JPWO2016171165A1 - カスパーゼ1活性化阻害剤 - Google Patents
カスパーゼ1活性化阻害剤 Download PDFInfo
- Publication number
- JPWO2016171165A1 JPWO2016171165A1 JP2017514157A JP2017514157A JPWO2016171165A1 JP WO2016171165 A1 JPWO2016171165 A1 JP WO2016171165A1 JP 2017514157 A JP2017514157 A JP 2017514157A JP 2017514157 A JP2017514157 A JP 2017514157A JP WO2016171165 A1 JPWO2016171165 A1 JP WO2016171165A1
- Authority
- JP
- Japan
- Prior art keywords
- hydrogen atom
- group
- atom
- alkyl group
- fluorine atom
- 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.)
- Granted
Links
- 108090000426 Caspase-1 Proteins 0.000 title claims abstract description 31
- 102100035904 Caspase-1 Human genes 0.000 title claims abstract description 31
- 230000004913 activation Effects 0.000 title claims abstract description 28
- 239000003112 inhibitor Substances 0.000 title claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 115
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 49
- 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 49
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 44
- 150000001875 compounds Chemical class 0.000 claims abstract description 43
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 23
- 201000010099 disease Diseases 0.000 claims abstract description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 17
- 230000002265 prevention Effects 0.000 claims abstract description 10
- 125000002252 acyl group Chemical group 0.000 claims description 37
- 239000003814 drug Substances 0.000 claims description 31
- 108010034143 Inflammasomes Proteins 0.000 claims description 26
- 125000004423 acyloxy group Chemical group 0.000 claims description 20
- 230000015572 biosynthetic process Effects 0.000 claims description 16
- 239000004480 active ingredient Substances 0.000 claims description 13
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
- 208000035475 disorder Diseases 0.000 claims description 5
- 208000015181 infectious disease Diseases 0.000 claims description 5
- 206010051379 Systemic Inflammatory Response Syndrome Diseases 0.000 claims description 4
- 208000011580 syndromic disease Diseases 0.000 claims description 4
- 208000023275 Autoimmune disease Diseases 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 102100022691 NACHT, LRR and PYD domains-containing protein 3 Human genes 0.000 claims description 3
- 206010028980 Neoplasm Diseases 0.000 claims description 3
- 208000036142 Viral infection Diseases 0.000 claims description 3
- 201000011510 cancer Diseases 0.000 claims description 3
- 230000030833 cell death Effects 0.000 claims description 3
- 208000030172 endocrine system disease Diseases 0.000 claims description 3
- 230000001506 immunosuppresive effect Effects 0.000 claims description 3
- 208000027866 inflammatory disease Diseases 0.000 claims description 3
- 230000004770 neurodegeneration Effects 0.000 claims description 3
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 3
- 210000000056 organ Anatomy 0.000 claims description 3
- 230000005855 radiation Effects 0.000 claims description 3
- 230000009385 viral infection Effects 0.000 claims description 3
