JP6932386B2 - 新しいカリクレイン7阻害剤 - Google Patents
新しいカリクレイン7阻害剤 Download PDFInfo
- Publication number
- JP6932386B2 JP6932386B2 JP2019091722A JP2019091722A JP6932386B2 JP 6932386 B2 JP6932386 B2 JP 6932386B2 JP 2019091722 A JP2019091722 A JP 2019091722A JP 2019091722 A JP2019091722 A JP 2019091722A JP 6932386 B2 JP6932386 B2 JP 6932386B2
- Authority
- JP
- Japan
- Prior art keywords
- phenyl
- alkyl
- ethyl
- nhc
- propyl
- 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.)
- Active
Links
- 229940099536 Kallikrein 7 inhibitor Drugs 0.000 title 1
- -1 5-methyl-3-isoxazolyl- Chemical group 0.000 claims description 119
- 150000001875 compounds Chemical class 0.000 claims description 48
- 201000004624 Dermatitis Diseases 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- 238000011282 treatment Methods 0.000 claims description 11
- 206010012438 Dermatitis atopic Diseases 0.000 claims description 10
- 201000008937 atopic dermatitis Diseases 0.000 claims description 10
- 208000017520 skin disease Diseases 0.000 claims description 10
- 208000011219 Netherton syndrome Diseases 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 239000000843 powder Substances 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 201000004681 Psoriasis Diseases 0.000 claims description 7
- 206010061218 Inflammation Diseases 0.000 claims description 5
- 208000003251 Pruritus Diseases 0.000 claims description 5
- 230000004054 inflammatory process Effects 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 208000002874 Acne Vulgaris Diseases 0.000 claims description 4
- 206010012442 Dermatitis contact Diseases 0.000 claims description 4
- 206010020649 Hyperkeratosis Diseases 0.000 claims description 4
- 206010000496 acne Diseases 0.000 claims description 4
- 208000010668 atopic eczema Diseases 0.000 claims description 4
- 208000010247 contact dermatitis Diseases 0.000 claims description 4
- 230000036566 epidermal hyperplasia Effects 0.000 claims description 4
- 239000002537 cosmetic Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000000344 soap Substances 0.000 claims description 3
- 239000006071 cream Substances 0.000 claims description 2
- 239000000499 gel Substances 0.000 claims description 2
- 239000000865 liniment Substances 0.000 claims description 2
- 239000006210 lotion Substances 0.000 claims description 2
- 239000002674 ointment Substances 0.000 claims description 2
- 239000006072 paste Substances 0.000 claims description 2
- 239000002453 shampoo Substances 0.000 claims description 2
- 239000007921 spray Substances 0.000 claims description 2
- 238000011200 topical administration Methods 0.000 claims description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims 6
- 125000005871 1,3-benzodioxolyl group Chemical group 0.000 claims 3
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims 3
- 239000003814 drug Substances 0.000 claims 1
- 229940079593 drug Drugs 0.000 claims 1
- 102100034867 Kallikrein-7 Human genes 0.000 description 45
- 101710176222 Kallikrein-7 Proteins 0.000 description 43
- 238000005160 1H NMR spectroscopy Methods 0.000 description 31
- 125000001072 heteroaryl group Chemical group 0.000 description 28
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
- 125000003118 aryl group Chemical group 0.000 description 24
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 22
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 18
- 125000000217 alkyl group Chemical group 0.000 description 17
- 230000000694 effects Effects 0.000 description 17
- 239000003112 inhibitor Substances 0.000 description 17
- 125000003107 substituted aryl group Chemical group 0.000 description 16
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 14
- NRPFNQUDKRYCNX-UHFFFAOYSA-M 2-(4-methoxyphenyl)acetate Chemical compound COC1=CC=C(CC([O-])=O)C=C1 NRPFNQUDKRYCNX-UHFFFAOYSA-M 0.000 description 11
- 102000004190 Enzymes Human genes 0.000 description 10
- 108090000790 Enzymes Proteins 0.000 description 10
- 229940088598 enzyme Drugs 0.000 description 10
- 230000002265 prevention Effects 0.000 description 9
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 9
- 125000000547 substituted alkyl group Chemical group 0.000 description 9
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 210000003491 skin Anatomy 0.000 description 8
- 210000000434 stratum corneum Anatomy 0.000 description 8
- 101001091388 Homo sapiens Kallikrein-7 Proteins 0.000 description 7
- 102000012479 Serine Proteases Human genes 0.000 description 7
- 108010022999 Serine Proteases Proteins 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 7
- 125000000753 cycloalkyl group Chemical group 0.000 description 7
- 229910052736 halogen Inorganic materials 0.000 description 7
- 150000002367 halogens Chemical class 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 6
