乙基)-2,4,6-三氧-六氢-嘧啶5-基氧]-苯氧}-苄基酰胺;
以及药理可以接受的盐类。
本发明也涉及一种药用组合物,包括一定有效剂量的式I化合物或药用盐和药用载体,用于治疗包括人在内的哺乳动物的结缔组织疾病,炎性疾病,免疫/过敏性疾病,传染性疾病,呼吸系统疾病,心血管疾病,眼类疾病,代谢疾病,中枢神经系统(CNS)疾病,肝/肾疾病,生殖健康疾病,胃病,皮肤疾病和肿瘤和其他以金属蛋白酶活性为特征的疾病。
本发明也涉及一种药用组合物,包括有效剂量的式I的化合物或药用盐,用来抑制包括人在内哺乳动物中,参与基质降解的,基质金属蛋白酶或其他的金属蛋白酶。
本发明也涉及一种治疗包括人在内的哺乳动物中以下疾病方法:结缔组织疾病,炎性疾病,免疫/过敏性疾病,传染性疾病,呼吸系统疾病,心血管疾病,眼类疾病,代谢疾病,中枢神经系统(CNS)疾病,肝/肾疾病,生殖健康疾病,胃疾病,皮肤疾病和肿瘤和其他以基质金属蛋白酶活性为特征的疾病,该方法包括给予哺乳动物剂一定量对上述疾病有效治疗的化合物式I或药用盐。
本发明也涉及一种用来抑制包括人在内的哺乳动物中参与基质降解的基质金属蛋白酶或其他金属蛋白酶的方法,包括给予哺乳动物有效剂量的式I化合物或其药用盐。
本发明者也发现可以由差异金属蛋白酶活性(优选MMP-13活性抑制)来确定式I抑制剂。发明者发现的优选式I抑制剂中的一组包括那些对MMP-13选择性抑制优于MMP-1的化合物。本发明的化合物也对一组相关的reprolysins酶具有选择性,如TACE和aggrecanase。发明者发现的优选式I抑制剂中的另一组,包括那些对MMP-13选择性抑制优于MMP-1和MMP-14的化合物。发明者已能确定的另一组优选的式I抑制剂包括那些选择性抑制MMP-13优于MMP-1和12的化合物。发明者已能确定的另一组优选的式I抑制剂包括那些选择性抑制MMP-13优于MMP-1,12和14的化合物。发明者已能确定的另一组优选的式I抑制剂包括那些选择性抑制MMP-13优于对MMP-1,2,3,7,9和14的抑制的化合物。本发明最优选的化合物选择性抑制MMP-13,优于对MMP-1,2,3,7,9,12和14以及哺乳动物reprolysins的抑制。
本发明也涉及一种治疗方法,针对的医疗状况以哺乳动物的关节软骨破坏为特征,方法包括给有提及状况的主体以治疗有效剂量的合适取代的嘧啶-2,4,6-三酮,其中提及的合适取代的嘧啶-2,4,6-三酮显示:i)MMP-13的IC50小于约100nM(更优选50nM,最优选小于20nM),MMP-13的IC50用重组MMP-13分析方法测量,ii)MMP-1的IC50大于约200nM(更优选大于500nM,最优选大于1μM),MMP-1的IC50用重组MMP-1分析方法测量;iii)MMP-14的IC50大于约200nM(更优选大于500nM,最优选大于1μM),MMP-14的IC50用重组MMP-14分析方法测量。
本发明也涉及一种治疗关节软骨破坏的方法,其中提及的嘧啶-2,4,6-三酮同时显示MMP-12的IC50大于约100nM(更优选大于200nM,最优选大于500nM),MMP-12的IC50用重组MMP-12分析方法测量。
本发明也涉及一种关节软骨破坏的治疗方法,其中提及的嘧啶-2,4,6-三酮同时显示i)MMP-2的IC50大于约200nM(更优选大于500nM,最优选大于1μM),MMP-2的IC50用重组MMP-12分析方法测量,ii).MMP-3的IC50大于约200nM(更优选大于500nM,最优选大于1μM),MMP-3的IC50用重组MMP-3分析方法测量,iii)MMP-7的IC50大于约200nM(更优选大于500nM,最优选大于1μM),MMP-7的IC50用重组MMP-7分析方法测量,以及iv)MMP-9的IC50大于约200nM(更优选大于500nM,最优选大于1μM),MMP-9的IC50用重组MMP-9分析方法测量。
″治疗″,这里指逆转,减轻,抑制发展,或预防疾病或状况,或一种或多种症状这些紊乱或状况。在这些情况下,使用这一术语。术语“进行治疗”包括如上定义的“治疗”这种行为。
″结缔组织疾病″这里指疾病如外伤引起的关节损伤后的退行性软骨丢失,骨关节炎,骨质疏松,Paget氏疾病,人造关节植入导致的松开,牙齿周围疾病和齿龈炎。
″关节软骨破坏″这里指结缔组织疾病导致关节软骨破坏,尤其是关节损伤,反应性关节炎,急性焦磷酸关节炎(假性痛风),牛皮癣患者关节炎,或青少年风湿性关节炎,更优选骨关节炎。
″炎性疾病″这里指风湿性关节炎,强直性脊椎炎,牛皮癣患者关节炎,牛皮癣,软骨钙质沉着,痛风,炎性肠病,溃疡性大肠炎,Crohn氏病及恶病体质。
″免疫/过敏疾病″这里指疾病如器官移植毒性,过敏反应,过敏接触超敏性,自身免疫疾病如肉芽肿炎症/组织再造(如哮喘),免疫抑制和芽肿性病变相关的疾病。
″传染性疾病″包括那些由病毒,细菌,真菌或分支杆菌感染,这里指如败血性关节炎,AIDS,发热;Prion疾病,重症肌无力,疟疾,败血症,血液动力学性休克,败血性休克类的疾病。
″呼吸系统疾病″这里指如慢性梗阻肺部疾病(包括肺气肿),急性呼吸窘迫综合症,哮喘,过氧小泡损伤和自发性肺部纤维化和其他的纤维性肺部疾病类的疾病。
″心血管疾病″这里指如动脉硬化症,包括动脉硬化斑破裂;大动脉动脉瘤,包括腹部大动脉动脉瘤和脑部大动脉动脉瘤;充血性心衰;心肌和脑梗塞;中风;脑贫血;凝结物及急性时期反应;左心室扩张;贫血性再灌流后损伤;血管纤维瘤;血管瘤以及再狭窄类的疾病。
″眼病″这里指如异常血管生成,眼睛血管生成,眼睛发炎,圆锥性角膜,Sjogren氏综合症,近视,眼睛肿瘤,角膜移植排斥,角膜损伤,新血管性青光眼,角膜溃疡,角膜瘢痕,视斑退化(包括年龄相关视斑退化(ARMD),包括湿形和千形),扩散性玻璃体视网膜病和早熟性视网膜病类的疾病。
″代谢病″指如糖尿病(包括非胰岛素依赖性糖尿病,糖尿病性视网膜病,胰岛素抗性,糖尿病性溃疡)类的疾病。
″中枢神经系统″(CNS)疾病这里指如头部外伤,脊髓损伤,中枢神经系统的炎性疾病,神经退行性疾病(急性和慢性),Alzheimer氏疾病,神经系统的脱髓鞘疾病,Huntington氏疾病,Parkinson氏疾病,外周神经病,疼痛,脑淀粉样血管病,情感或认知增加,肌萎缩性脊髓侧索硬化,多发性硬化,偏头疼,消沉,厌食类的疾病。
″肝/肾疾病″这里指如肾病综合症,如肾小球性肾炎和肾小球疾病,蛋白尿,肝硬变以及间质性肾炎类的疾病。
″生殖健康疾病″这里指如子宫内膜异位,避孕(男性/女性),月经困难,功能不全性子宫失血,胎膜早熟性脱落和堕胎类的疾病。
″胃疾病″这里指如结肠吻合术和胃溃疡类的疾病。
″皮肤疾病″这里指如皮肤老化,压疼,牛皮藓,湿疹,皮炎,辐射损害,组织溃疡,褥疮溃疡,大疱性表皮松懈,异常创伤康复(局部给药和口服剂型),烧伤和巩膜炎类的疾病。
″肿瘤″这里指如实体瘤,包括结肠瘤,乳腺瘤,肺癌以及prostrate肿瘤;肿瘤侵入,肿瘤生长,肿瘤转移,以及包括口腔和咽(嘴唇,舌,口,咽),食道,胃,小肠,大肠,直肠,肝和胆汁通道,胰腺,喉,肺,骨骼,结缔组织,皮肤,子宫颈,子宫体,卵巢,睾丸,膀胱,肾,和其他泌尿组织,眼脑和中枢神经系统,甲状腺和其他内分泌腺体肿瘤在内的肿瘤以及Hodgkin氏疾病,非Hodgkin氏淋巴瘤,多重骨髓瘤,和造血恶性瘤包括白血病和淋巴瘤,包括淋巴细胞淋巴瘤,粒性白细胞淋巴瘤和单核细胞淋巴瘤类的疾病。
本发明主题也包括同位素标记发化合物,结构上与式I相同,区别就在于一个或更多原子被与天然通常存在原子量或质量数不同的原子代替。可以用来标记本发明化合物的同位素包括氢,碳,氮,氧,磷,氟及氯,分别为2H,3H,13C,14C,15N,18O,17O,31P,32P,35S,18F和36CI。本发明化合物,对应的前药以及化合物及前药的药用盐的同位素及其他原子的同位素标记化合物都在本发明的范围之内。本发明的几种同位素标记的化合物,如用放射性同位素如3H及14C标记,在药物及/或底物的组织分布分析中有用。3H及14C这类同位素特别易于制备及检测。并且用原子量较大的同位素,如氘2H取代由于代谢稳定性增加会获得一些治疗优势,如增加体内的半衰期或减少需要的剂量,因此,在有些情况下会非常有利。本发明式I所示的同位素标记化合物及其前药,用易得的同位素标记试剂代替无同位素标记试剂,依照方案中的过程和/或后述的实施例及制备方法通常可以制备得到。
本为发明也包括式I化合物前药的药用组合物。本发明也包括利用式I化合物的前药通过抑制基质金属蛋白酶或抑制哺乳动物reprolysin来治疗或预防疾病的方法。式I化合物有游离氨基,酰氨基,羟基,磺酰氨或羧基可以衍生成前药。前药包括,利用氨基酸残基或2或多个(如,2,3或4个)或更多氨基酸残基的多肽链与式I化合物中的游离酰氨基,氨基,羟基或羧酸官能团形成共价的肽键得到的化合物。氨基酸包括通常用三字母表示的,天然存在的20种氨基酸,也包括4-羟基脯氨酸,羟基赖氨酸,demosine,异demosine,3-甲基组氨酸,正缬氨酸,beta-丙氨酸,gamma-氨基丁酸,瓜氨酸,高半光氨酸,高丝氨酸,鸟氨酸和蛋氨酸砜。前药也包括,碳酸酯,氨基甲酸酯,酰氨和烷基酯,通过碳基碳前药侧链与式I化合物中上述取代基共价结合形成的化合物,碳酸酯、氨基甲酸酯、酰胺和烷基酯。前药也包括式I化合物的二聚体。
本领域的普通技术人员将会认识到本发明的化合物对许多疾病的治疗有用。普通技术人员也会认识到用本发明化合物治疗特定的疾病时,本发明的化合物也可以与多种现用治疗该病的药物联合使用。
治疗风湿性关节炎时,本发明的化合物可以与其他药物一起使用。如,TNF-a抑制剂,如抗TNF单克隆抗体(如英夫单抗(infliximab),D2E7和CDP-870);TNF受体免疫球蛋白分子(如etanercept),ICE抑制剂,MEKKl抑制剂,COX-2抑制剂,如塞来昔布(celecoxib),洛芬昔布,valdecoxib和etoricoxib;低剂量甲氨蝶呤,来氟米特,甾体类,氨基葡糖类,chondrosamines/硫酸酯,gabapentin,A-激动剂,IL-1产生和释放抑制剂,IL-l受体拮抗剂,如Kineret,CCR-1拮抗剂,羟氯喹,d-青霉胺,醋硫葡金或羟嗪(parenteral)或口服金(oral gold)。
本发明化合物可以与现有的治疗骨关节炎药物一起使用。合适的现有联合使用治疗药物包括标准的非甾体抗炎药(以后用NSAID表示),如吡罗昔康,双氯酚酸钠;丙酸类,如萘普生,氟苯布洛芬,苯氧布洛芬钙,酮基布洛芬和异丁洛芬;安芬钠类如甲芬那酸,吲哚美辛,舒林酸,阿扎丙宗;吡唑酮类,如苯基保泰松;水杨酸盐类,如阿斯匹林;COX-2抑制剂,如塞来昔布,valdeoxib,paracoxib,etoricoxib和洛芬昔布;镇疼药类;甾体类;氨基葡糖类,半乳糖胺/硫酸酯,加巴喷丁;A-激动剂;IL-1产生和释放抑制剂;CCR-1拮抗剂,LTD-4,LTB-4和5-LO抑制剂;p38激酶抑制剂和关节内治疗药如皮质甾类和透明质酸类如透明质酸钠(hyalgan)和synvisc。
本发明的化合物也可以与抗肿瘤药联合使用,如endostatin和angiostatin或细胞毒性药如阿霉素,柔红霉素,顺铂,依托泊苷,紫杉醇,多西紫衫;生物碱类,如长春新碱;抗代谢药,如甲氨蝶呤。