- 208000024827 Alzheimer disease Diseases 0.000 claims description 2
- 208000033116 Asbestos intoxication Diseases 0.000 claims description 2
- 241001475178 Dira Species 0.000 claims description 2
- 208000017701 Endocrine disease Diseases 0.000 claims description 2
- 206010016207 Familial Mediterranean fever Diseases 0.000 claims description 2
- 208000009777 Majeed syndrome Diseases 0.000 claims description 2
- 101710126825 NACHT, LRR and PYD domains-containing protein 3 Proteins 0.000 claims description 2
- 201000008470 PAPA syndrome Diseases 0.000 claims description 2
- 206010072222 Pyogenic sterile arthritis pyoderma gangrenosum and acne syndrome Diseases 0.000 claims description 2
- 230000001154 acute effect Effects 0.000 claims description 2
- 206010003441 asbestosis Diseases 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 2
- 210000004969 inflammatory cell Anatomy 0.000 claims description 2
- 208000025487 periodic fever syndrome Diseases 0.000 claims description 2
- 208000022638 pyogenic arthritis-pyoderma gangrenosum-acne syndrome Diseases 0.000 claims description 2
- 239000003169 respiratory stimulant agent Substances 0.000 claims description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 2
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 claims description 2
- 208000026082 sterile multifocal osteomyelitis with periostitis and pustulosis Diseases 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims 2
- 229910052739 hydrogen Inorganic materials 0.000 claims 2
- 239000001257 hydrogen Substances 0.000 claims 2
- 230000000306 recurrent effect Effects 0.000 claims 1
- 208000011594 Autoinflammatory disease Diseases 0.000 abstract description 9
- 208000037976 chronic inflammation Diseases 0.000 abstract description 7
- 230000006020 chronic inflammation Effects 0.000 abstract description 7
- 239000008177 pharmaceutical agent Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 99
- 239000002904 solvent Substances 0.000 description 63
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- 239000000243 solution Substances 0.000 description 51
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 44
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 42
- 239000000203 mixture Substances 0.000 description 36
- 230000002829 reductive effect Effects 0.000 description 36
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
- 230000000638 stimulation Effects 0.000 description 33
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 30
- 238000000034 method Methods 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 26
- 238000010898 silica gel chromatography Methods 0.000 description 25
- 210000004027 cell Anatomy 0.000 description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- 230000008569 process Effects 0.000 description 19
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 18
- 230000002401 inhibitory effect Effects 0.000 description 18
- 229920006395 saturated elastomer Polymers 0.000 description 18
- 230000028327 secretion Effects 0.000 description 15
- 235000017557 sodium bicarbonate Nutrition 0.000 description 15
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 15
