JP2018524266A - グアニジン化合物及びその使用 - Google Patents
グアニジン化合物及びその使用 Download PDFInfo
- Publication number
- JP2018524266A JP2018524266A JP2017555763A JP2017555763A JP2018524266A JP 2018524266 A JP2018524266 A JP 2018524266A JP 2017555763 A JP2017555763 A JP 2017555763A JP 2017555763 A JP2017555763 A JP 2017555763A JP 2018524266 A JP2018524266 A JP 2018524266A
- Authority
- JP
- Japan
- Prior art keywords
- carboximidamide
- carbamimidoyl
- difluoropiperidine
- difluoropyrrolidine
- phenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000002357 guanidines Chemical class 0.000 title abstract description 7
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 44
- 201000011510 cancer Diseases 0.000 claims abstract description 34
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 23
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 19
- 201000010099 disease Diseases 0.000 claims abstract description 17
- 230000006705 mitochondrial oxidative phosphorylation Effects 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims description 143
- -1 and is at least H Inorganic materials 0.000 claims description 43
- 239000000126 substance Substances 0.000 claims description 24
- 125000003118 aryl group Chemical group 0.000 claims description 16
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 16
- 238000011282 treatment Methods 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 229920006395 saturated elastomer Polymers 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 230000001093 anti-cancer Effects 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 8
- 239000004480 active ingredient Substances 0.000 claims description 7
- 239000002246 antineoplastic agent Substances 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims description 6
- 206010027476 Metastases Diseases 0.000 claims description 6
- 206010012601 diabetes mellitus Diseases 0.000 claims description 6
- 230000009401 metastasis Effects 0.000 claims description 6
- 229940002612 prodrug Drugs 0.000 claims description 6
- 239000000651 prodrug Substances 0.000 claims description 6
- 239000012453 solvate Substances 0.000 claims description 6
- 206010006187 Breast cancer Diseases 0.000 claims description 5
- 208000026310 Breast neoplasm Diseases 0.000 claims description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 5
- 201000005202 lung cancer Diseases 0.000 claims description 5
- 208000020816 lung neoplasm Diseases 0.000 claims description 5
- 230000001629 suppression Effects 0.000 claims description 5
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 4
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 4
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 4
- 125000003282 alkyl amino group Chemical group 0.000 claims description 4
- 201000010881 cervical cancer Diseases 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 201000007270 liver cancer Diseases 0.000 claims description 4
- 208000014018 liver neoplasm Diseases 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 3
- NNFWQSFVMLUFLE-UHFFFAOYSA-N 4-fluoropiperidine-1-carboximidamide Chemical compound NC(=N)N1CCC(F)CC1 NNFWQSFVMLUFLE-UHFFFAOYSA-N 0.000 claims description 3
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- KHBYPKVVSKEXID-UHFFFAOYSA-N N'-(N'-cyclopropylcarbamimidoyl)-4,4-difluoropiperidine-1-carboximidamide Chemical compound NC(=NC(=N)NC1CC1)N1CCC(F)(F)CC1 KHBYPKVVSKEXID-UHFFFAOYSA-N 0.000 claims description 3
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 3
- 208000029742 colonic neoplasm Diseases 0.000 claims description 3
- 229940127089 cytotoxic agent Drugs 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 239000002955 immunomodulating agent Substances 0.000 claims description 3
- 229940043355 kinase inhibitor Drugs 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000003757 phosphotransferase inhibitor Substances 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- DDTNTQLCNJCVIC-MRVPVSSYSA-N (3R)-3-fluoro-N'-[N'-[4-(trifluoromethoxy)phenyl]carbamimidoyl]pyrrolidine-1-carboximidamide Chemical compound FC(OC1=CC=C(C=C1)NC(=N)NC(=N)N1C[C@@H](CC1)F)(F)F DDTNTQLCNJCVIC-MRVPVSSYSA-N 0.000 claims description 2
- DQTGYCQHYYMYBM-UHFFFAOYSA-N 3,3-difluoro-N'-[N'-(2-phenylethyl)carbamimidoyl]pyrrolidine-1-carboximidamide Chemical compound C(CC1=CC=CC=C1)NC(=N)NC(=N)N1CC(CC1)(F)F DQTGYCQHYYMYBM-UHFFFAOYSA-N 0.000 claims description 2
- NCIXYXUWSKFVRZ-UHFFFAOYSA-N 3,3-difluoro-N'-[N'-(2-propylphenyl)carbamimidoyl]pyrrolidine-1-carboximidamide Chemical compound C(CC)C1=C(C=CC=C1)NC(=N)NC(=N)N1CC(CC1)(F)F NCIXYXUWSKFVRZ-UHFFFAOYSA-N 0.000 claims description 2
- ABDRDPZNJDKADF-UHFFFAOYSA-N 3,3-difluoro-N'-[N'-(3,4,5-trimethoxyphenyl)carbamimidoyl]pyrrolidine-1-carboximidamide Chemical compound COC=1C=C(C=C(C=1OC)OC)NC(=N)NC(=N)N1CC(CC1)(F)F ABDRDPZNJDKADF-UHFFFAOYSA-N 0.000 claims description 2
- DRGHTTCZURGSOB-UHFFFAOYSA-N 3,3-difluoro-N'-[N'-(3-phenoxyphenyl)carbamimidoyl]pyrrolidine-1-carboximidamide Chemical compound O(C1=CC=CC=C1)C=1C=C(C=CC=1)NC(=N)NC(=N)N1CC(CC1)(F)F DRGHTTCZURGSOB-UHFFFAOYSA-N 0.000 claims description 2
- ZROJWOAFJNYKKQ-UHFFFAOYSA-N 3,3-difluoro-N'-[N'-(4-phenoxyphenyl)carbamimidoyl]pyrrolidine-1-carboximidamide Chemical compound O(C1=CC=CC=C1)C1=CC=C(C=C1)NC(=N)NC(=N)N1CC(CC1)(F)F ZROJWOAFJNYKKQ-UHFFFAOYSA-N 0.000 claims description 2
- MLHJFZKBHQHFTI-UHFFFAOYSA-N 3,3-difluoro-N'-[N'-[4-(trifluoromethoxy)phenyl]carbamimidoyl]piperidine-1-carboximidamide Chemical compound FC(OC1=CC=C(C=C1)NC(=N)NC(=N)N1CC(CCC1)(F)F)(F)F MLHJFZKBHQHFTI-UHFFFAOYSA-N 0.000 claims description 2
- LUVXRIMOYKRJEA-UHFFFAOYSA-N 3,3-difluoro-N'-[N'-[4-(trifluoromethoxy)phenyl]carbamimidoyl]pyrrolidine-1-carboximidamide Chemical compound FC(F)(F)OC1=CC=C(NC(=N)NC(=N)N2CCC(F)(F)C2)C=C1 LUVXRIMOYKRJEA-UHFFFAOYSA-N 0.000 claims description 2