本发明的化合物也可以与心血管类治疗药物联合使用,包括钙通道拮抗剂(如阿洛地平和尼非地平);降脂药如斯特汀类(如洛伐他汀,托伐他汀,洛普伐他汀和辛伐他汀),;肾上腺素类如多沙唑嗪和特拉唑嗪;fibrates,beta-阻滞剂,Ace抑制剂(如卡托普利,赖诺普利,福辛普利,依那普利和喹那普利);血管紧张素-2受体拮抗剂,如氯沙坦和依贝沙坦;硝酸酯类;CCB类;利尿剂如洋地黄,血小板凝聚抑制剂。本发明化合物血小板破裂预防药联合使用,如斯特汀,阿齐红霉素;NSAID类,包括阿司匹林,肝素,urarfarin,阿昔单抗,TPA和血小板抑制剂。本发明的化合物也可以与中风治疗药联合使用,如NIF,NHEI类和CCRIR拮抗剂。
本发明的化合物也可以与CNS药物联合使用,如抗抑郁药,(如珊特拉林);抗帕金森病药(如盐酸司来吉兰,卡巴多巴,L-多巴,多巴胺受体激动剂,如累匹利洛,硫丙麦角林和派拉米苏;MAOB抑制剂,如司来吉兰和rasagiline;儿茶酚-O-甲基转移酶抑制剂,如托卡朋,A-2抑制剂,多巴胺再摄取(reuptake)抑制剂,NMDA拮抗剂,尼古丁(Nicotine)激动剂,NK-1抑制剂,多巴胺激动剂和神经元氧化氮合成酶抑制剂)以及抗Alzheimer氏药,如杜尼匹次,他克林;COX-2抑制剂,丙戊茶碱或metryfonate。
本发明的化合物也可以与骨质疏松治疗药,如roloxifene,droloxifene,lasoxifene或fosomax,以及免疫抑制剂剂,如FK-506和瑞帕霉素联合使用。
本发明的化合物也可以与呼吸系统疾病治疗药联合使用,如PDE-IV抑制剂,甾族类如氟地松,去炎松,布地缩松,布地缩松和丙酸倍氯米松;抗胆碱药如异丙托品;拟交感神经药如沙美特罗,沙丁胺醇和左沙丁胺醇;抗过敏药如甲关芳铵,氯雷他定,和西替利嗪;白三烯拮抗药如扎鲁司特和motelukast;柱细胞稳定剂如弃白通。
本发明的化合物也可以与皮肤病治疗药联合使用,如维甲酸,异维甲酸,甾体类药物,如可的松和莫美达松;抗生素,如四环素;抗真菌药,如克霉唑,咪康唑和氟康唑以及PDE-IV抑制剂。
本发明的化合物也可以与糖尿病治疗药物联合用药,如胰岛素,包括人或人源化的胰岛素和胰岛素吸入剂,醛糖还原酶抑制剂;山梨醇脱氢酶抑制剂;抗糖尿病药,如双胍类二甲双胍;glitazones;糖苷酶抑制剂,如阿卡波糖,磺酰基脲如格列没脲和格列吡嗪;噻唑烷二酮类,如吡格列酮,罗格列酮和曲格列酮。优选联合给药有利于治疗糖尿病的副作用,如视网膜病,肾病和神经病,尤其是视网膜病。
发明详述
下列方案举例说明了制备本发明的化合物的方法。除另有说明外,下述方案及讨论中的X,Y,Ar1,Z,R1,R2及R3与上述定义相同。
方案1
方案2
方案3
方案4
方案5
方案6
方案1表示从式V所示化合物通过两个步骤制备式I化合物。参照方案1,式I化合物从化合物IV制备得到,其中L1及L2为离去基团,如甲氧基,乙氧基,苄氧基或氯,优选乙氧基,与化合物III(H2NCONH2)的脲在强碱性条件下极性溶剂中反应得到,适合的碱包括甲醇钠,乙醇钠及甲醇镁,优选乙醇钠。适合的溶剂包括醇类(如乙醇)或四氢呋喃,优选无水乙醇。反应在20℃-90℃进行,优选50℃-65℃,反应时间约为15分钟-16小时。
化合物IV由化合物V制备得到,其中L3是离去基团,如卤素,对甲苯基磺酰基氧(OTs)或甲基磺酰基氧(OMs),优选卤素,最优选氯或溴,在碱性条件下极性溶剂中与化合物II HX-A-Y-B-G反应。合适的溶剂包括二甲基甲酰胺(DMF),醇类(如乙醇)或四氢呋喃,优选乙醇。反应在20℃-90℃进行,优选50℃-65℃,反应时间约为15分钟-16小时。
化合物V由现有技术中己知的方法制备,可以参照WO98/58925中描述的方法,或The Organic Chemistry of Drug Synthesis,Lednicer D和Mitscher LA,1,167-277的综述及其引用文件。上述每个参考文献及应用这里都全面引用。
化合物III有商品供应,也可以参照专业人员已知方法的制备得到。
化合物II,HX-A-Y-B-G,有商品供应,也可以参照本领域普通技术人员已知方法制备得到,或参照方案5的方法制备得到。
方案2为另一种制备化合物I的方法,由化合物VI或VII经3步反应得到。参照方案2,化合物I由化合物IX与合适的碱和合适的烷基化试剂R1L4在溶剂中反应得到。合适的碱包括氢化钠,碳酸钾,碳酸钠,三乙胺,吡啶或三乙醇胺;最优选氢化钠。合适的烷基化试剂包括那些其中L4为卤素,对甲苯基磺酰基氧(OTs)或甲基磺酰基氧(OMs),优选卤素,最优选氯或溴的化合物;或如Eshenmoser氏盐的烷基化试剂;环氧化物或合适取代的亲电氮杂环丙烷类(aziridine)。合适的溶剂依赖使用的碱,但可以从包括N,N-二甲基甲酰胺(DMF),四氢呋喃和水中选择。反应温度约为0℃-30℃,优选约20℃~25℃,反应时间约15分钟-16小时。
化合物IX可由化合物VIII在强碱性条件下极性溶剂中与脲反应制得。合适的碱包括甲醇钠,乙醇钠,甲醇镁;优选乙醇钠。合适的溶剂包括醇类(如乙醇)或四氢呋喃,优选无水乙醇。反应温度约20℃-90℃,优选约50℃-65℃,反应时间约15分钟-16小时。
化合物VIII可从化合物VI制备得到,L3是离去基团,如卤素,对甲苯磺酰基氧(OTs)或甲基磺酰基氧(OMs),优选卤素,最优选氯,在极性溶剂中碱性条件下与化合物HX-A-Y-B-G反应。合适的碱包括甲醇钠,乙醇钠,碳酸钾以及氢化钠;优选乙醇钠。合适的溶剂包括二甲基甲酰胺(DMF),醇类(如乙醇)或四氢呋喃,优选乙醇。反应温度约20℃-90℃,优选约50℃-70℃,反应时间约15分钟-16小时,优选3小时。这种类型的反应在NiederlJ.B.及Roth R.T.的文章中(J.Amer.Chem.Soc.,1940,62,1154)也例举说明过。
化合物VIII也可以由VII在合适的催化剂的存在下制备得到,优选醋酸铑(11),参见CampbellM.等的方法(Aust.J.Chem.,1992,45,2061)。
化合物VI和VII已有商品化供应,也可以根据本领域的普通技术人员已知方法从易得的起始原料制备得到。如化合物VII可由Peace D.W.等的方法(Synthesis,1971,658)制备得到。
化合物III有商品供应,也可根据本领域的普通技术人员已知的方法制备得到。
方案3为另一种制备化合物1的方法;特别是X为氧或-OCH2-的那些化合物。参照方案3,化合物I可以通过化合物XI的烷基化得到,与式HO-A-Y-B-G的合适酚类化合物,参照Mitsonubu O.方法(Synthesis,1981,1)的方法制备得到;或与式L3CH2A-Y-B-G类合适的烷基化试剂,其中L3为离去基如卤素,对甲苯磺酰基氧(OTs)或甲基磺酰基氧(OMs),优选卤素,最优选氯或溴在合适的溶剂如N,N-二甲基甲酰胺,四氢呋喃,乙氰,合适的碱如氢化钠,碳酸钾,三乙基胺,吡啶或三乙醇胺存在条件下反应得到,上述反应温度约为0℃~50℃,优选约20℃,反应时间约为15分钟-16小时。
式XI所示的化合物也可以从化合物X制备得到,参照J.A.Vida等的方法(J.Med.Chem.,1974,17,732)。
式X的化合物可从式XII化合物制备得到,反应用合适的碱,在式R1L4的合适烷基化试剂和溶剂中进行,参照Biehl等的描述(J.Het.Chem.,1986,23,9)。合适碱如氢化钠,碳酸钾,三乙胺,吡啶,三乙醇胺;最优选三乙醇胺。合适的烷基化剂包括L4为卤素,对甲苯磺酰基氧(OTs)或甲磺酰基氧(OMs),优选卤素,最优选氯或溴的化合物;或如Eshenmoser盐类;环氧化物或合适取代亲电试剂氮杂环丙烷类。合适的溶剂依赖所使用的碱,可以从N,N-二甲基甲酰胺,四氢呋喃,乙氰和水中选择。反应温度约为0℃-30℃,优选约20℃-25℃,反应时间约15分钟-16小时。
化合物XII已有商品供应,也可以由本领域普通技术人员按照文献(Lednicer D.及Mitscher L.A.,The Organic Chemistry Drug Synthesis,第1卷:第167-277页)中的方法及其中引用的文献很方便制备得到。
方案4为另一种制备化合物1的方法。参照方案4,式I化合物可由化合物XIV的化合物与式HX-A-Y-B-G的化合物在碱性条件下烷基化得到。合适的碱包括聚合物结合的碱,如1,5,7-三氮杂二环[4.4.0]癸-5-烯固定在聚苯乙烯(PTBD),PTBD用2%二乙烯基苯(DVB)或碱金属的碳酸盐交联;优选PTBD。适合的溶剂包括醇类(如乙醇,甲醇和丁醇),DMF,THF或乙氰,优选乙氰。反应温度约20℃-90℃,优选约50℃-65℃,反应时间约15分钟-16小时。
化合物XIV从化合物X通过与合适的溴化试剂如Br2或Br2-Ph3P反应得到。溴化可在惰性溶剂如水(合适的碱存在),乙酸,乙氰或DMF,优选水中进行。反应温度0℃-40℃,优选20℃-35℃,反应时间约15分钟-16小时。
或者,化合物I,当其中X为S或-SCH2-,或对应的氧化衍生物>SO2,>SO,-SO2CH2-,-SOCH2-时,可通过式X化合物嘧啶-2,4,6-三酮环与适当的二硫化物(SA-Y-B-G)2或(SCH2A-Y-B-G)2在合适的溶剂如N,N-二甲基甲酰胺,四氢呋喃,乙氰中,在合适的碱存在条件,如氢化钠,碳酸钾,三乙胺,吡啶或三乙醇胺,制备得到。反应在20℃-70℃,优选20℃,反应时间约为15分钟-16小时。
二硫化物(SA-Y-B-G)2或(SCH2A-Y-B-G)2可由相应的硫醇化合物HSA-Y-B-G或HSCH2A-Y-B-G用本领域普通技术人员已知的氧化方法制备得到。
化合物X已有商品供应,也可以参照方案3或其他本领域普通技术人员已知的方法制备得到。
本领域普通技术人员也许会认识到侧链R1和X-A-YB-G可以作为一个单元加入,如上述讨论的那样;或作为单独单元如X-A加入,接着加入第二个单元L’-Y-B-G。这些都是本领域普通技术人员已知的方法。
方案5描述了式XV中间体的制备方法。式XV中间体是用来制备方案1-4式I化合物。参照方案5,式XV化合物(其中X’为>(C=O)-Cl,OH,SH,>NHR10,CH2OH,CH2SH,CH2NHR10和SO2NHR10),可从式XVI的合适化合物用本领域普通技术人员已知的脱保护方法制备得到,可以参考Greene和Wuts文章,″Protecting Groups in Organic Synthesis,″(John Wiley & SonPress,2nd Ed)。式XV的化合物(其中X’为-(C=O)-Cl)可以从式XVI的化合物(其中P为羟基)与氯代试剂,如亚硫酰(二)氯或磷酰氯反应制备得到。