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000002609 medium Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- OCLOLUFOLJIQDC-UHFFFAOYSA-N 1,5-AF Natural products OCC1OCC(=O)C(O)C1O OCLOLUFOLJIQDC-UHFFFAOYSA-N 0.000 description 10
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 241000699666 Mus <mouse, genus> Species 0.000 description 9
- 210000004979 bone marrow derived macrophage Anatomy 0.000 description 9
- 239000012043 crude product Substances 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 210000002540 macrophage Anatomy 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000012228 culture supernatant Substances 0.000 description 8
- DANUORFCFTYTSZ-UHFFFAOYSA-N epinigericin Natural products O1C2(C(CC(C)(O2)C2OC(C)(CC2)C2C(CC(O2)C2C(CC(C)C(O)(CO)O2)C)C)C)C(C)C(OC)CC1CC1CCC(C)C(C(C)C(O)=O)O1 DANUORFCFTYTSZ-UHFFFAOYSA-N 0.000 description 8
- DANUORFCFTYTSZ-BIBFWWMMSA-N nigericin Chemical compound C([C@@H]1C[C@H]([C@H]([C@]2([C@@H](C[C@](C)(O2)C2O[C@@](C)(CC2)C2[C@H](CC(O2)[C@@H]2[C@H](C[C@@H](C)[C@](O)(CO)O2)C)C)C)O1)C)OC)[C@H]1CC[C@H](C)C([C@@H](C)C(O)=O)O1 DANUORFCFTYTSZ-BIBFWWMMSA-N 0.000 description 8
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
- 235000019341 magnesium sulphate Nutrition 0.000 description 7
- 102100029647 Apoptosis-associated speck-like protein containing a CARD Human genes 0.000 description 6
- -1 cyclic ether compound Chemical class 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 206010061218 Inflammation Diseases 0.000 description 5
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 5
- 239000012300 argon atmosphere Substances 0.000 description 5
- 238000011534 incubation Methods 0.000 description 5
- 230000004054 inflammatory process Effects 0.000 description 5
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 5
- 235000019345 sodium thiosulphate Nutrition 0.000 description 5
- 239000006228 supernatant Substances 0.000 description 5
- SCHZCUMIENIQMY-UHFFFAOYSA-N tris(trimethylsilyl)silicon Chemical compound C[Si](C)(C)[Si]([Si](C)(C)C)[Si](C)(C)C SCHZCUMIENIQMY-UHFFFAOYSA-N 0.000 description 5
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 4
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 4
- YLMXRRAEDIWQKG-UHFFFAOYSA-N 6-(hydroxymethyl)-4H-pyran-3-one Chemical compound OCC1=CCC(CO1)=O YLMXRRAEDIWQKG-UHFFFAOYSA-N 0.000 description 4
- 108010076667 Caspases Proteins 0.000 description 4
- 102000011727 Caspases Human genes 0.000 description 4
- 102000053602 DNA Human genes 0.000 description 4
- 108020004414 DNA Proteins 0.000 description 4
- 239000012591 Dulbecco’s Phosphate Buffered Saline Substances 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- 108010002352 Interleukin-1 Proteins 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- 102000012064 NLR Proteins Human genes 0.000 description 4
- 108091005686 NOD-like receptors Proteins 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 229920001429 chelating resin Polymers 0.000 description 4
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 4
- 230000028709 inflammatory response Effects 0.000 description 4
- 239000003456 ion exchange resin Substances 0.000 description 4
