CA2884708A1 - Indolines - Google Patents
Indolines Download PDFInfo
- Publication number
- CA2884708A1 CA2884708A1 CA2884708A CA2884708A CA2884708A1 CA 2884708 A1 CA2884708 A1 CA 2884708A1 CA 2884708 A CA2884708 A CA 2884708A CA 2884708 A CA2884708 A CA 2884708A CA 2884708 A1 CA2884708 A1 CA 2884708A1
- Authority
- CA
- Canada
- Prior art keywords
- pharmaceutically acceptable
- acceptable salt
- alkyl
- phenyl
- methyl
- 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.)
- Abandoned
Links
- 150000002476 indolines Chemical class 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 145
- 150000003839 salts Chemical class 0.000 claims abstract description 96
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 23
- 201000011510 cancer Diseases 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 15
- 238000011282 treatment Methods 0.000 claims abstract description 8
- 125000003118 aryl group Chemical group 0.000 claims description 65
- 229910052736 halogen Inorganic materials 0.000 claims description 27
- 150000002367 halogens Chemical class 0.000 claims description 27
- -1 propanyl Chemical group 0.000 claims description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
- 230000001225 therapeutic effect Effects 0.000 claims description 7
- 239000004480 active ingredient Substances 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 238000011321 prophylaxis Methods 0.000 claims description 4
- JVKFCLCUILQTAK-GJULWVSJSA-N (2s)-n-(2,6-difluorophenyl)-3,3-dimethyl-1-[(2s)-3-methyl-2-[[(2s)-2-(methylamino)propanoyl]amino]butanoyl]-2h-indole-2-carboxamide Chemical compound O=C([C@H]1N(C2=CC=CC=C2C1(C)C)C(=O)[C@H](C(C)C)NC(=O)[C@H](C)NC)NC1=C(F)C=CC=C1F JVKFCLCUILQTAK-GJULWVSJSA-N 0.000 claims description 3
- 125000004431 deuterium atom Chemical group 0.000 claims description 3
- 239000013543 active substance Substances 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 25
- MIGUACSHWHEKTK-GKCIPKSASA-N CN[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N1[C@@H](Cc2ccccc12)C(=O)Nc1c(F)cccc1F Chemical compound CN[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N1[C@@H](Cc2ccccc12)C(=O)Nc1c(F)cccc1F MIGUACSHWHEKTK-GKCIPKSASA-N 0.000 claims 2
- ZESHOXYMIFEAJJ-CUEVJCNZSA-N Cl.CN[C@@H](C)C(=O)N[C@H](C(=O)N1[C@@H](Cc2ccccc12)C(=O)NCc1cc(F)ccc1C)c1ccccc1 Chemical compound Cl.CN[C@@H](C)C(=O)N[C@H](C(=O)N1[C@@H](Cc2ccccc12)C(=O)NCc1cc(F)ccc1C)c1ccccc1 ZESHOXYMIFEAJJ-CUEVJCNZSA-N 0.000 claims 2
- LNJVZIQSYQJJDL-XZTZNFCFSA-N (2S)-N-(2-methoxyphenyl)-1-[(2S)-2-[[(2S)-2-(methylamino)propanoyl]amino]-2-phenylacetyl]-2,3-dihydroindole-2-carboxamide hydrochloride Chemical compound Cl.CN[C@@H](C)C(=O)N[C@H](C(=O)N1[C@@H](Cc2ccccc12)C(=O)Nc1ccccc1OC)c1ccccc1 LNJVZIQSYQJJDL-XZTZNFCFSA-N 0.000 claims 1
- BUAAXJYLVOUDGL-RTFZILSDSA-N CN[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N1[C@@H](Cc2ccccc12)C(=O)NCc1cc(F)ccc1C Chemical compound CN[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N1[C@@H](Cc2ccccc12)C(=O)NCc1cc(F)ccc1C BUAAXJYLVOUDGL-RTFZILSDSA-N 0.000 claims 1
- BRAIPJPEKYOWOF-HSQYWUDLSA-N CN[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N1[C@@H](Cc2ccccc12)C(=O)NCc1ccccc1 Chemical compound CN[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N1[C@@H](Cc2ccccc12)C(=O)NCc1ccccc1 BRAIPJPEKYOWOF-HSQYWUDLSA-N 0.000 claims 1
- MQXBWRKEJIVKQK-RZDWPUGNSA-N CN[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N1[C@@H](Cc2ccccc12)C(=O)Nc1ccccc1C(=O)c1ccccc1 Chemical compound CN[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N1[C@@H](Cc2ccccc12)C(=O)Nc1ccccc1C(=O)c1ccccc1 MQXBWRKEJIVKQK-RZDWPUGNSA-N 0.000 claims 1
- GQOKLGQLZSGNEK-XERWJBQOSA-N Cl.CN[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N1[C@@H](Cc2ccccc12)C(N)=O Chemical compound Cl.CN[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N1[C@@H](Cc2ccccc12)C(N)=O GQOKLGQLZSGNEK-XERWJBQOSA-N 0.000 claims 1
- HZGCTAZDCKDJIJ-HJFUZJNISA-N Cl.CN[C@@H](C)C(=O)N[C@H](C(=O)N1[C@@H](Cc2ccccc12)C(=O)Nc1ccccc1)c1ccccc1 Chemical compound Cl.CN[C@@H](C)C(=O)N[C@H](C(=O)N1[C@@H](Cc2ccccc12)C(=O)Nc1ccccc1)c1ccccc1 HZGCTAZDCKDJIJ-HJFUZJNISA-N 0.000 claims 1
- DLFJLSUGARSODW-BGSGGWNSSA-N Cl.CN[C@@H](C)C(=O)N[C@H](C(=O)N1[C@@H](Cc2ccccc12)C(=O)Nc1ccccc1-c1ccccc1)c1ccccc1 Chemical compound Cl.CN[C@@H](C)C(=O)N[C@H](C(=O)N1[C@@H](Cc2ccccc12)C(=O)Nc1ccccc1-c1ccccc1)c1ccccc1 DLFJLSUGARSODW-BGSGGWNSSA-N 0.000 claims 1
- WHZUDFCJBPJMBV-QVVOIHHZSA-N Cl.CN[C@@H](C)C(=O)N[C@H](C(=O)N1[C@@H](Cc2ccccc12)C(N)=O)c1ccccc1 Chemical compound Cl.CN[C@@H](C)C(=O)N[C@H](C(=O)N1[C@@H](Cc2ccccc12)C(N)=O)c1ccccc1 WHZUDFCJBPJMBV-QVVOIHHZSA-N 0.000 claims 1
- 239000000243 solution Substances 0.000 description 45
- 125000000217 alkyl group Chemical group 0.000 description 34
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 28
- 239000011541 reaction mixture Substances 0.000 description 22
- 239000000203 mixture Substances 0.000 description 19
- 239000012044 organic layer Substances 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- TUMCWFMHZOUPDA-UHFFFAOYSA-N 2-ethylsulfanyl-1,3-benzothiazol-6-amine Chemical compound C1=C(N)C=C2SC(SCC)=NC2=C1 TUMCWFMHZOUPDA-UHFFFAOYSA-N 0.000 description 14
- 101100111638 Arabidopsis thaliana BIR2 gene Proteins 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- 108091007065 BIRCs Proteins 0.000 description 13
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 13
- 238000003818 flash chromatography Methods 0.000 description 13
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 102000050257 X-Linked Inhibitor of Apoptosis Human genes 0.000 description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- 239000000741 silica gel Substances 0.000 description 12
- 229910002027 silica gel Inorganic materials 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 108700031544 X-Linked Inhibitor of Apoptosis Proteins 0.000 description 11
- 230000010933 acylation Effects 0.000 description 11
- 238000005917 acylation reaction Methods 0.000 description 11
- 239000012267 brine Substances 0.000 description 11
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
- 102000011727 Caspases Human genes 0.000 description 10
- 108010076667 Caspases Proteins 0.000 description 10
- 102000055031 Inhibitor of Apoptosis Proteins Human genes 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- 239000013058 crude material Substances 0.000 description 10
- 238000010511 deprotection reaction Methods 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- ODUZJBKKYBQIBX-UHFFFAOYSA-N 2,6-difluoroaniline Chemical compound NC1=C(F)C=CC=C1F ODUZJBKKYBQIBX-UHFFFAOYSA-N 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 150000001412 amines Chemical class 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 239000002671 adjuvant Substances 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 235000019198 oils Nutrition 0.000 description 7
- 108090000765 processed proteins & peptides Proteins 0.000 description 7
- 238000002877 time resolved fluorescence resonance energy transfer Methods 0.000 description 7
- MAOBFOXLCJIFLV-UHFFFAOYSA-N (2-aminophenyl)-phenylmethanone Chemical compound NC1=CC=CC=C1C(=O)C1=CC=CC=C1 MAOBFOXLCJIFLV-UHFFFAOYSA-N 0.000 description 6
- KDOUBUZYGVSSLM-UHFFFAOYSA-N (5-fluoro-2-methylphenyl)methanamine Chemical compound CC1=CC=C(F)C=C1CN KDOUBUZYGVSSLM-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- 230000004913 activation Effects 0.000 description 5
- 230000006907 apoptotic process Effects 0.000 description 5
- JPYQFYIEOUVJDU-UHFFFAOYSA-N beclamide Chemical compound ClCCC(=O)NCC1=CC=CC=C1 JPYQFYIEOUVJDU-UHFFFAOYSA-N 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 125000004494 ethyl ester group Chemical group 0.000 description 5
- 239000006260 foam Substances 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- QHYYXPLERUSFAV-UHFFFAOYSA-N hydron;2-phenylaniline;chloride Chemical compound [Cl-].[NH3+]C1=CC=CC=C1C1=CC=CC=C1 QHYYXPLERUSFAV-UHFFFAOYSA-N 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- NNLWQJXKIXPTCK-UHFFFAOYSA-N (5-fluoro-2-methylphenyl)methanamine;hydrochloride Chemical compound Cl.CC1=CC=C(F)C=C1CN NNLWQJXKIXPTCK-UHFFFAOYSA-N 0.000 description 4
- 108010049207 Death Domain Receptors Proteins 0.000 description 4
- 102000009058 Death Domain Receptors Human genes 0.000 description 4
- 102100033189 Diablo IAP-binding mitochondrial protein Human genes 0.000 description 4
- MMCPOSDMTGQNKG-UHFFFAOYSA-N anilinium chloride Chemical compound Cl.NC1=CC=CC=C1 MMCPOSDMTGQNKG-UHFFFAOYSA-N 0.000 description 4
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 4
- 229960002685 biotin Drugs 0.000 description 4
- 239000011616 biotin Substances 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 235000015165 citric acid Nutrition 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 239000007903 gelatin capsule Substances 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 229920005862 polyol Polymers 0.000 description 4
- 150000003077 polyols Chemical class 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- VLHQXRIIQSTJCQ-LURJTMIESA-N (2s)-2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoic acid Chemical compound OC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C VLHQXRIIQSTJCQ-LURJTMIESA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- XCZCWGVXRBJCCD-UHFFFAOYSA-N 2-methoxyaniline;hydrochloride Chemical compound Cl.COC1=CC=CC=C1N XCZCWGVXRBJCCD-UHFFFAOYSA-N 0.000 description 3
- 108700003785 Baculoviral IAP Repeat-Containing 3 Proteins 0.000 description 3
- 102100021662 Baculoviral IAP repeat-containing protein 3 Human genes 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 239000007821 HATU Substances 0.000 description 3
- 102100024319 Intestinal-type alkaline phosphatase Human genes 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 125000006242 amine protecting group Chemical group 0.000 description 3
- 230000001640 apoptogenic effect Effects 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 239000008298 dragée Substances 0.000 description 3
- KISPUTPAKVZNBI-JTQLQIEISA-N ethyl (2s)-2,3-dihydro-1h-indole-2-carboxylate Chemical compound C1=CC=C2N[C@H](C(=O)OCC)CC2=C1 KISPUTPAKVZNBI-JTQLQIEISA-N 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
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- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- CHJNXKRZJYHZRQ-GJZGRUSLSA-N (2s)-1-[(2s)-3-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoyl]-2,3-dihydroindole-2-carboxylic acid Chemical compound C1=CC=C2N(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)[C@H](C(O)=O)CC2=C1 CHJNXKRZJYHZRQ-GJZGRUSLSA-N 0.000 description 2
- SZJPZVUZNHOPMZ-UWVGGRQHSA-N (2s)-3-methyl-2-[[(2s)-2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoyl]amino]butanoic acid Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C SZJPZVUZNHOPMZ-UWVGGRQHSA-N 0.000 description 2
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 2
- UWKQJZCTQGMHKD-UHFFFAOYSA-N 2,6-di-tert-butylpyridine Chemical compound CC(C)(C)C1=CC=CC(C(C)(C)C)=N1 UWKQJZCTQGMHKD-UHFFFAOYSA-N 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
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- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
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- JXCRODOXFYJLJE-UHFFFAOYSA-N CC1(C(N(C2=CC=CC=C12)C(=O)OC(C)(C)C)C(=O)OCC)C Chemical compound CC1(C(N(C2=CC=CC=C12)C(=O)OC(C)(C)C)C(=O)OCC)C JXCRODOXFYJLJE-UHFFFAOYSA-N 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 2
- 102000004039 Caspase-9 Human genes 0.000 description 2
- 108090000566 Caspase-9 Proteins 0.000 description 2
- 101710101225 Diablo IAP-binding mitochondrial protein Proteins 0.000 description 2
- 101710156605 Diablo homolog, mitochondrial Proteins 0.000 description 2
- 241000982822 Ficus obtusifolia Species 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 230000005775 apoptotic pathway Effects 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 229940098773 bovine serum albumin Drugs 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
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- 229910052801 chlorine Inorganic materials 0.000 description 2
- 210000001072 colon Anatomy 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 208000023958 prostate neoplasm Diseases 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 238000012216 screening Methods 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
- 230000001235 sensitizing effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- ABZLKHKQJHEPAX-UHFFFAOYSA-N tetramethylrhodamine Chemical compound C=12C=CC(N(C)C)=CC2=[O+]C2=CC(N(C)C)=CC=C2C=1C1=CC=CC=C1C([O-])=O ABZLKHKQJHEPAX-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 102000003390 tumor necrosis factor Human genes 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Indole Compounds (AREA)
- Epidemiology (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201261712317P | 2012-10-11 | 2012-10-11 | |
| US61/712,317 | 2012-10-11 | ||
| PCT/EP2013/070407 WO2014056755A1 (en) | 2012-10-11 | 2013-10-01 | Indolines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2884708A1 true CA2884708A1 (en) | 2014-04-17 |
Family
ID=49293651
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2884708A Abandoned CA2884708A1 (en) | 2012-10-11 | 2013-10-01 | Indolines |
Country Status (10)
| Country | Link |
|---|---|
| US (1) | US9403768B2 (enExample) |
| EP (1) | EP2906535B1 (enExample) |
| JP (1) | JP6333825B2 (enExample) |
| KR (1) | KR20150065718A (enExample) |
| CN (1) | CN104736519B (enExample) |
| CA (1) | CA2884708A1 (enExample) |
| HK (1) | HK1211025A1 (enExample) |
| MX (1) | MX2015004465A (enExample) |
| RU (1) | RU2015113959A (enExample) |
| WO (1) | WO2014056755A1 (enExample) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20170062481A (ko) | 2014-09-29 | 2017-06-07 | 뉴욕 인스티튜트 오브 테크놀로지 | 히스 전기도 교대맥을 기록하고 다양한 조건에 적용하는데 사용하기 위한 카테터 |
| WO2016079527A1 (en) | 2014-11-19 | 2016-05-26 | Tetralogic Birinapant Uk Ltd | Combination therapy |
| WO2016097773A1 (en) | 2014-12-19 | 2016-06-23 | Children's Cancer Institute | Therapeutic iap antagonists for treating proliferative disorders |
| CN109152843A (zh) | 2016-05-20 | 2019-01-04 | 豪夫迈·罗氏有限公司 | Protac抗体缀合物及其使用方法 |
| CA3148504A1 (en) | 2019-08-08 | 2021-02-11 | Institute For Cancer Research D/B/A/ The Research Institute Of Fox Chase Cancer Center | Combination therapy for treatment of cancer |
| WO2023056069A1 (en) | 2021-09-30 | 2023-04-06 | Angiex, Inc. | Degrader-antibody conjugates and methods of using same |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2733995B1 (fr) | 1995-05-09 | 1997-07-25 | Inst Nat Sante Rech Med | Inhibiteurs de l'inactivation de neuropeptides endogenes notamment la cholecystokinine, leurs procedes de preparation leur utilisation comme medicaments et procede de criblage de medicaments |
| CN1933847A (zh) * | 2004-01-16 | 2007-03-21 | 密歇根大学董事会 | Smac肽模拟物及其应用 |
| CA2573644A1 (en) * | 2004-07-12 | 2006-02-16 | Idun Pharmaceuticals, Inc. | Tetrapeptide analogs |
| CN101094833A (zh) * | 2004-07-12 | 2007-12-26 | 伊邓药品公司 | 四肽类似物 |
| NZ590550A (en) | 2008-08-02 | 2013-05-31 | Genentech Inc | Inhibitors of Apoptosis (IAP) for treating cancer |
-
2013
- 2013-10-01 EP EP13771145.3A patent/EP2906535B1/en not_active Not-in-force
- 2013-10-01 KR KR1020157009107A patent/KR20150065718A/ko not_active Withdrawn
- 2013-10-01 MX MX2015004465A patent/MX2015004465A/es unknown
- 2013-10-01 HK HK15111756.4A patent/HK1211025A1/xx unknown
- 2013-10-01 CA CA2884708A patent/CA2884708A1/en not_active Abandoned
- 2013-10-01 US US14/432,990 patent/US9403768B2/en not_active Expired - Fee Related
- 2013-10-01 JP JP2015536065A patent/JP6333825B2/ja not_active Expired - Fee Related
- 2013-10-01 CN CN201380052826.6A patent/CN104736519B/zh not_active Expired - Fee Related
- 2013-10-01 WO PCT/EP2013/070407 patent/WO2014056755A1/en not_active Ceased
- 2013-10-01 RU RU2015113959A patent/RU2015113959A/ru not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| WO2014056755A1 (en) | 2014-04-17 |
| MX2015004465A (es) | 2015-07-14 |
| HK1211025A1 (zh) | 2016-05-13 |
| JP2015534567A (ja) | 2015-12-03 |
| US9403768B2 (en) | 2016-08-02 |
| KR20150065718A (ko) | 2015-06-15 |
| EP2906535B1 (en) | 2018-08-08 |
| CN104736519A (zh) | 2015-06-24 |
| RU2015113959A (ru) | 2016-12-10 |
| EP2906535A1 (en) | 2015-08-19 |
| JP6333825B2 (ja) | 2018-05-30 |
| CN104736519B (zh) | 2018-12-04 |
| US20150246882A1 (en) | 2015-09-03 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Dead |
Effective date: 20181002 |