式XVI的化合物(Y为O,S,CH2O,CH2S,NR18,CH2NR18或SO2NR18)可由式XVII化合物(其中W为Br或I)与式G-Z-YH化合物在合适的碱,如碱金属碳酸盐或氢氧化物,优选碳酸钾,在合适的催化剂,如铜(O)催化剂,优选精细粉末状青铜,在极性非质子溶剂,如DMF或NMP,约80℃-140℃反应6-24小时制备得到。或者,当W为Cl,Br,I或三氟化物(trifalte)(TfO)时,偶合反应也可在Buchwald和Hartwig氏反应条件进行,用合适的碱,如醇盐类的碱,优选叔丁醇钠,在合适的溶剂中,如醚溶剂,优选二噁烷,在钯(O)催化剂,如Pd2(dba)3存在条件下,及合适的配基,如三芳香基膦,优选三(邻-甲苯基)膦,在温度约40℃~100℃反应约1-48小时。这些反应条件在Angew.Chem.Int.Ed.Engl.,1998,37,2046-2067中进行了评论,本领域普通技术人员都熟悉。当W为B(OH)2时,偶合反应也可以用铜催化剂,优选乙酸铜(II),在4分子筛及叔胺碱,如三乙胺或吡啶存在下,在合适的溶剂,如二氯甲烷,DMSO或THF中,在一大气压的氧气氛中进行,反应温度约为10℃-50℃,优选23℃反应约6-72小时。在几种情况(如,Y为CH2O,CH2S,CH2NR18或SO2NR18)下,更有利于利用式XVII的化合物(其中X为CHO,W为F),与式G-Z-YH的化合物,在合适的碱,如碱金属氢化物,优选氢化钠存在下,在非质子极性溶剂,如DMF或THF,反应温度0℃-140℃反应1-24小时得到式XVI的化合物。这些化合物可以用所谓的BayerVillager氧化条件转化为化合物XVI(X为O),或通过Curtius重排反应转化为化合物XVI(X为NR18),两种都是经典的有机化学转化方法,本领域普通技术人员都熟知。
化合物XVI(其中Y为>SO2,>S=O,-CH2SO-,-CH2SO2-,SO(CH2)n-,-SO2(CH2)n-,可以由相应的低氧化态的化合物(如Y为-S-,-CH2S-,-S-(CH2)n-)用合适的氧化剂,如过氧酸,优选过氧乙酸,或有机过氧化物,优选间氯过氧苯甲酸或过氧化氢叔丁基,在合适的溶剂,如二氯甲烷或叔丁醇,反应温度-10℃~30℃反应时间1-8小时制备得到。
式XVI的化合物(其中Y为O(CH2)n,S(CH2)n,NR18(CH2)n)可以由式XVII的化合物(其中W为L-(CH2)n-,其中L为卤素,甲磺酰基氧(MsO)或甲苯磺酰基氧(TsO)),与式G-Z-Y-H所示的合适化合物(其中Y为O,S或NR18),在合适的碱,如碱金属碳酸盐,优选碳酸钾或碳酸铯,在极性非质子溶剂,如DMF或THF中,于23℃-80℃,优选20-50℃,反应124小时制备得到。
式XVI所示的化合物(其中Y为>C=O或CH=CH),可由式XVII的化合物(其中W为-B(OH)2,-ZnX或-SnR3)与化合物G-Z-Y-X(其中X为卤素,优选Cl,Br或I),在钯或镍催化剂,优选Pd(PPh3)4存在下,在合适的溶剂如甲苯,THF,DMF或DMSO中,在23℃-110℃反应1-24小时制备得到。这类反应在铜盐,如碘化亚铜或溴化亚铜存在的条件下反应会加速。式XVI的化合物(其中Y为-C≡C-)可用式XVII化合物(W为卤素或三氟化物,优选Br或I),与式G-Z-Y-H所示的化合物,在合适的碱,如三烷基胺,优选三乙基胺和钯催化剂,优选Pd(PPh3)4存在下,在合适的溶剂中,如THF或DMF,在23-60℃反应1-24小时制备得到。本领域普通技术人员会认识到,式XVI的化合物(其中Y是-CH2(CH2)n-),用前述化合物(其中Y是-CH=CH-或-C=C-)还原得到,还原条件为50psi环境压力的氢气氛,在钯催化剂存在条件下,优选附着在焦碳上的钯,合适的溶剂,如甲醇或乙酸乙酯,在20℃-50℃反应1-24小时。
化合物I(其中P为合适的保护基,如Green和Wuts上述定义的那样),已有商品供应或本领域普通技术人员用知道的方法从市售起始原料制备得到。
方案6描述了式XVlll的化合物的制备过程,式XVIII中X为-OCH2-,SCH2-或-N(R10)CH2-。当R1为氢时,化合物XVIII就是方案1中的化合物IV。参照方案6,化合物XVIII可由化合物XIX与化合物G-B-Y-A-XH(其中X为O,S或NR10),在合适的碱,如碱金属氢化物,优选氢化钠,及合适的溶剂,如醇类溶剂,THF或DMF在-20-50℃,优选0℃-23℃反应1-24小时制备得到。
式I类的化合物,本质上是碱性的,可以与多种无机和有机酸形成多种盐。尽管这些盐对动物给药而言,必须是药用可接受的,在实际操作中,通常是将式I化合物以非药用盐的形式从反应混合物中的分离出来,然后简单地用碱试剂处理,将后者转换成游离碱,随后变成药用加酸盐。本发明化合物的加酸盐很方便制备,碱化合物与实质上等量所选的无机或有机酸在水溶性溶剂介质或合适的有机溶剂如甲醇或乙醇反应,小心蒸出溶剂,就得到需要的固体盐。
用来制备本发明碱性化合物的药用加酸盐的酸,必须形成无毒性加酸盐,即,盐必须包括药用阴离子,如盐酸盐,氢溴酸盐,氢碘酸盐,硝酸盐,硫酸盐或硫酸氢盐,磷酸盐或酸式磷酸盐,乙酸盐,乳酸盐,柠檬酸盐或酸式柠檬酸盐,酒石酸盐或酒石酸氢盐,琥珀酸盐,马来酸盐,延胡索酸,葡萄糖酸,糖酸盐,苯甲酸盐,甲磺酸盐和pamoate[即,1,1’-亚甲基-二-(2-羟基-3-萘甲酸盐)]。
式I化合物本质上也呈酸性,能与多种阳离子形成药用加碱盐。这些盐包括碱金属或碱土金属盐,特别是,钠和钾盐。用常规的技术可以制备得到这些盐。用来制备本发明的药用加碱盐的碱化学试剂为与式I的酸性化合物形成无毒性加碱盐的碱类。这些的无毒性加碱盐包括用药用阳离子如钠,钾,钙和镁等得到的那些盐。这些盐很方便制备得到,将相应酸化合物与包括合适药用阳离子的水溶液混合,然后蒸发所得到溶液至干,优选在减压下进行。
或者,它们也可以利用酸性化合物的低级烷醇溶液和合适的碱金属烷醇化物混合,与前述方式相同蒸干反应液,制备得到。在任何一种情况下,优选使用化学计量的试剂,以保证反应完全,得到最多产物。
生物活性分析
结构式I所示化合物或其药用盐(后面称之为本发明的化合物)对金属蛋白酶或哺乳动物reprolysins的抑制活性,以及由此证明它们对以金属蛋白酶活性为特征疾病的治疗效果,将用下述体外和体内分析实验来显示。
MMP分析
利用下述的MMP荧光分析筛选本发明的抑制剂,选择MMP-13/MMP-X抑制IC50比例大于或等于100以及活性小于100nM的化合物确定为MMP-13选择性抑制剂,这里MMP-X指一种或多种的其他MMP。
这里指的非选择性胶原酶抑制剂,除非另有为说明,指其对MMP-13酶的抑制选择性小于对MMP-X酶100倍或用下述MMP-13/MMP-X荧光分析IC50结果来判断的活性大于100nM的化合物。
胶原酶抑制剂对胶原酶活性有抑制作用已为本领域普通技术人员所熟悉。数个化合物对特定MMP抑制作用已有记载。本领域普通技术人员知道如何将不同分析方法的结果与这里所使用的方法进行标准化。下述分析方法可以用来判断基质金属蛋白酶抑制剂。
人胶原酶(MMP-1)抑制
重组人胶原酶用胰蛋白酶激活。每批胶原酶-1所需的胰蛋白酶量需要优化,但通常比例是:100μg胶原酶用5μg胰蛋白酶。胶原酶及胰蛋白酶在室温下孵育10分钟,然后加入5倍量(50mg/10mg胰蛋白酶)的大豆胰蛋白酶抑制剂。
配制抑制剂的二甲亚砜储藏液(10mM),按照下述方案稀释:
10mM----->120μM------>12μM------>1.2μM------>0.12μM
每个浓度取25μL,然后加到96孔显微荧光板上,重复三次。加入酶和底物后,抑制剂的终浓度为1∶4稀释。阳性对照(有酶,无抑制剂)在板上D7-D12位置,阴性对照(无酶,无抑制剂)在板上D1-D6的位置。
胶原酶-1稀释到240ng/ml,在显微荧光板上合适的孔中加入25μl。分析时胶原酶的终浓度为60ng/ml。
底物(DNP-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH2)配成5mM的二甲亚砜储存液,用分析缓冲液中稀释到20μM。显微荧光板的每孔中加入50μl底物启动分析,底物的终浓度为10μM。
在时间0点,进行荧光读数(360nm激发;460nm发射),随后每间隔20分钟读数一次。分析在室温条件下进行,通常的分析时间为3小时。
利用空白和包含胶原酶样品的荧光数据(数据为三次数据的平均值)对时间作图。由有好信号(至少5倍空白信号)和曲线上是线性部分的时间点(通常约120分钟)选择来确定IC50数值。每个化合物每个浓度零时间点作为空白,120分钟的数据减去这些数值。抑制剂浓度对百分抑制率作图(抑制剂荧光/只有胶原酶荧光X100)。IC50确定为产生50%抑制信号的抑制剂浓度。
如果IC50的值小于0.03μM,就对抑制剂浓度为0.3μM,0.03μM,0.003μM进行分析。
白明胶酶(MMP-2)抑制
重组人72kD白明胶酶(MMP-2,白明胶酶A)在4℃用1mM对氨基苯基乙酸汞(用新配的100mM的0.2N NaOH储存液),轻微震荡活化16-18小时。
抑制剂的10mM二甲基亚砜储存液按照下列方案用分析缓冲液(50mMTRIS,pH7.5,200mM NaCl,5mM CaCl2,20μM ZnCl2和0.02%BRIJ-35(v/v))进行连续稀释。
10mM----->120μM------>12μM------>1.2μM------>0.12μM
需要进一步稀释时按照同样方案进行。每个化合物至少分析四个抑制剂浓度。每个浓度取25μL,然后加到黑色U-型底96孔显微荧光板上,重复三次。分析终体积为100μL,抑制剂的浓度就进行了1∶4的稀释(即30μM------>3μM------>0.3μM------>0.03μM,等)。空白(无酶,无抑制剂)和阳性酶对照(有酶,无抑制剂)也分别制备三个孔。
激活的酶用分析缓冲液稀释成100ng/mL,在合适的孔中,每孔加入25μL。酶的分析终浓度为25ng/mL(0.34nM)。
底物(Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2)的5mM二甲基亚砜储存液用分析缓冲液稀释到20μM。加入50μL稀释的底物启动分析,底物的分析终浓度10μM。立即记录零时间点的荧光读数(320激发;390发射),随后每15分钟读数一次,实验在室温条件下,利用PerSeptive BiosystemssCytoluor Multi-Plate Reader(放大系数为90倍)进行。
酶和空白的荧光平均数值对时间作图。曲线上线性部分的早期时间点用来确定IC50。后续时间点数据减去每个化合物每个稀释液零时间点数据,得到的数据然后用来定义酶抑制百分率(抑制剂荧光/阳性酶对照荧光x100)。抑制剂浓度对酶抑制百分率作图。IC50定义为50%阳性酶对照荧光信号时的抑制剂浓度。
溶基质素(stromelysin)活性(MMP-3)抑制
重组人溶基质素(MMP-3,溶基质素-1)于37℃用2mM对氨基苯基乙酸汞(用新配100mM的0.2N NaOH储存液)活化20-22小时。
抑制剂的10mM二甲基亚砜储存液按照下列方案用分析缓冲液(50mMTRIS,pH 7.5,150mM NaCl,10mM CaCl2和0.05%BRIJ-35(v/v))进行连续稀释。
10mM----->120μM------>12μM------>1.2μM------>0.12μM
需要进一步稀释时按照同样方案进行。每个化合物至少分析四个抑制剂浓度。每个浓度取25μL,然后加到黑色U-型96孔显微荧光板上,重复三次。分析终体积为100μL,抑制剂的浓度就进行了1∶4的稀释(即30μM------>3μM------>0.3μM------>0.03μM,等)。空白(无酶,无抑制剂)和阳性酶对照(有酶,无抑制剂)也分别制备三个孔。
激活的酶用分析缓冲液稀释成200ng/mL,在合适的孔中,每孔加入25μL。分析时,酶的分析终浓度为50ng/mL(0.875nM)。