- 150000002632 lipids Chemical class 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- GJEFSGJBLTTZAO-UHFFFAOYSA-N propyl 2,2-diphenylacetate Chemical compound C=1C=CC=CC=1C(C(=O)OCCC)C1=CC=CC=C1 GJEFSGJBLTTZAO-UHFFFAOYSA-N 0.000 description 6
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 206010040844 Skin exfoliation Diseases 0.000 description 5
- 230000035618 desquamation Effects 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 5
- 238000012545 processing Methods 0.000 description 5
- 125000006413 ring segment Chemical group 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical compound OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 description 4
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 4
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 4
- 238000006731 degradation reaction Methods 0.000 description 4
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 4
- 102000055383 human KLK7 Human genes 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- OKKOZFNOMZSZBQ-UHFFFAOYSA-N propyl 2-(4-chlorophenyl)acetate Chemical compound CCCOC(=O)CC1=CC=C(Cl)C=C1 OKKOZFNOMZSZBQ-UHFFFAOYSA-N 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- QOUIVWCZJKTOBA-UHFFFAOYSA-N (2-anilino-2-oxo-1-phenylethyl) 2-(4-chlorophenyl)acetate Chemical compound ClC1=CC=C(C=C1)CC(=O)OC(C(=O)NC1=CC=CC=C1)C1=CC=CC=C1 QOUIVWCZJKTOBA-UHFFFAOYSA-N 0.000 description 3
- 108020005345 3' Untranslated Regions Proteins 0.000 description 3
- 108060005987 Kallikrein Proteins 0.000 description 3
- 102100034868 Kallikrein-5 Human genes 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 102000035195 Peptidases Human genes 0.000 description 3
- 108091005804 Peptidases Proteins 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000004365 Protease Substances 0.000 description 3
- 102000005806 Serine Peptidase Inhibitor Kazal-Type 5 Human genes 0.000 description 3
- 108010005020 Serine Peptidase Inhibitor Kazal-Type 5 Proteins 0.000 description 3
- 108010061312 Sphingomyelin Phosphodiesterase Proteins 0.000 description 3
- PZXWCSHIEIMQOK-UHFFFAOYSA-N [1-[(5-methyl-1,2-oxazol-3-yl)amino]-1-oxopropan-2-yl] 2,2-diphenylacetate Chemical compound CC(OC(=O)C(C1=CC=CC=C1)C1=CC=CC=C1)C(=O)NC1=NOC(C)=C1 PZXWCSHIEIMQOK-UHFFFAOYSA-N 0.000 description 3
- QKYBMTADHYYBQX-UHFFFAOYSA-N [2-(4-methoxyanilino)-2-oxo-1-phenylethyl] 2-(4-chlorophenyl)acetate Chemical compound ClC1=CC=C(C=C1)CC(=O)OC(C(=O)NC1=CC=C(C=C1)OC)C1=CC=CC=C1 QKYBMTADHYYBQX-UHFFFAOYSA-N 0.000 description 3
- FMYPQMVHTSOTJP-UHFFFAOYSA-N [2-(4-methoxyanilino)-2-oxo-1-phenylethyl] 2-(4-methoxyphenyl)acetate Chemical compound COC1=CC=C(C=C1)CC(=O)OC(C(=O)NC1=CC=C(C=C1)OC)C1=CC=CC=C1 FMYPQMVHTSOTJP-UHFFFAOYSA-N 0.000 description 3
- DLNAKEGHOHLNFN-UHFFFAOYSA-N [3-methyl-1-[(5-methyl-1,2-oxazol-3-yl)amino]-1-oxobutan-2-yl] 2,2-diphenylacetate Chemical compound C1(=CC=CC=C1)C(C(=O)OC(C(C)C)C(NC1=NOC(=C1)C)=O)C1=CC=CC=C1 DLNAKEGHOHLNFN-UHFFFAOYSA-N 0.000 description 3
- 238000007792 addition Methods 0.000 description 3
- 125000003710 aryl alkyl group Chemical group 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 125000002619 bicyclic group Chemical group 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 230000002068 genetic effect Effects 0.000 description 3
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 230000035772 mutation Effects 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- RIEKNUTZBRBQRY-UHFFFAOYSA-N propyl 2-(4-methoxyphenyl)acetate Chemical compound CCCOC(=O)CC1=CC=C(OC)C=C1 RIEKNUTZBRBQRY-UHFFFAOYSA-N 0.000 description 3
- 230000008591 skin barrier function Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 description 2
- 0 *C(*)C(OC(*)C(N*)=O)=O Chemical compound *C(*)C(OC(*)C(N*)=O)=O 0.000 description 2
- PYHXGXCGESYPCW-UHFFFAOYSA-M 2,2-diphenylacetate Chemical compound C=1C=CC=CC=1C(C(=O)[O-])C1=CC=CC=C1 PYHXGXCGESYPCW-UHFFFAOYSA-M 0.000 description 2
- 108090000317 Chymotrypsin Proteins 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- 108010017544 Glucosylceramidase Proteins 0.000 description 2
- 102000004547 Glucosylceramidase Human genes 0.000 description 2
- 101001091379 Homo sapiens Kallikrein-5 Proteins 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 102000011971 Sphingomyelin Phosphodiesterase Human genes 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- HHWBSAZZNWLOCS-UHFFFAOYSA-N [1-(4-methoxyanilino)-1-oxopropan-2-yl] 3-cyclopentylpropanoate Chemical compound C1(CCCC1)CCC(=O)OC(C(=O)NC1=CC=C(C=C1)OC)C HHWBSAZZNWLOCS-UHFFFAOYSA-N 0.000 description 2
- MZFHUFJGUSCBFL-UHFFFAOYSA-N [1-[(5-methyl-1,2-oxazol-3-yl)amino]-1-oxopropan-2-yl] 3-cyclopentylpropanoate Chemical compound CC(OC(=O)CCC1CCCC1)C(=O)NC1=NOC(C)=C1 MZFHUFJGUSCBFL-UHFFFAOYSA-N 0.000 description 2
- XWWCONKGTAPRAT-UHFFFAOYSA-N [2-(4-methoxyanilino)-2-oxoethyl] 2-(4-methoxyphenyl)acetate Chemical compound C1=CC(OC)=CC=C1CC(=O)OCC(=O)NC1=CC=C(OC)C=C1 XWWCONKGTAPRAT-UHFFFAOYSA-N 0.000 description 2