- 229920003303 ion-exchange polymer Polymers 0.000 description 4
- 230000037361 pathway Effects 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 229920005989 resin Polymers 0.000 description 4
- 239000011347 resin Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 3
- HEVMDQBCAHEHDY-UHFFFAOYSA-N (Dimethoxymethyl)benzene Chemical compound COC(OC)C1=CC=CC=C1 HEVMDQBCAHEHDY-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 3
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 229940125773 compound 10 Drugs 0.000 description 3
- 231100000673 dose–response relationship Toxicity 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- LALRXNPLTWZJIJ-UHFFFAOYSA-N triethylborane Chemical compound CCB(CC)CC LALRXNPLTWZJIJ-UHFFFAOYSA-N 0.000 description 3
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 2
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 2
- KEJGAYKWRDILTF-VVULQXIFSA-N (3ar,5s,6r,6ar)-5-[(4r)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-6-ol Chemical compound O1C(C)(C)OC[C@@H]1[C@@H]1[C@@H](O)[C@H]2OC(C)(C)O[C@H]2O1 KEJGAYKWRDILTF-VVULQXIFSA-N 0.000 description 2
- ATVAXTJIRCBICU-PHDIDXHHSA-N (5R,6R)-5-hydroxy-6-(hydroxymethyl)oxan-3-one Chemical compound C1[C@@H](O)[C@@H](CO)OCC1=O ATVAXTJIRCBICU-PHDIDXHHSA-N 0.000 description 2
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 2
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 2
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 229940126657 Compound 17 Drugs 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 2
- 102100023435 NLR family CARD domain-containing protein 4 Human genes 0.000 description 2
- 102000007399 Nuclear hormone receptor Human genes 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 2
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 2
- LPTITAGPBXDDGR-LYYZXLFJSA-N [(2r,3s,4s,5r,6s)-3,4,5,6-tetraacetyloxyoxan-2-yl]methyl acetate Chemical compound CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O LPTITAGPBXDDGR-LYYZXLFJSA-N 0.000 description 2
- 239000002250 absorbent Substances 0.000 description 2
- 230000002745 absorbent Effects 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000005129 aryl carbonyl group Chemical group 0.000 description 2
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 2
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 229940126543 compound 14 Drugs 0.000 description 2
- 229940125758 compound 15 Drugs 0.000 description 2
- 229940126142 compound 16 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940125810 compound 20 Drugs 0.000 description 2
- 229940126086 compound 21 Drugs 0.000 description 2
- 229940126208 compound 22 Drugs 0.000 description 2
- 229940125833 compound 23 Drugs 0.000 description 2
- 229940125961 compound 24 Drugs 0.000 description 2
- 229940125846 compound 25 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 108091007930 cytoplasmic receptors Proteins 0.000 description 2
- RAFNCPHFRHZCPS-UHFFFAOYSA-N di(imidazol-1-yl)methanethione Chemical compound C1=CN=CN1C(=S)N1C=CN=C1 RAFNCPHFRHZCPS-UHFFFAOYSA-N 0.000 description 2
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- HITOXZPZGPXYHY-UJURSFKZSA-N levoglucosenone Chemical compound O=C1C=C[C@H]2CO[C@@H]1O2 HITOXZPZGPXYHY-UJURSFKZSA-N 0.000 description 2