底物(Mca-Arg-Pro-Lys-Pro-Val-Glu-Nva-Trp-Arg-Lys(Dnp)-NH2)的10mM二甲基亚砜储存液用分析缓冲液稀释到6μM。加入50μL底物启动分析,底物的分析终浓度3μM。立即记录零时间点的荧光读数(320激发;390发射),随后每15分钟读数一次,实验在室温条件下,利用PerSeptiveBiosystemss Cytoluor Multi-Plate Reader(放大系数为90倍)进行。
酶和空白的荧光平均数值对时间作图。曲线上线性部分的早期时间点用来确定IC50。后续时间点数据减去每个化合物每个稀释液零时间点数据,得到的数据然后用来定义酶抑制百分率(抑制剂荧光/阳性酶对照荧光X100)。抑制剂浓度对酶抑制百分率作图。IC50定义为50%阳性酶对照荧光信号时的抑制剂浓度。
人92kD白明胶酶(MMP-9)抑制
92kD白明胶酶(MMP-9)抑制活性分析利用底物Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2(10μM)进行,类似于上述人胶原酶(MMP-1)抑制活性的实验条件。
重组人92kD白明胶酶(MMP-9,白明胶酶B)在37℃用1mM对氨基苯基乙酸汞(用新配100mM的0.2N NaOH储存液)活化2小时。
抑制剂的10mM二甲基亚砜储存液按照下列方案,用分析缓冲液(50mMTRIS,pH 7.5,200mM NaCl,5mM CaCl2,20mM ZnCl2和0.05%BRIJ-35(v/v))进行连续稀释。
10mM----->120μM------>12μM------>1.2μM------>0.12μM
需要进一步稀释时按照同样方案进行。每个化合物至少分析四个抑制剂浓度。每个浓度取25μL,然后加到黑色U-型96孔显微荧光上,重复三次。分析终体积为100μL,抑制剂的浓度就进行了1∶4的稀释(即30μM------>3μM------>0.3μM------>0.03μM,等)。空白(无酶,无抑制剂)和阳性酶对照(有酶,无抑制剂)也分别制备三个孔。
激活的酶用分析缓冲液稀释成100ng/mL,在合适的孔中,每孔加入25μL。酶的分析终浓度为25ng/mL(0.27nM)。
底物((Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2)的5mM二甲基亚砜储存液用分析缓冲液稀释到20μM。加入50μL稀释的底物启动分析,底物的分析终浓度10μM。立即记录零时间点的荧光读数(320激发;390发射),随后每15分钟读数一次,实验在室温条件下,利用PerSeptive BiosystemssCytoluorMulti-Plate Reader(放大系数为90倍)进行。
酶和空白的荧光平均数值对时间作图。曲线上线性部分的早期时间点用来确定IC50。后续时间点减去每个化合物每个稀释液零时间点,得到的数据然后用来定义酶抑制百分率(抑制剂荧光/荧光阳性酶x100)。抑制剂浓度对酶抑制百分率作图。IC50定义为50%阳性酶对照荧光信号时的抑制剂浓度。
MMP-13抑制
重组人MMP-13在37℃用2mM APMA(对氨基苯基乙酸汞)(用新配100mM的0.2N NaOH储存液)活化1.5小时。然后用分析缓冲液(50mM TRIS,pH 7.5,200mM NaCl,5mM CaCl2,20μM ZnCl2和0.02%BRIJ(v/v))稀释到400mg/mL。96孔显微荧光板中,每孔加入25μL经稀释酶。由于加入了抑制剂和底物,酶就进行了1∶4的稀释,终浓度为100mg/mL。
抑制剂的10mM二甲基亚砜储存液按照人胶原酶(MMP-1)抑制实验中每个抑制剂稀释方案进行。每个浓度取25μL,然后加到显微荧光板上,重复三次。抑制剂的终浓度为30μM,3μM,0.3μM,0.03μM。
底物(Dnp-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH2)按照人胶原酶(MMP-1)抑制实验配制。每孔中加入50μL底物启动分析,底物的分析终浓度10μM。荧光读数(360激发;450发射)在时间0点记录,每5分钟记录一次,连续记录1小时。
阳性对照包括为酶和底物,没有抑制剂;空白对照只有底物。
IC50按照人胶原酶(MMP-1)抑制方法来确定。如果得到的IC50小于0.03μM,然后抑制剂按终浓度0.3μM,0.03μM,0.003μM和0.0003μM进一步进行分析。
胶原膜MMP-13分析
I型大鼠胶原用14C乙酸酐进行放射标记(Cawston T.E.和BarrettA.J.,Anal.Biochem.,1979,99,340-345),用来制备96孔板,形成一层放射标记胶原膜(Barbara Johnson-Wint,Anal.Biochem.,1980,104,175-181)。孔中加入胶原酶溶液,酶就裂解处于展开状态的不溶的胶原,胶原就溶解到溶液中。由于胶原酶活性与溶解的胶原的量成比例,因此用标准的闪烁记数仪测量释放溶液中的放射活性比例,就可以确定胶原酶活性。胶原酶抑制剂,相对于没有抑制剂存在的对照而言,就是那些降低释放的放射记数的化合物。下面将详细描述该分析方法。
将按照下述操作方法,以胶原为底物,来判断化合物对MMP-13与MMP-1选择性。重组人原MMP-13或原MMP-1用前述方法激活。活化的MMP-13或MMP-1用缓冲液(50mM Tris,pH 7.5,150mM NaCl,10mM CaCl2,1μM ZnCl2和0.05%BRIJ(v/v),0.02%叠氮化钠)稀释至0.6μg/ml。
受试化合物的储存液(10mM)用二甲亚砜配制。用上述Tris缓冲液稀释,配制0.2,2.0,20,200,2000和20000nM受试化合物稀释液。
100μl药物稀释液和100μl酶稀释液吸到14C-胶原标记的含胶原膜的96孔板中。酶的终浓度为0.3μg/ml,药物终浓度为0.1,1.0,10,100,1000nM。每个药物浓度及对照分析三次。包含无酶和有酶无药的对照也分析三次。
板在37℃孵育,直至大约30-50%胶原溶解,参照多个时间点的另外的对照孔记数来确定。在大多数情况下,需要约孵育9小时。分析充分进行时,移出每孔的上清夜,闪烁记数仪记数。每个样品减去背景记数(无酶孔的记数),参照有酶无抑制剂孔的记数,计算出百分释放率。每个点的三个数值平均,百分释放率对药物浓度作图。IC50为50%抑制放射标记胶原的释放时的浓度点。
为判别软骨条件培养液中胶原酶活性的一致性,用胶原为底物,包括胶原酶和不同选择性抑制剂的软骨条件培养液来进行分析。发生胶原降解时,收集软骨条件培养液,用来代表分解胶原的胶原酶。分析按照前述方法进行,不同的是,软骨条件培养液作为酶源,代替重组MMP-13或重组MMP-1。
IL-1诱导降解来源于牛鼻软骨的软骨胶原
分析使用的牛鼻软骨外植片,通常用来评价化合物抑制IL-1诱导粘蛋白的降解或IL-1诱导胶原降解效果。牛鼻软骨是与关节软骨非常类似的组织,即单层软骨细胞被基质包围,基质主要是为II型胶原和聚集蛋白聚糖。利用该组织,主要因为(1)与关节软骨类似,(2)方便得到,(3)同一性较好,(4)IL-1诱导后,按照可预见的动力学降解。
有两种分析方法来评价化合物的活性。两种分析方法得到相似的数据。
下面介绍两种分析方法:
分析方法1
3个牛鼻软骨栓(直径约2mm,长1.5mm)放到24孔的组织培养板的孔中。每孔加入1ml无血清培养液。化合物配成10mM的DMSO储存液,用无血清培养基稀释成合适的终浓度,即,50,500和5000nM。每个浓度分析重复三次。
将重组人IL-1α(5ng/mL)(IL-1)加到三份对照孔和含牛鼻软骨栓的孔中。也设置无药无IL1三份对照孔。移出培养液,在第6,12,18和24天加入几-1的新鲜培养液和合适浓度的药物,必要的时候也可以每3-4天加一次。在每个时间点移出的培养液于-20℃保存,分析备用。当只有IL-1的孔中软骨的完全再吸收(约21天)的时候,终止实验。移出培养液,贮存。每孔每个时间点取出部分溶液(100μl),用木瓜蛋白酶裂解,分析羟脯氨酸含量。每个数据减去背景羟脯氨酸(无IL一1和无药孔数据平均),对三重数据平均。数据以相对于只有IL-1平均数据的百分率表示,作图。IC50从该图上确定。
分析方法2
至第12天,实验与上述分析方法1相同。第12天,从每孔中移出调理的培养液,冻存。然后每孔加入1ml含0.5μg/ml胰蛋白酶的磷酸盐缓冲液(PBS),37℃继续孵育48小时。胰蛋白酶孵育48小时后,移出PBS溶液。PBS/胰蛋白酶溶液(50μl)和前面的两个时间点(第6天和12天)混合,水解,确定羟基脯氨酸含量。每个数据点减去背景羟基脯氨酸(无IL-1和无药孔数据的平均),对三重数据平均。数据以相对于只有IL-1平均数据的百分率表示,作图。IC50从该图上确定。利用这种分析方法,分析时间大为缩短。IL-1诱导12天后,加入胰蛋白酶,孵育48小时,可能释放出被胶原酶破坏但还没从软骨基质中释放的所有II型胶原。胶原降解软骨外植片实验中,不用IL-1诱导,只用胰蛋白酶处理只能得到低水平的背景。
TNF产生抑制
化合物或药用盐对TNF产生抑制活性用下述体外分析方法评价。
人单核细胞分析
人单核细胞是用一步Ficoll-hypaque分离技术从抗凝聚的人血中分离得到。(2)单核细胞用含二价阳离子的Hanks平衡盐溶液(HBSS)洗涤3次,重新悬浮于含1%BSA的HBSS中,密度为2×106/ml。利用Abbott Cell Dyn3500分析仪进行差异记数,单核细胞占总细胞的17~24%。
细胞悬浮液移到平底96孔板(Costar)中,每孔加入180μl。加入化合物和LPS(100ng/ml终浓度),得到终体积为200μl。所有的条件重复3次。在增湿的CO2培养箱中,37℃孵育4小时,移出培养板,250g离心10分钟,移出上清液,用R&D ELISA试剂盒分析TNFa。
聚集蛋白聚糖酶分析
原代猪软骨细胞从关节软骨分离得到,连续用胰蛋白酶和胶原酶消化,随后用胶原酶消化过夜,按照每孔2×105细胞进行铺板,将细胞转移到48孔板,板为I型胶原质包埋且加有5μCi/ml 35S(1000Ci/mmol)硫。在37℃的5%CO2气中培养,细胞的蛋白聚糖基质中就会掺入标记(大约1星期)。
启动分析的前夜,软骨细胞用DMEM/1%PSF/G洗涤2次,然后在新鲜的DMEM/1%FBS中培养过夜。
次日上午软骨细胞用DMEM/1%PSF/G洗涤一次。在配制稀释液时,将最后的洗涤液保留在培养箱的板中。
按照下表配制培养液和稀释液。
对照介质 | 只有DMEM(对照介质)。 |
IL-1介质 | DMEM+IL-1(5ng/ml) |
药物稀释液 | 配制化合物的10mM DMSO储藏液用96孔板配制每个化合物的100μM DMEM储藏液。冰箱中冷冻过夜。第二天用DMEM和IL-1稀释液进行连续稀释,配制浓度为5μM,500nM,50nM的溶液。从孔中吸出终洗涤液,将50μl化合物的上述稀释液加入已有450μl IL-1溶液48孔板的合适的孔中。化合物的终浓度为500nM,50nM,和5nM。每块板上的所有样品,对照及单独IL-1都重复三次。 |
板进行标记,只使用板中间的24个孔。在其中的一块板上,几列标记为IL-1(无药)和对照(无IL-1,无药)。这些对照定时测量35S-蛋白聚糖的释放。对照和IL-1溶液加入孔中(450μl),随后加入化合物(50μl)启动分析。板在37℃的5%CO2气中培养。
用液闪记数(LSC)分析溶液样品,在40-50%释放(当IL-1溶液中CPM为对照溶液的4-5倍)时,分析终止(9-12小时)。移出所有孔中的溶液,放入闪烁管中。加入闪烁液,得到放射活性记数(LSC)。每孔加入500μl木瓜蛋白酶消化缓冲液(0.2M Tris,pH7.0,5mM EDTA,5mM DTT,和1mg/ml木瓜蛋白酶)溶解细胞层。板用裂解液于60℃孵育过夜。第二天移出板中细胞层,放入液闪管。加入闪烁液,样品放射活性记数(LSC)。
确定每个孔中释放量相对于总量的百分比。每孔数据减去对照背景,对三份数据取平均。化合物的抑制百分率,以IL-1样品为0%抑制(100%总记数)为基准计算。
本发明的所有受试化合物,利用上述分析方法,至少在一种分析方法中的IC50小于100μM,甚至小于100nM。优选的几组化合物对多种MMP’s或ADAMs具有差异选择性。一组优选化合物对MMP-13具有选择性活性优于MMP-1。另一组优选化合物对MMP-13具有选择性活性,优于MMP-1和MMP-12。
包括口服,肠胃外给药(如,静脉,肌肉或皮下),口腔,肛门和局部给药多种给药途径,可以用来给包括人在内哺乳动物给药,抑制基质金属蛋白酶或哺乳动物reprolysin。通常,本发明的化合物(下文也称为活性化合物)按照治疗对象的体重,以每天约0.1~25mg/kg剂量给药,优选约0.3~5mg/kg。优选活性化合物的给药方式为口服或肠胃外给药。但是,剂量应因治疗对象的状况而变。在任何情况下,负责给药的人确定个体给药量。
本发明化合物可以多种剂量给药,通常,本发明的治疗有效化合物的剂量浓度水平约为5.0%~70%(重量比)。
口服给药,采用片剂,片剂包括多种赋形剂,如微晶纤维素,柠檬酸钠,碳酸钙,磷酸二钙和甘氨酸;其他多种崩解剂,如淀粉(和优选玉米,马铃薯或木薯淀粉),海藻酸和某些复合硅酸盐;粒状粘合剂如聚乙烯吡咯烷酮,蔗糖,凝胶和阿拉伯树胶。润滑剂如硬脂酸镁,月桂硫酸钠和滑石对片剂的制备很有用。相似类型的固体组分也可以用来作为明胶胶囊的填料;就此而言,优选的材料也包括乳糖或牛奶糖以及高分子量的聚乙二醇。当水性混悬液和/或酏剂用于口服给药,可将活性组份与多种甜味或调味剂,成色物质或染料混合,需要时,还可与乳化和/或悬浮剂以及稀释剂如水,乙醇,丙二醇,丙三醇和多种类似物混合。如果对动物给药,通过动物饲料或饮用水给药更有利,浓度为5-5000ppm,优选25~500ppm。
肠胃外给药(肌肉,腹腔内,皮下和静脉)通常制备成活性组分的无菌注射溶液。可以使用本发明治疗化合物芝麻或花生油或水溶性的丙二醇溶液。水溶液应经适当的调节和缓冲,必要的时候,优选pH大于8,稀释液应该先成为等渗溶液。这些水溶液合适静脉注射。油溶液合适关节,肌肉和皮下注射。在无菌的条件下,利用本领域普通技术人员熟悉的标准的制药技术很方便制备这些溶液。如果是动物用药,化合物可以通过肌肉或皮下给药,剂量约为0.1~50mg/kg/天,优选单剂量为0.2~10mg/kg/天或分成3个以上的剂量给药。
本发明活性化合物也可以通过直肠给药如栓剂或保留灌肠剂(retention enemas),如,包括常用的栓剂基质如可可油或其他甘油脂。
鼻内给药或吸入给药时,本发明活性化合物可用溶液或混悬液的形式方便地给药,由病人挤压或抽吸泵喷射容器;或气雾给药形式,利用压缩容器或喷雾器,用合适的抛射剂,如,二氯二氟甲烷,三氯氟甲烷,二氯四氟乙烷,二氧化碳或其他合适气体。在压缩气溶胶给药时,药物的剂量单位由一个阀门控制,输出经过测定的剂量。压缩容器或喷雾器可以容纳活性化合物的溶液或混悬液。吸入器或吹药器中的胶囊和储库(cartridges)(由,如,明胶制备)包括本发明化合物和合适的粉状辅料如乳糖或淀粉的粉状混合物。
眼睛局部给药,可以直接对受侵袭的眼进行给药,制剂形式为滴眼剂,气溶胶,凝胶剂或软膏,或并入胶原(如聚-2-羟基乙基甲基丙烯酸酯以及共聚物),或亲水性的聚合物护罩(polymer shield)。材料也可制备成接触眼镜(contact lens)或通过局部的给药池(reservoir)或结膜下剂型(subconzunctival formulation)。
眼眶给药通常制备成活性组分的无菌注射液。给药时可以使用本发明治疗化合物的水溶液或混悬液(颗粒小于10微米)。水溶液应该经过合适的调节和缓冲,必要的时候,优选pH介于5~8;液体稀释液先进行等渗处理。可以加入小剂量的聚合物增加粘性或达到缓释的效果(如纤维素类的聚合物,右旋糖苷,聚乙二醇,或海藻酸)。这些溶液合适眼眶注射给药。这些溶液在无菌条件用本领域普通技术人员熟悉的技术可以很方便制备得到。在给动物给药时,化合物眼眶给药的剂量约为0.1~50mg/kg/天,优选单剂量0.2~10mg/kg/天或3个以上的分剂量。
与其他给药途径和相应剂型形式类似,口服给药的也合适制备成活性组份的控释,缓释,和/或延迟释放的剂型。通常,包括延迟释放口服片剂,胶囊和复合粒子(multiparticulates),包有肠溶衣的片剂和胶囊释放,可以避免活性组分在病人胃里的释放和吸收,加速转运到胃的远端,即,肠。其他典型的口服剂型包括缓释口服片剂,胶囊,和复合粒子(multiparticulates),可以在相当长的一段时间以可控的方式全身给药,如,24小时。当活性组分需要快速给药时,控释口服剂型可以制成快速溶解的片剂,也优选包括活性组分的易溶盐。
下述实施例举例说明了本发明化合物的制备方法。熔点未经校正。NMR数据以ppm(δ)表示并且参照样品溶剂的(除非说明,都为氘代氯仿)氘锁信号。商品化的试剂使用前未经进一步的纯化。THF指四氢呋喃。DMF指N,N-二甲基甲酰胺。色谱指柱色谱,用32-63mm硅胶,在氮气压力下进行(快速色谱)。室温或环境温度指20-25℃。所有的无水反应在氮气保护下进行并且优化了产率。减压或真空浓缩指使用了旋转蒸发仪。
实施例1
5-(2-乙氧乙基)-5-[4-(4-[1,3,4]噁二唑-2-基-苯氧基)-苯氧基]-嘧
啶-2.4.6-三酮
将4-(4-[1,3,4]噁二唑-2-基-苯氧基)-苯酚(0.90g,2.5mmol),5-溴5-(2-乙氧乙基)-嘧啶-2,4,6-三酮(1.0g,3.6mmol),连接到聚苯乙烯上的1,5,7-三氮杂二环[4.4.0]癸-5-烯(1,5,7-trazabicyclo[4.4.0]dec-5-ene)(聚苯乙烯用2%DVB(二乙烯基苯)交联)(PTBD,Fluka,2.4g,6.1mmol)和11.7mL乙氰混合,23℃振荡24小时。混合物用30mL 25%乙酸的甲醇溶液稀释,过滤,固体用乙酸-甲醇溶液洗两次。滤液真空浓缩,用径向(radical)色谱(2∶1~1∶1己烷-乙酸乙酯)纯化,得到600mg 5-(2-乙氧乙基)-5-[4-(4-[1,3,4]噁二唑-2-基-苯氧基)-苯氧基]-嘧啶-2,4,6-三酮,为无色固体。
1H NMR(CD3OD)8.98(s,1H),8.04(d,2H,J=9.0Hz),7.07(d,2H,J=9.5Hz),
7.04(d,2H,J=9.0Hz),6.91(d,2H,J=9.0Hz),3.61(t,2H,J=5.5Hz),3.42(q,2H,J=7.0Hz),2.58(t,2H,J=6.5Hz),1.15(t,3H,J=7.5Hz)ppm.
MS(m/z,APCI):496.3[M-H]-.
4-(4-[1,3,4]噁二唑-2-基-苯氧基)-苯酚
将2-[4-(4-甲氧基-苯氧基)-苯基]-[1,3,4]噁二唑(1.1g,4.1mmol),蛋氨酸(0.94g,4.9mmol),甲磺酸(20.5mL)混合,混合物在50℃加热1.5小时。倾入冰冷的5M氢氧化钠(60mL)溶液中,饱和碳酸氢钠水溶液稀释,乙酸乙酯萃取三次,合并有机相,硫酸钠干燥,过滤,真空浓缩,得到4-(4-[1,3,4]噁二唑-2-基-苯氧基)-苯酚,为无色固体(0.91g)。
1H NMR(CD3OD):8.97(s,1H),8.01(d,2H,J=9.0Hz),7.04(d,2H,J=9.0Hz),6.97(d,2H,J=9.0Hz),6.87(d,2H,J=9.0Hz)ppm
2-[4-(4-甲氧基-苯氧基)-苯基]-[1,3,4]噁二唑
将4-甲氧基苯基硼酸(1.9g,12mmol),4-(1,3,4)噁二唑-2-基苯酚(1.0g,6.2mmol),乙酸铜(II)(1.1g,6.2mmol),粉碎的4-分子筛(0.65g),三乙基胺(4.2mL)以及二氯甲烷(22.7mL)混合,混合物在1大气压的氧气下搅拌48小时。混合物滤过Celite层,真空浓缩,径向色谱纯化(2∶1,正己烷-乙酸乙酯),得到1.2g 2-[4-(4-甲氧基-苯氧基)-苯基]-[1,3,4]噁二唑。
1H NMR(CDCl3):8.44(s,1H),8.02(d,2H,J=9.0Hz),7.05(m,4H),6.95(d,2HaJ=7.0Hz),3.85(s,3H)ppm.
MS(m/z,APCI):300.2[M+H]+.
5-溴-5-(2-乙氧乙基)-嘧啶-2,4,6-三酮
在0℃下,向5-(2-乙氧乙基)-嘧啶-2,4,6-三酮(27.8g,139mmol)及1.5L水的混合物中,加入1M氢氧化钠(140mL)和溴(7.2mL,22.2g,139mmol)。恢复至室温,搅拌48小时,过滤,固体用水洗,醚洗,己烷洗,真空干燥,得到23g的5-溴-5-(2-乙氧乙基)-嘧啶-2,4,6-三酮。
1H NMR(CDCl3):8.37(bs,2H),3.53(t,2H,J=7.0Hz),3.35(q,2H,J=6.5Hz),2.99(t,2H,J=7.0Hz),1.05(t,3H,J=6.5Hz)ppm.
MS(m/z,APCI):468.2[M+H]+.
5-(2-乙氧乙基)-嘧啶-2.4,6-三酮
金属钠(8.6g,0.38mol)加到乙醇(375mL)中,混合物在室温下搅拌直到形成均相。加入丙二酸二乙酯(60g,0.38mol),然后加入溴乙基乙基醚(57.4g,0.38mol)。搅拌回流3小时,反应液冷却至室温,真空浓缩。残留物加入乙醇钠及乙醇混合物(由17.2g金属钠和600mL甲醇反应得到)。加入脲(24g),混合物回流2.5小时。冷却至室温,继续搅拌12小时,1M盐酸酸化,乙酸乙酯萃取三次,合并有机相,硫酸钠干燥,过滤,真空浓缩,得到无色的固体化合物5-(2-乙氧乙基)-嘧啶-2,4,6-三酮。
实施例2
N-(4-{4-[5-(2-乙氧乙基)-2,4,6-三氧-六氢-嘧啶-5-基氧]-苯氧基}
苄基)-丙酰胺
参照实施例1的制备工艺,将N-[4-(4-羟基-苯氧基)-苄基]-丙酰胺(0.13g,0.47mmol)与5-溴-5-(2-乙氧基乙基)-嘧啶-2,4,6-三酮(0.13g,0.48mmol),1,5,7-三氮杂二环[4.4.0]癸-5-烯(连接到聚苯乙烯-2%DVB交联体)(PTBD,Fluka,0.31g)和1.55mL乙氰反应后,得到无色的固体化合物N-(4-{4-[5-(2-乙氧乙基)-2,4,6-三氧-六氢-嘧啶-5-基氧]-苯氧基}苄基)-丙酰胺(0.060g)。
1H NMR(CD3OD):7.25(d,2H,J=8.5Hz),6.90(m,4H),6.89(d,2H,J=8.0Hz),4.33(s,2H),3.59(t,2H,J=6.0Hz),3.42(q,2H,J=7.0Hz),2.56(t,2H,J=6.5Hz),2.25(q,2H,J=7.5Hz),1.14(m,6H)ppm.
MS(m/z,APCI):468.3[M-H]-.
N-[4-(4-羟基-苯氧基)-苄基]-丙酰胺
将4-(4-氨基甲基-苯氧基)-苯酚(0.10g,0.47mmol),MMP树脂(聚苯乙烯N-甲基吗啉交联型碱,0.30g,1.04mmol)和1.9mL乙氰混合物,用丙酰氯(0.086mL,1.0mmol)处理,室温振荡24小时。滤出树脂后,滤液用2mL甲醇稀释,加入2mL的1M氢氧化锂(LiOH)水溶液,混合物室温搅拌24小时,用Amberlite IRP-64树脂处理至中性,过滤,真空浓缩,得到N-[4-(4-羟基-苯氧基)-苄基]-丙酰胺。MS(m/z):272.2[M+H]+。
实施例3
4-{4-[5-(2-乙氧乙基)-2,4,6-三氧-六氢-嘧啶-5-基氧]-苯氧}-N甲
基-苯甲酰胺
参照实施例1的制备过程,将4-(4-羟基-苯氧基)-N-甲基-苯甲酰胺(0.14g,0.58mmol)与5-溴-5-(2-乙氧乙基)-嘧啶-2,4,6-三酮(0.16g,0,58mmol),1,5,7-traza二环[4.4.0]癸-5-烯(连接到聚苯乙烯与2%DVB交联物)(PTBD,Fluka,0.40g)和2.0mL乙氰反应,得到无色固体化合物4-{4-[5-(2-乙氧乙基)-2,4,6-三氧-六氢-嘧啶-5-基氧]-苯氧基}-N-甲基-苯甲酰胺(0.040g)。
1H NMR(CD3OD):7.79(d,2H,J=9.0Hz),7.00(d,2H,J=9.5Hz),6.95(d,2H,J=8.5Hz),6.90(d,2H,J=9.0Hz),3.61(t,2H,J=5.5Hz),3.42(q,2H,J=7.5Hz),2.91(s,3H),2.57(t,2H,J=5.5Hz),1.14(t,3H,J=7.0Hz)ppm.MS(m/z,APCI):440.2[M-H]-.
14-(4-羟基-苯氧基)-N-甲基-苯甲酰胺
4-(4-羟基-苯氧基)-苯甲酸(0.25g,1.09mmol),三乙胺(0.15mL,1.07mmol)及THF(5.0mL)的混合物在0℃下,加入氯甲酸甲酯(0.084mL,0.10g,1.1mmol)。搅拌15分钟,用喷射管加入过量的甲胺,继续搅拌10分钟。混合物用水稀释,乙酸乙酯萃取三次,合并有机相,Na2SO4干燥,过滤,真空浓缩,得到无色糖浆状的14-(4-羟基-苯氧基)-N-甲基-苯甲酰胺。
1HNMR(CDCl3):7.70(d,2H,J=9.0Hz),6.87(m,6H),2.96(s,3H)ppm.MS(m/z,APCI):244.2[M-H]-.
实施例4
5-[4-(4-氨甲基-苯氧基)-苯氧基]-5-(2-乙氧乙基)-嘧啶-2,4,6三酮
参照实施例1的制备过程,4-(4-氨基甲基苯氧基)-苯酚(0.70g,3.32mmol)与5-溴-5-(2-乙氧乙基)-嘧啶-2,4,6-三酮(0.95g,2.4mmol),1,5,7-traza二环[4.4.0]癸-5-烯(结合到聚苯乙烯与2%DVB的交联物上)(PTBD,Fluka,2.22g)以及11mL乙氰反应,产物经反相HPLC纯化后得到5-[4-(4-氨甲基-苯氧基)-苯氧基-5-(2-乙氧乙基)-嘧啶-2,4,6-三酮(0.180g),为无色的固体化合物。
1H NMR(CD3OD):7.41(d,2H,J=9.0Hz),7.00(d,2H,J=9.0Hz),6.95(d,2H,J=8.5Hz),6.87(d,2H,J=9.0Hz),4.08(s,2H),3.60(t,2H,J=6.5Hz),3.42(q,2H,J=7.5Hz),2.57(t,2H,J=5.5Hz),1.14(t,3H,J=7.0Hz)ppm.
MS(m/z,APCI):414.2[M+H]+.
实施例5
N-(4-{5-[5-(2-乙氧乙基)-2,4,6-三氧-六氢-嘧啶-5-基氧]-吡啶--基
氧)-苄基)-乙酰胺
按照实施例1的制备过程,N-[4-(5-羟基-吡啶-2-基氧)-苄基]-乙酰胺(0.25g,0.97mmol)与5-溴-5-(2-乙氧乙基)-嘧啶-2,4,6-三酮(0.20g,0.80mmol),1,5,7-traza二环[4.4.0]癸-5-烯(连接到聚苯乙烯与2%DVB的交联物上)(PTBD,Fluka,0.77g)及4mL乙氰反应,得到N-(4-{5-[5-(2-乙氧乙基)-2,4,6-三氧-六氢-嘧啶-5-基氧]-吡啶-2基氧}-苯基)-乙酰胺。
MS(m/z,APCl):455[M-H]-.
下列化合物按照实施例1的方法制备,用合适的苯酚(如G-B-Y-A-OH)替代。
Claims (11)
1.式I的化合物,
其中,
A为任选取代的(C6-C10)芳基或(C1-C10)杂芳基;
B为任选取代的(C6-C10)芳基,(C3-C8)环烷基,(C1-C10)杂芳基,(C1-C10)杂环基,(C6-C10)芳基-(C1-C4)烷基,(C3-C8)环烷基-(C1-C4)烷基,(C1-C10)杂芳基-(C1-C4)烷基或(C1-C10)杂环-(C1-C4)烷基;其中任一个前述的(C3-C8)环烷基或(C1-C10)杂环基可以任选包含1-2个双键;
其中A和B上每一个环上可另成键碳原子可以被1-2个取代基独立地任选取代,取代基独立地为F,Cl,Br,CN,OH,(C1-C4)烷基,(C1-C4)全氟取代烷基,(C1-C4)全氟取代烷氧基,(C1-C4)烷氧基和((C3-C8)环烷氧基;
X选自氧,>C=O,S,>SO2,>S=O,>NR10,-CH2O-,-OCH2-,-CH2S-,-CH2(S=O)-,-CH2SO2-,-SCH2-,-SOCH2-,-SO2CH2-,-[N(R10)]CH2-,-CH2[N(R10)]-,-[N(R10)]SO和-SO2[N(R10)]-;
Y选自键,氧,S,>C=O,>SO2,>S=O,>NR12,-CH2-,-CH2O-,-OCH2-,-CH2S-,-CH2(S=O)-,-CH2SO2-,-SCH2-,-(S=O)CH2-,-SO2CH2-,-[N(R12)]CH2-,-CH2[N(R12)],-CH2CH2-,-CH=CH-,-[N(R12)]-SO2-和-SO2[N(R12)]-;
R1为氢,(R2)2n+1-(C)n-或(C3-C8)环烷基,其中(C3-C8)环烷基可以被1-2个取代基任选取代,取代基独立地为卤素,(C1-C4)烷基,(C1-C4)烯基,(C1-C4)炔基,R3,R3-O-,全氟取代(C1-C4)烷氧基,R3-(C1-C4)烷基-O-,R3-(C=O)-O-,(R3)2N-(C=O)-O-,-NO2,(R3)2N-,R3-(C=O)-(NR4)-,R3-(SO2)-(NR4)-,R3O-(C=O)-(NR4)-,(R3)2-N-(C=O)-(NR4)-,R3-S-,R3-(S=O)-,R3-(SO2)-,(R3)2N-(SO2)-,-CN,R3-(C=O)-,R3-O-(C=O)-和(R3)2N-(C=O)-;
n为1-10的整数;
每个R2可以独立地选自卤素,(C1-C4)烯基,(C1-C4)炔基,R3-,R3-O-,全氟取代(C1-C4)烷氧基,R3-(C=O)-O-,(R3)2N-(C=O)-O-,-NO2,(R3)2N-,R3-(SO2)-(NR4)-,(R3)2-N-(C=O)-,R3-(C=O)-(NR4)-,R3O-(C=O)-(NR4)-,(R3)2-N-(C=O)-(NR4)-,R3-S-,R3-(S=O)-,R3-(SO2)-,(R3)2N-(SO2)-,-CN,R3-O-(C=O)-和R3-(C=O)-;其中不多于3个R2取代基不是氢,-(C)n上的任何一个碳原子可以仅与杂原子形成一个键;其中任两个R2的碳原子可以与R2所转接的碳原子一起形成4-10元环;
每个R3可以独立地选自氢,(C1-C4)烷基,(C6-C10)芳基,(C3-C8)环烷基,(C1-C10)杂芳基和(C1-C10)杂环基;其中R3可支持另外取代基的碳原子每个烷基部分上可被1-3个取代基取代,每个环可被1-3个取代基取代,取代基独立地为卤素,羟基,氨基,-CN,(C1-C4)烷基,(C1-C4)烷氧基,(C1-C4)烷基-NH-,[(C1-C4)烷基]2-N-,(C6-C10)芳基,(C3-C8)环烷基,(C1-C10)杂芳基和(C1-C10)杂环基;其中(C3-C8)环烷基和(C1-C10)杂环基可被任选氧代;其中(C1-C10)杂芳基及(C1-C10)杂环基上每个环上任意一个可支持另外取代基的环上氮原子可被1-2个取代基取代,取代基独立地为(C1-C4)烷基,(C1-C4)烷基-(C=O)-,(C6-C10)芳基,(C3-C8)环烷基,(C1-C10)杂芳基和(C1-C10)杂环基;
其中R3任选地与R4形成3-8元环;其中两个R4也可以形成3-8元环;
若出现,R4独立地为氢和(C1-C4)烷基;
G为R5-或R6-(CHR13)p-;其中G为B上可另成键环碳原子的取代基,取代位置为B环与Y相连位置的邻位以外的其他位置;
p为1-6的整数;
其中R5选自R7-,R11-O-,R7-(C1-C4)烷基-O-,R8-(C=O)-O-,H2N(C=O)-O-,R8-NH(C=O)-O-,(R8)2N(C=O)-O-,R8-S-,R8-(S=O)-,R8(SO2)-,H2N-(SO2)-,R8-NH-(SO2)-,(R8)2N-(SO2)-,甲酰基,R8-(C=O)-,HO-(C=O)-,R8-O-(C=O)-,H2N-(C=O)-,R8NH-(C=O)-,(R8)2N-(C=O)-,-NO2,NH2,R8-NH-,(R8)2N-,H(C=O)-(NR9)-,R8-(C=O)-(NR9)-,H2N-(C=O)-(NR9)-,R8NH-(C=O)-(NR9)-,(R8)2N-(C=O)-(NR9)-,R8O-(C=O)-(NR9)-,R8-(C=O)-(NR9)-,R8-(SO2)-NH-和R8-(SO2)-(NR9)-;
R6选自(C1-C4)烯基,(C1-C4)炔基,R7,OH,R8-O-,R8-(C1-C4)烷基-O-,全氟取代(C1-C4)烷氧基,R8-(C=O)-O-,H2N(C=O)-O-,R8-NH(C=O)-O-,(R8)2N(C=O)-O-,R8-S-,R8-(S=O)-,R8-(SO2)-,H2N-(SO2)-,R8-NH-(SO2)-,(R8)2N-(SO2)-,甲酰基,-CN,R8-(C=O)-,HO-(C=O)-,R8-O-(C=O)-,H2N-(C=O)-,R8NH-(C=O)-,(R8)2N-(C=O)-,-NO2,NH2,R8-NH-,(R8)2N-,H(C=O)-(NR9)-,R8-(C=O)-(NR9)-,H2N-(C=O)-(NR9)-,R8NH-(C=O)-(NR9)-,(R8)2N-(C=O)-(NR9)-,R8O-(C=O)-(NR9)-,R8-(SO2)-NH-和R8-(SO2)-(NR9)-;
R7选自(C6-C10)芳基,(C3-C8)环烷基,(C1-C10)杂芳基和(C1-C10)杂环基;其中(C6-C10)芳基,(C3-C8)环烷基,(C1-C10)杂芳基和(C1-C10)杂环基部分每个环上可另成键碳原子可以被1-3取代基任选取代,取代基独立地为F,Cl,Br,CN,OH,(C1-C4)烷基,(C1-C4)全氟取代烷基,(C1-C4)全氟取代烷氧基,(C1-C4)烷氧基,氨基,(C1-C4)烷基-NH-,[(C1-C4)烷基]2-N-和(C3-C8)环烷氧基;其中(C3-C8)环烷基和(C1-C10)杂环基部分可以任选地被氧代;其中(C1-C10)杂芳基和(C1-C10)杂环基上每个环上可支持另外取代基的环氮原子可被1-2个取代基任选取代,取代基独立地为(C1-C4)烷基及(C1-C4)烷基-(C=O)-;
R8选自(C1-C4)烷基,(C6-C10)芳基,(C3-C8)环烷基,(C1-C10)杂芳基和(C1-C10)杂环基;其中每个R8中,可支持另外取代基的碳原子每烷基部分可被1-3个取代基任选取代,每环上可被1~3个取代基任选取代,取代基独立地为F,Cl,Br,CN,OH,(C1-C4)烷基,(C1-C4)全氟取代烷基,(C1-C4)全氟取代烷氧基,(C1-C4)烷氧基和(C3-C8)环烷基氧;其中(C3-C8)环烷基和(C1-C10)杂环基可任选被氧代;其中(C1-C10)杂芳基和(C1-C10)杂环基任何一个环上可支持另外取代基的环氮原子可被1-2个取代基任选取代,取代基独立地为(C1-C4)烷基和(C1-C4)烷基-(C=O)-;其中两个R8可以与其所连接的杂原子任选形成3~8元环;
若出现,R9独立地为氢和(C1-C4)烷基;其中R8和R9可以与其所连接的杂原子任选形成3-8元环;
R10出现时独立地为氢和(C1-C4)烷基;
R11选自(C6-C10)芳基,(C1-C10)杂芳基和(C1-C10)杂环基;其中(C6-C10)芳基,(C1-C10)杂芳基和(C1-C10)杂环基部分每一个环上可另成键环碳原子可被1-3个取代基任选取代,取代基选自F,Cl,Br,CN,OH,(C1-C4)烷基,(C1-C4)全氟取代烷基,(C1-C4)全氟取代烷氧基,(C1-C4)烷氧基和(C3-C8)环烷基氧;其中(C1-C10)杂环基可任选地被氧代;其中(C1-C10)杂芳基和(C1-C10)杂环基每环上任一个可支持另外取代基的环氮原子可被1-2个取代基任选取代,取代基独立地为(C1-C4)烷基和(C1-C4)烷基-(C=O)-;
R12出现时独立地选自氢和(C1-C4)烷基;
R13可以独立地选自氢和(C1-C4)烷基;其中,R13可以任选与R6形成4-1O元环;
以及上述化合物的药用盐。
2.如权利要求1所述的化合物,其中X为氧,-OCH2-或-CH2O-。
3.如权利要求1-2中任一项所述的化合物,其中Y为氧,-OCH2-或-CH2O-。
4.如权利要求1-3中任一项所述的化合物,其中A为任选取代的苯基。
5.如权利要求1-4中任一项所述的化合物,其中,B为任选取代的苯基(C1-C10)杂芳基。
6.如权利要求1-5中任一项所述的化合物,其中G为R5-。
7.如权利要求1-6中任一项所述的化合物,其中R5-为R7,R7为(C1-C10)杂芳基。
8.如权利要求1-7中任一项所述的化合物,其中R1为(R2)2n+1(C)n-,n为1-10的整数。
至少一个R2独立地选自R3-,R3O-,(R3)2N-,R3S-,R3-(S=O)-,R3(SO2)-,R3-(SO2)-(NR4)-,R3-NH-(SO2)-,(R3)2N-(SO2)-,R3-(C=O)-(NR4)-,R3-(C=O)-O-,R3-O-(C=O)-和R3-(C=O)-;和
每个R3独立地选自氢和(C1-C4)烷基;每个R3的(C1-C4)烷基部分可以任选被1~3个取代基任选取代,取代基可以独立地为卤素,羟基,氨基,-CN,(C1-C4)烷基,(C1-C4)烷氧基,(C1-C4)烷基-NH-,[(C1-C4)烷基]2-N-,(C6-C10)芳基,(C3-C8)环烷基,(C1-C10)杂芳基和(C1-C10)杂环基;其中R3可任选地与R4形成3-8元环。
9.如权利要求1所述的化合物,其中化合物为:
5-(2-乙氧乙基)-5-[4-(4-噻唑-2-基-苯氧基)-苯氧基]-嘧啶-2,4,6-三酮;
5-(2-乙氧乙基)-5-{4-[4-(2-甲基-2H-吡唑-3-基)-苯氧基]-苯氧基}-嘧啶-2,4,6-三酮;
5-(2-乙氧乙基)-5-{4-[4-(1-甲基-1H-吡唑-3-基)-苯氧基]-苯氧基}-嘧啶-2,4,6-三酮;
5-(4-{4-[5-(2-乙氧乙基)-2,4,6-三氧-六氢-嘧啶-5-基氧]-苯氧基}苯基)-戊腈;
5-(2-乙氧乙基)-5-{4-[4-(2-甲基-噻唑-4-基)-苯氧基]-苯氧基}-嘧啶-2,4,6-三酮;
5-(2-乙氧乙基)-5-{4-[4-(1H-吡唑-3-基)-苯氧基]-苯氧基}-嘧啶-2,4,6三酮;
5-(2-乙氧乙基)-5-[4-(4-噁唑-5-基-苯氧基)-苯氧基]-嘧啶-2,4,6-三酮;
及5-(2-乙氧乙基)-5-[4-(4-嘧啶-4-基-苯氧基)-苯氧基]-嘧啶-2,4,6-三酮;
以及上述化合物的药用盐。
10.一种用于治疗包括人在内的哺乳动物的疾病的药物组合物,所述疾病选自结缔组织疾病,炎性疾病,免疫/过敏疾病,传染性疾病,呼吸系统疾病,心血管疾病,眼类疾病,代谢疾病,中枢神经系统(CNS)疾病,肝/肾疾病,生殖健康疾病,胃疾病,皮肤疾病和肿瘤;该组合物包含一定量对上述疾病有效的如权利要求1-9任何一项所述的化合物及其药用载体。
11.一种治疗包括人在内的哺乳动物的疾病的方法,所述疾病选自结缔组织疾病,炎性疾病,免疫/过敏疾病,传染性疾病,呼吸系统疾病,心血管疾病,眼类疾病,代谢疾病,中枢神经系统(CNS)疾病,肝/肾疾病,生殖健康疾病,胃疾病,皮肤疾病和肿瘤,该方法包含用对上述疾病有效的如权利要求1-10任何一项所述的化合物对所述哺乳动物给药。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US24331400P | 2000-10-26 | 2000-10-26 | |
PCT/IB2001/001953 WO2002034726A2 (en) | 2000-10-26 | 2001-10-17 | Pyrimidine-2,4,6-trione metalloproteinase inhibitors |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1714084A true CN1714084A (zh) | 2005-12-28 |
Family
ID=36950891
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNA018180841A Pending CN1714084A (zh) | 2000-10-26 | 2001-10-17 | 嘧啶-2,4,6-三酮类金属蛋白酶抑制剂 |
Country Status (36)
Country | Link |
---|---|
US (2) | US6706723B2 (zh) |
EP (1) | EP1332136A2 (zh) |
JP (1) | JP2004512327A (zh) |
KR (1) | KR20030061825A (zh) |
CN (1) | CN1714084A (zh) |
AP (1) | AP2001002319A0 (zh) |
AR (1) | AR035362A1 (zh) |
AU (1) | AU2002210800A1 (zh) |
BG (1) | BG107651A (zh) |
BR (1) | BR0114917A (zh) |
CA (1) | CA2425280A1 (zh) |
CR (1) | CR6939A (zh) |
CZ (1) | CZ20031069A3 (zh) |
EA (1) | EA200300409A1 (zh) |
EC (1) | ECSP034568A (zh) |
EE (1) | EE200300195A (zh) |
GT (1) | GT200100214A (zh) |
HN (1) | HN2001000243A (zh) |
HR (1) | HRP20030331A2 (zh) |
HU (1) | HUP0302337A3 (zh) |
IL (1) | IL154946A0 (zh) |
IS (1) | IS6749A (zh) |
MA (1) | MA26956A1 (zh) |
MX (1) | MXPA03003734A (zh) |
NO (1) | NO20031852L (zh) |
NZ (1) | NZ524774A (zh) |
OA (1) | OA12528A (zh) |
PA (1) | PA8531501A1 (zh) |
PE (1) | PE20020585A1 (zh) |
PL (1) | PL362919A1 (zh) |
SK (1) | SK4872003A3 (zh) |
SV (1) | SV2003000704A (zh) |
TN (1) | TNSN01150A1 (zh) |
UY (1) | UY26981A1 (zh) |
WO (1) | WO2002034726A2 (zh) |
ZA (1) | ZA200302192B (zh) |
Families Citing this family (50)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL152021A0 (en) * | 2000-04-11 | 2003-04-10 | Sankyo Co | Pharmaceutical compositions containing pyridine derivatives |
BR0114917A (pt) * | 2000-10-26 | 2003-07-01 | Pfizer Prod Inc | Inibidores de pirimidina-2,4,6-triona metaloproteinase |
JP2004518726A (ja) | 2001-02-14 | 2004-06-24 | ワーナー−ランバート・カンパニー、リミテッド、ライアビリティ、カンパニー | ベンゾチアジアジンマトリックスメタロプロテイナーゼ阻害剤 |
DOP2002000332A (es) | 2001-02-14 | 2002-08-30 | Warner Lambert Co | Inhibidores de piridina de metaloproteinasas de la matriz |
PA8539501A1 (es) | 2001-02-14 | 2002-09-30 | Warner Lambert Co | Compuestos triazolo como inhibidores de mmp |
BR0207209A (pt) | 2001-02-14 | 2004-01-27 | Warner Lambert Co | Inibidores de metaloproteinase de matriz de pirimidina |
DOP2002000333A (es) | 2001-02-14 | 2002-09-30 | Warner Lambert Co | Derivados de acido isoftalico como inhibidores de metaloproteinasas de la matriz |
US6924276B2 (en) | 2001-09-10 | 2005-08-02 | Warner-Lambert Company | Diacid-substituted heteroaryl derivatives as matrix metalloproteinase inhibitors |
US6962922B2 (en) | 2001-10-12 | 2005-11-08 | Warner-Lambert Company Llc | Alkynylated quinazoline compounds |
EP1434585A1 (en) | 2001-10-12 | 2004-07-07 | Warner-Lambert Company LLC | Alkyne matrix metalloproteinase inhibitors |
WO2003053940A1 (en) | 2001-12-20 | 2003-07-03 | Bristol-Myers Squibb Company | Barbituric acid derivatives as inhibitors of tnf-$g(a) converting enzyme (tace) and/or matrix metalloproteinases |
WO2003053941A2 (en) * | 2001-12-20 | 2003-07-03 | Bristol-Myers Squibb Company | Barbituric acid derivatives as inhibitors of tnf-alpha converting enzyme (tace) and/or matrix metalloproteinases |
US6894057B2 (en) | 2002-03-08 | 2005-05-17 | Warner-Lambert Company | Oxo-azabicyclic compounds |
CA2480092A1 (en) * | 2002-04-26 | 2003-11-06 | Pfizer Products Inc. | N-substituted-heteroaryloxy-aryl-spiro-pyrimidine-2,4,6-trione metalloproteinase inhibitors |
CA2483075A1 (en) | 2002-04-26 | 2003-11-06 | Pfizer Products Inc. | Triaryl-oxy-aryl-spiro-pyrimidine-2, 4, 6-trione metalloproteinase inhibitors |
CA2483500A1 (en) * | 2002-04-26 | 2003-11-06 | Pfizer Products Inc. | Pyrimidine-2, 4, 6-trione metallo-proteinase inhibitors |
NI200300045A (es) | 2002-04-26 | 2005-07-08 | Pfizer Prod Inc | Inhibidores de triariloxiariloxipirimidin-2,4,6-triona de metaloproteinasa. |
MXPA05001783A (es) | 2002-08-13 | 2005-04-25 | Warner Lambert Co | Derivados de pirimidina-2,4-diona como inhibidores de las metaloproteinasas de matriz. |
WO2004014908A1 (en) | 2002-08-13 | 2004-02-19 | Warner-Lambert Company Llc | Heterobicylcic metalloproteinase inhibitors |
WO2004014923A1 (en) | 2002-08-13 | 2004-02-19 | Warner-Lambert Company Llc | Pyrimidinone fused bicyclic metalloproteinase inhibitors |
AU2003249540A1 (en) | 2002-08-13 | 2004-02-25 | Warner-Lambert Company Llc | Fused bicyclic metalloproteinase inhibitors |
MXPA05001785A (es) | 2002-08-13 | 2005-04-25 | Warner Lambert Co | Derivados de cromona como inhibidores de las metaloproteinasas de matriz. |
WO2004014378A1 (en) | 2002-08-13 | 2004-02-19 | Warner-Lambert Company Llc | 3-isoquinolinone derivatives as matrix metalloproteinase inhiitors |
JP2006504665A (ja) | 2002-08-13 | 2006-02-09 | ワーナー−ランバート・カンパニー、リミテッド、ライアビリティ、カンパニー | マトリックスメタロプロテイナーゼ阻害剤としてのアザイソキノリン誘導体 |
PA8578101A1 (es) | 2002-08-13 | 2004-05-07 | Warner Lambert Co | Derivados de heterobiarilo como inhibidores de metaloproteinasa de la matriz |
AU2003253186A1 (en) | 2002-08-13 | 2004-02-25 | Warner-Lambert Company Llc | Fused tetrahydropyridine derivatives as matrix metalloproteinase inhibitors |
JP2006501215A (ja) | 2002-08-13 | 2006-01-12 | ワーナー−ランバート・カンパニー、リミテッド、ライアビリティ、カンパニー | マトリックスメタロプロテイナーゼ阻害剤としての単環式誘導体 |
GB0223249D0 (en) * | 2002-10-08 | 2002-11-13 | Amersham Plc | Improved imaging agents |
WO2004084903A1 (en) * | 2003-03-27 | 2004-10-07 | F. Hoffmann-La Roche Ag | Use of a trioxopyrimidine for the treatment and prevention of ocular pathologic angiogenesis |
WO2004084902A1 (en) * | 2003-03-28 | 2004-10-07 | F. Hoffmann-La Roche Ag | Use of a trioxopyrimidine for the treatment of chronic wounds |
EP1613269B1 (en) | 2003-04-04 | 2015-02-25 | Incyte Corporation | Compositions, methods and kits relating to her-2 cleavage |
JP4584981B2 (ja) * | 2004-04-01 | 2010-11-24 | ユニベルシテ・ド・リエージュ | 気管支炎症疾患の処置および予防のためのトリオキソピリミジンの使用 |
DE602005025755D1 (de) | 2004-06-04 | 2011-02-17 | Teva Pharma | Irbesartan enthaltende pharmazeutische zusammensetzung |
TW200806648A (en) * | 2005-11-29 | 2008-02-01 | Sankyo Co | Acid addition salts of dihydropyridine derivatives |