- OBTOBGKTOSXRIN-UHFFFAOYSA-N [2-(benzylamino)-2-oxo-1-phenylethyl] 3-cyclopentylpropanoate Chemical compound C1(CCCC1)CCC(=O)OC(C(=O)NCC1=CC=CC=C1)C1=CC=CC=C1 OBTOBGKTOSXRIN-UHFFFAOYSA-N 0.000 description 2
- QPOHBZBUJFJVSK-UHFFFAOYSA-N [3-methyl-1-[(5-methyl-1,2-oxazol-3-yl)amino]-1-oxobutan-2-yl] 3-cyclopentylpropanoate Chemical compound C1(CCCC1)CCC(=O)OC(C(C)C)C(NC1=NOC(=C1)C)=O QPOHBZBUJFJVSK-UHFFFAOYSA-N 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 150000008378 aryl ethers Chemical class 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 229940110456 cocoa butter Drugs 0.000 description 2
- 235000019868 cocoa butter Nutrition 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 125000004663 dialkyl amino group Chemical group 0.000 description 2
- 210000002615 epidermis Anatomy 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 2
- 208000013403 hyperactivity Diseases 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
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 230000002018 overexpression Effects 0.000 description 2
- 125000004043 oxo group Chemical group O=* 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000000770 proinflammatory effect Effects 0.000 description 2
- DONVPVJCEGSTHD-UHFFFAOYSA-N propyl 3-cyclopentylpropanoate Chemical compound CCCOC(=O)CCC1CCCC1 DONVPVJCEGSTHD-UHFFFAOYSA-N 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 230000003236 psychic effect Effects 0.000 description 2
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 2
- 230000000306 recurrent effect Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 239000001993 wax Substances 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 1
- 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 1
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 1
- YJLIKUSWRSEPSM-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-phenylphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YJLIKUSWRSEPSM-WGQQHEPDSA-N 0.000 description 1
- ITOFPJRDSCGOSA-KZLRUDJFSA-N (2s)-2-[[(4r)-4-[(3r,5r,8r,9s,10s,13r,14s,17r)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H](CC[C@]13C)[C@@H]2[C@@H]3CC[C@@H]1[C@H](C)CCC(=O)N[C@H](C(O)=O)CC1=CNC2=CC=CC=C12 ITOFPJRDSCGOSA-KZLRUDJFSA-N 0.000 description 1
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 1
- 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 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- 125000006710 (C2-C12) alkenyl group Chemical group 0.000 description 1
- 125000006711 (C2-C12) alkynyl group Chemical group 0.000 description 1
- 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 1
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 1
- 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 1
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
- XRMJQPQWXZLSHM-UHFFFAOYSA-N 2-(4-chlorophenyl)-3-[(4-methoxyphenyl)carbamoyl]-4-methylpentanoic acid Chemical compound COc1ccc(NC(=O)C(C(C)C)C(C(O)=O)c2ccc(Cl)cc2)cc1 XRMJQPQWXZLSHM-UHFFFAOYSA-N 0.000 description 1
- NWQNOVAXJRAJFA-UHFFFAOYSA-N 2-(4-chlorophenyl)-4-methyl-3-(phenylcarbamoyl)pentanoic acid Chemical compound CC(C)C(C(C(O)=O)c1ccc(Cl)cc1)C(=O)Nc1ccccc1 NWQNOVAXJRAJFA-UHFFFAOYSA-N 0.000 description 1
- NPRYCHLHHVWLQZ-TURQNECASA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynylpurin-8-one Chemical compound NC1=NC=C2N(C(N(C2=N1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C NPRYCHLHHVWLQZ-TURQNECASA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 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 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 1
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 1
- HPDYJXRGNQGEGW-UHFFFAOYSA-N COC1=CC=C(C=C1)NC(=O)C(CC)C(C(=O)O)C1=CC=C(C=C1)Cl Chemical compound COC1=CC=C(C=C1)NC(=O)C(CC)C(C(=O)O)C1=CC=C(C=C1)Cl HPDYJXRGNQGEGW-UHFFFAOYSA-N 0.000 description 1
- 102000000905 Cadherin Human genes 0.000 description 1
- 108050007957 Cadherin Proteins 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 235000008474 Cardamine pratensis Nutrition 0.000 description 1
- 240000000606 Cardamine pratensis Species 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 102100031673 Corneodesmosin Human genes 0.000 description 1
- 101710139375 Corneodesmosin Proteins 0.000 description 1
- 108010002156 Depsipeptides Proteins 0.000 description 1
- 102100021202 Desmocollin-1 Human genes 0.000 description 1
- 101710157876 Desmocollin-1 Proteins 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- 108010062466 Enzyme Precursors Proteins 0.000 description 1
- 102000010911 Enzyme Precursors Human genes 0.000 description 1
- RRSNDVCODIMOFX-MPKOGUQCSA-N Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O Chemical compound Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O RRSNDVCODIMOFX-MPKOGUQCSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- 101150023007 KLK7 gene Proteins 0.000 description 1