- HITOXZPZGPXYHY-UHFFFAOYSA-N levoglucosenone Natural products O=C1C=CC2COC1O2 HITOXZPZGPXYHY-UHFFFAOYSA-N 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000009456 molecular mechanism Effects 0.000 description 2
- 230000003472 neutralizing effect Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 230000003068 static effect Effects 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 1
- 108060000255 AIM2 Proteins 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- ATVAXTJIRCBICU-NTSWFWBYSA-N C1[C@@H]([C@@H](CO)OCC1=O)O Chemical compound C1[C@@H]([C@@H](CO)OCC1=O)O ATVAXTJIRCBICU-NTSWFWBYSA-N 0.000 description 1
- 102000021350 Caspase recruitment domains Human genes 0.000 description 1
- 108091011189 Caspase recruitment domains Proteins 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- 208000002705 Glucose Intolerance Diseases 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 101000728679 Homo sapiens Apoptosis-associated speck-like protein containing a CARD Proteins 0.000 description 1
- 101001109463 Homo sapiens NACHT, LRR and PYD domains-containing protein 1 Proteins 0.000 description 1
- 101000979572 Homo sapiens NLR family CARD domain-containing protein 4 Proteins 0.000 description 1
- 208000006937 Hydatidiform mole Diseases 0.000 description 1
- 102100024064 Interferon-inducible protein AIM2 Human genes 0.000 description 1
- 239000012097 Lipofectamine 2000 Substances 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 101001033286 Mus musculus Interleukin-1 beta Proteins 0.000 description 1
- 101100294227 Mus musculus Nlrp1a gene Proteins 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 102100022698 NACHT, LRR and PYD domains-containing protein 1 Human genes 0.000 description 1
- 101710182264 NLR family CARD domain-containing protein 4 Proteins 0.000 description 1
- 101150061038 NLRP3 gene Proteins 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 239000004820 Pressure-sensitive adhesive Substances 0.000 description 1
- 108010001946 Pyrin Domain-Containing 3 Protein NLR Family Proteins 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- ZBIKORITPGTTGI-UHFFFAOYSA-N [acetyloxy(phenyl)-$l^{3}-iodanyl] acetate Chemical compound CC(=O)OI(OC(C)=O)C1=CC=CC=C1 ZBIKORITPGTTGI-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 210000002798 bone marrow cell Anatomy 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 244000005709 gut microbiome Species 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000008076 immune mechanism Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 210000005026 intestinal epithelial barrier Anatomy 0.000 description 1
- 230000004609 intestinal homeostasis Effects 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 244000000010 microbial pathogen Species 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 201000009104 prediabetes syndrome Diseases 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/30—Oxygen atoms, e.g. delta-lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/32—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
より具体的には、本発明は、自然免疫機構による生体の炎症応答に重要な役割を有するインフラマソームなどの複合体の形成や活性を阻害することによりカスパーゼ1の活性化を阻害する作用を有し、慢性炎症や自己炎症性疾患などの予防及び/又は治療のために有用な医薬に関するものである。
より具体的には、本発明は、インフラマソームなどの複合体の形成やインフラマソーム経路を阻害することによりカスパーゼ1の活性化を阻害する作用を有し、慢性炎症や自己炎症性疾患などの予防及び/又は治療のために有用な医薬を提供することにある。
また、本発明により提供される新規化合物は、上記の医薬の有効成分などに有用である。
(a)R1及びR2のいずれか一方が水酸基又はアシルオキシ基であり、他方が水素原子であり;R3及びR4がそれぞれ独立に水素原子又はフッ素原子を示し;式中の----は単結合又は二重結合を示し、----が二重結合を示す場合にはR1及びR4は存在せず;R5及びR6が水素原子であり;R7が-CH2-OR8であり、R8が水素原子、アルキル基、又はアシル基を示すか、あるいはR8はR6と結合して-R8-R6-となって単結合を示す場合;及び
(b)R2が水素原子又はフッ素原子であり;R3が水素原子又はフッ素原子であり;式中の----が二重結合を示し;R5及びR6が水素原子であり;R7が-CH2-OR8であり、R8が水素原子又はアシル基を示すか、あるいはR8はR6と結合して-R8-R6-となって単結合を示す場合を挙げることができる。
(c)R2が水素原子であり;R3が水素原子又はフッ素原子であり;式中の----が二重結合を示し;R5及びR6が水素原子であり;R7が-CH2-OR8であり、R8が水素原子又はアシル基を示すか、あるいはR8はR6と結合して-R8-R6-となって単結合を示す場合;及び
(d)R2が水素原子であり;R3が水素原子又はフッ素原子であり;式中の----が二重結合を示し;R5が水素原子であり;R7が-CH2-OR8であり、R8がR6と結合して-R8-R6-となって単結合を示す場合
を挙げることができる。
もっとも、好ましい組み合わせはこれらに限定されることはない。
(d)R11及びR12のいずれか一方が水酸基又はアシルオキシ基であり、他方が水素原子であり;R13が水素原子又はフッ素原子であり;R14がアシル基であり;R15及びR16がそれぞれ独立に水素原子又はフッ素原子であり;R17が-CH2-OR18であり、R18が水素原子、アルキル基、又はアシル基である場合を上げることができ、さらに好ましい組み合わせとしては、
(e)R11及びR12のいずれか一方がアシルオキシ基であり、他方が水素原子であり;R13が水素原子であり;R14がアシル基であり;R15及びR16が水素原子であり;R17が-CH2-OR18であり、R18が水素原子、アルキル基、又はアシル基である場合
を挙げることができる。
もっとも、好ましい組み合わせはこれらに限定されることはない。
(1)工程1
化合物10 1H NMR(600MHz, CDCl3): δ2.50(dd,1H), 3.78-3.82(m,1H), 3.85-3.88(m,1H), 4.18(dd,1H), 4.34(d,1H), 4.45-4.47(m,1H), 6.24(dd,1H), 7.01(d,1H).
化合物11 1H NMR(600MHz, CDCl3): δ2.12(s,3H), 4.16(dd,1H), 4.26(dd,1H), 4.34-4.36 (m,2H), 4.57-4.60(m,1H), 6.24(dd,1H), 6.99(dd,1H).
(1)工程1
化合物18 1H NMR(600MHz, CDCl3): δ2.13(s,3H), 4.21-4.25(m,2H), 4.36(dd,1H), 4.45 (dd,1H), 4.76-4.81(m,1H), 6.47(dd,1H).
(1)工程1
化合物27 1H NMR(600MHz,D2O): δ 1.82(dd, 0.55H), 1.96(dtr,0.55H), 2.50(dtr,0.45H), 2.82(dd,0.45H), 3.33(d,0.55H), 3.43-3.67(m,2.45H), 3.81-3.84(m,1H), 4.00-4.08(m,1H), 4.22-4.23(m,0.45H)
化合物28 1H NMR(600MHz, CDCl3): δ 2.08(s,3H), 2.11(s,3H), 2.15(s,3H), 3.81-3.83(m,1H), 4.10-4.13(m,1H), 4.18-4.21(m,1H), 4.25-4.31(m,1H), 5.36-5.38(m,1H), 5.62-5.64(m,1H)
(a)実験方法
(1)マウス骨髄由来マクロファージの培養
マウス骨髄由来マクロファージの調製は次のように行った。マクロファージ細胞への分化、維持に用いる培地の調製の為に、あらかじめL929細胞をD培地(DMEM/F12, 牛胎児血清10%、1%ペニシリンストレプトマイシンを含む)で培養し、その培養上清を回収し、遠心分離(3000rpm、5分、4℃)後に凍結した。マウス骨髄由来マクロファージ培養用培地(L培地)として、L929培養上清を0.22μmのろ過滅菌フィルターで滅菌後したものをD培地に25%の割合で加えたものを調製した。
7〜8週齢のC57BL/6系統オスマウスの大腿骨を無菌的に採取し、その内腔から骨髄細胞を取り出し、上記の方法で調製したL培地を用いて、7〜10日間培養し分化させた。
培養分化させたマクロファージはダルベッコリン酸緩衝生理食塩水(D-PBS)で洗浄後、セルストリッパー溶液でピペッティングにより細胞を剥離回収し、D培地を加えた後400G、5分の遠心操作を行った。遠心上清を除去後、D培地で再懸濁して細胞数をカウント後、96穴培養プレートには1穴あたり5×104個あるいは3.5 cmシャーレには1×106個播種した。培養プレートあるいはシャーレに播種した細胞は、一晩インキュベーターで培養後、D-PBSで洗浄して非接着細胞を除去し、再びD培地を加え実験に用いた。
マウス骨髄由来マクロファージへの刺激は、下記の方法で行った。
a)LPS及びNigericinによる刺激
マクロファージをまずLPS[LPS-EB Ultrapure (InvivoGen社製)]100 ng/mlを含む培地で4時間インキュベートした。LPS処理後、D-PBSで洗浄し、牛胎児血清を含まないDMEM/F12培地に溶解した各濃度の化合物溶液と45分〜1時間インキュベートした。インキュベート後に細胞から溶液を除去し、DMEM/F12培地に溶解したNigericin (5μM)で45分〜1時間インキュベートした後に細胞及び細胞上清を回収した。
上述の方法a)において、Nigericin(5μM)の代わりにATP(5 mM)又は尿酸結晶(100 μg /ml)でインキュベートした後に細胞及び細胞上清を回収した。
dsDNA(シグマ社製)と、Lipofectamine 2000 (ライフテクノロジー社製)はDMEM/F12培地でそれぞれ、10 μg/ml及び10 μl/mlの濃度に希釈後、1:1の割合で混合し20分間インキュベートした。上述の方法a)において、Nigericinの代わりにdsDNA:Lipofectamine 2000A混合液を加え、3時間インキュベートした後に細胞及び細胞上清を回収した。
マクロファージの刺激後培養細胞上清中の成熟型IL-1βの測定はMouse IL-1β ELISA kit (eBioscience社製)を用いて行った。また、活性型カスパーゼ1及び成熟型IL-1βは回収した細胞溶解液及び培養上清の濃縮液をSDS-PAGE電気泳動で分離後、ニトロセルロース膜に転写し特異的抗体により検出した。
マウス骨髄由来マクロファージのLPS及びNigericin刺激時のIL-1β分泌に及ぼす化合物の影響を調べた結果を図1(3de)及び図2(enone体)に示す。LPS/Nigericin刺激によって培養上清中にIL-1βが分泌されるが、Nigericin刺激前に化合物とインキュベートすることにより、用量依存的にIL-1β分泌は抑制された。
Claims (9)
- カスパーゼ1活性化に起因する疾患の予防及び/又は治療のための医薬であって、下記の一般式(I)又は(II):
- 一般式(I)において、R1及びR2のいずれか一方が水酸基又はアシルオキシ基であり、他方が水素原子であり;R3及びR4がそれぞれ独立に水素原子又はフッ素原子を示し;式中の----は単結合又は二重結合を示し、----が二重結合を示す場合にはR1及びR4は存在せず;R5及びR6が水素原子であり;R7が-CH2-OR8であり、R8が水素原子、アルキル基、又はアシル基を示すか、あるいはR8はR6と結合して-R8-R6-となって単結合を示す請求項1に記載の医薬。
- 一般式(I)において、R2が水素原子又はフッ素原子であり;R3が水素原子又はフッ素原子であり;式中の----が二重結合を示し;R5及びR6が水素原子であり;R7が-CH2-OR8であり、R8が水素原子又はアシル基を示すか、あるいはR8はR6と結合して-R8-R6-となって単結合を示す請求項1に記載の医薬。
- 上記一般式(II)において、R11及びR12のいずれか一方がアシルオキシ基であり、他方が水素原子であり;R13が水素原子であり;R14がアシル基であり;R15及びR16が水素原子であり;R17が-CH2-OR18であり、R18が水素原子、アルキル基、又はアシル基である請求項1に記載の医薬。
- カスパーゼ1活性化に起因する疾患が、がん、免疫抑制性疾患、自己免疫疾患、ウイルス感染症、神経変性疾患、内分泌疾患、炎症性疾患、臓器移植障害、及び放射線障害からなる群から選ばれる請求項1ないし4のいずれか1項に記載の医薬。
- カスパーゼ1活性化に起因する疾患が、全身性炎症性反応症候群SIRS、慢性関節リウマチ、アルツハイマー病、クライオピリン関連周期熱症候群、家族性地中海熱、PAPA症候群、Majeed症候群、高IgD症候群、反復性胞状奇胎、DIRA、炭素菌感染症、急性呼吸促拍症候群、炎症性細胞死、又は石綿肺からなる群から選ばれる請求項1ないし4のいずれか1項に記載の医薬。
- 請求項1に記載の一般式(I)又は(II)で表される化合物を有効成分として含むカスパーゼ1活性化阻害剤。
- 請求項1に記載の一般式(I)又は(II)で表される化合物を有効成分として含むインフラマソーム形成阻害剤。
- 請求項1に記載の一般式(I)又は(II)(式(I)中、R1及びR2のいずれか一方は水酸基又はアシルオキシ基を示し、他方は水素原子又はフッ素原子を示し;R3及びR4はそれぞれ独立に水素原子又はフッ素原子を示し;式中の----は単結合又は二重結合を示し、----が二重結合を示す場合にはR1及びR4は存在せず;R5及びR6はそれぞれ独立に水素原子、アルキル基、又はフッ素原子を示し;R7は-CH2-OR8、-CHF-OR8、-CF2-OR8、水素原子、アルキル基、又はトリフルオロメチル基を示し、R8は水素原子、アルキル基、又はアシル基を示すか、あるいはR8はR6と結合して-R8-R6-となって単結合を示し、式(II)中、R11及びR12のいずれか一方は水酸基又はアシルオキシ基を示し、他方は水素原子又はフッ素原子を示し;R13は水素原子又はフッ素原子を示し;R14はアシル基を示し;R15及びR16はそれぞれ独立に水素原子、アルキル基、又はフッ素原子を示し;R17は-CH2-OR18、-CHF-OR18、-CF2-OR18、水素原子、アルキル基、又はトリフルオロメチル基を示し、R18は水素原子、アルキル基、又はアシル基を示すか、あるいはR18はR16と結合して-R18-R16-となって単結合を示すが、ただし、式(I)においてR2が水素原子であり、R3が水素原子であり、式中の----が二重結合であり、R5が水素原子であり、R7が-CH2-OR8であり、R8がR6と結合して-R8-R6-となって単結合を示す場合を除く)で表される化合物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2015086485 | 2015-04-21 | ||
JP2015086485 | 2015-04-21 | ||
PCT/JP2016/062504 WO2016171165A1 (ja) | 2015-04-21 | 2016-04-20 | カスパーゼ1活性化阻害剤 |
Publications (2)
Publication Number | Publication Date |
---|---|
JPWO2016171165A1 true JPWO2016171165A1 (ja) | 2018-04-05 |
JP6722895B2 JP6722895B2 (ja) | 2020-07-15 |
Family
ID=57143107
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2017514157A Expired - Fee Related JP6722895B2 (ja) | 2015-04-21 | 2016-04-20 | カスパーゼ1活性化阻害剤 |
Country Status (2)
Country | Link |
---|---|
JP (1) | JP6722895B2 (ja) |
WO (1) | WO2016171165A1 (ja) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP7185226B2 (ja) * | 2018-11-22 | 2022-12-07 | 国立大学法人 鹿児島大学 | 1,5-アンヒドロフルクトース誘導体を含むampk活性化剤 |
JP7359377B2 (ja) * | 2019-06-03 | 2023-10-11 | 国立大学法人 鹿児島大学 | オキシトシン産生促進剤 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH0680565A (ja) * | 1992-09-03 | 1994-03-22 | Ishihara Sangyo Kaisha Ltd | 免疫機能抑制剤 |
WO2015016178A1 (ja) * | 2013-07-29 | 2015-02-05 | 国立大学法人鹿児島大学 | 1,5-d-アンヒドロフルクトースを含むアポトーシス関連スペック様カード蛋白質の機能阻害薬 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2358137B (en) * | 2000-01-14 | 2004-06-09 | Danisco | Compound |
