EP1087790A2 - Verwendung einer verbindung mit hoher affinität für den mitochondrialen benzodiazepine rezeptor in einem arzneimittel zur krebs-therapie - Google Patents

Verwendung einer verbindung mit hoher affinität für den mitochondrialen benzodiazepine rezeptor in einem arzneimittel zur krebs-therapie

Info

Publication number: EP1087790A2
Authority: EP; European Patent Office
Prior art keywords: group; phenyl; alkyl; carbon atoms; apoptosis
Prior art date: 1998-06-22
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 Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Withdrawn

Application number

EP99923718A

Other languages

English (en)

French (fr)

Inventor

Guido Kroemer

Tamara Hirsch

Didier Decaudin

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Centre National de la Recherche Scientifique CNRS

Original Assignee

Centre National de la Recherche Scientifique CNRS

Priority date (The priority date 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 date listed.)

1998-06-22

Filing date

1999-06-11

Publication date

2001-04-04

1999-06-11 Application filed by Centre National de la Recherche Scientifique CNRS filed Critical Centre National de la Recherche Scientifique CNRS

2001-04-04 Publication of EP1087790A2 publication Critical patent/EP1087790A2/de

Status Withdrawn legal-status Critical Current

Links

150000001875 compounds Chemical class 0.000 title claims abstract description 62
230000002438 mitochondrial effect Effects 0.000 title abstract description 17
SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 title abstract description 3
229940049706 benzodiazepine Drugs 0.000 title abstract description 3
238000011275 oncology therapy Methods 0.000 title description 3
230000006907 apoptotic process Effects 0.000 claims abstract description 53
239000003795 chemical substances by application Substances 0.000 claims abstract description 25
206010028980 Neoplasm Diseases 0.000 claims abstract description 17
230000001939 inductive effect Effects 0.000 claims abstract description 15
201000011510 cancer Diseases 0.000 claims abstract description 13
239000003814 drug Substances 0.000 claims abstract description 10
239000013066 combination product Substances 0.000 claims abstract description 6
229940127555 combination product Drugs 0.000 claims abstract description 6
229910052757 nitrogen Inorganic materials 0.000 claims description 54
125000000217 alkyl group Chemical group 0.000 claims description 34
239000000047 product Substances 0.000 claims description 30
125000004432 carbon atom Chemical group C* 0.000 claims description 28
-1 pyridyl radical Chemical group 0.000 claims description 27
125000004433 nitrogen atom Chemical group N* 0.000 claims description 24
238000011282 treatment Methods 0.000 claims description 19
125000000753 cycloalkyl group Chemical group 0.000 claims description 17
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
125000005843 halogen group Chemical group 0.000 claims description 16
230000006882 induction of apoptosis Effects 0.000 claims description 16
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
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 claims description 14
125000003545 alkoxy group Chemical group 0.000 claims description 14
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 14
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 14
LKJPYSCBVHEWIU-UHFFFAOYSA-N N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide Chemical compound C=1C=C(C#N)C(C(F)(F)F)=CC=1NC(=O)C(O)(C)CS(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-UHFFFAOYSA-N 0.000 claims description 12
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
239000003446 ligand Substances 0.000 claims description 11
108090000623 proteins and genes Proteins 0.000 claims description 11
102100031274 Translocator protein Human genes 0.000 claims description 10
101710166801 Translocator protein Proteins 0.000 claims description 10
125000001424 substituent group Chemical group 0.000 claims description 10
YDNKGFDKKRUKPY-JHOUSYSJSA-N C16 ceramide Natural products CCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)C=CCCCCCCCCCCCCC YDNKGFDKKRUKPY-JHOUSYSJSA-N 0.000 claims description 9
CRJGESKKUOMBCT-VQTJNVASSA-N N-acetylsphinganine Chemical compound CCCCCCCCCCCCCCC[C@@H](O)[C@H](CO)NC(C)=O CRJGESKKUOMBCT-VQTJNVASSA-N 0.000 claims description 9
229940106189 ceramide Drugs 0.000 claims description 9
ZVEQCJWYRWKARO-UHFFFAOYSA-N ceramide Natural products CCCCCCCCCCCCCCC(O)C(=O)NC(CO)C(O)C=CCCC=C(C)CCCCCCCCC ZVEQCJWYRWKARO-UHFFFAOYSA-N 0.000 claims description 9
238000004519 manufacturing process Methods 0.000 claims description 9
VVGIYYKRAMHVLU-UHFFFAOYSA-N newbouldiamide Natural products CCCCCCCCCCCCCCCCCCCC(O)C(O)C(O)C(CO)NC(=O)CCCCCCCCCCCCCCCCC VVGIYYKRAMHVLU-UHFFFAOYSA-N 0.000 claims description 9
125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 8
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 claims description 7
229960005420 etoposide Drugs 0.000 claims description 7
239000001257 hydrogen Substances 0.000 claims description 7
229910052739 hydrogen Inorganic materials 0.000 claims description 7
229910052760 oxygen Inorganic materials 0.000 claims description 7
239000001301 oxygen Substances 0.000 claims description 7
125000003884 phenylalkyl group Chemical group 0.000 claims description 7
125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 6
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 6
125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 6
RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 6
229910052794 bromium Inorganic materials 0.000 claims description 6
229960004679 doxorubicin Drugs 0.000 claims description 6
230000000861 pro-apoptotic effect Effects 0.000 claims description 6
125000001544 thienyl group Chemical group 0.000 claims description 6
210000004881 tumor cell Anatomy 0.000 claims description 6
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
125000003342 alkenyl group Chemical group 0.000 claims description 5
239000000460 chlorine Substances 0.000 claims description 5
229910052801 chlorine Inorganic materials 0.000 claims description 5
125000004076 pyridyl group Chemical group 0.000 claims description 5
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
108020004414 DNA Proteins 0.000 claims description 4
RAVIZVQZGXBOQO-UHFFFAOYSA-N PK-11195 Chemical compound N=1C(C(=O)N(C)C(C)CC)=CC2=CC=CC=C2C=1C1=CC=CC=C1Cl RAVIZVQZGXBOQO-UHFFFAOYSA-N 0.000 claims description 4
125000000304 alkynyl group Chemical group 0.000 claims description 4
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
125000005605 benzo group Chemical group 0.000 claims description 4
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
229910052731 fluorine Inorganic materials 0.000 claims description 4
125000005842 heteroatom Chemical group 0.000 claims description 4
229910052717 sulfur Inorganic materials 0.000 claims description 4
MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 3
102000003676 Glucocorticoid Receptors Human genes 0.000 claims description 3
108090000079 Glucocorticoid Receptors Proteins 0.000 claims description 3
108020004440 Thymidine kinase Proteins 0.000 claims description 3
125000004429 atom Chemical group 0.000 claims description 3
230000034994 death Effects 0.000 claims description 3
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 claims description 3
239000003862 glucocorticoid Substances 0.000 claims description 3
229910052740 iodine Inorganic materials 0.000 claims description 3
ZPYGDHPQNREYNO-UHFFFAOYSA-N isoquinoline;propanamide Chemical compound CCC(N)=O.C1=NC=CC2=CC=CC=C21 ZPYGDHPQNREYNO-UHFFFAOYSA-N 0.000 claims description 3
229960003538 lonidamine Drugs 0.000 claims description 3
WDRYRZXSPDWGEB-UHFFFAOYSA-N lonidamine Chemical compound C12=CC=CC=C2C(C(=O)O)=NN1CC1=CC=C(Cl)C=C1Cl WDRYRZXSPDWGEB-UHFFFAOYSA-N 0.000 claims description 3
125000004434 sulfur atom Chemical group 0.000 claims description 3
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 claims description 3
125000004455 (C1-C3) alkylthio group Chemical group 0.000 claims description 2
FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 claims description 2
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims description 2
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
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 claims description 2
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 claims description 2
229930012538 Paclitaxel Natural products 0.000 claims description 2
102000006601 Thymidine Kinase Human genes 0.000 claims description 2
239000000317 Topoisomerase II Inhibitor Substances 0.000 claims description 2
229940122803 Vinca alkaloid Drugs 0.000 claims description 2
125000004414 alkyl thio group Chemical group 0.000 claims description 2
229940100198 alkylating agent Drugs 0.000 claims description 2
239000002168 alkylating agent Substances 0.000 claims description 2
125000002947 alkylene group Chemical group 0.000 claims description 2
229940045799 anthracyclines and related substance Drugs 0.000 claims description 2
230000003432 anti-folate effect Effects 0.000 claims description 2
230000000340 anti-metabolite Effects 0.000 claims description 2
230000002927 anti-mitotic effect Effects 0.000 claims description 2
229940127074 antifolate Drugs 0.000 claims description 2
229940100197 antimetabolite Drugs 0.000 claims description 2
239000002256 antimetabolite Substances 0.000 claims description 2
239000003080 antimitotic agent Substances 0.000 claims description 2
VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical class C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 claims description 2
229910052799 carbon Inorganic materials 0.000 claims description 2
229960004397 cyclophosphamide Drugs 0.000 claims description 2
230000001461 cytolytic effect Effects 0.000 claims description 2
229960003901 dacarbazine Drugs 0.000 claims description 2
230000006378 damage Effects 0.000 claims description 2
229960003957 dexamethasone Drugs 0.000 claims description 2
239000003534 dna topoisomerase inhibitor Substances 0.000 claims description 2
239000011737 fluorine Substances 0.000 claims description 2
239000004052 folic acid antagonist Substances 0.000 claims description 2
229910052736 halogen Inorganic materials 0.000 claims description 2
150000002367 halogens Chemical class 0.000 claims description 2
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
229960000485 methotrexate Drugs 0.000 claims description 2
229960003539 mitoguazone Drugs 0.000 claims description 2
MXWHMTNPTTVWDM-NXOFHUPFSA-N mitoguazone Chemical compound NC(N)=N\N=C(/C)\C=N\N=C(N)N MXWHMTNPTTVWDM-NXOFHUPFSA-N 0.000 claims description 2
125000004043 oxo group Chemical group O=* 0.000 claims description 2
229960001592 paclitaxel Drugs 0.000 claims description 2
WSDQIHATCCOMLH-UHFFFAOYSA-N phenyl n-(3,5-dichlorophenyl)carbamate Chemical compound ClC1=CC(Cl)=CC(NC(=O)OC=2C=CC=CC=2)=C1 WSDQIHATCCOMLH-UHFFFAOYSA-N 0.000 claims description 2
150000004885 piperazines Chemical class 0.000 claims description 2
150000003057 platinum Chemical class 0.000 claims description 2
230000005855 radiation Effects 0.000 claims description 2
229940066771 systemic antihistamines piperazine derivative Drugs 0.000 claims description 2
229940063683 taxotere Drugs 0.000 claims description 2
BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical group C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 claims description 2
229940044693 topoisomerase inhibitor Drugs 0.000 claims description 2
239000013603 viral vector Substances 0.000 claims description 2
YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims 2
NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims 2
GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 claims 2
102000015790 Asparaginase Human genes 0.000 claims 1
108010024976 Asparaginase Proteins 0.000 claims 1
NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical class C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 claims 1
GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims 1
VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 claims 1
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 1
239000000365 Topoisomerase I Inhibitor Substances 0.000 claims 1
CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical group [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims 1
150000001335 aliphatic alkanes Chemical class 0.000 claims 1
229960003272 asparaginase Drugs 0.000 claims 1
DCXYFEDJOCDNAF-UHFFFAOYSA-M asparaginate Chemical compound [O-]C(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-M 0.000 claims 1
OYVAGSVQBOHSSS-WXFSZRTFSA-O bleomycin 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](OC1C(C(O)C(O)C(CO)O1)OC1C(C(OC(N)=O)C(O)C(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 OYVAGSVQBOHSSS-WXFSZRTFSA-O 0.000 claims 1
DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims 1
229960004316 cisplatin Drugs 0.000 claims 1
125000001316 cycloalkyl alkyl group Chemical group 0.000 claims 1
229960002949 fluorouracil Drugs 0.000 claims 1
125000000623 heterocyclic group Chemical group 0.000 claims 1
125000002768 hydroxyalkyl group Chemical group 0.000 claims 1
229960001330 hydroxycarbamide Drugs 0.000 claims 1
229960001428 mercaptopurine Drugs 0.000 claims 1
CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 claims 1
125000004430 oxygen atom Chemical group O* 0.000 claims 1
125000003386 piperidinyl group Chemical group 0.000 claims 1
229960003171 plicamycin Drugs 0.000 claims 1
239000011593 sulfur Substances 0.000 claims 1
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230000006698 induction Effects 0.000 abstract description 7
230000002459 sustained effect Effects 0.000 abstract 1
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 54
210000004027 cell Anatomy 0.000 description 46
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102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 31
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LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
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CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 22
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
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AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 7
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235000019364 tetracycline Nutrition 0.000 description 7
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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 1
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Classifications

- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/47—Quinolines; Isoquinolines

Definitions

the present invention relates to the use of the product described above for the manufacture of a medicament intended for the treatment of cancer.
said medicament is intended to induce the death of ct7 tumor cells or to facilitate apoptosis.
PKI 1 195 facilitates the induction of apoptosis by a variety of sti uli.
PK I 1 195 appears to be the most effective of the co- inducers of apoptosis (relative efficacy: PK I 1195 greater than 4'-chlordiazepam>diazepam> Ro-5-4864), this result correlates with the antagonistic potential of these compounds on the mBzR receptor (Zisterer et al 1997).
PK I 1195 The synergism between PK I 1195 and several pro-apoptotic agents extends to everything that characterizes the phenomenon of apoptosis. These phenomena include the early loss of mitochondrial transmembrane potential (measured using the potential-sensitive DiOC 6 (3) dye), increased generation of reactive oxygen species (measured by conversion of hydroethidine in ethidinc catalyzed by suproxide anions (see FIGS. 1 to 4), the eradication of phosphatidylserine residues on the surface of the plasma membrane measured using anncxinc V conjugated to F1TC (see FIG.
PKI 1195 overcomes the protection conferred by Bcl-2 against glucocorticoids (see Figure 3B), against ⁇ irradiation, doxorubicin, cyclosporin A (see Figure 4B), and etoposide. This effect is also observed in the mitochondrion, the cell redox potential, and the nuclei (see Figures 3 and 4).
the present invention relates to a new strategy for improving the susceptibility of cells by the induction of apoptosis.
Example 8 Process for the preparation of N, N-diélltyl [(pI ⁇ ényI-2 trifIuoro ⁇ néthyl-8 ⁇ i ⁇ oli ⁇ yl-4) oxy] -2 propanamide.
clones which were found to be significantly less sensitive to apoptosis induced by a range of concentrations of agents inducing apoptosis in the absence than in the presence of tetracycline in the culture medium, that is to say when they overexpress the protein Bcl2 rather than when they do not overexpress it.
the agents inducing apoptosis tested were for example adriamycin (10-100 ⁇ g / rnl), terbutyl-hydroperoxide (25-100 ⁇ M), vincristine (0.03-0.003 ⁇ g / ml) and camptothecin (0.01- 0.1 ⁇ g / ml).
To quantify the induction of apoptosis it is possible, for example, to use the method for assaying apoptosis induced in a cell population described in A.
the compound is incorporated into the cell culture medium in the absence of an apoptosis-inducing agent and the clone is cultured in the presence of tetracycline (1 ⁇ g / ml) or anhydrotetracycline (0.5 ⁇ g / ml), that is, it does not overexpress the Bcl2 protein. In this situation, the percentage of cells in apoptosis P4 is determined.

Landscapes

Health & Medical Sciences (AREA)
Chemical & Material Sciences (AREA)
Medicinal Chemistry (AREA)
Pharmacology & Pharmacy (AREA)
Epidemiology (AREA)
Life Sciences & Earth Sciences (AREA)
Animal Behavior & Ethology (AREA)
General Health & Medical Sciences (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

EP99923718A 1998-06-22 1999-06-11 Verwendung einer verbindung mit hoher affinität für den mitochondrialen benzodiazepine rezeptor in einem arzneimittel zur krebs-therapie Withdrawn EP1087790A2 (de)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
FR9807864		1998-06-22
FR9807864A FR2779963A1 (fr)	1998-06-22	1998-06-22	Utilisation d'un compose possedant une affinite pour le recepteur mitochondrial des benzodiazepines en therapie du cancer
PCT/FR1999/001383 WO1999066958A2 (fr)	1998-06-22	1999-06-11	Utilisation d'un compose possedant une affinite pour le recepteur mitochondrial des benzodiazepines en therapie du cancer

Publications (1)

Publication Number	Publication Date
EP1087790A2 true EP1087790A2 (de)	2001-04-04

Family

ID=9527686

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
EP99923718A Withdrawn EP1087790A2 (de)	1998-06-22	1999-06-11	Verwendung einer verbindung mit hoher affinität für den mitochondrialen benzodiazepine rezeptor in einem arzneimittel zur krebs-therapie

Country Status (6)

Country	Link
US (1)	US6319931B1 (de)
EP (1)	EP1087790A2 (de)
AU (1)	AU3508999A (de)
CA (1)	CA2274741A1 (de)
FR (1)	FR2779963A1 (de)
WO (1)	WO1999066958A2 (de)

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1998
- 1998-06-22 FR FR9807864A patent/FR2779963A1/fr not_active Withdrawn
1999
- 1999-06-11 WO PCT/FR1999/001383 patent/WO1999066958A2/fr not_active Ceased
- 1999-06-11 EP EP99923718A patent/EP1087790A2/de not_active Withdrawn
- 1999-06-14 US US09/332,152 patent/US6319931B1/en not_active Expired - Lifetime
- 1999-06-14 CA CA002274741A patent/CA2274741A1/fr not_active Abandoned
- 1999-06-16 AU AU35089/99A patent/AU3508999A/en not_active Abandoned

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9966958A3 *

Also Published As

Publication number	Publication date
WO1999066958A2 (fr)	1999-12-29
CA2274741A1 (fr)	1999-12-22
AU3508999A (en)	2000-01-06
WO1999066958A3 (fr)	2000-04-20
US6319931B1 (en)	2001-11-20
FR2779963A1 (fr)	1999-12-24

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