- VHLDZQXJTNDBOU-UHFFFAOYSA-N 3,3-difluoro-N'-[N'-[4-(trifluoromethyl)phenyl]carbamimidoyl]pyrrolidine-1-carboximidamide Chemical compound FC(C1=CC=C(C=C1)NC(=N)NC(=N)N1CC(CC1)(F)F)(F)F VHLDZQXJTNDBOU-UHFFFAOYSA-N 0.000 claims description 2
- ITQGJRWRQKAERQ-UHFFFAOYSA-N 3,3-difluoro-N'-[N'-[4-(trifluoromethylsulfanyl)phenyl]carbamimidoyl]pyrrolidine-1-carboximidamide Chemical compound FC(SC1=CC=C(C=C1)NC(=N)NC(=N)N1CC(CC1)(F)F)(F)F ITQGJRWRQKAERQ-UHFFFAOYSA-N 0.000 claims description 2
- MHRNBWBZQKQICZ-UHFFFAOYSA-N 3,4,4-trifluoro-N'-[N'-[4-(trifluoromethoxy)phenyl]carbamimidoyl]piperidine-1-carboximidamide Chemical compound FC(OC1=CC=C(C=C1)NC(=N)NC(=N)N1CC(C(CC1)(F)F)F)(F)F MHRNBWBZQKQICZ-UHFFFAOYSA-N 0.000 claims description 2
- VGKGZMVGFDEWAC-UHFFFAOYSA-N 4,4-difluoro-3-methyl-N'-[N'-[4-(trifluoromethoxy)phenyl]carbamimidoyl]piperidine-1-carboximidamide Chemical compound FC(OC1=CC=C(C=C1)NC(=N)NC(=N)N1CC(C(CC1)(F)F)C)(F)F VGKGZMVGFDEWAC-UHFFFAOYSA-N 0.000 claims description 2
- HEHHJNSJKLKLTM-UHFFFAOYSA-N 4,4-difluoro-N'-(N'-phenylcarbamimidoyl)piperidine-1-carboximidamide Chemical compound C1(=CC=CC=C1)NC(=N)NC(=N)N1CCC(CC1)(F)F HEHHJNSJKLKLTM-UHFFFAOYSA-N 0.000 claims description 2
- MKYBQRFFLAUALF-UHFFFAOYSA-N 4,4-difluoro-N'-[N'-(3-methoxyphenyl)carbamimidoyl]piperidine-1-carboximidamide Chemical compound COC=1C=C(C=CC=1)NC(=N)NC(=N)N1CCC(CC1)(F)F MKYBQRFFLAUALF-UHFFFAOYSA-N 0.000 claims description 2
- KLMCCDQKBISGLF-UHFFFAOYSA-N 4,4-difluoro-N'-[N'-(3-phenoxyphenyl)carbamimidoyl]piperidine-1-carboximidamide Chemical compound O(C1=CC=CC=C1)C=1C=C(C=CC=1)NC(=N)NC(=N)N1CCC(CC1)(F)F KLMCCDQKBISGLF-UHFFFAOYSA-N 0.000 claims description 2
- BCSKEWAPVVBLLE-UHFFFAOYSA-N 4,4-difluoro-N'-[N'-(4-methoxyphenyl)carbamimidoyl]piperidine-1-carboximidamide Chemical compound COC1=CC=C(C=C1)NC(=N)NC(=N)N1CCC(CC1)(F)F BCSKEWAPVVBLLE-UHFFFAOYSA-N 0.000 claims description 2
- WYBMWCWUJMQFTN-UHFFFAOYSA-N 4,4-difluoro-N'-[N'-(4-methylsulfanylphenyl)carbamimidoyl]piperidine-1-carboximidamide Chemical compound CSC1=CC=C(C=C1)NC(=N)NC(=N)N1CCC(CC1)(F)F WYBMWCWUJMQFTN-UHFFFAOYSA-N 0.000 claims description 2
- PUDYQFZHNPQQMC-UHFFFAOYSA-N 4,4-difluoro-N'-[N'-(4-phenoxyphenyl)carbamimidoyl]piperidine-1-carboximidamide Chemical compound O(C1=CC=CC=C1)C1=CC=C(C=C1)NC(=N)NC(=N)N1CCC(CC1)(F)F PUDYQFZHNPQQMC-UHFFFAOYSA-N 0.000 claims description 2
- FIFHTLUJKJZSAO-UHFFFAOYSA-N 4,4-difluoro-N'-[N'-(4-propan-2-ylphenyl)carbamimidoyl]piperidine-1-carboximidamide Chemical compound C(C)(C)C1=CC=C(C=C1)NC(=N)NC(=N)N1CCC(CC1)(F)F FIFHTLUJKJZSAO-UHFFFAOYSA-N 0.000 claims description 2
- VWSUZNJONCRCAY-UHFFFAOYSA-N 4,4-difluoro-N'-[N'-(5,6,7,8-tetrahydronaphthalen-1-yl)carbamimidoyl]piperidine-1-carboximidamide Chemical compound C1(=CC=CC=2CCCCC1=2)NC(=N)NC(=N)N1CCC(CC1)(F)F VWSUZNJONCRCAY-UHFFFAOYSA-N 0.000 claims description 2
- RBDXSFWJBGFXQJ-UHFFFAOYSA-N 4,4-difluoro-N'-[N'-(5,6,7,8-tetrahydronaphthalen-2-yl)carbamimidoyl]piperidine-1-carboximidamide Chemical compound FC1(F)CCN(CC1)C(=N)NC(=N)NC1=CC2=C(CCCC2)C=C1 RBDXSFWJBGFXQJ-UHFFFAOYSA-N 0.000 claims description 2
- WANQDAIUOOWGOP-UHFFFAOYSA-N 4,4-difluoro-N'-[N'-[4-(trifluoromethoxy)phenyl]carbamimidoyl]piperidine-1-carboximidamide Chemical compound FC(F)(F)OC1=CC=C(NC(=N)NC(=N)N2CCC(F)(F)CC2)C=C1 WANQDAIUOOWGOP-UHFFFAOYSA-N 0.000 claims description 2
- IJPZRYLWBRDZCH-UHFFFAOYSA-N 4,4-difluoro-N'-[N'-[4-(trifluoromethyl)phenyl]carbamimidoyl]piperidine-1-carboximidamide Chemical compound FC(C1=CC=C(C=C1)NC(=N)NC(=N)N1CCC(CC1)(F)F)(F)F IJPZRYLWBRDZCH-UHFFFAOYSA-N 0.000 claims description 2
- RWTAXHFLXAWSIH-UHFFFAOYSA-N 4,4-difluoro-N'-[N'-[4-(trifluoromethylsulfanyl)phenyl]carbamimidoyl]piperidine-1-carboximidamide Chemical compound FC(SC1=CC=C(C=C1)NC(=N)NC(=N)N1CCC(CC1)(F)F)(F)F RWTAXHFLXAWSIH-UHFFFAOYSA-N 0.000 claims description 2
- NGQKVCGQBXRDJT-UHFFFAOYSA-N 4,4-difluoro-N'-[N'-[[4-(trifluoromethoxy)phenyl]methyl]carbamimidoyl]piperidine-1-carboximidamide Chemical compound FC(OC1=CC=C(CNC(=N)NC(=N)N2CCC(CC2)(F)F)C=C1)(F)F NGQKVCGQBXRDJT-UHFFFAOYSA-N 0.000 claims description 2
- VDXVEYVJLAYDMQ-UHFFFAOYSA-N 4-chloro-N'-[N'-[4-(trifluoromethoxy)phenyl]carbamimidoyl]piperidine-1-carboximidamide Chemical compound FC(OC1=CC=C(C=C1)NC(=N)NC(=N)N1CCC(CC1)Cl)(F)F VDXVEYVJLAYDMQ-UHFFFAOYSA-N 0.000 claims description 2
- UOVRHXVGMSKEHN-UHFFFAOYSA-N 4-fluoro-N'-[N'-[4-(trifluoromethoxy)phenyl]carbamimidoyl]piperidine-1-carboximidamide Chemical compound FC(OC1=CC=C(C=C1)NC(=N)NC(=N)N1CCC(CC1)F)(F)F UOVRHXVGMSKEHN-UHFFFAOYSA-N 0.000 claims description 2
- 208000004930 Fatty Liver Diseases 0.000 claims description 2
- 206010019708 Hepatic steatosis Diseases 0.000 claims description 2
- 208000035150 Hypercholesterolemia Diseases 0.000 claims description 2
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 2
- 208000001145 Metabolic Syndrome Diseases 0.000 claims description 2
- 208000000112 Myalgia Diseases 0.000 claims description 2
- RMSWGCTTWFYWCZ-UHFFFAOYSA-N N'-(4,4-difluoropiperidine-1-carboximidoyl)-4,4-difluoropiperidine-1-carboximidamide Chemical compound FC1(CCN(CC1)C(NC(=N)N1CCC(CC1)(F)F)=N)F RMSWGCTTWFYWCZ-UHFFFAOYSA-N 0.000 claims description 2
- GNQUYYMYTOTYSP-UHFFFAOYSA-N N'-(N'-cyclohexylcarbamimidoyl)-3,3-difluoropyrrolidine-1-carboximidamide Chemical compound C1(CCCCC1)NC(=N)NC(=N)N1CC(CC1)(F)F GNQUYYMYTOTYSP-UHFFFAOYSA-N 0.000 claims description 2
- FAXTYXOQDMWKBR-UHFFFAOYSA-N N'-(N'-cyclohexylcarbamimidoyl)-4,4-difluoropiperidine-1-carboximidamide Chemical compound C1(CCCCC1)NC(=N)NC(=N)N1CCC(CC1)(F)F FAXTYXOQDMWKBR-UHFFFAOYSA-N 0.000 claims description 2
- DQHZXIZTTWBWND-UHFFFAOYSA-N N'-(N'-cyclopropylcarbamimidoyl)-3,3-difluoropyrrolidine-1-carboximidamide Chemical compound C1(CC1)NC(=N)NC(=N)N1CC(CC1)(F)F DQHZXIZTTWBWND-UHFFFAOYSA-N 0.000 claims description 2
- PHPCCHNIPJVYJQ-UHFFFAOYSA-N N'-[N'-(2,4-dichlorophenyl)carbamimidoyl]-3,3-difluoropyrrolidine-1-carboximidamide Chemical compound ClC1=C(C=CC(=C1)Cl)NC(=N)NC(=N)N1CC(CC1)(F)F PHPCCHNIPJVYJQ-UHFFFAOYSA-N 0.000 claims description 2
- PAMFUIWHXAKICU-UHFFFAOYSA-N N'-[N'-(2-bromophenyl)carbamimidoyl]-3,3-difluoropyrrolidine-1-carboximidamide Chemical compound BrC1=C(C=CC=C1)NC(=N)NC(=N)N1CC(CC1)(F)F PAMFUIWHXAKICU-UHFFFAOYSA-N 0.000 claims description 2
- HEIWJLOWQWJBOO-UHFFFAOYSA-N N'-[N'-(2-bromophenyl)carbamimidoyl]-4,4-difluoropiperidine-1-carboximidamide Chemical compound BrC1=C(C=CC=C1)NC(=N)NC(=N)N1CCC(CC1)(F)F HEIWJLOWQWJBOO-UHFFFAOYSA-N 0.000 claims description 2
- DZYIYZFIBXPDFL-UHFFFAOYSA-N N'-[N'-(2-chlorophenyl)carbamimidoyl]-3,3-difluoropyrrolidine-1-carboximidamide Chemical compound ClC1=C(C=CC=C1)NC(=N)NC(=N)N1CC(CC1)(F)F DZYIYZFIBXPDFL-UHFFFAOYSA-N 0.000 claims description 2
- IHBIUOSUEXAVPK-UHFFFAOYSA-N N'-[N'-(3,4-dibromophenyl)carbamimidoyl]-4,4-difluoropiperidine-1-carboximidamide Chemical compound BrC=1C=C(C=CC=1Br)NC(=N)NC(=N)N1CCC(CC1)(F)F IHBIUOSUEXAVPK-UHFFFAOYSA-N 0.000 claims description 2
- MUPJXMMFTSUXMZ-UHFFFAOYSA-N N'-[N'-(3,4-dichlorophenyl)carbamimidoyl]-4,4-difluoropiperidine-1-carboximidamide Chemical compound ClC=1C=C(C=CC=1Cl)NC(=N)NC(=N)N1CCC(CC1)(F)F MUPJXMMFTSUXMZ-UHFFFAOYSA-N 0.000 claims description 2
- DQZQJHXRVUSAHR-UHFFFAOYSA-N N'-[N'-(3-bromo-4-iodophenyl)carbamimidoyl]-4,4-difluoropiperidine-1-carboximidamide Chemical compound BrC=1C=C(C=CC=1I)NC(=N)NC(=N)N1CCC(CC1)(F)F DQZQJHXRVUSAHR-UHFFFAOYSA-N 0.000 claims description 2
- ATHRYIXOHYLVDQ-UHFFFAOYSA-N N'-[N'-(3-bromophenyl)carbamimidoyl]-4,4-difluoropiperidine-1-carboximidamide Chemical compound BrC=1C=C(C=CC=1)NC(=N)NC(=N)N1CCC(CC1)(F)F ATHRYIXOHYLVDQ-UHFFFAOYSA-N 0.000 claims description 2
- YMYQLQFWTFSBPC-UHFFFAOYSA-N N'-[N'-(3-chloro-4-fluorophenyl)carbamimidoyl]-4,4-difluoropiperidine-1-carboximidamide Chemical compound ClC=1C=C(C=CC=1F)NC(=N)NC(=N)N1CCC(CC1)(F)F YMYQLQFWTFSBPC-UHFFFAOYSA-N 0.000 claims description 2
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- RBEQHDKSKSASLD-UHFFFAOYSA-N N'-[N'-[2-(4-bromophenyl)ethyl]carbamimidoyl]-3,3-difluoropyrrolidine-1-carboximidamide Chemical compound BrC1=CC=C(CCNC(=N)NC(=N)N2CC(CC2)(F)F)C=C1 RBEQHDKSKSASLD-UHFFFAOYSA-N 0.000 claims description 2
- XCZBZKBJUPDPOP-UHFFFAOYSA-N N'-[N'-[3-bromo-4-(trifluoromethoxy)phenyl]carbamimidoyl]-3,3-difluoropyrrolidine-1-carboximidamide Chemical compound BrC=1C=C(C=CC=1OC(F)(F)F)NC(=N)NC(=N)N1CC(CC1)(F)F XCZBZKBJUPDPOP-UHFFFAOYSA-N 0.000 claims description 2
- LGWUEMVBFRDWTH-UHFFFAOYSA-N N'-[N'-[4-(trifluoromethoxy)phenyl]carbamimidoyl]-1,3-thiazolidine-3-carboximidamide Chemical compound FC(OC1=CC=C(C=C1)NC(=N)NC(=N)N1CSCC1)(F)F LGWUEMVBFRDWTH-UHFFFAOYSA-N 0.000 claims description 2
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- 229960001924 melphalan Drugs 0.000 description 1
- 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 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000037353 metabolic pathway Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000001617 migratory effect Effects 0.000 description 1
- 238000004264 monolayer culture Methods 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- YFJAIURZMRJPDB-UHFFFAOYSA-N n,n-dimethylpiperidin-4-amine Chemical compound CN(C)C1CCNCC1 YFJAIURZMRJPDB-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 210000000822 natural killer cell Anatomy 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
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100001083 no cytotoxicity Toxicity 0.000 description 1
- 108010007425 oligomycin sensitivity conferring protein Proteins 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- LRTFPLFDLJYEKT-UHFFFAOYSA-N para-isopropylaniline Chemical compound CC(C)C1=CC=C(N)C=C1 LRTFPLFDLJYEKT-UHFFFAOYSA-N 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 229940117803 phenethylamine Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229940043441 phosphoinositide 3-kinase inhibitor Drugs 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 208000016691 refractory malignant neoplasm Diseases 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- RCINICONZNJXQF-VAZQATRQSA-N s1150_selleck 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(C21)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-VAZQATRQSA-N 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 108091006024 signal transducing proteins Proteins 0.000 description 1
- 102000034285 signal transducing proteins Human genes 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- 102000009076 src-Family Kinases Human genes 0.000 description 1
- 108010087686 src-Family Kinases Proteins 0.000 description 1
- 229960005322 streptomycin Drugs 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
- JDVPQXZIJDEHAN-UHFFFAOYSA-N succinamic acid Chemical compound NC(=O)CCC(O)=O JDVPQXZIJDEHAN-UHFFFAOYSA-N 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 210000001519 tissue Anatomy 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
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 229960004066 trametinib Drugs 0.000 description 1
- LIRYPHYGHXZJBZ-UHFFFAOYSA-N trametinib Chemical compound CC(=O)NC1=CC=CC(N2C(N(C3CC3)C(=O)C3=C(NC=4C(=CC(I)=CC=4)F)N(C)C(=O)C(C)=C32)=O)=C1 LIRYPHYGHXZJBZ-UHFFFAOYSA-N 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- IUCJMVBFZDHPDX-UHFFFAOYSA-N tretamine Chemical compound C1CN1C1=NC(N2CC2)=NC(N2CC2)=N1 IUCJMVBFZDHPDX-UHFFFAOYSA-N 0.000 description 1
- 229950001353 tretamine Drugs 0.000 description 1
- 230000004102 tricarboxylic acid cycle Effects 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 230000004222 uncontrolled growth Effects 0.000 description 1
- 229960001055 uracil mustard Drugs 0.000 description 1
- 229960003862 vemurafenib Drugs 0.000 description 1
- GPXBXXGIAQBQNI-UHFFFAOYSA-N vemurafenib Chemical compound CCCS(=O)(=O)NC1=CC=C(F)C(C(=O)C=2C3=CC(=CN=C3NC=2)C=2C=CC(Cl)=CC=2)=C1F GPXBXXGIAQBQNI-UHFFFAOYSA-N 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000002689 xenotransplantation Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/38—Halogen atoms or nitro radicals
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
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- 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
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- 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
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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- C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
- C07C279/24—Y being a hetero atom
- C07C279/26—X and Y being nitrogen atoms, i.e. biguanides
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
Description
R1及びR2は独立的にH,C1-C6アルキル又はC1-C6ハロアルキルであり;又はそれらにNが一緒に結合して3〜8員の飽和又は不飽和のヘテロシクロアルキル基、好ましくは5〜6員の飽和又は不飽和のヘテロシクロアルキル基を形成し、ヘテロシクロアルキル環は少なくともN,O及びSからなる群から選ばれたヘテロ原子を任意で含んでも良く、少なくともH,ハロゲン,C1-C4アルキル,C1-C4ハロアルキル,C1-C4アルコキシ及びC1-C2アルキルアミノからなる群から選ばれた基で置換されており、
R3及びR4は独立的にH又はC1-C4アルキルであり、
nは0,1又は2であり、
R5はH,C3-C7シクロアルキル又は化学式2で表されるアリール基である。
R6,R7,R8,R9及びR10は隣接する置換基に連結され、5〜6員の飽和環を形成する。
R3及びR4は独立的にHであり、
nは0,1又は2であり、
R5は化学式2で表されるアリール基であり、R6,R7,R8,R9及びR10は上述のように化学式1と同様に定義される。
R3及びR4は独立的にHであり、
nは0であり、
R5は化学式2で表されるアリール基であり、R6,R7,R8,R9及びR10は独立的にC1-C4ハロアルコキシである。
N-(N-フェニルカルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(5,6,7,8-テトラヒドロナフタレン-2-イル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(3,4-ジクロロフェニル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(2-ブロモフェニル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(3-ブロモフェニル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(4-ブロモフェニル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(4-(トリフルオロメトキシ)フェニル)カルバムイミドイル)-4-(ジメチルアミノ)ピペリジン-1-カルボキシイミドアミド,
N-(N-(4-(メチルチオ)フェニル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(4-(トリフルオロメチルチオ)フェニル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(4-イソプロピルフェニル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(3-クロロ-4-フルオロフェニル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(5,6,7,8-テトラヒドロナフタレン-1-イル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(3-フェノキシフェニル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(4-(トリフルオロメチルチオ)フェニル)カルバムイミドイル)チアゾリジン-3-カルボキシイミドアミド,
N-(N-(3,4,5-トリメトキシフェニル)カルバムイミドイル)-3,3-ジフルオロピロリジン-1-カルボキシイミドアミド,
N-(N-(4-(トリフルオロメトキシ)フェニル)カルバムイミドイル)-4-クロロピペリジン-1-カルボキシイミドアミド,
N-(N-(4-(トリフルオロメトキシ)フェニル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(3-クロロ-4-ヨードフェニル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(4-メトキシフェニル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(3-メトキシフェニル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(4-(トリフルオロメチル)フェニル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(3-ブロモ-4-ヨードフェニル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(4-フェノキシフェニル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(4-(トリフルオロメトキシ)カルバムイミドイル)-4-エトキシピペリジン-1-カルボキシイミドアミド,
N-(N-(4-(トリフルオロメトキシ)フェニル)カルバムイミドイル)-3,3-ジフルオロピロリジン-1-カルボキシイミドアミド,
N-(N-(3,4-ジブロモフェニル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(3-フルオロ-4-(トリフルオロメトキシ)フェニル)カルバムイミドイル)-4,4-フルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(4-フェノキシフェニル)カルバムイミドイル)-3,3-ジフルオロピロリジン-1-カルボキシイミドアミド,
N-(N-(3-フェノキシフェニル)カルバムイミドイル)-3,3-ジフルオロピロリジン-1-カルボキシイミドアミド,
N-(N-(4-(トリフルオロメチル)フェニル)カルバムイミドイル)-3,3-ジフルオロピロリジン-1-カルボキシイミドアミド,
N-(N-(3-クロロ-4-ヨードフェニル)カルバムイミドイル)-3,3-ジフルオロピロリジン-1-カルボキシイミドアミド,
N-(N-(4-(トリフルオロメチルチオ)フェニル)カルバムイミドイル)-3,3-ジフルオロピロリジン-1-カルボキシイミドアミド,
N-(N-(2-クロロフェニル)カルバムイミドイル)-3,3-ジフルオロピロリジン-1-カルボキシイミドアミド,
N-(N-(2-ブロモフェニル)カルバムイミドイル)-3,3-ジフルオロピロリジン-1-カルボキシイミドアミド,
N-(N-(2,4-ジクロロフェニル)カルバムイミドイル)-3,3-ジフルオロピロリジン-1-カルボキシイミドアミド,
N-(N-(2-プロピルフェニル)カルバムイミドイル)-3,3-ジフルオロピロリジン-1-カルボキシイミドアミド,
N-(N-3,4-ジメトキシフェニル)カルバムイミドイル)-3,3-ジフルオロピロリジン-1-カルボキシイミドアミド,
N-(N-(3-クロロ-4-(トリフルオロメトキシ)フェニル)カルバムイミドイル)-3,3-ジフルオロピロリジン-1-カルボキシイミドアミド,
N-(N-(3-ブロモ-4-(トリフルオロメトキシ)フェニル)カルバムイミドイル)-3,3-ジフルオロピロリジン-1-カルボキシイミドアミド,
N-(N-(2-ブロモベンジル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(4-(トリフルオロメトキシ)ベンジル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(3,4-ジクロロベンジル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(4-トリフルオロメチル)ベンジル)カルバムイミドイル)-3,3-ジフルオロピロリジン-1-カルボキシイミドアミド,
N-(N-(3-トリフルオロメチル)ベンジル)カルバムイミドイル)-3,3-ジフルオロピロリジン-1-カルボキシイミドアミド,
N-(N-(3,4-ジクロロ)ベンジル)カルバムイミドイル)-3,3-ジフルオロピロリジン-1-カルボキシイミドアミド,
N-(N-フェネチルカルバムイミドイル)-3,3-ジフルオロピロリジン-1-カルボキシイミドアミド,
N-(N-(4-ブロモフェネチル)カルバムイミドイル)-3,3-ジフルオロピロリジン-1-カルボキシイミドアミド,
N-(N-(シクロプロピルメチル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-シクロプロピルカルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-シクロヘキシルカルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(シクロプロピルメチル)カルバムイミドイル)-3,3-ジフルオロピロリジン-1-カルボキシイミドアミド,
N-(N-(シクロプロピルカルバムイミドイル)-3,3-ジフルオロピロリジン-1-カルボキシイミドアミド,
N-(N-(シクロヘキシルカルバムイミドイル)-3,3-ジフルオロピロリジン-1-カルボキシイミドアミド,
N-(N-(3-ブロモベンジル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(4-ブロモベンジル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(4-(トリフルオロメトキシ)フェニル)カルバムイミドイル)-3,3-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(4-(トリフルオロメトキシ)フェニル)カルバムイミドイル)チアゾリジン-3-カルボキシイミドアミド,
N-(N-(4-(トリフルオロメトキシ)フェニル)カルバムイミドイル)-N-2,2-2-トリフルオロエチルアミノカルボキシイミドアミド,
N-(N-(4-(トリフルオロメトキシ)フェニル)カルバムイミドイル)-4-(トリフルオロメチル)ピペリジン-1-カルボキシイミドアミド,
N-(N-(4-(トリフルオロメトキシ)フェニル)カルバムイミドイル)-N-1-シクロプロピルメチルアミノカルボキシイミドアミド,
N-(N-(4-(トリフルオロメトキシ)フェニル)カルバムイミドイル)-3,4,4-トリフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(4-(トリフルオロメトキシ)フェニル)カルバムイミドイル)-4,4-ジフルオロ-3-メチルピペリジン-1-カルボキシイミドアミド,
N-(N-(4-(トリフルオロメトキシ)フェニル)カルバムイミドイル)-4-フルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(4-(トリフルオロメトキシ)フェニル)カルバムイミドイル)-(R)-3-フルオロピロリジン-1-カルボキシイミドアミド,
N-(N-(4-(トリフルオロメトキシ)フェニル)カルバムイミドイル)-6-アザスピロ[2.5]オクタン-6-カルボキシイミドアミド,
N-(N-(4-(トリフルオロメトキシ)フェニル)カルバムイミドイル)-3-アザビシクロ[3.1.0]ヘキサン-3-カルボキシイミドアミド,
N-カルバムイミドイル-3,3-ジフルオロピロリジン-1-カルボキシイミドアミド
N-カルバムイミドイル-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,及び
N-((4,4-ジフルオロピペリジン-1-イル)(イミノ)メチル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド。
ミトコンドリア内の電子伝達複合体は5つの複合体で構成されている。複雑体Iは解糖及びTCAサイクルで生成されたNADHから電子を受容し、電子は複合体II,III及びIVに移動し、最終的にO2に伝達され、水分子が生成される。電子伝達の際にプロトン勾配が発生し、この化学的勾配は複合体VでATPを合成する駆動源となる。複合体Iのミトコンドリア抑制は、複合体IVでの酸素消費速度(OCR)を測定することにより間接的に評価される。ミトコンドリアのETCが抑制されると、解糖がアップレギュレートし、乳酸の生産が増加する。
乳酸が細胞外に輸送されるにつれて、細胞外の溶液が酸性(低pH)になる。OCR及び細胞外酸性化速度(ECAR)はXFアナライザー(Seahorse Biosciences)により測定される。本発明の化合物は複合体Iの抑制によりOCRを低下させ、細胞代謝から解糖にリダイレクトすることによりECARを高める。
正常細胞は低グルコースのようなエネルギーストレス条件下で代償メカニズムを有すると想定されるため、通常のグルコース条件下では酸化的リン酸化(OXPHOS)の抑制による細胞毒性はない。しかしOXPHOS阻害剤は、グルコース欠乏条件(BirsoyK,2014)において細胞に対して毒性効果を示す。グルコース欠乏条件は、乏しい血管新生により起こり得る腫瘍微小環境で観察される。従って、OXPHOS阻害剤は、腫瘍微小環境を作り得る低グルコース条件の癌細胞に対して抗癌効果を示すことができる。
本発明の化合物をマウスにおける異種移植ヒト癌モデルを用いて生体内で評価した。本発明の化合物を経口又は腹腔内注射で投与された。腫瘍細胞株を単層培養で生体外培養した。免疫系が破損した雌BALB/cヌードマウスを使用し、腫瘍が発達するように腫瘍細胞を各マウスの右脇腹に皮下接種した。腫瘍の大きさが約100 mm3に達したときに処理を開始した。
1H NMR (600MHz, DMSO-d6) δ 10.04 (s, 1H), 7.95 (s, 2H), 7.37 (d, J=7.8Hz, 2H), 7.31 (t, J=7.8Hz, 2H), 7.24 (s, 2H), 7.05 (t, J=7.2HZ, 1H), 3.60 (m, 4H), 2.08 (m, 4H) LCMS 382.1 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 9.98 (s, 1H), 7.95 (s, 2H), 7.31 (s, 2H), 7.08 (d, J=7.8Hz, 1H), 7.01 (s, 1H), 6.99 (d, J=7.8Hz, 1H), 3.61 (m, 4H), 2.66 (m, 4H), 2.07 (m, 4H), 1.70 (m, 4H) LCMS 336.1[M+H]+
1H NMR (600MHz, DMSO-d6) δ 10.43 (s, 1H), 8.09 (s, 2H), 7.74 (d, J=2.4Hz, 1H), 7.55 (d, J=9.0HZ, 1H), 7.34 (d, J=9.0Hz, 1H), 7.25 (s, 2H), 3.62 (m, 4H), 2.10 (m, 4H) LCMS 350.0, 352.0 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 9.02 (s, 1H), 7.89 (s, 1H), 7.65 (d, J=7.8Hz, 1H), 7.60 (d, J=8.4Hz, 1H), 7.39 (s, 2H), 7.35 (t, J=7.2Hz, 2H), 7.11 (t, J=7.8Hz, 1H), 3.55 (m, 4H), 2.04 (m, 4H) LCMS 360.0, 362.0[M+H]+
1H NMR (600MHz, DMSO-d6) δ 10.21 (s, 1H), 8.01 (s, 2H), 7.67 (s, 1H), 7.34 (d, J=7.8Hz, 1H), 7.24 (t, J=8.4Hz, 1H), 7.22 (s, 2H), 3.61 (m, 4H), 2.10 (m, 4H) LCMS 360.0, 362.0 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 10.35 (s, 1H), 8.08 (s, 2H), 7.48 (d, J=8.4Hz, 2H), 7.37 (d, J=8.4HZ, 2H), 7.31 (s, 4H), 3.63 (m, 4H), 2.11 (m, 4H) LCMS 360.0, 362.0 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 10.31 (s, 1H), 7.93 (s, 2H), 7.50 (d, J=9.6Hz, 2H)(, 7.31 (d, J=8.4Hz, 2H), 7.18 (s, 2H), 4.45 (s, 1H), 4.19 (d, J=12.6Hz, 1H), 3.43 (m, 1H), 2.97 (m, 1H), 2.68 (s, 6H), 2.15 (m, 2H), 1.72 (m, 2H) LCMS 373.1 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 9.99 (s, 1H), 7.92 (s, 2H), 7.32 (d, J=8.4Hz, 2H), 7.23 (d, J=8.4Hz, 2H), 7.20 (s, 2H), 3.60 (m, 4H), 2.44 (s, 3H), 2.08 (m, 4H) LCMS 328.3 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 10.35 (s, 1H), 8.06 (s, 2H), 7.62 (m, 2H), 7.56 (m, 2H), 7.23 (s, 2H), 3.61 (s, 4H), 2.10 (m, 4H) LCMS 382.3 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 9.91 (s, 1H), 7.90 (s, 2H), 7.26 (m, 2H), 7.25 (s, 2H), 7.18 (m, 2H), 3.60 (m, 4H), 2.84 (m, 1H), 2.07 (m, 4H) 1.18 (d, J= 7.2Hz, 6H) LCMS 324.3 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 10.30 (s, 1H), 8.05 (s, 2H)), 7.66 (m, 1H), 7.36 (s, 2H), 7.32 (m, 1H), 7.30 (s, 2H), 3.61 (m, 4H), 1.99 (m, 4H) LCMS 334.1 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 9.34 (s, 1H), 7.83 (s, 2H), 7.44 (s, 2H), 7.18 (d, J=7.8HZ, 1H), 7.06 (t, J=7.8Hz, 1H), 6.94 (d, J=7.8Hz, 1H), 3.36 (m, 4H), 2.71 (m, 4H), 2.03 (m, 4H), 1.69 (m, 4H) LCMS 336.4 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 10.10 (s, 1H), 7.91 (s, 2H), 7.42 (m, 2H), 7.27 (m, 1H), 7.25 (s, 1H), 7.18 (s, 2H), 7.15 (m, 1H), 7.13 (m, 1H), 7.07 (m, 1H), 7.00 (m, 2H), 3.56 (s, 4H), 2.03 (s, 4H) LCMS 374.1 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 10.23 (brs, 0.5H), 7.92 (brs, 1H), 7.63 (m, 2H), 7.19 (m, 1H), 4.50 (s, 1H), 3.68 (m, 1H), 3.14 (m, 1H), 3.55 (m, 2H) LCMS 350.0 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 6.43 (brs, 2H), 3.76 (t, J=13.2 Hz, 2H), 3.71 (s, 3H), 3.59 (s, 3H), 3.55 (t, J=7.2 Hz, 2H), 2.44 (m, 2H), 1.76 (s, 3H) LCMS 358.2 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 7.79 (m, 1H), 7.46 (d, J=9.0 Hz, 1H), 7.29 (m, 1H), 7.22 (m, 1H), 4.45 (m, 1H), 3.71 (m, 2H), 3.38 (m, 2H), 2.10 (m, 2H), 1.79 (m, 2H) LCMS 364.1 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 7.31 (s, 2H), 7.22 (d, J=9.0Hz, 2H), 3.58 (m, 4H), 2.00 (m, 4H), 175 (s, 3H) LCMS 366.1 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 10.52 (s, 1H), 8.08 (s, 2H), 7.81 (d, J=8.4Hz, 1H), 7.71 (d, J=2.4Hz, 1H), 7.29 (s, 2H), 7.10 (dd, J=8.4Hz, 2.4Hz, 1H), 3.62 (s, 4H), 1.90 (s, 4H) LCMS 442.0 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 7.17 (s, 2H), 6.81 (m, 2H), 3.54 (s, 4H), 1.98 (s, 4H), 1.71 (s, 3H) LCMS 312.2 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 7.13 (t, J=8.4Hz, 1H), 6.90 (s, 1H), 6.81 (d, J=7.2Hz, 1H), 6.54 (dd, J=8.4Hz, 1H), 3.57 (m, 4H), 2.01 (m, 4H), 1.73 (s, 3H) LCMS 312.2 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 7.57 (d, J=8.4Hz, 2H), 7.49 (d, J=7.2Hz, 2H), 3.60 (m, 4H), 2.04 (m, 4H), 1.76 (s, 3H) LCMS 350.2 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 7.74 (d, J=8.4Ha, 1H), 7.68 (s, 1H), 7.03 (d, J=7.2Hz, 1H), 3.59 (m, 4H), 2.50 (m, 4H), 1.76 (s, 3H) LCMS 487.0, 488.0[M+H]+
1H NMR (600MHz, DMSO-d6) δ 7.36 (m, 1H), 7.26 (s, 1H), 7.07 (m, 1H), 6.93 (m, 1H), 3.58 (m, 4H), 2.00 (m, 4H), 1.73 (s, 3H) LCMS 374.2 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 7.43 (m, 2H), 7.22 (m, 2H), 3.72 (m, 2H), 3.52 (q, 2H), 3.17 (m, 2H), 1.85 (m, 2H), 1.82 (s, 3H), 1.45 (m, 2H), 1.11 (t, 3H) LCMS 374.2 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 7.36 (s, 2H), 7.23 (d, J=9.0Hz, 2H), 7.78 (t, J=12.6Hz, 2H), 2.57 (t, J=7.2Hz, 2H), 2.47 (m, 2H), 1.75 (s, 3H) LCMS 352.1 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 10.42 (s, 1H), 8.06 (s, 2H), 7.86 (m, 1H), 7.65 (d, J= 8.4Hz, 1H), 7.31 (m, 1H), 7.23 (s, 2H), 3.62 (s, 4H), 2.10 (s, 4H) LCMS 440.1 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 6.73 (m, 1H), 6.40 (m, 1H), 6.37 (m, 1H), 2.91 (s, 4H), 1.28 (s, 4H), 1.14 (s, 3H) LCMS 3842 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 7.35 (m, 2H), 7.18 (m, 2H), 7.18 (brs, 2H), 7.07 (m, 2H), 6.94 (m, 2H), 3.76 (m, 2H), 3.56 (m, 2H), 2.46 (m, 2H), 1.76 (s, 3H) LCMS 360.0 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 7.37 (t, J=7.8Hz, 2H), 7.12 (m, 2H), 7.01 (m, 4H), 6.57 (m, 1H), 3.70 (t, J=7.2Hz, 2H), 2.44 (m, 2H), 1.74 (s, 3H) LCMS 360.0 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 7.55 (m, 2H), 7.55 (m, 2H), 7.44 (brs, 2H), 3.79 (t, J=12.6Hz, 2H), 3.58 (t, J=7.8 Hz, 2H), 2.48 (m, 2H), 1.77 (s, 3H) LCMS 368.0 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 7.55 (m, 2H), 7.70 (m, 1H), 7.37 (brs, 1H), 6.87 (brs, 1H), 3.77 (t, J=13.2Hz, 2H), 3.56 (t, J=7.2 Hz, 2H), 2.47 (m, 2H), 1.80 (s, 3H) LCMS 427.9 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 7.55 (m, 2H), 7.35 (m, 2H), 3.79 (t, J=12.6Hz, 2H), 3.58 (t, J=7.8 Hz, 2H), 2.48 (m, 2H), 1.80 (s, 3H) LCMS 336.0 [M+H]+
1H NMR (600MHz, DMSO-d6) δ .37 (dd, J=7.2 Hz, 1H), 7.20 (m, 1H), 7.06 (brs, 1H), 6.91 (m, 1H), 3.75 (t, J=13.2 Hz, 2H), 3.54 (t, J=7.8 Hz, 2H), 2.46 (m, 2H), 1.88 (s, 3H) LCMS 302.0 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 7.53 (dd, J=18 Hz, 1H), 7.22 (m, 1H), 7.00 (d, J=7.2 Hz, 1H), 6.88 (m, 1H), 3.76 (t, J=13.2 Hz, 2H), 3.55 (t, J=7.2 Hz, 2H), 2.45 (m, 2H), 1.88 (s, 3H) LCMS 345.9, 347.0 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 7.42 (m, 1H), 7.21 (m, 2H), 7.0 (m, 1H), 3.68 (m, 2H), 3.54 (m, 2H), 2.42 (m, 2H), 1.89 (s, 3H) LCMS 336.0, 337.9 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 7.17 (m, 2H), 6.85 (m, 2H), 3.65 (m, 2H), 3.49 (s, 2H), 2.48 (m, 4H), 1.78 (s, 3H), 1.51 (m, 2H), 0.86 (s, 3H) LCMS 310.1 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 6.41 (brs, 2H), 6.11 (d, J=18 Hz, 2H),3.77 (t, J=12.6 Hz, 2H), 3.55 (s, 3H), 3.56 (t, J=6.6 Hz, 2H), 2.46 (m, 2H), 1.76 (s, 3H) LCMS 328.1 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 7.36 (m, 2H), 7.19 (brs, 1H), 3.77 (t, J=13.8 Hz, 2H), 3.56 (m, 2H), 2.46 (m, 2H), 1.81 (s, 3H) LCMS 386.1 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 7.51 (brs, 1H), 7.35 (d, J=8.4 Hz, 2H), 7.20 (brs, 2H), 3.78 (t, J=13.2 Hz, 2H), 3.37 (m, 2H), 2.46 (m, 2H), 1.80 (s, 3H) LCMS 432.0 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 7.69 (s, 1H), 7.62 (d, J=8.4Hz, 1H), 7.45 (d, J=6.6Hz, 1H), 7.40 (t, J=7.8Hz, 1H), 7.24 (t, J=7.2HZ, 1H), 7.11 (s, 2H), 4.40 (s, 2H), 3.54 (s, 4H), 2.09 (s, 4H) LCMS 374.1, 376.1 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 7.70 (s, 1H), 7.48 (s, 2H), 7.35 (d, J=7.8Hz, 2H), 7.05 (s, 2H), 4.44 (s, 2H), 3.56 (s, 4H), 1.98 (s, 4H) LCMS 380.4 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 7.62 (d, J=7.8Hz, 2H), 7.35 (s, 1H), 7.03 (s, 3H), 4.38 (s, 2H), 3.56 (s, 4H), 2.08 (s, 4H) LCMS 364.1 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 7.69 (m, 2H), 7.51(m, 2H), 4.42 (d, J=4.8Hz, 2H), 3.67 (brs, 2H), 3.50 (m, 2H), 2.45 (m, 2H) LCMS: 350.1 [M+H]+
1H NMR (600MHz, CD3OD) δ 7.64 (m, 4H), 7.54 (m, 3H), 4.50 (s, 2H), 3.71 (brs, 2H), 3.62 (m, 2H) 2.46 (m, 2H) LCMS: 350.2 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 8.01 (m, 1H), 7.58 (m, 2H), 7.47 (brs, 2H), 7.29 (m, 2H), 7.07 (brs, 2H), 4.33 (d, J=6.0Hz, 2H), 3.70 (brs, 2H), 3.52 (brs, 2H), 2.48 (m, 2H) LCMS: 350.0, 352.0 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 7.33 (s, 1H), 7.25 (m, 5H), 3.75 (m, 2H), 3.57 (m, 2H), 3.34 (m, 2H), 2.78 (m, 2H), 2.49 (m, 2H) LCMS 266.1 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 7.48 (m, 2H), 7.24 (m, 2H), 3.78 (m, 2H), 3.57 (m, 2H), 3.35 (m, 2H), 2.76 (m, 2H), 2.49 (m, 2H) LCMS 374.0 376.0 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 8.19 (s, 1H), 7.59 (s, 2H), 6.89 (s 1H), 3.59 (s, 4H), 3.12 (s, 2H) 1.98 (s, 4H), 0.99 (s, 2H), 0.45 (s, 2H), 0.21 (s, 2H) LCMS 260.1 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 8.10 (s, 1H), 7.59 (s, 2H), 6.83 (s 1H), 3.31 (s, 4H), 3.22 (s, 1H), 1.88 (s, 4H), 1.12 (s, 4H) LCMS 246.1[M+H]+
1H NMR (600MHz, DMSO-d6) δ 8.19 (s, 1H), 7.34 (s, 2H), 7.00 (s, 2H), 3.81 (m, 4H), 3.63 (m, 1H), 3.31 (m, 2H), 2.99 (m, 2H), 2.30 (m, 4H), 2.20 (m, 4H), 1.02 (m, 2H) LCMS 288.0 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 8.02 (s, 1H), 7.48 (s, 2H), 6.88(s 1H), 3.31 (m, 4H), 3.31 (s, 2H), 2.00 (s, 2H), 1.01 (s, 1H) 0.45 (s, 2H), 0.21 (s, 2H) LCMS 246.0 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 8.12 (s, 1H), 7.58 (s, 2H), 6.78(s 1H), 3.31 (m, 4H), 3.31 (s, 1H), 2.00 (s, 2H), 089 (s, 4H) LCMS 232.0 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 8.00 (s, 1H), 7.12 (s, 2H), 6.93 (s, 2H), 3.91 (m, 4H), 3.77 (m, 1H), 3.31 (m, 4H), 2.97 (m, 2H), 232 (m, 2H), 2.19 (m, 4H), 1.05 (m, 2H)
1H NMR (600MHz, DMSO-d6) δ 7.59 (s, 1H), 7.46 (d, J=7.8Hz, 1H), 7.30 (m, 1H), 4.33 (s, 2H), 3.52 (s, 4H), 3.34 (s, 3H), 1.97 (s, 4H) LCMS 374.1, 376.1 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 7.54 (d, J=8.4Hz, 2H), 7.26 (d, J=7.8Hz, 2H), 4.29 (s, 2H), 3.56 (s, 4H), 3.32 (s, 3H), 1.98 (s, 4H) LCMS 374.1, 376.1 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 7.91 (m, 1H), 7.44 (m, 1H), 7.28 (m, 1H), 7.15 (m, 1H), 3.84 (t, J=12 Hz, 1H), 3.50 (m, 5H), 2.08 (m, 1H), 1.70 (m, 1H) LCMS 366.1 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 7.82 (m, 1H), 7.49 (m, 1H), 7.30 (d, J=18 Hz, 1H), 7.13 (m, 1H), 4.76 (brs, 2H), 4.47 (m, 1H), 3.64 (d, J=6.6 Hz, 1H), 3.12 (m, 1H), 1.70 (m, 1H) LCMS 334.0 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 8.27 (brs, 1H), 7.51 (m, 2H), 7.44 (m, 2H), 7.28 (m, 2H), 6.00 (brs, 3H), 4.00 (m, 2H) LCMS 344.1 [M+H]+
1H NMR (600MHz, CD3OD) δ 7.46 (m, 2H), 7.25 (d, J=9.0 Hz, 2H), 7.29 (m, 1H), 7.21 (d, J=12.6Hz, 1H), 3.05 (t, J=12.6Hz, 2H), 2.54 (m, 1H), 1.95 (m, 2H),1.60 (m, 2H) LCMS 398.1 [M+H]+
1H NMR (600MHz, DMSO-d6) δ 9.86 (brs, 1H), 7.84 (brs, 1H), 7.47 (m, J=7.2Hz, 2H), 7.29 (m,2H), 7.15 (brs, 1H), 2.99 (d, J=5.4Hz, 2H), 1.16 (m, 1H), 0.44 (m, 2H) 0.22 (m, 2H) LCMS 316.11 [M+H]+
1H NMR (600MHz, CD3OD) δ 7.43 (m, 2H), 7.25 (m, 2H), 4.82 (m, 2H), 4.39 (m, 1H), 4.05 (m, 1H), 3.56 (m, 1H), 2.27 (m, 1H), 2.13 (m, 1H) LCMS 384.1 [M+H]+
1H NMR (600MHz, CD3OD) δ 7.43 (m, 2H), 7.25 (m, 2H), 3.95 (m, 2H), 3.34 (m, 1H), 3.06 (m, 1H), 2.15 (m, 1H), 1.99 (m, 1H), 1.03 (s, 3H) LCMS 380.1 [M+H]+
1H NMR (600MHz, CD3OD) δ 7.44 (m, 2H), 7.23 (m, 2H), 4.93 (m, 1H), 3.62 (m, 4H), 1.89 (m, 4H) LCMS 348.1 [M+H]+
1H NMR (600MHz, CD3OD) δ 7.45 (d, J=9.0Hz, 2H), 7.22 (d, J=9.0Hz, 2H), 5.24 (m, 1H), 3.63 (m, 4H), 2.59 (m, 2H) LCMS 334.1 [M+H]+
1H NMR (600MHz, CD3OD) δ 7.45 (d, J=9.0Hz, 2H), 7.22 (d, J=9.0Hz, 2H), 3.60 (t, J=5.4Hz, 4H), 1.47 (t, J=6.0Hz, 4H), 1.47 (m, 4H) LCMS 356.1 [M+H]+
1H NMR (600MHz, CD3OD) δ 7.45 (m, 2H), 7.22 (m, 2H), 3.69 (m, 1H), 3.54 (m, 3H), 3.31 (m, 1H), 1.74(m, 1H), 0.84 (m, 1H), 0.21 (m, 1H) LCMS 328.1 [M+H]+
1H NMR (600MHz, DMSO) δ 7.37 (s, 2H), 7.02 (s , 3H), 3.78 (m, 2H), 3.57 (m, 4H) LCMS 191.1 [M+H]+
1H NMR (600MHz, CD3OD) δ 3.69 (m, 4H), 2.06 (m, 4H) LCMS: 206.1 [M+H]+
1H NMR (600MHz, CD3OD) δ 3.65 (m, 8H), 1.99 (m, 8H) LCMS: 310.1[M+H]+
米国培養細胞系統保存機関から購入したA549細胞[CCL-185(登録商標)]を、10%ウシ胎児血清(FBS)及び抗生物質-抗真菌剤(LifetecH、CA)が添加されたRPMI 1640で培養した。A549細胞を0.5%トリプシンEDTAで分離し、3000個の細胞を1mg/mlのポリ-D-リジン(Sigma、P6407)がコーティングされたXF 96ウェル培地にプレーティングした。A549細胞を、37℃の温度及び5%CO2の条件下で24時間ウェルに付着させた。XFアナライザーのセンサーカートリッジを、透明な96ウェルプレート内の20μlの較正溶液(Seahorse、MA)に37℃で24時間浸漬させた。本発明の化合物をFBS無添加RPMI 1640で希釈し、XF 96ウェルプレート上のA549細胞に移した後、37℃及び5%CO2で23時間さらに培養した。培養後、化合物溶液を15 mMのD-グルコース(Sigma),15 mMのピルビン酸ナトリウム(Lifetechnologies、CA)及び4mMのL-グルタミン(Lifetechnologies、CA)が添加され、予熱及びpH調節(pH 7.4)を施したXFアッセイ培地(Seahorse)に交換した。本発明の化合物をXFアッセイ培地に準備し、アッセイプレートに追加した。アッセイプレートをXFアナライザーで1時間平衡化し、センサーカートリッジで判読を開始した。細胞毒性アッセイは、化合物の細胞毒性の抑制を較正するためにCyquant(Lifetechnologies、CA)を使用して行った。前記化合物を0,0.5,1,5,10及び20μMの濃度で試験し、阻害値からIC50値を得た。すなわち、化合物の各濃度におけるOCR阻害値から、プリズムの用量反応曲線フィッティングによりIC50を計算した。
Aレベル:IC50 < 2μM
Bレベル:IC50 = 2〜4μM
Cレベル:IC50 > 4μM
化合物の試験結果により、化合物をA,B及びCに分類した。試験結果を表1にまとめる。試験化合物は良好なOCR抑制効果を有し、優れたOXPHOX阻害剤であることを示した。OCR抑制活性を有する化合物のほとんどはECARが増加した。
ATCC(MA)から購入したメラノーマ細胞株SK-MEL-28(HTB-72)を10%FBS及び抗生物質-抗真菌剤(Lifetechnologies、CA)が添加されたRPMI 1640培地(Lifetechnologies、CA)で培養した。RPMI 1640(-グルコース)を用いて低グルコース培地を調製し、0.75 mMのグルコースにSigma社のD-(+)-グルコース溶液を添加した。SK-MEL-28細胞を0.5%トリプシン-EDTAを用いて培養プレートから分離し、1,250個の細胞を低グルコース培地を有する96ウェルプレートにプレーティングした。37℃及び5%CO2で24時間培養した後、FBSフリー培地において細胞を本発明の化合物で72時間処理した。細胞毒性をMTT(AMRESCO、OH)アッセイにより測定した。NADH依存性細胞の酸化還元酵素は、MTTを紫色の不溶性テトラゾリウムに還元させる。酵素は、細胞数又は細胞のエネルギー状態に依存する。5mg/mlのMTT溶液をアッセイプレートの各ウェルに10μl添加し、ブランクウェルは除外した。プレートを37℃及び5%CO2で2時間培養した。MTT溶液を各ウェルから除去し、DMSOを100μl添加した。プレートを550 nmの波長でビクターX3マルチラベルカウンターにより判読した。
Aレベル:IC50 < 6μM
Bレベル:IC50 = 6~15μM
Cレベル:IC50 > 15μM
0.75 mMのグルコースにおいて化合物をSK-MEL-28細胞に処理したとき、細胞群の半分を死滅させるための化合物の濃度(IC50レベル)に応じて化合物をA、B及びCに分類した。試験結果を表1にまとめた。試験化合物は、低濃度で良好な細胞死滅効果を示し、優れた抗癌活性を示す。
A549,H1975(CRL5908、ATCC)又はU937細胞[CRL1593.2(登録商標)、ATCC]株を10%FBS及び抗生物質-抗真菌剤(Lifetechnologies、CA)が添加されたRPMI 1640培地(Lifetechnologies、CA)で培養した。ダサチニブ(Combi-Blocks、San Diego、CA)は、CMLの治療用として認可されたBcr-Abl-チロシンキナーゼ阻害剤及びSrcファミリーチロシンキナーゼ阻害剤である。GDC094(Selleckchem、Houston、TX)は、pan-PI3K阻害剤であり、種々の癌細胞に効果がある。H1975又はA549細胞を0.5%トリプシン-EDTA(Lifetechnologies、CA)を用いて培養プレートから分離し、懸濁させた。U937細胞を遠心分離法により遠心沈殿させた。96ウェルプレートにA549細胞を3,000細胞/ウェルの密度で播種し、H1975又はU937細胞を5,000細胞/ウェルの密度で播種し、37℃及び5%CO2で24時間付着させた。併用治療試験の前に、各化合物のIC50を各細胞株から得た。本発明の化合物の4つの濃度のうち、最高濃度をIC80とし、最低濃度を約IC30にした。他の抗癌剤の濃度は、IC80〜IC30の範囲にあった。96ウェルプレート内の培地を調製した化合物溶液と交換した。U937細胞以外の細胞の生存率を決めるために、72時間処理後にD-PBS(Lifetechnologies、CA)中の5mg/mlのMTTを各ウェルに10μl添加し、プレートを37℃及び5%CO2で2時間培養した。各ウェルからMTT溶液を除去した後にDMSOを100μl添加し、550 nmの波長でビクターX3マルチラベルカウンターにより判読した。併用指数をCalcusyn(Biosoft、UK)を用いて計算した。
SK-MEL-239腫瘍細胞株を、10%熱失活ウシ胎児血清,100 U/mlのペニシリン及び100μg/mlのストレプトマイシン及びL-グルタミン(2mM)を添加したRPMI 1640培地に単層として生体外の37℃及び空気中5%CO2環境下で維持した。腫瘍細胞を0.5%トリプシン-EDTA処理しながら週2回定期的に継代培養した。指数増殖期の増殖細胞を収穫し、腫瘍細胞接種のためにカウントした。
Claims (15)
- 化学式1を有する化合物,化学式6を有する化合物,薬学的に許容される塩,薬学的に許容される溶媒和物及びプロドラッグ誘導体からなる群から選ばれた化合物:
R3及びR4は独立的にH又はC1-C4アルキルであり、
nは0,1又は2であり、
R5はH,C3-C7シクロアルキル又は化学式2で表されるアリール基であり、
- 請求項1に記載の化合物であって、化学式1のR3及びR4は水素であることを特徴とする化合物。
- 請求項1に記載の化合物であって、前記化学式1を有する化合物は化学式4を有する化合物,薬学的に許容される塩,薬学的に許容される溶媒和物及びプロドラッグ誘導体からなる群から選ばれたものであり:
nは0,1又は2であり、
R5はH,C3-C7シクロアルキル又は化学式2で表されるアリール基であり、
- 請求項1に記載の化合物であって、化学式1においてR1及びR2はNが一緒に結合して5〜6員の飽和又は不飽和のヘテロシクロアルキル基を形成し、ハロゲンで置換され、
R3及びR4は独立的にHであり、
nは0,1又は2であり、
R5は化学式2で表されるアリール基であり、R6,R7,R8,R9及びR10は独立的にH,ハロゲン,C1-C4アルキル,C1-C4アルコキシ,C1-C4ハロアルキル,C1-C4ハロアルコキシ,SR11又はOR12であり、R11及びR12は独立的にC1-C3アルキル,C1-C3ハロアルキル又はC6-C10アリールであり、又は隣接する置換基に連結され、5〜6員の飽和環を形成することを特徴とする化合物。 - 請求項1に記載の化合物であって、化学式1においてR1及びR2はNが一緒に結合して5〜6員の飽和又は不飽和のヘテロシクロアルキル基を形成し、ハロゲンで置換され、
R3及びR4は独立的にHであり、
nは0であり、
R5は化学式2で表されるアリール基であり、R6,R7,R8,R9及びR10は独立的にC1-C4ハロアルコキシであることを特徴とする化合物。 - 以下の化合物,薬学的に許容される塩,薬学的に許容される溶媒和物及びプロドラッグ誘導体からなる群から選ばれた化合物:
N-(N-フェニルカルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(5,6,7,8-テトラヒドロナフタレン-2-イル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(3,4-ジクロロフェニル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(2-ブロモフェニル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(3-ブロモフェニル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(4-ブロモフェニル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(4-(トリフルオロメトキシ)フェニル)カルバムイミドイル)-4-(ジメチルアミノ)ピペリジン-1-カルボキシイミドアミド,
N-(N-(4-(メチルチオ)フェニル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(4-(トリフルオロメチルチオ)フェニル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(4-イソプロピルフェニル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(3-クロロ-4-フルオロフェニル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(5,6,7,8-テトラヒドロナフタレン-1-イル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(3-フェノキシフェニル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(4-(トリフルオロメチルチオ)フェニル)カルバムイミドイル)チアゾリジン-3-カルボキシイミドアミド,
N-(N-(3,4,5-トリメトキシフェニル)カルバムイミドイル)-3,3-ジフルオロピロリジン-1-カルボキシイミドアミド,
N-(N-(4-(トリフルオロメトキシ)フェニル)カルバムイミドイル)-4-クロロピペリジン-1-カルボキシイミドアミド,
N-(N-(4-(トリフルオロメトキシ)フェニル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(3-クロロ-4-ヨードフェニル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(4-メトキシフェニル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(3-メトキシフェニル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(4-(トリフルオロメチル)フェニル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(3-ブロモ-4-ヨードフェニル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(4-フェノキシフェニル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(4-(トリフルオロメトキシ)カルバムイミドイル)-4-エトキシピペリジン-1-カルボキシイミドアミド,
N-(N-(4-(トリフルオロメトキシ)フェニル)カルバムイミドイル)-3,3-ジフルオロピロリジン-1-カルボキシイミドアミド,
N-(N-(3,4-ジブロモフェニル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(3-フルオロ-4-(トリフルオロメトキシ)フェニル)カルバムイミドイル)-4,4-フルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(4-フェノキシフェニル)カルバムイミドイル)-3,3-ジフルオロピロリジン-1-カルボキシイミドアミド,
N-(N-(3-フェノキシフェニル)カルバムイミドイル)-3,3-ジフルオロピロリジン-1-カルボキシイミドアミド,
N-(N-(4-(トリフルオロメチル)フェニル)カルバムイミドイル)-3,3-ジフルオロピロリジン-1-カルボキシイミドアミド,
N-(N-(3-クロロ-4-ヨードフェニル)カルバムイミドイル)-3,3-ジフルオロピロリジン-1-カルボキシイミドアミド,
N-(N-(4-(トリフルオロメチルチオ)フェニル)カルバムイミドイル)-3,3-ジフルオロピロリジン-1-カルボキシイミドアミド,
N-(N-(2-クロロフェニル)カルバムイミドイル)-3,3-ジフルオロピロリジン-1-カルボキシイミドアミド,
N-(N-(2-ブロモフェニル)カルバムイミドイル)-3,3-ジフルオロピロリジン-1-カルボキシイミドアミド,
N-(N-(2,4-ジクロロフェニル)カルバムイミドイル)-3,3-ジフルオロピロリジン-1-カルボキシイミドアミド,
N-(N-(2-プロピルフェニル)カルバムイミドイル)-3,3-ジフルオロピロリジン-1-カルボキシイミドアミド,
N-(N-3,4-ジメトキシフェニル)カルバムイミドイル)-3,3-ジフルオロピロリジン-1-カルボキシイミドアミド,
N-(N-(3-クロロ-4-(トリフルオロメトキシ)フェニル)カルバムイミドイル)-3,3-ジフルオロピロリジン-1-カルボキシイミドアミド,
N-(N-(3-ブロモ-4-(トリフルオロメトキシ)フェニル)カルバムイミドイル)-3,3-ジフルオロピロリジン-1-カルボキシイミドアミド,
N-(N-(2-ブロモベンジル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(4-(トリフルオロメトキシ)ベンジル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(3,4-ジクロロベンジル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(4-トリフルオロメチル)ベンジル)カルバムイミドイル)-3,3-ジフルオロピロリジン-1-カルボキシイミドアミド,
N-(N-(3-トリフルオロメチル)ベンジル)カルバムイミドイル)-3,3-ジフルオロピロリジン-1-カルボキシイミドアミド,
N-(N-(3,4-ジクロロ)ベンジル)カルバムイミドイル)-3,3-ジフルオロピロリジン-1-カルボキシイミドアミド,
N-(N-フェネチルカルバムイミドイル)-3,3-ジフルオロピロリジン-1-カルボキシイミドアミド,
N-(N-(4-ブロモフェネチル)カルバムイミドイル)-3,3-ジフルオロピロリジン-1-カルボキシイミドアミド,
N-(N-(シクロプロピルメチル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-シクロプロピルカルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-シクロヘキシルカルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(シクロプロピルメチル)カルバムイミドイル)-3,3-ジフルオロピロリジン-1-カルボキシイミドアミド,
N-(N-(シクロプロピルカルバムイミドイル)-3,3-ジフルオロピロリジン-1-カルボキシイミドアミド,
N-(N-(シクロヘキシルカルバムイミドイル)-3,3-ジフルオロピロリジン-1-カルボキシイミドアミド,
N-(N-(3-ブロモベンジル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(4-ブロモベンジル)カルバムイミドイル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(4-(トリフルオロメトキシ)フェニル)カルバムイミドイル)-3,3-ジフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(4-(トリフルオロメトキシ)フェニル)カルバムイミドイル)チアゾリジン-3-カルボキシイミドアミド,
N-(N-(4-(トリフルオロメトキシ)フェニル)カルバムイミドイル)-N-2,2-2-トリフルオロエチルアミノカルボキシイミドアミド,
N-(N-(4-(トリフルオロメトキシ)フェニル)カルバムイミドイル)-4-(トリフルオロメチル)ピペリジン-1-カルボキシイミドアミド,
N-(N-(4-(トリフルオロメトキシ)フェニル)カルバムイミドイル)-N-1-シクロプロピルメチルアミノカルボキシイミドアミド,
N-(N-(4-(トリフルオロメトキシ)フェニル)カルバムイミドイル)-3,4,4-トリフルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(4-(トリフルオロメトキシ)フェニル)カルバムイミドイル)-4,4-ジフルオロ-3-メチルピペリジン-1-カルボキシイミドアミド,
N-(N-(4-(トリフルオロメトキシ)フェニル)カルバムイミドイル)-4-フルオロピペリジン-1-カルボキシイミドアミド,
N-(N-(4-(トリフルオロメトキシ)フェニル)カルバムイミドイル)-(R)-3-フルオロピロリジン-1-カルボキシイミドアミド,
N-(N-(4-(トリフルオロメトキシ)フェニル)カルバムイミドイル)-6-アザスピロ[2.5]オクタン-6-カルボキシイミドアミド,
N-(N-(4-(トリフルオロメトキシ)フェニル)カルバムイミドイル)-3-アザビシクロ[3.1.0]ヘキサン-3-カルボキシイミドアミド,
N-カルバムイミドイル-3,3-ジフルオロピロリジン-1-カルボキシイミドアミド,
N-カルバムイミドイル-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド,及び
N-((4,4-ジフルオロピペリジン-1-イル)(イミノ)メチル)-4,4-ジフルオロピペリジン-1-カルボキシイミドアミド。 - 請求項1〜6のいずれかに記載の化合物又はその薬学的に許容される塩を有効成分として含む、ミトコンドリアの酸化的リン酸化に関連する疾患予防又は治療するための医薬組成物。
- 請求項7に記載の医薬組成物であって、前記疾患は糖尿病,肥満,高脂血症,高コレステロール血症,脂肪肝,冠動脈疾患,骨粗しょう症,多嚢胞性卵巣症候群,メタボリック症候群,癌,筋肉痛,筋細胞の損傷及び横紋筋融解からなる群から選ばれた少なくとも1つであることを特徴とする医薬組成物。
- 請求項8に記載の医薬組成物であって、前記糖尿病はインスリン非依存性糖尿病であることを特徴とする医薬組成物。
- 請求項8に記載の医薬組成物であって、前記癌は子宮頸癌,乳癌,胃癌,脳腫瘍,大腸癌,肺癌,皮膚癌,血液癌及び肝臓癌からなる群から選ばれることを特徴とする医薬組成物。
- 請求項8に記載の医薬組成物であって、前記癌の治療が癌の再発又は転移の抑制を含むことを特徴とする医薬組成物。
- 請求項7に記載の医薬組成物であって、化学療法剤,抗癌剤,抗癌抗体薬剤,放射線,免疫療法剤及びキナーゼ阻害剤からなる群から選ばれた少なくとも1つの有効成分をさらに含むことを特徴とする医薬組成物。
- 請求項7に記載の医薬組成物であって、錠剤、カプセル剤、丸剤、顆粒剤、散剤、注射剤又は液剤として製剤化されることを特徴とする医薬組成物。
- 有効成分として、請求項1〜6のいずれかに記載の化合物又はその薬学的に許容される塩を必要とする対象体に投与することを含む、ミトコンドリアの酸化的リン酸化に関連する疾患を予防又は治療する方法。
- ミトコンドリアの酸化的リン酸化に関連する疾患の予防又は治療用の薬剤の製造において、請求項1〜6のいずれかに記載の化合物又はその薬学的に許容される塩の使用。
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KR20180087189A (ko) * | 2017-01-24 | 2018-08-01 | 연세대학교 산학협력단 | 염증성 질환, 자가면역 질환, 또는 이들의 조합을 예방 또는 치료하기 위한 약학적 조성물 및 이를 이용한 방법 |
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KR102364358B1 (ko) | 2022-02-17 |
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CN107635963A (zh) | 2018-01-26 |
CN107635963B (zh) | 2020-11-20 |
CA2984119A1 (en) | 2016-11-03 |
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US10590081B2 (en) | 2020-03-17 |
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