US7649016B2 (en) * | 2003-10-28 | 2010-01-19 | Nihon Starch Co., Ltd. | Antitumor medicine |
JP2012518640A (ja) * | 2009-02-23 | 2012-08-16 | メルク・シャープ・エンド・ドーム・コーポレイション | ピラゾロ[4,3−c]シンノリン−3−オンM1受容体陽性アロステリックモジュレーター |
-
2016
- 2016-04-20 JP JP2017514157A patent/JP6722895B2/ja not_active Expired - Fee Related
- 2016-04-20 WO PCT/JP2016/062504 patent/WO2016171165A1/ja active Application Filing
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH0680565A (ja) * | 1992-09-03 | 1994-03-22 | Ishihara Sangyo Kaisha Ltd | 免疫機能抑制剤 |
WO2015016178A1 (ja) * | 2013-07-29 | 2015-02-05 | 国立大学法人鹿児島大学 | 1,5-d-アンヒドロフルクトースを含むアポトーシス関連スペック様カード蛋白質の機能阻害薬 |
Also Published As
Publication number | Publication date |
---|---|
JP6722895B2 (ja) | 2020-07-15 |
WO2016171165A1 (ja) | 2016-10-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6283033B2 (ja) | ウイルス感染症およびさらなる疾患の処置のためのアシルアミノピリミジン誘導体 | |
US11530200B2 (en) | Compounds | |
US11834433B2 (en) | Compounds | |
US11667663B2 (en) | Cyclic dinucleotides as anticancer agents | |
KR20200087759A (ko) | 신규한 설폰아마이드 카복스아마이드 화합물 | |
JP2022547882A (ja) | Nlrp3阻害剤 | |
KR20200041919A (ko) | Nlrp3 저해제로서의 설포닐유레아 및 설포닐티오유레아 | |
US11427610B2 (en) | Cyclic dinucleotides as anticancer agents | |
CN105682655B (zh) | 抗微生物化合物 | |
WO2019166624A1 (en) | Novel compounds | |
US20220289766A1 (en) | Macrocyclic sulfonylurea derivatives useful as nlrp3 inhibitors | |
EP3759073A1 (en) | Sulfonamide derivates as nlrp3 inhibitors | |
EA015424B1 (ru) | Соединения диосметина, способ их получения и фармацевтические композиции, которые их содержат | |
JP6722895B2 (ja) | カスパーゼ1活性化阻害剤 | |
TW201408672A (zh) | □烷化合物 | |
JP2023543908A (ja) | トリアゾロピラジン系化合物及びその用途 | |
KR20220137555A (ko) | 신규 화합물 및 이의 건선, 천식 또는 전신홍반루푸스의 치료 용도 | |
CN118103045A (zh) | 用于治疗川崎病的α蛋白激酶1抑制剂 | |
WO2021183760A1 (en) | Methods of modulating t-cell activation using estrogen receptor beta (erβ) agonists | |
JPS6366168A (ja) | プロスタサイクリン(pgi↓2)類縁体 | |
JP4182218B2 (ja) | アポトーシスを誘導する新規なグルコース誘導体、その製造方法及び医薬としてのその用途 | |
WO2011013398A1 (ja) | Cd22分子に対する高親和性を有しb細胞の増殖を増強する化合物 | |
RU2800877C2 (ru) | Агонист tlr8 | |
JP6359409B2 (ja) | トール様受容体4活性化作用を有するフニクロシン誘導体及びその用途 | |
CN108929292B (zh) | 2-甲烯基型取代型裂木脂素类衍生物及其医药用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A529 | Written submission of copy of amendment under article 34 pct |
Free format text: JAPANESE INTERMEDIATE CODE: A5211 Effective date: 20171020 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20171020 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20171025 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20190311 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20190311 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20200114 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20200207 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20200526 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20200605 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6722895 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
LAPS | Cancellation because of no payment of annual fees |