- 102000001399 Kallikrein Human genes 0.000 description 1
- 101710176223 Kallikrein-5 Proteins 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241000446313 Lamella Species 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- LVDRREOUMKACNJ-BKMJKUGQSA-N N-[(2R,3S)-2-(4-chlorophenyl)-1-(1,4-dimethyl-2-oxoquinolin-7-yl)-6-oxopiperidin-3-yl]-2-methylpropane-1-sulfonamide Chemical compound CC(C)CS(=O)(=O)N[C@H]1CCC(=O)N([C@@H]1c1ccc(Cl)cc1)c1ccc2c(C)cc(=O)n(C)c2c1 LVDRREOUMKACNJ-BKMJKUGQSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 101150049485 SPINK5 gene Proteins 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- RMVNTAFCFMONHS-UHFFFAOYSA-N [2-(4-methoxyanilino)-2-oxoethyl] 2-(4-chlorophenyl)acetate Chemical compound C1=CC(OC)=CC=C1NC(=O)COC(=O)CC1=CC=C(Cl)C=C1 RMVNTAFCFMONHS-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 150000003869 acetamides Chemical class 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 102000010126 acid sphingomyelin phosphodiesterase activity proteins Human genes 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 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 1
- 125000004429 atom Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 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 1
- 125000002527 bicyclic carbocyclic group Chemical group 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 150000001717 carbocyclic compounds Chemical class 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 229940106189 ceramide Drugs 0.000 description 1
- 150000001783 ceramides Chemical class 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000037012 chymotrypsin-like activity Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
- 229940125961 compound 24 Drugs 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 229940125878 compound 36 Drugs 0.000 description 1
- 229940125807 compound 37 Drugs 0.000 description 1
- 210000000736 corneocyte Anatomy 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000002704 decyl group Chemical group [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])C([H])([H])C([H])([H])* 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 210000005175 epidermal keratinocyte Anatomy 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 210000001723 extracellular space Anatomy 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 150000002305 glucosylceramides Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 229960003130 interferon gamma Drugs 0.000 description 1
- 108010052790 interleukin 1 precursor Proteins 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 description 1
- 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 1
- 239000008101 lactose Substances 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 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
- 125000002347 octyl 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])[H] 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 102000054765 polymorphisms of proteins Human genes 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000006308 propyl amino group Chemical group 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000006513 pyridinyl methyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000037204 skin physiology Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
- 125000004426 substituted alkynyl group Chemical group 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000002889 sympathetic effect Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229920003051 synthetic elastomer Polymers 0.000 description 1
- 239000005061 synthetic rubber Substances 0.000 description 1
- 239000007885 tablet disintegrant Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 125000006168 tricyclic group Chemical group 0.000 description 1
- 125000002948 undecyl 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])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
Images
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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
- A61K8/42—Amides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
-
- 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
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- 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
- A61P17/04—Antipruritics
-
- 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
- A61P17/06—Antipsoriatics
-
- 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
- A61P17/10—Anti-acne 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C235/16—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C235/38—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D261/14—Nitrogen atoms
-
- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Dermatology (AREA)
- Emergency Medicine (AREA)
- Birds (AREA)
- Immunology (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Peptides Or Proteins (AREA)
- Cosmetics (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Enzymes And Modification Thereof (AREA)
Description
(Descargues et al. 2006. Corneodesmosomal cadherins are preferential targets of stratum corneum trypsin− and chymotrypsin−like hyperactivity in Netherton syndrome. J. Invest. Dermatol. 126, 1622−1632; Hachem et al. 2006. Serine protease activity and residual LEKTI expression determine phenotype in Netherton syndrome. J. Invest. Dermatol. 126, 1609−1621.)。第2に、ヒトのカリクレイン7を過剰発現する遺伝子組み換えマウスは、アトピー性皮膚炎の患者に見られる皮膚表現型に類似した皮膚表現型を示す(Hansson et al. 2002. Epidermal Overexpression of Stratum Corneum Chymotryptic Enzyme in Mice: A Model for Chronic Itchy Dermatitis. J. Invest. Dermatol. 1 18, 444−449; Ny & Egelrud. 2003. Transgenic mice over−expressing a serine protease in the skin: evidence of interferon gamma−independent MHC II expression by epidermal keratinocytes. Acta Derm. Venereol. 83, 322−327; Ny & Egelrud. 2004. Epidermal hyperproliferation and decreased skin barrier function in mice overexpressing stratum corneum chymotryptic enzyme. Acta Derm. Venereol. 84, 18−22)。第3に、アトピー性皮膚炎および乾癬の患者の皮膚におけるKLK7のレベルの上昇が記載された(Ekholm & Egelrud. 1999. Stratum corneum chymotryptic enzyme in psoriasis. Arch. Dermatol. Res. 291 , 195−200)。それ故、KLK7は、アトピー性皮膚炎、乾癬またはネザートン症候群のような炎症性皮膚疾患の処置の標的であると考えられ、その特異的阻害剤が必要とされている。
R2は、水素、アルキル、置換されたアルキル、アリール、および置換されたアリールから選択され;
R3は、アルキル、置換されたアルキル、シクロアルキル、置換されたシクロアルキル、アリール、置換されたアリール、ヘテロアリール、置換されたヘテロアリール、および−C1−C3−アルキル−R5から選択され、ここでR5は、シクロアルキル、置換されたシクロアルキル、アリール、置換されたアリール、ヘテロアリール、置換されたヘテロアリールから選択され;
R4は、水素、アルキル、置換されたアルキル、アリール、置換されたアリール、ヘテロアリール、および置換されたヘテロアリール、および−NH−CO−R6から選択され、ここでR6は、アリール、置換されたアリール、ヘテロアリール、および置換されたヘテロアリールから選択される。
好ましくは、R2に共有結合する炭素のまわりの立体化学的配置は、(S)である。
R2は、水素、アルキル、置換されたアルキル、アリール、および置換されたアリールから選択され;
R3は、アルキル、置換されたアルキル、シクロアルキル、置換されたシクロアルキル、アリール、置換されたアリール、ヘテロアリール、置換されたヘテロアリール、および−C1−C3−アルキル−R5から選択され、ここでR5は、シクロアルキル、置換されたシクロアルキル、アリール、置換されたアリール、ヘテロアリール、および置換されたヘテロアリールから選択され;
R4は、水素、アルキル、置換されたアルキル、アリール、置換されたアリール、ヘテロアリール、置換されたヘテロアリール、および−NH−CO−R6から選択され、ここでR6は、アリール、置換されたアリール、ヘテロアリール、および置換されたヘテロアリールから選択される。
(1) [1−メチル−2−[(5−メチルイソキサゾール−3−イル)アミノ]−2−オキソ−エチル]2−(4−クロロフェニル)酢酸エステル
(3) 1−[(5−メチルイソキサゾール−3−イル)カルバモイル]プロピル2−(4−クロロフェニル)酢酸エステル
(7) [1−メチル−2−[(5−メチルイソキサゾール−3−イル)アミノ]−2−オキソ−エチル]2−(4−メトキシフェニル)酢酸エステル
(12) 1−[(5−メチルイソキサゾール−3−イル)カルバモイル]プロピル2−(4−メトキシフェニル)酢酸エステル
(14) [1−メチル−2−[(5−メチルイソキサゾール−3−イル)アミノ]−2−オキソ−エチル]3−シクロペンチルプロパノアート
(15) [2−(4−メトキシアニリノ)−1−メチル−2−オキソ−エチル]2−(4−メトキシフェニル)酢酸エステル
(16) 1−[(5−メチルイソキサゾール−3−イル)カルバモイル]プロピル3−シクロペンチルプロパノアート
(17) [2−[(5−メチルイソキサゾール−3−イル)アミノ]−2−オキソ−l−フェニル−エチル]2−(4−クロロフェニル)酢酸エステル
(20) [2−[(5−メチルイソキサゾール−3−イル)アミノ]−2−オキソ−1−フェニル−エチル]3−シクロペンチルプロパノアート
(23) 1−[(5−メチルイソキサゾール−3−イル)カルバモイル]プロピル2−(4−メトキシフェニル)酢酸エステル
(26) 1−[(5−メチルイソキサゾール−3−イル)カルバモイル]プロピル2−(1,3−ベンゾジオキソール−5−イル)酢酸エステル
(36) [2−[(5−メチルイソキサゾール−3−イル)アミノ]−2−オキソ−1−フェニル−エチル]2−(4−メトキシフェニル)酢酸エステル
(39) 1−[(5−メチルイソキサゾール−3−イル)カルバモイル]プロピル2−(3,4−ジクロロフェニル)酢酸エステル
(41) 1−[(5−メチルイソキサゾール−3−イル)カルバモイル]プロピル2−(3,4−ジメトキシフェニル)酢酸エステル
(47) [1−メチル−2−[(5−メチルイソキサゾール−3−イル)アミノ]−2−オキソ−エチル]2,2−ジフェニル酢酸エステル
(49) [2−[(5−メチルイソキサゾール−3−イル)アミノ]−2−オキソ−1−フェニル−エチル]2−ベンズアミド−2−フェニル−酢酸エステル
(52) [1−メチル−2−[(5−メチルイソキサゾール−3−イル)アミノ]−2−オキソ−エチル]2−ベンズアミド−2−フェニル−酢酸エステル
(54) [2−[(5−メチルイソキサゾール−3−イル)アミノ]−2−オキソ−1−フェニル−エチル]2,2−ジフェニル酢酸エステル
(60) [2−[(5−メチルイソキサゾール−3−イル)アミノ]−2−オキソ−エチル]2−ベンズアミド−2−フェニル−酢酸エステル
(70) [2−メチル−1−[(5−メチルイソキサゾール−3−イル)カルバモイル]プロピル]2−(4−クロロフェニル)酢酸エステル
(72) [2−メチル−1−[(5−メチルイソキサゾール−3−イル)カルバモイル]プロピル]3−シクロペンチルプロパノアート
(75) [2−メチル−1−[(5−メチルイソキサゾール−3−イル)カルバモイル]プロピル]2−ベンズアミド−2−フェニル−酢酸エステル
(79) [2−メチル−1−[(5−メチルイソキサゾール−3−イル)カルバモイル]プロピル]2,2−ジフェニル酢酸エステル
(81) [2−[(5−メチルイソキサゾール−3−イル)アミノ]−2−オキソ−エチル]2−(4−クロロフェニル)酢酸エステル
(84) [2−メチル−1−[(5−メチルイソキサゾール−3−イル)カルバモイル]プロピル]2−(4−メトキシフェニル)酢酸エステル。
(4) [2−(4−メトキシアニリノ)−1−メチル−2−オキソ−エチル]2−(4−クロロフェニル)酢酸エステル
(6) 1−[(4−メトキシフェニル)カルバモイル]プロピル2−(4−クロロフェニル)酢酸エステル
(8) l−[(4−フルオロフェニル)カルバモイル]プロピル2−(4−クロロフェニル)酢酸エステル
(9) 1−(フェニルカルバモイル)プロピル2−(4−クロロフェニル)酢酸エステル
(10) [2−(4−メトキシアニリノ)−1−メチル−2−オキソ−エチル]3−シクロペンチルプロパノアート
(11) 1−[(4−メトキシフェニル)カルバモイル]プロピル3−シクロペンチルプロパノアート
(13) [2−(4−メトキシアニリノ)−2−オキソ−1−フェニル−エチル]2−(4−クロロフェニル)酢酸エステル
(19) [2−(4−メトキシアニリノ)−2−オキソ−l−フェニル−エチル]3−シクロペンチルプロパノアート
(24) 1−[(4−メトキシフェニル)カルバモイル]プロピル2−(4−メトキシフェニル)酢酸エステル
(25) 1−[(4−フルオロフェニル)カルバモイル]プロピル3−シクロペンチルプロパノアート
(30) 1−[(4−フルオロフェニル)カルバモイル]プロピル2−(4−メトキシフェニル)酢酸エステル
(31) (2−アニリノ−1−メチル−2−オキソ−エチル)3−シクロペンチルプロパノアート
(32) (2−アニリノ−2−オキソ−1−フェニル−エチル)2−(4−クロロフェニル)酢酸エステル
(34) 1−(フェニルカルバモイル)プロピル2−(4−メトキシフェニル)酢酸エステル
(35) [2−(4−メトキシアニリノ)−2−オキソ−1−フェニル−エチル]2−(4−メトキシフェニル)酢酸エステル
(37) [2−(ベンジルアミノ)−2−オキソ−1−フェニル−エチル]3−シクロペンチルプロパノアート
(42) [2−(4−メトキシアニリノ)−2−オキソ−エチル]2−(4−メトキシフェニル)酢酸エステル
(43) 1−[(4−メトキシフェニル)カルバモイル]プロピル2,2−ジフェニル酢酸エステル
(44) 1−[(4−フルオロフェニル)カルバモイル]プロピル2,2−ジフェニル酢酸エステル
(48) 1−(フェニルカルバモイル)プロピル2,2−ジフェニル酢酸エステル
(59) [2−(4−メトキシアニリノ)−2−オキソ−エチル]2−ベンズアミド−2−フェニル−酢酸エステル
(61) [2−(4−フルオロアニリノ)−2−オキソ−エチル]2−ベンズアミド−2−フェニル−酢酸エステル
(62) (2−アニリノ−2−オキソ−エチル)2−ベンズアミド−2−フェニル−酢酸エステル
(64) 1−[(4−メトキシフェニル)カルバモイル]プロピル2−ベンズアミド−2−フェニル−酢酸エステル
(65) 1−[(4−フルオロフェニル)カルバモイル]プロピル2−ベンズアミド−2−フェニル−酢酸エステル
(66) (2−アニリノ−1−メチル−2−オキソ−エチル)2−ベンズアミド−2−フェニル−酢酸エステル
(71) [2−(4−メトキシアニリノ)−1−メチル−2−オキソ−エチル]2−ベンズアミド−2−フェニル−酢酸エステル
(76) (2−アニリノ−2−オキソ−1−フェニル−エチル)2−ベンズアミド−2−フェニル−酢酸エステル
(78) [2−(4−メトキシアニリノ)−2−オキソ−1−フェニル−エチル]2,2−ジフェニル酢酸エステル
(83) [2−(ベンジルアミノ)−1−メチル−2−オキソ−エチル]2−ベンズアミド−2−フェニル−酢酸エステル
(91) [2−メチル−1−(フェニルカルバモイル)プロピル]2−(4−クロロフェニル)酢酸エステル
(92) [1−[(4−メトキシフェニル)カルバモイル]−2−メチル−プロピル]2−(4−クロロフェニル)酢酸エステル
(93) [2−メチル−1−(フェニルカルバモイル)プロピル]2−ベンズアミド−2−フェニル−酢酸エステル
(94) [2−メチル−1−(フェニルカルバモイル)プロピル]2−(4−メトキシフェニル)酢酸エステル
(95) [1−[(4−メトキシフェニル)カルバモイル]−2−メチル−プロピル]2−ベンズアミド−2−フェニル−酢酸エステル
(96) [1−[(4−フルオロフフェニル)カルバモイル]−2−メチル−プロピル]2−ベンズアミド−2−フェニル−酢酸エステル。
用語「アルキル」は、本明細書で使用されるように、1乃至3、1乃至12、または1乃至6の炭素原子をそれぞれ含有している、「C1−C3アルキル」、「C1−C6アルキル」、または「C1−C12アルキル」などの、飽和した、直鎖の、または分枝鎖の炭化水素ラジカルを指す。C1−C3アルキルラジカルの例は、メチル、エチル、プロピルおよびイソプロピルのラジカルを含み;C1−C6アルキルラジカルの例は、限定されないが、メチル、エチル、プロピル、イソプロピル、n−ブチル、tert−ブチル、sec−ブチル、n−ペンチル、ネオペンチルおよびn−ヘキシルのラジカルを含み;およびC1−C12アルキルラジカルの例は、限定されないが、エチル、プロピル、イソプロピル、ヘキシル、ヘプチル、オクチル、ノニル、デシル、ウンデシル、ドデシルのラジカルを含む。
[1,3]ジオキソラン、ピロリジニル、ピラゾリニル、ピラゾリジニル、イミダゾリニル、イミダゾリジニル、ピペリジニル、ピペラジニル、オキサゾリジニル、イソキサゾリジニル モルホリニル、チアゾリジニル、イソチアゾリジニル、キノキサリニル、ピリダジノニル、およびテトラヒドロフリルを含む。
基質:(MeO−Suc−Arg−Pro−Tyr−pNA)、酢酸塩、Peptide international, lot #906841(以前にS−2586と名付けられた)
酵素:0.3MのNaCl中の活性なヒトのKLK7(SCCE)0.62mg/ml、10mMのNaAc、pH4
緩衝液:10mMのNaPhospate、0.5MのNaCl、pH7.2
10μlのDMSOを、ブランクおよび対照のウェルに加えた。
DMSO中の10μlの物質を、ウェルに加え、20μΜ、10μΜ、5μΜ、2.5μΜ、1.25μΜ、0.625μΜ、0.3125μΜ、および0.15625μΜの終末濃度を与えた。
40μlの活性なKLK7(SCCE)(活性緩衝液中で12.5μg/mlに希釈した)を、ブランク以外のすべてのウェルに加え、そこに活性緩衝液を加えた。
SCCEの追加の直後、プレートを、Spectramax 250 Microplate Reader (Molecular Devices)に移し、酵素活性(V)を、30秒ごとに読み取りながら、15分間37℃において405nmで吸光度を測定するpNaの放出として測定した。
各サンプルの平均値Vを計算した(物質に対してn=2および対照に対してn=4)。
Vの値から、総活性の%を、(Vinhibitor/Vcontrol(阻害剤なし))x100として計算した。
その後、プロッティング(Plotting)および計算を、originProにおいて行った。
総活性(y)の%を、対数(log)[阻害剤](対数x)に対してプロットし(plotted)、用量応答の関数:
y=A1+(A2−A1)/(1+10^((LOG(x0)−x)*p))
(ここでA1=最下位のプラトー(Bottom platue)、A2=最上位のプラトー(Top platue)、x0=EC50およびp=丘の傾斜(Hill slope))を、曲線に合わした。y=50と設定して、xの値を求めることによって、IC50濃度を計算した。
本発明によるKLK7阻害剤を特定するために、IC50値を使用した。
丸底フラスコに、対応する酸A(3.6mmol)、DIPEA(3.6mmol)およびDMF(1mL)を満たした。適切な2−ブロモ置換した又は2−クロロ置換したアセトアミドB(3.0mmol)を、撹拌下で加えた。結果として生じた混合物を、2時間100℃で撹拌した。その後、それを、周囲温度に冷却し、NaHCO3の溶液(2%、7mL)に注いだ。油状生成物が、周囲温度で静置した(2−5時間)後に凝固した。沈殿物を、濾過し、NaHCO3の溶液(2%、2×7mL)、2−プロパノールと水の混合物(1:1、7mL)、水(7mL)で洗浄し、乾燥した。粗製物質を、イソプロパノールから再結晶化した。
[1−メチル−2−[(5−メチルイソキサゾール−3−イル)アミノ]−2−オキソ−エチル]2−(4−クロロフェニル)酢酸エステル
1H−NMR(400MHz、DMSO−d6+CCl4)δppm:1.43(3H、d、J=6.4Hz、CH3)、2.38(3H、s、CH3)、3.69(2H、m、CH2)、5.09(1H、q、J=6.4Hz、OCH)、6.60(1H、s、イソキサゾール)、7.27(4H、s、Ar)、10.89(1H、br s、NH)。
1−[(5−メチルイソキサゾール−3−イル)カルバモイル]プロピル2−(4−クロロフェニル)酢酸エステル
1H−NMR(400MHz、DMSO−d6+CCl4)δppm:0.92(3H、t、J=7.2Hz、CH3)、1.81(2H、m、CH2)、2.38(3H、s、CH3)、3.70(2H、s、CH2)、4.94(1H、m、OCH)、6.61(1H、s、イソキサゾール)、7.27(4H、s、Ar)、10.93(1H、br s、NH)。
[2−(4−メトキシアニリノ)−1−メチル−2−オキソ−エチル]2−(4−クロロフェニル)酢酸エステル
1H−NMR(400MHz、DMSO−d6)図1
1−[(4−メトキシフェニル)カルバモイル]プロピル2−(4−クロロフェニル)酢酸エステル
1H−NMR(400MHz、DMSO−d6)図2
[1−メチル−2−[(5−メチルイソキサゾール−3−イル)アミノ]−2−オキソ−エチル]2−(4−メトキシフェニル)酢酸エステル
1H−NMR(400MHz、DMSO−d6+CCl4)δppm:1.42(3H、d、J=6.8Hz、CH3)、2.38(3H、s、CH3)、3.60(2H、s、CH2)、3.75(3H、s、OCH3)、5.05(1H、q、J=6.8Hz、OCH)、6.61(1H、s、イソキサゾール)、6.79(2H、d、J=8.4Hz、Ar)、7.15(2H、d、J=8.4Hz、Ar)、10.93(1H、br s、NH)。
1−[(4−フルオロフェニル)カルバモイル]プロピル2−(4−クロロフェニル)酢酸エステル
1H−NMR(400MHz、DMSO−d6)図3
1−(フェニルカルバモイル)プロピル2−(4−クロロフェニル)酢酸エステル
1H−NMR(500MHz、DMSO)図4
[2−(4−メトキシアニリノ)−1−メチル−2−オキソ−エチル]3−シクロペンチルプロパノアート
1H−NMR(400MHz、DMSO−d6)図5
1−[(4−メトキシフェニル)カルバモイル]プロピル3−シクロペンチルプロパノアート
1H−NMR(400MHz、DMSO−d6+CCl4)図6
[2−(4−メトキシアニリノ)−2−オキソ−1−フェニル−エチル]2−(4−クロロフェニル)酢酸エステル
1H−NMR(400MHz、DMSO−d6)図7
[1−メチル−2−[(5−メチルイソキサゾール−3−イル)アミノ]−2−オキソ−エチル]3−シクロペンチルプロパノアート
1H−NMR(400MHz、DMSO−d6)図8
[2−(4−メトキシアニリノ)−1−メチル−2−オキソ−エチル]2−(4−メトキシフェニル)酢酸エステル
1H−NMR(400MHz、DMSO−d6)図9
1−[(5−メチルイソキサゾール−3−イル)カルバモイル]プロピル3−シクロペンチルプロパノアート
1H−NMR(400MHz、DMSO−d6)図10
[2−(4−メトキシアニリノ)−2−オキソ−1−フェニル−エチル]3−シクロペンチルプロパノアート
1H−NMR(400MHz、DMSO−d6)図11
[2−[(5−メチルイソキサゾール−3−イル)アミノ]−2−オキソ−1−フェニル−エチル]3−シクロペンチルプロパノアート
1H−NMR(400MHz、DMSO−d6)図12
1−[(5−メチルイソキサゾール−3−イル)カルバモイル]プロピル2−(4−メトキシフェニル)酢酸エステル
1H−NMR(400MHz、DMSO−d6+CCl4)図13
1−[(4−メトキシフェニル)カルバモイル]プロピル2−(4−メトキシフェニル)酢酸エステル
1H−NMR(500MHz、DMSO)図14
1−[(4−フルオロフェニル)カルバモイル]プロピル3−シクロペンチルプロパノアート
1H−NMR(400MHz、DMSO−d6)図15
1−[(4−フルオロフェニル)カルバモイル]プロピル2−(4−メトキシフェニル)酢酸エステル
1H−NMR(400MHz、DMSO−d6)図16
(2−アニリノ−2−オキソ−1−フェニル−エチル)2−(4−クロロフェニル)酢酸エステル
1H−NMR(400MHz、DMSO−d6)図17
[2−(4−メトキシアニリノ)−2−オキソ−1−フェニル−エチル]2−(4−メトキシフェニル)酢酸エステル
1H−NMR(400MHz、DMSO−d6+CCl4)δppm:3.65−3.75(5H、m、CH2、OCH3)、3.76(3H、s、OCH3)、5.98(1H、s、OCH)、6.76(2H、d、J=8.0Hz、Ar)、6.81(2H、d、J=8.0Hz、Ar)、7.21(2H、d、J=8.0Hz、Ar)、7.26−7.38(3H、m、Ar)、7.45(2H、d、J=8.0Hz、Ar)、7.53(2H、d、J=6.8Hz、Ar)、9.91(1H、br s、NH)。
[2−[(5−メチルイソキサゾール−3−イル)アミノ]−2−オキソ−1−フェニル−エチル]2−(4−メトキシフェニル)酢酸エステル
1H−NMR(400MHz、DMSO−d6)図18
[2−(ベンジルアミノ)−2−オキソ−1−フェニル−エチル]3−シクロペンチルプロパノアート
1H−NMR(400MHz、DMSO−d6)図19
[2−(4−メトキシアニリノ)−2−オキソ−エチル]2−(4−クロロフェニル)酢酸エステル
1H−NMR(400MHz、DMSO−d6+CCl4)δppm:1.44(3H、d、J=6.8Hz、CH3)、3.63(2H、m、CH2)、3.75(3H、s、OCH3)、5.07(1H、q、J=6.8Hz、CH)、6.80(2H、d、J=8.4Hz、Ar)、6.96(2H、m、Ar)、7.18(2H、d、J=8.4Hz、Ar)、7.58(2H、m、Ar)、9.74(1H、br s、NH)。
1−[(4−フルオロフェニル)カルバモイル]プロピル2,2−ジフェニル酢酸エステル
1H−NMR(500MHz、DMSO−d6+CCl4)δppm:0.87(3H、t、J=7.5Hz、CH3)、1.82(2H、m、CH2)、4.97(1H、m、OCH)、5.21(1H、s、CH)、6.99(2H、m、Ar)、7.18−7.38(10H、m、Ar)、7.59(2H、m、Ar)、9.87(IH、br s、NH)。
[1−メチル−2−[(5−メチルイソキサゾール−3−イル)アミノ]−2−オキソ−エチル]2,2−ジフェニル酢酸エステル
1H−NMR(400MHz、DMSO−d6+CCl4)δppm:1.42(3H、d、J=6.8Hz、CH3)、2.39(3H、s、CH3)、5.11(1H、q、J=6.8Hz、OCH)、5.16(1H、s、CH)、6.64(1H、s、イソキサゾール)、7.15−7.35(10H、m、Ar)、11.01(1H、s、NH)。
1−(フェニルカルバモイル)プロピル2,2−ジフェニル酢酸エステル
1H−NMR(400MHz、DMSO−d6)図20
[1−メチル−2−[(5−メチルイソキサゾール−3−イル)アミノ]−2−オキソ−エチル]2−ベンズアミド−2−フェニル−酢酸エステル
1H−NMR(500MHz、DMSO)図21
[2−[(5−メチルイソキサゾール−3−イル)アミノ]−2−オキソ−エチル]2−ベンズアミド−2−フェニル−酢酸エステル
1H−NMR(500MHz、CDCl3)図22
[2−メチル−1−[(5−メチルイソキサゾール−3−イル)カルバモイル]プロピル]2,2−ジフェニル酢酸エステル
1H−NMR(500MHz、DMSO−d6+CCl4)δppm:0.75(3H、d、J=6.5Hz、CH3)、0.78(3H、d、J=6.5Hz、CH3)、2.09(1H、m、CH)、2.35(3H、s、CH3)、4.83(1H、d、J=5.0Hz、OCH)、5.32(1H、s、CH)、6.61(1H、s、イソキサゾール)、7.20−7.39(10H、m、Ar)、11.17(1H、s、NH)。
[2−メチル−1−(フェニルカルバモイル)プロピル]2−(4−メトキシフェニル)酢酸エステル
1H−NMR(500MHz、DMSO−d6+CCl4)δppm:0.94(6H、d、J=6.5Hz、CH3)、2.19(1H、m、CH)、3.66(2H、m、CH2)、3.76(3H、s、OCH3)、4.80(1H、d、J=5.5Hz、OCH)、6.81(2H、d、J=8.5Hz、Ar)、6.99(1H、t、J=7.3Hz、Ar)、7.18−7.26(4H、m、Ar)、7.56(2H、d、J=8.0Hz、Ar)、9.66(1H、s、NH)。
Claims (4)
- 式Iの化合物、またはその薬学的に許容可能な塩を含む、炎症性皮膚疾患の処置のための医薬組成物であって、
R1は、5−メチル−3−イソキサゾリル−、4−フルオロフェニル−、4−メトキシフェニル−、および−フェニルから選択され;
R2は、水素、−メチル、−エチル、フェニル、−プロピル、−ブチル、メトキシ−プロピル−、および−イソプロピルから選択され;
R3は、4−クロロフェニル−、4−メトキシフェニル−、シクロペンチルメチル−、−フェニル、1,3−ベンゾジオキソリル−、3,4−ジクロロフェニル、およびベンズアミドから選択され;
R4は、水素、−フェニル、2−メチルスルファニルエチル−、および−イソブタニルから選択される、医薬組成物。 - 炎症性皮膚疾患は、ネザートン症候群、アトピー性皮膚炎、接触皮膚炎、湿疹、乾癬、ざ瘡、表皮過角化症、表皮肥厚症、表皮炎症、皮膚炎症、およびそう痒症から選択される、請求項1に記載の医薬組成物。
- 皮膚病の処置のための薬物の製造における式Iの化合物、またはその薬学的に許容可能な塩の使用であって、
R1は、5−メチル−3−イソキサゾリル−、4−フルオロフェニル−、4−メトキシフェニル−、および−フェニルから選択され;
R2は、水素、−メチル、−エチル、フェニル、−プロピル、−ブチル、メトキシ−プロピル−、および−イソプロピルから選択され;
R3は、4−クロロフェニル−、4−メトキシフェニル−、シクロペンチルメチル−、−フェニル、1,3−ベンゾジオキソリル−、3,4−ジクロロフェニル、およびベンズアミドから選択され;
R4は、水素、−フェニル、2−メチルスルファニルエチル−、および−イソブタニルから選択される、使用。 - 式Iの少なくとも1つの化合物、またはその薬学的に許容可能な塩を含む、化粧品またはスキンケア用の組成物であって、
R1は、5−メチル−3−イソキサゾリル−、4−フルオロフェニル−、4−メトキシフェニル−、および−フェニルから選択され;
R2は、水素、−メチル、−エチル、フェニル、−プロピル、−ブチル、メトキシ−プロピル−、および−イソプロピルから選択され;
R3は、4−クロロフェニル−、4−メトキシフェニル−、シクロペンチルメチル−、−フェニル、1,3−ベンゾジオキソリル−、3,4−ジクロロフェニル、およびベンズアミドから選択され;
R4は、水素、−フェニル、2−メチルスルファニルエチル−、および−イソブタニルから選択され、
前記組成物が、局所投与に適した形態であり、およびクリーム、軟膏、ローション、リニメント、ゲル、ペースト、スティック、スプレー、シャンプー、石鹸、ヘアコンディショナーおよび粉末から成る群から選択される、化粧品またはスキンケア用の組成物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE1430004-0 | 2014-01-23 | ||
SE1430004 | 2014-01-23 | ||
JP2016544671A JP6552010B2 (ja) | 2014-01-23 | 2015-01-22 | 新しいカリクレイン7阻害剤 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2016544671A Division JP6552010B2 (ja) | 2014-01-23 | 2015-01-22 | 新しいカリクレイン7阻害剤 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2019163296A JP2019163296A (ja) | 2019-09-26 |
JP6932386B2 true JP6932386B2 (ja) | 2021-09-08 |
Family
ID=53681745
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2016544671A Active JP6552010B2 (ja) | 2014-01-23 | 2015-01-22 | 新しいカリクレイン7阻害剤 |
JP2019091722A Active JP6932386B2 (ja) | 2014-01-23 | 2019-05-14 | 新しいカリクレイン7阻害剤 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2016544671A Active JP6552010B2 (ja) | 2014-01-23 | 2015-01-22 | 新しいカリクレイン7阻害剤 |
Country Status (16)
Country | Link |
---|---|
US (1) | US9744148B2 (ja) |
EP (1) | EP3097084B1 (ja) |
JP (2) | JP6552010B2 (ja) |
CN (1) | CN106132940B (ja) |
AU (1) | AU2015209759B2 (ja) |
CA (1) | CA2934024C (ja) |
CY (1) | CY1123707T1 (ja) |
DK (1) | DK3097084T3 (ja) |
ES (1) | ES2834851T3 (ja) |
HR (1) | HRP20201915T1 (ja) |
HU (1) | HUE052990T2 (ja) |
LT (1) | LT3097084T (ja) |
PT (1) | PT3097084T (ja) |
RS (1) | RS61142B1 (ja) |
SI (1) | SI3097084T1 (ja) |
WO (1) | WO2015112079A1 (ja) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9744148B2 (en) * | 2014-01-23 | 2017-08-29 | Sixera Pharma Ab | Kallikrein 7 inhibitors |
EP3305781A1 (en) * | 2016-10-07 | 2018-04-11 | Deutsches Krebsforschungszentrum | Chemical substances which inhibit the enzymatic activity of human kallikrein-related peptidase 6 (klk6) |
US20200040103A1 (en) | 2018-03-14 | 2020-02-06 | Genentech, Inc. | Anti-klk5 antibodies and methods of use |
GB201809378D0 (en) * | 2018-06-07 | 2018-07-25 | Glaxosmithkline Ip Dev Ltd | Novel compounds |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2514355A1 (fr) * | 1981-10-14 | 1983-04-15 | Fabre Sa Pierre | Derives de biphenyl alcoyl carboxylates, leur procede de preparation et leur utilisation comme medicaments |
WO2003101941A2 (en) | 2002-05-31 | 2003-12-11 | Genzyme Corporation | Alpha acyloxyacetamides for kallikrein and urokinase inhibition |
