WO2010123049A1 - 癌治療のための選択的ep4受容体拮抗物質 - Google Patents
癌治療のための選択的ep4受容体拮抗物質 Download PDFInfo
- Publication number
- WO2010123049A1 WO2010123049A1 PCT/JP2010/057114 JP2010057114W WO2010123049A1 WO 2010123049 A1 WO2010123049 A1 WO 2010123049A1 JP 2010057114 W JP2010057114 W JP 2010057114W WO 2010123049 A1 WO2010123049 A1 WO 2010123049A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- ethyl
- chloro
- amino
- benzoic acid
- Prior art date
Links
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 155
- 201000011510 cancer Diseases 0.000 title claims abstract description 90
- 238000011282 treatment Methods 0.000 title claims abstract description 22
- 101150109738 Ptger4 gene Proteins 0.000 title abstract description 23
- 239000000126 substance Substances 0.000 title description 10
- 230000001270 agonistic effect Effects 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 192
- 150000003839 salts Chemical class 0.000 claims abstract description 47
- 241001465754 Metazoa Species 0.000 claims abstract description 25
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 21
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 17
- 238000004519 manufacturing process Methods 0.000 claims abstract description 9
- -1 oxopiperidyl group Chemical group 0.000 claims description 184
- 125000004432 carbon atom Chemical group C* 0.000 claims description 181
- 125000000217 alkyl group Chemical group 0.000 claims description 80
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 75
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 71
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 67
- 125000003545 alkoxy group Chemical group 0.000 claims description 54
- 125000005843 halogen group Chemical group 0.000 claims description 54
- 239000004202 carbamide Substances 0.000 claims description 46
- 125000003118 aryl group Chemical group 0.000 claims description 40
- 239000003814 drug Substances 0.000 claims description 35
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 34
- 239000013543 active substance Substances 0.000 claims description 31
- 125000001424 substituent group Chemical group 0.000 claims description 31
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 30
- 125000003277 amino group Chemical group 0.000 claims description 28
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 27
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 26
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 26
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 23
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 23
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 23
- 239000003112 inhibitor Substances 0.000 claims description 22
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 20
- 125000004434 sulfur atom Chemical group 0.000 claims description 20
- 229910052757 nitrogen Inorganic materials 0.000 claims description 19
- 125000001072 heteroaryl group Chemical group 0.000 claims description 18
- 208000020816 lung neoplasm Diseases 0.000 claims description 18
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 18
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 17
- 125000002252 acyl group Chemical group 0.000 claims description 17
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 claims description 17
- 201000005202 lung cancer Diseases 0.000 claims description 17
- 229910052717 sulfur Inorganic materials 0.000 claims description 17
- 206010006187 Breast cancer Diseases 0.000 claims description 16
- 208000026310 Breast neoplasm Diseases 0.000 claims description 16
- 125000004414 alkyl thio group Chemical group 0.000 claims description 16
- 125000002947 alkylene group Chemical group 0.000 claims description 16
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 16
- 229960002986 dinoprostone Drugs 0.000 claims description 16
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 claims description 16
- 150000002148 esters Chemical class 0.000 claims description 15
- 125000002950 monocyclic group Chemical group 0.000 claims description 15
- 230000010261 cell growth Effects 0.000 claims description 14
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 14
- 206010060862 Prostate cancer Diseases 0.000 claims description 13
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 13
- 239000002246 antineoplastic agent Substances 0.000 claims description 13
- 229940002612 prodrug Drugs 0.000 claims description 13
- 239000000651 prodrug Substances 0.000 claims description 13
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 12
- 125000003342 alkenyl group Chemical group 0.000 claims description 12
- 125000002619 bicyclic group Chemical group 0.000 claims description 12
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 12
- 239000003102 growth factor Substances 0.000 claims description 12
- 125000000304 alkynyl group Chemical group 0.000 claims description 11
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 11
- 125000001188 haloalkyl group Chemical group 0.000 claims description 11
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 10
- 125000004760 (C1-C4) alkylsulfonylamino group Chemical group 0.000 claims description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- 230000009471 action Effects 0.000 claims description 10
- 125000004429 atom Chemical group 0.000 claims description 10
- 125000005842 heteroatom Chemical group 0.000 claims description 10
- 125000000623 heterocyclic group Chemical group 0.000 claims description 10
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 9
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 239000001301 oxygen Substances 0.000 claims description 9
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 8
- 239000003098 androgen Substances 0.000 claims description 7
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 7
- 229940127089 cytotoxic agent Drugs 0.000 claims description 7
- 239000000328 estrogen antagonist Substances 0.000 claims description 7
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 6
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 6
- 229940121381 gonadotrophin releasing hormone (gnrh) antagonists Drugs 0.000 claims description 6
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 6
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 6
- 210000004798 organs belonging to the digestive system Anatomy 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 5
- FKXDPPYCCKCVCW-LBPRGKRZSA-N 4-[(1s)-1-[[5-chloro-2-(3-fluorophenoxy)pyridine-3-carbonyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CN=C1OC1=CC=CC(F)=C1 FKXDPPYCCKCVCW-LBPRGKRZSA-N 0.000 claims description 5
- MWBNCZHVEXULBD-ZDUSSCGKSA-N Benzoic acid, 4-[(1s)-1-[[5-chloro-2-(4-fluorophenoxy)benzoyl]amino]ethyl]- Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CC=C1OC1=CC=C(F)C=C1 MWBNCZHVEXULBD-ZDUSSCGKSA-N 0.000 claims description 5
- 230000001919 adrenal effect Effects 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 4
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 4
- 125000001140 1,4-phenylene group Chemical group [H]C1=C([H])C([*:2])=C([H])C([H])=C1[*:1] 0.000 claims description 4
- JAICNNPTGAKFEH-AWEZNQCLSA-N 4-[(1s)-1-[(5-chloro-2-cyclohexyloxybenzoyl)amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CC=C1OC1CCCCC1 JAICNNPTGAKFEH-AWEZNQCLSA-N 0.000 claims description 4
- BTXUOUJHLMYLQA-ZDUSSCGKSA-N 4-[(1s)-1-[[2-[(4-chlorophenoxy)methyl]-5-fluoropyridine-3-carbonyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(F)=CN=C1COC1=CC=C(Cl)C=C1 BTXUOUJHLMYLQA-ZDUSSCGKSA-N 0.000 claims description 4
- ZGFNLKCVKKEJKU-LBPRGKRZSA-N 4-[(1s)-1-[[5-chloro-2-(2,3-difluorophenoxy)benzoyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CC=C1OC1=CC=CC(F)=C1F ZGFNLKCVKKEJKU-LBPRGKRZSA-N 0.000 claims description 4
- VKIBSGBBHPHLTP-NSHDSACASA-N 4-[(1s)-1-[[5-chloro-2-(2,3-difluorophenoxy)pyridine-3-carbonyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CN=C1OC1=CC=CC(F)=C1F VKIBSGBBHPHLTP-NSHDSACASA-N 0.000 claims description 4
- POCXSXWWUUVJIB-NSHDSACASA-N 4-[(1s)-1-[[5-chloro-2-(2-chloro-4-fluorophenoxy)pyridine-3-carbonyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CN=C1OC1=CC=C(F)C=C1Cl POCXSXWWUUVJIB-NSHDSACASA-N 0.000 claims description 4
- AMOAVOIZVZLGMJ-LBPRGKRZSA-N 4-[(1s)-1-[[5-chloro-2-(3,4-difluorophenoxy)benzoyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CC=C1OC1=CC=C(F)C(F)=C1 AMOAVOIZVZLGMJ-LBPRGKRZSA-N 0.000 claims description 4
- NWAARQJHDWAZKA-NSHDSACASA-N 4-[(1s)-1-[[5-chloro-2-(3,4-difluorophenoxy)pyridine-3-carbonyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CN=C1OC1=CC=C(F)C(F)=C1 NWAARQJHDWAZKA-NSHDSACASA-N 0.000 claims description 4
- JDYZXLWEPUFOQR-NSHDSACASA-N 4-[(1s)-1-[[5-chloro-2-(3-chloro-5-fluorophenoxy)pyridine-3-carbonyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CN=C1OC1=CC(F)=CC(Cl)=C1 JDYZXLWEPUFOQR-NSHDSACASA-N 0.000 claims description 4
- PSRWNAXGTLCGIF-ZDUSSCGKSA-N 4-[(1s)-1-[[5-chloro-2-(3-chlorophenoxy)benzoyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CC=C1OC1=CC=CC(Cl)=C1 PSRWNAXGTLCGIF-ZDUSSCGKSA-N 0.000 claims description 4
- PAASJZUYDQEILO-LBPRGKRZSA-N 4-[(1s)-1-[[5-chloro-2-(3-chlorophenoxy)pyridine-3-carbonyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CN=C1OC1=CC=CC(Cl)=C1 PAASJZUYDQEILO-LBPRGKRZSA-N 0.000 claims description 4
- QEJPFCHVBBYBQL-ZDUSSCGKSA-N 4-[(1s)-1-[[5-chloro-2-(3-cyanophenoxy)pyridine-3-carbonyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CN=C1OC1=CC=CC(C#N)=C1 QEJPFCHVBBYBQL-ZDUSSCGKSA-N 0.000 claims description 4
- HXOWIUWRSXNBNJ-ZDUSSCGKSA-N 4-[(1s)-1-[[5-chloro-2-(3-fluorophenoxy)benzoyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CC=C1OC1=CC=CC(F)=C1 HXOWIUWRSXNBNJ-ZDUSSCGKSA-N 0.000 claims description 4
- KQRDIJJCEPLGDK-LBPRGKRZSA-N 4-[(1s)-1-[[5-chloro-2-(4-fluorophenoxy)pyridine-3-carbonyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CN=C1OC1=CC=C(F)C=C1 KQRDIJJCEPLGDK-LBPRGKRZSA-N 0.000 claims description 4
- ORGDRAHMWPTIER-ZDUSSCGKSA-N 4-[(1s)-1-[[5-chloro-2-(cyclobutylmethoxy)benzoyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CC=C1OCC1CCC1 ORGDRAHMWPTIER-ZDUSSCGKSA-N 0.000 claims description 4
- XWIHFKIHPJOELR-INIZCTEOSA-N 4-[(1s)-1-[[5-chloro-2-(cyclohexylmethoxymethyl)benzoyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CC=C1COCC1CCCCC1 XWIHFKIHPJOELR-INIZCTEOSA-N 0.000 claims description 4
- ATOZZVAPMQDUSI-ZDUSSCGKSA-N 4-[(1s)-1-[[5-chloro-2-[(2,4-difluorophenoxy)methyl]benzoyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CC=C1COC1=CC=C(F)C=C1F ATOZZVAPMQDUSI-ZDUSSCGKSA-N 0.000 claims description 4
- PQRPZORUHMEONY-ZDUSSCGKSA-N 4-[(1s)-1-[[5-chloro-2-[(2-chloro-4-fluorophenyl)methoxy]benzoyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CC=C1OCC1=CC=C(F)C=C1Cl PQRPZORUHMEONY-ZDUSSCGKSA-N 0.000 claims description 4
- PFUKEMYXFXSGBL-AWEZNQCLSA-N 4-[(1s)-1-[[5-chloro-2-[(2-chlorophenyl)methoxy]benzoyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CC=C1OCC1=CC=CC=C1Cl PFUKEMYXFXSGBL-AWEZNQCLSA-N 0.000 claims description 4
- ASOVXFSDXUYSFQ-ZDUSSCGKSA-N 4-[(1s)-1-[[5-chloro-2-[(2-chlorophenyl)methoxy]pyridine-3-carbonyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CN=C1OCC1=CC=CC=C1Cl ASOVXFSDXUYSFQ-ZDUSSCGKSA-N 0.000 claims description 4
- FPEMSQLPUZGAMA-HNNXBMFYSA-N 4-[(1s)-1-[[5-chloro-2-[(2-cyanophenyl)methoxy]benzoyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CC=C1OCC1=CC=CC=C1C#N FPEMSQLPUZGAMA-HNNXBMFYSA-N 0.000 claims description 4
- KYKVWMBQMHXMLJ-ZDUSSCGKSA-N 4-[(1s)-1-[[5-chloro-2-[(3,4-difluorophenoxy)methyl]benzoyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CC=C1COC1=CC=C(F)C(F)=C1 KYKVWMBQMHXMLJ-ZDUSSCGKSA-N 0.000 claims description 4
- CFRRXXZVKGXOHU-ZDUSSCGKSA-N 4-[(1s)-1-[[5-chloro-2-[(3,5-difluorophenoxy)methyl]benzoyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CC=C1COC1=CC(F)=CC(F)=C1 CFRRXXZVKGXOHU-ZDUSSCGKSA-N 0.000 claims description 4
- SUVMFTDFDQKTFU-ZDUSSCGKSA-N 4-[(1s)-1-[[5-chloro-2-[(3,5-difluorophenyl)methoxy]benzoyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CC=C1OCC1=CC(F)=CC(F)=C1 SUVMFTDFDQKTFU-ZDUSSCGKSA-N 0.000 claims description 4
- ATUADYJYXJTVGY-AWEZNQCLSA-N 4-[(1s)-1-[[5-chloro-2-[(3-chlorophenoxy)methyl]benzoyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CC=C1COC1=CC=CC(Cl)=C1 ATUADYJYXJTVGY-AWEZNQCLSA-N 0.000 claims description 4
- JJWCQIGUTYSYQF-ZDUSSCGKSA-N 4-[(1s)-1-[[5-chloro-2-[(3-chlorophenoxy)methyl]pyridine-3-carbonyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CN=C1COC1=CC=CC(Cl)=C1 JJWCQIGUTYSYQF-ZDUSSCGKSA-N 0.000 claims description 4
- FJESKJHTHSGROA-AWEZNQCLSA-N 4-[(1s)-1-[[5-chloro-2-[(3-chlorophenyl)methoxy]benzoyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CC=C1OCC1=CC=CC(Cl)=C1 FJESKJHTHSGROA-AWEZNQCLSA-N 0.000 claims description 4
- IJIDEDSKWSQAIX-AWEZNQCLSA-N 4-[(1s)-1-[[5-chloro-2-[(3-fluorophenoxy)methyl]benzoyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CC=C1COC1=CC=CC(F)=C1 IJIDEDSKWSQAIX-AWEZNQCLSA-N 0.000 claims description 4
- DECBEHHVPVQTHX-ZDUSSCGKSA-N 4-[(1s)-1-[[5-chloro-2-[(4-chloro-2-fluorophenyl)methoxy]benzoyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CC=C1OCC1=CC=C(Cl)C=C1F DECBEHHVPVQTHX-ZDUSSCGKSA-N 0.000 claims description 4
- VXYYNZFXXXAZLQ-AWEZNQCLSA-N 4-[(1s)-1-[[5-chloro-2-[(4-chlorophenoxy)methyl]benzoyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CC=C1COC1=CC=C(Cl)C=C1 VXYYNZFXXXAZLQ-AWEZNQCLSA-N 0.000 claims description 4
- CKZQTYHFWWIBDY-AWEZNQCLSA-N 4-[(1s)-1-[[5-chloro-2-[(4-chlorophenyl)methoxy]benzoyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CC=C1OCC1=CC=C(Cl)C=C1 CKZQTYHFWWIBDY-AWEZNQCLSA-N 0.000 claims description 4
- DBXKGNAPIGCOHG-ZDUSSCGKSA-N 4-[(1s)-1-[[5-chloro-2-[(4-chlorophenyl)methoxy]pyridine-3-carbonyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CN=C1OCC1=CC=C(Cl)C=C1 DBXKGNAPIGCOHG-ZDUSSCGKSA-N 0.000 claims description 4
- XOPAHUQVADLGQK-AWEZNQCLSA-N 4-[(1s)-1-[[5-chloro-2-[(4-fluorophenyl)methoxy]benzoyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CC=C1OCC1=CC=C(F)C=C1 XOPAHUQVADLGQK-AWEZNQCLSA-N 0.000 claims description 4
- KTWLXIKXZRSWDD-AWEZNQCLSA-N 4-[(1s)-1-[[5-chloro-2-[2-(2,6-difluorophenyl)ethoxy]benzoyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CC=C1OCCC1=C(F)C=CC=C1F KTWLXIKXZRSWDD-AWEZNQCLSA-N 0.000 claims description 4
- CXQFNBARRBKQGT-HNNXBMFYSA-N 4-[(1s)-1-[[5-chloro-2-[2-(2-fluorophenyl)ethoxy]benzoyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CC=C1OCCC1=CC=CC=C1F CXQFNBARRBKQGT-HNNXBMFYSA-N 0.000 claims description 4
- INCRGILKVZOQIY-AWEZNQCLSA-N 4-[(1s)-1-[[5-chloro-2-[2-(4-chlorophenyl)ethoxy]pyridine-3-carbonyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CN=C1OCCC1=CC=C(Cl)C=C1 INCRGILKVZOQIY-AWEZNQCLSA-N 0.000 claims description 4
- XSOPNDUAGOMVGY-HNNXBMFYSA-N 4-[(1s)-1-[[5-chloro-2-[2-(4-fluorophenyl)ethoxy]benzoyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CC=C1OCCC1=CC=C(F)C=C1 XSOPNDUAGOMVGY-HNNXBMFYSA-N 0.000 claims description 4
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 4
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 4
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- 125000004450 alkenylene group Chemical group 0.000 claims description 4
- 125000003282 alkyl amino group Chemical group 0.000 claims description 4
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 4
- 239000003886 aromatase inhibitor Substances 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000002474 gonadorelin antagonist Substances 0.000 claims description 4
- 238000001794 hormone therapy Methods 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000004043 oxo group Chemical group O=* 0.000 claims description 4
- 125000005476 oxopyrrolidinyl group Chemical group 0.000 claims description 4
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 4
- 125000005936 piperidyl group Chemical group 0.000 claims description 4
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 4
- 125000006413 ring segment Chemical group 0.000 claims description 4
- RYTPCTBNJWUUHU-AWEZNQCLSA-N 4-[(1s)-1-[[5-chloro-2-[(4-fluorophenoxy)methyl]benzoyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CC=C1COC1=CC=C(F)C=C1 RYTPCTBNJWUUHU-AWEZNQCLSA-N 0.000 claims description 3
- 239000005711 Benzoic acid Substances 0.000 claims description 3
- 125000001091 aminosulfinyl group Chemical group [H]N([H])S(*)=O 0.000 claims description 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
- 235000010233 benzoic acid Nutrition 0.000 claims description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 3
- 125000002993 cycloalkylene group Chemical group 0.000 claims description 3
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 3
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 125000006590 (C2-C6) alkenylene group Chemical group 0.000 claims description 2
- 125000006591 (C2-C6) alkynylene group Chemical group 0.000 claims description 2
- YXFXSKVEOJIGTI-ZDUSSCGKSA-N 4-[(1s)-1-[(5-chloro-2-phenoxypyridine-3-carbonyl)amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CN=C1OC1=CC=CC=C1 YXFXSKVEOJIGTI-ZDUSSCGKSA-N 0.000 claims description 2
- KNAYVCAULIPBRJ-HNNXBMFYSA-N 4-[(1s)-1-[(5-chloro-2-phenylmethoxybenzoyl)amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CC=C1OCC1=CC=CC=C1 KNAYVCAULIPBRJ-HNNXBMFYSA-N 0.000 claims description 2
- YPTHWKLHJGBLPK-NSHDSACASA-N 4-[(1s)-1-[[5-chloro-2-(2,3-dichlorophenoxy)pyridine-3-carbonyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CN=C1OC1=CC=CC(Cl)=C1Cl YPTHWKLHJGBLPK-NSHDSACASA-N 0.000 claims description 2
- WMDQZTNZXDPFDN-LBPRGKRZSA-N 4-[(1s)-1-[[5-chloro-2-(2,5-difluorophenoxy)benzoyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CC=C1OC1=CC(F)=CC=C1F WMDQZTNZXDPFDN-LBPRGKRZSA-N 0.000 claims description 2
- VEOFQJJMHQFJCU-NSHDSACASA-N 4-[(1s)-1-[[5-chloro-2-(2,5-difluorophenoxy)pyridine-3-carbonyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CN=C1OC1=CC(F)=CC=C1F VEOFQJJMHQFJCU-NSHDSACASA-N 0.000 claims description 2
- OABBIWZKQQRFNA-LBPRGKRZSA-N 4-[(1s)-1-[[5-chloro-2-(2,6-difluorophenoxy)benzoyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CC=C1OC1=C(F)C=CC=C1F OABBIWZKQQRFNA-LBPRGKRZSA-N 0.000 claims description 2
- RCTVPEUEZURVAL-NSHDSACASA-N 4-[(1s)-1-[[5-chloro-2-(2,6-difluorophenoxy)pyridine-3-carbonyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CN=C1OC1=C(F)C=CC=C1F RCTVPEUEZURVAL-NSHDSACASA-N 0.000 claims description 2
- YWMHIFDHUSWUPQ-NSHDSACASA-N 4-[(1s)-1-[[5-chloro-2-(2-chloro-5-fluorophenoxy)pyridine-3-carbonyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CN=C1OC1=CC(F)=CC=C1Cl YWMHIFDHUSWUPQ-NSHDSACASA-N 0.000 claims description 2
- RNBZNYZYQYXCRM-INIZCTEOSA-N 4-[(1s)-1-[[5-chloro-2-(2-phenoxyethoxy)benzoyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CC=C1OCCOC1=CC=CC=C1 RNBZNYZYQYXCRM-INIZCTEOSA-N 0.000 claims description 2
- MXUQJWKBNVDIGU-NSHDSACASA-N 4-[(1s)-1-[[5-chloro-2-(3,4-dichlorophenoxy)pyridine-3-carbonyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CN=C1OC1=CC=C(Cl)C(Cl)=C1 MXUQJWKBNVDIGU-NSHDSACASA-N 0.000 claims description 2
- FCGPTSVPTMARLR-NSHDSACASA-N 4-[(1s)-1-[[5-chloro-2-(3,5-dichlorophenoxy)pyridine-3-carbonyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CN=C1OC1=CC(Cl)=CC(Cl)=C1 FCGPTSVPTMARLR-NSHDSACASA-N 0.000 claims description 2
- XAJIBCVYDLMFFP-LBPRGKRZSA-N 4-[(1s)-1-[[5-chloro-2-(3,5-difluorophenoxy)benzoyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CC=C1OC1=CC(F)=CC(F)=C1 XAJIBCVYDLMFFP-LBPRGKRZSA-N 0.000 claims description 2
- DFIPXHHBUZAAEU-NSHDSACASA-N 4-[(1s)-1-[[5-chloro-2-(3,5-difluorophenoxy)pyridine-3-carbonyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CN=C1OC1=CC(F)=CC(F)=C1 DFIPXHHBUZAAEU-NSHDSACASA-N 0.000 claims description 2
- ACFXHKRTFYNQPW-ZDUSSCGKSA-N 4-[(1s)-1-[[5-chloro-2-(3-chloro-5-methylphenoxy)pyridine-3-carbonyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CN=C1OC1=CC(C)=CC(Cl)=C1 ACFXHKRTFYNQPW-ZDUSSCGKSA-N 0.000 claims description 2
- ZGUZHAIQRCPMTK-ZDUSSCGKSA-N 4-[(1s)-1-[[5-chloro-2-(3-fluoro-4-methylphenoxy)pyridine-3-carbonyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CN=C1OC1=CC=C(C)C(F)=C1 ZGUZHAIQRCPMTK-ZDUSSCGKSA-N 0.000 claims description 2
- DVJPOMYDCNVEJN-AWEZNQCLSA-N 4-[(1s)-1-[[5-chloro-2-(3-methylbutoxy)benzoyl]amino]ethyl]benzoic acid Chemical compound CC(C)CCOC1=CC=C(Cl)C=C1C(=O)N[C@@H](C)C1=CC=C(C(O)=O)C=C1 DVJPOMYDCNVEJN-AWEZNQCLSA-N 0.000 claims description 2
- PHKYEQDBKJKLES-HNNXBMFYSA-N 4-[(1s)-1-[[5-chloro-2-(3-methylphenoxy)benzoyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CC=C1OC1=CC=CC(C)=C1 PHKYEQDBKJKLES-HNNXBMFYSA-N 0.000 claims description 2
- VDYXVRZMLYFTSE-AWEZNQCLSA-N 4-[(1s)-1-[[5-chloro-2-(3-methylphenoxy)pyridine-3-carbonyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CN=C1OC1=CC=CC(C)=C1 VDYXVRZMLYFTSE-AWEZNQCLSA-N 0.000 claims description 2
- QRPQXHWSXCFMEC-ZDUSSCGKSA-N 4-[(1s)-1-[[5-chloro-2-[(2,3-difluorophenoxy)methyl]benzoyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CC=C1COC1=CC=CC(F)=C1F QRPQXHWSXCFMEC-ZDUSSCGKSA-N 0.000 claims description 2
- SOVFEBNEMFTGDJ-ZDUSSCGKSA-N 4-[(1s)-1-[[5-chloro-2-[(2,5-difluorophenoxy)methyl]benzoyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CC=C1COC1=CC(F)=CC=C1F SOVFEBNEMFTGDJ-ZDUSSCGKSA-N 0.000 claims description 2
- GFZRPVAVCOXGIN-ZDUSSCGKSA-N 4-[(1s)-1-[[5-chloro-2-[(2,5-difluorophenyl)methoxy]benzoyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CC=C1OCC1=CC(F)=CC=C1F GFZRPVAVCOXGIN-ZDUSSCGKSA-N 0.000 claims description 2
- KMCGRMBZIGFFJO-ZDUSSCGKSA-N 4-[(1s)-1-[[5-chloro-2-[(2,6-difluorophenoxy)methyl]benzoyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CC=C1COC1=C(F)C=CC=C1F KMCGRMBZIGFFJO-ZDUSSCGKSA-N 0.000 claims description 2
- HGDAPQIZHQIIPZ-AWEZNQCLSA-N 4-[(1s)-1-[[5-chloro-2-[(2-chlorophenoxy)methyl]benzoyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CC=C1COC1=CC=CC=C1Cl HGDAPQIZHQIIPZ-AWEZNQCLSA-N 0.000 claims description 2
- PTBZKIYFZISXHX-AWEZNQCLSA-N 4-[(1s)-1-[[5-chloro-2-[(2-fluorophenoxy)methyl]benzoyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CC=C1COC1=CC=CC=C1F PTBZKIYFZISXHX-AWEZNQCLSA-N 0.000 claims description 2
- BNLKPUVTKTWIBC-ZDUSSCGKSA-N 4-[(1s)-1-[[5-chloro-2-[(3,4-difluorophenyl)methoxy]benzoyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CC=C1OCC1=CC=C(F)C(F)=C1 BNLKPUVTKTWIBC-ZDUSSCGKSA-N 0.000 claims description 2
- JGECSXITSDIWOZ-ZDUSSCGKSA-N 4-[(1s)-1-[[5-chloro-2-[(4-chlorophenoxy)methyl]pyridine-3-carbonyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CN=C1COC1=CC=C(Cl)C=C1 JGECSXITSDIWOZ-ZDUSSCGKSA-N 0.000 claims description 2
- HNQRKSYCUAMFTB-INIZCTEOSA-N 4-[(1s)-1-[[5-chloro-2-[(4-methylphenoxy)methyl]benzoyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CC=C1COC1=CC=C(C)C=C1 HNQRKSYCUAMFTB-INIZCTEOSA-N 0.000 claims description 2
- TWVFVJSMMWIAOT-KRWDZBQOSA-N 4-[(1s)-1-[[5-chloro-2-[2-(2-methylphenyl)ethoxy]benzoyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CC=C1OCCC1=CC=CC=C1C TWVFVJSMMWIAOT-KRWDZBQOSA-N 0.000 claims description 2
- JXZQEYSMZRDUNM-KRWDZBQOSA-N 4-[(1s)-1-[[5-chloro-2-[2-(4-methylphenyl)ethoxy]benzoyl]amino]ethyl]benzoic acid Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CC=C1OCCC1=CC=C(C)C=C1 JXZQEYSMZRDUNM-KRWDZBQOSA-N 0.000 claims description 2
- VDEHYASNJQVDEG-UHFFFAOYSA-N 4-[[[5-chloro-2-[2-(2-methylphenyl)ethoxy]benzoyl]amino]methyl]benzoic acid Chemical compound CC1=CC=CC=C1CCOC1=CC=C(Cl)C=C1C(=O)NCC1=CC=C(C(O)=O)C=C1 VDEHYASNJQVDEG-UHFFFAOYSA-N 0.000 claims description 2
- 125000006618 5- to 10-membered aromatic heterocyclic group Chemical group 0.000 claims description 2
- 229940122815 Aromatase inhibitor Drugs 0.000 claims description 2
- 229940124139 Hydroxysteroid dehydrogenase inhibitor Drugs 0.000 claims description 2
- 229940122907 Phosphatase inhibitor Drugs 0.000 claims description 2
- 229940123934 Reductase inhibitor Drugs 0.000 claims description 2
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 2
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 claims description 2
- 125000005114 heteroarylalkoxy group Chemical group 0.000 claims description 2
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 2
- 239000003956 nonsteroidal anti androgen Substances 0.000 claims description 2
- 230000003637 steroidlike Effects 0.000 claims description 2
- 125000001589 carboacyl group Chemical group 0.000 claims 3
- 230000000694 effects Effects 0.000 abstract description 17
- 230000002401 inhibitory effect Effects 0.000 abstract description 3
- 239000008177 pharmaceutical agent Substances 0.000 abstract 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 40
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 33
- 239000000203 mixture Substances 0.000 description 28
- 235000013877 carbamide Nutrition 0.000 description 27
- 229940079593 drug Drugs 0.000 description 25
- 238000001990 intravenous administration Methods 0.000 description 23
- 210000004027 cell Anatomy 0.000 description 20
- 229910052697 platinum Inorganic materials 0.000 description 20
- 238000009472 formulation Methods 0.000 description 18
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 17
- 241000699666 Mus <mouse, genus> Species 0.000 description 16
- 230000003115 biocidal effect Effects 0.000 description 16
- 210000001519 tissue Anatomy 0.000 description 16
- 206010009944 Colon cancer Diseases 0.000 description 15
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 14
- 150000003230 pyrimidines Chemical class 0.000 description 14
- 102000005962 receptors Human genes 0.000 description 14
- 108020003175 receptors Proteins 0.000 description 14
- 229940124087 DNA topoisomerase II inhibitor Drugs 0.000 description 13
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 13
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 13
- 239000000317 Topoisomerase II Inhibitor Substances 0.000 description 13
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 13
- 229960004316 cisplatin Drugs 0.000 description 13
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 13
- 229960005420 etoposide Drugs 0.000 description 13
- 229960002949 fluorouracil Drugs 0.000 description 13
- 229960004961 mechlorethamine Drugs 0.000 description 13
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 13
- 229960000485 methotrexate Drugs 0.000 description 13
- 239000002464 receptor antagonist Substances 0.000 description 13
- 229940044551 receptor antagonist Drugs 0.000 description 13
- 230000009467 reduction Effects 0.000 description 13
- 239000003981 vehicle Substances 0.000 description 13
- 150000002224 folic acids Chemical class 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 11
- 239000003826 tablet Substances 0.000 description 11
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 10
- 241000699670 Mus sp. Species 0.000 description 10
- 208000005718 Stomach Neoplasms Diseases 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 239000004480 active ingredient Substances 0.000 description 10
- 150000003838 adenosines Chemical class 0.000 description 10
- 229960004397 cyclophosphamide Drugs 0.000 description 10
- 229960004679 doxorubicin Drugs 0.000 description 10
- 206010017758 gastric cancer Diseases 0.000 description 10
- 208000032839 leukemia Diseases 0.000 description 10
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 10
- 201000011549 stomach cancer Diseases 0.000 description 10
- 230000003442 weekly effect Effects 0.000 description 10
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 9
- 239000005557 antagonist Substances 0.000 description 9
- 230000003474 anti-emetic effect Effects 0.000 description 9
- 239000002111 antiemetic agent Substances 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 8
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 8
- 229940126062 Compound A Drugs 0.000 description 8
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 8
- 206010027476 Metastases Diseases 0.000 description 8
- 206010033128 Ovarian cancer Diseases 0.000 description 8
- 206010061535 Ovarian neoplasm Diseases 0.000 description 8
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 8
- 229960004562 carboplatin Drugs 0.000 description 8
- 208000029742 colonic neoplasm Diseases 0.000 description 8
- 229960003901 dacarbazine Drugs 0.000 description 8
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 8
- 230000009401 metastasis Effects 0.000 description 8
- 229960004857 mitomycin Drugs 0.000 description 8
- 150000003212 purines Chemical class 0.000 description 8
- 239000012453 solvate Substances 0.000 description 8
- 208000024891 symptom Diseases 0.000 description 8
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 8
- 229960001278 teniposide Drugs 0.000 description 8
- 229940124597 therapeutic agent Drugs 0.000 description 8
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 7
- 206010005003 Bladder cancer Diseases 0.000 description 7
- 108010092160 Dactinomycin Proteins 0.000 description 7
- 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 7
- 241000124008 Mammalia Species 0.000 description 7
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 7
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 7
- 230000000340 anti-metabolite Effects 0.000 description 7
- 229940125683 antiemetic agent Drugs 0.000 description 7
- 229940100197 antimetabolite Drugs 0.000 description 7
- 239000002256 antimetabolite Substances 0.000 description 7
- 239000002775 capsule Substances 0.000 description 7
- 229960000640 dactinomycin Drugs 0.000 description 7
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 7
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 7
- GURKHSYORGJETM-WAQYZQTGSA-N irinotecan hydrochloride (anhydrous) Chemical compound Cl.C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 GURKHSYORGJETM-WAQYZQTGSA-N 0.000 description 7
- 229960001924 melphalan Drugs 0.000 description 7
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 7
- 229960001756 oxaliplatin Drugs 0.000 description 7
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 7
- 229960005079 pemetrexed Drugs 0.000 description 7
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 description 7
- 125000006239 protecting group Chemical group 0.000 description 7
- 229940083542 sodium Drugs 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 229910052708 sodium Inorganic materials 0.000 description 7
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 7
- 230000001225 therapeutic effect Effects 0.000 description 7
- 201000005112 urinary bladder cancer Diseases 0.000 description 7
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 6
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 6
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 6
- 229930012538 Paclitaxel Natural products 0.000 description 6
- 229940009456 adriamycin Drugs 0.000 description 6
- 239000002168 alkylating agent Substances 0.000 description 6
- 229940100198 alkylating agent Drugs 0.000 description 6
- 229940046836 anti-estrogen Drugs 0.000 description 6
- 230000001833 anti-estrogenic effect Effects 0.000 description 6
- 150000001721 carbon Chemical group 0.000 description 6
- 229960002436 cladribine Drugs 0.000 description 6
- 229960000684 cytarabine Drugs 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- 210000002919 epithelial cell Anatomy 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 239000011888 foil Substances 0.000 description 6
- 229960005277 gemcitabine Drugs 0.000 description 6
- 150000002430 hydrocarbons Chemical class 0.000 description 6
- 239000004615 ingredient Substances 0.000 description 6
- 229960001592 paclitaxel Drugs 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- 230000001629 suppression Effects 0.000 description 6
- 150000003672 ureas Chemical class 0.000 description 6
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 5
- 206010004146 Basal cell carcinoma Diseases 0.000 description 5
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 5
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 5
- 206010008342 Cervix carcinoma Diseases 0.000 description 5
- 208000017604 Hodgkin disease Diseases 0.000 description 5
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 5
- 208000000453 Skin Neoplasms Diseases 0.000 description 5
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 5
- 239000000654 additive Substances 0.000 description 5
- 230000000996 additive effect Effects 0.000 description 5
- 150000008052 alkyl sulfonates Chemical group 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 229960002092 busulfan Drugs 0.000 description 5
- 229960004117 capecitabine Drugs 0.000 description 5
- 201000010881 cervical cancer Diseases 0.000 description 5
- 229960004630 chlorambucil Drugs 0.000 description 5
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 5
- 229960000975 daunorubicin Drugs 0.000 description 5
- 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 5
- 239000002552 dosage form Substances 0.000 description 5
- 239000000262 estrogen Substances 0.000 description 5
- 229940011871 estrogen Drugs 0.000 description 5
- 201000010536 head and neck cancer Diseases 0.000 description 5
- 208000014829 head and neck neoplasm Diseases 0.000 description 5
- 229960001330 hydroxycarbamide Drugs 0.000 description 5
- 229960004768 irinotecan Drugs 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 201000007270 liver cancer Diseases 0.000 description 5
- 208000014018 liver neoplasm Diseases 0.000 description 5
- 229960001156 mitoxantrone Drugs 0.000 description 5
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 5
- 238000011580 nude mouse model Methods 0.000 description 5
- 229960000435 oblimersen Drugs 0.000 description 5
- MIMNFCVQODTQDP-NDLVEFNKSA-N oblimersen Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP(S)(=O)O[C@@H]2[C@H](O[C@H](C2)N2C3=NC=NC(N)=C3N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=NC=NC(N)=C3N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)CO)[C@@H](O)C1 MIMNFCVQODTQDP-NDLVEFNKSA-N 0.000 description 5
- 229960002340 pentostatin Drugs 0.000 description 5
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 5
- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- 201000000849 skin cancer Diseases 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000006467 substitution reaction Methods 0.000 description 5
- AYNNSCRYTDRFCP-UHFFFAOYSA-N triazene Chemical compound NN=N AYNNSCRYTDRFCP-UHFFFAOYSA-N 0.000 description 5
- LBYVZRFDLNAPRC-UHFFFAOYSA-N 2-sulfanylguanidine Chemical compound NC(=N)NS LBYVZRFDLNAPRC-UHFFFAOYSA-N 0.000 description 4
- 208000003174 Brain Neoplasms Diseases 0.000 description 4
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 4
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 206010061968 Gastric neoplasm Diseases 0.000 description 4
- 102000004877 Insulin Human genes 0.000 description 4
- 108090001061 Insulin Proteins 0.000 description 4
- 108010002350 Interleukin-2 Proteins 0.000 description 4
- 102100020873 Interleukin-2 Human genes 0.000 description 4
- 206010025323 Lymphomas Diseases 0.000 description 4
- 241000699660 Mus musculus Species 0.000 description 4
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 4
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 4
- 102100024450 Prostaglandin E2 receptor EP4 subtype Human genes 0.000 description 4
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 4
- 208000024313 Testicular Neoplasms Diseases 0.000 description 4
- 206010057644 Testis cancer Diseases 0.000 description 4
- 239000000051 antiandrogen Substances 0.000 description 4
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 4
- 125000002837 carbocyclic group Chemical group 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 238000004113 cell culture Methods 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 229960003957 dexamethasone Drugs 0.000 description 4
- 238000001647 drug administration Methods 0.000 description 4
- 201000004101 esophageal cancer Diseases 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 230000012010 growth Effects 0.000 description 4
- 229940125396 insulin Drugs 0.000 description 4
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 201000001441 melanoma Diseases 0.000 description 4
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 4
- 229960001428 mercaptopurine Drugs 0.000 description 4
- OSTGTTZJOCZWJG-UHFFFAOYSA-N nitrosourea Chemical group NC(=O)N=NO OSTGTTZJOCZWJG-UHFFFAOYSA-N 0.000 description 4
- 201000002528 pancreatic cancer Diseases 0.000 description 4
- 208000008443 pancreatic carcinoma Diseases 0.000 description 4
- 230000001575 pathological effect Effects 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 229920003023 plastic Polymers 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 201000003120 testicular cancer Diseases 0.000 description 4
- 229960004528 vincristine Drugs 0.000 description 4
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 4
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 4
- FELGMEQIXOGIFQ-CYBMUJFWSA-N (3r)-9-methyl-3-[(2-methylimidazol-1-yl)methyl]-2,3-dihydro-1h-carbazol-4-one Chemical compound CC1=NC=CN1C[C@@H]1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 FELGMEQIXOGIFQ-CYBMUJFWSA-N 0.000 description 3
- 208000005440 Basal Cell Neoplasms Diseases 0.000 description 3
- 108010006654 Bleomycin Proteins 0.000 description 3
- 206010005949 Bone cancer Diseases 0.000 description 3
- 208000018084 Bone neoplasm Diseases 0.000 description 3
- 201000009030 Carcinoma Diseases 0.000 description 3
- 102400001368 Epidermal growth factor Human genes 0.000 description 3
- 101800003838 Epidermal growth factor Proteins 0.000 description 3
- 102000003951 Erythropoietin Human genes 0.000 description 3
- 108090000394 Erythropoietin Proteins 0.000 description 3
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 3
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 3
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 3
- 102100039619 Granulocyte colony-stimulating factor Human genes 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 3
- 206010062038 Lip neoplasm Diseases 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- 208000003445 Mouth Neoplasms Diseases 0.000 description 3
- 108091034117 Oligonucleotide Proteins 0.000 description 3
- 229940122294 Phosphorylase inhibitor Drugs 0.000 description 3
- 102000008866 Prostaglandin E receptors Human genes 0.000 description 3
- 108010088540 Prostaglandin E receptors Proteins 0.000 description 3
- 208000006265 Renal cell carcinoma Diseases 0.000 description 3
- 206010039491 Sarcoma Diseases 0.000 description 3
- 102000013275 Somatomedins Human genes 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 3
- 208000009956 adenocarcinoma Diseases 0.000 description 3
- 239000000556 agonist Substances 0.000 description 3
- 125000004849 alkoxymethyl group Chemical group 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 230000002280 anti-androgenic effect Effects 0.000 description 3
- 229940041181 antineoplastic drug Drugs 0.000 description 3
- 229960001561 bleomycin Drugs 0.000 description 3
- 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 3
- 229960005243 carmustine Drugs 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 238000011443 conventional therapy Methods 0.000 description 3
- 229940111134 coxibs Drugs 0.000 description 3
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 229960003668 docetaxel Drugs 0.000 description 3
- 150000002066 eicosanoids Chemical class 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 229940116977 epidermal growth factor Drugs 0.000 description 3
- 229940105423 erythropoietin Drugs 0.000 description 3
- IIUMCNJTGSMNRO-VVSKJQCTSA-L estramustine sodium phosphate Chemical compound [Na+].[Na+].ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)OP([O-])([O-])=O)[C@@H]4[C@@H]3CCC2=C1 IIUMCNJTGSMNRO-VVSKJQCTSA-L 0.000 description 3
- 229940126864 fibroblast growth factor Drugs 0.000 description 3
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229960001101 ifosfamide Drugs 0.000 description 3
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 3
- 201000006721 lip cancer Diseases 0.000 description 3
- 238000010172 mouse model Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 229960005343 ondansetron Drugs 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 239000004033 plastic Substances 0.000 description 3
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 230000003405 preventing effect Effects 0.000 description 3
- 238000001959 radiotherapy Methods 0.000 description 3
- 208000015347 renal cell adenocarcinoma Diseases 0.000 description 3
- 238000012552 review Methods 0.000 description 3
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 3
- 150000003384 small molecules Chemical class 0.000 description 3
- 230000002269 spontaneous effect Effects 0.000 description 3
- 206010041823 squamous cell carcinoma Diseases 0.000 description 3
- 208000017572 squamous cell neoplasm Diseases 0.000 description 3
- 238000001356 surgical procedure Methods 0.000 description 3
- 229940063683 taxotere Drugs 0.000 description 3
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 3
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 3
- 229960002066 vinorelbine Drugs 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- HZSBSRAVNBUZRA-RQDPQJJXSA-J (1r,2r)-cyclohexane-1,2-diamine;tetrachloroplatinum(2+) Chemical compound Cl[Pt+2](Cl)(Cl)Cl.N[C@@H]1CCCC[C@H]1N HZSBSRAVNBUZRA-RQDPQJJXSA-J 0.000 description 2
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 description 2
- 101710175516 14 kDa zinc-binding protein Proteins 0.000 description 2
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 2
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 2
- 108010070743 3(or 17)-beta-hydroxysteroid dehydrogenase Proteins 0.000 description 2
- AKJHMTWEGVYYSE-AIRMAKDCSA-N 4-HPR Chemical compound C=1C=C(O)C=CC=1NC(=O)/C=C(\C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C AKJHMTWEGVYYSE-AIRMAKDCSA-N 0.000 description 2
- PXLPCZJACKUXGP-UHFFFAOYSA-N 5-(3,4-dichlorophenyl)-6-ethylpyrimidine-2,4-diamine Chemical class CCC1=NC(N)=NC(N)=C1C1=CC=C(Cl)C(Cl)=C1 PXLPCZJACKUXGP-UHFFFAOYSA-N 0.000 description 2
- XAUDJQYHKZQPEU-KVQBGUIXSA-N 5-aza-2'-deoxycytidine Chemical compound O=C1N=C(N)N=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XAUDJQYHKZQPEU-KVQBGUIXSA-N 0.000 description 2
- GOJJWDOZNKBUSR-UHFFFAOYSA-N 7-sulfamoyloxyheptyl sulfamate Chemical compound NS(=O)(=O)OCCCCCCCOS(N)(=O)=O GOJJWDOZNKBUSR-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- RTHKPHCVZVYDFN-UHFFFAOYSA-N 9-amino-5-(2-aminopyrimidin-4-yl)pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidin-4-ol Chemical compound NC1=NC=CC(C=2C3=C(O)C=CN=C3N3C(N)=NC=CC3=2)=N1 RTHKPHCVZVYDFN-UHFFFAOYSA-N 0.000 description 2
- 244000215068 Acacia senegal Species 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- NQGMIPUYCWIEAW-UHFFFAOYSA-N Antibiotic SF 2738 Natural products COc1cc(nc(C=NO)c1SC)-c1ccccn1 NQGMIPUYCWIEAW-UHFFFAOYSA-N 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 2
- 102100023995 Beta-nerve growth factor Human genes 0.000 description 2
- LDZJNMJIPNOYGA-UHFFFAOYSA-N C1=C(OC(C)=O)C(OC)=CC=C1C1=C2C3=CC(OC)=C(OC(C)=O)C=C3C=CN2C2=C1C(C=C(OC)C(OC(C)=O)=C1)=C1OC2=O Chemical compound C1=C(OC(C)=O)C(OC)=CC=C1C1=C2C3=CC(OC)=C(OC(C)=O)C=C3C=CN2C2=C1C(C=C(OC)C(OC(C)=O)=C1)=C1OC2=O LDZJNMJIPNOYGA-UHFFFAOYSA-N 0.000 description 2
- FVLVBPDQNARYJU-XAHDHGMMSA-N C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O Chemical compound C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O FVLVBPDQNARYJU-XAHDHGMMSA-N 0.000 description 2
- WEAHRLBPCANXCN-UHFFFAOYSA-N Daunomycin Natural products CCC1(O)CC(OC2CC(N)C(O)C(C)O2)c3cc4C(=O)c5c(OC)cccc5C(=O)c4c(O)c3C1 WEAHRLBPCANXCN-UHFFFAOYSA-N 0.000 description 2
- 102100034067 Dehydrogenase/reductase SDR family member 11 Human genes 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
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- ZQZFYGIXNQKOAV-OCEACIFDSA-N Droloxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=C(O)C=CC=1)\C1=CC=C(OCCN(C)C)C=C1 ZQZFYGIXNQKOAV-OCEACIFDSA-N 0.000 description 2
- CYQFCXCEBYINGO-DLBZAZTESA-N Dronabinol Natural products C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@H]21 CYQFCXCEBYINGO-DLBZAZTESA-N 0.000 description 2
- 108090000385 Fibroblast growth factor 7 Proteins 0.000 description 2
- 102000003972 Fibroblast growth factor 7 Human genes 0.000 description 2
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 2
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 2
- JRZJKWGQFNTSRN-UHFFFAOYSA-N Geldanamycin Natural products C1C(C)CC(OC)C(O)C(C)C=C(C)C(OC(N)=O)C(OC)CCC=C(C)C(=O)NC2=CC(=O)C(OC)=C1C2=O JRZJKWGQFNTSRN-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- NMJREATYWWNIKX-UHFFFAOYSA-N GnRH Chemical compound C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CC(C)C)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)CNC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 NMJREATYWWNIKX-UHFFFAOYSA-N 0.000 description 2
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 2
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- 229940125497 HER2 kinase inhibitor Drugs 0.000 description 2
- 108090000100 Hepatocyte Growth Factor Proteins 0.000 description 2
- 102100021866 Hepatocyte growth factor Human genes 0.000 description 2
- 102000006992 Interferon-alpha Human genes 0.000 description 2
- 108010047761 Interferon-alpha Proteins 0.000 description 2
- 102000014150 Interferons Human genes 0.000 description 2
- 108010050904 Interferons Proteins 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 2
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 2
- LMVRPBWWHMVLPC-KBPJCXPTSA-N Leptolstatin Natural products CC(CC=CC(=CC(C)C(=O)C(C)C(O)C(C)CC(=CCO)C)C)C=C(C)/C=C/C1CC=CC(=O)O1 LMVRPBWWHMVLPC-KBPJCXPTSA-N 0.000 description 2
- 108010000817 Leuprolide Proteins 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- LYPFDBRUNKHDGX-SOGSVHMOSA-N N1C2=CC=C1\C(=C1\C=CC(=N1)\C(=C1\C=C/C(/N1)=C(/C1=N/C(/CC1)=C2/C1=CC(O)=CC=C1)C1=CC(O)=CC=C1)\C1=CC(O)=CC=C1)C1=CC(O)=CC=C1 Chemical compound N1C2=CC=C1\C(=C1\C=CC(=N1)\C(=C1\C=C/C(/N1)=C(/C1=N/C(/CC1)=C2/C1=CC(O)=CC=C1)C1=CC(O)=CC=C1)\C1=CC(O)=CC=C1)C1=CC(O)=CC=C1 LYPFDBRUNKHDGX-SOGSVHMOSA-N 0.000 description 2
- 108010025020 Nerve Growth Factor Proteins 0.000 description 2
- 206010029260 Neuroblastoma Diseases 0.000 description 2
- 108010040718 Neurokinin-1 Receptors Proteins 0.000 description 2
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 2
- VTAZRSXSBIHBMH-UHFFFAOYSA-N Ophiocordin Natural products OC1=CC(C(=O)O)=CC(O)=C1C(=O)C1=C(O)C=CC=C1C(=O)NC1C(OC(=O)C=2C=CC(O)=CC=2)CCCNC1 VTAZRSXSBIHBMH-UHFFFAOYSA-N 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- 108010057150 Peplomycin Proteins 0.000 description 2
- 102000009097 Phosphorylases Human genes 0.000 description 2
- 108010073135 Phosphorylases Proteins 0.000 description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 description 2
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 2
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 2
- 102100035842 Prostaglandin E2 receptor EP1 subtype Human genes 0.000 description 2
- 102100024448 Prostaglandin E2 receptor EP2 subtype Human genes 0.000 description 2
- 102100024447 Prostaglandin E2 receptor EP3 subtype Human genes 0.000 description 2
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 2
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 description 2
- 229940123924 Protein kinase C inhibitor Drugs 0.000 description 2
- PICZCWCKOLHDOJ-UHFFFAOYSA-N Pseudoaxinellin Natural products N1C(=O)C2CCCN2C(=O)C(CC(N)=O)NC(=O)C(C(C)C)NC(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C(C(C)C)NC(=O)C1CC1=CC=CC=C1 PICZCWCKOLHDOJ-UHFFFAOYSA-N 0.000 description 2
- 101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 description 2
- 102100037346 Substance-P receptor Human genes 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- CYQFCXCEBYINGO-UHFFFAOYSA-N THC Natural products C1=C(C)CCC2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3C21 CYQFCXCEBYINGO-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical compound [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 2
- 102000036693 Thrombopoietin Human genes 0.000 description 2
- 108010041111 Thrombopoietin Proteins 0.000 description 2
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 2
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 2
- 108010050144 Triptorelin Pamoate Proteins 0.000 description 2
- 208000036029 Uterine contractions during pregnancy Diseases 0.000 description 2
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 2
- 239000000205 acacia gum Substances 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- USZYSDMBJDPRIF-SVEJIMAYSA-N aclacinomycin A Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1CCC(=O)[C@H](C)O1 USZYSDMBJDPRIF-SVEJIMAYSA-N 0.000 description 2
- 229960004176 aclarubicin Drugs 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 2
- 229960000473 altretamine Drugs 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 229960002932 anastrozole Drugs 0.000 description 2
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940030495 antiandrogen sex hormone and modulator of the genital system Drugs 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 239000003420 antiserotonin agent Substances 0.000 description 2
- 229960003121 arginine Drugs 0.000 description 2
- 229940046844 aromatase inhibitors Drugs 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 108010093161 axinastatin 1 Proteins 0.000 description 2
- PICZCWCKOLHDOJ-GHTSNYPWSA-N axinastatin 1 Chemical compound C([C@H]1C(=O)N[C@H](C(=O)N[C@H](C(=O)N2CCC[C@H]2C(=O)N[C@H](C(N[C@@H](CC(N)=O)C(=O)N2CCC[C@H]2C(=O)N1)=O)C(C)C)C(C)C)C(C)C)C1=CC=CC=C1 PICZCWCKOLHDOJ-GHTSNYPWSA-N 0.000 description 2
- XYUFCXJZFZPEJD-PGRDOPGGSA-N balanol Chemical compound OC(=O)C1=CC=CC(O)=C1C(=O)C1=C(O)C=C(C(=O)O[C@H]2[C@H](CNCCC2)NC(=O)C=2C=CC(O)=CC=2)C=C1O XYUFCXJZFZPEJD-PGRDOPGGSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 229940049706 benzodiazepine Drugs 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 230000004097 bone metabolism Effects 0.000 description 2
- 229930003827 cannabinoid Natural products 0.000 description 2
- 239000003557 cannabinoid Substances 0.000 description 2
- XREUEWVEMYWFFA-CSKJXFQVSA-N carminomycin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=C(O)C=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XREUEWVEMYWFFA-CSKJXFQVSA-N 0.000 description 2
- XREUEWVEMYWFFA-UHFFFAOYSA-N carminomycin I Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=C(O)C=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XREUEWVEMYWFFA-UHFFFAOYSA-N 0.000 description 2
- 229950001725 carubicin Drugs 0.000 description 2
- 229960000590 celecoxib Drugs 0.000 description 2
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 2
- 210000002421 cell wall Anatomy 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- NQGMIPUYCWIEAW-OVCLIPMQSA-N chembl1834105 Chemical compound O/N=C/C1=C(SC)C(OC)=CC(C=2N=CC=CC=2)=N1 NQGMIPUYCWIEAW-OVCLIPMQSA-N 0.000 description 2
- UKTAZPQNNNJVKR-KJGYPYNMSA-N chembl2368925 Chemical compound C1=CC=C2C(C(O[C@@H]3C[C@@H]4C[C@H]5C[C@@H](N4CC5=O)C3)=O)=CNC2=C1 UKTAZPQNNNJVKR-KJGYPYNMSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 239000003246 corticosteroid Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 125000003074 decanoyl 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(*)=O 0.000 description 2
- 229960003603 decitabine Drugs 0.000 description 2
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- 230000001079 digestive effect Effects 0.000 description 2
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 2
- NOPFSRXAKWQILS-UHFFFAOYSA-N docosan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCO NOPFSRXAKWQILS-UHFFFAOYSA-N 0.000 description 2
- 229960003413 dolasetron Drugs 0.000 description 2
- 229950004203 droloxifene Drugs 0.000 description 2
- 229960004242 dronabinol Drugs 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 229950003662 fenretinide Drugs 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 229960000390 fludarabine Drugs 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 238000001640 fractional crystallisation Methods 0.000 description 2
- CHPZKNULDCNCBW-UHFFFAOYSA-N gallium nitrate Chemical compound [Ga+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O CHPZKNULDCNCBW-UHFFFAOYSA-N 0.000 description 2
- 108700032141 ganirelix Proteins 0.000 description 2
- GJNXBNATEDXMAK-PFLSVRRQSA-N ganirelix Chemical compound C([C@@H](C(=O)N[C@H](CCCCN=C(NCC)NCC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN=C(NCC)NCC)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 GJNXBNATEDXMAK-PFLSVRRQSA-N 0.000 description 2
- 229960003794 ganirelix Drugs 0.000 description 2
- 230000027119 gastric acid secretion Effects 0.000 description 2
- QTQAWLPCGQOSGP-GBTDJJJQSA-N geldanamycin Chemical compound N1C(=O)\C(C)=C/C=C\[C@@H](OC)[C@H](OC(N)=O)\C(C)=C/[C@@H](C)[C@@H](O)[C@H](OC)C[C@@H](C)CC2=C(OC)C(=O)C=C1C2=O QTQAWLPCGQOSGP-GBTDJJJQSA-N 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 2
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 230000004968 inflammatory condition Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 229940079322 interferon Drugs 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 108010021336 lanreotide Proteins 0.000 description 2
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 2
- 229960004338 leuprorelin Drugs 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 231100000782 microtubule inhibitor Toxicity 0.000 description 2
- 230000003278 mimic effect Effects 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- JZGDNMXSOCDEFQ-UHFFFAOYSA-N napavin Chemical compound C1C(CC)(O)CC(C2)CN1CCC(C1=CC=CC=C1N1)=C1C2(C(=O)OC)C(C(=C1)OC)=CC2=C1N(C)C1C2(C23)CCN3CC=CC2(CC)C(O)C1(O)C(=O)NCCNC1=CC=C(N=[N+]=[N-])C=C1[N+]([O-])=O JZGDNMXSOCDEFQ-UHFFFAOYSA-N 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 229940053128 nerve growth factor Drugs 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 229950008017 ormaplatin Drugs 0.000 description 2
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 125000001312 palmitoyl group Chemical group O=C([*])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])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229950003180 peplomycin Drugs 0.000 description 2
- QIMGFXOHTOXMQP-GFAGFCTOSA-N peplomycin 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)NCCCN[C@@H](C)C=1C=CC=CC=1)[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=1NC=NC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C QIMGFXOHTOXMQP-GFAGFCTOSA-N 0.000 description 2
- NDTYTMIUWGWIMO-UHFFFAOYSA-N perillyl alcohol Chemical compound CC(=C)C1CCC(CO)=CC1 NDTYTMIUWGWIMO-UHFFFAOYSA-N 0.000 description 2
- 230000008855 peristalsis Effects 0.000 description 2
- 229950000688 phenothiazine Drugs 0.000 description 2
- 150000003058 platinum compounds Chemical class 0.000 description 2
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 2
- 229960004618 prednisone Drugs 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 2
- 150000003180 prostaglandins Chemical class 0.000 description 2
- 239000003881 protein kinase C inhibitor Substances 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 2
- BBNQQADTFFCFGB-UHFFFAOYSA-N purpurin Chemical compound C1=CC=C2C(=O)C3=C(O)C(O)=CC(O)=C3C(=O)C2=C1 BBNQQADTFFCFGB-UHFFFAOYSA-N 0.000 description 2
- 229960004641 rituximab Drugs 0.000 description 2
- MOCVYVBNJQIVOV-TVQRCGJNSA-N rohitukine Chemical compound O[C@@H]1CN(C)CC[C@@H]1C1=C(O)C=C(O)C2=C1OC(C)=CC2=O MOCVYVBNJQIVOV-TVQRCGJNSA-N 0.000 description 2
- 229930195734 saturated hydrocarbon Natural products 0.000 description 2
- 229960003440 semustine Drugs 0.000 description 2
- 210000000813 small intestine Anatomy 0.000 description 2
- 201000002314 small intestine cancer Diseases 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 125000006850 spacer group Chemical group 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 230000004936 stimulating effect Effects 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- PVYJZLYGTZKPJE-UHFFFAOYSA-N streptonigrin Chemical compound C=1C=C2C(=O)C(OC)=C(N)C(=O)C2=NC=1C(C=1N)=NC(C(O)=O)=C(C)C=1C1=CC=C(OC)C(OC)=C1O PVYJZLYGTZKPJE-UHFFFAOYSA-N 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 229960001603 tamoxifen Drugs 0.000 description 2
- 229960001674 tegafur Drugs 0.000 description 2
- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 description 2
- 229960002197 temoporfin Drugs 0.000 description 2
- 229960004964 temozolomide Drugs 0.000 description 2
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 2
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 2
- 229960000303 topotecan Drugs 0.000 description 2
- TVPNFKRGOFJQOO-UHFFFAOYSA-N topsentin b1 Chemical compound C1=CC=C2C(C3=CN=C(N3)C(=O)C=3C4=CC=C(C=C4NC=3)O)=CNC2=C1 TVPNFKRGOFJQOO-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- 239000006163 transport media Substances 0.000 description 2
- 229960001727 tretinoin Drugs 0.000 description 2
- VXKHXGOKWPXYNA-PGBVPBMZSA-N triptorelin Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 VXKHXGOKWPXYNA-PGBVPBMZSA-N 0.000 description 2
- 229960004824 triptorelin Drugs 0.000 description 2
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- ZQFGRJWRSLZCSQ-ZSFNYQMMSA-N verteporfin Chemical compound C=1C([C@@]2([C@H](C(=O)OC)C(=CC=C22)C(=O)OC)C)=NC2=CC(C(=C2C=C)C)=NC2=CC(C(=C2CCC(O)=O)C)=NC2=CC2=NC=1C(C)=C2CCC(=O)OC ZQFGRJWRSLZCSQ-ZSFNYQMMSA-N 0.000 description 2
- 229960003895 verteporfin Drugs 0.000 description 2
- QDLHCMPXEPAAMD-QAIWCSMKSA-N wortmannin Chemical compound C1([C@]2(C)C3=C(C4=O)OC=C3C(=O)O[C@@H]2COC)=C4[C@@H]2CCC(=O)[C@@]2(C)C[C@H]1OC(C)=O QDLHCMPXEPAAMD-QAIWCSMKSA-N 0.000 description 2
- QDLHCMPXEPAAMD-UHFFFAOYSA-N wortmannin Natural products COCC1OC(=O)C2=COC(C3=O)=C2C1(C)C1=C3C2CCC(=O)C2(C)CC1OC(C)=O QDLHCMPXEPAAMD-UHFFFAOYSA-N 0.000 description 2
- BMKDZUISNHGIBY-ZETCQYMHSA-N (+)-dexrazoxane Chemical compound C([C@H](C)N1CC(=O)NC(=O)C1)N1CC(=O)NC(=O)C1 BMKDZUISNHGIBY-ZETCQYMHSA-N 0.000 description 1
- 229930007631 (-)-perillyl alcohol Natural products 0.000 description 1
- OTWVIYXCRFLDJW-QMVMUTFZSA-N (1-hydroxy-1-phosphonooxyethyl) dihydrogen phosphate;rhenium-186 Chemical compound [186Re].OP(=O)(O)OC(O)(C)OP(O)(O)=O OTWVIYXCRFLDJW-QMVMUTFZSA-N 0.000 description 1
- GCPUVEMWOWMALU-HZMBPMFUSA-N (1s,3s)-1-hydroxy-8-methoxy-3-methyl-1,2,3,4-tetrahydrobenzo[a]anthracene-7,12-dione Chemical compound C1[C@H](C)C[C@H](O)C2=C1C=CC1=C2C(=O)C(C=CC=C2OC)=C2C1=O GCPUVEMWOWMALU-HZMBPMFUSA-N 0.000 description 1
- MXABZXILAJGOTL-AUYMZICSSA-N (2S)-N-[(2S)-1-[(2S)-1-[(2S,3S)-1-[(2S)-1-[2-[(2S)-1,3-dihydroxy-1-[(E)-1-hydroxy-1-[(2S,3S)-1-hydroxy-3-methyl-1-[[(2Z,6S,9S,12R)-5,8,11-trihydroxy-9-(2-methylpropyl)-6-propan-2-yl-1-thia-4,7,10-triazacyclotrideca-2,4,7,10-tetraen-12-yl]imino]pentan-2-yl]iminobut-2-en-2-yl]iminopropan-2-yl]imino-2-hydroxyethyl]imino-1,5-dihydroxy-5-iminopentan-2-yl]imino-1-hydroxy-3-methylpentan-2-yl]imino-1-hydroxy-3-methylbutan-2-yl]imino-1-hydroxy-3-phenylpropan-2-yl]-2-[[(2S)-2-[[(2S)-2-[[(Z)-2-[[(2S)-2-[[(Z)-2-[[(2S)-2-[[[(2S)-1-[(Z)-2-[[(2S)-2-(dimethylamino)-1-hydroxypropylidene]amino]but-2-enoyl]pyrrolidin-2-yl]-hydroxymethylidene]amino]-1-hydroxypropylidene]amino]-1-hydroxybut-2-enylidene]amino]-1-hydroxy-3-phenylpropylidene]amino]-1-hydroxybut-2-enylidene]amino]-1-hydroxy-3-methylbutylidene]amino]-1-hydroxypropylidene]amino]pentanediimidic acid Chemical compound CC[C@H](C)[C@H](\N=C(/O)[C@@H](\N=C(/O)[C@H](Cc1ccccc1)\N=C(/O)[C@H](CCC(O)=N)\N=C(/O)[C@H](C)\N=C(/O)[C@@H](\N=C(/O)\C(=C\C)\N=C(/O)[C@H](Cc1ccccc1)\N=C(/O)\C(=C\C)\N=C(/O)[C@H](C)\N=C(/O)[C@@H]1CCCN1C(=O)\C(=C\C)\N=C(/O)[C@H](C)N(C)C)C(C)C)C(C)C)C(\O)=N\[C@@H](CCC(O)=N)C(\O)=N\C\C(O)=N\[C@@H](CO)C(\O)=N\C(=C\C)\C(\O)=N\[C@@H]([C@@H](C)CC)C(\O)=N\[C@H]1CS\C=C/N=C(O)\[C@@H](\N=C(O)/[C@H](CC(C)C)\N=C1\O)C(C)C MXABZXILAJGOTL-AUYMZICSSA-N 0.000 description 1
- BUSGWUFLNHIBPT-XYBORKQMSA-N (2e,4e,6e)-7-[(1r,5r,6s)-3-[[(2e,4e)-5-cyclohexylpenta-2,4-dienoyl]amino]-5-hydroxy-2-oxo-7-oxabicyclo[4.1.0]hept-3-en-5-yl]hepta-2,4,6-trienoic acid Chemical compound C([C@]([C@H]1O[C@H]1C1=O)(O)/C=C/C=C/C=C/C(=O)O)=C1NC(=O)\C=C\C=C\C1CCCCC1 BUSGWUFLNHIBPT-XYBORKQMSA-N 0.000 description 1
- LCADVYTXPLBAGB-AUQKUMLUSA-N (2e,4e,6z,8e,10e,14e)-13-hydroxy-n-(1-hydroxypropan-2-yl)-2,10,12,14,16-pentamethyl-18-phenyloctadeca-2,4,6,8,10,14-hexaenamide Chemical compound OCC(C)NC(=O)C(\C)=C\C=C\C=C/C=C/C(/C)=C/C(C)C(O)C(\C)=C\C(C)CCC1=CC=CC=C1 LCADVYTXPLBAGB-AUQKUMLUSA-N 0.000 description 1
- RCGXNDQKCXNWLO-WLEIXIPESA-N (2r)-n-[(2s)-5-amino-1-[[(2r,3r)-1-[[(3s,6z,9s,12r,15r,18r,19s)-9-benzyl-15-[(2r)-butan-2-yl]-6-ethylidene-19-methyl-2,5,8,11,14,17-hexaoxo-3,12-di(propan-2-yl)-1-oxa-4,7,10,13,16-pentazacyclononadec-18-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-1-oxopent Chemical compound N([C@@H](CCCN)C(=O)N[C@H]([C@H](C)CC)C(=O)N[C@H]1C(N[C@@H](C(=O)N[C@@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)NC(/C(=O)N[C@H](C(=O)O[C@H]1C)C(C)C)=C\C)C(C)C)[C@H](C)CC)=O)C(=O)[C@H]1CCCN1C(=O)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](NC(=O)CCCC(C)C)C(C)C)[C@@H](C)O)C(C)C)C(C)C RCGXNDQKCXNWLO-WLEIXIPESA-N 0.000 description 1
- PAYBYKKERMGTSS-MNCSTQPFSA-N (2r,3r,3as,9ar)-7-fluoro-2-(hydroxymethyl)-6-imino-2,3,3a,9a-tetrahydrofuro[1,2][1,3]oxazolo[3,4-a]pyrimidin-3-ol Chemical compound N=C1C(F)=CN2[C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3OC2=N1 PAYBYKKERMGTSS-MNCSTQPFSA-N 0.000 description 1
- XDZGQQRZJDKPTG-HBNQUELISA-N (2s)-2-[(3s,6s)-6-[2-[(1r,2r,4as,8as)-1-hydroxy-2,4a,5,5,8a-pentamethyl-2,3,4,6,7,8-hexahydronaphthalen-1-yl]ethyl]-6-methyldioxan-3-yl]propanoic acid Chemical compound O1O[C@H]([C@H](C)C(O)=O)CC[C@@]1(C)CC[C@]1(O)[C@@]2(C)CCCC(C)(C)[C@]2(C)CC[C@H]1C XDZGQQRZJDKPTG-HBNQUELISA-N 0.000 description 1
- CUCSSYAUKKIDJV-FAXBSAIASA-N (2s)-2-[[(2r)-2-[[(2s)-2-[[(2r)-2-[[(2s)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]-3-(1h-indol-3-yl)propanoyl]-methylamino]-3-phenylpropanoyl]amino]-3-(1h-indol-3-yl)propanoyl]amino]-n-[(2s)-1-amino-4-methylsulfanyl-1-oxobutan-2-yl]-4-methylpent Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)N(C)C(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 CUCSSYAUKKIDJV-FAXBSAIASA-N 0.000 description 1
- ZUQBAQVRAURMCL-DOMZBBRYSA-N (2s)-2-[[4-[2-[(6r)-2-amino-4-oxo-5,6,7,8-tetrahydro-1h-pyrido[2,3-d]pyrimidin-6-yl]ethyl]benzoyl]amino]pentanedioic acid Chemical compound C([C@@H]1CC=2C(=O)N=C(NC=2NC1)N)CC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 ZUQBAQVRAURMCL-DOMZBBRYSA-N 0.000 description 1
- HJNZCKLMRAOTMA-BRBGIFQRSA-N (2s)-n-[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2r)-1-[[(2s)-1-[[(2s)-5-(diaminomethylideneamino)-1-[(2s)-2-(ethylcarbamoyl)pyrrolidin-1-yl]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(2-methyl-1h-indol-3-yl)-1-oxopropan-2-yl]amino]-3-(4-hydr Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=C(C)NC2=CC=CC=C12 HJNZCKLMRAOTMA-BRBGIFQRSA-N 0.000 description 1
- HWMMBHOXHRVLCU-QOUANJGESA-N (2s,4s,5s)-4-[(1e,3e,5e)-7-[(2r,6r)-6-[(2r,3s,4ar,12bs)-2,3,4a,8,12b-pentahydroxy-3-methyl-1,7,12-trioxo-2,4-dihydrobenzo[a]anthracen-9-yl]-2-methyloxan-3-yl]oxy-7-oxohepta-1,3,5-trienyl]-2,5-dimethyl-1,3-dioxolane-2-carboxylic acid Chemical compound C[C@@H]1O[C@](C)(C(O)=O)O[C@H]1\C=C\C=C\C=C\C(=O)OC1[C@@H](C)O[C@@H](C=2C(=C3C(=O)C4=C([C@]5(C(=O)[C@H](O)[C@@](C)(O)C[C@@]5(O)C=C4)O)C(=O)C3=CC=2)O)CC1 HWMMBHOXHRVLCU-QOUANJGESA-N 0.000 description 1
- NAALWFYYHHJEFQ-ZASNTINBSA-N (2s,5r,6r)-6-[[(2r)-2-[[6-[4-[bis(2-hydroxyethyl)sulfamoyl]phenyl]-2-oxo-1h-pyridine-3-carbonyl]amino]-2-(4-hydroxyphenyl)acetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC(O)=CC=1)C(=O)C(C(N1)=O)=CC=C1C1=CC=C(S(=O)(=O)N(CCO)CCO)C=C1 NAALWFYYHHJEFQ-ZASNTINBSA-N 0.000 description 1
- VEEGZPWAAPPXRB-BJMVGYQFSA-N (3e)-3-(1h-imidazol-5-ylmethylidene)-1h-indol-2-one Chemical compound O=C1NC2=CC=CC=C2\C1=C/C1=CN=CN1 VEEGZPWAAPPXRB-BJMVGYQFSA-N 0.000 description 1
- DIWRORZWFLOCLC-HNNXBMFYSA-N (3s)-7-chloro-5-(2-chlorophenyl)-3-hydroxy-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound N([C@H](C(NC1=CC=C(Cl)C=C11)=O)O)=C1C1=CC=CC=C1Cl DIWRORZWFLOCLC-HNNXBMFYSA-N 0.000 description 1
- FRCJDPPXHQGEKS-BCHFMIIMSA-N (4S,5R)-N-[4-[(2,3-dihydroxybenzoyl)amino]butyl]-N-[3-[(2,3-dihydroxybenzoyl)amino]propyl]-2-(2-hydroxyphenyl)-5-methyl-4,5-dihydro-1,3-oxazole-4-carboxamide Chemical compound C[C@H]1OC(=N[C@@H]1C(=O)N(CCCCNC(=O)c1cccc(O)c1O)CCCNC(=O)c1cccc(O)c1O)c1ccccc1O FRCJDPPXHQGEKS-BCHFMIIMSA-N 0.000 description 1
- DEQANNDTNATYII-OULOTJBUSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-benzyl-n-[(2r,3r)-1,3-dihydroxybutan-2-yl]-7-[(1r)-1-hydroxyethyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxa Chemical compound C([C@@H](N)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)N[C@H](CO)[C@H](O)C)C1=CC=CC=C1 DEQANNDTNATYII-OULOTJBUSA-N 0.000 description 1
- PUDHBTGHUJUUFI-SCTWWAJVSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-n-[(2s,3r)-1-amino-3-hydroxy-1-oxobutan-2-yl]-19-[[(2r)-2-amino-3-naphthalen-2-ylpropanoyl]amino]-16-[(4-hydroxyphenyl)methyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-7-propan-2-yl-1,2-dithia-5,8,11,14,17-p Chemical compound C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(N)=O)=O)C(C)C)C1=CC=C(O)C=C1 PUDHBTGHUJUUFI-SCTWWAJVSA-N 0.000 description 1
- HLAKJNQXUARACO-ZDUSSCGKSA-N (5'r)-5'-hydroxy-2',5',7'-trimethylspiro[cyclopropane-1,6'-indene]-4'-one Chemical compound O=C([C@@]1(O)C)C2=CC(C)=CC2=C(C)C21CC2 HLAKJNQXUARACO-ZDUSSCGKSA-N 0.000 description 1
- LKBBOPGQDRPCDS-YAOXHJNESA-N (7s,9r,10r)-7-[(2r,4s,5s,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-9-ethyl-4,6,9,10,11-pentahydroxy-8,10-dihydro-7h-tetracene-5,12-dione Chemical compound O([C@H]1C[C@]([C@@H](C2=C(O)C=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)O)(O)CC)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 LKBBOPGQDRPCDS-YAOXHJNESA-N 0.000 description 1
- MWWSFMDVAYGXBV-FGBSZODSSA-N (7s,9s)-7-[(2r,4s,5r,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydron;chloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-FGBSZODSSA-N 0.000 description 1
- RCFNNLSZHVHCEK-YGCMNLPTSA-N (7s,9s)-7-[(2s,4r,6s)-4-amino-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydrochloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)C[C@H](C)O1 RCFNNLSZHVHCEK-YGCMNLPTSA-N 0.000 description 1
- VHZXNQKVFDBFIK-NBBHSKLNSA-N (8r,9s,10r,13s,14s,16r)-16-fluoro-10,13-dimethyl-1,2,3,4,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-one Chemical compound C1CCC[C@]2(C)[C@H]3CC[C@](C)(C([C@H](F)C4)=O)[C@@H]4[C@@H]3CC=C21 VHZXNQKVFDBFIK-NBBHSKLNSA-N 0.000 description 1
- IEXUMDBQLIVNHZ-YOUGDJEHSA-N (8s,11r,13r,14s,17s)-11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(3-hydroxypropyl)-13-methyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one Chemical compound C1=CC(N(C)C)=CC=C1[C@@H]1C2=C3CCC(=O)C=C3CC[C@H]2[C@H](CC[C@]2(O)CCCO)[C@@]2(C)C1 IEXUMDBQLIVNHZ-YOUGDJEHSA-N 0.000 description 1
- 125000005859 (C1-C6)alkanoyloxymethyl group Chemical group 0.000 description 1
- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 description 1
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UWTATZPHSA-M (R)-lactate Chemical compound C[C@@H](O)C([O-])=O JVTAAEKCZFNVCJ-UWTATZPHSA-M 0.000 description 1
- OJRZEKJECRTBPJ-NGAMADIESA-N (z,5s)-5-acetamido-1-diazonio-6-hydroxy-6-oxohex-1-en-2-olate Chemical compound CC(=O)N[C@H](C(O)=O)CC\C([O-])=C\[N+]#N OJRZEKJECRTBPJ-NGAMADIESA-N 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
- RCLLNBVPCJDIPX-UHFFFAOYSA-N 1-(2-chloroethyl)-3-[2-(dimethylsulfamoyl)ethyl]-1-nitrosourea Chemical compound CN(C)S(=O)(=O)CCNC(=O)N(N=O)CCCl RCLLNBVPCJDIPX-UHFFFAOYSA-N 0.000 description 1
- JQJSFAJISYZPER-UHFFFAOYSA-N 1-(4-chlorophenyl)-3-(2,3-dihydro-1h-inden-5-ylsulfonyl)urea Chemical compound C1=CC(Cl)=CC=C1NC(=O)NS(=O)(=O)C1=CC=C(CCC2)C2=C1 JQJSFAJISYZPER-UHFFFAOYSA-N 0.000 description 1
- SNYUHPPZINRDSG-UHFFFAOYSA-N 1-(oxiran-2-ylmethyl)-4-[1-(oxiran-2-ylmethyl)piperidin-4-yl]piperidine Chemical compound C1CC(C2CCN(CC3OC3)CC2)CCN1CC1CO1 SNYUHPPZINRDSG-UHFFFAOYSA-N 0.000 description 1
- ZKFNOUUKULVDOB-UHFFFAOYSA-N 1-amino-1-phenylmethyl phosphonic acid Chemical compound OP(=O)(O)C(N)C1=CC=CC=C1 ZKFNOUUKULVDOB-UHFFFAOYSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 description 1
- 125000004797 2,2,2-trichloroethoxy group Chemical group ClC(CO*)(Cl)Cl 0.000 description 1
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000004778 2,2-difluoroethyl group Chemical group [H]C([H])(*)C([H])(F)F 0.000 description 1
- YGTUPRIZNBMOFV-UHFFFAOYSA-N 2-(4-hydroxybenzoyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1C(=O)C1=CC=C(O)C=C1 YGTUPRIZNBMOFV-UHFFFAOYSA-N 0.000 description 1
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- PXJJOGITBQXZEQ-JTHROIFXSA-M 2-[4-[(z)-1,2-diphenylbut-1-enyl]phenoxy]ethyl-trimethylazanium;iodide Chemical compound [I-].C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCC[N+](C)(C)C)=CC=1)/C1=CC=CC=C1 PXJJOGITBQXZEQ-JTHROIFXSA-M 0.000 description 1
- BLJLWFKNTKAUDA-UHFFFAOYSA-N 2-[[2-(2-naphthalen-1-ylpropanoylamino)phenyl]methyl]benzoic acid Chemical compound C=1C=CC2=CC=CC=C2C=1C(C)C(=O)NC1=CC=CC=C1CC1=CC=CC=C1C(O)=O BLJLWFKNTKAUDA-UHFFFAOYSA-N 0.000 description 1
- VDCRFBBZFHHYGT-IOSLPCCCSA-N 2-amino-9-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-enyl-3h-purine-6,8-dione Chemical compound O=C1N(CC=C)C=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O VDCRFBBZFHHYGT-IOSLPCCCSA-N 0.000 description 1
- NIXVOFULDIFBLB-QVRNUERCSA-N 2-amino-9-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]purine-6-sulfinamide Chemical compound C12=NC(N)=NC(S(N)=O)=C2N=CN1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NIXVOFULDIFBLB-QVRNUERCSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000004791 2-fluoroethoxy group Chemical group FCCO* 0.000 description 1
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
- PWMYMKOUNYTVQN-UHFFFAOYSA-N 3-(8,8-diethyl-2-aza-8-germaspiro[4.5]decan-2-yl)-n,n-dimethylpropan-1-amine Chemical compound C1C[Ge](CC)(CC)CCC11CN(CCCN(C)C)CC1 PWMYMKOUNYTVQN-UHFFFAOYSA-N 0.000 description 1
- QGJZLNKBHJESQX-UHFFFAOYSA-N 3-Epi-Betulin-Saeure Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C(=C)C)C5C4CCC3C21C QGJZLNKBHJESQX-UHFFFAOYSA-N 0.000 description 1
- GTJXPMSTODOYNP-BTKVJIOYSA-N 3-[(e)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-2-phenylbut-1-enyl]phenol;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1C(/CC)=C(C=1C=C(O)C=CC=1)\C1=CC=C(OCCN(C)C)C=C1 GTJXPMSTODOYNP-BTKVJIOYSA-N 0.000 description 1
- UZFPOOOQHWICKY-UHFFFAOYSA-N 3-[13-[1-[1-[8,12-bis(2-carboxyethyl)-17-(1-hydroxyethyl)-3,7,13,18-tetramethyl-21,24-dihydroporphyrin-2-yl]ethoxy]ethyl]-18-(2-carboxyethyl)-8-(1-hydroxyethyl)-3,7,12,17-tetramethyl-22,23-dihydroporphyrin-2-yl]propanoic acid Chemical compound N1C(C=C2C(=C(CCC(O)=O)C(C=C3C(=C(C)C(C=C4N5)=N3)CCC(O)=O)=N2)C)=C(C)C(C(C)O)=C1C=C5C(C)=C4C(C)OC(C)C1=C(N2)C=C(N3)C(C)=C(C(O)C)C3=CC(C(C)=C3CCC(O)=O)=NC3=CC(C(CCC(O)=O)=C3C)=NC3=CC2=C1C UZFPOOOQHWICKY-UHFFFAOYSA-N 0.000 description 1
- QNKJFXARIMSDBR-UHFFFAOYSA-N 3-[2-[bis(2-chloroethyl)amino]ethyl]-1,3-diazaspiro[4.5]decane-2,4-dione Chemical compound O=C1N(CCN(CCCl)CCCl)C(=O)NC11CCCCC1 QNKJFXARIMSDBR-UHFFFAOYSA-N 0.000 description 1
- WELIVEBWRWAGOM-UHFFFAOYSA-N 3-amino-n-[2-[2-(3-aminopropanoylamino)ethyldisulfanyl]ethyl]propanamide Chemical compound NCCC(=O)NCCSSCCNC(=O)CCN WELIVEBWRWAGOM-UHFFFAOYSA-N 0.000 description 1
- CLOUCVRNYSHRCF-UHFFFAOYSA-N 3beta-Hydroxy-20(29)-Lupen-3,27-oic acid Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C(O)=O)CCC5(C)CCC(C(=C)C)C5C4CCC3C21C CLOUCVRNYSHRCF-UHFFFAOYSA-N 0.000 description 1
- PDQGEKGUTOTUNV-TZSSRYMLSA-N 4'-deoxy-4'-iododoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](I)[C@H](C)O1 PDQGEKGUTOTUNV-TZSSRYMLSA-N 0.000 description 1
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 1
- JARCFMKMOFFIGZ-UHFFFAOYSA-N 4,6-dioxo-n-phenyl-2-sulfanylidene-1,3-diazinane-5-carboxamide Chemical compound O=C1NC(=S)NC(=O)C1C(=O)NC1=CC=CC=C1 JARCFMKMOFFIGZ-UHFFFAOYSA-N 0.000 description 1
- CLPFFLWZZBQMAO-UHFFFAOYSA-N 4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)benzonitrile Chemical compound C1=CC(C#N)=CC=C1C1N2C=NC=C2CCC1 CLPFFLWZZBQMAO-UHFFFAOYSA-N 0.000 description 1
- MTDIMKNAJUQTIO-UHFFFAOYSA-N 4-[4-cyano-2-[2-(4-fluoronaphthalen-1-yl)propanoylamino]phenyl]butanoic acid Chemical compound C=1C=C(F)C2=CC=CC=C2C=1C(C)C(=O)NC1=CC(C#N)=CC=C1CCCC(O)=O MTDIMKNAJUQTIO-UHFFFAOYSA-N 0.000 description 1
- CTSNHMQGVWXIEG-UHFFFAOYSA-N 4-amino-n-(5-chloroquinoxalin-2-yl)benzenesulfonamide Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=CN=C(C(Cl)=CC=C2)C2=N1 CTSNHMQGVWXIEG-UHFFFAOYSA-N 0.000 description 1
- 125000006281 4-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Br)C([H])([H])* 0.000 description 1
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 1
- AKJHMTWEGVYYSE-FXILSDISSA-N 4-hydroxyphenyl retinamide Chemical compound C=1C=C(O)C=CC=1NC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C AKJHMTWEGVYYSE-FXILSDISSA-N 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000006181 4-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])C([H])([H])* 0.000 description 1
- APNRZHLOPQFNMR-WEIUTZTHSA-N 5-[(e)-5-[(1s)-2,2-dimethyl-6-methylidenecyclohexyl]-3-methylpent-2-enyl]phenazin-1-one Chemical compound C12=CC=CC=C2N=C(C(C=CC=2)=O)C=2N1C\C=C(/C)CC[C@@H]1C(=C)CCCC1(C)C APNRZHLOPQFNMR-WEIUTZTHSA-N 0.000 description 1
- IDPUKCWIGUEADI-UHFFFAOYSA-N 5-[bis(2-chloroethyl)amino]uracil Chemical compound ClCCN(CCCl)C1=CNC(=O)NC1=O IDPUKCWIGUEADI-UHFFFAOYSA-N 0.000 description 1
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 1
- DQOGWKZQQBYYMW-LQGIGNHCSA-N 5-methyl-6-[(3,4,5-trimethoxyanilino)methyl]quinazoline-2,4-diamine;(2s,3s,4s,5r,6s)-3,4,5,6-tetrahydroxyoxane-2-carboxylic acid Chemical compound O[C@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O.COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=NC(N)=NC3=CC=2)C)=C1 DQOGWKZQQBYYMW-LQGIGNHCSA-N 0.000 description 1
- PXBZKHOQHTVCSQ-QZTJIDSGSA-N 5-nitro-2-[(2r)-1-[2-[[(2r)-2-(5-nitro-1,3-dioxobenzo[de]isoquinolin-2-yl)propyl]amino]ethylamino]propan-2-yl]benzo[de]isoquinoline-1,3-dione Chemical compound [O-][N+](=O)C1=CC(C(N([C@@H](CNCCNC[C@@H](C)N2C(C=3C=C(C=C4C=CC=C(C=34)C2=O)[N+]([O-])=O)=O)C)C2=O)=O)=C3C2=CC=CC3=C1 PXBZKHOQHTVCSQ-QZTJIDSGSA-N 0.000 description 1
- ATCGGEJZONJOCL-UHFFFAOYSA-N 6-(2,5-dichlorophenyl)-1,3,5-triazine-2,4-diamine Chemical compound NC1=NC(N)=NC(C=2C(=CC=C(Cl)C=2)Cl)=N1 ATCGGEJZONJOCL-UHFFFAOYSA-N 0.000 description 1
- WYWHKKSPHMUBEB-UHFFFAOYSA-N 6-Mercaptoguanine Natural products N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 1
- LRHPCRBOMKRVOA-UHFFFAOYSA-N 6-[2-(2-hydroxyethylamino)ethyl]indeno[1,2-c]isoquinoline-5,11-dione Chemical compound C12=CC=CC=C2C(=O)N(CCNCCO)C2=C1C(=O)C1=CC=CC=C12 LRHPCRBOMKRVOA-UHFFFAOYSA-N 0.000 description 1
- KXBCLNRMQPRVTP-UHFFFAOYSA-N 6-amino-1,5-dihydroimidazo[4,5-c]pyridin-4-one Chemical compound O=C1NC(N)=CC2=C1N=CN2 KXBCLNRMQPRVTP-UHFFFAOYSA-N 0.000 description 1
- VVIAGPKUTFNRDU-UHFFFAOYSA-N 6S-folinic acid Natural products C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-UHFFFAOYSA-N 0.000 description 1
- GOYNNCPGHOBFCK-UHFFFAOYSA-N 7-[4-(dimethylamino)-5-[(2,9-dimethyl-3-oxo-4,4a,5a,6,7,9,9a,10a-octahydrodipyrano[4,2-a:4',3'-e][1,4]dioxin-7-yl)oxy]-6-methyloxan-2-yl]oxy-9-ethyl-4,6,9,10,11-pentahydroxy-8,10-dihydro-7h-tetracene-5,12-dione Chemical compound O=C1C2=C(O)C=CC=C2C(=O)C2=C1C(O)=C1C(OC3OC(C)C(OC4OC(C)C5OC6OC(C)C(=O)CC6OC5C4)C(C3)N(C)C)CC(CC)(O)C(O)C1=C2O GOYNNCPGHOBFCK-UHFFFAOYSA-N 0.000 description 1
- KABRXLINDSPGDF-UHFFFAOYSA-N 7-bromoisoquinoline Chemical compound C1=CN=CC2=CC(Br)=CC=C21 KABRXLINDSPGDF-UHFFFAOYSA-N 0.000 description 1
- ZGXJTSGNIOSYLO-UHFFFAOYSA-N 88755TAZ87 Chemical compound NCC(=O)CCC(O)=O ZGXJTSGNIOSYLO-UHFFFAOYSA-N 0.000 description 1
- ITPDYQOUSLNIHG-UHFFFAOYSA-N Amiodarone hydrochloride Chemical compound [Cl-].CCCCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(I)=C(OCC[NH+](CC)CC)C(I)=C1 ITPDYQOUSLNIHG-UHFFFAOYSA-N 0.000 description 1
- BOJKULTULYSRAS-OTESTREVSA-N Andrographolide Chemical compound C([C@H]1[C@]2(C)CC[C@@H](O)[C@]([C@H]2CCC1=C)(CO)C)\C=C1/[C@H](O)COC1=O BOJKULTULYSRAS-OTESTREVSA-N 0.000 description 1
- 101150071279 Apc gene Proteins 0.000 description 1
- 102000015790 Asparaginase Human genes 0.000 description 1
- 108010024976 Asparaginase Proteins 0.000 description 1
- 241001263178 Auriparus Species 0.000 description 1
- DGAKHGXRMXWHBX-ONEGZZNKSA-N Azoxymethane Chemical compound C\N=[N+](/C)[O-] DGAKHGXRMXWHBX-ONEGZZNKSA-N 0.000 description 1
- VGGGPCQERPFHOB-MCIONIFRSA-N Bestatin Chemical compound CC(C)C[C@H](C(O)=O)NC(=O)[C@@H](O)[C@H](N)CC1=CC=CC=C1 VGGGPCQERPFHOB-MCIONIFRSA-N 0.000 description 1
- DIZWSDNSTNAYHK-XGWVBXMLSA-N Betulinic acid Natural products CC(=C)[C@@H]1C[C@H]([C@H]2CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@@]34C)[C@@H]12)C(=O)O DIZWSDNSTNAYHK-XGWVBXMLSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 229940122361 Bisphosphonate Drugs 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 241000219198 Brassica Species 0.000 description 1
- 235000003351 Brassica cretica Nutrition 0.000 description 1
- 235000003343 Brassica rupestris Nutrition 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 108070000006 Cannabinoids receptors Proteins 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229940122537 Casein kinase inhibitor Drugs 0.000 description 1
- JDVVGAQPNNXQDW-WCMLQCRESA-N Castanospermine Natural products O[C@H]1[C@@H](O)[C@H]2[C@@H](O)CCN2C[C@H]1O JDVVGAQPNNXQDW-WCMLQCRESA-N 0.000 description 1
- JDVVGAQPNNXQDW-TVNFTVLESA-N Castinospermine Chemical compound C1[C@H](O)[C@@H](O)[C@H](O)[C@H]2[C@@H](O)CCN21 JDVVGAQPNNXQDW-TVNFTVLESA-N 0.000 description 1
- 102000053642 Catalytic RNA Human genes 0.000 description 1
- 108090000994 Catalytic RNA Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 102000011022 Chorionic Gonadotropin Human genes 0.000 description 1
- 108010062540 Chorionic Gonadotropin Proteins 0.000 description 1
- 101150065749 Churc1 gene Proteins 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
- HVXBOLULGPECHP-WAYWQWQTSA-N Combretastatin A4 Chemical compound C1=C(O)C(OC)=CC=C1\C=C/C1=CC(OC)=C(OC)C(OC)=C1 HVXBOLULGPECHP-WAYWQWQTSA-N 0.000 description 1
- DFDTZECTHJFPHE-UHFFFAOYSA-N Crambescidin 816 Natural products C1CC=CC(CC)OC11NC(N23)=NC4(OC(C)CCC4)C(C(=O)OCCCCCCCCCCCCCCCC(=O)N(CCCN)CC(O)CCN)C3(O)CCC2C1 DFDTZECTHJFPHE-UHFFFAOYSA-N 0.000 description 1
- LUEYTMPPCOCKBX-UHFFFAOYSA-N Curacin A Natural products C=CCC(OC)CCC(C)=CC=CCCC=CC1CSC(C2C(C2)C)=N1 LUEYTMPPCOCKBX-UHFFFAOYSA-N 0.000 description 1
- LUEYTMPPCOCKBX-KWYHTCOPSA-N Curacin A Chemical compound C=CC[C@H](OC)CC\C(C)=C\C=C\CC\C=C/[C@@H]1CSC([C@H]2[C@H](C2)C)=N1 LUEYTMPPCOCKBX-KWYHTCOPSA-N 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- SPKNARKFCOPTSY-UHFFFAOYSA-N D-asperlin Natural products CC1OC1C1C(OC(C)=O)C=CC(=O)O1 SPKNARKFCOPTSY-UHFFFAOYSA-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
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 1
- GSDBGCKBBJVPNC-UHFFFAOYSA-N D-lombricine Natural products OC(=O)C(N)COP(O)(=O)OCCN=C(N)N GSDBGCKBBJVPNC-UHFFFAOYSA-N 0.000 description 1
- GJKXGJCSJWBJEZ-XRSSZCMZSA-N Deslorelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CNC2=CC=CC=C12 GJKXGJCSJWBJEZ-XRSSZCMZSA-N 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- HWMMBHOXHRVLCU-UHFFFAOYSA-N Dioxamycin Natural products CC1OC(C)(C(O)=O)OC1C=CC=CC=CC(=O)OC1C(C)OC(C=2C(=C3C(=O)C4=C(C5(C(=O)C(O)C(C)(O)CC5(O)C=C4)O)C(=O)C3=CC=2)O)CC1 HWMMBHOXHRVLCU-UHFFFAOYSA-N 0.000 description 1
- MWWSFMDVAYGXBV-RUELKSSGSA-N Doxorubicin hydrochloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-RUELKSSGSA-N 0.000 description 1
- VQNATVDKACXKTF-UHFFFAOYSA-N Duocarmycin SA Natural products COC1=C(OC)C(OC)=C2NC(C(=O)N3C4=CC(=O)C5=C(C64CC6C3)C=C(N5)C(=O)OC)=CC2=C1 VQNATVDKACXKTF-UHFFFAOYSA-N 0.000 description 1
- 102000001301 EGF receptor Human genes 0.000 description 1
- 108060006698 EGF receptor Proteins 0.000 description 1
- DYEFUKCXAQOFHX-UHFFFAOYSA-N Ebselen Chemical compound [se]1C2=CC=CC=C2C(=O)N1C1=CC=CC=C1 DYEFUKCXAQOFHX-UHFFFAOYSA-N 0.000 description 1
- NBEALWAVEGMZQY-UHFFFAOYSA-N Enpromate Chemical compound C=1C=CC=CC=1C(C#C)(C=1C=CC=CC=1)OC(=O)NC1CCCCC1 NBEALWAVEGMZQY-UHFFFAOYSA-N 0.000 description 1
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 1
- VAPSMQAHNAZRKC-PQWRYPMOSA-N Epristeride Chemical compound C1C=C2C=C(C(O)=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)NC(C)(C)C)[C@@]1(C)CC2 VAPSMQAHNAZRKC-PQWRYPMOSA-N 0.000 description 1
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 1
- 108091008794 FGF receptors Proteins 0.000 description 1
- 108090000386 Fibroblast Growth Factor 1 Proteins 0.000 description 1
- 102000044168 Fibroblast Growth Factor Receptor Human genes 0.000 description 1
- 102100031706 Fibroblast growth factor 1 Human genes 0.000 description 1
- 108090001047 Fibroblast growth factor 10 Proteins 0.000 description 1
- 102100028412 Fibroblast growth factor 10 Human genes 0.000 description 1
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 description 1
- 102100024785 Fibroblast growth factor 2 Human genes 0.000 description 1
- 108090000270 Ficain Proteins 0.000 description 1
- 108010029961 Filgrastim Proteins 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 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
- 108010010803 Gelatin Proteins 0.000 description 1
- 229940121800 Gelatinase inhibitor Drugs 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- 206010066476 Haematological malignancy Diseases 0.000 description 1
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- 101000582950 Homo sapiens Platelet factor 4 Proteins 0.000 description 1
- 101001073427 Homo sapiens Prostaglandin E2 receptor EP1 subtype Proteins 0.000 description 1
- 101001117519 Homo sapiens Prostaglandin E2 receptor EP2 subtype Proteins 0.000 description 1
- 101001117517 Homo sapiens Prostaglandin E2 receptor EP3 subtype Proteins 0.000 description 1
- 101000836978 Homo sapiens Sperm-associated antigen 11B Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 208000004454 Hyperalgesia Diseases 0.000 description 1
- 208000035154 Hyperesthesia Diseases 0.000 description 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102000048143 Insulin-Like Growth Factor II Human genes 0.000 description 1
- 108090001117 Insulin-Like Growth Factor II Proteins 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- 208000032177 Intestinal Polyps Diseases 0.000 description 1
- 229930194542 Keto Natural products 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
- KJQFBVYMGADDTQ-CVSPRKDYSA-N L-buthionine-(S,R)-sulfoximine Chemical compound CCCCS(=N)(=O)CC[C@H](N)C(O)=O KJQFBVYMGADDTQ-CVSPRKDYSA-N 0.000 description 1
- GSDBGCKBBJVPNC-BYPYZUCNSA-N L-lombricine Chemical compound NC(=[NH2+])NCCOP([O-])(=O)OC[C@H]([NH3+])C([O-])=O GSDBGCKBBJVPNC-BYPYZUCNSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 108010043135 L-methionine gamma-lyase Proteins 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 108010062867 Lenograstim Proteins 0.000 description 1
- 229920001491 Lentinan Polymers 0.000 description 1
- HLFSDGLLUJUHTE-SNVBAGLBSA-N Levamisole Chemical compound C1([C@H]2CN3CCSC3=N2)=CC=CC=C1 HLFSDGLLUJUHTE-SNVBAGLBSA-N 0.000 description 1
- 102000009151 Luteinizing Hormone Human genes 0.000 description 1
- 108010073521 Luteinizing Hormone Proteins 0.000 description 1
- 108090000856 Lyases Proteins 0.000 description 1
- 102000004317 Lyases Human genes 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-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
- 101710170181 Metalloproteinase inhibitor Proteins 0.000 description 1
- 108700021154 Metallothionein 3 Proteins 0.000 description 1
- 102100028708 Metallothionein-3 Human genes 0.000 description 1
- 102100030173 Muellerian-inhibiting factor Human genes 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- HFPXYDFQVINJBV-UHFFFAOYSA-N Mycaperoxide B Natural products O1OC(C(C)C(O)=O)CCC1(C)CCC1(O)C2(C)CCCC(C)(C)C2CCC1C HFPXYDFQVINJBV-UHFFFAOYSA-N 0.000 description 1
- WUKZPHOXUVCQOR-UHFFFAOYSA-N N-(1-azabicyclo[2.2.2]octan-3-yl)-6-chloro-4-methyl-3-oxo-1,4-benzoxazine-8-carboxamide Chemical compound C1N(CC2)CCC2C1NC(=O)C1=CC(Cl)=CC2=C1OCC(=O)N2C WUKZPHOXUVCQOR-UHFFFAOYSA-N 0.000 description 1
- QJMCKEPOKRERLN-UHFFFAOYSA-N N-3,4-tridhydroxybenzamide Chemical compound ONC(=O)C1=CC=C(O)C(O)=C1 QJMCKEPOKRERLN-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 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
- BUSGWUFLNHIBPT-UHFFFAOYSA-N Nisamycin Natural products O=C1C2OC2C(C=CC=CC=CC(=O)O)(O)C=C1NC(=O)C=CC=CC1CCCCC1 BUSGWUFLNHIBPT-UHFFFAOYSA-N 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- KYRVNWMVYQXFEU-UHFFFAOYSA-N Nocodazole Chemical compound C1=C2NC(NC(=O)OC)=NC2=CC=C1C(=O)C1=CC=CS1 KYRVNWMVYQXFEU-UHFFFAOYSA-N 0.000 description 1
- 108010016076 Octreotide Proteins 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- LKBBOPGQDRPCDS-UHFFFAOYSA-N Oxaunomycin Natural products C12=C(O)C=3C(=O)C4=C(O)C=CC=C4C(=O)C=3C(O)=C2C(O)C(CC)(O)CC1OC1CC(N)C(O)C(C)O1 LKBBOPGQDRPCDS-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 101150053131 PTGER3 gene Proteins 0.000 description 1
- FRCJDPPXHQGEKS-UHFFFAOYSA-N Parabactin Natural products CC1OC(=NC1C(=O)N(CCCCNC(=O)c1cccc(O)c1O)CCCNC(=O)c1cccc(O)c1O)c1ccccc1O FRCJDPPXHQGEKS-UHFFFAOYSA-N 0.000 description 1
- BYPFEZZEUUWMEJ-UHFFFAOYSA-N Pentoxifylline Chemical compound O=C1N(CCCCC(=O)C)C(=O)N(C)C2=C1N(C)C=N2 BYPFEZZEUUWMEJ-UHFFFAOYSA-N 0.000 description 1
- 229940083963 Peptide antagonist Drugs 0.000 description 1
- APNRZHLOPQFNMR-UHFFFAOYSA-N Phenazinomycin Natural products C12=CC=CC=C2N=C(C(C=CC=2)=O)C=2N1CC=C(C)CCC1C(=C)CCCC1(C)C APNRZHLOPQFNMR-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- KMSKQZKKOZQFFG-HSUXVGOQSA-N Pirarubicin Chemical compound O([C@H]1[C@@H](N)C[C@@H](O[C@H]1C)O[C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1CCCCO1 KMSKQZKKOZQFFG-HSUXVGOQSA-N 0.000 description 1
- 102000010752 Plasminogen Inactivators Human genes 0.000 description 1
- 108010077971 Plasminogen Inactivators Proteins 0.000 description 1
- 102100030304 Platelet factor 4 Human genes 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- HRHKSTOGXBBQCB-UHFFFAOYSA-N Porfiromycine Chemical compound O=C1C(N)=C(C)C(=O)C2=C1C(COC(N)=O)C1(OC)C3N(C)C3CN12 HRHKSTOGXBBQCB-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 229940079156 Proteasome inhibitor Drugs 0.000 description 1
- 102100038239 Protein Churchill Human genes 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 229940123827 Purine nucleoside phosphorylase inhibitor Drugs 0.000 description 1
- XESARGFCSKSFID-UHFFFAOYSA-N Pyrazofurin Natural products OC1=C(C(=O)N)NN=C1C1C(O)C(O)C(CO)O1 XESARGFCSKSFID-UHFFFAOYSA-N 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 102000003901 Ras GTPase-activating proteins Human genes 0.000 description 1
- 108090000231 Ras GTPase-activating proteins Proteins 0.000 description 1
- 229940078123 Ras inhibitor Drugs 0.000 description 1
- OWPCHSCAPHNHAV-UHFFFAOYSA-N Rhizoxin Natural products C1C(O)C2(C)OC2C=CC(C)C(OC(=O)C2)CC2CC2OC2C(=O)OC1C(C)C(OC)C(C)=CC=CC(C)=CC1=COC(C)=N1 OWPCHSCAPHNHAV-UHFFFAOYSA-N 0.000 description 1
- GCPUVEMWOWMALU-UHFFFAOYSA-N Rubiginone B1 Natural products C1C(C)CC(O)C2=C1C=CC1=C2C(=O)C(C=CC=C2OC)=C2C1=O GCPUVEMWOWMALU-UHFFFAOYSA-N 0.000 description 1
- 101150114751 SEM1 gene Proteins 0.000 description 1
- 201000011683 Small Cell Sarcoma Diseases 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- OCOKWVBYZHBHLU-UHFFFAOYSA-N Sobuzoxane Chemical compound C1C(=O)N(COC(=O)OCC(C)C)C(=O)CN1CCN1CC(=O)N(COC(=O)OCC(C)C)C(=O)C1 OCOKWVBYZHBHLU-UHFFFAOYSA-N 0.000 description 1
- 208000021712 Soft tissue sarcoma Diseases 0.000 description 1
- UIRKNQLZZXALBI-MSVGPLKSSA-N Squalamine Chemical compound C([C@@H]1C[C@H]2O)[C@@H](NCCCNCCCCN)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@H](C)CC[C@H](C(C)C)OS(O)(=O)=O)[C@@]2(C)CC1 UIRKNQLZZXALBI-MSVGPLKSSA-N 0.000 description 1
- UIRKNQLZZXALBI-UHFFFAOYSA-N Squalamine Natural products OC1CC2CC(NCCCNCCCCN)CCC2(C)C2C1C1CCC(C(C)CCC(C(C)C)OS(O)(=O)=O)C1(C)CC2 UIRKNQLZZXALBI-UHFFFAOYSA-N 0.000 description 1
- 229940122743 Stromelysin inhibitor Drugs 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- WFWLQNSHRPWKFK-UHFFFAOYSA-N Tegafur Chemical compound O=C1NC(=O)C(F)=CN1C1OCCC1 WFWLQNSHRPWKFK-UHFFFAOYSA-N 0.000 description 1
- 229940123582 Telomerase inhibitor Drugs 0.000 description 1
- WXZSUBHBYQYTNM-UHFFFAOYSA-N Tetrazomine Natural products C1=CC=2CC(N34)C(N5C)C(CO)CC5C4OCC3C=2C(OC)=C1NC(=O)C1NCCCC1O WXZSUBHBYQYTNM-UHFFFAOYSA-N 0.000 description 1
- UPGGKUQISSWRJJ-XLTUSUNSSA-N Thiocoraline Chemical compound O=C([C@H]1CSSC[C@@H](N(C(=O)CNC2=O)C)C(=O)N(C)[C@@H](C(SC[C@@H](C(=O)NCC(=O)N1C)NC(=O)C=1C(=CC3=CC=CC=C3N=1)O)=O)CSC)N(C)[C@H](CSC)C(=O)SC[C@@H]2NC(=O)C1=NC2=CC=CC=C2C=C1O UPGGKUQISSWRJJ-XLTUSUNSSA-N 0.000 description 1
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- IVTVGDXNLFLDRM-HNNXBMFYSA-N Tomudex Chemical compound C=1C=C2NC(C)=NC(=O)C2=CC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)S1 IVTVGDXNLFLDRM-HNNXBMFYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 102000007537 Type II DNA Topoisomerases Human genes 0.000 description 1
- 108010046308 Type II DNA Topoisomerases Proteins 0.000 description 1
- VGQOVCHZGQWAOI-UHFFFAOYSA-N UNPD55612 Natural products N1C(O)C2CC(C=CC(N)=O)=CN2C(=O)C2=CC=C(C)C(O)=C12 VGQOVCHZGQWAOI-UHFFFAOYSA-N 0.000 description 1
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 1
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- MHDDZDPNIDVLNK-ZGIWMXSJSA-N Zanoterone Chemical compound C1C2=NN(S(C)(=O)=O)C=C2C[C@]2(C)[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CC[C@H]21 MHDDZDPNIDVLNK-ZGIWMXSJSA-N 0.000 description 1
- OGQICQVSFDPSEI-UHFFFAOYSA-N Zorac Chemical compound N1=CC(C(=O)OCC)=CC=C1C#CC1=CC=C(SCCC2(C)C)C2=C1 OGQICQVSFDPSEI-UHFFFAOYSA-N 0.000 description 1
- ZZWKZQDOSJAGGF-VRSYWUPDSA-N [(1s,2e,7s,10e,12r,13r,15s)-12-hydroxy-7-methyl-9-oxo-8-oxabicyclo[11.3.0]hexadeca-2,10-dien-15-yl] 2-(dimethylamino)acetate Chemical compound O[C@@H]1\C=C\C(=O)O[C@@H](C)CCC\C=C\[C@@H]2C[C@H](OC(=O)CN(C)C)C[C@H]21 ZZWKZQDOSJAGGF-VRSYWUPDSA-N 0.000 description 1
- SPKNARKFCOPTSY-XWPZMVOTSA-N [(2r,3s)-2-[(2s,3r)-3-methyloxiran-2-yl]-6-oxo-2,3-dihydropyran-3-yl] acetate Chemical compound C[C@H]1O[C@@H]1[C@H]1[C@@H](OC(C)=O)C=CC(=O)O1 SPKNARKFCOPTSY-XWPZMVOTSA-N 0.000 description 1
- KMLCRELJHYKIIL-UHFFFAOYSA-N [1-(azanidylmethyl)cyclohexyl]methylazanide;platinum(2+);sulfuric acid Chemical compound [Pt+2].OS(O)(=O)=O.[NH-]CC1(C[NH-])CCCCC1 KMLCRELJHYKIIL-UHFFFAOYSA-N 0.000 description 1
- JJULHOZRTCDZOH-JGJFOBQESA-N [1-[[[(2r,3s,4s,5r)-5-(4-amino-2-oxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl]oxy-3-octadecylsulfanylpropan-2-yl] hexadecanoate Chemical compound O[C@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(CSCCCCCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)O[C@H]1N1C(=O)N=C(N)C=C1 JJULHOZRTCDZOH-JGJFOBQESA-N 0.000 description 1
- XSMVECZRZBFTIZ-UHFFFAOYSA-M [2-(aminomethyl)cyclobutyl]methanamine;2-oxidopropanoate;platinum(4+) Chemical compound [Pt+4].CC([O-])C([O-])=O.NCC1CCC1CN XSMVECZRZBFTIZ-UHFFFAOYSA-M 0.000 description 1
- 108010023617 abarelix Proteins 0.000 description 1
- AIWRTTMUVOZGPW-HSPKUQOVSA-N abarelix Chemical compound C([C@@H](C(=O)N[C@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCNC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)N(C)C(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 AIWRTTMUVOZGPW-HSPKUQOVSA-N 0.000 description 1
- 229960002184 abarelix Drugs 0.000 description 1
- 229960000853 abiraterone Drugs 0.000 description 1
- GZOSMCIZMLWJML-VJLLXTKPSA-N abiraterone Chemical compound C([C@H]1[C@H]2[C@@H]([C@]3(CC[C@H](O)CC3=CC2)C)CC[C@@]11C)C=C1C1=CC=CN=C1 GZOSMCIZMLWJML-VJLLXTKPSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000003070 absorption delaying agent Substances 0.000 description 1
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 description 1
- RUGAHXUZHWYHNG-NLGNTGLNSA-N acetic acid;(4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-n-[(2s,3r)-1-amino-3-hydroxy-1-oxobutan-2-yl]-19-[[(2r)-2-amino-3-naphthalen-2-ylpropanoyl]amino]-16-[(4-hydroxyphenyl)methyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-7-propan-2-yl-1,2-dithia-5, Chemical compound CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(N)=O)=O)C(C)C)C1=CC=C(O)C=C1.C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(N)=O)=O)C(C)C)C1=CC=C(O)C=C1 RUGAHXUZHWYHNG-NLGNTGLNSA-N 0.000 description 1
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- QAWIHIJWNYOLBE-OKKQSCSOSA-N acivicin Chemical compound OC(=O)[C@@H](N)[C@@H]1CC(Cl)=NO1 QAWIHIJWNYOLBE-OKKQSCSOSA-N 0.000 description 1
- 229950008427 acivicin Drugs 0.000 description 1
- 125000003647 acryloyl group Chemical group O=C([*])C([H])=C([H])[H] 0.000 description 1
- HLAKJNQXUARACO-UHFFFAOYSA-N acylfulvene Natural products CC1(O)C(=O)C2=CC(C)=CC2=C(C)C21CC2 HLAKJNQXUARACO-UHFFFAOYSA-N 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- WJSAFKJWCOMTLH-UHFFFAOYSA-N adecypenol Natural products OC1C(O)C(CO)=CC1N1C(NC=NCC2O)=C2N=C1 WJSAFKJWCOMTLH-UHFFFAOYSA-N 0.000 description 1
- DPGOLRILOKERAV-AAWJQDODSA-N adecypenol Chemical compound OC1C(CO)=CCC1(O)N1C(N=CNC[C@H]2O)C2N=C1 DPGOLRILOKERAV-AAWJQDODSA-N 0.000 description 1
- 238000011226 adjuvant chemotherapy Methods 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 108700025316 aldesleukin Proteins 0.000 description 1
- 229960005310 aldesleukin Drugs 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000005092 alkenyloxycarbonyl group Chemical group 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 1
- 125000004419 alkynylene group Chemical group 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229950010817 alvocidib Drugs 0.000 description 1
- BIIVYFLTOXDAOV-YVEFUNNKSA-N alvocidib Chemical compound O[C@@H]1CN(C)CC[C@@H]1C1=C(O)C=C(O)C2=C1OC(C=1C(=CC=CC=1)Cl)=CC2=O BIIVYFLTOXDAOV-YVEFUNNKSA-N 0.000 description 1
- 229950004821 ambomycin Drugs 0.000 description 1
- 229960002749 aminolevulinic acid Drugs 0.000 description 1
- 229960002550 amrubicin Drugs 0.000 description 1
- VJZITPJGSQKZMX-XDPRQOKASA-N amrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC=C4C(=O)C=3C(O)=C21)(N)C(=O)C)[C@H]1C[C@H](O)[C@H](O)CO1 VJZITPJGSQKZMX-XDPRQOKASA-N 0.000 description 1
- 229960001220 amsacrine Drugs 0.000 description 1
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 description 1
- 229960001694 anagrelide Drugs 0.000 description 1
- OTBXOEAOVRKTNQ-UHFFFAOYSA-N anagrelide Chemical compound N1=C2NC(=O)CN2CC2=C(Cl)C(Cl)=CC=C21 OTBXOEAOVRKTNQ-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229940030486 androgens Drugs 0.000 description 1
- ASLUCFFROXVMFL-UHFFFAOYSA-N andrographolide Natural products CC1(CO)C(O)CCC2(C)C(CC=C3/C(O)OCC3=O)C(=C)CCC12 ASLUCFFROXVMFL-UHFFFAOYSA-N 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 1
- 210000001557 animal structure Anatomy 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- VGQOVCHZGQWAOI-HYUHUPJXSA-N anthramycin Chemical compound N1[C@@H](O)[C@@H]2CC(\C=C\C(N)=O)=CN2C(=O)C2=CC=C(C)C(O)=C12 VGQOVCHZGQWAOI-HYUHUPJXSA-N 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 229940082988 antihypertensives serotonin antagonists Drugs 0.000 description 1
- 229940045687 antimetabolites folic acid analogs Drugs 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 239000003972 antineoplastic antibiotic Substances 0.000 description 1
- 229940045985 antineoplastic platinum compound Drugs 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000000074 antisense oligonucleotide Substances 0.000 description 1
- 238000012230 antisense oligonucleotides Methods 0.000 description 1
- IOASYARYEYRREA-LQAJYKIKSA-N aphidicolin glycinate Chemical compound C1[C@]23[C@]4(C)CC[C@H](O)[C@](C)(CO)[C@H]4CC[C@@H]3C[C@@H]1[C@@](COC(=O)CN)(O)CC2 IOASYARYEYRREA-LQAJYKIKSA-N 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 229960001372 aprepitant Drugs 0.000 description 1
- ATALOFNDEOCMKK-OITMNORJSA-N aprepitant Chemical compound O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NNC(=O)N1 ATALOFNDEOCMKK-OITMNORJSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000001124 arachidoyl group Chemical group O=C([*])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])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
- 108010055530 arginyl-tryptophyl-N-methylphenylalanyl-tryptophyl-leucyl-methioninamide Proteins 0.000 description 1
- 229910052785 arsenic Inorganic materials 0.000 description 1
- 229940091658 arsenic Drugs 0.000 description 1
- RQNWIZPPADIBDY-UHFFFAOYSA-N arsenic atom Chemical compound [As] RQNWIZPPADIBDY-UHFFFAOYSA-N 0.000 description 1
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 description 1
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 1
- 229960003272 asparaginase Drugs 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-M asparaginate Chemical compound [O-]C(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-M 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 239000000305 astragalus gummifer gum Substances 0.000 description 1
- 108010092978 axinastatin 3 Proteins 0.000 description 1
- ANLDPEXRVVIABH-WUUSPZRJSA-N axinastatin 3 Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CC(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C(=O)N[C@@H](CC(N)=O)C(=O)N2CCC[C@H]2C(=O)N1)C(C)C)=O)[C@@H](C)CC)C1=CC=CC=C1 ANLDPEXRVVIABH-WUUSPZRJSA-N 0.000 description 1
- RTGMQVUKARGBNM-UHFFFAOYSA-N axinastatin 3 Natural products CCC(C)C1NC(=O)C(CC(C)C)NC(=O)C2CCCN2C(=O)C(NC(=O)C(CC(=O)N)NC(=O)C3CCCN3C(=O)C(Cc4ccccc4)NC1=O)C(C)C RTGMQVUKARGBNM-UHFFFAOYSA-N 0.000 description 1
- 229960002756 azacitidine Drugs 0.000 description 1
- OPWOOOGFNULJAQ-UHFFFAOYSA-L azane;cyclopentanamine;2-hydroxybutanedioate;platinum(2+) Chemical compound N.[Pt+2].NC1CCCC1.[O-]C(=O)C(O)CC([O-])=O OPWOOOGFNULJAQ-UHFFFAOYSA-L 0.000 description 1
- KLNFSAOEKUDMFA-UHFFFAOYSA-N azanide;2-hydroxyacetic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OCC(O)=O KLNFSAOEKUDMFA-UHFFFAOYSA-N 0.000 description 1
- 229950005951 azasetron Drugs 0.000 description 1
- HRXVDDOKERXBEY-UHFFFAOYSA-N azatepa Chemical compound C1CN1P(=O)(N1CC1)N(CC)C1=NN=CS1 HRXVDDOKERXBEY-UHFFFAOYSA-N 0.000 description 1
- 150000004200 baccatin III derivatives Chemical class 0.000 description 1
- XFILPEOLDIKJHX-QYZOEREBSA-N batimastat Chemical compound C([C@@H](C(=O)NC)NC(=O)[C@H](CC(C)C)[C@H](CSC=1SC=CC=1)C(=O)NO)C1=CC=CC=C1 XFILPEOLDIKJHX-QYZOEREBSA-N 0.000 description 1
- 229950001858 batimastat Drugs 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 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
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- MMIMIFULGMZVPO-UHFFFAOYSA-N benzyl 3-bromo-2,6-dinitro-5-phenylmethoxybenzoate Chemical compound [O-][N+](=O)C1=C(C(=O)OCC=2C=CC=CC=2)C([N+](=O)[O-])=C(Br)C=C1OCC1=CC=CC=C1 MMIMIFULGMZVPO-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
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- QGJZLNKBHJESQX-FZFNOLFKSA-N betulinic acid Chemical compound C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C(=C)C)[C@@H]5[C@H]4CC[C@@H]3[C@]21C QGJZLNKBHJESQX-FZFNOLFKSA-N 0.000 description 1
- 229940087430 biaxin Drugs 0.000 description 1
- 229960000997 bicalutamide Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 238000010170 biological method Methods 0.000 description 1
- 238000001815 biotherapy Methods 0.000 description 1
- 125000006267 biphenyl group Chemical group 0.000 description 1
- QKSKPIVNLNLAAV-UHFFFAOYSA-N bis(2-chloroethyl) sulfide Chemical compound ClCCSCCCl QKSKPIVNLNLAAV-UHFFFAOYSA-N 0.000 description 1
- 229950002370 bisnafide Drugs 0.000 description 1
- 150000004663 bisphosphonates Chemical class 0.000 description 1
- NPSOIFAWYAHWOH-UHFFFAOYSA-N bistratene A Natural products O1C(CC(=O)C=CC)CCC(O2)(O)CC(C)C2CCCNC(=O)C(C)C2OC(CCC(C)C=C(C)C(C)O)CCCCC(C)C1CC(=O)NC2 NPSOIFAWYAHWOH-UHFFFAOYSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 125000006015 bromomethoxy group Chemical group 0.000 description 1
- 125000005997 bromomethyl group Chemical group 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- FFSAXUULYPJSKH-UHFFFAOYSA-N butyrophenone Chemical compound CCCC(=O)C1=CC=CC=C1 FFSAXUULYPJSKH-UHFFFAOYSA-N 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000003491 cAMP production Effects 0.000 description 1
- 229960002882 calcipotriol Drugs 0.000 description 1
- LWQQLNNNIPYSNX-UROSTWAQSA-N calcipotriol Chemical compound C1([C@H](O)/C=C/[C@@H](C)[C@@H]2[C@]3(CCCC(/[C@@H]3CC2)=C\C=C\2C([C@@H](O)C[C@H](O)C/2)=C)C)CC1 LWQQLNNNIPYSNX-UROSTWAQSA-N 0.000 description 1
- 229960005084 calcitriol Drugs 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- LSUTUUOITDQYNO-UHFFFAOYSA-N calphostin C Chemical compound C=12C3=C4C(CC(C)OC(=O)C=5C=CC=CC=5)=C(OC)C(O)=C(C(C=C5OC)=O)C4=C5C=1C(OC)=CC(=O)C2=C(O)C(OC)=C3CC(C)OC(=O)OC1=CC=C(O)C=C1 LSUTUUOITDQYNO-UHFFFAOYSA-N 0.000 description 1
- 229940065144 cannabinoids Drugs 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000004709 cell invasion Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- HZCWPKGYTCJSEB-UHFFFAOYSA-N chembl118841 Chemical compound C12=CC(OC)=CC=C2NC2=C([N+]([O-])=O)C=CC3=C2C1=NN3CCCN(C)C HZCWPKGYTCJSEB-UHFFFAOYSA-N 0.000 description 1
- OWSKEUBOCMEJMI-KPXOXKRLSA-N chembl2105946 Chemical compound [N-]=[N+]=CC(=O)CC[C@H](NC(=O)[C@@H](N)C)C(=O)N[C@H](CCC(=O)C=[N+]=[N-])C(O)=O OWSKEUBOCMEJMI-KPXOXKRLSA-N 0.000 description 1
- ZWVZORIKUNOTCS-OAQYLSRUSA-N chembl401930 Chemical compound C1([C@H](O)CNC2=C(C(NC=C2)=O)C=2NC=3C=C(C=C(C=3N=2)C)N2CCOCC2)=CC=CC(Cl)=C1 ZWVZORIKUNOTCS-OAQYLSRUSA-N 0.000 description 1
- DCKFXSZUWVWFEU-JECTWPLRSA-N chembl499423 Chemical compound O1[C@@H](CC)CCCC[C@]11NC(N23)=N[C@]4(O[C@H](C)CCC4)[C@@H](C(=O)OCCCCCCCCCCCCCCCC(=O)N(CCCN)C[C@@H](O)CCN)[C@@]3(O)CC[C@H]2C1 DCKFXSZUWVWFEU-JECTWPLRSA-N 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- SURLGNKAQXKNSP-DBLYXWCISA-N chlorin Chemical compound C\1=C/2\N/C(=C\C3=N/C(=C\C=4NC(/C=C\5/C=CC/1=N/5)=CC=4)/C=C3)/CC\2 SURLGNKAQXKNSP-DBLYXWCISA-N 0.000 description 1
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 description 1
- 125000004651 chloromethoxy group Chemical group ClCO* 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- ARUGKOZUKWAXDS-SEWALLKFSA-N cicaprost Chemical compound C1\C(=C/COCC(O)=O)C[C@@H]2[C@@H](C#C[C@@H](O)[C@@H](C)CC#CCC)[C@H](O)C[C@@H]21 ARUGKOZUKWAXDS-SEWALLKFSA-N 0.000 description 1
- 229950000634 cicaprost Drugs 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- 229950011359 cirolemycin Drugs 0.000 description 1
- JKNIRLKHOOMGOJ-UHFFFAOYSA-N cladochrome D Natural products COC1=C(CC(C)OC(=O)Oc2ccc(O)cc2)c3c4C(=C(OC)C(=O)c5c(O)cc(OC)c(c45)c6c(OC)cc(O)c(C1=O)c36)CC(C)OC(=O)c7ccc(O)cc7 JKNIRLKHOOMGOJ-UHFFFAOYSA-N 0.000 description 1
- SRJYZPCBWDVSGO-UHFFFAOYSA-N cladochrome E Natural products COC1=CC(O)=C(C(C(OC)=C(CC(C)OC(=O)OC=2C=CC(O)=CC=2)C2=3)=O)C2=C1C1=C(OC)C=C(O)C(C(C=2OC)=O)=C1C=3C=2CC(C)OC(=O)C1=CC=CC=C1 SRJYZPCBWDVSGO-UHFFFAOYSA-N 0.000 description 1
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 description 1
- GKIRPKYJQBWNGO-OCEACIFDSA-N clomifene Chemical class C1=CC(OCCN(CC)CC)=CC=C1C(\C=1C=CC=CC=1)=C(\Cl)C1=CC=CC=C1 GKIRPKYJQBWNGO-OCEACIFDSA-N 0.000 description 1
- VNFPBHJOKIVQEB-UHFFFAOYSA-N clotrimazole Chemical compound ClC1=CC=CC=C1C(N1C=NC=C1)(C=1C=CC=CC=1)C1=CC=CC=C1 VNFPBHJOKIVQEB-UHFFFAOYSA-N 0.000 description 1
- 229960004022 clotrimazole Drugs 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 230000000112 colonic effect Effects 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 229960005537 combretastatin A-4 Drugs 0.000 description 1
- HVXBOLULGPECHP-UHFFFAOYSA-N combretastatin A4 Natural products C1=C(O)C(OC)=CC=C1C=CC1=CC(OC)=C(OC)C(OC)=C1 HVXBOLULGPECHP-UHFFFAOYSA-N 0.000 description 1
- 150000004814 combretastatins Chemical class 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000002591 computed tomography Methods 0.000 description 1
- GLESHRYLRAOJPS-DHCFDGJBSA-N conagenin Chemical compound C[C@@H](O)[C@H](C)[C@@H](O)C(=O)N[C@@](C)(CO)C(O)=O GLESHRYLRAOJPS-DHCFDGJBSA-N 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- PSNOPSMXOBPNNV-VVCTWANISA-N cryptophycin 1 Chemical class C1=C(Cl)C(OC)=CC=C1C[C@@H]1C(=O)NC[C@@H](C)C(=O)O[C@@H](CC(C)C)C(=O)O[C@H]([C@H](C)[C@@H]2[C@H](O2)C=2C=CC=CC=2)C/C=C/C(=O)N1 PSNOPSMXOBPNNV-VVCTWANISA-N 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000004976 cyclobutylene group Chemical group 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000004977 cycloheptylene group Chemical group 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
- 125000004956 cyclohexylene group Chemical group 0.000 description 1
- 125000006547 cyclononyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- MKNXBRLZBFVUPV-UHFFFAOYSA-L cyclopenta-1,3-diene;dichlorotitanium Chemical compound Cl[Ti]Cl.C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 MKNXBRLZBFVUPV-UHFFFAOYSA-L 0.000 description 1
- 125000004979 cyclopentylene group Chemical group 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000004980 cyclopropylene group Chemical group 0.000 description 1
- 108010041566 cypemycin Proteins 0.000 description 1
- 230000001461 cytolytic effect Effects 0.000 description 1
- 229960003109 daunorubicin hydrochloride Drugs 0.000 description 1
- 229940026692 decadron Drugs 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
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 108700025485 deslorelin Proteins 0.000 description 1
- 229960005408 deslorelin Drugs 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 229960000605 dexrazoxane Drugs 0.000 description 1
- SGTNSNPWRIOYBX-HHHXNRCGSA-N dexverapamil Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCC[C@@](C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-HHHXNRCGSA-N 0.000 description 1
- 229950005878 dexverapamil Drugs 0.000 description 1
- 229950010621 dezaguanine Drugs 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 229910003460 diamond Inorganic materials 0.000 description 1
- 239000010432 diamond Substances 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- PZXJOHSZQAEJFE-UHFFFAOYSA-N dihydrobetulinic acid Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C(C)C)C5C4CCC3C21C PZXJOHSZQAEJFE-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
- 229950010286 diolamine Drugs 0.000 description 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 238000002224 dissection Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229940110377 dl- arginine Drugs 0.000 description 1
- 229960000735 docosanol Drugs 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 229940115080 doxil Drugs 0.000 description 1
- 229960002918 doxorubicin hydrochloride Drugs 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 229950005133 duazomycin Drugs 0.000 description 1
- 229930192837 duazomycin Natural products 0.000 description 1
- VQNATVDKACXKTF-XELLLNAOSA-N duocarmycin Chemical compound COC1=C(OC)C(OC)=C2NC(C(=O)N3C4=CC(=O)C5=C([C@@]64C[C@@H]6C3)C=C(N5)C(=O)OC)=CC2=C1 VQNATVDKACXKTF-XELLLNAOSA-N 0.000 description 1
- 229960005510 duocarmycin SA Drugs 0.000 description 1
- 229950010033 ebselen Drugs 0.000 description 1
- 229960001776 edrecolomab Drugs 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- VLCYCQAOQCDTCN-UHFFFAOYSA-N eflornithine Chemical compound NCCCC(N)(C(F)F)C(O)=O VLCYCQAOQCDTCN-UHFFFAOYSA-N 0.000 description 1
- 229960002759 eflornithine Drugs 0.000 description 1
- 229940000733 emcyt Drugs 0.000 description 1
- JOZGNYDSEBIJDH-UHFFFAOYSA-N eniluracil Chemical compound O=C1NC=C(C#C)C(=O)N1 JOZGNYDSEBIJDH-UHFFFAOYSA-N 0.000 description 1
- 229950001022 enpromate Drugs 0.000 description 1
- 229950004926 epipropidine Drugs 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- 229960003265 epirubicin hydrochloride Drugs 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 229950009537 epristeride Drugs 0.000 description 1
- 229940082789 erbitux Drugs 0.000 description 1
- 229950001426 erbulozole Drugs 0.000 description 1
- KLEPCGBEXOCIGS-QPPBQGQZSA-N erbulozole Chemical compound C1=CC(NC(=O)OCC)=CC=C1SC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C=CC(OC)=CC=2)OC1 KLEPCGBEXOCIGS-QPPBQGQZSA-N 0.000 description 1
- 229960001433 erlotinib Drugs 0.000 description 1
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 1
- FRPJXPJMRWBBIH-RBRWEJTLSA-N estramustine Chemical class ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 description 1
- 229960001766 estramustine phosphate sodium Drugs 0.000 description 1
- WCDWBPCFGJXFJZ-UHFFFAOYSA-N etanidazole Chemical compound OCCNC(=O)CN1C=CN=C1[N+]([O-])=O WCDWBPCFGJXFJZ-UHFFFAOYSA-N 0.000 description 1
- 229950006566 etanidazole Drugs 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- LIQODXNTTZAGID-OCBXBXKTSA-N etoposide phosphate Chemical compound COC1=C(OP(O)(O)=O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 LIQODXNTTZAGID-OCBXBXKTSA-N 0.000 description 1
- 229960000752 etoposide phosphate Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- NMUSYJAQQFHJEW-ARQDHWQXSA-N fazarabine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-ARQDHWQXSA-N 0.000 description 1
- 229950005096 fazarabine Drugs 0.000 description 1
- POTUGHMKJGOKRI-UHFFFAOYSA-N ficin Chemical compound FI=CI=N POTUGHMKJGOKRI-UHFFFAOYSA-N 0.000 description 1
- 235000019836 ficin Nutrition 0.000 description 1
- 229960004177 filgrastim Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- DBEPLOCGEIEOCV-WSBQPABSSA-N finasteride Chemical compound N([C@@H]1CC2)C(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)NC(C)(C)C)[C@@]2(C)CC1 DBEPLOCGEIEOCV-WSBQPABSSA-N 0.000 description 1
- 229960004039 finasteride Drugs 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 229960000961 floxuridine Drugs 0.000 description 1
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 229950005682 flurocitabine Drugs 0.000 description 1
- VVIAGPKUTFNRDU-ABLWVSNPSA-N folinic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-ABLWVSNPSA-N 0.000 description 1
- 235000008191 folinic acid Nutrition 0.000 description 1
- 239000011672 folinic acid Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000003838 furazanyl group Chemical group 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229940044658 gallium nitrate Drugs 0.000 description 1
- 229950004410 galocitabine Drugs 0.000 description 1
- 229960002963 ganciclovir Drugs 0.000 description 1
- IRSCQMHQWWYFCW-UHFFFAOYSA-N ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 239000002406 gelatinase inhibitor Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229960005144 gemcitabine hydrochloride Drugs 0.000 description 1
- 229940080856 gleevec Drugs 0.000 description 1
- 229940084910 gliadel Drugs 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 229940097042 glucuronate Drugs 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- MFWNKCLOYSRHCJ-BTTYYORXSA-N granisetron Chemical compound C1=CC=C2C(C(=O)N[C@H]3C[C@H]4CCC[C@@H](C3)N4C)=NN(C)C2=C1 MFWNKCLOYSRHCJ-BTTYYORXSA-N 0.000 description 1
- 229960003727 granisetron Drugs 0.000 description 1
- 150000004820 halides Chemical group 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 229960003878 haloperidol Drugs 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- MCAHMSDENAOJFZ-BVXDHVRPSA-N herbimycin Chemical compound N1C(=O)\C(C)=C\C=C/[C@H](OC)[C@@H](OC(N)=O)\C(C)=C\[C@H](C)[C@@H](OC)[C@@H](OC)C[C@H](C)[C@@H](OC)C2=CC(=O)C=C1C2=O MCAHMSDENAOJFZ-BVXDHVRPSA-N 0.000 description 1
- 229930193320 herbimycin Natural products 0.000 description 1
- 229940022353 herceptin Drugs 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 229950000177 hibenzate Drugs 0.000 description 1
- 229940084986 human chorionic gonadotropin Drugs 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- SOCGJDYHNGLZEC-UHFFFAOYSA-N hydron;n-methyl-n-[4-[(7-methyl-3h-imidazo[4,5-f]quinolin-9-yl)amino]phenyl]acetamide;chloride Chemical compound Cl.C1=CC(N(C(C)=O)C)=CC=C1NC1=CC(C)=NC2=CC=C(NC=N3)C3=C12 SOCGJDYHNGLZEC-UHFFFAOYSA-N 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 229960001176 idarubicin hydrochloride Drugs 0.000 description 1
- 229960002411 imatinib Drugs 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 229960002751 imiquimod Drugs 0.000 description 1
- DOUYETYNHWVLEO-UHFFFAOYSA-N imiquimod Chemical compound C1=CC=CC2=C3N(CC(C)C)C=NC3=C(N)N=C21 DOUYETYNHWVLEO-UHFFFAOYSA-N 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000005414 inactive ingredient Substances 0.000 description 1
- 210000003000 inclusion body Anatomy 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 238000007373 indentation Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 102000028416 insulin-like growth factor binding Human genes 0.000 description 1
- 108091022911 insulin-like growth factor binding Proteins 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 229950010897 iproplatin Drugs 0.000 description 1
- 229960000779 irinotecan hydrochloride Drugs 0.000 description 1
- 229950000855 iroplact Drugs 0.000 description 1
- 229950010984 irsogladine Drugs 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000005929 isobutyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])OC(*)=O 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- RWXRJSRJIITQAK-ZSBIGDGJSA-N itasetron Chemical compound C12=CC=CC=C2NC(=O)N1C(=O)N[C@H](C1)C[C@H]2CC[C@@H]1N2C RWXRJSRJIITQAK-ZSBIGDGJSA-N 0.000 description 1
- 229950007654 itasetron Drugs 0.000 description 1
- 108010091711 kahalalide F Proteins 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 229960002437 lanreotide Drugs 0.000 description 1
- 229960001739 lanreotide acetate Drugs 0.000 description 1
- 125000000400 lauroyl group Chemical group O=C([*])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])C([H])([H])[H] 0.000 description 1
- 229960002618 lenograstim Drugs 0.000 description 1
- 229940115286 lentinan Drugs 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 229960001691 leucovorin Drugs 0.000 description 1
- 229960001614 levamisole Drugs 0.000 description 1
- 229950008991 lobaplatin Drugs 0.000 description 1
- 229950000909 lometrexol Drugs 0.000 description 1
- 229960003538 lonidamine Drugs 0.000 description 1
- WDRYRZXSPDWGEB-UHFFFAOYSA-N lonidamine Chemical compound C12=CC=CC=C2C(C(=O)O)=NN1CC1=CC=C(Cl)C=C1Cl WDRYRZXSPDWGEB-UHFFFAOYSA-N 0.000 description 1
- 229960004391 lorazepam Drugs 0.000 description 1
- 229950005634 loxoribine Drugs 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 201000001037 lung lymphoma Diseases 0.000 description 1
- 208000030758 lung non-Hodgkin lymphoma Diseases 0.000 description 1
- 208000037841 lung tumor Diseases 0.000 description 1
- RVFGKBWWUQOIOU-NDEPHWFRSA-N lurtotecan Chemical compound O=C([C@]1(O)CC)OCC(C(N2CC3=4)=O)=C1C=C2C3=NC1=CC=2OCCOC=2C=C1C=4CN1CCN(C)CC1 RVFGKBWWUQOIOU-NDEPHWFRSA-N 0.000 description 1
- 229950002654 lurtotecan Drugs 0.000 description 1
- 229940040129 luteinizing hormone Drugs 0.000 description 1
- 235000018977 lysine Nutrition 0.000 description 1
- 229960003646 lysine Drugs 0.000 description 1
- 230000002101 lytic effect Effects 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229940091250 magnesium supplement Drugs 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 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
- 125000000628 margaroyl group Chemical group O=C([*])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])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229960004296 megestrol acetate Drugs 0.000 description 1
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 229960003846 melengestrol acetate Drugs 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000003475 metalloproteinase inhibitor Substances 0.000 description 1
- 229940126170 metalloproteinase inhibitor Drugs 0.000 description 1
- 108700025096 meterelin Proteins 0.000 description 1
- BKBBTCORRZMASO-ZOWNYOTGSA-M methotrexate monosodium Chemical compound [Na+].C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C([O-])=O)C=C1 BKBBTCORRZMASO-ZOWNYOTGSA-M 0.000 description 1
- 229960003058 methotrexate sodium Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 229960004503 metoclopramide Drugs 0.000 description 1
- TTWJBBZEZQICBI-UHFFFAOYSA-N metoclopramide Chemical compound CCN(CC)CCNC(=O)C1=CC(Cl)=C(N)C=C1OC TTWJBBZEZQICBI-UHFFFAOYSA-N 0.000 description 1
- BMGQWWVMWDBQGC-IIFHNQTCSA-N midostaurin Chemical class CN([C@H]1[C@H]([C@]2(C)O[C@@H](N3C4=CC=CC=C4C4=C5C(=O)NCC5=C5C6=CC=CC=C6N2C5=C43)C1)OC)C(=O)C1=CC=CC=C1 BMGQWWVMWDBQGC-IIFHNQTCSA-N 0.000 description 1
- 229960003248 mifepristone Drugs 0.000 description 1
- VKHAHZOOUSRJNA-GCNJZUOMSA-N mifepristone Chemical compound C1([C@@H]2C3=C4CCC(=O)C=C4CC[C@H]3[C@@H]3CC[C@@]([C@]3(C2)C)(O)C#CC)=CC=C(N(C)C)C=C1 VKHAHZOOUSRJNA-GCNJZUOMSA-N 0.000 description 1
- 229960003775 miltefosine Drugs 0.000 description 1
- PQLXHQMOHUQAKB-UHFFFAOYSA-N miltefosine Chemical compound CCCCCCCCCCCCCCCCOP([O-])(=O)OCC[N+](C)(C)C PQLXHQMOHUQAKB-UHFFFAOYSA-N 0.000 description 1
- 229950008541 mirimostim Drugs 0.000 description 1
- 230000000116 mitigating effect Effects 0.000 description 1
- 229950002137 mitocarcin Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000007932 molded tablet Substances 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- VOWOEBADKMXUBU-UHFFFAOYSA-J molecular oxygen;tetrachlorite;hydrate Chemical compound O.O=O.[O-]Cl=O.[O-]Cl=O.[O-]Cl=O.[O-]Cl=O VOWOEBADKMXUBU-UHFFFAOYSA-J 0.000 description 1
- FOYWNSCCNCUEPU-UHFFFAOYSA-N mopidamol Chemical compound C12=NC(N(CCO)CCO)=NC=C2N=C(N(CCO)CCO)N=C1N1CCCCC1 FOYWNSCCNCUEPU-UHFFFAOYSA-N 0.000 description 1
- 229950010718 mopidamol Drugs 0.000 description 1
- AARXZCZYLAFQQU-UHFFFAOYSA-N motexafin gadolinium Chemical compound [Gd].CC(O)=O.CC(O)=O.C1=C([N-]2)C(CC)=C(CC)C2=CC(C(=C2C)CCCO)=NC2=CN=C2C=C(OCCOCCOCCOC)C(OCCOCCOCCOC)=CC2=NC=C2C(C)=C(CCCO)C1=N2 AARXZCZYLAFQQU-UHFFFAOYSA-N 0.000 description 1
- WIQKYZYFTAEWBF-UHFFFAOYSA-L motexafin lutetium hydrate Chemical compound O.[Lu+3].CC([O-])=O.CC([O-])=O.C1=C([N-]2)C(CC)=C(CC)C2=CC(C(=C2C)CCCO)=NC2=CN=C2C=C(OCCOCCOCCOC)C(OCCOCCOCCOC)=CC2=NC=C2C(C)=C(CCCO)C1=N2 WIQKYZYFTAEWBF-UHFFFAOYSA-L 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 235000010460 mustard Nutrition 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 125000001419 myristoyl group Chemical group O=C([*])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])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- NKFHKYQGZDAKMX-PPRKPIOESA-N n-[(e)-1-[(2s,4s)-4-[(2r,4s,5s,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-3,4-dihydro-1h-tetracen-2-yl]ethylideneamino]benzamide;hydrochloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 NKFHKYQGZDAKMX-PPRKPIOESA-N 0.000 description 1
- TVYPSLDUBVTDIS-FUOMVGGVSA-N n-[1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-methyloxolan-2-yl]-5-fluoro-2-oxopyrimidin-4-yl]-3,4,5-trimethoxybenzamide Chemical compound COC1=C(OC)C(OC)=CC(C(=O)NC=2C(=CN(C(=O)N=2)[C@H]2[C@@H]([C@H](O)[C@@H](C)O2)O)F)=C1 TVYPSLDUBVTDIS-FUOMVGGVSA-N 0.000 description 1
- ARKYUICTMUZVEW-UHFFFAOYSA-N n-[5-[[5-[(3-amino-3-iminopropyl)carbamoyl]-1-methylpyrrol-3-yl]carbamoyl]-1-methylpyrrol-3-yl]-4-[[4-[bis(2-chloroethyl)amino]benzoyl]amino]-1-methylpyrrole-2-carboxamide Chemical compound C1=C(C(=O)NCCC(N)=N)N(C)C=C1NC(=O)C1=CC(NC(=O)C=2N(C=C(NC(=O)C=3C=CC(=CC=3)N(CCCl)CCCl)C=2)C)=CN1C ARKYUICTMUZVEW-UHFFFAOYSA-N 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
- 229960004127 naloxone Drugs 0.000 description 1
- UZHSEJADLWPNLE-GRGSLBFTSA-N naloxone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C UZHSEJADLWPNLE-GRGSLBFTSA-N 0.000 description 1
- 125000005487 naphthalate group Chemical group 0.000 description 1
- 108010032539 nartograstim Proteins 0.000 description 1
- 229950010676 nartograstim Drugs 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229950007221 nedaplatin Drugs 0.000 description 1
- CTMCWCONSULRHO-UHQPFXKFSA-N nemorubicin Chemical compound C1CO[C@H](OC)CN1[C@@H]1[C@H](O)[C@H](C)O[C@@H](O[C@@H]2C3=C(O)C=4C(=O)C5=C(OC)C=CC=C5C(=O)C=4C(O)=C3C[C@](O)(C2)C(=O)CO)C1 CTMCWCONSULRHO-UHQPFXKFSA-N 0.000 description 1
- 229950010159 nemorubicin Drugs 0.000 description 1
- QZGIWPZCWHMVQL-UIYAJPBUSA-N neocarzinostatin chromophore Chemical compound O1[C@H](C)[C@H](O)[C@H](O)[C@@H](NC)[C@H]1O[C@@H]1C/2=C/C#C[C@H]3O[C@@]3([C@@H]3OC(=O)OC3)C#CC\2=C[C@H]1OC(=O)C1=C(O)C=CC2=C(C)C=C(OC)C=C12 QZGIWPZCWHMVQL-UIYAJPBUSA-N 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
- MQYXUWHLBZFQQO-UHFFFAOYSA-N nepehinol Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C)CCC(C(=C)C)C5C4CCC3C21C MQYXUWHLBZFQQO-UHFFFAOYSA-N 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- XWXYUMMDTVBTOU-UHFFFAOYSA-N nilutamide Chemical compound O=C1C(C)(C)NC(=O)N1C1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 XWXYUMMDTVBTOU-UHFFFAOYSA-N 0.000 description 1
- 229960002653 nilutamide Drugs 0.000 description 1
- 229940125745 nitric oxide modulator Drugs 0.000 description 1
- 229950006344 nocodazole Drugs 0.000 description 1
- 125000001402 nonanoyl group Chemical group O=C([*])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
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 125000002801 octanoyl group Chemical group C(CCCCCCC)(=O)* 0.000 description 1
- 229960002700 octreotide Drugs 0.000 description 1
- 229950004864 olamine Drugs 0.000 description 1
- 229950011093 onapristone Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical compound OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 229940127084 other anti-cancer agent Drugs 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003544 oxime group Chemical group 0.000 description 1
- 125000006505 p-cyanobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C#N)C([H])([H])* 0.000 description 1
- 125000003232 p-nitrobenzoyl group Chemical group [N+](=O)([O-])C1=CC=C(C(=O)*)C=C1 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 238000012858 packaging process Methods 0.000 description 1
- WRUUGTRCQOWXEG-UHFFFAOYSA-N pamidronate Chemical compound NCCC(O)(P(O)(O)=O)P(O)(O)=O WRUUGTRCQOWXEG-UHFFFAOYSA-N 0.000 description 1
- 229960003978 pamidronic acid Drugs 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- VOKSWYLNZZRQPF-GDIGMMSISA-N pentazocine Chemical compound C1C2=CC=C(O)C=C2[C@@]2(C)[C@@H](C)[C@@H]1N(CC=C(C)C)CC2 VOKSWYLNZZRQPF-GDIGMMSISA-N 0.000 description 1
- 229960005301 pentazocine Drugs 0.000 description 1
- 229960001476 pentoxifylline Drugs 0.000 description 1
- WTWWXOGTJWMJHI-UHFFFAOYSA-N perflubron Chemical compound FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)Br WTWWXOGTJWMJHI-UHFFFAOYSA-N 0.000 description 1
- 229960001217 perflubron Drugs 0.000 description 1
- 235000005693 perillyl alcohol Nutrition 0.000 description 1
- LCADVYTXPLBAGB-GNCBHIOISA-N phenalamide A1 Natural products CC(CO)NC(=O)C(=CC=CC=C/C=C/C(=C/C(C)C(O)C(=CC(C)CCc1ccccc1)C)/C)C LCADVYTXPLBAGB-GNCBHIOISA-N 0.000 description 1
- 125000006678 phenoxycarbonyl group Chemical group 0.000 description 1
- YNFAEFZZHQSSDP-UHFFFAOYSA-N phenyl acetate;sodium Chemical compound [Na].CC(=O)OC1=CC=CC=C1 YNFAEFZZHQSSDP-UHFFFAOYSA-N 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 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
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- RNAICSBVACLLGM-GNAZCLTHSA-N pilocarpine hydrochloride Chemical compound Cl.C1OC(=O)[C@@H](CC)[C@H]1CC1=CN=CN1C RNAICSBVACLLGM-GNAZCLTHSA-N 0.000 description 1
- 229960002139 pilocarpine hydrochloride Drugs 0.000 description 1
- 229960001221 pirarubicin Drugs 0.000 description 1
- XESARGFCSKSFID-FLLFQEBCSA-N pirazofurin Chemical compound OC1=C(C(=O)N)NN=C1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 XESARGFCSKSFID-FLLFQEBCSA-N 0.000 description 1
- 239000002797 plasminogen activator inhibitor Substances 0.000 description 1
- 229950008499 plitidepsin Drugs 0.000 description 1
- 108010049948 plitidepsin Proteins 0.000 description 1
- UUSZLLQJYRSZIS-LXNNNBEUSA-N plitidepsin Chemical compound CN([C@H](CC(C)C)C(=O)N[C@@H]1C(=O)N[C@@H]([C@H](CC(=O)O[C@H](C(=O)[C@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N2CCC[C@H]2C(=O)N(C)[C@@H](CC=2C=CC(OC)=CC=2)C(=O)O[C@@H]1C)C(C)C)O)[C@@H](C)CC)C(=O)[C@@H]1CCCN1C(=O)C(C)=O UUSZLLQJYRSZIS-LXNNNBEUSA-N 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229960004293 porfimer sodium Drugs 0.000 description 1
- 150000004032 porphyrins Chemical class 0.000 description 1
- 230000035409 positive regulation of cell proliferation Effects 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229960003975 potassium Drugs 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- 229960001586 procarbazine hydrochloride Drugs 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- WIKYUJGCLQQFNW-UHFFFAOYSA-N prochlorperazine Chemical compound C1CN(C)CCN1CCCN1C2=CC(Cl)=CC=C2SC2=CC=CC=C21 WIKYUJGCLQQFNW-UHFFFAOYSA-N 0.000 description 1
- 229960003111 prochlorperazine Drugs 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005767 propoxymethyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])[#8]C([H])([H])* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- UQOQENZZLBSFKO-POPPZSFYSA-N prostaglandin J2 Chemical compound CCCCC[C@H](O)\C=C\[C@@H]1[C@@H](C\C=C/CCCC(O)=O)C=CC1=O UQOQENZZLBSFKO-POPPZSFYSA-N 0.000 description 1
- 102000017953 prostanoid receptors Human genes 0.000 description 1
- 108050007059 prostanoid receptors Proteins 0.000 description 1
- 239000003207 proteasome inhibitor Substances 0.000 description 1
- 239000003528 protein farnesyltransferase inhibitor Substances 0.000 description 1
- 229940126731 protein tyrosine phosphatase inhibitor Drugs 0.000 description 1
- 239000003806 protein tyrosine phosphatase inhibitor Substances 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 239000000784 purine nucleoside phosphorylase inhibitor Substances 0.000 description 1
- 229950010131 puromycin Drugs 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 229960004432 raltitrexed Drugs 0.000 description 1
- NTHPAPBPFQJABD-LLVKDONJSA-N ramosetron Chemical compound C12=CC=CC=C2N(C)C=C1C(=O)[C@H]1CC(NC=N2)=C2CC1 NTHPAPBPFQJABD-LLVKDONJSA-N 0.000 description 1
- 229950001588 ramosetron Drugs 0.000 description 1
- 102000016914 ras Proteins Human genes 0.000 description 1
- 229940116176 remicade Drugs 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- OWPCHSCAPHNHAV-LMONGJCWSA-N rhizoxin Chemical compound C/C([C@H](OC)[C@@H](C)[C@@H]1C[C@H](O)[C@]2(C)O[C@@H]2/C=C/[C@@H](C)[C@]2([H])OC(=O)C[C@@](C2)(C[C@@H]2O[C@H]2C(=O)O1)[H])=C\C=C\C(\C)=C\C1=COC(C)=N1 OWPCHSCAPHNHAV-LMONGJCWSA-N 0.000 description 1
- 108091092562 ribozyme Proteins 0.000 description 1
- 229940116736 romycin Drugs 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
- 125000005930 sec-butyloxycarbonyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- 230000009758 senescence Effects 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 229950010372 sobuzoxane Drugs 0.000 description 1
- YBZRLMLGUBIIDN-NZSGCTDASA-N spicamycin Chemical compound O1[C@@H](C(O)CO)[C@H](NC(=O)CNC(=O)CCCCCCCCCCCCC(C)C)[C@@H](O)[C@@H](O)[C@H]1NC1=NC=NC2=C1N=CN2 YBZRLMLGUBIIDN-NZSGCTDASA-N 0.000 description 1
- YBZRLMLGUBIIDN-UHFFFAOYSA-N spicamycin Natural products O1C(C(O)CO)C(NC(=O)CNC(=O)CCCCCCCCCCCCC(C)C)C(O)C(O)C1NC1=NC=NC2=C1NC=N2 YBZRLMLGUBIIDN-UHFFFAOYSA-N 0.000 description 1
- 229950006315 spirogermanium Drugs 0.000 description 1
- 229950006050 spiromustine Drugs 0.000 description 1
- 229950004330 spiroplatin Drugs 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 229950001248 squalamine Drugs 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 125000003696 stearoyl group Chemical group O=C([*])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])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
- 229960001052 streptozocin Drugs 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- WPLOVIFNBMNBPD-ATHMIXSHSA-N subtilin Chemical compound CC1SCC(NC2=O)C(=O)NC(CC(N)=O)C(=O)NC(C(=O)NC(CCCCN)C(=O)NC(C(C)CC)C(=O)NC(=C)C(=O)NC(CCCCN)C(O)=O)CSC(C)C2NC(=O)C(CC(C)C)NC(=O)C1NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C1NC(=O)C(=C/C)/NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)CNC(=O)C(NC(=O)C(NC(=O)C2NC(=O)CNC(=O)C3CCCN3C(=O)C(NC(=O)C3NC(=O)C(CC(C)C)NC(=O)C(=C)NC(=O)C(CCC(O)=O)NC(=O)C(NC(=O)C(CCCCN)NC(=O)C(N)CC=4C5=CC=CC=C5NC=4)CSC3)C(C)SC2)C(C)C)C(C)SC1)CC1=CC=CC=C1 WPLOVIFNBMNBPD-ATHMIXSHSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 description 1
- 229960000894 sulindac Drugs 0.000 description 1
- 229950007841 sulofenur Drugs 0.000 description 1
- 230000002483 superagonistic effect Effects 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- FIAFUQMPZJWCLV-UHFFFAOYSA-N suramin Chemical compound OS(=O)(=O)C1=CC(S(O)(=O)=O)=C2C(NC(=O)C3=CC=C(C(=C3)NC(=O)C=3C=C(NC(=O)NC=4C=C(C=CC=4)C(=O)NC=4C(=CC=C(C=4)C(=O)NC=4C5=C(C=C(C=C5C(=CC=4)S(O)(=O)=O)S(O)(=O)=O)S(O)(=O)=O)C)C=CC=3)C)=CC=C(S(O)(=O)=O)C2=C1 FIAFUQMPZJWCLV-UHFFFAOYSA-N 0.000 description 1
- 229960005314 suramin Drugs 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 229960005566 swainsonine Drugs 0.000 description 1
- FXUAIOOAOAVCGD-UHFFFAOYSA-N swainsonine Natural products C1CCC(O)C2C(O)C(O)CN21 FXUAIOOAOAVCGD-UHFFFAOYSA-N 0.000 description 1
- FXUAIOOAOAVCGD-FKSUSPILSA-N swainsonine Chemical compound C1CC[C@H](O)[C@H]2[C@H](O)[C@H](O)CN21 FXUAIOOAOAVCGD-FKSUSPILSA-N 0.000 description 1
- VAZAPHZUAVEOMC-UHFFFAOYSA-N tacedinaline Chemical compound C1=CC(NC(=O)C)=CC=C1C(=O)NC1=CC=CC=C1N VAZAPHZUAVEOMC-UHFFFAOYSA-N 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
- 229950010168 tauromustine Drugs 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- 150000004579 taxol derivatives Chemical class 0.000 description 1
- 229960000565 tazarotene Drugs 0.000 description 1
- 239000003277 telomerase inhibitor Substances 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
- 238000012360 testing method Methods 0.000 description 1
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000004187 tetrahydropyran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- WXZSUBHBYQYTNM-WMDJANBXSA-N tetrazomine Chemical compound C=1([C@@H]2CO[C@@H]3[C@H]4C[C@@H](CO)[C@H](N4C)[C@@H](N23)CC=1C=C1)C(OC)=C1NC(=O)C1NCCC[C@H]1O WXZSUBHBYQYTNM-WMDJANBXSA-N 0.000 description 1
- ZCTJIMXXSXQXRI-KYJUHHDHSA-N thalicarpine Chemical compound CN1CCC2=CC(OC)=C(OC)C3=C2[C@@H]1CC1=C3C=C(OC)C(OC2=C(C[C@H]3C4=CC(OC)=C(OC)C=C4CCN3C)C=C(C(=C2)OC)OC)=C1 ZCTJIMXXSXQXRI-KYJUHHDHSA-N 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 108010062880 thiocoraline Proteins 0.000 description 1
- UPGGKUQISSWRJJ-UHFFFAOYSA-N thiocoraline Natural products CN1C(=O)CNC(=O)C(NC(=O)C=2C(=CC3=CC=CC=C3N=2)O)CSC(=O)C(CSC)N(C)C(=O)C(N(C(=O)CNC2=O)C)CSSCC1C(=O)N(C)C(CSC)C(=O)SCC2NC(=O)C1=NC2=CC=CC=C2C=C1O UPGGKUQISSWRJJ-UHFFFAOYSA-N 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- YFTWHEBLORWGNI-UHFFFAOYSA-N tiamiprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC(N)=NC2=C1NC=N2 YFTWHEBLORWGNI-UHFFFAOYSA-N 0.000 description 1
- 229950011457 tiamiprine Drugs 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- MNRILEROXIRVNJ-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=NC=N[C]21 MNRILEROXIRVNJ-UHFFFAOYSA-N 0.000 description 1
- 229950002376 tirapazamine Drugs 0.000 description 1
- QVMPZNRFXAKISM-UHFFFAOYSA-N tirapazamine Chemical compound C1=CC=C2[N+]([O-])=NC(=N)N(O)C2=C1 QVMPZNRFXAKISM-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- ONYVJPZNVCOAFF-UHFFFAOYSA-N topsentin Natural products Oc1ccc2cc([nH]c2c1)C(=O)c3ncc([nH]3)c4c[nH]c5ccccc45 ONYVJPZNVCOAFF-UHFFFAOYSA-N 0.000 description 1
- 229960005026 toremifene Drugs 0.000 description 1
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 150000004654 triazenes Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000004784 trichloromethoxy group Chemical group ClC(O*)(Cl)Cl 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 229950003873 triciribine Drugs 0.000 description 1
- HOGVTUZUJGHKPL-HTVVRFAVSA-N triciribine Chemical compound C=12C3=NC=NC=1N(C)N=C(N)C2=CN3[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O HOGVTUZUJGHKPL-HTVVRFAVSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- FEZBIKUBAYAZIU-UHFFFAOYSA-N trimethobenzamide Chemical compound COC1=C(OC)C(OC)=CC(C(=O)NCC=2C=CC(OCCN(C)C)=CC=2)=C1 FEZBIKUBAYAZIU-UHFFFAOYSA-N 0.000 description 1
- 229960004161 trimethobenzamide Drugs 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229960000538 trimetrexate glucuronate Drugs 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- UIVFDCIXTSJXBB-ITGUQSILSA-N tropisetron Chemical compound C1=CC=C[C]2C(C(=O)O[C@H]3C[C@H]4CC[C@@H](C3)N4C)=CN=C21 UIVFDCIXTSJXBB-ITGUQSILSA-N 0.000 description 1
- 229960003688 tropisetron Drugs 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 229950009811 ubenimex Drugs 0.000 description 1
- 241001446247 uncultured actinomycete Species 0.000 description 1
- 125000000297 undecanoyl group Chemical group O=C([*])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
- 229960001055 uracil mustard Drugs 0.000 description 1
- AUFUWRKPQLGTGF-FMKGYKFTSA-N uridine triacetate Chemical compound CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](COC(=O)C)O[C@H]1N1C(=O)NC(=O)C=C1 AUFUWRKPQLGTGF-FMKGYKFTSA-N 0.000 description 1
- 229960005356 urokinase Drugs 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- XLQGICHHYYWYIU-UHFFFAOYSA-N veramine Natural products O1C2CC3C4CC=C5CC(O)CCC5(C)C4CC=C3C2(C)C(C)C21CCC(C)CN2 XLQGICHHYYWYIU-UHFFFAOYSA-N 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- 229960004982 vinblastine sulfate Drugs 0.000 description 1
- KDQAABAKXDWYSZ-PNYVAJAMSA-N vinblastine sulfate Chemical compound OS(O)(=O)=O.C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 KDQAABAKXDWYSZ-PNYVAJAMSA-N 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- AQTQHPDCURKLKT-JKDPCDLQSA-N vincristine sulfate Chemical compound OS(O)(=O)=O.C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C=O)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 AQTQHPDCURKLKT-JKDPCDLQSA-N 0.000 description 1
- 229960002110 vincristine sulfate Drugs 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960005212 vindesine sulfate Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229960001771 vorozole Drugs 0.000 description 1
- XLMPPFTZALNBFS-INIZCTEOSA-N vorozole Chemical compound C1([C@@H](C2=CC=C3N=NN(C3=C2)C)N2N=CN=C2)=CC=C(Cl)C=C1 XLMPPFTZALNBFS-INIZCTEOSA-N 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- DVPVGSLIUJPOCJ-XXRQFBABSA-N x1j761618a Chemical compound OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(=O)CN(C)C)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21.C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(=O)CN(C)C)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 DVPVGSLIUJPOCJ-XXRQFBABSA-N 0.000 description 1
- 229940053867 xeloda Drugs 0.000 description 1
- 229950005561 zanoterone Drugs 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- 229950009268 zinostatin Drugs 0.000 description 1
- XRASPMIURGNCCH-UHFFFAOYSA-N zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 description 1
- 229960004276 zoledronic acid Drugs 0.000 description 1
- 150000003952 β-lactams Chemical class 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
- A61K31/185—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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- 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
- A61K31/275—Nitriles; Isonitriles
- A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
-
- 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
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- 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
-
- 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
- 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
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- 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
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/60—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2121/00—Preparations for use in therapy
Definitions
- the present invention relates to compounds that inhibit the activity of prostaglandin E2 receptor (EP4 receptor) represented by the following general formula (I), (II), (III), or (IV), and their pharmacological properties It is related to the use of a pharmaceutically acceptable salt (hereinafter sometimes referred to as the compound of the present invention) or a pharmaceutical composition containing them for the manufacture of a medicament for treating cancer.
- the present invention also relates to a method for treating cancer, which comprises administering a compound of the present invention or a pharmaceutical composition containing them to humans or animals. Furthermore, it is related with the pharmaceutical composition and kit containing the compound of this invention used for cancer treatment, or its pharmaceutically acceptable salt.
- Prostaglandins are a group of bioactive substances associated with various symptoms such as pain, fever, and inflammation.
- prostaglandin E2 PGE2
- PGE2 is a major eicosanoid detected in inflammatory conditions, and is hyperalgesia, uterine contraction, digestive peristalsis, awakening, suppression of gastric acid secretion, blood pressure, platelet function, bone metabolism, vascular It is also associated with various physiological and / or pathological conditions such as formation, cancer cell invasion and metastasis.
- EP4 receptor There are four subtypes of PGE2 receptors, EP1, EP2, EP3 and EP4 receptors that exhibit different pharmacological characteristics.
- the EP4 receptor is a seven-transmembrane receptor belonging to the G protein-coupled receptor subfamily and plays a major role in biological phenomena involving PGE2 by stimulating cAMP production. From the viewpoint of studying the pharmacological activity of EP4 receptor, EP4 receptor antagonists have been searched so far, and selective antagonists are also known.
- PGE2 is a major eicosanoid detected in inflammatory conditions, and various physiology such as pain control, uterine contraction, digestive peristalsis, awakening, suppression of gastric acid secretion, blood pressure, platelet function, bone metabolism, angiogenesis, cancer metastasis, etc. It is known to be related to physical and / or pathological conditions.
- Non-Patent Documents 1 to 3 describe the nature of prostanoid receptors, their relevance to treatment, and the most commonly used selective agonists and antagonists.
- PGE2 has been reported to be highly expressed in cancer tissues in many cancer types, and the occurrence of cancer and its involvement in pathological conditions have been clarified. PGE2 is known to play an important role in the process of cancer progression and metastasis, and is involved in activation of cell proliferation and suppression of cell death (apoptosis). However, there are many different reports regarding the various functions related to these cancers caused by PGE2 through which PGE2 receptors are mediated by differences in various situations such as the type of cancer and the progression process. The given view has not been obtained.
- Non-patent document 4 showing inhibition of colon cancer cell (HCA-7) growth using the EP4 receptor antagonist L-161,982.
- Non-patent Document 5 showing suppression of breast cancer cell metastasis using EP4 receptor antagonist AH23848 or ONO-AE3-208.
- EP4 receptor is involved in the development, growth, and metastasis of cancer in some form, and a report suggesting prevention of cancer, suppression of growth, and suppression of cancer metastasis by EP4 receptor antagonists.
- the basis of cancer chemotherapy is “reducing the already formed cancer tissue”, and there are still no known examples of EP4 receptor antagonists that have shown the reduction of tumor tissue already formed in animal organs. There was no real need for such compounds.
- An object of the present invention is to provide a drug effective for treating cancer because it causes reduction of cancer tissue.
- the present invention conducted an administration experiment of an EP4 receptor antagonist to a gastric cancer spontaneous model mouse (K19-Wnt1 / C2mE mouse, Gastroenterology Volume 131, Pages 1086-1095, 2006), and analyzed the action on gastric tumor tissue.
- a gastric cancer spontaneous model mouse K19-Wnt1 / C2mE mouse, Gastroenterology Volume 131, Pages 1086-1095, 2006
- the compounds of the present invention having EP4 selective antagonistic activity are based on the discovery that cancer tissue has been reduced.
- This gastric cancer model is a cancer in which PGE2 is involved, and the compound of the present invention has been found for the first time in the world to be effective in reducing cancer tissue in cancers in which PGE2 is involved.
- the compounds of the present invention are also effective in digestive organ cancer, prostate cancer, lung cancer, breast cancer models and the like.
- cancers involving PGE2 include brain tumors, bone cancers, epithelial cell-derived neoplasms (epithelial cancers) such as basal cell carcinomas, adenocarcinomas, digestive organ cancers (eg lip cancer, oral cancer, esophageal cancer, small intestine cancer , Colon cancer and stomach cancer), liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer (eg squamous cell and basal cell cancer), prostate cancer, renal cell cancer, and in the body Other known cancers that affect epithelial cells are included.
- the cancer is selected from gastrointestinal cancer, prostate cancer, lung cancer, and breast cancer.
- the compound useful for cancer treatment of the present invention is a compound represented by the following general formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof.
- the compounds of the present invention include those solvates, complexes, polymorphs, prodrugs, isomers, and isotope-labeled compounds described below.
- Y 1 , Y 2 , Y 3 , and Y 4 are independently selected from a nitrogen atom, a CH group, or a C (L) group;
- R 1 is hydrogen atom, C 1-8 alkyl groups, C 2-8 alkenyl groups, C 2-8 alkynyl groups, C 3-7 cycloalkyl groups, C 1-8 alkoxy groups, C substituted with a halogen atom 1-8 alkoxy group, C 1-8 alkyl-S (O) m- group, Q 1 -group, pyrrolidinyl group, piperidyl group, oxopyrrolidinyl group, oxopiperidyl group, amino group, mono- or di- ( A C 1-8 alkyl) amino group, a C 1-4 alkyl-C ( ⁇ O) —N (R 3 ) — group, or a C 1-4 alkyl-S (O) m—N (R 3 ) — group.
- C 1-4 alkyl groups hydroxy groups, C 1-4 alkoxy, C 1-4 alkoxy group substituted with a halogen atom, C 1-4 alkylthio group, a nitro group, an amino group, a mono - or di - ( C 1-4 alkyl) amino group, cyano group, HO—C 1-4 alkyl group, C 1-4 alkoxy-C 1-4 alkyl group, C 1-4 alkylsulfonyl group, aminosulfonyl group, C 1-4 Alkyl C ( ⁇ O) — group, HO (O ⁇ ) C— group, C 1-4 alkyl-O (O ⁇ ) C— group, R 3 N (R 4 ) C ( ⁇ O) — group, C 1 -4 alkylsulfonylamino group, C 3- 5- to 12-membered monocyclic or bicyclic optionally substituted with 7 cycloalkyl, R 3 C ( ⁇ O) N (R 4 ) —, or NH 2 (
- A is a 5- to 6-membered monocyclic aromatic ring group that may optionally contain 3 or less heteroatoms selected from an oxygen atom, a nitrogen atom, and a sulfur atom, wherein The 6-membered monocyclic aromatic ring group may optionally be a halogen atom, a C 1-4 alkyl group, a C 1-4 alkyl group substituted with a halogen atom, a hydroxy group, a C 1-4 alkoxy group, a halogen atom.
- B represents a C 1-6 alkylene group substituted with a halogen atom, a C 3-7 cycloalkylene group, a C 2-6 alkenylene group, a C 2-6 alkynylene group, an —O—C 1-5 alkylene group, C 1 -2 alkylene-O-C 1-2 alkylene group, or C 1-6 alkylene group, optionally substituted with an oxo group or a C 1-3 alkyl group;
- W is an NH group, an N—C 1-4 alkyl group, an oxygen atom, a sulfur atom, an N—OR 5 group, or a covalent bond;
- R 2 is a hydrogen atom, a C 1-4 alkyl group, an OH group, or a C 1-4 alkoxy group
- Z is a 5- to 12-membered monocyclic or bicyclic aromatic ring group that may optionally contain no more than 3 heteroatoms selected from oxygen, nitrogen, and sulfur atoms, where The 5- to 12-membered monocyclic or bicyclic aromatic ring group may optionally be a halogen atom, a C 1-4 alkyl group, a C 1-4 alkyl group substituted with a halogen atom, C 1-4 alkenyl group, C 1-4 alkynyl group, hydroxy group, C 1-4 alkoxy, C 1-4 alkoxy group substituted with a halogen atom, C 1-4 alkylthio group, a nitro group, an amino group, a mono - or di -(C 1-4 alkyl) amino group, cyano group, HO-C 1-4 alkyl group, C 1-4 alkoxy-C
- R 3 and R 4 are independently selected from a hydrogen atom and a C 1-4 alkyl group
- R 5 is a hydrogen atom, a C 1-4 alkyl group, a C 1-4 alkyl- (O ⁇ ) C— group, or a C 1-4 alkyl-O— (O ⁇ ) C— group
- Q 2 Is a 5- to 12-membered monocyclic or bicyclic aromatic ring group, or a 5- to 12-membered tricyclic ring group, optionally selected from an oxygen atom, a nitrogen atom, and a sulfur atom
- the 5- to 12-membered monocyclic or bicyclic aromatic ring group may optionally be substituted with a halogen atom, a C 1-4 alkyl group, or a halogen atom.
- Ring A represents a phenyl group or a pyridyl group
- Ring B represents an aryl group or a heteroaryl group
- Ring C represents a 1,4-phenylene group
- R 1 and R 2 are a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a haloalkyl group having 1 to 4 carbon atoms, 1 to Independently represents a haloalkoxy group having 4 carbon atoms, a cyano group or an aminocarbonyl group
- R 3 and R 4 independently represent a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms, or R 3 and R 4 groups bonded together to have an alkylene having 2 to 6 carbon atoms Forming a chain
- R 5 is —CO 2 H, CO 2 W,
- R 6 represents an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 ring atoms, an aryl group or a heteroaryl group
- X represents a methylene group, an oxygen atom or a sulfur atom
- the aryl group has 6 to 10 carbon atoms
- the heteroaryl group is a 5- to 10-membered aromatic heterocyclic group containing 1 to 3 heteroatoms selected from the group consisting of a sulfur atom, an oxygen atom and a nitrogen atom;
- Said aryl group and said heteroaryl group referred to in the definition of ring B are unsubstituted or substituted by at least one substituent selected from the group consisting of substituent ⁇ ;
- Said 1,4-phenylene group mentioned in the definition of ring C is unsubstituted or substituted by at least one substituent selected from the group consisting of substituents ⁇ ;
- Said aryl group and said heteroaryl group referred to in the definition of R 6 and ⁇ are unsubstituted or substituted by at least one substituent selected from the group consisting of substituent ⁇ ;
- the substituent ⁇ is a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a haloalkyl group having 1 to 4 carbon atoms, 1 to 4 carbons Haloalkoxy group having atoms, cyano group, alkynyl group having 2 to 6 carbon atoms, alkanoyl group having 1 to 5 carbon atoms, cycloalkyl group having 3 to 7 ring atoms, heteroaryl group An aryl group, an aralkoxy group having 7 to 10 carbon atoms, an arylcarbonyl group, an aminocarbonyl group, an alkenyl group having 2 to 5 carbon atoms, an alkylthio group having 1 to 4 carbon atoms, an aminosulfinyl Group, aminosulfonyl group, hydroxyl group, hydroxyalkyl group having 1 to 4 carbon atoms, nitro group, amino group, A ruxoxy group,
- alkanoylamino group having 1 to 6 carbon atoms an alkanoylaminoalkyl group having 1 to 6 carbon atoms in both the alkanoyl part and the alkyl part, an alkanoyl part and each alkyl part Any of these alkanoyl (alkyl) aminoalkyl groups having 1 to 6 carbon atoms, alkylsulfonylamino groups having 1 to 4 carbon atoms, mono- or di-alkyl having 1 to 6 carbon atoms Aminocarbonyl group mono- or di-alkyl having 1 to 6 carbon atoms Aminosulfinyl group, mono- or di-alkylaminosulfonyl group having 1 to 6 carbon atoms, aminoalkyl group having 1 to 4 carbon atoms, mono- or di- having 1 to 6 carbon atoms Alkylamino groups, mono- or di-alkylaminoalkyl groups having 1 to 6 carbon atoms in each alkyl moiety, a
- the substituent ⁇ is a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a haloalkyl group having 1 to 4 carbon atoms, 1 to 4 carbons Selected from the group consisting of haloalkoxy groups having atoms and cyano groups; W is a pharmaceutically acceptable ester prodrug group]
- X represents —CH— or a nitrogen atom
- Y represents —NR 4 , an oxygen atom or a sulfur atom
- R 4 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms
- Z represents a hydrogen atom or a halogen atom
- R 1 is an alkyl group having 1 to 6 carbon atoms, optionally substituted with an alkoxy group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 7 carbon atoms
- a phenyl group optionally substituted with one or more substituents ⁇
- Het1 is a 4-7 ring containing either 1 to 4 ring nitrogen heteroatoms or 0 to 2 nitrogen ring heteroatoms and one oxygen ring heteroatom or one sulfur ring hetero
- R 2 and R 3 independently represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms; or the R 2 and R 3 groups represent an alkylene chain having 3 to 6 carbon atoms.
- the substituent ⁇ is a halogen atom, an alkyl group having 1 to 4 carbon atoms, a haloalkyl group having 1 to 4 carbon atoms, a hydroxy group, an alkoxy group having 1 to 4 carbon atoms, 1 A haloalkoxy group having 4 carbon atoms, a cyano group, a hydroxyalkyl group having 1 to 4 carbon atoms, an alkoxy group and an alkoxyalkyl group having 1 to 4 carbon atoms in the alkyl group, 1 to An alkylsulfonyl group having 4 carbon atoms, an alkanoyl group having 2 to 5 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, an alkynyl group having 2 to 4 carbon atoms,
- X represents —CH— or a nitrogen atom
- Y represents NR 4 , an oxygen atom or a sulfur atom
- R 4 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms
- Z represents a hydrogen atom or a halogen atom
- R 1 represents an alkoxy group having 1 to 6 carbon atoms, a trifluoromethyl group, an alkanoyl group having 2 to 5 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a phenyl group, phenoxy
- An alkyl group having 1 to 6 carbon atoms optionally substituted with 1 to 2 groups independently selected from a group, heterocyclic group and heteroaryl group; having 1 to 3 carbon atoms
- R 2 and R 3 independently represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, or the R 2 and R 3 groups together are an alkylene chain having 3 to 6 carbon atoms
- the heteroaryl group is a 4- to 7-membered aromatic ring system having 1 to 4 ring nitrogen heteroatoms or 0 to 2 nitrogen ring heteroatoms and one oxygen or one sulfur ring heteroatom.
- the heterocyclic group is a 4 to 7 membered saturated ring system having 1 to 4 ring nitrogen heteroatoms or 0 to 2 nitrogen ring heteroatoms and one oxygen or one sulfur ring heteroatom;
- the phenyl group, phenoxy group and heteroaryl group referred to in the definition of R 1 are unsubstituted or substituted by at least one substituent selected from the group consisting of the substituent ⁇ ;
- the substituent ⁇ is a halogen atom, an alkyl group having 1 to 4 carbon atoms, a haloalkyl group having 1 to 4 carbon atoms, a hydroxy group, an alkoxy group having 1 to 4 carbon atoms, 1 to Haloalkoxy groups having 4 carbon atoms, cyano groups, hydroxyalkyl groups having 1 to 4 carbon atoms, alkoxyalkyl groups having 1 to 4 carbon atoms in the alkoxy and alkyl groups, 1 to 4 Alkylsulfonyl groups having carbon atoms, alkanoyl groups having 2 to 5 carbon atoms, alkenyl groups having 2 to 4 carbon atoms, alkynyl groups having 2 to 4 carbon atoms, 1 to 4 carbons
- An alkylthio group having an atom, a nitro group, an amino group, a mono- or dialkylamino group having 1 to 4 carbon atoms, an aminosulfonyl group, and 1 to 4 carbon
- the compounds useful for cancer treatment of the present invention are compounds wherein formula (I) is: 3- [2- (4- ⁇ 2-Ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl ⁇ phenyl) ethyl] -1-[(4-methylbenzene) sulfonyl ]urea; 1- (4- ⁇ 2-Ethyl-4,6-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl ⁇ phenyl) propan-2-yl N-[(4-methylbenzene) sulfonyl] Carbamate; 3- [2- (4- ⁇ 2-Ethyl-4,6-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl ⁇ phenyl) ethyl] -1-[(4-methylbenzene) sulfonyl ]urea; 1- ⁇ 2- [4- (5-acety
- a compound wherein formula (II) is: 4-((1S) -1- ⁇ [5-chloro-2- (4-fluorophenoxy) benzoyl] amino ⁇ ethyl) benzoic acid; 4-[(1S) -1-( ⁇ [5-chloro-2- (4-fluorophenoxy) pyridin-3-yl] carbonyl ⁇ amino) ethyl] benzoic acid; 4-[(1S) -1 ( ⁇ [5 chloro-2- (3-cyanophenoxy) pyridin-3-yl] carbonyl ⁇ amino) ethyl] benzoic acid; 4-[(1S) -1-( ⁇ [5-chloro-2- (3-fluorophenoxy) pyridin-3-yl] carbonyl ⁇ amino) ethyl] benzoic acid; 4-[(1S) -1-( ⁇ [5-chloro-2- (3-fluorophenoxy) pyridin-3-yl] carbonyl ⁇ amino) e
- a compound wherein formula (IV) is: 4-[(1S) -1-( ⁇ 5-chloro-2-[(2-chlorobenzyl) oxy] benzoyl ⁇ amino) ethyl] benzoic acid; 4-[(1S) -1-( ⁇ 5-chloro-2- [2- (2-methylphenyl) ethoxy] benzoyl ⁇ amino) ethyl] benzoic acid; 4-[(1S) -1-( ⁇ 5-chloro-2- [2- (4-methylphenyl) ethoxy] benzoyl ⁇ amino) ethyl] benzoic acid; 4-[(1S) -1-( ⁇ 5-chloro-2-[(3-chlorobenzyl) oxy] benzoyl ⁇ amino) ethyl] benzoic acid; 4-[(1S) -1-( ⁇ 5-chloro-2-[(4-chlorobenzyl) oxy] benzoyl ⁇ amino) ethyl]
- the compound useful for cancer treatment of the present invention is a compound wherein formula (I) is: 3- [2- (4- ⁇ 2-Ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl ⁇ phenyl) ethyl] -1-[(4-methylbenzene) sulfonyl ]urea; 3- [2- (4- ⁇ 2-Ethyl-4,6-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl ⁇ phenyl) ethyl] -1-[(4-methylbenzene) sulfonyl ]urea; 1- ⁇ 2- [4- (5-acetyl-2-ethyl-1H-1,3-benzodiazol-1-yl) phenyl] ethyl ⁇ -3-[(4-methylbenzene) sulfonyl] urea; 3- ⁇ 2- [4- (2-ethyl)
- a compound wherein the general formula (II) is: 4-((1S) -1- ⁇ [5-chloro-2- (4-fluorophenoxy) benzoyl] amino ⁇ ethyl) benzoic acid; 4-[(1S) -1-( ⁇ [5-chloro-2- (4-fluorophenoxy) pyridin-3-yl] carbonyl ⁇ amino) ethyl] benzoic acid; 4-[(1S) -1 ( ⁇ [5-chloro-2- (3-cyanophenoxy) pyridin-3-yl] carbonyl ⁇ amino) ethyl] benzoic acid; 4-[(1S) -1-( ⁇ [5-chloro-2- (3-fluorophenoxy) pyridin-3-yl] carbonyl ⁇ amino) ethyl] benzoic acid; 4-[(1S) -1-( ⁇ [5-chloro-2- (3-fluorophenoxy) pyridin-3-yl] carbonyl ⁇
- a compound wherein the general formula (III) is: 4-[(1S) -1-( ⁇ 5-chloro-2-[(4-chlorophenoxy) methyl] benzoyl ⁇ amino) ethyl] benzoic acid; 4-[(1S) -1-( ⁇ 5-chloro-2-[(3-chlorophenoxy) methyl] benzoyl ⁇ amino) ethyl] benzoic acid; 4-[(1S) -1-( ⁇ 5-chloro-2-[(4-fluorophenoxy) methyl] benzoyl ⁇ amino) ethyl] benzoic acid; 4-[(1S) -1-( ⁇ 5-chloro-2-[(3,4-difluorophenoxy) methyl] benzoyl ⁇ amino) ethyl] benzoic acid; 4-[(1S) -1-( ⁇ 5-chloro-2-[(2,4-difluorophenoxy) methyl] benzoyl ⁇ amino) e
- suitable acid addition salts are usually formed from acids that form non-toxic salts.
- acids include acetate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, cansylate, citrate, edisylate, esylate Acid salt, formate, fumarate, glycoheptonate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / Iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methyl sulfate, naphthylate, 2-naphthylate, nicotinate, nitrate, orotate, Oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, sugar salt,
- Suitable base salts are usually formed from bases that form non-toxic salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
- the pharmaceutically acceptable salt of the compound represented by the general formula (I), (II), (III), or (IV) is usually represented by the general formula (I), (II), (III), or ( It can be prepared by combining the compound represented by IV) and a desired acid or base solution corresponding to each.
- the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
- the degree of ionization in the salt can vary from fully ionized to nearly non-ionized.
- solvate is used to describe a molecular complex comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules, such as ethanol.
- complexes such as inclusion bodies, drug-host inclusion complexes, etc. in which the drug and host are present in stoichiometric or non-stoichiometric amounts are also within the scope of the compounds of the present invention. Contained within. Also included are complexes of drugs containing two or more organic and / or inorganic components that may be in stoichiometric or non-stoichiometric amounts. The resulting complex may be ionized, partially ionized, or non-ionized. For a review of such complexes, see Haleblian J Pharm Sci, 64 (8), 1269-1288 (August 1975).
- the compounds of the invention include polymorphs, prodrugs, isomers thereof (including optical isomers, geometric isomers and tautomers) as defined herein, and isotopic labels of the compounds of the invention Contains compounds.
- the present invention includes all polymorphs of the compounds of the present invention as defined above.
- prodrugs of the compounds of the present invention are also within the scope of the present invention. That is, the specific derivative of the compound represented by the general formula (I), (II), (III), or (IV), which has little or no pharmacological activity per se, is in the body or body surface. May be converted to a compound represented by general formula (I), (II), (III), or (IV) having a desired activity, for example, by hydrolysis. Such derivatives are referred to as “prodrugs”. Further information on the use of prodrugs can be found in Pro-drugs asvel Delivery Systems, Vol. 14, ACS Symposium Series (T.Higuchi and W.Stella) and ⁇ BioreversibleversCarriers in Drug Design '', Pergamon Press, 1987 ( EBRoche (American Pharmaceutical Association).
- Prodrugs of the compounds of the present invention are, for example, suitable functional groups present in compounds of the general formula (I), (II), (III) or (IV), for example according to H Bundgaard's “ It can be produced by replacing with a specific part known to those skilled in the art as “pro-moieties” as described in “Design of Prodrugs” (Elsevier, 1985).
- prodrugs according to the present invention include: (i) when the compound of the present invention contains a carboxylic acid functional group (—COOH), substitution of its ester, for example, hydrogen of —COOH with (C1-C8) alkyl; (ii) if the compound of the present invention contains an alcohol functional group (—OH), its ether, for example, substitution of —OH hydrogen with (C1-C6) alkanoyloxymethyl, and (iii) the compound of the present invention is primary Or, if it contains a secondary amino function (—NH 2 or NHR (R is not H)), substitution of one or both hydrogens of the amide, eg —NH 2 or NHR, with (C1-C10) alkanoyl Is included.
- —COOH carboxylic acid functional group
- substitution of its ester for example, hydrogen of —COOH with (C1-C8) alkyl
- an alcohol functional group —OH
- its ether for example, substitution of —OH hydrogen with (C1-C
- Certain compounds represented by general formula (I), (II), (III), or (IV) may themselves serve as prodrugs of other compounds included in the present invention.
- the compounds of the present invention containing one or more asymmetric carbon atoms may exist as two or more stereoisomers.
- a compound of the invention contains an alkenyl or alkenylene group
- geometric cis / trans (ie, Z / E) isomers are possible.
- a compound of the invention contains, for example, a keto or oxime group or an aromatic moiety
- tautomeric isomerization (“tautomerism") may exist.
- a single compound may exhibit more than one type of isomerism.
- the cis / trans isomers can be separated by conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization.
- racemic compound or racemic precursor
- a suitable optically active compound such as an alcohol, or an acid or base such as tartaric acid or 1-phenylethylamine if the compound of the invention contains an acidic or basic moiety.
- a suitable optically active compound such as an alcohol, or an acid or base such as tartaric acid or 1-phenylethylamine if the compound of the invention contains an acidic or basic moiety.
- the resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization, wherein one or both of the diastereoisomers are pure one or more corresponding by means well known to those skilled in the art.
- the chiral compounds of the present invention are hydrocarbons containing 0-50% isopropanol, usually 2-20%, and 0-5% alkylamine, usually 0.1% diethylamine. It can be obtained in enantiomerically enriched form using chromatography on an asymmetric resin, usually HPLC, with a moving bed usually composed of heptane or hexane. Concentration of the eluate gives an enriched mixture.
- Stereomeric aggregates can be separated by conventional techniques known to those skilled in the art. For example, “Stereochemistry” of “Organic” Compounds by EoundL Eliel (Wiley, New York, 1994).
- the present invention includes a pharmaceutically acceptable invention in which one or more atoms are replaced by an atom having the same atomic number but having an atomic weight or mass number different from the atomic weight or mass number normally found in nature. All of the isotopically labeled compounds of
- Suitable isotopes for inclusion in the compounds of the present invention include hydrogen such as 2 H and 3 H, carbon such as 11 C, 13 C and 14 C, chlorine such as 38 Cl, fluorine such as 18 F , Iodine such as 123 I and 125 I, nitrogen such as 13 N and 15 N, oxygen such as 15 O, 17 O and 18 O, phosphorus such as 32 P, and sulfur isotopes such as 35 S.
- isotope-labeled compounds included in the compounds of the present invention are used in the treatment of cancer (including diagnosis, alleviation of symptoms, improvement in QOL, prevention) and Useful for studying tissue distribution of the matrix.
- the radioactive isotopes tritium, ie 3 H, and carbon-14, ie 14 C are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
- substitution with heavier isotopes such as deuterium, ie 2 H may provide certain therapeutic benefits derived from greater metabolic stability, for example increased in vivo half-life or reduced dose requirements Therefore, it may be preferable in certain environments.
- positron emitting isotopes such as 11 C, 18 F, 15 O and 13 N
- PET positron emission tomography
- the isotope-labeled compounds included in the compounds of the present invention can be prepared using conventional techniques known to those skilled in the art, or using appropriate isotope-labeled reagents in place of previously used unlabeled reagents and the accompanying examples. And can be prepared by methods analogous to those described in the preparation.
- solvates according to the invention include solvates in which the crystallization solvent is isotopically substituted, for example D 2 O, d6-acetone, d6-DMSO.
- the compounds of the present invention for pharmaceutical use can be administered as crystalline products or amorphous products. They can be obtained by methods such as precipitation, crystallization, freeze drying or spray drying or evaporative drying, for example as solid plugs, powders or films. Microwave or radio frequency drying can be used for this purpose.
- additives are used to describe any ingredient other than one or more compounds of the invention. The choice of additive is in most cases dependent on factors such as the particular mode of administration, the effect of the additive on solubility and stability, and the nature of the dosage form.
- the present invention provides a compound (or compound group, second therapeutic agent) selected from a compound, solvate or prodrug of the present invention, and one or more other pharmacologically active agents. Combinations including are also provided. Also provided is a pharmaceutical composition for treating cancer, particularly involving an EP4 antagonist, comprising such a combination with a pharmaceutically acceptable additive, diluent or carrier.
- a first pharmaceutical composition comprising a compound represented by general formula (I), (II), (III) or (IV), or a pharmaceutically acceptable salt thereof; and a second active agent; Providing a kit comprising a container;
- a kit used for the treatment of cancer comprising a compound represented by the general formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof is also one of the present invention. It is.
- a pharmaceutical composition comprising a compound represented by the general formula (I), (II), (III) or (IV), or a pharmaceutically acceptable salt thereof, and a description relating to the pharmaceutical composition,
- a product containing a description that can be used or should be used to treat cancer is also one aspect of the present invention.
- EP4 receptor activity or “EP4 activity” means an increase in cAMP levels associated with PGE 2 stimulation via the EP4 receptor.
- a “selective” EP4 receptor antagonist is at least 10 times, preferably at least, greater than the IC 50 for inhibition of EP1, EP2 or EP3 activity, as measured by standard methods known in the art. Suppose that with an IC 50 that is 100 times smaller, EP4 activity is “selectively” inhibited.
- halo and halogen atom mean a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, and a fluorine atom or a chlorine atom is preferable.
- alkyl group means a linear or branched monovalent saturated hydrocarbon group such as, but not limited to, methyl group, ethyl group, propyl group.
- alkenyl group means a hydrocarbon group having at least one double bond, such as, but not limited to, an ethenyl group, a propenyl group, a 1-butenyl group, 2 -Butenyl group and the like can be mentioned.
- alkynyl group means a hydrocarbon group having at least one triple bond, such as, but not limited to, an ethynyl group, a propenyl group, a 1-butynyl group, a 2- A butynyl group etc. can be mentioned.
- cycloalkyl group means a saturated carbocyclic ring group, for example, but not limited to, cyclopropyl group, cyclobutyl group, cyclohexyl group, cycloheptyl group, cyclooctyl. Group, cyclononyl group, cyclodecyl group and the like.
- alkoxy group means an O-alkyl group (where “alkyl” has the same meaning as defined above).
- alkyl means alkyl-O-, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, secondary-butoxy, tertiary-butoxy, etc. Can be mentioned.
- C 1-4 alkyl group and “alkyl group having 1 to 4 carbon atoms” are synonymous.
- alkylene group means a saturated hydrocarbon (straight or branched) from which one hydrogen atom has been removed from each terminal carbon atom, such as a methylene group, an ethylene group, Examples thereof include a propylene group, a butylene group, a pentylene group, and a hexylene group.
- cycloalkylene group means a divalent cycloalkyl group, such as, but not limited to, a cyclopropylene group, a cyclobutylene group, a cyclopentylene group, a cyclohexylene group. , And cycloheptylene groups.
- alkenylene group means a linear or branched hydrocarbon chain spacer group having at least one double bond, and is limited to the following, for example. Although not included, —CH ⁇ CH— group, —CH ⁇ CHCH— group, —CH ⁇ CHCH (CH 3 ) — group and the like can be mentioned.
- alkynylene group means a linear or branched hydrocarbon chain spacer group having at least one triple bond, for example, but not limited to the following: C ⁇ C— group, —C—C ⁇ CCH 2 — group, —C ⁇ CCH (CH 3 ) — group and the like can be mentioned.
- alkanoyl refers to a group having a carbonyl, such as R′—C (O) —, wherein R ′ is C 1-4 alkyl or C 3-4 cycloalkyl, for example, although not limited to the following, formyl group, acetyl group, ethyl-C (O)-, n-propyl-C (O)-, isopropyl-C (O)-, n-butyl-C (O)- , Iso-butyl-C (O)-, secondary-butyl-C (O)-, tertiary-butyl-C (O)-, cyclopropyl-C (O)-, cyclobutyl-C (O) -Can be mentioned.
- haloalkyl refers to an alkyl radical substituted with a halogen atom as defined above, for example, but not limited to, a fluoromethyl group, a difluoromethyl group, Trifluoromethyl group, 2-fluoroethyl group, 2,2-difluoroethyl group, 2,2,2-trifluoroethyl group, 2,2,2-trichloroethyl group, 3-fluoropropyl group, 4-fluorobutyl Group, chloromethyl group, trichloromethyl group, iodomethyl group, bromomethyl group and the like.
- haloalkoxy means haloalkyl-O—, for example, but not limited to, a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a 2-fluoroethoxy group, 2,2-difluoroethoxy group, 2,2,2-trifluoroethoxy group, 2,2,2-trichloroethoxy group, 3-fluoropropoxy group, 4-fluorobutoxy group, chloromethoxy group, trichloromethoxy group, iodo A methoxy group, a bromomethoxy group, etc. can be mentioned.
- aryl group means an aromatic group, and examples thereof include, but are not limited to, a phenyl group, a naphthyl group, a tetrahydronaphthyl group, an indanyl group, and a biphenyl group. it can.
- the term “monocyclic aromatic ring group” refers to a carbocyclic or heterocyclic (including 0 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur atoms) monocycles.
- Means an aromatic ring group for example, but not limited to, phenyl group, pyrazolyl group, furyl group, thienyl group, oxazolyl group, tetrazolyl group, thiazolyl group, imidazolyl group, thiadiazolyl group, pyridyl group, A pyrimidinyl group, a pyrrolyl group, a thiophenyl group, a pyrazinyl group, a pyridazinyl group, an isoxazolyl group, an isothiazolyl group, a triazolyl group, a furazanyl group, and the like can be given.
- bicyclic aromatic ring group refers to a carbocyclic or heterocyclic (including 0 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur atoms) monocycles.
- a bicyclic aromatic ring group for example, but not limited to, naphthyl group, benzofuranyl group, isobenzofuranyl group, benzothiophenyl group, indolyl group, isoindolyl group, benzoxazolyl Group, benzothiazolyl group, indazolyl group, benzimidazolyl group, quinolyl group, isoquinolyl group, cinnolinyl group, phthalazinyl group, quinazolinyl group, quinoxalinyl group and the like.
- tricyclic ring group means a saturated carbocyclic ring group, for example, but not limited to, an adamantyl group, tricyclo [5.2.1.0 2, 6 ] A decyl group and the like can be mentioned.
- two adjacent L groups optionally together, have 3 or 4 ring members, one carbon atom or (non-adjacent) carbon atom within said ring member.
- “Although two may form an alkylene chain optionally substituted with an oxygen atom” is not limited to the following: —O—CH 2 —O— group, —CH 2 —O— CH 2 — group, —O—CH 2 CH 2 — group, —CH 2 CH 2 —O— group, —O—CH 2 CH 2 —O— group, —CH 2 CH 2 CH 2 —O— group, — It means O—CH 2 CH 2 CH 2 — group, —CH 2 —O—CH 2 CH 2 — group, —CH 2 CH 2 —O—CH 2 — group and the like.
- “two adjacent L groups” means two L groups bonded to each adjacent carbon atom.
- the above “two (non-adjacent) carbon atoms” means that two adjacent carbon atoms or two
- esters means a protecting group that can be cleaved in vivo by biological methods such as hydrolysis and forms free acids or their salts. Whether a compound is such a derivative can be administered intravenously to a laboratory animal such as a rat or mouse and then the compound or a pharmaceutically acceptable salt thereof can be detected. This can be determined by examining the body fluids of the animal to determine whether or not.
- esters of carboxyl or hydroxy groups include: (1) Aliphatic alkanoyl group, for example: formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, pentanoyl group, pivalolyl group, valeryl group, isovaleryl group, octanoyl group, nonanoyl group, decanoyl group, 3-methylnonanoyl group 8-methylnonanoyl group, 3-ethyloctanoyl group, 3,7-dimethyloctanoyl group, undecanoyl group, dodecanoyl group, tridecanoyl group, tetradecanoyl group, pentadecanoyl group, hexadecanoyl group, 1-methylpentanoyl group Decanoyl group, 14-methylpentadecanoyl group, 13,13-dimethyltetradecanoyl group
- Aromatic alkanoyl groups for example: arylcarbonyl groups such as benzoyl, ⁇ -naphthoyl and ⁇ -naphthoyl groups; halogenated arylcarbonyls such as 2-bromobenzoyl and 4-chlorobenzoyol groups Groups; alkylated arylcarbonyl groups such as 2,4,6-trimethylbenzoyl group and 4-toluoyl group; alkoxylated arylcarbonyl groups such as 4-anisoyl group; 4-nitrobenzoyl group and 2-nitrobenzoyl group Nitrated arylcarbonyl groups such as; alkoxycarbonylated arylcarbonyl groups such as 2- (methoxycarbonyl) benzoyl groups; and arylated arylcarbonyl groups such as 4-phenylbenzoyl groups;
- alkoxycarbonyl groups for example: alkoxycarbonyl groups such as methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, butoxycarbonyl group, sec-butoxycarbonyl group, t-butoxycarbonyl group and isobutoxycarbonyl group; and 2 Halogen- or tri (alkyl) silyl-substituted alkoxycarbonyl groups such as 1,2,2-trichloroethoxycarbonyl group and 2-trimethylsilylethoxycarbonyl group;
- Silyl groups for example: tri (alkyl) such as trimethylsilyl group, triethylsilyl group, isopropyldimethylsilyl group, t-butyldimethylsilyl group, methyldiisopropylsilyl group, methyldi-t-butylsilyl group and triisopropylsilyl group Silyl groups; and silyl groups substituted with one or more aryl groups and alkyl groups, such as diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl and phenyldiisopropylsilyl groups;
- alkoxymethyl groups such as: methoxymethyl group, 1,1-dimethyl-1-methoxymethyl group, ethoxymethyl group, propoxymethyl group, isopropoxymethyl group, butoxymethyl group and t-butoxymethyl group Alkoxymethyl groups; alkoxylated alkoxymethyl groups such as 2-methoxyethoxymethyl groups; and halo (alkoxy) methyl groups such as 2,2,2-trichloroethoxymethyl groups and bis (2-chloroethoxy) methyl groups;
- substituted ethyl groups eg: alkoxylated ethyl groups such as 1-ethoxyethyl and 1- (isopropoxy) ethyl groups; and ethyl halide groups such as 2,2,2-trichloroethyl groups;
- Aralkyl groups such as: 1 to benzyl group, ⁇ -naphthylmethyl group, ⁇ -naphthylmethyl group, diphenylmethyl group, triphenylmethyl group, ⁇ -naphthyldiphenylmethyl group and 9-anthrylmethyl group
- protecting group refers to a hydroxy protecting group selected from the typical hydroxy protecting groups or amino protecting groups described in “Protective Groups in Organics Synthesis, TW Greene et al., John Wiley & Sons, 1991”. Means amino protecting group.
- hydrate is used when the solvent is water.
- treatment reverses the progression of a disorder or symptom to which the term applies, or one or more symptoms within such disorder or symptom, refers to mitigating, inhibiting or preventing it.
- Treatment includes not only reducing enlarged tumor tissue, but also alleviating symptoms and improving QOL, so-called prevention (radiation therapy, recurrence prevention after surgery, adjuvant chemotherapy, etc.).
- the compound of the present invention is administered in an amount sufficient to reduce cancer metastasis, reduce cancer and / or enhance the effectiveness of cancer treatment.
- a therapeutically effective amount will vary depending on the particular condition to be treated, the condition of the patient, the route of administration, the formulation, the judgment of the practitioner, and other factors. It will depend on what will be apparent to those skilled in the art in light of this disclosure and will be determined using routine optimization techniques.
- the compound represented by general formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof can be incorporated into a therapeutic composition.
- Such agents are mixed with a pharmaceutically acceptable transport medium or carrier.
- Pharmaceutically acceptable transport media include solvents, dispersion media, coatings, antibacterial and antifungal agents, and isotonic and absorption delaying agents that are compatible with pharmaceutical administration.
- the medium can also contain other active or inactive ingredients and targets cancerous tissue based on its composition.
- the therapeutic effect of the compounds of the present invention can be measured by standard therapeutic procedures in cell culture or laboratory animals, for example, by determining ED 50 (a therapeutically effective dose in 50% of the population). .
- Data obtained from cell culture assays and animal studies can be used in determining the range of dosages prescribed to humans. This dosage may vary according to the formulation and route of administration.
- this therapeutically effective dose can be estimated initially from cell culture assays. Doses can be formulated in animal models to achieve a circulating plasma drug concentration range with reference to the IC 50 determined in cell culture. Such information is used to more accurately determine useful doses in humans. The level in plasma is measured by, for example, high performance liquid chromatography or a mass spectrometer.
- treatment of a mammal with a compound of the present invention using a therapeutically effective amount can include, but is not limited to, a single treatment, treatment every other day, or continuous administration.
- the exact amount of compound administered to human patients will be at the discretion of the physician. However, the dose used will depend on a number of factors, including the age and sex of the patient, the precise symptoms to be treated and their severity, and the route of administration.
- compositions are administered in the form of pharmaceutical compositions. It is common practice to provide such compositions in admixture with one or more pharmaceutically acceptable carriers or excipients. Preferably, it is a pharmaceutical composition used for the treatment of cancer.
- a pharmaceutical composition comprising a compound of the present invention for use in the treatment of cancer is also one aspect of the present invention.
- the compound of the present invention can be administered as a raw chemical, but is preferably provided as a pharmaceutical preparation.
- the formulation contains the compound together with one or more acceptable carriers or diluents therefor, optionally with other therapeutic ingredients.
- the carrier must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
- the therapeutic composition is formulated to suit the intended route of administration.
- routes of administration include parenteral (eg, intravenous, intradermal, subcutaneous), oral (eg, oral ingestion or inhalation), transdermal (topical), transmucosal, and rectal and topical (dermal, oral and Administration (including sublingual). Solutions or suspensions can be prepared as described in Remington's Pharmacentical Sciences, (18 th ed., Gennaro, ed., Mack Publishing Co., Easton, PA, (1990)).
- the formulation may be given in unit dosage form and may be prepared by any method well known in the pharmaceutical art. All methods include the step of bringing the compound ("active ingredient") into association with a carrier which constitutes one or more accessory ingredients. In general, formulations are prepared by uniformly and uniformly associating the active ingredient with liquid carriers or finely divided solid carriers or both, and if necessary, shaping the product into the desired formulation.
- Formulations suitable for oral administration are as individual units, such as capsules, cachets or tablets (eg chewable tablets, especially for pediatric administration) each containing a predetermined amount of active ingredient; as a powder or granules; Or as a suspension in a non-aqueous solution; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
- the active ingredient may be provided as a bolus, electuary or paste.
- Tablets may be produced by compression or molding together with one or more accessory ingredients as desired.
- Compressed tablets are made by compressing, in a suitable machine, the active ingredient in a fluid form such as a powder or granules mixed with a binder, lubricant, inert diluent, lubricant, surfactant or dispersant as desired. What is necessary is just to manufacture. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Tablets may be provided with any coating or scoring that may be formulated so that the release of the active ingredient is slowed or controlled there if desired.
- Formulations for parenteral administration include aqueous and non-aqueous sterile injectable solutions that may contain antioxidants, buffers, bacteriostats and solutes that render the formulation isotonic with the blood of the intended recipient; Aqueous and non-aqueous sterile suspensions which may contain agents and thickeners.
- the formulations may be provided in unit-dose or multi-dose containers, such as enclosed ampoules and vials, and may be stored in a freeze-dried (lyophilized) state that requires only the addition of a sterile liquid carrier, such as water for injection, just prior to use.
- Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
- Rectal preparations may be provided as suppositories using ordinary carriers such as cocoa butter, hardened fat or polyethylene glycol.
- Formulations for topical administration in the mouth include lozenges containing the active ingredient in a flavor base such as sucrose and gum arabic or tragacanth gum; and gelatin and glycerin or sucrose and gum arabic And a base tablet containing an active ingredient in the base.
- a flavor base such as sucrose and gum arabic or tragacanth gum
- gelatin and glycerin or sucrose and gum arabic a base tablet containing an active ingredient in the base.
- the compound of the present invention or a pharmaceutically acceptable salt thereof may be formulated as a depot preparation (sustained preparation). Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
- the compounds may be formulated, for example, with a suitable polymeric or hydrophobic material (eg, as an acceptable emulsion in oil) or an ion exchange resin, or as a slowly soluble derivative, such as a slowly soluble salt.
- Formulations may include those suitable for oral administration, such as other agents common in the art, such as flavoring agents, particularly in view of the type of formulation in question, in addition to the ingredients described above.
- the compound of the present invention or a pharmaceutically acceptable salt thereof is a steroidal or non-steroidal antiandrogen or antiestrogen, chemotherapeutic agent, peptidic GnRH antagonist, ⁇ -reductase inhibitor, ⁇ -receptor Inhibitors, aromatase inhibitors, 17 ⁇ -hydroxysteroid dehydrogenase inhibitors, adrenal androgen production inhibitors, phosphorylase inhibitors, hormone therapy agents, drugs that inhibit the action of cell growth factors or their receptors, etc. It is also effective to use with one kind.
- chemotherapeutic agents include Ifosfamide, Adriamycin, Peplomycin, Cisplatin, Cyclophosphamide, 5-FU, UFT, Methotrexate, Mitomycin C (Mitomycin C), mitoxantrone and the like.
- peptidic GnRH antagonist examples include parenteral-administered peptidic GnRH antagonists such as Cetrorrelix, Ganirelix, Abarelix and the like.
- adrenal androgen production inhibitor examples include lyase (C17,20-lyase) inhibitor and the like.
- Examples of the “phosphorase inhibitor” include tyrosine kinase.
- hormone therapeutic agent examples include antiestrogens, luteinizing hormones (eg, MPA), androgens, estrogens, antiandrogens and the like.
- the “cell growth factors” may be any substance that promotes cell growth, and is usually a peptide with a molecular weight of 20,000 or less, which acts at a low concentration by binding to a receptor. Specifically, (1) EGF (epidermal growth factor) or a substance having substantially the same activity (eg, EGF, haregulin (HER2 ligand), etc.), (2) Insulin or a substance having substantially the same activity (eg, insulin, IGF (insulin-like growth factor) -1, IGF-2, etc.), (3) FGF (fibroblast growth factor) or substantially the same Substances with activity (eg, aFGF, bFGF, KGF (Keratinocyte Growth Factor), HGF (Hepatocyte Growth Factor), FGF-10, etc.), (4) Other cell growth factors (eg, CSF (colony stimulation stimulating factor), EPO (Erythropoietin), IL-2 (interleukin-2), NGF (nerve growth factor), PDGF (platelet-derived
- the “cell growth factor receptor” may be any receptor capable of binding to the above-mentioned cell growth factor, and specifically, EGF receptor, haregulin receptor (HER2) Insulin receptor-1, insulin receptor-2, IGF receptor, FGF receptor-1 or FGF receptor-2, and the like.
- EGF receptor EGF receptor
- HER2 haregulin receptor
- agent that inhibits the action of the cell growth factor examples include Herceptin (HER2 receptor antibody).
- Examples of the agent that inhibits the action of the cell growth factor or its receptor include herbimycin, PD153035 (Science 265 (5175) p1093, (1994)) and the like.
- HER2 inhibitors can be cited as drugs that inhibit the action of cell growth factors or their receptors.
- a HER2 inhibitor if it is a substance that inhibits HER2 activity (eg, phosphorylation activity), antibody, low molecular weight compound (synthetic compound, natural product), antisense, HER2 ligand, haregulin or their structure Any of those modified or modified may be used. Further, it may be a substance that inhibits HER2 activity by inhibiting HER2 receptor (eg, HER2 receptor antibody).
- GnRH hyperagonists for prostate cancer, GnRH hyperagonists, antiandrogens, antiestrogens, chemotherapeutic agents [eg, Ifosfamide, UFT, Adriamycin, Peplomycin, Cisplatin, etc.], Peptide GnRH antagonist, aromatase inhibitor, 17 ⁇ -hydroxysteroid dehydrogenase inhibitor, adrenal androgen production inhibitor, phosphorylase inhibitor, hormone therapy [eg, estrogen (eg, DSB, EMP, etc.), Anti-androgen agents (eg, CMA, etc.)], drugs such as agents that inhibit the action of cell growth factor or its receptor, and the compounds of the present invention.
- chemotherapeutic agents eg, Ifosfamide, UFT, Adriamycin, Peplomycin, Cisplatin, etc.
- Peptide GnRH antagonist for prostate cancer, GnRH hyperagonists, antiandrogens, antiestrogens, chemotherapeutic agents [eg, Ifos
- GnRH superagonists for breast cancer, GnRH superagonists, antiestrogens, chemotherapeutic agents (eg, cyclophosphamide, 5-FU, UFT, methotrexate, adriamycin, mitomycin C) ), Mitoxantrone, etc.], peptide GnRH antagonists, aromatase inhibitors, adrenal androgen production inhibitors, phosphorylase inhibitors, hormone therapy agents (eg, antiestrogens (eg, Tamoxifen, etc.), Luteinizing hormone agents (eg, MPA, etc.), androgen agents, estrogen agents, etc.], drugs such as agents that inhibit the action of cell growth factors or their receptors, and combinations of the compounds of the present invention.
- chemotherapeutic agents eg, cyclophosphamide, 5-FU, UFT, methotrexate, adriamycin, mitomycin C)
- Mitoxantrone etc.
- chemotherapeutic agents eg, cyclophosphamide, 5-FU, UFT, methotrexate, levofolinate, gemcitabine, adriamycin, mitomycin C (Mitomycin C), mitoxantrone, etc.], microtubule inhibitors [eg, vincristine, paclitaxel, etc.], platinum preparations [eg, cisplatin, etc.], topoisomerase inhibitors [eg , Irinotecan, etoposide, etc.], COX-2 inhibitor, phosphorylase inhibitor, cell growth factor, or a drug that inhibits the action of its receptor, and the compound of the present invention can be used in combination.
- chemotherapeutic agents eg, cyclophosphamide, 5-FU, UFT, methotrexate, levofolinate, gemcitabine, adriamycin, mitomycin C (Mitomycin C), mitoxantrone, etc.]
- chemotherapeutic agents eg, Cyclophosphamide, 5-FU, UFT, Methotrexate, Adriamycin, Mitomycin C, Mitoxantrone, etc.
- Microtubule inhibitors eg, vincristine, paclitaxel, etc.
- platinum preparations eg, cisplatin, etc.
- topoisomerase inhibitors eg, irinotecan, etoposide, etc.
- a combination of a compound of the present invention and a drug such as a phosphorylase inhibitor, a drug that inhibits the action of a cell growth factor or its receptor, and the like.
- a second active agent that is a small molecule can be used to reduce adverse effects associated with administration of the compounds of the present invention.
- small molecule second active agents include, but are not limited to, anticancer agents, antibiotics, immunosuppressive factors, and steroids.
- anticancer agents include alkylating agents, antineoplastic agents, antimetabolites (e.g., folic acid analogs, purine analogs, adenosine analogs, pyrimidine analogs and substituted ureas), platinum coordination compounds, topoisomerase II Including but not limited to inhibitors and radiation.
- anticancer agents include alkylating agents, antineoplastic agents, antimetabolites (e.g., folic acid analogs, purine analogs, adenosine analogs, pyrimidine analogs and substituted ureas), platinum coordination compounds, topoisomerase II Including but not limited to inhibitors and radiation.
- Specific anti-cancer drugs include, but are not limited to: acivicin; aclarubicin; acodazole hydrochloride; acronin; adzelesin; aldesleukin; altretamine; ambomycin; amethanetron acetate; Anastrozole; Anthramycin; Asparaginase; Asperlin; Azacitidine; Azetepa; Carctinine; carbestine; carubicin; carubicin; carzeleci; Celecoxib (COX-2 inhibitor); chlorambucil; cirolemycin; cisplatin; cladribine; krisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine; Dezaguanine; desaguanine mesylate; diazicon; docetaxel; doxor
- anti-cancer agents include, but are not limited to: 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adzelesin; Leukin; ALL-TK antagonist; altretamine; amambastine; amidox; amifoxine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitor; antagonist D; antagonist G; Anti-androgen, prostate cancer; anti-estrogen; antineoplastic drug; antisense oligonucleotide; aphidicolin glycinate; apoptotic gene modulator; Apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; aslacline; atamestan; atrimtin; axinastatin 1; axi
- Specific second active agents include, but are not limited to: rituximab, oblimersen (Genasense®), remicade, docetaxel, celecoxib, melphalan, dexamethasone (Decadron®), steroids, gemcitabine, cisplatin, temozolomide, etoposide, cyclophosphamide, temodal, carboplatin, procarbazine, gliadel, tamoxifen, topotecan, methotrexate, Arisa (registered trademark), taxol , Taxotere, fluorouracil, leucovorin, irinotecan, xeloda, CPT-11, interferon alpha, pegylated interferon alpha (e.g.
- PEGINTRON-A capecitabine, cisplatin, thiotepa, fludarabine, carbop Tin, liposomal daunorubicin, cytarabine, doxetaxol, pacilitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin, busulfan, prednisone, bisphosphonate, trioxide Arsenic, vincristine, doxorubicin (Doxil (R)), paclitaxel, ganciclovir, adriamycin, estramustine sodium phosphate (Emcyt (R)), sulindac and etoposide.
- the second active agent is etoposide, daunomycin, actinomycin D, mitomycin C, cisplatin, carboplatin, pemetrexed, methotrexate, Ara-C, 5-FU, wortmannin, gemcitabine, geldanamycin or them Or a combination of two or more.
- the second active agent is an adjunct therapeutic agent.
- An example of an adjuvant treatment is an antiemetic.
- Specific antiemetics include, but are not limited to, phenothiazine, butyrophenone, benzodiazepine, corticosteroids, serotonin antagonists, cannabinoids and NK1 receptor antagonists.
- phenothiazine antiemetics include, but are not limited to, prochlorperazine and trimethobenzamide.
- Examples of butiophenone antiemetics include but are not limited to haloperidol.
- Examples of benzodiazepine antiemetics include but are not limited to lorazepam.
- corticosteroid antiemetics include, but are not limited to, dexamethasone.
- serotonin antagonist antiemetics include but are not limited to ondansetron, granisetron and dolasetron.
- cannabinoid antiemetics include, but are not limited to dronabinol.
- NK1 receptor antagonists include, but are not limited to, aprepitant.
- the dose and dosing schedule of the antiemetic should depend on the specific indicators being treated, the age and condition of the patient, and the severity of the adverse effects and can thus be adjusted by one skilled in the art. Examples of doses and dosing schedules can be found, for example, in the Physician's Desk Reference.
- the present invention can also combine separate pharmaceutical compositions into a kit form.
- the kit includes two or more separate pharmaceutical compositions: a compound of the invention; a second active agent as described herein.
- the kit typically includes containers for containing separate compositions, such as, for example, split bottles or split foil packets, but separate compositions can also be included in a single unsplit container.
- Kit forms are those where the separate components are preferably administered in different dosage forms (eg, oral and parenteral), where the separate components are administered at different dosage intervals, or the individual components combined by the prescribing physician Is particularly useful when it is necessary to titrate.
- Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, etc.). Blister packs generally consist of a sheet of relatively hard material, preferably covered by a foil of transparent plastic material. During the packaging process, recesses are formed in the plastic foil. These indentations have the size and shape of the individual tablets or capsules to be packed. The tablet or capsule is then placed in the recess and the sheet of relatively hard material is sealed against the plastic foil at the foil surface opposite to the direction in which the recess was formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet.
- the strength of the sheet is such that the tablet or capsule can be removed from the blister pack by manually applying pressure to the recess so that an opening is formed in the sheet at the location of the recess. The tablet or capsule can then be removed through the opening.
- the methods provided herein are used in combination with one or more second active agents and / or in combination with radiation therapy or surgery.
- Administering a compound comprising administering a compound.
- Administration of the compound of the present invention and the second active agent to the patient can be performed simultaneously or sequentially by the same or different routes of administration.
- the suitability of a particular route of administration used for a particular active agent is treated and the active agent itself (e.g., whether it can be administered orally without degradation before entering the bloodstream) Depends on the disease.
- Recommended routes of administration for the second active agent are known to those of skill in the art. See, for example, the Physician's DESK Reference.
- the second active agent is intravenously or subcutaneously and once or twice a day, usually 1 to about 1,000 mg, about 5 to about 500 mg, about 10 to about 375 mg or It is administered in an amount of about 50 to about 200 mg.
- the second active agent is rituximab, oblimersen (Genasense®), GM-CSF, G-CSF, EPO, taxotere, irinotecan, dacarbazine, transretinoic acid, topotecan, Pentoxifylline, ciprofloxacin, dexamethasone, vincristine, doxorubicin, COX-2 inhibitor, IL2, IL8, IL-18, IFN, Ara-C, vinorelbine or combinations thereof.
- the second active agent is etoposide, daunomycin, actinomycin D, mitomycin C, cisplatin, carboplatin, pemetrexed, methotrexate, Ara-C, 5-FU, wortmannin, geldanamycin, gemcitabine or theirs It is a combination.
- a method of treating, preventing and / or managing a hematological malignancy comprising treating, preventing or managing surgery, immunotherapy, biological therapy, radiation therapy or cancer.
- a method comprising administering a compound of the present invention in combination (e.g., before, during, or after) with a conventional therapy including, but not limited to, other non-drug-based therapies currently used to Are provided by this specification.
- a conventional therapy including, but not limited to, other non-drug-based therapies currently used to Are provided by this specification.
- the compounds of the present invention may provide an additive or synergistic effect when given concurrently with conventional therapy.
- the second active agent is co-administered with a compound of the invention or is usually administered with a delay of about 1 to 50 hours.
- the compounds of the invention are administered first, followed by administration with the second active agent, usually with a delay of about 1 to 50 hours.
- the second active agent is administered first, followed by administration with the compound of the invention, usually with a delay of about 1-50 hours. In some embodiments, the delay is preferably 24 hours.
- the compound of the invention is usually in an amount of about 1 to 5000 mg as a daily dose, either alone or in combination with a second active agent disclosed herein, prior to use of conventional therapy. Can be administered during, after or after.
- the methods provided herein include: a) administering a daily dosage of about 1 to 5000 mg of a compound of the invention to a patient in need thereof; and b) administering a therapeutically effective amount of a second active agent, such as an adjunct therapeutic agent.
- the second active agent is an alkylating agent.
- the alkylating agent is an alkyl sulfonate and the cancer being treated is usually leukemia or lymphoma.
- the alkyl sulfonate is busulfan.
- the alkyl sulfonate is busulfan and the therapeutically effective amount is usually a daily dose of at least 1 mg.
- the alkyl sulfonate is busulfan and the therapeutically effective amount is usually a daily oral dose of between about 2 mg to 8 mg.
- the alkyl sulfonate is busulfan and the therapeutically effective amount is usually a daily oral dose of between about 1 mg to about 3 mg.
- the alkylating agent is nitrogen mustard and the cancer being treated is usually bladder cancer, breast cancer, Hodgkin's disease, leukemia, lung cancer, melanoma, ovarian cancer or testicular cancer.
- the nitrogen mustard is chlorambucil.
- the nitrogen mustard is chlorambucil and the therapeutically effective amount is usually at least 0.1 mg / kg.
- the nitrogen mustard is chlorambucil and the therapeutically effective amount is a daily oral dose usually between about 0.1 mg / kg to about 0.2 mg / kg during 3-6 weeks.
- the nitrogen mustard is chlorambucil and the therapeutically effective amount is usually a dose of 0.4 mg / kg every 3-4 weeks.
- the nitrogen mustard is cyclophosphamide. In another embodiment, the nitrogen mustard is cyclophosphamide and the therapeutically effective amount is usually an intravenous dose of at least 10 mg / kg. In another embodiment, the nitrogen mustard is cyclophosphamide and the therapeutically effective amount is usually intravenous administration between about 10 mg / kg and about 15 mg / kg every 7-10 days. In another embodiment, the nitrogen mustard is cyclophosphamide and the therapeutically effective amount is usually an oral daily dose of between about 1 mg / kg to about 5 mg / kg. In another embodiment, the nitrogen mustard is melphalan. In another embodiment, the nitrogen mustard is melphalan and the therapeutically effective amount is usually a daily oral dose of at least 2 mg.
- the nitrogen mustard is melphalan and the therapeutically effective amount is usually 6 mg daily oral dose during 2-3 weeks, no melphalan for 2-4 weeks, and then usually Daily oral dose between about 2 mg to about 4 mg.
- the nitrogen mustard is melphalan and the therapeutically effective amount is a daily oral dose of usually every 4-6 weeks 4 days 10 mg / m 2 (per body surface area).
- the alkylating agent is nitrosourea and the cancer being treated is usually brain tumor, colorectal cancer including colorectal cancer, Hodgkin's disease, liver cancer, lung cancer, lymphoma or melanoma.
- the nitrosourea is carmustine.
- the nitrosourea is carmustine and the therapeutically effective amount is usually at least 150 mg / m 2 .
- the nitrosourea is carmustine and the therapeutically effective amount is an intravenous dose between about 150mg / m 2 ⁇ 200mg / m 2 to normal every 6-8 weeks.
- the alkylating agent is triazene and the cancer being treated is usually Hodgkin's disease, melanoma, neuroblastoma or soft tissue sarcoma.
- the triazene is dacarbazine.
- the triazene is dacarbazine and the therapeutically effective amount is a daily intravenous dose of between about 2.0 mg / kg to about 4.5 mg / kg, usually for 10 days every 4 weeks.
- the triazene is dacarbazine and the therapeutically effective amount is usually a daily intravenous dose of 250 mg / m 2 for 5 days every 3 weeks.
- the triazene is dacarbazine and the therapeutically effective amount is usually administered intravenously at 375 mg / m 2 every 16 days. In another embodiment, the triazene is dacarbazine and the therapeutically effective amount is an intravenous administration of 150 mg / m 2 usually for 5 days every 4 weeks.
- the second active agent is an antineoplastic antibiotic and the cancer being treated is usually bladder cancer, breast cancer, cervical cancer, head and neck cancer, Hodgkin's disease, leukemia, multiple myeloma Neuroblastoma, ovarian cancer, sarcoma, skin cancer, testicular cancer or thyroid cancer.
- the antibiotic is bleomycin.
- the antibiotic is bleomycin and the therapeutically effective amount is usually at least 10 units / m 2 .
- the antibiotic is bleomycin and the therapeutically effective amount is usually between about 10 units / m 2 to about 20 units / m 2 , intravenously, subcutaneously or muscle, usually weekly or twice weekly. It is an internal dose.
- the antibiotic is dactinomycin. In another embodiment, the antibiotic is dactinomycin and the therapeutically effective amount is usually at least 0.01 mg / kg. In another embodiment, the antibiotic is dactinomycin and the therapeutically effective amount is usually daily intravenous administration between about 0.010 mg / kg and about 0.015 mg / kg for 5 days every 3 weeks. . In another embodiment, the antibiotic is dactinomycin and the therapeutically effective amount is usually 2 mg / m 2 intravenously every 3 or 4 weeks. In another embodiment, the antibiotic is daunorubicin. In another embodiment, the antibiotic is daunorubicin and the therapeutically effective amount is usually at least 30 mg / m 2 .
- the antibiotic is daunorubicin and the therapeutically effective amount is an daily intravenous dose of between about 30 mg / m 2 ⁇ about 45 mg / m 2 typically 3 days.
- the antibiotic is a liposomal formulation of daunorubicin and the therapeutically effective amount is usually administered intravenously at 40 mg / m 2 every 2 weeks.
- the antibiotic is doxorubicin.
- the antibiotic is doxorubicin and the therapeutically effective amount is usually at least 15 mg / m 2 .
- the antibiotic is doxorubicin and the therapeutically effective amount is an intravenous dose between about 60 mg / m 2 ⁇ about 90 mg / m 2 every normal 3 weeks.
- the antibiotic is doxorubicin and the therapeutically effective amount is usually weekly intravenous administration between about 15 mg / m 2 and about 20 mg / m 2 .
- the antibiotic is doxorubicin and the therapeutically effective amount is usually in a cycle comprising 30 mg / m 2 weekly intravenous administration for 2 weeks followed by 2 weeks without doxorubicin. is there.
- the second agent is an antimetabolite.
- the antimetabolite is a folic acid analog and the cancer being treated is usually breast cancer, head and neck cancer, leukemia, lung cancer, non-Hodgkin lymphoma or osteosarcoma.
- the folic acid analog is methotrexate.
- the folate analog is methotrexate and the therapeutically effective amount is usually at least 2.5 mg.
- the folate analog is methotrexate and the therapeutically effective amount is usually a daily oral dose of between about 2.5 mg to about 5 mg.
- the folate analog is methotrexate and the therapeutically effective amount is usually dose twice weekly between about 5 mg / m 2 ⁇ about 25 mg / m 2. In another embodiment, the folate analog is methotrexate and the therapeutically effective amount is usually a weekly intravenous dose of 50 mg / m 2 every 2-3 weeks.
- the folic acid analog is pemetrexed. In another embodiment, the folate analog is pemetrexed and the therapeutically effective amount is usually at least 300 mg / m 2 . In another embodiment, the folate analog is pemetrexed and the therapeutically effective amount is an intravenous dose between about 300 mg / m 2 ⁇ about 600 mg / m 2 every normal 2 or 3 weeks. In another embodiment, the folate analog is pemetrexed and the therapeutically effective amount is usually administered intravenously at 500 mg / m 2 every 3 weeks.
- the antimetabolite is a purine analog and the cancer being treated is colorectal cancer, usually including colorectal cancer, leukemia or myeloma.
- the purine analog is mercaptopurine.
- the purine analog is mercaptopurine and the therapeutically effective amount is at least 1.5 mg / kg.
- the purine analog is mercaptopurine and the therapeutically effective amount is usually a daily oral dose of between about 1.5 mg / kg to about 5 mg / kg.
- the purine analog is thioguanidine.
- the purine analog is thioguanidine and the therapeutically effective amount is usually at least 2 mg / kg.
- the purine analog is thioguanidine and the therapeutically effective amount is usually a daily oral dose between about 2 mg / kg and about 3 mg / kg.
- the antimetabolite is an adenosine analog and the cancer being treated is usually leukemia or lymphoma.
- the adenosine analog is cladribine.
- the adenosine analog is cladribine and the therapeutically effective amount is usually at least 0.09 mg / kg.
- the adenosine analog is cladribine and the therapeutically effective amount is a daily intravenous dose of 0.09 mg / kg usually during 7 days.
- the adenosine analog is cladribine and the therapeutically effective amount is a daily intravenous dose of 4 mg / m 2 usually during 7 days.
- the adenosine analog is pentostatin. In another embodiment, the adenosine analog is pentostatin and the therapeutically effective amount is usually 4 mg / m 2 . In another embodiment, the adenosine analog is pentostatin and the therapeutically effective amount is usually 4 mg / m 2 intravenously administered every other week. In another embodiment, the adenosine analog is pentostatin and the therapeutically effective amount is usually 4 mg / m 2 intravenously administered every 3 weeks.
- the antimetabolite is a pyrimidine analog and the cancer being treated is usually bladder cancer, breast cancer, colorectal cancer including colorectal cancer, esophageal cancer, head and neck cancer, leukemia, liver cancer, lymphoma Ovarian cancer, pancreatic cancer, skin cancer or stomach cancer.
- the pyrimidine analog is cytarabine.
- the pyrimidine analog is cytarabine and the therapeutically effective amount is usually at least 100 mg / m 2 .
- the pyrimidine analog is cytarabine and the therapeutically effective amount is a daily intravenous dose of 100 mg / m 2 usually during 7 days.
- the pyrimidine analog is capecitabine. In another embodiment, the pyrimidine analog is capecitabine and the therapeutically effective amount is usually a daily dose of at least 2000 mg / m 2 . In another embodiment, the pyrimidine analog is capecitabine and the therapeutically effective amount is a twice oral daily dose of between about 1200 mg / m 2 ⁇ about 1300 mg / m 2 during normal 14 days is there. In another embodiment, the pyrimidine analog is capecitabine and the therapeutically effective amount is usually administered as a twice daily dose of about 1250 mg / m 2 for 14 days followed by a one week rest. It is a weekly cycle. In another embodiment, the pyrimidine analog is fluorouracil.
- the pyrimidine analog is fluorouracil and the therapeutically effective amount is usually at least 10 mg / kg. In another example, the pyrimidine analog is fluorouracil and the therapeutically effective amount is usually daily intravenous administration between about 300 mg / m 2 to about 500 mg / m 2 for at least 3 days. In another example, the pyrimidine analog is fluorouracil and the therapeutically effective amount is a daily intravenous dose of 12 mg / kg during 3-5 days. In another embodiment, the pyrimidine analog is fluorouracil and the therapeutically effective amount is usually weekly intravenous administration between about 10 mg / kg and about 15 mg / kg.
- the antimetabolite is a substituted urea and the cancer being treated is usually head and neck cancer, leukemia, melanoma or ovarian cancer.
- the substituted urea is hydroxyurea.
- the substituted urea is hydroxyurea and the therapeutically effective amount is usually at least 20 mg / kg.
- the substituted urea is hydroxyurea and the therapeutically effective amount is an oral dose of 80 mg / kg every 3 days.
- the substituted urea is hydroxyurea and the therapeutically effective amount is usually a daily oral dose of between about 20 mg / kg to about 30 mg / kg.
- the second active agent is a platinum coordination compound and the cancer being treated is usually bladder cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, leukemia, lung cancer, lymphoma, ovary Cancer, sarcoma, testicular cancer or uterine cancer.
- the platinum coordination compound is carboplatin.
- the platinum coordination compound is carboplatin and the therapeutically effective amount is usually at least 300 mg / m 2.
- the platinum coordination compound is carboplatin and the therapeutically effective amount is usually at least 300 mg / m 2 every 4 weeks.
- the platinum coordination compound is carboplatin and the therapeutically effective amount is usually 300 mg / m 2 every 4 weeks.
- the platinum coordination compound is carboplatin and the therapeutically effective amount is usually at least 360 mg / m 2 every 4 weeks. In another embodiment, the platinum coordination compound is cisplatin. In another embodiment, the platinum coordination compound is cisplatin and the therapeutically effective amount is usually at least 20 mg / m 2 . In another embodiment, the platinum coordination compound is cisplatin and the therapeutically effective amount is a daily intravenous dose of 20 mg / m 2 , usually for 4-5 days every 3-4 weeks. In another embodiment, the platinum coordination compound is cisplatin and the therapeutically effective amount is usually administered intravenously at 50 mg / m 2 every 3 weeks. In another embodiment, the platinum coordination compound is oxaliplatin.
- the platinum coordination compound is oxaliplatin and the therapeutically effective amount is usually at least 75 mg / m 2 . In another embodiment, the platinum coordination compound is oxaliplatin and the therapeutically effective amount is usually between about 50 mg / m 2 and about 100 mg / m 2 . In another embodiment, the platinum coordination compound is oxaliplatin and the therapeutically effective amount is an IV infusion of between about 50 mg / m 2 ⁇ about 100 mg / m 2 every normal 2 weeks. In another embodiment, the platinum coordination compound is oxaliplatin and the therapeutically effective amount is an IV infusion of between about 80 mg / m 2 ⁇ about 90 mg / m 2 every normal 2 weeks. In another embodiment, the platinum coordination compound is oxaliplatin and the therapeutically effective amount is usually a 2-hour IV infusion of 85 mg / m 2 every two weeks.
- the second active agent is a topoisomerase II inhibitor and the cancer being treated is usually Hodgkin's disease, leukemia, small cell lung cancer, sarcoma or testicular cancer.
- the topoisomerase II inhibitor is etoposide.
- the topoisomerase II inhibitor is etoposide and the therapeutically effective amount is usually at least 35 mg / m 2 .
- the topoisomerase II inhibitor is etoposide and the therapeutically effective amount is usually between about 50 mg / m 2 and about 100 mg / m 2 .
- the topoisomerase II inhibitor is etoposide and the therapeutically effective amount is usually about 35 mg / m 2 to about 50 mg / m 2 per day, usually at least 3 times every 5 days every 3 or 4 weeks. Intravenous administration between 2 . In another embodiment, the topoisomerase II inhibitor is etoposide and the therapeutically effective amount is usually about 50 mg / m 2 to about 100 mg / day at least three times every five days every three or four weeks. Intravenous administration between m 2 . In another embodiment, the topoisomerase II inhibitor is etoposide and the therapeutically effective amount is an oral dose of 100 mg / m 2 per day, usually at least three times every five days every three or four weeks. .
- the topoisomerase II inhibitor is teniposide. In another embodiment, the topoisomerase II inhibitor is teniposide and the therapeutically effective amount is usually at least 20 mg / m 2 . In another embodiment, the topoisomerase II inhibitor is teniposide and the therapeutically effective amount is usually a dose of 100 mg / m 2 weekly. In another embodiment, the topoisomerase II inhibitor is teniposide and the therapeutically effective amount is usually a dose of 100 mg / m 2 twice weekly. In another embodiment, the topoisomerase II inhibitor is teniposide and the therapeutically effective amount is a dosage of between about 20 mg / m 2 ⁇ about 60 mg / m 2 daily during normal 5 days. In another embodiment, the topoisomerase II inhibitor is teniposide and the therapeutically effective amount is a dosage of between about 80 mg / m 2 ⁇ about 90 mg / m 2 daily during normal 5 days.
- the administration mode of the compound of the present invention and the concomitant drug is not particularly limited as long as the compound of the present invention and the concomitant drug are combined at the time of administration.
- administration forms include, for example, (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug, and (2) separate preparation of the compound of the present invention and the concomitant drug. Simultaneous administration of the two preparations obtained by the same route by the same route of administration, (3) with a time difference in the same route of administration of the two formulations obtained by separately formulating the compound of the present invention and the concomitant drug.
- either sequential or simultaneous administration may be performed by any suitable route.
- Preferred unit dosage forms are those containing an effective daily dose of the active ingredient as hereinbefore described or a suitable fraction thereof.
- the daily dose of the compound of the present invention is preferably about 1 mg to 5000 mg, more preferably about 10 mg to 500 mg. As described above, the dose varies depending on the circumstances of each patient and is not limited thereto.
- a suitable administration subject of the compound of the present invention or the pharmaceutical composition containing the compound is a mammal including a human.
- mammals that have developed cancer are preferred. More preferably, it is a mammal that has developed cancer involving PGE2.
- Cancers involving PGE2 include brain tumors, bone cancers, epithelial cell-derived neoplasms (epithelial cancers) such as basal fine cell cancers, adenocarcinomas, digestive organ cancers (eg, lip cancer, oral cancer, esophageal cancer, small intestine cancer, Colorectal and gastric cancer), liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer (eg, squamous cell and basal cell cancer), prostate cancer, renal cell cancer, and in the body Other known cancers that affect epithelial cells are included.
- a mammal preferably a human who has developed at least one cancer selected from gastrointestinal cancer, prostate cancer, lung cancer,
- a method for reducing cancer cells in which a compound represented by the above general formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof is contacted with a cancer cell is also described in this document. It is one of the inventions.
- the compounds and preferred embodiments thereof in the present invention are the same as described above.
- As a method for shrinking cancer cells that contact a cancer cell with a compound represented by the general formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof The amount of the compound represented by the general formula (I), (II), (III), or (IV) is usually orally or parenterally administered. be able to.
- the second active agent described above may be used in combination.
- Example 1 EP4 receptor selective antagonist: Compound A: 4-((1S) -1- ⁇ [5-chloro-2- (4-fluorophenoxy) benzoyl] amino ⁇ ethyl) benzoic acid)
- K19-Wnt1 / C2mE mice Gastroenterology Volume 131, Pages 1086-1095, 2006
- tumors develop due to the interaction between Wnt signal enhancement and COX-2 / PGE2 pathway induction.
- Wnt enhancement was observed in 30-50%, and COX-2 induction was reported in 70% or more. Therefore, the K19-Wnt1 / C2mE mouse is positioned as a model extrapolating the occurrence of human gastric cancer from the molecular mechanism (Nature Review Cancer, Volume 7, Pages 645-658, 2007).
- mice were 50-week-old mice with spontaneous development of gastric cancer.
- a large tumor tissue is formed in the stomach at the age of 50 weeks, and the size of the tumor can be measured using X-ray CT.
- X-ray CT was used to measure and compare tumor sizes before drug administration and at 1, 2, and 3 weeks after administration.
- Compound A 100 mg / kg was orally administered twice a day for 3 weeks.
- Methylcellulose was used as the vehicle.
- FIG. 1 In two individuals that had formed particularly large tumors before the start of administration, a significant reduction in tumor size was observed in the first week (FIG. 1). As shown in FIG.
- Example 2 (EP4 receptor selective antagonist: Compound B: 4-[(1S) -1-( ⁇ [5-chloro-2- (3-fluorophenoxy) pyridin-3-yl] carbonyl ⁇ amino) ethyl ]benzoic acid)
- the tumor size was measured in the same manner as in Example 1. X-ray CT scans confirmed that the tumor size increased in the two vehicle control animals over time.
- FIG. 3 the average tumor area of each mouse before administration (week 0 (0 W)) was taken as 100, and the area after treatment was converted to a relative value and shown over time.
- the solid line is a square, and the solid line is a diamond, which is a control model mouse.
- Triangles on the broken line and crosses (x) on the broken line are model mice administered with Compound B at 3 mg / kg, respectively.
- the solid line * and the solid line circle ( ⁇ ) are model mice administered with Compound B at 30 mg / kg, respectively.
- tumor size increased in the vehicle group a significant decrease in tumor size was observed at any dose in the compound B administration group.
- tumor lesions at the time of pathological dissection were significantly reduced in the drug-administered group compared to vehicle control. That is, it was confirmed that the tumor size of the compound B administration group was significantly reduced as compared with the tumor tissue of the vehicle group.
- Example 3 (Compound C: 3- [2- (4- ⁇ 2-Ethyl-4,6-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl ⁇ phenyl) ethyl] -1- [ (4-Methylbenzene) sulfonyl] urea)
- Compound C was used instead of Compound B.
- Compound C also showed the same effect as Compound B, confirming that the tumor size of the Compound C administration group was significantly reduced compared to the tumor tissue of the vehicle group.
- Example 4 Human prostate cancer cell xenograft model animals (animals with tumors produced by transplanting human prostate cancer cells into nude mice) are treated with compound A, B or compound C to confirm changes in tumor size. In this experimental system, tumor reduction is observed in animals using compounds A, B and C as described above.
- Example 5 A human breast cancer cell xenograft model animal (animal having a tumor produced by transplanting human prostate cancer cells into nude mice) is treated with Compound A, B or Compound C to confirm the change in tumor size.
- Compound A, B or Compound C is treated with Compound A, B or Compound C to confirm the change in tumor size.
- tumor reduction is observed in animals using compounds A, B and C as described above.
- Example 6 CD2F1 mice were transplanted subcutaneously with mouse colon cancer-derived cell line colon26 (in the method described in Int. J. Cancer. Volume 121, Pages 878-883, 2007, this model extrapolated the development and growth of colon cancer) Considered a model).
- the tumor weight was calculated by measuring the minor axis and major axis of the tumor and calculating the major axis x (minor axis) 2 x 0.5.
- FIG. 4 shows changes over time in the tumor size of each group. In FIG.
- the solid line is a square ( ⁇ ), the solid line is a triangle ( ⁇ ), and the solid line is a circle ( ⁇ ), respectively, are a vehicle administration group (control), a compound B administration group, and a compound C administration group.
- control a compound administration group
- compound B administration group a compound B administration group
- compound C administration group a compound C administration group.
- Example 7 In an experimental system using a human colon cancer cell xenograft model animal (an animal having a tumor produced by transplanting human colon cancer cells into nude mice), the tumor was reduced in the animal using the compounds A, B and C as described above. Is seen.
- Example 8 A mouse lung cancer-derived cell line LL / 2 was subcutaneously transplanted into C57BL / 6 mice (the method described in Cancer Research. Volume 58, Pages 2583-2587, 1998. This model extrapolated the occurrence and proliferation of lung cancer. it is conceivable that).
- the tumor weight was calculated by measuring the minor axis and major axis of the tumor and calculating the major axis x (minor axis) 2 x 0.5.
- FIG. 5 shows changes over time in the tumor size of each group. In FIG.
- the solid line is a square ( ⁇ ), the solid line is a triangle ( ⁇ ), and the solid line is a circle ( ⁇ ), respectively, are a vehicle administration group (control), a compound B administration group, and a compound C administration group.
- control a compound administration group
- compound B administration group a compound B administration group
- compound C administration group a compound C administration group.
- Example 9 In an experimental system using a human lung cancer cell xenograft model animal (an animal having a tumor produced by transplanting human lung cancer cells into a nude mouse), reduction of tumor was observed in animals using compounds A, B and C as described above. It is done.
- “Cancers involving PGE2” include brain tumors, bone cancers, epithelial cell-derived neoplasms (epithelial cancers) such as basal cell carcinomas, adenocarcinomas, digestive organ cancers (eg lip cancer, oral cancer, esophageal cancer, small intestine) Cancer, colon cancer and stomach cancer), liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer (eg, squamous cell and basal cell cancer), prostate cancer, renal cell cancer, and in the body There are other known cancers that affect other epithelial cells.
- epithelial cell-derived neoplasms epithelial cancers
- basal cell carcinomas eg lip cancer, oral cancer, esophageal cancer, small intestine Cancer, colon cancer and stomach cancer
- liver cancer eg lip cancer, oral cancer, esophageal cancer, small intestine) Cancer, colon cancer and stomach cancer
- liver cancer e
- the compound of the present invention is administered and treated to the above-mentioned human cancer cell xenograft model animal (animal having tumor produced by transplanting the above human cancer cells into nude mice), and the change in tumor size is confirmed.
- the therapeutic effect of the cancer of the present invention can be confirmed.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
R1は、水素原子、C1-8アルキル基、C2-8アルケニル基、C2-8アルキニル基、C3-7シクロアルキル基、C1-8アルコキシ基、ハロゲン原子で置換されたC1-8アルコキシ基、C1-8アルキル-S(O)m-基、Q1-基、ピロリジニル基、ピペリジル基、オキソピロリジニル基、オキソピペリジル基、アミノ基、モノ-又はジ-(C1-8アルキル)アミノ基、C1-4アルキル-C(=O)-N(R3)-基、又はC1-4アルキル-S(O)m-N(R3)-基であり、ここで、前記C1-8アルキル基、C2-8アルケニル基、及びC2-8アルキニル基は、場合により、ハロゲン原子、C1-3アルキル基、ヒドロキシ基、オキソ基、C1-4アルコキシ-基、C1-4アルキル-S(O)m-基、C3-7シクロアルキル-基、シアノ基、インダニル基、1,2,3,4-テトラヒドロナフチル基、1,2-ジヒドロナフチル基、ピロリジニル基、ピペリジル基、オキソピロリジニル基、オキソピペリジル基、Q1-基、Q1-C(=O)-基、Q1-O-基、Q1-S(O)m-基、Q1-C1-4アルキル-O-基、Q1-C1-4アルキル-S(O)m-基、Q1-C1-4アルキル-C(O)-N(R3)-基、Q1-C1-4アルキル-N(R3)-基、又はC1-4アルキル-C(O)-N(R3)-基で置換されていることがあり;
Q1は、場合により、酸素原子、窒素原子、及びイオウ原子から選択されるヘテロ原子4つ以下を含むことがあり、且つ場合により、ハロゲン原子、C1-4アルキル基、ハロゲン原子で置換されたC1-4アルキル基、ヒドロキシ基、C1-4アルコキシ基、ハロゲン原子で置換されたC1-4アルコキシ基、C1-4アルキルチオ基、ニトロ基、アミノ基、モノ-又はジ-(C1-4アルキル)アミノ基、シアノ基、HO-C1-4アルキル基、C1-4アルコキシ-C1-4アルキル基、C1-4アルキルスルホニル基、アミノスルホニル基、C1-4アルキルC(=O)-基、HO(O=)C-基、C1-4アルキル-O(O=)C-基、R3N(R4)C(=O)-基、C1-4アルキルスルホニルアミノ基、C3-7シクロアルキル基、R3C(=O)N(R4)-基、又はNH2(HN=)C-基で置換されていることがある5~12員の単環式又は二環式芳香族環基であり;
Wは、NH基、N-C1-4アルキル基、酸素原子、イオウ原子、N-OR5基、又は共有結合であり;
Zは、場合により、酸素原子、窒素原子、及びイオウ原子から選択されるヘテロ原子3つ以下を含むことがある5~12員の単環式又は二環式芳香族環基であり、ここで、前記5~12員の単環式又は二環式芳香族環基は、場合により、ハロゲン原子、C1-4アルキル基、ハロゲン原子で置換されたC1-4アルキル基、C1-4アルケニル基、C1-4アルキニル基、ヒドロキシ基、C1-4アルコキシ基、ハロゲン原子で置換されたC1-4アルコキシ基、C1-4アルキルチオ基、ニトロ基、アミノ基、モノ-又はジ-(C1-4アルキル)アミノ基、シアノ基、HO-C1-4アルキル基、C1-4アルコキシ-C1-4アルキル基、C1-4アルキルスルホニル基、アミノスルホニル基、C1-4アルキルC(=O)-基、R3C(=O)N(R4)-基、HO(O=)C-基、C1-4アルキル-O(O=)C-基、C1-4アルキルスルホニルアミノ基、C3-7シクロアルキル基、NH2(HN=)C-基、Q2-S(O)m-基、Q2-O-基、Q2-N(R3)-基、又はQ2-基で置換されていることがあり;
Lは、ハロゲン原子、C1-4アルキル基、ハロゲン原子で置換されたC1-4アルキル基、ヒドロキシ基、C1-4アルコキシ基、ハロゲン原子で置換されたC1-4アルコキシ基、C1-4アルキルチオ基、ニトロ基、アミノ基、モノ-又はジ-(C1-4アルキル)アミノ基、シアノ基、HO-C1-4アルキル基、C1-4アルコキシ-C1-4アルキル基、C1-4アルキルスルホニル基、アミノスルホニル基、C1-4アルキルC(=O)-基、HO(O=)C-基、C1-4アルキル-O(O=)C-基、C1-4アルキルスルホニルアミノ基、C3-7シクロアルキル基、R3C(=O)N(R4)-基、NH2(HN=)C-基、R3N(R4)C(=O)-基、R3N(R4)S(O)m-基、Q2-基、Q2-C(=O)-基、Q2-O-基、Q2-C1-4アルキル-O-基であるか、あるいは隣接するL基2つが、場合により一緒になって、環メンバー3又は4つを有し、前記環メンバーの内の炭素原子1つ又は(隣接していない)炭素原子2つが酸素原子で場合により置換されていることがあるアルキレン鎖を形成することがあり;
R3及びR4は、水素原子及びC1-4アルキル基から独立して選択され;
R5は、水素原子、C1-4アルキル基、C1-4アルキル-(O=)C-基、又はC1-4アルキル-O-(O=)C-基であり;そして
Q2は、5~12員の単環式もしくは二環式芳香族環基、又は5~12員の三環式環基であって、場合により、酸素原子、窒素原子、及びイオウ原子から選択されるヘテロ原子3つ以下を含むことがあり、ここで、前記5~12員の単環式又は二環式芳香族環基は、場合により、ハロゲン原子、C1-4アルキル基、ハロゲン原子で置換されたC1-4アルキル基、C1-4アルケニル基、C1-4アルキニル基、ヒドロキシ基、C1-4アルコキシ基、ハロゲン原子で置換されたC1-4アルコキシ基、C1-4アルキルチオ基、ニトロ基、アミノ基、モノ-又はジ-(C1-4アルキル)アミノ基、シアノ基、HO-C1-4アルキル基、C1-4アルコキシ-C1-4アルキル基、C1-4アルキルスルホニル基、アミノスルホニル基、C1-4アルキル-(O=)C-基、R3(R4)C(=O)N-基、HO(O=)C-基、C1-4アルキル-O(O=)C-基、C1-4アルキルスルホニルアミノ基、C3-7シクロアルキル基、C1-4アルキル-C(=O)NH-基、又はNH2(HN=)C-基で置換されていることがあり;
OH、及び/又はCO2Hを含む場合、OH及び-COOHは、それぞれ独立に薬学的に許容されるエステルであってもよい]、
環Bがアリール基又はヘテロアリール基を表し;
環Cが1,4-フェニレン基を表し;
R1及びR2が水素原子、ハロゲン原子、1から4個の炭素原子を有するアルキル基、1から4個の炭素原子を有するアルコキシ基、1から4個の炭素原子を有するハロアルキル基、1から4個の炭素原子を有するハロアルコキシ基、シアノ基又はアミノカルボニル基を独立して表し;
R3及びR4が水素原子、又は1から4個の炭素原子を有するアルキル基を独立して表すか、又はR3及びR4基が共に結合して2から6個の炭素原子を有するアルキレン鎖を形成し;
R5が-CO2H、CO2W、
R6が1から6個の炭素原子を有するアルキル基、3から7個の環原子を有するシクロアルキル基、アリール基又はヘテロアリール基を表し;
Xがメチレン基、酸素原子又は硫黄原子を表し;
前記アリール基が6から10個の炭素原子を有し;
前記へテロアリール基が硫黄原子、酸素原子及び窒素原子からなる群から選択される1から3個のヘテロ原子を含む5から10員環芳香族複素環基であり;
環Cの定義で言及される前記1,4-フェニレン基が未置換であるか、又は置換基βからなる群から選択される少なくとも1つの置換基により置換され;
R6及びαの定義において言及される前記アリール基及び前記へテロアリール基が未置換であるか又は置換基βからなる群から選択される少なくとも1つの置換基により置換され;
Wが薬学的に許容できるエステルプロドラッグ基である]、
Yは-NR4、酸素原子又は硫黄原子を表し;
R4は水素原子又は1~3個の炭素原子を有するアルキル基を表し;
Zは水素原子又はハロゲン原子を表し;
R1は、1~6個の炭素原子を有するアルコキシ基もしくは3~7個の炭素原子を有するシクロアルキル基で場合により置換された、1~6個の炭素原子を有するアルキル基;1~3個の炭素原子を有するアルキル基で場合により置換された、3~7個の炭素原子を有するシクロアルキル基;1つもしくはそれ以上の置換基αで場合により置換されたフェニル基;又は1つもしくはそれ以上の置換基αで場合により置換された基Het1を表し;
Het1は、1~4個の環窒素ヘテロ原子又は0~2個の窒素環ヘテロ原子及び1個の酸素環ヘテロ原子又は1個の硫黄環ヘテロ原子のいずれかを含有する4~7個の環原子を有する複素環式基を表し;
そして該置換基αは、ハロゲン原子、1~4個の炭素原子を有するアルキル基、1~4個の炭素原子を有するハロアルキル基、ヒドロキシ基、1~4個の炭素原子を有するアルコキシ基、1~4個の炭素原子を有するハロアルコキシ基、シアノ基、1~4個の炭素原子を有するヒドロキシアルキル基、アルコキシ基及びアルキル基中に1~4個の炭素原子を有するアルコキシアルキル基、1~4個の炭素原子を有するアルキルスルホニル基、2~5個の炭素原子を有するアルカノイル基、2~4個の炭素原子を有するアルケニル基、2~4個の炭素原子を有するアルキニル基、1~4個の炭素原子を有するアルキルチオ基、ニトロ基、アミノ基、1~4個の炭素原子を有するモノ-又はジ-アルキルアミノ基、アミノスルホニル基、1~4個の炭素原子を有するアルコキシカルボニル基、1~4個の炭素原子を有するアルキルスルホニルアミノ基、3~7個の炭素原子を有するシクロアルキル基及び1~6個の炭素原子を有するモノ-又はジ-アルキルアミノカルボニル基からなる群より選択され;
OHを含む場合、薬学的に許容されるエステルであってもよいし、CO2Hも独立に薬学的に許容されるエステルであってもよい]、
Yは、NR4、酸素原子又はイオウ原子を表し、
R4は、水素原子又は1~3個の炭素原子を有するアルキル基を表し、
Zは、水素原子又はハロゲン原子を表し、
R1は、1~6個の炭素原子を有するアルコキシ基、トリフルオロメチル基、2~5個の炭素原子を有するアルカノイル基、3~7個の炭素原子を有するシクロアルキル基、フェニル基、フェノキシ基、複素環基及びヘテロアリール基から独立して選択される1~2個の基で置換されていてもよい1~6個の炭素原子を有するアルキル基;1~3個の炭素原子を有するアルキル基で置換されていてもよい3~7個の炭素原子を有するシクロアルキル基;又は複素環基を表し、
前記ヘテロアリール基は、1~4個の環窒素ヘテロ原子又は0~2個の窒素環ヘテロ原子及び1個の酸素もしくは1個のイオウ環ヘテロ原子を有する4~7員芳香族環系であり、
前記複素環基は、1~4個の環窒素ヘテロ原子又は0~2個の窒素環ヘテロ原子及び1個の酸素もしくは1個のイオウ環ヘテロ原子を有する4~7員飽和環系であり、
R1の定義において言及される前記フェニル基、フェノキシ基及び前記ヘテロアリール基は、非置換であるか、あるいは置換基αからなる群から選択される少なくとも1個の置換基によって置換されており、
OHを含む場合、該OHは薬学的に許容されるエステルであってもよいし、CO2Hを含む場合、該COOHも独立に薬学的に許容されるエステルであってもよい]。
3-[2-(4-{2-エチル-5,7-ジメチル-3H-イミダゾ[4,5-b]ピリジン-3-イル}フェニル)エチル]-1-[(4-メチルベンゼン)スルホニル]尿素;
1-(4-{2-エチル-4,6-ジメチル-1H-イミダゾ[4,5-c]ピリジン-1-イル}フェニル)プロパン-2-イル N-[(4-メチルベンゼン)スルホニル]カルバメート;
3-[2-(4-{2-エチル-4,6-ジメチル-1H-イミダゾ[4,5-c]ピリジン-1-イル}フェニル)エチル]-1-[(4-メチルベンゼン)スルホニル]尿素;
1-{2-[4-(5-アセチル-2-エチル-1H-1,3-ベンゾジアゾール-1-イル)フェニル]エチル}-3-[(4-メチルベンゼン)スルホニル]尿素;
3-{2-[4-(2-エチル-5-メトキシ-1H-1,3-ベンゾジアゾール-1-イル)フェニル]エチル}-1-[(4-メチルベンゼン)スルホニル]尿素;
2-{4-[6-クロロ-2-エチル-5-(トリフルオロメチル)-1H-1,3-ベンゾジアゾール-1-イル]フェニル}エチル N-[(4-メチルベンゼン)スルホニル]カルバメート;
3-{2-[4-(6-クロロ-5-シアノ-2-エチル-1H-1,3-ベンゾジアゾール-1-イル)フェニル]エチル}-1-[(4-メチルベンゼン)スルホニル]尿素;
2-(4-{2-エチル-4,6-ジメチル-1H-イミダゾ[4,5-c]ピリジン-1-イル}フェニル)エチル N-[(4-メチルベンゼン)スルホニル]カルバメート;
2-(4-{2-ブチル-4,6-ジメチル-1H-イミダゾ[4,5-c]ピリジン-1-イル}フェニル)エチル N-[(4-メチルベンゼン)スルホニル]カルバメート;
2-(4-{2-ターシャリ-ブチル-4,6-ジメチル-1H-イミダゾ[4,5-c]ピリジン-1-イル}フェニル)エチル N-[(4-メチルベンゼン)スルホニル]カルバメート;
2-(4-{2-アミノ-5,7-ジメチル-3H-イミダゾ[4,5-b]ピリジン-3-イル}フェニル)エチル N-[(4-メチルベンゼン)スルホニル]カルバメート;
3-{2-[4-(6-クロロ-2-エチル-5-メタンスルホニル-1H-1,3-ベンゾジアゾール-1-イル)フェニル]エチル}-1-[(4-メチルベンゼン)スルホニル]尿素;
2-[4-(5-カルバモイル-6-クロロ-2-エチル-1H-1,3-ベンゾジアゾール-1-イル)フェニル]エチル N-[(4-メチルベンゼン)スルホニル]カルバメート;
1-(2-{4-[2-エチル-5-(1-ヒドロキシエチル)-1H-1,3-ベンゾジアゾール-1-イル]フェニル}エチル)-3-[(4-メチルベンゼン)スルホニル]尿素;
1-(2-{4-[2-エチル-5-(2-ヒドロキシプロパン-2-イル)-1H-1,3-ベンゾジアゾール-1-イル]フェニル}エチル)-3-[(4-メチルベンゼン)スルホニル]尿素;
1-(2-{4-[6-クロロ-2-(2-ヒドロキシプロパン-2-イル)-5-(トリフルオロメチル)-1H-1,3-ベンゾジアゾール-1-イル]フェニル}エチル)-3-[(4-メチルベンゼン)スルホニル]尿素;
N-[1-(6-クロロ-1-{4-[2-({[(4-メチルベンゼン)スルホニル]カルバモイル}アミノ)エチル]フェニル}-5-(トリフルオロメチル)-1H-1,3-ベンゾジアゾール-2-イル)エチル]アセトアミド;
6-クロロ-2-エチル-1-(4-{2-[メチル({[(4-メチルベンゼン)スルホニル]カルバモイル})アミノ]エチル}フェニル)-1H-1,3-ベンゾジアゾール-5-カルボキシアミド;
2-{4-[6-クロロ-2-(ピリジン-2-イル)-5-(トリフルオロメチル)-1H-1,3-ベンゾジアゾール-1-イル]フェニル}エチル N-[(4-メチルベンゼン)スルホニル]カルバメート;
3-(2-{5-[6-クロロ-2-エチル-5-(トリフルオロメチル)-1H-1,3-ベンゾジアゾール-1-イル]ピリジン-2-イル}エチル)-1-[(4-メチルベンゼン)スルホニル]尿素;
2-{4-[6-クロロ-2-エチル-5-(トリフルオロメチル)-1H-1,3-ベンゾジアゾール-1-イル]フェニル}エチル N-[(2-クロロベンゼン)スルホニル]カルバメート;又は
3-(2-{4-[5,7-ジメチル-2-(メチルアミノ)-3H-イミダゾ[4,5-b]ピリジン-3-イル]フェニル}エチル)-1-[(4-メチルベンゼン)スルホニル]尿素;
4-((1S)-1-{[5-クロロ-2-(4-フルオロフェノキシ)ベンゾイル]アミノ}エチル)安息香酸;
4-[(1S)-1-({[5-クロロ-2-(4-フルオロフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-[(1S)-1({[5クロロ-2-(3-シアノフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-[(1S)-1-({[5-クロロ-2-(3-フルオロフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-[(1S)-1-({[5-クロロ-2-(3-クロロフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-((1S)-1-{[5-クロロ-2-(3-フルオロフェノキシ)ベンゾイル]アミノ}エチル)安息香酸;
4-((1S)-1-{[5-クロロ-2-(3-クロロフェノキシ)ベンゾイル]アミノ}エチル)安息香酸;
4-[(1S)-1-({[5-クロロ-2-(2-クロロ-4-フルオロフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-[(1S)-1-({[5-クロロ-2-(2,6-ジフルオロフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-[(1S)-1-({[5-クロロ-2-(3,4-ジフルオロフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-[(1S)-1-({[5-クロロ-2-(2,3-ジフルオロフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-[(1S)-1-({[5-クロロ-2-(2,5-ジフルオロフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-[(1S)-1-({[5-クロロ-2-(2-クロロ-5-フルオロフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-[(1S)-1-({[5-クロロ-2-(3-メチルフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-[(1S)-1-({[5-クロロ-2-(3,5-ジフルオロフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-((1S)-1-{[5-クロロ-2-(2,3-ジフルオロフェノキシ)ベンゾイル]アミノ}エチル)安息香酸;
4-((1S)-1-{[5-クロロ-2-(3,4-ジフルオロフェノキシ)ベンゾイル]アミノ}エチル)安息香酸;
4-[(1S)-1-({[5-クロロ-2-(3-クロロ-5-フルオロフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-((1S)-1-{[5-クロロ-2-(3,5-ジフルオロフェノキシ)ベンゾイル]アミノ}エチル)安息香酸;
4-((1S)-1-{[5-クロロ-2-(2,5-ジフルオロフェノキシ)ベンゾイル]アミノ}エチル)安息香酸;
4-[(1S)-1-({[5-クロロ-2-(3-クロロ-5-メチルフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-((1S)-1-{[5-クロロ-2-(3-メチルフェノキシ)ベンゾイル]アミノ}エチル)安息香酸;
((1S)-1-{[5-クロロ-2-(3-クロロ-5-フルオロフェノキシ)ベンゾイル]アミノ}エチル)安息香酸;
4-((1S)-1-{[5-クロロ-2-(2,6-ジフルオロフェノキシ)ベンゾイル]アミノ}エチル)安息香酸;
4-((1S)-1-{[(5-クロロ-2-フェノキシピリジン-3-イル)カルボニル]アミノ}エチル)安息香酸;
4-[(1S)-1-({[5-クロロ-2-(2,3-ジクロロフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-[(1S)-1-({[5-クロロ-2-(3,4-ジクロロフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-[(1S)-1-({[5-クロロ-2-(3,5-ジクロロフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;又は
4-[(1S)-1-({[5-クロロ-2-(3-フルオロ-4-メチルフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(4-クロロフェノキシ)メチル]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(4-メチルフェノキシ)メチル]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(3-クロロフェノキシ)メチル]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(4-フルオロフェノキシ)メチル]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(2,3-ジフルオロフェノキシ)メチル]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(3,4-ジフルオロフェノキシ)メチル]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(2,4-ジフルオロフェノキシ)メチル]ベンゾイル}アミノ)エチル]安息香酸;
4-{(1S)-1-[({5-クロロ-2-[(3-クロロフェノキシ)メチル]ピリジン-3-イル}カルボニル)アミノ]エチル}安息香酸;
4-[(1S)-1-({5-クロロ-2-[(2-クロロフェノキシ)メチル]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(3,5-ジフルオロフェノキシ)メチル]ベンゾイル}アミノ)エチル]安息香酸;
4-{(1S)-1-[({5-クロロ-2-[(4-クロロフェノキシ)メチル]ピリジン-3-イル}カルボニル)アミノ]エチル}安息香酸;
4-[(1S)-1-({5-クロロ-2-[(3-フルオロフェノキシ)メチル]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(2,6-ジフルオロフェノキシ)メチル]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(2-フルオロフェノキシ)メチル]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(2,5-ジフルオロフェノキシ)メチル]ベンゾイル}アミノ)エチル]安息香酸;
4-{(1S)-1-[({2-[(4-クロロフェノキシ)メチル]-5-フルオロピリジン-3-イル}カルボニル)アミノ]エチル}安息香酸;又は
4-{(1S)-1-({5-クロロ-2-[(シクロヘキシルメトキシ)メチル]ベンゾイル}アミノ)エチル}安息香酸;
4-[(1S)-1-({5-クロロ-2-[(2-クロロベンジル)オキシ]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[2-(2-メチルフェニル)エトキシ]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[2-(4-メチルフェニル)エトキシ]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(3-クロロベンジル)オキシ]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(4-クロロベンジル)オキシ]ベンゾイル}アミノ)エチル]安息香酸;
4-((1S)-1-{[5-クロロ-2-(シクロブチルメトキシ)ベンゾイル]アミノ}エチル)安息香酸;
4-((1S)-1-{[5-クロロ-2-(シクロヘキシルオキシ)ベンゾイル]アミノ}エチル)安息香酸;
4-[(1S)-1-({5-クロロ-2-[(2-シアノベンジル)オキシ]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[2-(4-フルオロフェニル)エトキシ]ベンゾイル}アミノ)エチル]安息香酸;
4-((1S)-1-{[5-クロロ-2-(3-メチルブトキシ)ベンゾイル]アミノ}エチル)安息香酸;
4-[(1S)-1-({5-クロロ-2-[(4-フルオロベンジル)オキシ]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[2-(2-フルオロフェニル)エトキシ]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(2,5-ジフルオロベンジル)オキシ]ベンゾイル}アミノ)エチル]安息香酸;
4-[({5-クロロ-2-[2-(2-メチルフェニル)エトキシ]ベンゾイル}アミノ)メチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(2-クロロ-4-フルオロベンジル)オキシ]ベンゾイル}アミノ)エチル]安息香酸;
4-((1S)-1-{[5-クロロ-2-(2-フェノキシエトキシ)ベンゾイル]アミノ}エチル)安息香酸;
4-[(1S)-1-({5-クロロ-2-[(3,4-ジフルオロベンジル)オキシ]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(4-クロロ-2-フルオロベンジル)オキシ]ベンゾイル}アミノ)エチル]安息香酸;
4-{(1S)-1-[({5-クロロ-2-[(4-クロロベンジル)オキシ]ピリジン-3-イル}カルボニル)アミノ]エチル}安息香酸;
4-((1S)-1-{[2-(ベンジルオキシ)-5-クロロベンゾイル]アミノ}エチル)安息香酸;
4-{(1S)-1-[({5-クロロ-2-[(2-クロロベンジル)オキシ]ピリジン-3-イル}カルボニル)アミノ]エチル}安息香酸;
4-{(1S)-1-[({5-クロロ-2-[2-(4-クロロフェニル)エトキシ]ピリジン-3-イル}カルボニル)アミノ]エチル}安息香酸;
4-[(1S)-1-({5-クロロ-2-[(3,5-ジフルオロベンジル)オキシ]ベンゾイル}アミノ)エチル]安息香酸;又は
4-[(1S)-1-({5-クロロ-2-[2-(2,6-ジフルオロフェニル)エトキシ]ベンゾイル}アミノ)エチル]安息香酸;
又はこれらの薬学的に許容される塩である。
3-[2-(4-{2-エチル-5,7-ジメチル-3H-イミダゾ[4,5-b]ピリジン-3-イル}フェニル)エチル]-1-[(4-メチルベンゼン)スルホニル]尿素;
3-[2-(4-{2-エチル-4,6-ジメチル-1H-イミダゾ[4,5-c]ピリジン-1-イル}フェニル)エチル]-1-[(4-メチルベンゼン)スルホニル]尿素;
1-{2-[4-(5-アセチル-2-エチル-1H-1,3-ベンゾジアゾール-1-イル)フェニル]エチル}-3-[(4-メチルベンゼン)スルホニル]尿素;
3-{2-[4-(2-エチル-5-メトキシ-1H-1,3-ベンゾジアゾール-1-イル)フェニル]エチル}-1-[(4-メチルベンゼン)スルホニル]尿素;
2-{4-[6-クロロ-2-エチル-5-(トリフルオロメチル)-1H-1,3-ベンゾジアゾール-1-イル]フェニル}エチル N-[(4-メチルベンゼン)スルホニル]カルバメート;
3-{2-[4-(6-クロロ-5-シアノ-2-エチル-1H-1,3-ベンゾジアゾール-1-イル)フェニル]エチル}-1-[(4-メチルベンゼン)スルホニル]尿素;
2-(4-{2-エチル-4,6-ジメチル-1H-イミダゾ[4,5-c]ピリジン-1-イル}フェニル)エチル N-[(4-メチルベンゼン)スルホニル]カルバメート;
2-(4-{2-tert-ブチル-4,6-ジメチル-1H-イミダゾ[4,5-c]ピリジン-1-イル}フェニル)エチル N-[(4-メチルベンゼン)スルホニル]カルバメート;
2-[4-(5-カルバモイル-6-クロロ-2-エチル-1H-1,3-ベンゾジアゾール-1-イル)フェニル]エチル N-[(4-メチルベンゼン)スルホニル]カルバメート;
1-(2-{4-[2-エチル-5-(1-ヒドロキシエチル)-1H-1,3-ベンゾジアゾール-1-イル]フェニル}エチル)-3-[(4-メチルベンゼン)スルホニル]尿素;
1-(2-{4-[6-クロロ-2-(2-ヒドロキシプロパン-2-イル)-5-(トリフルオロメチル)-1H-1,3-ベンゾジアゾール-1-イル]フェニル}エチル)-3-[(4-メチルベンゼン)スルホニル]尿素;
2-{4-[6-クロロ-2-(ピリジン-2-イル)-5-(トリフルオロメチル)-1H-1,3-ベンゾジアゾール-1-イル]フェニル}エチル N-[(4-メチルベンゼン)スルホニル]カルバメート;
3-(2-{5-[6-クロロ-2-エチル-5-(トリフルオロメチル)-1H-1,3-ベンゾジアゾール-1-イル]ピリジン-2-イル}エチル)-1-[(4-メチルベンゼン)スルホニル]尿素;
2-{4-[6-クロロ-2-エチル-5-(トリフルオロメチル)-1H-1,3-ベンゾジアゾール-1-イル]フェニル}エチル N-[(2-クロロベンゼン)スルホニル]カルバメート;又は
3-(2-{4-[5,7-ジメチル-2-(メチルアミノ)-3H-イミダゾ[4,5-b]ピリジン-3-イル]フェニル}エチル)-1-[(4-メチルベンゼン)スルホニル]尿素;
4-((1S)-1-{[5-クロロ-2-(4-フルオロフェノキシ)ベンゾイル]アミノ}エチル)安息香酸;
4-[(1S)-1-({[5-クロロ-2-(4-フルオロフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-[(1S)-1({[5-クロロ-2-(3-シアノフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-[(1S)-1-({[5-クロロ-2-(3-フルオロフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-[(1S)-1-({[5-クロロ-2-(3-クロロフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-((1S)-1-{[5-クロロ-2-(3-フルオロフェノキシ)ベンゾイル]アミノ}エチル)安息香酸;
4-((1S)-1-{[5-クロロ-2-(3-クロロフェノキシ)ベンゾイル]アミノ}エチル)安息香酸;
4-[(1S)-1-({[5-クロロ-2-(2-クロロ-4-フルオロフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-[(1S)-1-({[5-クロロ-2-(3,4-ジフルオロフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-[(1S)-1-({[5-クロロ-2-(2,3-ジフルオロフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-((1S)-1-{[5-クロロ-2-(2,3-ジフルオロフェノキシ)ベンゾイル]アミノ}エチル)安息香酸;
4-((1S)-1-{[5-クロロ-2-(3,4-ジフルオロフェノキシ)ベンゾイル]アミノ}エチル)安息香酸;又は
4-[(1S)-1-({[5-クロロ-2-(3-クロロ-5-フルオロフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(4-クロロフェノキシ)メチル]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(3-クロロフェノキシ)メチル]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(4-フルオロフェノキシ)メチル]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(3,4-ジフルオロフェノキシ)メチル]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(2,4-ジフルオロフェノキシ)メチル]ベンゾイル}アミノ)エチル]安息香酸;
4-{(1S)-1-[({5-クロロ-2-[(3-クロロフェノキシ)メチル]ピリジン-3-イル}カルボニル)アミノ]エチル}安息香酸;
4-[(1S)-1-({5-クロロ-2-[(3,5-ジフルオロフェノキシ)メチル]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(3-フルオロフェノキシ)メチル]ベンゾイル}アミノ)エチル]安息香酸;
4-{(1S)-1-[({2-[(4-クロロフェノキシ)メチル]-5-フルオロピリジン-3-イル}カルボニル)アミノ]エチル}安息香酸;又は
4-{(1S)-1-({5-クロロ-2-[(シクロヘキシルメトキシ)メチル]ベンゾイル}アミノ)エチル}安息香酸;
4-[(1S)-1-({5-クロロ-2-[(2-クロロベンジル)オキシ]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(3-クロロベンジル)オキシ]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(4-クロロベンジル)オキシ]ベンゾイル}アミノ)エチル]安息香酸;
4-((1S)-1-{[5-クロロ-2-(シクロブチルメトキシ)ベンゾイル]アミノ}エチル)安息香酸;
4-((1S)-1-{[5-クロロ-2-(シクロヘキシルオキシ)ベンゾイル]アミノ}エチル)安息香酸;
4-[(1S)-1-({5-クロロ-2-[(2-シアノベンジル)オキシ]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[2-(4-フルオロフェニル)エトキシ]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(4-フルオロベンジル)オキシ]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[2-(2-フルオロフェニル)エトキシ]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(2-クロロ-4-フルオロベンジル)オキシ]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(4-クロロ-2-フルオロベンジル)オキシ]ベンゾイル}アミノ)エチル]安息香酸;
4-{(1S)-1-[({5-クロロ-2-[(4-クロロベンジル)オキシ]ピリジン-3-イル}カルボニル)アミノ]エチル}安息香酸;
4-{(1S)-1-[({5-クロロ-2-[(2-クロロベンジル)オキシ]ピリジン-3-イル}カルボニル)アミノ]エチル}安息香酸;
4-{(1S)-1-[({5-クロロ-2-[2-(4-クロロフェニル)エトキシ]ピリジン-3-イル}カルボニル)アミノ]エチル}安息香酸;
4-[(1S)-1-({5-クロロ-2-[(3,5-ジフルオロベンジル)オキシ]ベンゾイル}アミノ)エチル]安息香酸;又は
4-[(1S)-1-({5-クロロ-2-[2-(2,6-ジフルオロフェニル)エトキシ]ベンゾイル}アミノ)エチル]安息香酸;
又はこれらの薬学的に許容される塩である。
(i)本発明の化合物がカルボン酸官能基(-COOH)を含む場合はそのエステル、例えば、-COOHの水素の(C1~C8)アルキルによる置換、
(ii)本発明の化合物がアルコール官能基(-OH)を含む場合はそのエーテル、例えば、-OHの水素の(C1~C6)アルカノイルオキシメチルによる置換、及び
(iii)本発明の化合物が一級又は二級アミノ官能基(-NH2又はNHR(RはHではない))を含む場合はそのアミド、例えば、-NH2又はNHRの一方又は両方の水素の(C1~C10)アルカノイルによる置換を含むものである。
当業者は、本発明を記載した本明細書及び添付の請求の範囲中に使用される用語を十分に理解できると思われるが、以下の用語は、以下に説明するような意味をもつ。
(1)脂肪族アルカノイル基、例えば:ホルミル基、アセチル基、プロピオニル基、ブチリル基、イソブチリル基、ペンタノイル基、ピバロリル基、バレリル基、イソバレリル基、オクタノイル基、ノナノイル基、デカノイル基、3-メチルノナノイル基、8-メチルノナノイル基、3-エチルオクタノイル基、3,7-ジメチルオクタノイル基、ウンデカノイル基、ドデカノイル基、トリデカノイル基、テトラデカノイル基、ペンタデカノイル基、ヘキサデカノイル基、1-メチルペンタデカノイル基、14-メチルペンタデカノイル基、13,13-ジメチルテトラデカノイル基、ヘプタデカノイル基、15-メチルヘキサデカノイル基、オクタデカノイル基、1-メチルヘプタデカノイル基、ノナデカノイル基、イコサノイル基及びヘニコサノイル基のようなアルカノイル基;クロロアセチル基、ジクロロアセチル基、トリクロロアセチル基、及びトリフルオロアセチル基のようなハロゲン化アルキルカルボニル基;メトキシアセチル基のようなアルコキシアルカノイル基;並びにアクリロイル基、プロピオロイル基、メタクリロリル基、クロトノイル基、イソクロトノイル基及び(E)-2-メチル-2-ブテノイル基のような不飽和アルカノイル基;
;並びに4-フェニルベンゾイル基のようなアリール化アリールカルボニル基;
特定の実施態様において、本明細書に提供される方法は、1つ以上の第二の活性薬剤と組み合わせて、及び/又は放射線療法もしくは外科手術と組み合わせて、本発明の化合物を投与することを含む。患者に対する本発明の化合物及び第二の活性薬剤の投与は、同じか、又は異なる投与経路によって同時に、又は連続して行うことができる。特定の活性薬剤のために使用される特定の投与経路の適合性は、活性薬剤自体(例えば、それが血流に入る前に分解することなく経口投与することができるかどうか)及び治療される疾患に依存する。第二の活性薬剤のための投与の推奨される経路は、当業者に公知である。例えば、医師用卓上参考書(Physician's DESK Reference)を参照されたい。
K19-Wnt1/C2mEマウス(Gastroenterology Volume 131, Pages 1086-1095, 2006)の胃では、Wntシグナル亢進とCOX-2/PGE2経路誘導の相互作用により腫瘍が発生する。一方、ヒト胃癌では30~50%でWnt亢進が認められ、70%以上でCOX-2誘導が報告されている。したがって、K19-Wnt1/C2mEマウスは、ヒト胃癌の発生を分子機序から外挿したモデルと位置づけられている(Nature Review Cancer, Volume 7, Pages 645-658, 2007)。
なお、図2に示すグラフにおいて、縦軸は腫瘍の相対体積(relative tumor volume)である。また、「EP inhibitor」が化合物A投与群である。
46-68週齢の胃癌自然発症モデルマウス(K19-Wnt1/C2mEマウス)6匹を用いて実験を行った。化合物Bを3 mg/kg(n=2)、30 mg/kg(n=2)及びベヒクルコントロール(vehicle control)(n=2)で1日1回、5週間連続経口投与した。腫瘍サイズの測定は、実施例1と同様に行った。X線CT撮影により、ベヒクルコントロールの2匹では腫瘍サイズが経時的に増加した事を確認した。一方、化合物B投与群では用量依存的な腫瘍サイズの減少が認められ、3 mg/kg投与においても効果的な減少が観察された(図3)。図3においては、投与前(0週(0W))の各マウスの平均腫瘍面積を100として、治療後の面積を相対的数値に換算して経時的に示した。図3中、実線に四角、及び実線に菱型は、コントロールのモデルマウスである。破線に三角、及び破線にバツ(×)はそれぞれ、化合物Bを3mg/kg投与したモデルマウスである。実線に*、及び実線に丸(●)は、それぞれ、化合物Bを30mg/kg投与したモデルマウスである。ベヒクル群での腫瘍サイズが増大したのに対して化合物B投与群ではいずれの用量においても顕著な腫瘍サイズの減少を認めた。また、病理解剖時の腫瘍病変は、ベヒクルコントロールに比較しても、薬物投与群で顕著な縮小を認めた。つまり、ベヒクル群の腫瘍組織と比較して、化合物B投与群の腫瘍サイズは顕著に縮小したことを確認した。
化合物Bの代わりに化合物Cを用いたこと以外は、実施例2と同様にして実験を行なった。その結果、化合物Cも、化合物Bと同様の効果を示し、ベヒクル群の腫瘍組織と比較して、化合物C投与群の腫瘍サイズは顕著に縮小したことを確認した。
ヒト前立腺癌細胞異種移植モデル動物(ヒト前立腺癌細胞をヌードマウスに移植して生じる腫瘍を持つ動物)に対して化合物A、Bあるいは化合物Cを用いて治療を行い腫瘍サイズの変化を確認する。この実験系において、前記と同様化合物A、B及びCを用いた動物において腫瘍の縮小が見られる。
ヒト乳癌細胞異種移植モデル動物(ヒト前立腺癌細胞をヌードマウスに移植して生じる腫瘍を持つ動物)に対して化合物A、Bあるいは化合物Cを用いて治療を行い腫瘍サイズの変化を確認する。この実験系において、前記と同様化合物A、B及びCを用いた動物において腫瘍の縮小が見られる。
CD2F1マウスにマウス大腸癌由来細胞株colon26を皮下移植した(Int. J. Cancer. Volume 121, Pages 878-883, 2007に記載の方法で、このモデルは、大腸癌の発生と増殖を外挿したモデルと考えられる)。平均腫瘍重量が100 mgに到達した時点でベヒクル (n=10)、化合物B 30mg/kg 1日1回 (n=10)、または化合物C 200mg/kg 1日2回 (n=10)をそれぞれ20日間投与した。腫瘍重量は腫瘍の短径と長径を測定し長径x(短径)2x0.5で計算した。図4は、各群の腫瘍サイズの経時的な変化を示したものである。図4中、実線に四角(■)、実線に三角(▲)、および実線に丸(●)はそれぞれベヒクル投与群(コントロール)、化合物B投与群、および化合物C投与群である。化合物投与群ではいずれの化合物においてもベヒクル群と比較して顕著な腫瘍の縮小が見られた。
ヒト大腸癌細胞異種移植モデル動物(ヒト大腸癌細胞をヌードマウスに移植して生じる腫瘍を持つ動物)を用いた実験系において、前記と同様化合物A、B及びCを用いた動物において腫瘍の縮小が見られる。
C57BL/6マウスにマウス肺癌由来細胞株LL/2を皮下移植した(Cancer Research. Volume 58, Pages 2583-2587, 1998に記載の方法で、このモデルは、肺癌の発生と増殖を外挿したモデルと考えられる)。平均腫瘍重量が100 mgに到達した時点でベヒクル (n=10)、化合物B 0.3mg/kg 1日1回 (n=10)、または 化合物C10mg/kg 1日2回 (n=10)をそれぞれ25日間投与した。腫瘍重量は腫瘍の短径と長径を測定し長径x(短径)2x0.5で計算した。図5は、各群の腫瘍サイズの経時的な変化を示したものである。図5中、実線に四角(■)、実線に三角(▲)、および実線に丸(●)はそれぞれベヒクル投与群(コントロール)、化合物B投与群、および化合物C投与群である。化合物投与群ではいずれの化合物においてもベヒクル群と比較して顕著な腫瘍の縮小が見られた。
ヒト肺癌細胞異種移植モデル動物(ヒト肺癌細胞をヌードマウスに移植して生じる腫瘍を持つ動物)を用いた実験系において、前記と同様化合物A、B及びCを用いた動物において腫瘍の縮小が見られる。
したがって、本発明の化合物を、ヒトの上記癌細胞異種移植モデル動物(ヒトの上記癌細胞をヌードマウスに移植して生じる腫瘍を持つ動物)に投与・治療を行い、腫瘍サイズの変化を確認することで本発明の癌の治療効果が確認できる。
Claims (15)
- ヒト又は動物の癌の治療用医薬品の製造のための以下の一般式(I)、(II)、(III)、又は(IV)で表される化合物、又はその薬学的に許容される塩の使用:
R1は、水素原子、C1-8アルキル基、C2-8アルケニル基、C2-8アルキニル基、C3-7シクロアルキル基、C1-8アルコキシ基、ハロゲン原子で置換されたC1-8アルコキシ基、C1-8アルキル-S(O)m-基、Q1-基、ピロリジニル基、ピペリジル基、オキソピロリジニル基、オキソピペリジル基、アミノ基、モノ-又はジ-(C1-8アルキル)アミノ基、C1-4アルキル-C(=O)-N(R3)-基、又はC1-4アルキル-S(O)m-N(R3)-基であり、ここで、前記C1-8アルキル基、C2-8アルケニル基、及びC2-8アルキニル基は、場合により、ハロゲン原子、C1-3アルキル基、ヒドロキシ基、オキソ基、C1-4アルコキシ-基、C1-4アルキル-S(O)m-基、C3-7シクロアルキル-基、シアノ基、インダニル基、1,2,3,4-テトラヒドロナフチル基、1,2-ジヒドロナフチル基、ピロリジニル基、ピペリジル基、オキソピロリジニル基、オキソピペリジル基、Q1-基、Q1-C(=O)-基、Q1-O-基、Q1-S(O)m-基、Q1-C1-4アルキル-O-基、Q1-C1-4アルキル-S(O)m-基、Q1-C1-4アルキル-C(O)-N(R3)-基、Q1-C1-4アルキル-N(R3)-基、又はC1-4アルキル-C(O)-N(R3)-基で置換されていることがあり;
Q1は、場合により、酸素原子、窒素原子、及びイオウ原子から選択されるヘテロ原子4つ以下を含むことがあり、且つ場合により、ハロゲン原子、C1-4アルキル基、ハロゲン原子で置換されたC1-4アルキル基、ヒドロキシ基、C1-4アルコキシ基、ハロゲン原子で置換されたC1-4アルコキシ基、C1-4アルキルチオ基、ニトロ基、アミノ基、モノ-又はジ-(C1-4アルキル)アミノ基、シアノ基、HO-C1-4アルキル基、C1-4アルコキシ-C1-4アルキル基、C1-4アルキルスルホニル基、アミノスルホニル基、C1-4アルキルC(=O)-基、HO(O=)C-基、C1-4アルキル-O(O=)C-基、R3N(R4)C(=O)-基、C1-4アルキルスルホニルアミノ基、C3-7シクロアルキル基、R3C(=O)N(R4)-基、又はNH2(HN=)C-基で置換されていることがある5~12員の単環式又は二環式芳香族環基であり;
Aは、場合により、酸素原子、窒素原子、及びイオウ原子から選択されるヘテロ原子3つ以下を含むことがある5~6員の単環式芳香族環基であり、ここで、前記5~6員の単環式芳香族環基は、場合により、ハロゲン原子、C1-4アルキル基、ハロゲン原子で置換されたC1-4アルキル基、ヒドロキシ基、C1-4アルコキシ基、ハロゲン原子で置換されたC1-4アルコキシ基、C1-4アルキルチオ基、ニトロ基、アミノ基、モノ-又はジ-(C1-4アルキル)アミノ基、シアノ基、HO-C1-4アルキル基、C1-4アルコキシ-C1-4アルキル基、C1-4アルキルスルホニル基、アミノスルホニル基、アセチル基、R3N(R4)C(=O)-基、HO(O=)C-基、C1-4アルキル-O(O=)C-基、C1-4アルキルスルホニルアミノ基、C3-7シクロアルキル基、R3C(=O)N(R4)-基、及びNH2(HN=)C-基から選択される置換基3つ以下で置換されていることがあり;
Bは、ハロゲン原子で置換されたC1-6アルキレン基、C3-7シクロアルキレン基、C2-6アルケニレン基、C2-6アルキニレン基、-O-C1-5アルキレン基、C1-2アルキレン-O-C1-2アルキレン基、又はC1-6アルキレン基であって、場合により、オキソ基又はC1-3アルキル基で置換されていることがあり;
Wは、NH基、N-C1-4アルキル基、酸素原子、イオウ原子、N-OR5基、又は共有結合であり;
R2は、水素原子、C1-4アルキル基、OH基、又はC1-4アルコキシ基であり;
Zは、場合により、酸素原子、窒素原子、及びイオウ原子から選択されるヘテロ原子3つ以下を含むことがある5~12員の単環式又は二環式芳香族環基であり、ここで、前記5~12員の単環式又は二環式芳香族環基は、場合により、ハロゲン原子、C1-4アルキル基、ハロゲン原子で置換されたC1-4アルキル基、C1-4アルケニル基、C1-4アルキニル基、ヒドロキシ基、C1-4アルコキシ基、ハロゲン原子で置換されたC1-4アルコキシ基、C1-4アルキルチオ基、ニトロ基、アミノ基、モノ-又はジ-(C1-4アルキル)アミノ基、シアノ基、HO-C1-4アルキル基、C1-4アルコキシ-C1-4アルキル基、C1-4アルキルスルホニル基、アミノスルホニル基、C1-4アルキルC(=O)-基、R3C(=O)N(R4)-基、HO(O=)C-基、C1-4アルキル-O(O=)C-基、C1-4アルキルスルホニルアミノ基、C3-7シクロアルキル基、NH2(HN=)C-基、Q2-S(O)m-基、Q2-O-基、Q2-N(R3)-基、又はQ2-基で置換されていることがあり;
Lは、ハロゲン原子、C1-4アルキル基、ハロゲン原子で置換されたC1-4アルキル基、ヒドロキシ基、C1-4アルコキシ基、ハロゲン原子で置換されたC1-4アルコキシ基、C1-4アルキルチオ基、ニトロ基、アミノ基、モノ-又はジ-(C1-4アルキル)アミノ基、シアノ基、HO-C1-4アルキル基、C1-4アルコキシ-C1-4アルキル基、C1-4アルキルスルホニル基、アミノスルホニル基、C1-4アルキルC(=O)-基、HO(O=)C-基、C1-4アルキル-O(O=)C-基、C1-4アルキルスルホニルアミノ基、C3-7シクロアルキル基、R3C(=O)N(R4)-基、NH2(HN=)C-基、R3N(R4)C(=O)-基、R3N(R4)S(O)m-基、Q2-基、Q2-C(=O)-基、Q2-O-基、Q2-C1-4アルキル-O-基であるか、あるいは隣接するL基2つが、場合により一緒になって、環メンバー3又は4つを有し、前記環メンバーの内の炭素原子1つ又は(隣接していない)炭素原子2つが酸素原子で場合により置換されていることがあるアルキレン鎖を形成することがあり;
mは、0、1、又は2であり;
R3及びR4は、水素原子及びC1-4アルキル基から独立して選択され;
R5は、水素原子、C1-4アルキル基、C1-4アルキル-(O=)C-基、又はC1-4アルキル-O-(O=)C-基であり;そして
Q2は、5~12員の単環式もしくは二環式芳香族環基、又は5~12員の三環式環基であって、場合により、酸素原子、窒素原子、及びイオウ原子から選択されるヘテロ原子3つ以下を含むことがあり、ここで、前記5~12員の単環式又は二環式芳香族環基は、場合により、ハロゲン原子、C1-4アルキル基、ハロゲン原子で置換されたC1-4アルキル基、C1-4アルケニル基、C1-4アルキニル基、ヒドロキシ基、C1-4アルコキシ基、ハロゲン原子で置換されたC1-4アルコキシ基、C1-4アルキルチオ基、ニトロ基、アミノ基、モノ-又はジ-(C1-4アルキル)アミノ基、シアノ基、HO-C1-4アルキル基、C1-4アルコキシ-C1-4アルキル基、C1-4アルキルスルホニル基、アミノスルホニル基、C1-4アルキル-(O=)C-基、R3(R4)C(=O)N-基、HO(O=)C-基、C1-4アルキル-O(O=)C-基、C1-4アルキルスルホニルアミノ基、C3-7シクロアルキル基、C1-4アルキル-C(=O)NH-基、又はNH2(HN=)C-基で置換されていることがあり;
OH、及び/又はCO2Hを含む場合、OH及び-COOHは、それぞれ独立に薬学的に許容されるエステルであってもよい]、
環Bがアリール基又はヘテロアリール基を表し;
環Cが1,4-フェニレン基を表し;
R1及びR2が水素原子、ハロゲン原子、1から4個の炭素原子を有するアルキル基、1から4個の炭素原子を有するアルコキシ基、1から4個の炭素原子を有するハロアルキル基、1から4個の炭素原子を有するハロアルコキシ基、シアノ基又はアミノカルボニル基を独立して表し;
R3及びR4が水素原子、又は1から4個の炭素原子を有するアルキル基を独立して表すか、又はR3及びR4基が共に結合して2から6個の炭素原子を有するアルキレン鎖を形成し;
R5が-CO2H、CO2W、
R6が1から6個の炭素原子を有するアルキル基、3から7個の環原子を有するシクロアルキル基、アリール基又はヘテロアリール基を表し;
Xがメチレン基、酸素原子又は硫黄原子を表し;
前記アリール基が6から10個の炭素原子を有し;
前記へテロアリール基が硫黄原子、酸素原子及び窒素原子からなる群から選択される1から3個のヘテロ原子を含む5から10員環芳香族複素環基であり;
環Bの定義で言及される前記アリール基及び前記へテロアリール基が未置換であるか又は置換基αからなる群から選択される少なくとも1つの置換基により置換され;
環Cの定義で言及される前記1,4-フェニレン基が未置換であるか、又は置換基βからなる群から選択される少なくとも1つの置換基により置換され;
R6及びαの定義において言及される前記アリール基及び前記へテロアリール基が未置換であるか又は置換基βからなる群から選択される少なくとも1つの置換基により置換され;
前記置換基αがハロゲン原子、1から4個の炭素原子を有するアルキル基、1から4個の炭素原子を有するアルコキシ基、1から4個の炭素原子を有するハロアルキル基、1から4個の炭素原子を有するハロアルコキシ基、シアノ基、2から6個の炭素原子を有するアルキニル基、1から5個の炭素原子を有するアルカノイル基、3から7個の環原子を有するシクロアルキル基、ヘテロアリール基、アリール基、7から10個の炭素原子を有するアラルコキシ基、アリールカルボニル基、アミノカルボニル基、2から5個の炭素原子を有するアルケニル基、1から4個の炭素原子を有するアルキルチオ基、アミノスルフィニル基、アミノスルホニル基、水酸基、1から4個の炭素原子を有するヒドロキシアルキル基、ニトロ基、アミノ基、カルボキシ基、2から5個の炭素原子を有するアルコキシカルボニル基、1から4個の炭素原子を有するアルコキシアルキル基、1から4個の炭素原子を有するアルキルスルホニル基、1から4個の炭素原子を有するアルカノイルアミノ基、1から6個の炭素原子を有するアルカノイル(アルキル)アミノ基、アルカノイル部分とアルキル部分のいずれにも1から6個の炭素原子を有するアルカノイルアミノアルキル基、アルカノイル部分と各アルキル部分のいずれにも1から6個の炭素原子を有するアルカノイル(アルキル)アミノアルキル基、1から4個の炭素原子を有するアルキルスルホニルアミノ基、1から6個の炭素原子を有するモノ-又はジ-アルキルアミノカルボニル基、1から6個の炭素原子を有するモノ-又はジ-アルキルアミノスルフィニル基、1から6個の炭素原子を有するモノ-又はジ-アルキルアミノスルホニル基、1から4個の炭素原子を有するアミノアルキル基、1から6個の炭素原子を有するモノ-又はジ-アルキルアミノ基、各アルキル部分に1から6個の炭素原子を有するモノ-又はジ-アルキルアミノアルキル基、7から10個の炭素原子を有するアラルキル基、アルキル部分に1から4個の炭素原子を有するヘテロアリールアルキル基、アルコキシ部分に1から4個の炭素原子を有するヘテロアリールアルコキシ基及び1から4個の炭素原子を有するアルキルスルホニルアミノ基からなる群から選択され、又は、2個の隣接するα基が共に結合して3又は4個の炭素原子を有するアルキレン又はアルケニレン鎖を形成してもよく;
前記置換基βがハロゲン原子、1から4個の炭素原子を有するアルキル基、1から4個の炭素原子を有するアルコキシ基、1から4個の炭素原子を有するハロアルキル基、1から4個の炭素原子を有するハロアルコキシ基及びシアノ基からなる群から選択され;
Wが薬学的に許容できるエステルプロドラッグ基である]、
Yは-NR4、酸素原子又は硫黄原子を表し;
R4は水素原子又は1~3個の炭素原子を有するアルキル基を表し;
Zは水素原子又はハロゲン原子を表し;
R1は、1~6個の炭素原子を有するアルコキシ基もしくは3~7個の炭素原子を有するシクロアルキル基で場合により置換された、1~6個の炭素原子を有するアルキル基;1~3個の炭素原子を有するアルキル基で場合により置換された、3~7個の炭素原子を有するシクロアルキル基;1つもしくはそれ以上の置換基αで場合により置換されたフェニル基;又は1つもしくはそれ以上の置換基αで場合により置換された基Het1を表し;
Het1は、1~4個の環窒素ヘテロ原子又は0~2個の窒素環ヘテロ原子及び1個の酸素環ヘテロ原子又は1個の硫黄環ヘテロ原子のいずれかを含有する4~7個の環原子を有する複素環式基を表し;
R2及びR3は独立して、水素原子もしくは1~3個の炭素原子を有するアルキル基を表すか;又はR2基及びR3基は、3~6個の炭素原子を有するアルキレン鎖を共に形成し;
そして該置換基αは、ハロゲン原子、1~4個の炭素原子を有するアルキル基、1~4個の炭素原子を有するハロアルキル基、ヒドロキシ基、1~4個の炭素原子を有するアルコキシ基、1~4個の炭素原子を有するハロアルコキシ基、シアノ基、1~4個の炭素原子を有するヒドロキシアルキル基、アルコキシ基及びアルキル基中に1~4個の炭素原子を有するアルコキシアルキル基、1~4個の炭素原子を有するアルキルスルホニル基、2~5個の炭素原子を有するアルカノイル基、2~4個の炭素原子を有するアルケニル基、2~4個の炭素原子を有するアルキニル基、1~4個の炭素原子を有するアルキルチオ基、ニトロ基、アミノ基、1~4個の炭素原子を有するモノ-又はジ-アルキルアミノ基、アミノスルホニル基、1~4個の炭素原子を有するアルコキシカルボニル基、1~4個の炭素原子を有するアルキルスルホニルアミノ基、3~7個の炭素原子を有するシクロアルキル基及び1~6個の炭素原子を有するモノ-又はジ-アルキルアミノカルボニル基からなる群より選択され;
OHを含む場合、薬学的に許容されるエステルであってもよいし、CO2Hも独立に薬学的に許容されるエステルであってもよい]、
Yは、NR4、酸素原子又はイオウ原子を表し、
R4は、水素原子又は1~3個の炭素原子を有するアルキル基を表し、
Zは、水素原子又はハロゲン原子を表し、
R1は、1~6個の炭素原子を有するアルコキシ基、トリフルオロメチル基、2~5個の炭素原子を有するアルカノイル基、3~7個の炭素原子を有するシクロアルキル基、フェニル基、フェノキシ基、複素環基及びヘテロアリール基から独立して選択される1~2個の基で置換されていてもよい1~6個の炭素原子を有するアルキル基;1~3個の炭素原子を有するアルキル基で置換されていてもよい3~7個の炭素原子を有するシクロアルキル基;又は複素環基を表し、
R2及びR3は、水素原子又は1~3個の炭素原子を有するアルキル基を独立して表すか、あるいはR2及びR3基は一緒に、3~6個の炭素原子を有するアルキレン鎖を形成し、
前記ヘテロアリール基は、1~4個の環窒素ヘテロ原子又は0~2個の窒素環ヘテロ原子及び1個の酸素もしくは1個のイオウ環ヘテロ原子を有する4~7員芳香族環系であり、
前記複素環基は、1~4個の環窒素ヘテロ原子又は0~2個の窒素環ヘテロ原子及び1個の酸素もしくは1個のイオウ環ヘテロ原子を有する4~7員飽和環系であり、
R1の定義において言及される前記フェニル基、フェノキシ基及び前記ヘテロアリール基は、非置換であるか、あるいは置換基αからなる群から選択される少なくとも1個の置換基によって置換されており、
前記置換基αは、ハロゲン原子、1~4個の炭素原子を有するアルキル基、1~4個の炭素原子を有するハロアルキル基、ヒドロキシ基、1~4個の炭素原子を有するアルコキシ基、1~4個の炭素原子を有するハロアルコキシ基、シアノ基、1~4個の炭素原子を有するヒドロキシアルキル基、アルコキシ及びアルキル基に1~4個の炭素原子を有するアルコキシアルキル基、1~4個の炭素原子を有するアルキルスルホニル基、2~5個の炭素原子を有するアルカノイル基、2~4個の炭素原子を有するアルケニル基、2~4個の炭素原子を有するアルキニル基、1~4個の炭素原子を有するアルキルチオ基、ニトロ基、アミノ基、1~4個の炭素原子を有するモノ又はジアルキルアミノ基、アミノスルホニル基、1~4個の炭素原子を有するアルコキシカルボニル基、1~4個の炭素原子を有するアルキルスルホニルアミノ基、3~7個の炭素原子を有するシクロアルキル基及び1~6個の炭素原子を有するモノ又はジアルキルアミノカルボニル基からなる群から選択され;
OHを含む場合、該OHは薬学的に許容されるエステルであってもよいし、CO2Hを含む場合、該COOHも独立に薬学的に許容されるエステルであってもよい]。 - 一般式(I)で表わされる化合物が、
3-[2-(4-{2-エチル-5,7-ジメチル-3H-イミダゾ[4,5-b]ピリジン-3-イル}フェニル)エチル]-1-[(4-メチルベンゼン)スルホニル]尿素;
1-(4-{2-エチル-4,6-ジメチル-1H-イミダゾ[4,5-c]ピリジン-1-イル}フェニル)プロパン-2-イル N-[(4-メチルベンゼン)スルホニル]カルバメート;
3-[2-(4-{2-エチル-4,6-ジメチル-1H-イミダゾ[4,5-c]ピリジン-1-イル}フェニル)エチル]-1-[(4-メチルベンゼン)スルホニル]尿素;
1-{2-[4-(5-アセチル-2-エチル-1H-1,3-ベンゾジアゾール-1-イル)フェニル]エチル}-3-[(4-メチルベンゼン)スルホニル]尿素;
3-{2-[4-(2-エチル-5-メトキシ-1H-1,3-ベンゾジアゾール-1-イル)フェニル]エチル}-1-[(4-メチルベンゼン)スルホニル]尿素;
2-{4-[6-クロロ-2-エチル-5-(トリフルオロメチル)-1H-1,3-ベンゾジアゾール-1-イル]フェニル}エチル N-[(4-メチルベンゼン)スルホニル]カルバメート;
3-{2-[4-(6-クロロ-5-シアノ-2-エチル-1H-1,3-ベンゾジアゾール-1-イル)フェニル]エチル}-1-[(4-メチルベンゼン)スルホニル]尿素;
2-(4-{2-エチル-4,6-ジメチル-1H-イミダゾ[4,5-c]ピリジン-1-イル}フェニル)エチル N-[(4-メチルベンゼン)スルホニル]カルバメート;
2-(4-{2-ブチル-4,6-ジメチル-1H-イミダゾ[4,5-c]ピリジン-1-イル}フェニル)エチル N-[(4-メチルベンゼン)スルホニル]カルバメート;
2-(4-{2-ターシャリ(tert)-ブチル-4,6-ジメチル-1H-イミダゾ[4,5-c]ピリジン-1-イル}フェニル)エチル N-[(4-メチルベンゼン)スルホニル]カルバメート;
2-(4-{2-アミノ-5,7-ジメチル-3H-イミダゾ[4,5-b]ピリジン-3-イル}フェニル)エチル N-[(4-メチルベンゼン)スルホニル]カルバメート;
3-{2-[4-(6-クロロ-2-エチル-5-メタンスルホニル-1H-1,3-ベンゾジアゾール-1-イル)フェニル]エチル}-1-[(4-メチルベンゼン)スルホニル]尿素;
2-[4-(5-カルバモイル-6-クロロ-2-エチル-1H-1,3-ベンゾジアゾール-1-イル)フェニル]エチル N-[(4-メチルベンゼン)スルホニル]カルバメート;
1-(2-{4-[2-エチル-5-(1-ヒドロキシエチル)-1H-1,3-ベンゾジアゾール-1-イル]フェニル}エチル)-3-[(4-メチルベンゼン)スルホニル]尿素;
1-(2-{4-[2-エチル-5-(2-ヒドロキシプロパン-2-イル)-1H-1,3-ベンゾジアゾール-1-イル]フェニル}エチル)-3-[(4-メチルベンゼン)スルホニル]尿素;
1-(2-{4-[6-クロロ-2-(2-ヒドロキシプロパン-2-イル)-5-(トリフルオロメチル)-1H-1,3-ベンゾジアゾール-1-イル]フェニル}エチル)-3-[(4-メチルベンゼン)スルホニル]尿素;
N-[1-(6-クロロ-1-{4-[2-({[(4-メチルベンゼン)スルホニル]カルバモイル}アミノ)エチル]フェニル}-5-(トリフルオロメチル)-1H-1,3-ベンゾジアゾール-2-イル)エチル]アセトアミド;
6-クロロ-2-エチル-1-(4-{2-[メチル({[(4-メチルベンゼン)スルホニル]カルバモイル})アミノ]エチル}フェニル)-1H-1,3-ベンゾジアゾール-5-カルボキシアミド;
2-{4-[6-クロロ-2-(ピリジン-2-イル)-5-(トリフルオロメチル)-1H-1,3-ベンゾジアゾール-1-イル]フェニル}エチル N-[(4-メチルベンゼン)スルホニル]カルバメート;
3-(2-{5-[6-クロロ-2-エチル-5-(トリフルオロメチル)-1H-1,3-ベンゾジアゾール-1-イル]ピリジン-2-イル}エチル)-1-[(4-メチルベンゼン)スルホニル]尿素;
2-{4-[6-クロロ-2-エチル-5-(トリフルオロメチル)-1H-1,3-ベンゾジアゾール-1-イル]フェニル}エチル N-[(2-クロロベンゼン)スルホニル]カルバメート;又は
3-(2-{4-[5,7-ジメチル-2-(メチルアミノ)-3H-イミダゾ[4,5-b]ピリジン-3-イル]フェニル}エチル)-1-[(4-メチルベンゼン)スルホニル]尿素であり;
一般式(II)で表わされる化合物が、
4-((1S)-1-{[5-クロロ-2-(4-フルオロフェノキシ)ベンゾイル]アミノ}エチル)安息香酸;
4-[(1S)-1-({[5-クロロ-2-(4-フルオロフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-[(1S)-1({[5-クロロ-2-(3-シアノフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-[(1S)-1-({[5-クロロ-2-(3-フルオロフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-[(1S)-1-({[5-クロロ-2-(3-クロロフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-((1S)-1-{[5-クロロ-2-(3-フルオロフェノキシ)ベンゾイル]アミノ}エチル)安息香酸;
4-((1S)-1-{[5-クロロ-2-(3-クロロフェノキシ)ベンゾイル]アミノ}エチル)安息香酸;
4-[(1S)-1-({[5-クロロ-2-(2-クロロ-4-フルオロフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-[(1S)-1-({[5-クロロ-2-(2,6-ジフルオロフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-[(1S)-1-({[5-クロロ-2-(3,4-ジフルオロフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-[(1S)-1-({[5-クロロ-2-(2,3-ジフルオロフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-[(1S)-1-({[5-クロロ-2-(2,5-ジフルオロフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-[(1S)-1-({[5-クロロ-2-(2-クロロ-5-フルオロフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-[(1S)-1-({[5-クロロ-2-(3-メチルフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-[(1S)-1-({[5-クロロ-2-(3,5-ジフルオロフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-((1S)-1-{[5-クロロ-2-(2,3-ジフルオロフェノキシ)ベンゾイル]アミノ}エチル)安息香酸;
4-((1S)-1-{[5-クロロ-2-(3,4-ジフルオロフェノキシ)ベンゾイル]アミノ}エチル)安息香酸;
4-[(1S)-1-({[5-クロロ-2-(3-クロロ-5-フルオロフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-((1S)-1-{[5-クロロ-2-(3,5-ジフルオロフェノキシ)ベンゾイル]アミノ}エチル)安息香酸;
4-((1S)-1-{[5-クロロ-2-(2,5-ジフルオロフェノキシ)ベンゾイル]アミノ}エチル)安息香酸;
4-[(1S)-1-({[5-クロロ-2-(3-クロロ-5-メチルフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-((1S)-1-{[5-クロロ-2-(3-メチルフェノキシ)ベンゾイル]アミノ}エチル)安息香酸;
((1S)-1-{[5-クロロ-2-(3-クロロ-5-フルオロフェノキシ)ベンゾイル]アミノ}エチル)安息香酸;
4-((1S)-1-{[5-クロロ-2-(2,6-ジフルオロフェノキシ)ベンゾイル]アミノ}エチル)安息香酸;
4-((1S)-1-{[(5-クロロ-2-フェノキシピリジン-3-イル)カルボニル]アミノ}エチル)安息香酸;
4-[(1S)-1-({[5-クロロ-2-(2,3-ジクロロフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-[(1S)-1-({[5-クロロ-2-(3,4-ジクロロフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-[(1S)-1-({[5-クロロ-2-(3,5-ジクロロフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;又は
4-[(1S)-1-({[5-クロロ-2-(3-フルオロ-4-メチルフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸であり;
一般式(III)で表わされる化合物が、
4-[(1S)-1-({5-クロロ-2-[(4-クロロフェノキシ)メチル]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(4-メチルフェノキシ)メチル]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(3-クロロフェノキシ)メチル]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(4-フルオロフェノキシ)メチル]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(2,3-ジフルオロフェノキシ)メチル]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(3,4-ジフルオロフェノキシ)メチル]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(2,4-ジフルオロフェノキシ)メチル]ベンゾイル}アミノ)エチル]安息香酸;
4-{(1S)-1-[({5-クロロ-2-[(3-クロロフェノキシ)メチル]ピリジン-3-イル}カルボニル)アミノ]エチル}安息香酸;
4-[(1S)-1-({5-クロロ-2-[(2-クロロフェノキシ)メチル]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(3,5-ジフルオロフェノキシ)メチル]ベンゾイル}アミノ)エチル]安息香酸;
4-{(1S)-1-[({5-クロロ-2-[(4-クロロフェノキシ)メチル]ピリジン-3-イル}カルボニル)アミノ]エチル}安息香酸;
4-[(1S)-1-({5-クロロ-2-[(3-フルオロフェノキシ)メチル]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(2,6-ジフルオロフェノキシ)メチル]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(2-フルオロフェノキシ)メチル]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(2,5-ジフルオロフェノキシ)メチル]ベンゾイル}アミノ)エチル]安息香酸;
4-{(1S)-1-[({2-[(4-クロロフェノキシ)メチル]-5-フルオロピリジン-3-イル}カルボニル)アミノ]エチル}安息香酸;又は
4-{(1S)-1-({5-クロロ-2-[(シクロヘキシルメトキシ)メチル]ベンゾイル}アミノ)エチル}安息香酸であり;
一般式(IV)で表わされる化合物が、
4-[(1S)-1-({5-クロロ-2-[(2-クロロベンジル)オキシ]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[2-(2-メチルフェニル)エトキシ]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[2-(4-メチルフェニル)エトキシ]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(3-クロロベンジル)オキシ]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(4-クロロベンジル)オキシ]ベンゾイル}アミノ)エチル]安息香酸;
4-((1S)-1-{[5-クロロ-2-(シクロブチルメトキシ)ベンゾイル]アミノ}エチル)安息香酸;
4-((1S)-1-{[5-クロロ-2-(シクロヘキシルオキシ)ベンゾイル]アミノ}エチル)安息香酸;
4-[(1S)-1-({5-クロロ-2-[(2-シアノベンジル)オキシ]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[2-(4-フルオロフェニル)エトキシ]ベンゾイル}アミノ)エチル]安息香酸;
4-((1S)-1-{[5-クロロ-2-(3-メチルブトキシ)ベンゾイル]アミノ}エチル)安息香酸;
4-[(1S)-1-({5-クロロ-2-[(4-フルオロベンジル)オキシ]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[2-(2-フルオロフェニル)エトキシ]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(2,5-ジフルオロベンジル)オキシ]ベンゾイル}アミノ)エチル]安息香酸;
4-[({5-クロロ-2-[2-(2-メチルフェニル)エトキシ]ベンゾイル}アミノ)メチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(2-クロロ-4-フルオロベンジル)オキシ]ベンゾイル}アミノ)エチル]安息香酸;
4-((1S)-1-{[5-クロロ-2-(2-フェノキシエトキシ)ベンゾイル]アミノ}エチル)安息香酸;
4-[(1S)-1-({5-クロロ-2-[(3,4-ジフルオロベンジル)オキシ]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(4-クロロ-2-フルオロベンジル)オキシ]ベンゾイル}アミノ)エチル]安息香酸;
4-{(1S)-1-[({5-クロロ-2-[(4-クロロベンジル)オキシ]ピリジン-3-イル}カルボニル)アミノ]エチル}安息香酸;
4-((1S)-1-{[2-(ベンジルオキシ)-5-クロロベンゾイル]アミノ}エチル)安息香酸;
4-{(1S)-1-[({5-クロロ-2-[(2-クロロベンジル)オキシ]ピリジン-3-イル}カルボニル)アミノ]エチル}安息香酸;
4-{(1S)-1-[({5-クロロ-2-[2-(4-クロロフェニル)エトキシ]ピリジン-3-イル}カルボニル)アミノ]エチル}安息香酸;
4-[(1S)-1-({5-クロロ-2-[(3,5-ジフルオロベンジル)オキシ]ベンゾイル}アミノ)エチル]安息香酸;又は
4-[(1S)-1-({5-クロロ-2-[2-(2,6-ジフルオロフェニル)エトキシ]ベンゾイル}アミノ)エチル]安息香酸;
である請求項1に記載の使用。 - 一般式(I)で表わされる化合物が、3-[2-(4-{2-エチル-5,7-ジメチル-3H-イミダゾ[4,5-b]ピリジン-3-イル}フェニル)エチル]-1-[(4-メチルベンゼン)スルホニル]尿素;
3-[2-(4-{2-エチル-4,6-ジメチル-1H-イミダゾ[4,5-c]ピリジン-1-イル}フェニル)エチル]-1-[(4-メチルベンゼン)スルホニル]尿素;
1-{2-[4-(5-アセチル-2-エチル-1H-1,3-ベンゾジアゾール-1-イル)フェニル]エチル}-3-[(4-メチルベンゼン)スルホニル]尿素;
3-{2-[4-(2-エチル-5-メトキシ-1H-1,3-ベンゾジアゾール-1-イル)フェニル]エチル}-1-[(4-メチルベンゼン)スルホニル]尿素;
2-{4-[6-クロロ-2-エチル-5-(トリフルオロメチル)-1H-1,3-ベンゾジアゾール-1-イル]フェニル}エチル N-[(4-メチルベンゼン)スルホニル]カルバメート;
3-{2-[4-(6-クロロ-5-シアノ-2-エチル-1H-1,3-ベンゾジアゾール-1-イル)フェニル]エチル}-1-[(4-メチルベンゼン)スルホニル]尿素;
2-(4-{2-エチル-4,6-ジメチル-1H-イミダゾ[4,5-c]ピリジン-1-イル}フェニル)エチル N-[(4-メチルベンゼン)スルホニル]カルバメート;
2-(4-{2-tert-ブチル-4,6-ジメチル-1H-イミダゾ[4,5-c]ピリジン-1-イル}フェニル)エチル N-[(4-メチルベンゼン)スルホニル]カルバメート;
2-[4-(5-カルバモイル-6-クロロ-2-エチル-1H-1,3-ベンゾジアゾール-1-イル)フェニル]エチル N-[(4-メチルベンゼン)スルホニル]カルバメート;
1-(2-{4-[2-エチル-5-(1-ヒドロキシエチル)-1H-1,3-ベンゾジアゾール-1-イル]フェニル}エチル)-3-[(4-メチルベンゼン)スルホニル]尿素;
1-(2-{4-[6-クロロ-2-(2-ヒドロキシプロパン-2-イル)-5-(トリフルオロメチル)-1H-1,3-ベンゾジアゾール-1-イル]フェニル}エチル)-3-[(4-メチルベンゼン)スルホニル]尿素;
2-{4-[6-クロロ-2-(ピリジン-2-イル)-5-(トリフルオロメチル)-1H-1,3-ベンゾジアゾール-1-イル]フェニル}エチル N-[(4-メチルベンゼン)スルホニル]カルバメート;
3-(2-{5-[6-クロロ-2-エチル-5-(トリフルオロメチル)-1H-1,3-ベンゾジアゾール-1-イル]ピリジン-2-イル}エチル)-1-[(4-メチルベンゼン)スルホニル]尿素;
2-{4-[6-クロロ-2-エチル-5-(トリフルオロメチル)-1H-1,3-ベンゾジアゾール-1-イル]フェニル}エチル N-[(2-クロロベンゼン)スルホニル]カルバメート;又は
3-(2-{4-[5,7-ジメチル-2-(メチルアミノ)-3H-イミダゾ[4,5-b]ピリジン-3-イル]フェニル}エチル)-1-[(4-メチルベンゼン)スルホニル]尿素であり;
一般式(II)で表わされる化合物が、4-((1S)-1-{[5-クロロ-2-(4-フルオロフェノキシ)ベンゾイル]アミノ}エチル)安息香酸;
4-[(1S)-1-({[5-クロロ-2-(4-フルオロフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-[(1S)-1({[5-クロロ-2-(3-シアノフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-[(1S)-1-({[5-クロロ-2-(3-フルオロフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-[(1S)-1-({[5-クロロ-2-(3-クロロフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-((1S)-1-{[5-クロロ-2-(3-フルオロフェノキシ)ベンゾイル]アミノ}エチル)安息香酸;
4-((1S)-1-{[5-クロロ-2-(3-クロロフェノキシ)ベンゾイル]アミノ}エチル)安息香酸;
4-[(1S)-1-({[5-クロロ-2-(2-クロロ-4-フルオロフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-[(1S)-1-({[5-クロロ-2-(3,4-ジフルオロフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-[(1S)-1-({[5-クロロ-2-(2,3-ジフルオロフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸;
4-((1S)-1-{[5-クロロ-2-(2,3-ジフルオロフェノキシ)ベンゾイル]アミノ}エチル)安息香酸;
4-((1S)-1-{[5-クロロ-2-(3,4-ジフルオロフェノキシ)ベンゾイル]アミノ}エチル)安息香酸;又は
4-[(1S)-1-({[5-クロロ-2-(3-クロロ-5-フルオロフェノキシ)ピリジン-3-イル]カルボニル}アミノ)エチル]安息香酸であり;
一般式(III)で表わされる化合物が、
4-[(1S)-1-({5-クロロ-2-[(4-クロロフェノキシ)メチル]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(3-クロロフェノキシ)メチル]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(4-フルオロフェノキシ)メチル]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(3,4-ジフルオロフェノキシ)メチル]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(2,4-ジフルオロフェノキシ)メチル]ベンゾイル}アミノ)エチル]安息香酸;
4-{(1S)-1-[({5-クロロ-2-[(3-クロロフェノキシ)メチル]ピリジン-3-イル}カルボニル)アミノ]エチル}安息香酸;
4-[(1S)-1-({5-クロロ-2-[(3,5-ジフルオロフェノキシ)メチル]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(3-フルオロフェノキシ)メチル]ベンゾイル}アミノ)エチル]安息香酸;
4-{(1S)-1-[({2-[(4-クロロフェノキシ)メチル]-5-フルオロピリジン-3-イル}カルボニル)アミノ]エチル}安息香酸;又は
4-{(1S)-1-({5-クロロ-2-[(シクロヘキシルメトキシ)メチル]ベンゾイル}アミノ)エチル}安息香酸であり;
一般式(IV)で表わされる化合物が、4-[(1S)-1-({5-クロロ-2-[(2-クロロベンジル)オキシ]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(3-クロロベンジル)オキシ]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(4-クロロベンジル)オキシ]ベンゾイル}アミノ)エチル]安息香酸;
4-((1S)-1-{[5-クロロ-2-(シクロブチルメトキシ)ベンゾイル]アミノ}エチル)安息香酸;
4-((1S)-1-{[5-クロロ-2-(シクロヘキシルオキシ)ベンゾイル]アミノ}エチル)安息香酸;
4-[(1S)-1-({5-クロロ-2-[(2-シアノベンジル)オキシ]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[2-(4-フルオロフェニル)エトキシ]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(4-フルオロベンジル)オキシ]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[2-(2-フルオロフェニル)エトキシ]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(2-クロロ-4-フルオロベンジル)オキシ]ベンゾイル}アミノ)エチル]安息香酸;
4-[(1S)-1-({5-クロロ-2-[(4-クロロ-2-フルオロベンジル)オキシ]ベンゾイル}アミノ)エチル]安息香酸;
4-{(1S)-1-[({5-クロロ-2-[(4-クロロベンジル)オキシ]ピリジン-3-イル}カルボニル)アミノ]エチル}安息香酸;
4-{(1S)-1-[({5-クロロ-2-[(2-クロロベンジル)オキシ]ピリジン-3-イル}カルボニル)アミノ]エチル}安息香酸;
4-{(1S)-1-[({5-クロロ-2-[2-(4-クロロフェニル)エトキシ]ピリジン-3-イル}カルボニル)アミノ]エチル}安息香酸;
4-[(1S)-1-({5-クロロ-2-[(3,5-ジフルオロベンジル)オキシ]ベンゾイル}アミノ)エチル]安息香酸;又は
4-[(1S)-1-({5-クロロ-2-[2-(2,6-ジフルオロフェニル)エトキシ]ベンゾイル}アミノ)エチル]安息香酸;
である請求項1に記載の使用。 - 癌の種類が、消化器癌、前立腺癌、肺癌、及び乳癌からなる群より少なくとも1つ選択される癌である、請求項1から請求項3のいずれかに記載の使用。
- 癌の種類がPGE2が関与する癌である請求項1から請求項3のいずれかに記載の使用。
- 1種類以上の第二の活性薬剤と組み合わせた、請求項1から請求項3のいずれかに記載した化合物、又はその薬学的に許容される塩の使用。
- 第二の活性薬剤が、ステロイド性又は非ステロイド性の抗アンドロゲン剤又は抗エストロゲン剤、化学療法剤、ペプチド性GnRH拮抗薬、α-レダクターゼ阻害薬、α-受容体阻害薬、アロマターゼ阻害薬、17β-ヒドロキシステロイド脱水素酵素阻害薬、副腎系アンドロゲン産生阻害薬、りん酸化酵素阻害薬、ホルモン療法剤、細胞増殖因子又はその受容体の作用を阻害する薬剤のいずれかであってよい、請求項6に記載の使用。
- 請求項1から請求項3のいずれかに記載した化合物、又はその薬学的に許容される塩の有効量をヒト又は動物に投与することを含む、癌を治療するための方法。
- 癌の治療に用いる、請求項1から請求項3のいずれかに記載した化合物、又はその薬学的に許容される塩を含む医薬組成物。
- 癌の種類が、消化器癌、前立腺癌、肺癌、及び乳癌からなる群より少なくとも1つ選択される癌である、請求項9に記載の医薬組成物。
- 癌の種類がPGE2が関与する癌である、請求項9に記載の医薬組成物。
- 請求項1から請求項3のいずれかに記載した化合物、又はその薬学的に許容される塩を含む癌の治療に使用されるキット。
- 請求項1から請求項3のいずれかに記載した化合物、又はその薬学的に許容される塩と1種類以上の第二の活性薬剤と容器を含む請求項12に記載したキット。
- 請求項1から請求項3に記載した化合物、又はその薬学的に許容される塩を含む医薬組成物、並びに当該医薬組成物に関する記載物であって、癌を治療するために使用され得る又は使用されるべき旨が記された記載物を含む製品。
- 請求項1に記載されている一般式(I)、(II)、(III)、又は(IV)で表わされる化合物、又はその薬学的に許容される塩と、癌細胞とを接触させることを特徴とする、癌細胞を縮小させる方法。
Priority Applications (17)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
MX2016008394A MX369117B (es) | 2009-04-22 | 2010-04-22 | Antagonistas del receptor ep4 para el tratamiento de cancer. |
EP10767106.7A EP2422779B1 (en) | 2009-04-22 | 2010-04-22 | Selective ep4 receptor antagonistic substance for treatment of cancer |
MX2011011058A MX345032B (es) | 2009-04-22 | 2010-04-22 | Antagonistas del receptor ep4 para el tratamiento de cáncer. |
US13/265,216 US8921391B2 (en) | 2009-04-22 | 2010-04-22 | Selective EP4 receptor antagonistic substance for treatment of cancer |
RU2011147194/15A RU2563817C2 (ru) | 2009-04-22 | 2010-04-22 | Селективные антагонисты рецептора ep4 для лечения рака |
EP15182580.9A EP2965756B1 (en) | 2009-04-22 | 2010-04-22 | Selective ep4 receptor antagonistic substance for treatment of cancer |
EP18191714.7A EP3431085B1 (en) | 2009-04-22 | 2010-04-22 | Selective ep4 receptor antagonistic substance for treatment of cancer |
ES10767106.7T ES2562814T3 (es) | 2009-04-22 | 2010-04-22 | Sustancia antagonista selectiva del receptor EP4 para el tratamiento del cáncer |
CN201080017743.XA CN102421429B (zh) | 2009-04-22 | 2010-04-22 | 癌症治疗用选择性ep4受体拮抗物质 |
BRPI1014174A BRPI1014174B8 (pt) | 2009-04-22 | 2010-04-22 | uso de um composto selecionado a partir de 4-((1s)-1-{[5-cloro-2-(4-fluorofenóxi)benzoil]amino}etil)ácido benzóico, 4-[(1s)-1-({[5-cloro-2-(3-fluorofenóxi)piridin-3-il]carbonil}amino)etil]ácido benzóico e 3-[2-(4-{2-etil-4,6-dimetil-1h-imidazo[4,5-c]piridin-1-il}fenil)etil]-1-[(4-metilbenzeno)sulfonil]urea para tratamento de um câncer epitelial relacionado à pge2 |
CA2754702A CA2754702C (en) | 2009-04-22 | 2010-04-22 | Selective ep4 antagonistic substance for treatment of cancer |
JP2011510353A JP5668219B2 (ja) | 2009-04-22 | 2010-04-22 | 癌治療のための選択的ep4受容体拮抗物質 |
HK12107420.1A HK1166700A1 (zh) | 2009-04-22 | 2012-07-30 | 用於癌症治療的選擇性 受體拮抗性物質 |
US14/547,247 US9688674B2 (en) | 2009-04-22 | 2014-11-19 | Selective EP4 receptor antagonistic substance for treatment of cancer |
US15/602,686 US10611761B2 (en) | 2009-04-22 | 2017-05-23 | Selective EP4 receptor antagonistic substance for treatment of cancer |
US16/803,163 US10947235B2 (en) | 2009-04-22 | 2020-02-27 | Selective EP4 receptor antagonistic substance for treatment of cancer |
US17/201,102 US11840530B2 (en) | 2009-04-22 | 2021-03-15 | Selective EP4 receptor antagonistic substance for treatment of cancer |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2009-104568 | 2009-04-22 | ||
JP2009104568 | 2009-04-22 | ||
JP2010-015445 | 2010-01-27 | ||
JP2010015445 | 2010-01-27 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US13/265,216 A-371-Of-International US8921391B2 (en) | 2009-04-22 | 2010-04-22 | Selective EP4 receptor antagonistic substance for treatment of cancer |
US14/547,247 Continuation US9688674B2 (en) | 2009-04-22 | 2014-11-19 | Selective EP4 receptor antagonistic substance for treatment of cancer |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2010123049A1 true WO2010123049A1 (ja) | 2010-10-28 |
Family
ID=43011165
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2010/057114 WO2010123049A1 (ja) | 2009-04-22 | 2010-04-22 | 癌治療のための選択的ep4受容体拮抗物質 |
Country Status (12)
Country | Link |
---|---|
US (5) | US8921391B2 (ja) |
EP (3) | EP3431085B1 (ja) |
JP (1) | JP5668219B2 (ja) |
KR (1) | KR101575706B1 (ja) |
CN (2) | CN105596320B (ja) |
BR (1) | BRPI1014174B8 (ja) |
CA (1) | CA2754702C (ja) |
ES (3) | ES2562814T3 (ja) |
HK (2) | HK1214763A1 (ja) |
MX (2) | MX369117B (ja) |
RU (1) | RU2563817C2 (ja) |
WO (1) | WO2010123049A1 (ja) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2017516775A (ja) * | 2014-05-23 | 2017-06-22 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | がんの処置のための併用治療 |
JP2018535939A (ja) * | 2016-11-04 | 2018-12-06 | 株式会社AskAt | Nash関連肝臓癌を治療するためのep4受容体拮抗薬の使用 |
JP2022500485A (ja) * | 2018-09-27 | 2022-01-04 | アリーズ セラピューティクス, インコーポレイテッド | グラピプラント単位剤形 |
US11471455B2 (en) | 2018-10-05 | 2022-10-18 | Annapurna Bio, Inc. | Compounds and compositions for treating conditions associated with APJ receptor activity |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8921391B2 (en) * | 2009-04-22 | 2014-12-30 | Raqualia Pharma Inc. | Selective EP4 receptor antagonistic substance for treatment of cancer |
CN107383004B (zh) * | 2017-07-05 | 2020-04-17 | 浙江大学 | 2-氨基咪唑并吡啶类衍生物及制备和应用 |
CN112292128A (zh) * | 2018-04-16 | 2021-01-29 | 阿瑞斯医疗有限公司 | Ep4抑制剂和其用途 |
CN113301896A (zh) * | 2018-07-11 | 2021-08-24 | 阿瑞斯医疗有限公司 | Ep4抑制剂和其合成 |
WO2020251957A1 (en) * | 2019-06-11 | 2020-12-17 | Teon Therapeutics, Inc. | Prostaglandin e2 receptor 4 antagonists and uses thereof |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001062708A1 (fr) * | 2000-02-22 | 2001-08-30 | Ono Pharmaceutical Co., Ltd. | Derives d'acide benzoique, procede de production desdits derives, et medicament contenant ces derives comme principe actif |
WO2002032900A2 (en) | 2000-10-19 | 2002-04-25 | Pfizer Pharmaceuticals Inc. | Aryl or heteroaryl fused imidazole compounds as anti-inflammatory and analgesic agents |
WO2005021508A1 (en) | 2003-09-03 | 2005-03-10 | Pfizer Inc. | Phenyl or pyridyl amide compounds as prostaglandin e2 antagonists |
WO2005105733A1 (en) | 2004-05-04 | 2005-11-10 | Pfizer Japan Inc. | Ortho substituted aryl or heteroaryl amide compounds |
WO2005105732A1 (en) | 2004-05-04 | 2005-11-10 | Pfizer Japan Inc. | Substituted methyl aryl or heteroaryl amide compounds |
JP2008540584A (ja) * | 2005-05-19 | 2008-11-20 | メルク フロスト カナダ リミテツド | Ep4アンタゴニストとしてのキノリン誘導体 |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1304318A (zh) * | 1999-03-16 | 2001-07-18 | 东丽株式会社 | 前列腺素ep4受体作用药和治疗方法 |
ES2225199T3 (es) | 1999-08-10 | 2005-03-16 | Glaxo Group Limited | Uso de ligandos del receptor ep4 en el tratamiento del dolor neuropatico. |
US6710205B2 (en) | 2000-02-22 | 2004-03-23 | Ono Pharmaceutical Co., Ltd. | Benzoic acid derivatives, processes for producing the same and drugs containing the same as the active ingredient |
BR0309305A (pt) * | 2002-04-12 | 2005-02-15 | Pfizer | Compostos de imidazol como agentes antiinflamatórios e analgésicos |
EP1494669A1 (en) | 2002-04-16 | 2005-01-12 | Fujisawa Pharmaceutical Co., Ltd. | Medicament for preventing and/or treating chronic rejection |
BRPI0509993A (pt) * | 2004-04-20 | 2007-10-16 | Pfizer Prod Inc | combinações compreendendo ligandos de alfa-2-delta |
WO2006095268A1 (en) | 2005-03-11 | 2006-09-14 | Pfizer Japan Inc. | Crystal forms of an imidazole derivative |
US8921391B2 (en) | 2009-04-22 | 2014-12-30 | Raqualia Pharma Inc. | Selective EP4 receptor antagonistic substance for treatment of cancer |
KR101539436B1 (ko) | 2013-12-30 | 2015-07-24 | 주식회사 효성 | 가스 절연 개폐기의 부분 방전 검출 장치 |
-
2010
- 2010-04-22 US US13/265,216 patent/US8921391B2/en active Active
- 2010-04-22 CN CN201510982848.3A patent/CN105596320B/zh active Active
- 2010-04-22 KR KR1020117027678A patent/KR101575706B1/ko active IP Right Grant
- 2010-04-22 CA CA2754702A patent/CA2754702C/en active Active
- 2010-04-22 MX MX2016008394A patent/MX369117B/es unknown
- 2010-04-22 RU RU2011147194/15A patent/RU2563817C2/ru active
- 2010-04-22 CN CN201080017743.XA patent/CN102421429B/zh active Active
- 2010-04-22 ES ES10767106.7T patent/ES2562814T3/es active Active
- 2010-04-22 MX MX2011011058A patent/MX345032B/es active IP Right Grant
- 2010-04-22 EP EP18191714.7A patent/EP3431085B1/en active Active
- 2010-04-22 ES ES15182580T patent/ES2698508T3/es active Active
- 2010-04-22 EP EP15182580.9A patent/EP2965756B1/en active Active
- 2010-04-22 EP EP10767106.7A patent/EP2422779B1/en active Active
- 2010-04-22 WO PCT/JP2010/057114 patent/WO2010123049A1/ja active Application Filing
- 2010-04-22 BR BRPI1014174A patent/BRPI1014174B8/pt active IP Right Grant
- 2010-04-22 ES ES18191714T patent/ES2960438T3/es active Active
- 2010-04-22 JP JP2011510353A patent/JP5668219B2/ja active Active
-
2012
- 2012-07-30 HK HK16102723.2A patent/HK1214763A1/zh unknown
- 2012-07-30 HK HK12107420.1A patent/HK1166700A1/zh unknown
-
2014
- 2014-11-19 US US14/547,247 patent/US9688674B2/en active Active
-
2017
- 2017-05-23 US US15/602,686 patent/US10611761B2/en active Active
-
2020
- 2020-02-27 US US16/803,163 patent/US10947235B2/en active Active
-
2021
- 2021-03-15 US US17/201,102 patent/US11840530B2/en active Active
Patent Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001062708A1 (fr) * | 2000-02-22 | 2001-08-30 | Ono Pharmaceutical Co., Ltd. | Derives d'acide benzoique, procede de production desdits derives, et medicament contenant ces derives comme principe actif |
WO2002032900A2 (en) | 2000-10-19 | 2002-04-25 | Pfizer Pharmaceuticals Inc. | Aryl or heteroaryl fused imidazole compounds as anti-inflammatory and analgesic agents |
JP2004517054A (ja) * | 2000-10-19 | 2004-06-10 | ファイザー株式会社 | 抗炎症剤及び鎮痛剤としてのアリール又はヘテロアリール縮合イミダゾール化合物 |
WO2005021508A1 (en) | 2003-09-03 | 2005-03-10 | Pfizer Inc. | Phenyl or pyridyl amide compounds as prostaglandin e2 antagonists |
JP2007504210A (ja) * | 2003-09-03 | 2007-03-01 | ファイザー株式会社 | プロスタグランジンe2拮抗薬としてのフェニルまたはピリジルアミド化合物 |
WO2005105733A1 (en) | 2004-05-04 | 2005-11-10 | Pfizer Japan Inc. | Ortho substituted aryl or heteroaryl amide compounds |
WO2005105732A1 (en) | 2004-05-04 | 2005-11-10 | Pfizer Japan Inc. | Substituted methyl aryl or heteroaryl amide compounds |
JP2007536367A (ja) * | 2004-05-04 | 2007-12-13 | ファイザー株式会社 | オルト置換アリールまたはヘテロアリールアミド化合物 |
JP2007536366A (ja) * | 2004-05-04 | 2007-12-13 | ファイザー株式会社 | 置換メチルアリール又はヘテロアリールアミド化合物 |
JP2008540584A (ja) * | 2005-05-19 | 2008-11-20 | メルク フロスト カナダ リミテツド | Ep4アンタゴニストとしてのキノリン誘導体 |
Non-Patent Citations (23)
Title |
---|
"Eicosanoids: From Biotechnology to Therapeutic Applications", 1996, PLENUM PRESS, pages: 137 - 154 |
"Pergamon Press", 1987, AMERICAN PHARMACEUTICAL ASSOCIATION, article "Bioreversible Carriers in Drug Design" |
"Remington's Pharmacentical Sciences", 1990, MACK PUBLISHING CO. |
CANCER RESEARCH, vol. 58, 1998, pages 2583 - 2587 |
CANCER RESEARCH, vol. 62, no. 1, 1 January 2002 (2002-01-01), pages 28 - 32 |
CANCER RESEARCH, vol. 66, no. 6, 15 March 2006 (2006-03-15) |
CHERUKURI, D.P. ET AL.: "The EP4 receptor antagonist, L-161, 982, blocks prostaglandin E2-induced signal transduction and cell proliferation in HCA-7 colon cancer cells", EXPERIMENTAL CELL RESEARCH, vol. 313, no. 14, 2007, pages 2969 - 2979 * |
E L ELIEL: "Stereochemistry of Organic Compounds", 1994, WILEY |
EXPERIMENTAL CELL RESEARCH, vol. 313, no. 14, 15 August 2007 (2007-08-15), pages 2969 - 2979 |
GASTROENTEROLOGY, vol. 131, 2006, pages 1086 - 1095 |
H BUNDGAARD: "Design of Prodrugs", 1985, ELSEVIER |
HALEBLIAN, J PHARM SCI, vol. 64, no. 8, August 1975 (1975-08-01), pages 1269 - 1288 |
INT. J. CANCER, vol. 121, 2007, pages 878 - 883 |
JOURNAL OF LIPID MEDIATORS AND CELL SIGNALLING, vol. 14, 1996, pages 83 - 87 |
KITAMURA, T. ET AL.: "Combined effects of prostaglandin E receptor subtype EP1 and subtype EP4 antagonists on intestinal tumorigenesis in adenomatous polyposis coli gene knockout mice", CANCER SCIENCE, vol. 94, no. 7, 2003, pages 618 - 621 * |
MA, X. ET AL.: "Prostaglandin E receptor EP4 antagonism inhibits breast cancer metastasis", CANCER RESEARCH, vol. 66, no. 6, 2006, pages 2923 - 2927 * |
NATURE REVIEW CANCER, vol. 7, 2007, pages 645 - 658 |
PROSTAGLANDINS AND OTHER LIPID MEDIATORS, vol. 69, 2002, pages 557 - 573 |
SCIENCE, vol. 265, no. 5175, 1994, pages 1093 |
SCIENCE, vol. 94, no. 7, 1 July 2003 (2003-07-01), pages 618 - 621 |
STAHL, WERMUTH: "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", 2002, WILEY-VCH |
T. HIGUCHI, W. STELLA: "Pro-drugs as Novel Delivery Systems", vol. 14, ACS SYMPOSIUM SERIES |
T. W. GREENE ET AL.: "Protective Groups in Organic Synthesi", 1991, JOHN WILEY & SONS |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2017516775A (ja) * | 2014-05-23 | 2017-06-22 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | がんの処置のための併用治療 |
JP2020128432A (ja) * | 2014-05-23 | 2020-08-27 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | がんの処置のための併用治療 |
US11707448B2 (en) | 2014-05-23 | 2023-07-25 | Eisai R&D Management Co., Ltd. | Combination therapies for the treatment of cancer |
JP2018535939A (ja) * | 2016-11-04 | 2018-12-06 | 株式会社AskAt | Nash関連肝臓癌を治療するためのep4受容体拮抗薬の使用 |
JP2022500485A (ja) * | 2018-09-27 | 2022-01-04 | アリーズ セラピューティクス, インコーポレイテッド | グラピプラント単位剤形 |
US11471455B2 (en) | 2018-10-05 | 2022-10-18 | Annapurna Bio, Inc. | Compounds and compositions for treating conditions associated with APJ receptor activity |
US11944622B2 (en) | 2018-10-05 | 2024-04-02 | Annapurna Bio, Inc. | Compounds and compositions for treating conditions associated with APJ receptor activity |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5668219B2 (ja) | 癌治療のための選択的ep4受容体拮抗物質 | |
TWI289449B (en) | Compositions and methods for the treatment of cancer | |
KR101483802B1 (ko) | 외투층 세포 림프종의 치료에 있어서 3-(4-아미노-1-옥소-1,3-디히드로-이소인돌-2-일)-피페리딘-2,6-디온의 용도 | |
KR101224279B1 (ko) | 골수증식 질환의 치료 및 관리를 위한 면역조절 화합물의 사용 방법 및 이를 포함하는 조성물 | |
KR102272274B1 (ko) | (s)-3-(4-((4-(모르폴리노메틸)벤질)옥시)-1-옥소이소인돌린-2-일)피페리딘-2,6-디온의 제제 | |
US8435992B2 (en) | Multiple myeloma treatments | |
AU2022358409A1 (en) | Combination therapy using a ptpn11 inhibitor and a kras g12c inhibitor | |
JP2007510671A (ja) | アスベスト関連疾患および障害の治療および管理のための、jnk阻害剤の使用方法およびそれを含む組成物 | |
JP2013512195A5 (ja) | ||
TW202135808A (zh) | 組合 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 201080017743.X Country of ref document: CN |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 10767106 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2011510353 Country of ref document: JP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2754702 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: MX/A/2011/011058 Country of ref document: MX |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2010767106 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 20117027678 Country of ref document: KR Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 2011147194 Country of ref document: RU Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 13265216 Country of ref document: US |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: PI1014174 Country of ref document: BR |
|
ENP | Entry into the national phase |
Ref document number: PI1014174 Country of ref document: BR Kind code of ref document: A2 Effective date: 20111021 |