EA038226B1 - Синтез ингибитора mcl-1 - Google Patents
Синтез ингибитора mcl-1 Download PDFInfo
- Publication number
- EA038226B1 EA038226B1 EA201992235A EA201992235A EA038226B1 EA 038226 B1 EA038226 B1 EA 038226B1 EA 201992235 A EA201992235 A EA 201992235A EA 201992235 A EA201992235 A EA 201992235A EA 038226 B1 EA038226 B1 EA 038226B1
- Authority
- EA
- Eurasian Patent Office
- Prior art keywords
- methyl
- mol
- solvent
- dimethyl
- mixture
- Prior art date
Links
- 101001056180 Homo sapiens Induced myeloid leukemia cell differentiation protein Mcl-1 Proteins 0.000 title description 12
- 102100026539 Induced myeloid leukemia cell differentiation protein Mcl-1 Human genes 0.000 title description 12
- 230000015572 biosynthetic process Effects 0.000 title description 6
- 238000003786 synthesis reaction Methods 0.000 title description 5
- 239000003112 inhibitor Substances 0.000 title description 4
- 150000003839 salts Chemical class 0.000 abstract description 6
- 239000000543 intermediate Substances 0.000 description 150
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 144
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 76
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 72
- 239000000243 solution Substances 0.000 description 72
- 239000002904 solvent Substances 0.000 description 70
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 64
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 60
- 239000000203 mixture Substances 0.000 description 56
- -1 p-methoxybenzyl Chemical group 0.000 description 56
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 51
- 150000001875 compounds Chemical class 0.000 description 49
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 40
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 38
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 38
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- 238000000034 method Methods 0.000 description 32
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 31
- 239000002002 slurry Substances 0.000 description 28
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 26
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 22
- 239000012065 filter cake Substances 0.000 description 22
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical group CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 21
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical group [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 20
- 239000003795 chemical substances by application Substances 0.000 description 20
- 235000011121 sodium hydroxide Nutrition 0.000 description 20
- 238000007792 addition Methods 0.000 description 19
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 19
- 230000002194 synthesizing effect Effects 0.000 description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 18
- 125000006239 protecting group Chemical group 0.000 description 17
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
- 238000003756 stirring Methods 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 229940125904 compound 1 Drugs 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 13
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 13
- 238000005481 NMR spectroscopy Methods 0.000 description 13
- 239000002253 acid Substances 0.000 description 13
- 238000010438 heat treatment Methods 0.000 description 13
- 239000011541 reaction mixture Substances 0.000 description 13
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 13
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical group [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 12
- 239000003638 chemical reducing agent Substances 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 11
- 238000004458 analytical method Methods 0.000 description 11
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical group [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 description 11
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 11
- 238000001816 cooling Methods 0.000 description 10
- 239000012280 lithium aluminium hydride Substances 0.000 description 10
- 229910052763 palladium Inorganic materials 0.000 description 10
- 235000011118 potassium hydroxide Nutrition 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 9
- 239000003929 acidic solution Substances 0.000 description 9
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical group [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- 239000012279 sodium borohydride Substances 0.000 description 9
- 229910000033 sodium borohydride Inorganic materials 0.000 description 9
- 239000011780 sodium chloride Substances 0.000 description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical group CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- 206010028980 Neoplasm Diseases 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 238000002425 crystallisation Methods 0.000 description 8
- 230000008025 crystallization Effects 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 8
- 239000012071 phase Substances 0.000 description 8
- 238000000634 powder X-ray diffraction Methods 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- 239000003643 water by type Substances 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- PPHQKSSISUZPSX-UHFFFAOYSA-N 3-(2-carboxyethyl)-6-chloro-7-[3-[(4-methoxyphenyl)methoxymethyl]-1,5-dimethylpyrazol-4-yl]-1-methylindole-2-carboxylic acid Chemical compound C(=O)(O)CCC1=C(N(C2=C(C(=CC=C12)Cl)C=1C(=NN(C=1C)C)COCC1=CC=C(C=C1)OC)C)C(=O)O PPHQKSSISUZPSX-UHFFFAOYSA-N 0.000 description 7
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 7
- 150000001412 amines Chemical class 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 229910052739 hydrogen Chemical group 0.000 description 7
- 239000001257 hydrogen Chemical group 0.000 description 7
- RHTVZWCYCZFACI-UHFFFAOYSA-N methyl 5-(chloromethyl)-1-methylpyrazole-3-carboxylate Chemical compound ClCC1=CC(=NN1C)C(=O)OC RHTVZWCYCZFACI-UHFFFAOYSA-N 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 239000012011 nucleophilic catalyst Substances 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- 238000005292 vacuum distillation Methods 0.000 description 7
- SJKMBYJMUXVKHO-UHFFFAOYSA-N (3-acetylsulfanylnaphthalen-1-yl) acetate Chemical compound C(C)(=O)OC1=CC(=CC2=CC=CC=C12)SC(C)=O SJKMBYJMUXVKHO-UHFFFAOYSA-N 0.000 description 6
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 6
- XXDQHHLUXXFCCB-UHFFFAOYSA-N 3-[[5-(chloromethyl)-2-methylpyrazol-3-yl]methylsulfanyl]naphthalen-1-ol Chemical compound ClCC1=NN(C(=C1)CSC=1C=C(C2=CC=CC=C2C=1)O)C XXDQHHLUXXFCCB-UHFFFAOYSA-N 0.000 description 6
- KENDNOYJRXNRLF-UHFFFAOYSA-N 3-[[5-(hydroxymethyl)-2-methylpyrazol-3-yl]methylsulfanyl]naphthalen-1-ol Chemical compound OCC1=NN(C(=C1)CSC=1C=C(C2=CC=CC=C2C=1)O)C KENDNOYJRXNRLF-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 239000012346 acetyl chloride Substances 0.000 description 6
- 238000000113 differential scanning calorimetry Methods 0.000 description 6
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical group OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 6
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 239000012022 methylating agents Substances 0.000 description 6
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 6
- 239000002243 precursor Substances 0.000 description 6
- 239000008213 purified water Substances 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 238000002411 thermogravimetry Methods 0.000 description 6
- XSECUJSMUXCNJW-UHFFFAOYSA-N (4-bromo-1,5-dimethylpyrazol-3-yl)methanol Chemical compound CC1=C(Br)C(CO)=NN1C XSECUJSMUXCNJW-UHFFFAOYSA-N 0.000 description 5
- MOKZLNVPSPAZJM-UHFFFAOYSA-N COC1=CC=C(COCC2=NN(C(=C2B2OC(C(O2)(C)C)(C)C)C)C)C=C1 Chemical compound COC1=CC=C(COCC2=NN(C(=C2B2OC(C(O2)(C)C)(C)C)C)C)C=C1 MOKZLNVPSPAZJM-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 5
- 230000002378 acidificating effect Effects 0.000 description 5
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 238000010931 ester hydrolysis Methods 0.000 description 5
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 5
- 229940011051 isopropyl acetate Drugs 0.000 description 5
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 5
- BNOIAOZCIQESFA-UHFFFAOYSA-N methyl 7-bromo-6-chloro-3-(3-methoxy-3-oxopropyl)-1H-indole-2-carboxylate Chemical compound BrC=1C(=CC=C2C(=C(NC=12)C(=O)OC)CCC(=O)OC)Cl BNOIAOZCIQESFA-UHFFFAOYSA-N 0.000 description 5
- VGKONPUVOVVNSU-UHFFFAOYSA-N naphthalen-1-yl acetate Chemical compound C1=CC=C2C(OC(=O)C)=CC=CC2=C1 VGKONPUVOVVNSU-UHFFFAOYSA-N 0.000 description 5
- 235000015320 potassium carbonate Nutrition 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 5
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- TWBPWBPGNQWFSJ-UHFFFAOYSA-N 2-phenylaniline Chemical group NC1=CC=CC=C1C1=CC=CC=C1 TWBPWBPGNQWFSJ-UHFFFAOYSA-N 0.000 description 4
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 4
- 239000012448 Lithium borohydride Substances 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 239000012320 chlorinating reagent Substances 0.000 description 4
- LZWLLMFYVGUUAL-UHFFFAOYSA-L ditert-butyl(cyclopenta-1,3-dien-1-yl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.CC(C)(C)P(C(C)(C)C)C1=CC=C[CH-]1.CC(C)(C)P(C(C)(C)C)C1=CC=C[CH-]1 LZWLLMFYVGUUAL-UHFFFAOYSA-L 0.000 description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 4
- PZBBESSUKAHBHD-UHFFFAOYSA-N methyl 2-oxocyclopentane-1-carboxylate Chemical compound COC(=O)C1CCCC1=O PZBBESSUKAHBHD-UHFFFAOYSA-N 0.000 description 4
- RPVIPTBAZCTTAF-UHFFFAOYSA-N methyl 6-chloro-3-(3-methoxy-3-oxopropyl)-7-[3-[(4-methoxyphenyl)methoxymethyl]-1,5-dimethylpyrazol-4-yl]-1H-indole-2-carboxylate Chemical compound ClC1=CC=C2C(=C(NC2=C1C=1C(=NN(C=1C)C)COCC1=CC=C(C=C1)OC)C(=O)OC)CCC(=O)OC RPVIPTBAZCTTAF-UHFFFAOYSA-N 0.000 description 4
- 150000004682 monohydrates Chemical class 0.000 description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical group [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 4
- 239000003444 phase transfer catalyst Substances 0.000 description 4
- 235000011181 potassium carbonates Nutrition 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- 239000012258 stirred mixture Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- XJBMHIHXRARJJS-UHFFFAOYSA-N (1,5-dimethylpyrazol-3-yl)methanol Chemical compound CC1=CC(CO)=NN1C XJBMHIHXRARJJS-UHFFFAOYSA-N 0.000 description 3
- HFXVLGOYQIKRTO-FYZOBXCZSA-N (1r)-1-(2-nitrophenyl)ethanamine;hydrochloride Chemical compound Cl.C[C@@H](N)C1=CC=CC=C1[N+]([O-])=O HFXVLGOYQIKRTO-FYZOBXCZSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- MOHYOXXOKFQHDC-UHFFFAOYSA-N 1-(chloromethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CCl)C=C1 MOHYOXXOKFQHDC-UHFFFAOYSA-N 0.000 description 3
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 3
- QPILTVBKDGNKLA-UHFFFAOYSA-N 3-sulfanylnaphthalen-1-ol Chemical compound OC1=CC(S)=CC2=CC=CC=C12 QPILTVBKDGNKLA-UHFFFAOYSA-N 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- YFIOJIDNKOWSFV-UHFFFAOYSA-N 4-bromo-3-[(4-methoxyphenyl)methoxymethyl]-1,5-dimethylpyrazole Chemical compound BrC=1C(=NN(C=1C)C)COCC1=CC=C(C=C1)OC YFIOJIDNKOWSFV-UHFFFAOYSA-N 0.000 description 3
- DWOZNANUEDYIOF-UHFFFAOYSA-L 4-ditert-butylphosphanyl-n,n-dimethylaniline;dichloropalladium Chemical compound Cl[Pd]Cl.CN(C)C1=CC=C(P(C(C)(C)C)C(C)(C)C)C=C1.CN(C)C1=CC=C(P(C(C)(C)C)C(C)(C)C)C=C1 DWOZNANUEDYIOF-UHFFFAOYSA-L 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 208000034578 Multiple myelomas Diseases 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- 206010035226 Plasma cell myeloma Diseases 0.000 description 3
- 239000000010 aprotic solvent Substances 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000011067 equilibration Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 229910052738 indium Inorganic materials 0.000 description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 3
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C245/00—Compounds containing chains of at least two nitrogen atoms with at least one nitrogen-to-nitrogen multiple bond
- C07C245/02—Azo compounds, i.e. compounds having the free valencies of —N=N— groups attached to different atoms, e.g. diazohydroxides
- C07C245/06—Azo compounds, i.e. compounds having the free valencies of —N=N— groups attached to different atoms, e.g. diazohydroxides with nitrogen atoms of azo groups bound to carbon atoms of six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C251/72—Hydrazones
- C07C251/74—Hydrazones having doubly-bound carbon atoms of hydrazone groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C251/76—Hydrazones having doubly-bound carbon atoms of hydrazone groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of a saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Lubricants (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
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| US201762479493P | 2017-03-31 | 2017-03-31 | |
| PCT/EP2018/058056 WO2018178227A1 (en) | 2017-03-31 | 2018-03-29 | Synthesis of mcl-1 inhibitor |
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| EA201992235A1 EA201992235A1 (ru) | 2020-02-10 |
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| US11691989B2 (en) | 2018-11-22 | 2023-07-04 | Ascentage Pharma (Suzhou) Co., Ltd. | Macrocyclic indoles as Mcl-1 inhibitors |
| US12319703B2 (en) | 2019-01-23 | 2025-06-03 | Ascentage Pharma (Suzhou) Co., Ltd. | Macrocyclic fused pyrazoles as Mcl-1 inhibitors |
| KR20220024694A (ko) | 2019-06-21 | 2022-03-03 | 얀센 파마슈티카 엔.브이. | Mcl-1의 거대환식 억제제 |
| WO2021005043A1 (en) | 2019-07-09 | 2021-01-14 | Janssen Pharmaceutica Nv | Macrocyclic spirocycle derivatives as mcl-1 inhibitors |
| WO2021092053A1 (en) * | 2019-11-08 | 2021-05-14 | Unity Biotechnology, Inc. | Mcl-1 inhibitor macrocycle compounds for use in clinical management of conditions caused or mediated by senescent cells and for treating cancer |
| WO2021099579A1 (en) | 2019-11-21 | 2021-05-27 | Janssen Pharmaceutica Nv | Macrocyclic indole derivatives as mcl-1 inhibitors |
| MX2022006180A (es) | 2019-11-21 | 2022-06-14 | Janssen Pharmaceutica Nv | Derivados macrociclicos de sulfonilo como inhibidores de mcl-1. |
| JP2023514364A (ja) | 2020-02-21 | 2023-04-05 | ヤンセン ファーマシューティカ エヌ．ベー． | Ｍｃｌ－１の阻害剤としての大環状インドール誘導体 |
| EP4157852A1 (en) | 2020-05-29 | 2023-04-05 | JANSSEN Pharmaceutica NV | Macrocyclic 7-pyrazol-5-yl-indole derivatives as inhibitors of mcl-1 |
| MX2022015998A (es) * | 2020-06-19 | 2023-04-12 | Janssen Pharmaceutica Nv | Derivados de 4-(pirazol-5-il)-indol macrocíclico unidos a n como inhibidores de mcl-1. |
| WO2021255257A1 (en) | 2020-06-19 | 2021-12-23 | Janssen Pharmaceutica Nv | N-linked macrocyclic 7-(pyrazol-5-yl)-indole derivatives as inhibitors of mcl-1 |
| CA3184877A1 (en) | 2020-07-08 | 2022-01-13 | Benoit Christian Albert Ghislain De Boeck | Macrocyclic ether containing indole derivatives as inhibitors of mcl-1 |
| WO2022032284A1 (en) * | 2020-08-07 | 2022-02-10 | Zeno Management, Inc. | Macrocyclic compounds |
| JP2023553719A (ja) | 2020-12-17 | 2023-12-25 | ヤンセン ファーマシューティカ エヌ．ベー． | Ｍｃｌ－１阻害剤としての分岐大環状４－（ピラゾール－５－イル）－インドール誘導体 |
| JP2024506648A (ja) | 2021-02-12 | 2024-02-14 | ヤンセン ファーマシューティカ エヌ．ベー． | がんの治療のためのｍｃｌ－１阻害剤としての大環状１，３－架橋６－クロロ－７－ピラゾール－４－イル－１ｈ－インドール－２－カルボキシレート及び６－クロロ－７－ピリミジン－５－イル－１ｈ－インドール－２－カルボキシレート誘導体 |
| US11931424B2 (en) | 2021-06-11 | 2024-03-19 | Gilead Sciences, Inc. | Combination MCL-1 inhibitors with anti-body drug conjugates |
| WO2022261301A1 (en) | 2021-06-11 | 2022-12-15 | Gilead Sciences, Inc. | Combination mcl-1 inhibitors with anti-cancer agents |
Citations (2)
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|---|---|---|---|---|
| US20160106731A1 (en) * | 2014-10-17 | 2016-04-21 | Vanderbilt University | Tricyclic indole mcl-1 inhibitors and uses thereof |
| WO2017182625A1 (en) * | 2016-04-22 | 2017-10-26 | Astrazeneca Ab | Macrocyclic mcl1 inhibitors for treating cancer |
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| EP2915811A1 (en) * | 2014-03-04 | 2015-09-09 | Centre Régional de Lutte contre le Cancer - Centre François Baclesse | MCL-1 modulating compounds for cancer treatment |
| CN105061315B (zh) * | 2015-08-06 | 2017-10-24 | 大连理工大学 | 一类1,5‑二苯基吡唑‑3‑羧酸类化合物及其应用 |
| CN106478606B (zh) * | 2016-09-21 | 2019-05-10 | 沈阳药科大学 | N-取代吲哚类衍生物及其应用 |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20160106731A1 (en) * | 2014-10-17 | 2016-04-21 | Vanderbilt University | Tricyclic indole mcl-1 inhibitors and uses thereof |
| WO2017182625A1 (en) * | 2016-04-22 | 2017-10-26 | Astrazeneca Ab | Macrocyclic mcl1 inhibitors for treating cancer |
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| CA3056712A1 (en) | 2018-10-04 |
| CO2019010035A2 (es) | 2019-09-30 |
| US20210122735A1 (en) | 2021-04-29 |
| IL269410A (en) | 2019-11-28 |
| ZA201905645B (en) | 2020-05-27 |
| KR102604876B1 (ko) | 2023-11-22 |
| EA201992235A1 (ru) | 2020-02-10 |
| MX2019011468A (es) | 2019-11-01 |
| AU2018244180A1 (en) | 2019-11-07 |
| TW201902868A (zh) | 2019-01-16 |
| KR20190136039A (ko) | 2019-12-09 |
| CN110536884A (zh) | 2019-12-03 |
| TWI781996B (zh) | 2022-11-01 |
| AR111304A1 (es) | 2019-06-26 |
| JP7032428B2 (ja) | 2022-03-08 |
| EP3601230A1 (en) | 2020-02-05 |
| EP3601230B1 (en) | 2022-01-26 |
| JP2020515557A (ja) | 2020-05-28 |
| IL269410B2 (en) | 2023-03-01 |
| CN110536884B (zh) | 2023-05-02 |
| WO2018178227A1 (en) | 2018-10-04 |
| ES2909751T3 (es) | 2022-05-10 |
| MX387814B (es) | 2025-03-04 |
| US11149024B2 (en) | 2021-10-19 |
| AU2018244180B2 (en) | 2021-03-04 |
| IL269410B (en) | 2022-11-01 |
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