TW200736245A (en) * | 2005-11-29 | 2007-10-01 | Sankyo Co | Acid addition salts of optically active dihydropyridine derivatives |
EP3144299A1 (en) | 2009-05-05 | 2017-03-22 | Cambria Pharmaceuticals, Inc. | Pyrimidine-2,4,6-triones for use in the treatment of amyotrophic lateral sclerosis |
RU2400233C1 (ru) | 2009-07-07 | 2010-09-27 | Общество с ограниченной ответственностью "Вирфарм" | Способ лечения заболеваний печени различного генеза |
KR101301533B1 (ko) * | 2010-02-09 | 2013-09-04 | 한미사이언스 주식회사 | 암세포 성장 억제 효과를 갖는 신규 피리미딘 유도체 |
CN103415513B (zh) | 2011-03-14 | 2016-01-20 | 勃林格殷格翰国际有限公司 | 白三烯产物的苯并二氧杂环己烷抑制剂 |
JP5987220B2 (ja) * | 2011-07-19 | 2016-09-07 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | ロイコトリエンa4ヒドロラーゼの阻害剤としてのアリールピラゾールエーテル |
CA2866471A1 (en) | 2012-03-06 | 2013-09-12 | Boehringer Ingelheim International Gmbh | Benzodioxanes in combination with other actives for inhibiting leukotriene production |
EP2822942B1 (en) | 2012-03-06 | 2017-05-10 | Boehringer Ingelheim International GmbH | Benzodioxanes for inhibiting leukotriene production |
JP6256467B2 (ja) | 2012-07-17 | 2018-01-10 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | ロイコトリエン生成を阻害するピラゾール誘導体 |
RU2644250C2 (ru) * | 2012-09-14 | 2018-02-08 | Элизабет ЛЕВИНА | Лекарственное средство с активностью против грамположительных бактерий, микобактерий и грибов |
TW201512171A (zh) | 2013-04-19 | 2015-04-01 | Pfizer Ltd | 化學化合物 |
WO2015009611A1 (en) | 2013-07-15 | 2015-01-22 | Boehringer Ingelheim International Gmbh | Inhibitors of leukotriene production |
EP3022193B1 (en) | 2013-07-15 | 2017-04-26 | Boehringer Ingelheim International GmbH | Inhibitors of leukotriene production |
WO2018002673A1 (en) | 2016-07-01 | 2018-01-04 | N4 Pharma Uk Limited | Novel formulations of angiotensin ii receptor antagonists |
CN112955439A (zh) * | 2018-08-24 | 2021-06-11 | 赛尼欧普罗有限责任公司 | 用于治疗病理状况的芳族分子 |
US11957671B2 (en) | 2021-11-01 | 2024-04-16 | Alkahest, Inc. | Benzodioxane modulators of leukotriene A4 hydrolase (LTA4H) for prevention and treatment of aging-associated diseases |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE19548624A1 (de) | 1995-12-23 | 1997-06-26 | Boehringer Mannheim Gmbh | Neue Barbitursäure-Derivate, Verfahren zu deren Herstellung und diese Verbindungen enthaltende Arzneimittel |
DE69831233T2 (de) * | 1997-06-21 | 2006-06-01 | Roche Diagnostics Gmbh | Barbitursaure derivaten mit antimetastatischer und antitumorischer wirkung |
DE19726427A1 (de) | 1997-06-23 | 1998-12-24 | Boehringer Mannheim Gmbh | Pyrimidin-2,4,6-trion-Derivate, Verfahren zu deren Herstellung und diese Verbindungen enthaltende Arzneimittel |
US6265578B1 (en) * | 1999-02-12 | 2001-07-24 | Hoffmann-La Roche Inc. | Pyrimidine-2,4,6-triones |
PA8498701A1 (es) * | 1999-08-12 | 2002-08-26 | Pfizer Prod Inc | Pirimidina-2,4,6-trionas inhibidores de metaloproteinasas |
BR0114917A (pt) * | 2000-10-26 | 2003-07-01 | Pfizer Prod Inc | Inibidores de pirimidina-2,4,6-triona metaloproteinase |
-
2001
- 2001-10-17 BR BR0114917-2A patent/BR0114917A/pt not_active IP Right Cessation
- 2001-10-17 EE EEP200300195A patent/EE200300195A/xx unknown
- 2001-10-17 EA EA200300409A patent/EA200300409A1/ru unknown
- 2001-10-17 SK SK487-2003A patent/SK4872003A3/sk unknown
- 2001-10-17 WO PCT/IB2001/001953 patent/WO2002034726A2/en not_active Application Discontinuation
- 2001-10-17 KR KR10-2003-7005756A patent/KR20030061825A/ko not_active Application Discontinuation
- 2001-10-17 CZ CZ20031069A patent/CZ20031069A3/cs unknown
- 2001-10-17 PL PL01362919A patent/PL362919A1/xx not_active Application Discontinuation
- 2001-10-17 AP APAP/P/2001/002319A patent/AP2001002319A0/en unknown
- 2001-10-17 NZ NZ524774A patent/NZ524774A/en unknown
- 2001-10-17 OA OA1200300122A patent/OA12528A/en unknown
- 2001-10-17 HU HU0302337A patent/HUP0302337A3/hu unknown
- 2001-10-17 AU AU2002210800A patent/AU2002210800A1/en not_active Abandoned
- 2001-10-17 JP JP2002537717A patent/JP2004512327A/ja not_active Withdrawn
- 2001-10-17 CA CA002425280A patent/CA2425280A1/en not_active Abandoned
- 2001-10-17 EP EP01978707A patent/EP1332136A2/en not_active Withdrawn
- 2001-10-17 IL IL15494601A patent/IL154946A0/xx unknown
- 2001-10-17 CN CNA018180841A patent/CN1714084A/zh active Pending
- 2001-10-17 MX MXPA03003734A patent/MXPA03003734A/es unknown
- 2001-10-23 UY UY26981A patent/UY26981A1/es not_active Application Discontinuation
- 2001-10-24 AR ARP010104976A patent/AR035362A1/es unknown
- 2001-10-24 PE PE2001001051A patent/PE20020585A1/es not_active Application Discontinuation
- 2001-10-24 HN HN2001000243A patent/HN2001000243A/es unknown
- 2001-10-25 US US10/032,837 patent/US6706723B2/en not_active Expired - Fee Related
- 2001-10-25 GT GT200100214A patent/GT200100214A/es unknown
- 2001-10-25 TN TNTNSN01150A patent/TNSN01150A1/fr unknown
- 2001-10-25 SV SV2001000704A patent/SV2003000704A/es unknown
- 2001-10-26 PA PA20018531501A patent/PA8531501A1/es unknown
-
2003
- 2003-03-17 IS IS6749A patent/IS6749A/is unknown
- 2003-03-19 ZA ZA200302192A patent/ZA200302192B/en unknown
- 2003-03-20 BG BG107651A patent/BG107651A/bg unknown
- 2003-03-26 CR CR6939A patent/CR6939A/es not_active Application Discontinuation
- 2003-04-21 MA MA27114A patent/MA26956A1/fr unknown
- 2003-04-24 NO NO20031852A patent/NO20031852L/no not_active Application Discontinuation
- 2003-04-25 EC EC2003004568A patent/ECSP034568A/es unknown
- 2003-04-28 HR HR20030331A patent/HRP20030331A2/hr not_active Application Discontinuation
-
2004
- 2004-02-13 US US10/778,990 patent/US20050107414A1/en not_active Abandoned
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1714084A (zh) | 嘧啶-2,4,6-三酮类金属蛋白酶抑制剂 | |
CN1097051C (zh) | N-杂芳基吡啶磺酰胺衍生物及其作为内皮素拮抗剂的用途 | |
CN1263755C (zh) | 作为选择性cox-2抑制剂的吡唑并吡啶衍生物 | |
CN1067071C (zh) | 咔啉衍生物 | |
CN1214008C (zh) | 治疗用的联芳基衍生物 | |
CN1501937A (zh) | 螺-嘧啶-2,4,6-三酮金属蛋白酶抑制剂 | |
CN1549817A (zh) | 作为半胱氨酸蛋白酶抑制剂的吡咯并嘧啶化合物 | |
CN1929848A (zh) | 用于治疗或预防rsv感染的苯并二氮杂䓬 | |
CN1649863A (zh) | 具有cdk抑制活性的4-(咪唑-5-基)-2-(4-磺基苯胺基)嘧啶衍生物 | |
CN1795174A (zh) | 新型取代的3-硫吲哚 | |
CN1745063A (zh) | 阻碍二肽基肽酶ⅳ的化合物 | |
CN1582277A (zh) | 用作糖原合酶激酶3β抑制剂的酰胺衍生物 | |
CN1316995A (zh) | 用作mmp抑制剂的羟基2-哌啶酸酯异羟肟酸衍生物 | |
CN86108308A (zh) | 杂环氧代-2,3-二氮杂萘基乙酸 | |
CN1431999A (zh) | 具有血管损伤活性的吲哚衍生物 | |
CN1009645B (zh) | 7-氧杂二环庚烷取代的二酰胺及其同种类前列腺素类似物制造方法 | |
CN1542002A (zh) | 金属蛋白酶抑制剂,含有它们的药物组合物和其药物用途,其制备方法和中间体 | |
CN1294126C (zh) | N-苯基芳基磺酰胺化合物、包括该化合物作为活性成分的药物组合物、该化合物的合成中间体及其制备方法 | |
CN1034864C (zh) | 咪唑烷-4-酮和噻唑烷-4-酮的衍生物的制备方法 | |
CN1642927A (zh) | 环状酰胺 | |
CN1738806A (zh) | 氧代-氮杂双环化合物 | |
CN85108556A (zh) | 新型苯并唑基及苯并噻唑基胺类衍生物的制备方法及其应用 | |
CN1303072C (zh) | 7-氧代吡啶并嘧啶 | |
CN1250542C (zh) | 具有抗肿瘤活性的2-(1h-吲哚-3-基)-2-氧代-乙酰胺 | |
CN1058401A (zh) | 抗肿瘤组合物和治疗方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |