JP2021119190A - 線維症疾患の治療及び/又は予防用インドリン誘導体 - Google Patents
線維症疾患の治療及び/又は予防用インドリン誘導体 Download PDFInfo
- Publication number
- JP2021119190A JP2021119190A JP2021078805A JP2021078805A JP2021119190A JP 2021119190 A JP2021119190 A JP 2021119190A JP 2021078805 A JP2021078805 A JP 2021078805A JP 2021078805 A JP2021078805 A JP 2021078805A JP 2021119190 A JP2021119190 A JP 2021119190A
- Authority
- JP
- Japan
- Prior art keywords
- nhc
- day
- fibrosis
- pharmaceutical composition
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 33
- 238000011282 treatment Methods 0.000 title claims abstract description 27
- 206010016654 Fibrosis Diseases 0.000 title claims abstract description 18
- 230000004761 fibrosis Effects 0.000 title claims abstract description 17
- 230000002265 prevention Effects 0.000 title claims abstract description 14
- 125000003387 indolinyl group Chemical class N1(CCC2=CC=CC=C12)* 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 67
- 238000000034 method Methods 0.000 claims abstract description 46
- 208000005069 pulmonary fibrosis Diseases 0.000 claims description 28
- 239000008194 pharmaceutical composition Substances 0.000 claims description 25
- 150000003839 salts Chemical class 0.000 claims description 24
- 239000004480 active ingredient Substances 0.000 claims description 23
- 230000003510 anti-fibrotic effect Effects 0.000 claims description 21
- 201000010099 disease Diseases 0.000 claims description 21
- 239000012453 solvate Substances 0.000 claims description 21
- ISWRGOKTTBVCFA-UHFFFAOYSA-N pirfenidone Chemical group C1=C(C)C=CC(=O)N1C1=CC=CC=C1 ISWRGOKTTBVCFA-UHFFFAOYSA-N 0.000 claims description 16
- 229960003073 pirfenidone Drugs 0.000 claims description 16
- 239000003795 chemical substances by application Substances 0.000 claims description 14
- 125000001072 heteroaryl group Chemical group 0.000 claims description 14
- 239000000651 prodrug Substances 0.000 claims description 14
- 229940002612 prodrug Drugs 0.000 claims description 14
- 230000003176 fibrotic effect Effects 0.000 claims description 13
- 239000002552 dosage form Substances 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 10
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
- 125000004366 heterocycloalkenyl group Chemical group 0.000 claims description 10
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 10
- 210000004072 lung Anatomy 0.000 claims description 10
- KPWYNAGOBXLMSE-UHFFFAOYSA-N Tipelukast Chemical compound CCCC1=C(O)C(C(C)=O)=CC=C1SCCCOC1=CC=C(C(C)=O)C(OCCCC(O)=O)=C1CCC KPWYNAGOBXLMSE-UHFFFAOYSA-N 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000000304 alkynyl group Chemical group 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- 239000002775 capsule Substances 0.000 claims description 7
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- MGTIFSBCGGAZDB-UHFFFAOYSA-N 3-[1-(benzenesulfonyl)-2,3-dihydroindol-5-yl]-n-hydroxyprop-2-enamide Chemical compound C1CC2=CC(C=CC(=O)NO)=CC=C2N1S(=O)(=O)C1=CC=CC=C1 MGTIFSBCGGAZDB-UHFFFAOYSA-N 0.000 claims description 5
- 102100031168 CCN family member 2 Human genes 0.000 claims description 5
- 101000777550 Homo sapiens CCN family member 2 Proteins 0.000 claims description 5
- 101001043352 Homo sapiens Lysyl oxidase homolog 2 Proteins 0.000 claims description 5
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 claims description 5
- 102100021948 Lysyl oxidase homolog 2 Human genes 0.000 claims description 5
- 238000011260 co-administration Methods 0.000 claims description 5
- 208000036971 interstitial lung disease 2 Diseases 0.000 claims description 5
- XZXHXSATPCNXJR-ZIADKAODSA-N nintedanib Chemical compound O=C1NC2=CC(C(=O)OC)=CC=C2\C1=C(C=1C=CC=CC=1)\NC(C=C1)=CC=C1N(C)C(=O)CN1CCN(C)CC1 XZXHXSATPCNXJR-ZIADKAODSA-N 0.000 claims description 5
- 229960004378 nintedanib Drugs 0.000 claims description 5
- 229950009513 simtuzumab Drugs 0.000 claims description 5
- 206010072877 Intestinal fibrosis Diseases 0.000 claims description 4
- 150000001345 alkine derivatives Chemical class 0.000 claims description 4
- 125000004104 aryloxy group Chemical group 0.000 claims description 4
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 201000002793 renal fibrosis Diseases 0.000 claims description 4
- 208000005641 Adenomyosis Diseases 0.000 claims description 3
- 206010061692 Benign muscle neoplasm Diseases 0.000 claims description 3
- 201000003883 Cystic fibrosis Diseases 0.000 claims description 3
- 201000004458 Myoma Diseases 0.000 claims description 3
- 230000009787 cardiac fibrosis Effects 0.000 claims description 3
- 201000009274 endometriosis of uterus Diseases 0.000 claims description 3
- 238000002560 therapeutic procedure Methods 0.000 claims description 3
- 238000002639 hyperbaric oxygen therapy Methods 0.000 claims description 2
- 238000011321 prophylaxis Methods 0.000 claims description 2
- 230000002685 pulmonary effect Effects 0.000 claims description 2
- 229910052705 radium Inorganic materials 0.000 claims description 2
- 238000002054 transplantation Methods 0.000 claims description 2
- 231100000135 cytotoxicity Toxicity 0.000 abstract description 7
- 230000003013 cytotoxicity Effects 0.000 abstract description 7
- 230000001738 genotoxic effect Effects 0.000 abstract description 6
- 231100000025 genetic toxicology Toxicity 0.000 abstract description 5
- 241000699670 Mus sp. Species 0.000 description 32
- 239000000203 mixture Substances 0.000 description 25
- 108010006654 Bleomycin Proteins 0.000 description 19
- 229960001561 bleomycin Drugs 0.000 description 19
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 19
- 210000001519 tissue Anatomy 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- 238000009472 formulation Methods 0.000 description 12
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 12
- 239000003814 drug Substances 0.000 description 10
- -1 1-benzenesulfonyl-2,3-dihydro-1H-indole-5-yl Chemical group 0.000 description 9
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 9
- 229960003957 dexamethasone Drugs 0.000 description 9
- 208000035475 disorder Diseases 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 208000024891 symptom Diseases 0.000 description 8
- 229940124597 therapeutic agent Drugs 0.000 description 8
- 230000001225 therapeutic effect Effects 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- 238000003556 assay Methods 0.000 description 7
- 230000000069 prophylactic effect Effects 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 239000000377 silicon dioxide Substances 0.000 description 6
- 230000008901 benefit Effects 0.000 description 5
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 230000001629 suppression Effects 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 239000000443 aerosol Substances 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- 239000003276 histone deacetylase inhibitor Substances 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- 229920001817 Agar Polymers 0.000 description 3
- 238000010953 Ames test Methods 0.000 description 3
- 231100000039 Ames test Toxicity 0.000 description 3
- 208000011231 Crohn disease Diseases 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 239000008272 agar Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- ZNMRDZZRAFJOKY-UHFFFAOYSA-N ethanesulfonic acid methyl 2-hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylate Chemical compound CCS(=O)(=O)O.CN1CCN(CC1)CC(=O)N(C)C2=CC=C(C=C2)N=C(C3=CC=CC=C3)C4=C(NC5=C4C=CC(=C5)C(=O)OC)O ZNMRDZZRAFJOKY-UHFFFAOYSA-N 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 229950002183 lebrikizumab Drugs 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 229940015847 ofev Drugs 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000003449 preventive effect Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 229950004996 tipelukast Drugs 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 206010009900 Colitis ulcerative Diseases 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 102000003964 Histone deacetylase Human genes 0.000 description 2
- 108090000353 Histone deacetylase Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 238000000692 Student's t-test Methods 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 208000020832 chronic kidney disease Diseases 0.000 description 2
- 210000002808 connective tissue Anatomy 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 2
- 229940043264 dodecyl sulfate Drugs 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005538 encapsulation Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 2
- 239000007943 implant Substances 0.000 description 2
- 150000002476 indolines Chemical class 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 239000007928 intraperitoneal injection Substances 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- 231100000299 mutagenicity Toxicity 0.000 description 2
- 230000007886 mutagenicity Effects 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 235000021317 phosphate Nutrition 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000037390 scarring Effects 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 238000012353 t test Methods 0.000 description 2
- 230000008719 thickening Effects 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- LSPHULWDVZXLIL-UHFFFAOYSA-N (+/-)-Camphoric acid Chemical compound CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
- FFRUQSUMDFNBLG-UHFFFAOYSA-N 2-(2,4,5-trichlorophenoxy)ethyl 2,2,2-trichloroacetate Chemical compound ClC1=CC(Cl)=C(OCCOC(=O)C(Cl)(Cl)Cl)C=C1Cl FFRUQSUMDFNBLG-UHFFFAOYSA-N 0.000 description 1
- 229940080296 2-naphthalenesulfonate Drugs 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical compound OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-M 3-phenylpropionate Chemical compound [O-]C(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-M 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 1
- 208000022309 Alcoholic Liver disease Diseases 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 102000008131 Bone Morphogenetic Protein 7 Human genes 0.000 description 1
- 108010049870 Bone Morphogenetic Protein 7 Proteins 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- 0 CC*C1c(c(*)c(*)c(C)c2*)c2N(*)C1 Chemical compound CC*C1c(c(*)c(*)c(C)c2*)c2N(*)C1 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 206010007572 Cardiac hypertrophy Diseases 0.000 description 1
- 208000006029 Cardiomegaly Diseases 0.000 description 1
- 208000031404 Chromosome Aberrations Diseases 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- NBSCHQHZLSJFNQ-GASJEMHNSA-N D-Glucose 6-phosphate Chemical compound OC1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H](O)[C@H]1O NBSCHQHZLSJFNQ-GASJEMHNSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 101001036711 Gallus gallus Heat shock protein beta-1 Proteins 0.000 description 1
- VFRROHXSMXFLSN-UHFFFAOYSA-N Glc6P Natural products OP(=O)(O)OCC(O)C(O)C(O)C(O)C=O VFRROHXSMXFLSN-UHFFFAOYSA-N 0.000 description 1
- 108091005772 HDAC11 Proteins 0.000 description 1
- 102100039869 Histone H2B type F-S Human genes 0.000 description 1
- 102100039996 Histone deacetylase 1 Human genes 0.000 description 1
- 102100039385 Histone deacetylase 11 Human genes 0.000 description 1
- 102100021454 Histone deacetylase 4 Human genes 0.000 description 1
- 102100022537 Histone deacetylase 6 Human genes 0.000 description 1
- 108010033040 Histones Proteins 0.000 description 1
- 101001035372 Homo sapiens Histone H2B type F-S Proteins 0.000 description 1
- 101001035024 Homo sapiens Histone deacetylase 1 Proteins 0.000 description 1
- 101000899259 Homo sapiens Histone deacetylase 4 Proteins 0.000 description 1
- 101000899330 Homo sapiens Histone deacetylase 6 Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- WWGBHDIHIVGYLZ-UHFFFAOYSA-N N-[4-[3-[[[7-(hydroxyamino)-7-oxoheptyl]amino]-oxomethyl]-5-isoxazolyl]phenyl]carbamic acid tert-butyl ester Chemical compound C1=CC(NC(=O)OC(C)(C)C)=CC=C1C1=CC(C(=O)NCCCCCCC(=O)NO)=NO1 WWGBHDIHIVGYLZ-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 231100000000 OECD 487 In Vitro Mammalian Cell Micronucleus Test Toxicity 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 206010050207 Skin fibrosis Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- 102000046299 Transforming Growth Factor beta1 Human genes 0.000 description 1
- 101800002279 Transforming growth factor beta-1 Proteins 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000008055 alkyl aryl sulfonates Chemical class 0.000 description 1
- 229940045714 alkyl sulfonate alkylating agent Drugs 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 208000036878 aneuploidy Diseases 0.000 description 1
- 231100001075 aneuploidy Toxicity 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000000022 bacteriostatic agent Substances 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N beta-phenylpropanoic acid Natural products OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- 230000008512 biological response Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- FATUQANACHZLRT-KMRXSBRUSA-L calcium glucoheptonate Chemical compound [Ca+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O FATUQANACHZLRT-KMRXSBRUSA-L 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000007705 chemical test Methods 0.000 description 1
- 235000015111 chews Nutrition 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 231100000005 chromosome aberration Toxicity 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- JVHIPYJQMFNCEK-UHFFFAOYSA-N cytochalasin Natural products N1C(=O)C2(C(C=CC(C)CC(C)CC=C3)OC(C)=O)C3C(O)C(=C)C(C)C2C1CC1=CC=CC=C1 JVHIPYJQMFNCEK-UHFFFAOYSA-N 0.000 description 1
- ZMAODHOXRBLOQO-UHFFFAOYSA-N cytochalasin-A Natural products N1C(=O)C23OC(=O)C=CC(=O)CCCC(C)CC=CC3C(O)C(=C)C(C)C2C1CC1=CC=CC=C1 ZMAODHOXRBLOQO-UHFFFAOYSA-N 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 239000007933 dermal patch Substances 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 210000005069 ears Anatomy 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940079360 enema for constipation Drugs 0.000 description 1
- 230000008029 eradication Effects 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 230000005713 exacerbation Effects 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000013100 final test Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 231100000024 genotoxic Toxicity 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000003709 heart valve Anatomy 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 229940121372 histone deacetylase inhibitor Drugs 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 230000003463 hyperproliferative effect Effects 0.000 description 1
- 238000011532 immunohistochemical staining Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 108700016226 indium-bleomycin Proteins 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- 229940099584 lactobionate Drugs 0.000 description 1
- JYTUSYBCFIZPBE-AMTLMPIISA-N lactobionic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-N 0.000 description 1
- 229940070765 laurate Drugs 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 210000001853 liver microsome Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 230000003228 microsomal effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 231100000219 mutagenic Toxicity 0.000 description 1
- 231100000243 mutagenic effect Toxicity 0.000 description 1
- 230000003505 mutagenic effect Effects 0.000 description 1
- SWKDMSRRIBZZAY-UHFFFAOYSA-N n-benzyl-n-(4,5-dihydro-1h-imidazol-2-ylmethyl)aniline;hydrochloride Chemical compound Cl.N=1CCNC=1CN(C=1C=CC=CC=1)CC1=CC=CC=C1 SWKDMSRRIBZZAY-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 230000036573 scar formation Effects 0.000 description 1
- 208000013220 shortness of breath Diseases 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 238000001238 wet grinding Methods 0.000 description 1
- 230000029663 wound healing Effects 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Cardiology (AREA)
- Pulmonology (AREA)
- Heart & Thoracic Surgery (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Indole Compounds (AREA)
Abstract
Description
nは0、1、又は2であり、
R1はSO2Raであり、Raは、アルケニル、アルキニル、フェニル、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、又はヘテロシクロアルケニルであり、
R2は、アルキル、アルケニル、アルキニル、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、ヘテロシクロアルケニル、ハロゲン、シアノ、ニトロ、ORb、SRb、S(O)Rb、NHC(O)−CH=CH−C(O)Rb、NHC(O)−CH=CH−C(O)NRcRd、SO2NRcRd、OC(O)Rb、C(O)NRcRd、NRcRd、NHC(O)Rb、NHC(O)NRcRd、又はNHC(S)Rcであり、Rb、Rc及びRdはそれぞれ独立してH、ヒドロキシ、アルコキシ、アリールオキシ、ヘテロアリールオキシ、アルキル、アルケニル、アルキニル、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、又はヘテロシクロアルケニルであり、
R3、R4、R5及びR6はそれぞれ独立してH、アルキル、アルケニル、アルキニル、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、ヘテロシクロアルケニル、ハロゲン、シアノ、ニトロ、ORb、SRb、S(O)Rb、CH=CH−C(O)NRcRd、NHC(O)−CH=CH−C(O)Rb、NHC(O)−CH=CH−C(O)NRcRd、SO2NRcRd、OC(O)Rb、C(O)NRcRd、NRcRd、NHC(O)Rb、NHC(O)NRcRd、又はNHC(S)Rcであり、Rb、Rc及びRdはそれぞれ独立してH、ヒドロキシ、アルコキシ、アリールオキシ、ヘテロアリールオキシ、アルキル、アルケニル、アルキニル、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、又はヘテロシクロアルケニルである。
〈実施例〉
化合物3−(1−ベンゼンスルホニル−2,3−ジヒドロ−1H−インドール−5−イル)−N−ヒドロキシアクリルアミド(以下、「TMU−C−0012」と称する)を、変異原性潜在力を評価するために、エイムス試験を用いて評価した。ネズミチフス菌の2つのヒスチジン栄養素要求性突然変異体(TA98及びTA100)を使用した。試験菌株は、凍結された作業ストックバイアルから得られ、室温で解凍された。0.2mLのアリコートを、25mLの栄養ブイヨウ培地に接種し、次いで振盪(120rpm)しながら35〜37℃で16〜18時間培養した。30,000、3,000、300及び30μg/mLの4つのストック濃度を得るように、試験物質を10倍希釈でDMSOに溶解した。8mMのMgCl2、33mMのKCl、4mMのNADP、5mMのグルコース−6−リン酸、100mMのNaH2PO4(pH7.4)及び4%(v/v)のアクロール1254誘発性雄性ラット肝臓ミクロソーム酵素ホモジネート(S9)を含有するラット肝臓ミクロソーム酵素ホモジネート(S9)混合物を調製した。試験化合物ストック溶液の0.2mLのアリコートを、0.1mLの菌株培養物及び0.5mLのラット肝臓酵素ホモジネート(S9)混合物又は0.5mLのPBSと組み合わせ、次いで、混合物を、35〜37℃で振盪(120rpm)しながら20min培養した。溶解した上層寒天(2mL、0.05mMのヒスタジン及び0.05mMのビオチンを含む)を加え、そして、混合物を最小グルコース寒天プレート(ペトリプレートあたり30mLの下層寒天)の表面に注いで、3000、300、30及び3μg/プレートの最終試験物質濃度を得た。プレートを37℃で72時間培養し、次いでHis+復帰突然変異コロニーの数を数えた。ビヒクル対照と比較して復帰突然変異コロニーを3倍増加(3×)させた治療を変異原性とみなした。コロニー数をビヒクル対照の≦50%に低減した治療を細胞毒性とみなした。アッセイは3回実施した。
インビトロ小核(MNvit)アッセイは、培養ヒト細胞を用いて、異数性誘発物質及び染色体異常誘発物質の両方を検出することにより、染色体損傷の可能性をインビトロで調べるための包括的な基礎を提供する。アッセイは、OECD化学物質試験法ガイドライン-TG487、インビトロ哺乳類細胞小核試験(MNvit)(2014)に従って、アクチン重合阻害剤であるサイトカラシン(Cyto B)を用いて行われた。
PREC 顕微鏡下で観察可能な沈殿物。
CYTO 不十分な数のスコアされた細胞をもたらす高い細胞毒性(≧80%細胞毒性)。
注:
「+」 t−試験によってp<0.05であり、小核の細胞の%がバックグラウンドレベルより少なくとも3倍高い。
「+/−」 t−試験によってp<0.05であり、小核の細胞の%がバックグラウンドレベルより少なくとも2倍高い。
実施例3 インビボ有効性:ブレオマイシン(BLM)誘発性肺線維症マウスモデルアッセイ
実施例4 インビボ有効性:OVA肺線維症マウスモデルアッセイ
実施例5 マウスのシリカ誘発性肺線維症に対するTMU−C−0012の効果
実施例6 マウスのCCl4誘発性肝線維症に対するTMU−C−0012の効果
Claims (27)
- 対象の線維症疾患の予防及び/又は治療のための方法であって、有効量の式(I)の化合物又は薬学的に許容される塩、溶媒和化合物若しくはプロドラッグを活性成分として対象に投与することを含み、
nは0、1、又は2であり、
R1はSO2Raであり、Raは、アルケニル、アルキニル、フェニル、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、又はヘテロシクロアルケニルであり、
R2は、アルキル、アルケニル、アルキニル、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、ヘテロシクロアルケニル、ハロゲン、シアノ、ニトロ、ORb、SRb、S(O)Rb、NHC(O)−CH=CH−C(O)Rb、NHC(O)−CH=CH−C(O)NRcRd、SO2NRcRd、OC(O)Rb、C(O)NRcRd、NRcRd、NHC(O)Rb、NHC(O)NRcRd、又はNHC(S)Rcであり、Rb、Rc及びRdはそれぞれ独立してH、ヒドロキシ、アルコキシ、アリールオキシ、ヘテロアリールオキシ、アルキル、アルケニル、アルキニル、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、又はヘテロシクロアルケニルであり、
R3、R4、R5及びR6はそれぞれ独立してH、アルキル、アルケニル、アルキニル、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、ヘテロシクロアルケニル、ハロゲン、シアノ、ニトロ、ORb、SRb、S(O)Rb、CH=CH−C(O)NRcRd、NHC(O)−CH=CH−C(O)Rb、NHC(O)−CH=CH−C(O)NRcRd、SO2NRcRd、OC(O)Rb、C(O)NRcRd、NRcRd、NHC(O)Rb、NHC(O)NRcRd、又はNHC(S)Rcであり、Rb、Rc及びRdはそれぞれ独立してH、ヒドロキシ、アルコキシ、アリールオキシ、ヘテロアリールオキシ、アルキル、アルケニル、アルキニル、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、又はヘテロシクロアルケニルである、ことを特徴とする方法。 - R4は、CH=CH−C(O)NRcRd、NHC(O)−CH=CH−C(O)Rb、又はNHC(O)−CH=CH−C(O)NRcRdである、ことを特徴とする請求項1に記載の方法。
- R4は、C(O)NHOH、CH=CH−C(O)NHOH、NHC(O)−CH=CH−C(O)OH、又はNHC(O)−CH=CH−C(O)NHOHである、ことを特徴とする請求項1に記載の方法。
- R4は、CH=CH−C(O)NHOHである、ことを特徴とする請求項1に記載の方法。
- R1はSO2Raであり、Raは、ハロゲン、ヒドロキシ、アルコキシ、アミノ、シアノ、又はニトロで置換されてもよいヘテロアリール又はフェニルである、ことを特徴とする請求項1に記載の方法。
- R2は、NHC(O)−CH=CH−C(O)Rb又はNHC(O)−CH=CH−C(O)NRcRdであり、R3、R5及びR6は独立してCH=CH−C(O)NRcRd、NHC(O)−CH=CH−C(O)Rb、又はNHC(O)−CH=CH−C(O)NRcRdである、ことを特徴とする請求項1に記載の方法。
- R2は、NHC(O)−CH=CH−C(O)OH、又はNHC(O)−CH=CH−C(O)NHOHであり、R3、R5、及びR6は独立してCH=CH−C(O)NHOH、NHC(O)−CH=CH−C(O)OH、又はNHC(O)−CH=CH−C(O)NHOHであり、R1はSO2Raであり、Raはハロゲン、ヒドロキシ、アルコキシ、アミノ、シアノ、又はニトロで置換されてもよいヘテロアリール又はフェニルである、ことを特徴とする請求項1に記載の方法。
- 前記方法に使用される前記活性成分の前記有効量は、約1.5mg/kg/日〜約20mg/kg/日の範囲にある、ことを特徴とする請求項1に記載の方法。
- 治療のための前記有効量は、約5.0mg/kg/日〜約20mg/kg/日である、ことを特徴とする請求項1に記載の方法。
- 予防のための前記有効量は、約1.5mg/kg/日〜約10mg/kg/日である、ことを特徴とする請求項1に記載の方法。
- 前記活性成分は、さらに、第2抗線維症剤と共投与される、ことを特徴とする請求項1に記載の方法。
- 前記第2抗線維症剤は、ピルフェニドン、ニンテダニブ、LOXL2抗体、シムツズマブ、IL−13抗体、レブリキズマブ、αVβ6抗体、STX−100、CTGF抗体、FG−3019、タイペルカスト、MN−001、エアロゾル状ピルフェニドン又はGP−101である、ことを特徴とする請求項13に記載の方法。
- 前記共投与は、同時投与、個別投与又は逐次投与である、ことを特徴とする請求項13に記載の方法。
- 前記線維症疾患は、皮膚線維症、肺線維症、腎線維症、肝線維症、腸管線維症、嚢胞性繊維症、心線維症、子宮平滑筋腫又は腺筋症である、ことを特徴とする請求項1に記載の方法。
- 前記肺線維症は、特発性肺線維症である、ことを特徴とする請求項16に記載の方法。
- 前記肺線維症又は特発性肺線維症の治療は、肺移植、高圧酸素療法(HBOT)又は肺リハビリテーションと共投与された療法をさらに含む、ことを特徴とする請求項16に記載の方法。
- 医薬組成物であって、活性成分として、約1日量が約100mg〜約1,400mgの範囲の請求項1に記載の式(I)の化合物又は薬学的に許容される塩、溶媒和化合物若しくはプロドラッグを1つ以上の単位剤形で含む、ことを特徴とする医薬組成物。
- 1つ以上のカプセル形態又は錠剤形態である、ことを特徴とする請求項19に記載の医薬組成物。
- 1日量が約140mg〜約1,050mgの範囲の前記活性成分を1つ以上の単位剤形で含む、ことを特徴とする請求項19に記載の医薬組成物。
- 約100mg〜約300の前記活性成分を単一の錠剤に含む、ことを特徴とする請求項19に記載の医薬組成物。
- 約100mg〜約500mgの前記活性成分を単一のカプセルに含む、ことを特徴とする請求項19に記載の医薬組成物。
- 第2抗線維症剤を更に含む、ことを特徴とする請求項19に記載の医薬組成物。
- 前記第2抗線維症剤は、ピルフェニドン、ニンテダニブ、LOXL2抗体、シムツズマブ、IL−13抗体、レブリキズマブ、αVβ6抗体、STX−100、CTGF抗体、FG−3019、タイペルカスト、MN−001、エアロゾル状ピルフェニドン又はGP−101である、ことを特徴とする請求項24に記載の医薬組成物。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2021078805A JP2021119190A (ja) | 2015-10-27 | 2021-05-06 | 線維症疾患の治療及び/又は予防用インドリン誘導体 |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2018521343A JP7302120B2 (ja) | 2015-10-27 | 2015-10-27 | 線維症疾患の治療及び/又は予防用インドリン誘導体 |
PCT/US2015/057600 WO2017074317A1 (en) | 2015-10-27 | 2015-10-27 | Indoline derivatives for treatment and/or prevention of fibrosis diseases |
JP2021078805A JP2021119190A (ja) | 2015-10-27 | 2021-05-06 | 線維症疾患の治療及び/又は予防用インドリン誘導体 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2018521343A Division JP7302120B2 (ja) | 2015-10-27 | 2015-10-27 | 線維症疾患の治療及び/又は予防用インドリン誘導体 |
Publications (1)
Publication Number | Publication Date |
---|---|
JP2021119190A true JP2021119190A (ja) | 2021-08-12 |
Family
ID=58630805
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2018521343A Active JP7302120B2 (ja) | 2015-10-27 | 2015-10-27 | 線維症疾患の治療及び/又は予防用インドリン誘導体 |
JP2021078805A Pending JP2021119190A (ja) | 2015-10-27 | 2021-05-06 | 線維症疾患の治療及び/又は予防用インドリン誘導体 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2018521343A Active JP7302120B2 (ja) | 2015-10-27 | 2015-10-27 | 線維症疾患の治療及び/又は予防用インドリン誘導体 |
Country Status (9)
Country | Link |
---|---|
US (2) | US11278523B2 (ja) |
EP (1) | EP3368512B1 (ja) |
JP (2) | JP7302120B2 (ja) |
CN (2) | CN108368043B (ja) |
ES (1) | ES2965877T3 (ja) |
HR (1) | HRP20240306T1 (ja) |
RS (1) | RS65201B1 (ja) |
TW (1) | TWI663973B (ja) |
WO (1) | WO2017074317A1 (ja) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11278523B2 (en) * | 2015-10-27 | 2022-03-22 | Taipei Medical University | Indoline derivatives for treatment and/or prevention of fibrosis diseases |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2013523747A (ja) * | 2010-03-29 | 2013-06-17 | タイペイ・メディカル・ユニバーシティ | インドリルヒドロキサメート化合物又はインドリニルヒドロキサメート化合物 |
JP2014526518A (ja) * | 2011-09-15 | 2014-10-06 | タイペイ メディカル ユニバーシティ | 心不全またはニューロン損傷を治療するための化合物およびその方法 |
JP2018531959A (ja) * | 2015-10-27 | 2018-11-01 | タイペイ メディカル ユニバーシティ | 線維症疾患の治療及び/又は予防用インドリン誘導体 |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8158589B2 (en) * | 2003-08-22 | 2012-04-17 | Proyecto Biomedicine Cima, S.L. | Peptides with the capacity to bind to transforming growth factor β1 (TGF-β1) |
AU2007328206B2 (en) | 2006-12-04 | 2013-08-01 | Promedior, Inc. | Conjoint therapy for treating fibrotic diseases |
EP2100879A1 (en) * | 2008-03-13 | 2009-09-16 | 4Sc Ag | Novel N-substituted tetrahydroisoquinoline/isoindoline hydroxamic acid compounds |
SG11201405830VA (en) * | 2012-03-27 | 2014-10-30 | Genentech Inc | Methods of prognosing, diagnosing and treating idiopathic pulmonary fibrosis |
CN105008323B (zh) * | 2012-10-31 | 2018-11-06 | 密歇根大学董事会 | 纤溶酶原激活物抑制因子-1抑制剂和其使用方法 |
MX2016006633A (es) | 2013-11-24 | 2016-12-02 | Univ Taipei Medical | Uso de hidroxamatos de indolilo e indolinilo para tratar trastornos neurodegenerativos o deficiencias cognitivas. |
US20150368195A1 (en) * | 2014-06-20 | 2015-12-24 | Taipei Medical University | Indoline compounds for treatment and/or prevention of inflammation diseases |
US20220072082A1 (en) * | 2017-03-01 | 2022-03-10 | Chengdu Huitai Biomedicine Co., Ltd. | Polypeptide, polypeptide fragment, derivative thereof, and applications thereof |
-
2015
- 2015-10-27 US US15/771,476 patent/US11278523B2/en active Active
- 2015-10-27 CN CN201580084223.3A patent/CN108368043B/zh active Active
- 2015-10-27 ES ES15907425T patent/ES2965877T3/es active Active
- 2015-10-27 CN CN202211450662.XA patent/CN116077489A/zh active Pending
- 2015-10-27 JP JP2018521343A patent/JP7302120B2/ja active Active
- 2015-10-27 WO PCT/US2015/057600 patent/WO2017074317A1/en active Application Filing
- 2015-10-27 RS RS20240213A patent/RS65201B1/sr unknown
- 2015-10-27 HR HRP20240306TT patent/HRP20240306T1/hr unknown
- 2015-10-27 EP EP15907425.1A patent/EP3368512B1/en active Active
- 2015-11-30 TW TW104139995A patent/TWI663973B/zh active
-
2021
- 2021-05-06 JP JP2021078805A patent/JP2021119190A/ja active Pending
-
2022
- 2022-03-02 US US17/653,251 patent/US20220184032A1/en not_active Abandoned
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2013523747A (ja) * | 2010-03-29 | 2013-06-17 | タイペイ・メディカル・ユニバーシティ | インドリルヒドロキサメート化合物又はインドリニルヒドロキサメート化合物 |
JP2014526518A (ja) * | 2011-09-15 | 2014-10-06 | タイペイ メディカル ユニバーシティ | 心不全またはニューロン損傷を治療するための化合物およびその方法 |
JP2018531959A (ja) * | 2015-10-27 | 2018-11-01 | タイペイ メディカル ユニバーシティ | 線維症疾患の治療及び/又は予防用インドリン誘導体 |
Non-Patent Citations (6)
Title |
---|
CELL DEATH AND DISEASE, vol. 5, JPN6019033911, 2014, pages 1166, ISSN: 0005012367 * |
CHEM. BIO. CHEM., vol. 14, JPN6019033916, 20 June 2013 (2013-06-20), pages 1248 - 1254, ISSN: 0005012369 * |
EUR RESPIR J 2014; 43: 1448-1458, JPN6020025588, ISSN: 0005012371 * |
ORG. BIOMOL. CHEM., vol. 12, JPN6019033918, 2014, pages 8966 - 8976, ISSN: 0005012370 * |
PLOS ONE, vol. Vol.7, Issue8, JPN6019033914, 22 August 2012 (2012-08-22), pages 43645, ISSN: 0005012368 * |
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 335, no. 2, JPN6019033921, 18 August 2010 (2010-08-18), pages 266 - 272, ISSN: 0005012366 * |
Also Published As
Publication number | Publication date |
---|---|
CN108368043B (zh) | 2022-11-29 |
JP7302120B2 (ja) | 2023-07-04 |
EP3368512C0 (en) | 2023-12-06 |
TWI663973B (zh) | 2019-07-01 |
WO2017074317A1 (en) | 2017-05-04 |
ES2965877T3 (es) | 2024-04-17 |
CN116077489A (zh) | 2023-05-09 |
HRP20240306T1 (hr) | 2024-05-10 |
JP2018531959A (ja) | 2018-11-01 |
US20180243264A1 (en) | 2018-08-30 |
TW201714614A (zh) | 2017-05-01 |
EP3368512A1 (en) | 2018-09-05 |
US11278523B2 (en) | 2022-03-22 |
EP3368512A4 (en) | 2019-06-26 |
EP3368512B1 (en) | 2023-12-06 |
US20220184032A1 (en) | 2022-06-16 |
CN108368043A (zh) | 2018-08-03 |
RS65201B1 (sr) | 2024-03-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2006248812B2 (en) | Antifungal agents | |
EP2477625A2 (en) | Pharmaceutical compositions and formulations including inhibitors of the pleckstrin homology domain and methods for using same | |
CN106573058B (zh) | 用于纤维化疾病的治疗用途的ppar化合物 | |
US11298346B2 (en) | Methods for treatment of fibrotic diseases | |
JP2015529234A (ja) | 癌を治療するためのレゴラフェニブおよびアセチルサリチル酸の組み合わせ | |
CN114026072A (zh) | 治疗特发性肺纤维化的方法 | |
KR20140129030A (ko) | 캔디다증 및 아스퍼질러스 감염을 치료하기 위한 화합물 및 방법 | |
AU2017361856A1 (en) | Use of sanglifehrin macrocyclic analogues as anticancer compounds | |
US20110288093A1 (en) | Compounds, Compositions, and Methods Comprising Pyridazine Sulfonamide Derivatives | |
US20210379040A1 (en) | Combination treatment of liver disorders | |
CN112638866B (zh) | 索拉非尼衍生物的共晶体及其制备方法 | |
JP2021119190A (ja) | 線維症疾患の治療及び/又は予防用インドリン誘導体 | |
JP6860677B2 (ja) | グローコカリキシンa誘導体、その医薬的に許容できる塩または医薬組成物、およびこれらの乾癬治療用医薬の調製における使用 | |
JP2014502267A (ja) | 炎症及び血管増殖に関連する眼疾患の治療法 | |
CA3141869A1 (en) | Methods of treating cholangiocarcinoma | |
US11958869B2 (en) | Ruthenium arene Schiff-base complexes and uses thereof | |
EP4349341A1 (en) | Pharmaceutical preparation for preventing or treating pulmonary fibrosis | |
WO2023060161A1 (en) | Anti-fungals compounds targeting the synthesis of fungal sphingolipids | |
JPH11189529A (ja) | 抗ヘリコバクター・ピロリ剤 | |
CA3098522A1 (en) | Process for preparing a potent thiazole compound, pharmaceutical formulation and uses thereof | |
CN108863914A (zh) | 吡啶取代的酰肼衍生物及其用途 | |
CN108864033A (zh) | 苯基取代的酰肼衍生物及其用途 | |
CN108863948A (zh) | 嘧啶取代的酰肼衍生物及其用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20210604 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20210604 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20220621 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20220921 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20221115 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20221221 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20230314 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20230714 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20230725 |
|
A912 | Re-examination (zenchi) completed and case transferred to appeal board |
Free format text: JAPANESE INTERMEDIATE CODE: A912 Effective date: 20230825 |