CA2525383C (en) | 2003-06-06 | 2012-03-06 | Arexis Ab | Use of heterocyclic compounds as scce inhibitors |
EP2094082A2 (en) * | 2006-11-23 | 2009-09-02 | Vib Vzw | Activators of lateral root formation |
EA018050B1 (ru) * | 2007-06-28 | 2013-05-30 | Новартис Аг | Модуляторы калликреина 7, фармацевтическая композиция, содержащая эти соединения, способ лечения нарушений, опосредуемых активностью калликреина 7 |
US8415305B2 (en) | 2007-08-17 | 2013-04-09 | Novartis Ag | Use of cyclic depsipeptides to inhibit kallikrein 7 |
PT2183273T (pt) | 2007-08-17 | 2017-05-22 | Novartis Ag | Depsipéptidos cíclicos |
US8143269B2 (en) | 2008-10-03 | 2012-03-27 | Calcimedica, Inc. | Inhibitors of store operated calcium release |
EP2545916A1 (en) * | 2011-07-15 | 2013-01-16 | Universite Pierre Et Marie Curie - Paris 6 | Use of coumarin derivatives for the preparation of drugs for treating skin diseases |
US9744148B2 (en) * | 2014-01-23 | 2017-08-29 | Sixera Pharma Ab | Kallikrein 7 inhibitors |
-
2015
- 2015-01-22 US US15/113,658 patent/US9744148B2/en active Active
- 2015-01-22 EP EP15740983.0A patent/EP3097084B1/en active Active
- 2015-01-22 LT LTEP15740983.0T patent/LT3097084T/lt unknown
- 2015-01-22 RS RS20201461A patent/RS61142B1/sr unknown
- 2015-01-22 CA CA2934024A patent/CA2934024C/en active Active
- 2015-01-22 CN CN201580005402.3A patent/CN106132940B/zh active Active
- 2015-01-22 DK DK15740983.0T patent/DK3097084T3/da active
- 2015-01-22 AU AU2015209759A patent/AU2015209759B2/en not_active Ceased
- 2015-01-22 JP JP2016544671A patent/JP6552010B2/ja active Active
- 2015-01-22 WO PCT/SE2015/050060 patent/WO2015112079A1/en active Application Filing
- 2015-01-22 ES ES15740983T patent/ES2834851T3/es active Active
- 2015-01-22 PT PT157409830T patent/PT3097084T/pt unknown
- 2015-01-22 HU HUE15740983A patent/HUE052990T2/hu unknown
- 2015-01-22 SI SI201531440T patent/SI3097084T1/sl unknown
-
2019
- 2019-05-14 JP JP2019091722A patent/JP6932386B2/ja active Active
-
2020
- 2020-12-01 HR HRP20201915TT patent/HRP20201915T1/hr unknown
- 2020-12-04 CY CY20201101150T patent/CY1123707T1/el unknown
Also Published As
Publication number | Publication date |
---|---|
JP6552010B2 (ja) | 2019-07-31 |
AU2015209759B2 (en) | 2018-11-29 |
CA2934024A1 (en) | 2015-07-30 |
EP3097084A1 (en) | 2016-11-30 |
US9744148B2 (en) | 2017-08-29 |
HUE052990T2 (hu) | 2021-05-28 |
JP2019163296A (ja) | 2019-09-26 |
AU2015209759A1 (en) | 2016-07-07 |
RS61142B1 (sr) | 2020-12-31 |
SI3097084T1 (sl) | 2021-01-29 |
US20170000753A1 (en) | 2017-01-05 |
LT3097084T (lt) | 2020-12-28 |
DK3097084T3 (da) | 2020-12-21 |
HRP20201915T1 (hr) | 2021-01-22 |
CA2934024C (en) | 2022-08-23 |
WO2015112079A1 (en) | 2015-07-30 |
PT3097084T (pt) | 2020-12-09 |
JP2017505299A (ja) | 2017-02-16 |
ES2834851T3 (es) | 2021-06-18 |
EP3097084B1 (en) | 2020-09-30 |
CY1123707T1 (el) | 2022-03-24 |
EP3097084A4 (en) | 2017-10-04 |
CN106132940B (zh) | 2019-04-23 |
CN106132940A (zh) | 2016-11-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6932386B2 (ja) | 新しいカリクレイン7阻害剤 | |
JP6858286B2 (ja) | ライソゾーム蓄積症を治療するためのシクロデキストリン | |
JP6464266B2 (ja) | 皮膚状態改善活性を有するペプチド及びその用途 | |
EP3097085B1 (en) | Benzoxazinone derivatives for treatment of skin diseases | |
WO2014059306A1 (en) | Pyrimidine hydroxy amide compounds as protein deacetylase inhibitors and methods of use thereof | |
BG103338A (bg) | Нови производни на пиперидинкетокарбоксилни киселини, тяхното получаване и използването им | |
KR101370670B1 (ko) | 플라본 화합물의 15-하이드록시프로스타글란딘 탈수소효소 활성의 억제 효능 및 그의 용도 | |
JP2017505299A5 (ja) | ||
TW201331202A (zh) | [1,2,4]三唑并吡啶及其作為磷酸二酯酶抑制劑之用途 | |
JP7433625B2 (ja) | Mmp発現抑制剤 | |
GB2450780A (en) | Compositions containing serine protease inhibitors |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20190604 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20190604 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20200427 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20200721 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20201216 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20210416 |
|
C60 | Trial request (containing other claim documents, opposition documents) |
Free format text: JAPANESE INTERMEDIATE CODE: C60 Effective date: 20210416 |
|
C11 | Written invitation by the commissioner to file amendments |
Free format text: JAPANESE INTERMEDIATE CODE: C11 Effective date: 20210506 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20210610 |
|
C21 | Notice of transfer of a case for reconsideration by examiners before appeal proceedings |
Free format text: JAPANESE INTERMEDIATE CODE: C21 Effective date: 20210614 |
|
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: 20210804 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20210811 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6932386 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |