WO2015145369A1 - Process for the preparation of substituted imidazo[4,5-c]quinoline compounds, intermediates and polymorphs thereof - Google Patents
Process for the preparation of substituted imidazo[4,5-c]quinoline compounds, intermediates and polymorphs thereof Download PDFInfo
- Publication number
- WO2015145369A1 WO2015145369A1 PCT/IB2015/052194 IB2015052194W WO2015145369A1 WO 2015145369 A1 WO2015145369 A1 WO 2015145369A1 IB 2015052194 W IB2015052194 W IB 2015052194W WO 2015145369 A1 WO2015145369 A1 WO 2015145369A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- pyridin
- crystalline
- pharmaceutically acceptable
- methyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 77
- 230000008569 process Effects 0.000 title claims abstract description 69
- 238000002360 preparation method Methods 0.000 title abstract description 60
- 239000000543 intermediate Chemical class 0.000 title abstract description 26
- ITIRVXDSMXFTPW-UHFFFAOYSA-N 1H-imidazo[4,5-c]quinoline Chemical class C1=CC=CC2=C(NC=N3)C3=CN=C21 ITIRVXDSMXFTPW-UHFFFAOYSA-N 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 198
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 31
- 238000011282 treatment Methods 0.000 claims abstract description 24
- 229940126062 Compound A Drugs 0.000 claims description 209
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 209
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 108
- 239000000203 mixture Substances 0.000 claims description 79
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 50
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 40
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- 150000003839 salts Chemical class 0.000 claims description 38
- 239000002904 solvent Substances 0.000 claims description 34
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 28
- VJLRLTSXTLICIR-UHFFFAOYSA-N [8-[6-amino-5-(trifluoromethyl)pyridin-3-yl]-1-[6-(2-cyanopropan-2-yl)pyridin-3-yl]-3-methylimidazo[4,5-c]quinolin-2-ylidene]cyanamide Chemical compound N#CN=C1N(C)C2=CN=C3C=CC(C=4C=C(C(N)=NC=4)C(F)(F)F)=CC3=C2N1C1=CC=C(C(C)(C)C#N)N=C1 VJLRLTSXTLICIR-UHFFFAOYSA-N 0.000 claims description 28
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- 201000011510 cancer Diseases 0.000 claims description 21
- 238000000746 purification Methods 0.000 claims description 20
- 239000012453 solvate Substances 0.000 claims description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 17
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 17
- 239000003960 organic solvent Substances 0.000 claims description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 16
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- 239000002002 slurry Substances 0.000 claims description 13
- 238000010438 heat treatment Methods 0.000 claims description 12
- AMKJVYOALDEARM-UHFFFAOYSA-N 6-bromo-3-nitro-1h-quinolin-4-one Chemical compound C1=C(Br)C=C2C(=O)C([N+](=O)[O-])=CNC2=C1 AMKJVYOALDEARM-UHFFFAOYSA-N 0.000 claims description 11
- 239000002585 base Substances 0.000 claims description 11
- 239000003054 catalyst Substances 0.000 claims description 11
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 11
- 229910052742 iron Inorganic materials 0.000 claims description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 claims description 9
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
- 239000012312 sodium hydride Substances 0.000 claims description 9
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 9
- 230000001035 methylating effect Effects 0.000 claims description 8
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 7
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 7
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 7
- 239000008096 xylene Substances 0.000 claims description 7
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- IULFXBLVJIPESI-UHFFFAOYSA-N bis(methylsulfanyl)methylidenecyanamide Chemical compound CSC(SC)=NC#N IULFXBLVJIPESI-UHFFFAOYSA-N 0.000 claims description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 6
- PHCKNSBYAFTJKZ-UHFFFAOYSA-N 2-(5-nitropyridin-2-yl)acetonitrile Chemical compound [O-][N+](=O)C1=CC=C(CC#N)N=C1 PHCKNSBYAFTJKZ-UHFFFAOYSA-N 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical class CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 4
- 238000002441 X-ray diffraction Methods 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 31
- 230000002062 proliferating effect Effects 0.000 abstract description 7
- 238000006243 chemical reaction Methods 0.000 description 48
- 235000002639 sodium chloride Nutrition 0.000 description 39
- 239000000243 solution Substances 0.000 description 38
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 125000000217 alkyl group Chemical group 0.000 description 26
- 238000000634 powder X-ray diffraction Methods 0.000 description 26
- 239000007787 solid Substances 0.000 description 23
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- -1 diphenyl cyanodithioimino carbonate Chemical compound 0.000 description 19
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 18
- 201000010099 disease Diseases 0.000 description 16
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 15
- PNKJBXJDULKQKM-UHFFFAOYSA-N 2-[5-[(3-amino-6-bromoquinolin-4-yl)amino]pyridin-2-yl]-2-methylpropanenitrile Chemical compound C1=NC(C(C)(C#N)C)=CC=C1NC1=C(N)C=NC2=CC=C(Br)C=C12 PNKJBXJDULKQKM-UHFFFAOYSA-N 0.000 description 14
- 208000035475 disorder Diseases 0.000 description 14
- CWOILGDOLWCMDI-UHFFFAOYSA-N BrC1=CC=2C3=C(C=NC2C=C1)NC(N3C=3C=NC(=CC3)C(C)(C)C#N)=NC#N Chemical compound BrC1=CC=2C3=C(C=NC2C=C1)NC(N3C=3C=NC(=CC3)C(C)(C)C#N)=NC#N CWOILGDOLWCMDI-UHFFFAOYSA-N 0.000 description 13
- 230000015572 biosynthetic process Effects 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
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 12
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 12
- KQPQAPCKSKAMMG-UHFFFAOYSA-N [8-bromo-1-[6-(2-cyanopropan-2-yl)pyridin-3-yl]-3-methylimidazo[4,5-c]quinolin-2-ylidene]cyanamide Chemical compound N#CN=C1N(C)C2=CN=C3C=CC(Br)=CC3=C2N1C1=CC=C(C(C)(C)C#N)N=C1 KQPQAPCKSKAMMG-UHFFFAOYSA-N 0.000 description 12
- 229910052736 halogen Inorganic materials 0.000 description 12
- 150000002367 halogens Chemical class 0.000 description 12
- 125000001072 heteroaryl group Chemical group 0.000 description 12
- 239000002245 particle Substances 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- 102000038030 PI3Ks Human genes 0.000 description 11
- 108091007960 PI3Ks Proteins 0.000 description 11
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 description 11
- 238000004440 column chromatography Methods 0.000 description 11
- 239000000725 suspension Substances 0.000 description 11
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 125000004093 cyano group Chemical group *C#N 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- 238000001819 mass spectrum Methods 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 235000019270 ammonium chloride Nutrition 0.000 description 9
- 125000003118 aryl group Chemical group 0.000 description 9
- 230000009467 reduction Effects 0.000 description 9
- ONYGTHTZAUUIJI-UHFFFAOYSA-N 2-(5-aminopyridin-2-yl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)C1=CC=C(N)C=N1 ONYGTHTZAUUIJI-UHFFFAOYSA-N 0.000 description 8
- WGTZNLRJXIIZEB-UHFFFAOYSA-N 2-methyl-2-(5-nitropyridin-2-yl)propanenitrile Chemical compound N#CC(C)(C)C1=CC=C([N+]([O-])=O)C=N1 WGTZNLRJXIIZEB-UHFFFAOYSA-N 0.000 description 8
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- KHKPVEMMXJCWGP-UHFFFAOYSA-N 6-bromo-4-chloro-3-nitroquinoline Chemical compound C1=CC(Br)=CC2=C(Cl)C([N+](=O)[O-])=CN=C21 KHKPVEMMXJCWGP-UHFFFAOYSA-N 0.000 description 7
- 239000013543 active substance Substances 0.000 description 7
- 238000003556 assay Methods 0.000 description 7
- 238000001228 spectrum Methods 0.000 description 7
- IPXWGSQUQJHDEL-UHFFFAOYSA-N 2-[5-[(6-bromo-3-nitroquinolin-4-yl)amino]pyridin-2-yl]-2-methylpropanenitrile Chemical compound C1=NC(C(C)(C#N)C)=CC=C1NC1=C([N+]([O-])=O)C=NC2=CC=C(Br)C=C12 IPXWGSQUQJHDEL-UHFFFAOYSA-N 0.000 description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-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
- 238000009826 distribution Methods 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 125000004076 pyridyl group Chemical group 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 238000012216 screening Methods 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- KXUHSQYYJYAXGZ-UHFFFAOYSA-N isobutylbenzene Chemical compound CC(C)CC1=CC=CC=C1 KXUHSQYYJYAXGZ-UHFFFAOYSA-N 0.000 description 5
- 230000001404 mediated effect Effects 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
- LTVHRJMMNGJPNB-UHFFFAOYSA-N BrC=1C=C2C(=C(C=NC2=CC1)[N+](=O)[O-])NC=1C=CC(=NC1)C(C#N)(C)CC Chemical compound BrC=1C=C2C(=C(C=NC2=CC1)[N+](=O)[O-])NC=1C=CC(=NC1)C(C#N)(C)CC LTVHRJMMNGJPNB-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- GCHYJXFMRFGJQV-UHFFFAOYSA-N NC=1C=NC2=CC=C(C=C2C1NC=1C=CC(=NC1)C(C#N)(C)CC)Br Chemical compound NC=1C=NC2=CC=C(C=C2C1NC=1C=CC(=NC1)C(C#N)(C)CC)Br GCHYJXFMRFGJQV-UHFFFAOYSA-N 0.000 description 4
- 108091000080 Phosphotransferase Proteins 0.000 description 4
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 238000000113 differential scanning calorimetry Methods 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 239000012091 fetal bovine serum Substances 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 102000020233 phosphotransferase Human genes 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- 102000005768 DNA-Activated Protein Kinase Human genes 0.000 description 3
- 108010006124 DNA-Activated Protein Kinase Proteins 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 208000034578 Multiple myelomas Diseases 0.000 description 3
- 206010035226 Plasma cell myeloma Diseases 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 108091008611 Protein Kinase B Proteins 0.000 description 3
- 102100033810 RAC-alpha serine/threonine-protein kinase Human genes 0.000 description 3
- 102100034136 Serine/threonine-protein kinase receptor R3 Human genes 0.000 description 3
- 101710082813 Serine/threonine-protein kinase receptor R3 Proteins 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 230000033115 angiogenesis Effects 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 229940088679 drug related substance Drugs 0.000 description 3
- 230000003511 endothelial effect Effects 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- 238000001757 thermogravimetry curve Methods 0.000 description 3
- RHKWIGHJGOEUSM-UHFFFAOYSA-N 3h-imidazo[4,5-h]quinoline Chemical class C1=CN=C2C(N=CN3)=C3C=CC2=C1 RHKWIGHJGOEUSM-UHFFFAOYSA-N 0.000 description 2
- OQZKROYNCVLJKM-UHFFFAOYSA-N 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-amine Chemical compound O1C(C)(C)C(C)(C)OB1C1=CN=C(N)C(C(F)(F)F)=C1 OQZKROYNCVLJKM-UHFFFAOYSA-N 0.000 description 2
- QUYZBNHTYCLZLW-UHFFFAOYSA-N 5-bromo-3-(trifluoromethyl)pyridin-2-amine Chemical compound NC1=NC=C(Br)C=C1C(F)(F)F QUYZBNHTYCLZLW-UHFFFAOYSA-N 0.000 description 2
- BUVTWYTUHAHUDO-UHFFFAOYSA-N 6-bromo-3-nitroquinoline Chemical compound C1=CC(Br)=CC2=CC([N+](=O)[O-])=CN=C21 BUVTWYTUHAHUDO-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 2
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 2
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 2
- 206010003571 Astrocytoma Diseases 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 238000001157 Fourier transform infrared spectrum Methods 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 description 2
- 239000012823 PI3K/mTOR inhibitor Substances 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 2
- 102100024908 Ribosomal protein S6 kinase beta-1 Human genes 0.000 description 2
- 101710108924 Ribosomal protein S6 kinase beta-1 Proteins 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 229940035676 analgesics Drugs 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].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 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 239000003610 charcoal Substances 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000001747 exhibiting effect Effects 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 229960003444 immunosuppressant agent Drugs 0.000 description 2
- 239000003018 immunosuppressive agent Substances 0.000 description 2
- 208000027866 inflammatory disease Diseases 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- 238000000021 kinase assay Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 108010082117 matrigel Proteins 0.000 description 2
- 238000010297 mechanical methods and process Methods 0.000 description 2
- 230000005226 mechanical processes and functions Effects 0.000 description 2
- 230000011987 methylation Effects 0.000 description 2
- 238000007069 methylation reaction Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 235000021317 phosphate Nutrition 0.000 description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- YKYONYBAUNKHLG-UHFFFAOYSA-N propyl acetate Chemical compound CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 2
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 2
- 239000011535 reaction buffer Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 125000003107 substituted aryl group Chemical group 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 230000014616 translation Effects 0.000 description 2
- 0 *c(ccc1ncc2N(*)C3=NC#N)cc1c2N3I1NC1 Chemical compound *c(ccc1ncc2N(*)C3=NC#N)cc1c2N3I1NC1 0.000 description 1
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- KPGXRSRHYNQIFN-UHFFFAOYSA-N 2-oxoglutaric acid Chemical class OC(=O)CCC(=O)C(O)=O KPGXRSRHYNQIFN-UHFFFAOYSA-N 0.000 description 1
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 description 1
- NUFBIAUZAMHTSP-UHFFFAOYSA-N 3-(n-morpholino)-2-hydroxypropanesulfonic acid Chemical compound OS(=O)(=O)CC(O)CN1CCOCC1 NUFBIAUZAMHTSP-UHFFFAOYSA-N 0.000 description 1
- YWOWJQMFMXHLQD-UHFFFAOYSA-N 3-(trifluoromethyl)pyridin-2-amine Chemical compound NC1=NC=CC=C1C(F)(F)F YWOWJQMFMXHLQD-UHFFFAOYSA-N 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- 108010013238 70-kDa Ribosomal Protein S6 Kinases Proteins 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 206010060971 Astrocytoma malignant Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010006143 Brain stem glioma Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 description 1
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 206010007953 Central nervous system lymphoma Diseases 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 102100030013 Endoribonuclease Human genes 0.000 description 1
- 101710199605 Endoribonuclease Proteins 0.000 description 1
- 241000854350 Enicospilus group Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010014967 Ependymoma Diseases 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 208000006168 Ewing Sarcoma Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 102000003974 Fibroblast growth factor 2 Human genes 0.000 description 1
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical class F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 208000021309 Germ cell tumor Diseases 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical class OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- 150000000994 L-ascorbates Chemical class 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 208000030289 Lymphoproliferative disease Diseases 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 206010025557 Malignant fibrous histiocytoma of bone Diseases 0.000 description 1
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 description 1
- 208000000172 Medulloblastoma Diseases 0.000 description 1
- 206010027406 Mesothelioma Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 208000003445 Mouth Neoplasms Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 208000014767 Myeloproliferative disease Diseases 0.000 description 1
- 201000007224 Myeloproliferative neoplasm Diseases 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- 208000034176 Neoplasms, Germ Cell and Embryonal Diseases 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 208000007641 Pinealoma Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 102000007327 Protamines Human genes 0.000 description 1
- 108010007568 Protamines Proteins 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 102000009516 Protein Serine-Threonine Kinases Human genes 0.000 description 1
- 108010009341 Protein Serine-Threonine Kinases Proteins 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 201000000582 Retinoblastoma Diseases 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 101710113029 Serine/threonine-protein kinase Proteins 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Chemical group IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 229940063655 aluminum stearate Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000011122 anti-angiogenic therapy Methods 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-L aspartate group Chemical class N[C@@H](CC(=O)[O-])C(=O)[O-] CKLJMWTZIZZHCS-REOHCLBHSA-L 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 238000010923 batch production Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical class OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 125000005874 benzothiadiazolyl group Chemical group 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000010256 biochemical assay Methods 0.000 description 1
- 230000008436 biogenesis Effects 0.000 description 1
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M bisulphate group Chemical group S([O-])(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000010322 bone marrow transplantation Methods 0.000 description 1
- 150000001642 boronic acid derivatives Chemical class 0.000 description 1
- DJACTCNGCHPGOI-UHFFFAOYSA-N butyl 2-cyanoacetate Chemical group CCCCOC(=O)CC#N DJACTCNGCHPGOI-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 230000033077 cellular process Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 201000007335 cerebellar astrocytoma Diseases 0.000 description 1
- 208000030239 cerebral astrocytoma Diseases 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 208000006990 cholangiocarcinoma Diseases 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N cinnamic acid Chemical class OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 239000010432 diamond Substances 0.000 description 1
- CVKBMWWNKUWISK-UHFFFAOYSA-L dichloromethane;dichloropalladium Chemical compound ClCCl.Cl[Pd]Cl CVKBMWWNKUWISK-UHFFFAOYSA-L 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 125000001664 diethylamino group Chemical class [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- FSBVERYRVPGNGG-UHFFFAOYSA-N dimagnesium dioxido-bis[[oxido(oxo)silyl]oxy]silane hydrate Chemical compound O.[Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O FSBVERYRVPGNGG-UHFFFAOYSA-N 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical class CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 125000004612 furopyridinyl group Chemical group O1C(=CC2=C1C=CC=N2)* 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000004153 glucose metabolism Effects 0.000 description 1
- 150000002306 glutamic acid derivatives Chemical class 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 201000009277 hairy cell leukemia Diseases 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000001794 hormone therapy Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000002267 hypothalamic effect Effects 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 description 1
- 229940035429 isobutyl alcohol Drugs 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 238000010902 jet-milling Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 208000022013 kidney Wilms tumor Diseases 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 150000003893 lactate salts Chemical class 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 230000007775 late Effects 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 229940124302 mTOR inhibitor Drugs 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 229940099273 magnesium trisilicate Drugs 0.000 description 1
- 229910000386 magnesium trisilicate Inorganic materials 0.000 description 1
- 235000019793 magnesium trisilicate Nutrition 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 208000030883 malignant astrocytoma Diseases 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 150000002690 malonic acid derivatives Chemical class 0.000 description 1
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000013642 negative control Substances 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
- 150000002823 nitrates Chemical class 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 230000000414 obstructive effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- JAFQDGMSDBAEPM-UHFFFAOYSA-N oxolane;2-propan-2-yloxypropane Chemical compound C1CCOC1.CC(C)OC(C)C JAFQDGMSDBAEPM-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 238000010951 particle size reduction Methods 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical class OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 150000003905 phosphatidylinositols Chemical class 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000000865 phosphorylative effect Effects 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical class OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 208000016800 primary central nervous system lymphoma Diseases 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229950008679 protamine sulfate Drugs 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000006085 pyrrolopyridyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000007420 radioactive assay Methods 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 201000003233 renal Wilms' tumor Diseases 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 239000011369 resultant mixture Substances 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 150000003873 salicylate salts Chemical class 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000013341 scale-up 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
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000011476 stem cell transplantation Methods 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-M sulfamate Chemical compound NS([O-])(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-M 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 201000008205 supratentorial primitive neuroectodermal tumor Diseases 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000000101 thioether group Chemical group 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 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
- LBLYYCQCTBFVLH-UHFFFAOYSA-M toluenesulfonate group Chemical group C=1(C(=CC=CC1)S(=O)(=O)[O-])C LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical class CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Substances C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 210000003606 umbilical vein Anatomy 0.000 description 1
- 208000018417 undifferentiated high grade pleomorphic sarcoma of bone Diseases 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 210000000239 visual pathway Anatomy 0.000 description 1
- 230000004400 visual pathway Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The present invention relates to a process for preparation of substituted imidazo[4,5- c]quinoline compounds (the compounds of formula I as described) and intermediates thereof. The present invention also relates to polymorphs of a compound encompassed in the compound of formula I and their use in the treatment of proliferative disorders, particularly cancers.
Description
PROCESS FOR THE PREPARATION OF SUBSTITUTED IMIDAZO[4,5- CJQUINOLINE COMPOUNDS, INTERMEDIATES AND POLYMORPHS THEREOF Field of the invention
The present invention relates to a process for the preparation of substituted imidazo[4,5-c]quinoline compounds represented by formula I (as described herein) and intermediates thereof. Further the present invention relates to polymorphs of N-(8-(6-amino- 5-(trifluoromethyl)pyridin-3-yl)-l-(6-(2-cyanopropan-2-yl)pyridin-3-yl)-3-methyl-lH- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide (referred to herein as Compound A), their preparation and pharmaceutical compositions containing them. The compounds of formula I (as described herein) are useful in the treatment of proliferative diseases or disorders such as cancer.
Background of the invention
In spite of extensive research and efforts directed to provide effective treatments for cancer, it still remains one of the few diseases that are extremely difficult to treat. Treatment regimens for cancer are determined by the type and stage of the cancer, and include surgery, radiation therapy, chemotherapy, bone marrow transplantation, stem cell transplantation, hormonal therapy, immunotherapy, anti-angiogenic therapy, targeted therapy, gene therapy and others. Phosphoinositide 3-kinases (PI3Ks) and mammalian target of rapamycin (mTOR) are attractive therapeutic targets in various diseases, such as autoimmune and inflammatory disorders and cancer.
PI3K mediated signaling pathway plays a very important role in cancer cell survival, cell proliferation, angiogenesis and metastasis. Activation of PI3K results in a disturbance of control of cell growth and survival, and hence this pathway is an attractive target for the development of novel anticancer agents (Nat. Rev. Drug Discov., 2005, 4, 988-1004). Activation of PI3K results in the recruitment and activation of protein kinase B (AKT) onto the membrane, which gets phosphorylated at Serine 473 (Ser-473).
AKT is a serine/threonine protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, cell proliferation, apoptosis, transcription and cell migration. It is known to positively regulate cell growth (accumulation of cell mass) by activating the mTOR (mammalian target of rapamycin) serine threonine kinase. mTOR
serves as a molecular sensor that regulates protein synthesis on the basis of nutrients. mTOR regulates biogenesis by phosphorylating and activating p70S6 kinase (S6K1), which in turn enhances translation of mRNAs that have polypyrimidine tracts. The phosphorylation status of S6K1 is a bonafide read-out of mTOR function. Most tumors have an aberrant PI3K pathway (Nat. Rev. Drug Discov., 2005, 4, 988-1004). Since mTOR lies immediately downstream of PI3K, these tumors also have hyperactive mTOR function. Thus, most of the cancer types will potentially benefit from molecules that target PI3K and mTOR pathways.
Certain imidazoquinoline compounds are disclosed in WO2006122806 (WO' 806 patent application) as lipid kinase inhibitors that are used alone or in combination with one or more pharmaceutically active compounds for the treatment of an inflammatory or obstructive airway disease such as asthma or a proliferative disease such as cancer. The WO' 806 patent application also discloses synthesis of imidazoquinoline compounds and intermediates thereof. In particular, an intermediate, 6-bromo-4-chloro-3-nitroquinoline was prepared by treating 6-bromo-3-nitroquinolin-4-ol with 4 volumes of POCI3. Further, the example lg of WO' 806 patent application describes reduction of 2-(5-((6-bromo-3-nitroquinolin-4- yl)amino)pyridin-2-yl)-2-methylpropanenitrile using Raney-Ni as catalyst to obtain 2-(5-((3- amino-6-bromoquinolin-4-yl)amino)pyridin-2-yl)-2- ethylpropanenitrile.
WO2012007926 (WO'926 patent application) discloses substituted imidazo[4,5- c]quinoline compounds, which are reported to be PI3K/mTOR inhibitors. The said imidazo[4,5-c]quinoline compounds are reported to inhibit other kinases such as DNA-PK and ALK-1 . WO'926 patent application also describes processes for the manufacture of the imidazo[4,5-c]quinoline compounds. Particular reference is made to example 5 wherein preparation of the compound, N-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-l-(6-(2- cyanopropan-2-yl)pyridin-3-yl)-3-methyl-lH-imidazo[4,5-c]quinolin-2(3H)- ylidene)cyanamide is described. The process described in the example 5 comprises the steps of: a) methylating 2-5-nitropyridine-2-yl)acetonitrile in the presence of sodium hydride and tetrahydrofuran (THF) as the solvent to obtain 2-methyl-2-(5-nitropyridin-2-yl)propanenitrile which was purified by column chromatography; b) the resulting compound, 2-methyl-2-(5- nitropyridin-2-yl)propanenitrile was subjected to reduction using Raney-Ni to obtain 2-(5- aminopyridin-2-yl)-2-methylpropanenitrile, which was purified by column chromatography; c) 6-bromo-3-nitroquinolin-4-ol was treated with phosphorous oxy chloride (POCI3) (4 volumes) at 120°C to obtain 6-bromo-4-chloro-3-nitroquinoline which was treated with 2-(5-
aminopyridin-2-yl)-2-methylpropanenitrile to obtain 2-(5-((6-bromo-3-nitroquinolin-4- yl)amino)pyridin-2-yl)-2-ethylpropanenitrile; d) the resulting compound, 2-(5-((6-bromo-3- nitroquinolin-4-yl)amino)pyridin-2-yl)-2- ethylpropanenitrile was subjected to reduction using Raney-Ni to obtain 2-(5-((6-bromo-3- aminoquinolin-4-yl)amino)pyridin-2-yl)-2-ethylpropanenitrile which was purified by column chromatography; e) 2-(5-((6-bromo-3-aminoquinolin-4-yl)amino)pyridin-2-yl)-2- ethylpropanenitrile was then cyclised using diphenyl cyanodithioimino carbonate and cesium carbonate in the presence of dimethylformamide (DMF) to obtain N-(8-bromo-l-(6-(2- cyanopropan-2-yl)pyridin-3-yl)-lH-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide which was purified by column chromatography; f) the resulting compound was subjected to methylation to obtain N-(8-bromo-l-(6-(2-cyanopropan-2-yl)pyridin-3-yl)-3-methyl-lH- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide which was purified by column chromatography; and g) the purified methylated compound was treated with boronic acid compound to obtain the desired N-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-l-(6-(2- cyanopropan-2-yl)pyridin-3-yl)-3-methyl-lH-imidazo[4,5-c]quinolin-2(3H)- ylidene)cyanamide which was further purified by column chromatography to obtain the pure compound.
WO2012034526 (WO'526 patent application) describes heteroaryl compounds that are PI3K and/or mTOR inhibitors. WO'526 patent application also discloses process for preparation of heteroaryl compounds and its intermediates. This patent application describes a process for the preparation of an intermediate compound (1-1) represented by formula 1-1 as depicted in the following Scheme I. The process comprises overnight reaction of tertiary butyl 2-cyanoacetate and iodomethane in the presence of potassium carbonate in C¾CN at 40°C to obtain the compound of formula I-ld (2-methyl-2-(5-nitropyridin-2- yl)propanenitrile), which was reduced using SnCl2 to obtain 2-(5-aminopyridin-2-yl)-2- methylpropanenitrile. The resulting compound was purified by column chromatography.
T-lc I-ld i-l
Scheme I
The process for the preparation of intermediate compounds which are useful for preparation of the compound of formula I, as described in the afore discussed patent documents, involves purification of each intermediate using column chromatography which is time consuming and renders the process costly. Moreover, processes involving use of column chromatography are not viable at commercial scale. Further, the processes which involve usage of large volume of POCI3 for chlorinating 6-bromo-3-nitroquinolin-4-ol as well as usage of Raney-Ni catalyst and SnCi2 catalyst for reduction, as discussed above, are tedious and not feasible for scale-up.
Considering the fact that the substituted imidazo[4,5-c]quinoline compounds (the compounds of formula I) being potent PI3K/mTOR inhibitors, have potential for development for use in the treatment of certain proliferative disorders, particularly cancers, there is a need for improved process for the synthesis of such compounds i.e. the compounds of Formula (I). Particularly, there is a need to provides a simple, industrially scalable, efficient and cost-effective process in comparison to the process reported in the cited documents. The inventors of the present invention have made efforts in this direction to provide a process which is not only simple, cost-effective and industrially viable but also provide the compounds of formula I in good yield and enhanced purity. In fact, the process of the instant invention overcomes the drawbacks associated with the prior art processes and affords operational advantages on large scale production. Summary of the invention
In one aspect, the present invention relates to a process for the preparation of a compound of formula I (as described herein) or a stereoisomer, a tautomer, a polymorph, a pharmaceutically acceptable salt or a solvate thereof.
In another aspect, the present invention relates to a process for the preparation of one or more intermediates used for preparing the compound of formula I or a pharmaceutically acceptable salt or solvate thereof.
In a further aspect, the present invention relates to a process for preparation of compound of formula IA (as described herein) or a stereoisomer, a tautomer, a polymorph, a pharmaceutically acceptable salt or a solvate thereof.
In a further aspect, the present invention relates to a process for the preparation of N-
(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-l-(6-(2-cyanopropan-2-
yl)pyridin-3-yl)-3-memyl-lH-inndazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide (referred to herein as 'Compound A') or a stereoisomer, a tautomer, a polymorph, a pharmaceutically acceptable salt or a solvate thereof.
In a further aspect, the present invention relates to a process for preparing intermediates for the preparation of N-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-l-(6-(2- cyanopropan-2-yl)pyridin-3-yl)-3-methyl-lH-imidazo[4,5-c]quinolin-2(3H)-ylidene) cyanamide (Compound A) or a stereoisomer, a tautomer, a polymorph, a pharmaceutically acceptable salt or a solvate thereof.
In another aspect, the present invention relates to a process for the purification of N- (8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-l-(6-(2- cyanopropan-2-yl)pyridin-3-yl)-3-methyl-lH-imidazo[4,5-c]quinolin-2(3H)- ylidene)cyanamide (Compound A) or a pharmaceutically acceptable salt or a solvate thereof.
In another aspect, the present invention relates to a process for the purification of N- (8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-l-(6-(2- cyanopropan-2-yl)pyridin-3-yl)-3-methyl-lH-imidazo[4,5-c]quinolin-2(3H)- ylidene)cyanamide (Compound A).
In an aspect, the present invention relates to polymorphs of N-(8-(6-amino-5- (trifluoromethyl)pyridin-3-yl)-l-(6-(2-cyanopropan-2-yl)pyridin-3-yl)-3-methyl-lH- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide (Compound A) or a pharmaceutically acceptable salt or a solvate thereof.
In an aspect, the present invention relates to polymorphs of N-(8-(6-amino-5- (trifluoromethyl)pyridin-3-yl)-l-(6-(2-cyanopropan-2-yl)pyridin-3-yl)-3-methyl-lH- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide (Compound A).
In another aspect, the present invention relates to crystalline polymorph of N-(8-(6- amino-5-(trifluoromethyl)pyridin-3-yl)- 1 -(6-(2- cyanopropan-2-yl)pyridin-3-yl)-3-methyl-lH-imidazo[4,5-c]quinolin-2(3H)- ylidene)cyanamide (Compound A). The said polymorph is referred to herein as Form A.
In another further aspect, the present invention relates to a process for the preparation of Form A of N-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-l-(6-(2-cyanopropan-2- yl)pyridin-3-yl)-3-memyl-lH-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide (Compound A).
In another aspect, the present invention relates to crystalline polymorph of N-(8-(6- amino-5-(trifluoromethyl)pyridin-3-yl)-l-(6-(2-cyanopropan-2-yl)pyridin-3-yl)-3-methyl-lH-
imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide (Compound A). The said polymorph is referred to herein as Form B.
In another aspect, the present invention relates to a process for the preparation of Form B of N-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-l-(6-(2-cyanopropan-2-yl)pyridin- 3-yl)-3-methyl-lH-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide (Compound A).
In another aspect the present invention relates to a mixture of crystalline and amorphous forms of N-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-l-(6-(2-cyanopropan-2- yl)pyridin-3-yl)-3-memyl-lH-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide (Compound A) or a pharmaceutically acceptable salt or a solvate thereof.
In another aspect the present invention relates to a mixture of crystalline and amorphous forms of N-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-l-(6-(2-cyanopropan-2- yl)pyridin-3-yl)-3-memyl-lH-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide (Compound A).
In yet another aspect the present invention relates to process for the preparation of a mixture of crystalline and amorphous forms of N-(8-(6-amino-5-(trifluoromethyl)pyridin-3- yl)-l-(6-(2-cyanopropan-2-yl)pyridin-3-yl)-3-methyl-lH-imidazo[4,5-c]quinolin-2(3H)- ylidene)cyanamide (Compound A).
In another aspect the present invention relates to use of Form A of the Compound A or pharmaceutically acceptable salts thereof for the treatment of cancers.
In another aspect the present invention relates to use of Form B of Compound A or pharmaceutically acceptable salts thereof for the treatment of cancers.
In another aspect the present invention relates to use of a mixture of crystalline and amorphous form of Compound A or pharmaceutically acceptable salts thereof; for the treatment of cancers.
In another aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of at least one polymorphic form of the Compound A and at least one pharmaceutically acceptable excipient; wherein the said polymorphic form is Form A, Form B or a mixture of crystalline and amorphous form of the Compound A.
In another aspect, the present invention relates to use of pharmaceutical composition comprising a therapeutically effective amount of at least one polymorphic form of the Compound A for the manufacture of a medicament for the treatment of cancers wherein the
said polymorphic form is Form A, Form B or a mixture of crystalline and amorphous form of the Compound A.
In yet another aspect the present invention relates to a method of treating cancer comprising administrating to a subject in need thereof, a therapeutically effective amount of Form A of the Compound A or a pharmaceutical composition of the present invention.
In another further aspect the present invention relates to a method of treating cancer comprising administrating to a subject in need thereof, a therapeutically effective amount of Form A of the Compound A or a pharmaceutical composition containing the Form A in combination with a known therapeutically active agent.
These and other objectives and advantages of the present invention will be apparent to those skilled in the art from the following description.
Brief Description of the drawings
Figure 1 shows characteristic X-Ray powder diffraction (diffractogram) of crystalline Form A of the Compound A.
Figure 2 shows characteristic differential scanning calorimetric (DSC) thermogram of crystalline Form A of the Compound A.
Figure 3 shows characteristic Fourier Transform Infrared (FTIR) spectrum of crystalline Form A of the Compound A.
Figure 4 shows characteristic X-Ray powder diffraction (diffractogram) of crystalline Form B of Compound A.
Figure 5 shows characteristic differential scanning calorimetric (DSC) thermogram of crystalline Form B of the Compound A.
Figure 6 shows characteristic Fourier Transform Infrared (FTIR) spectrum of crystalline Form B of the Compound A.
Figure 7 shows characteristic X-Ray powder diffraction (diffractogram) of a mixture of crystalline and amorphous form of the Compound A.
Figure 8 shows characteristic differential scanning calorimetric (DSC) thermogram of a mixture of crystalline and amorphous form of the Compound A.
Figure 9 shows characteristic Fourier Transform Infrared (FTIR) spectrum of a mixture of crystalline and amorphous form of Compound A.
Detailed description of the invention
It should be understood that the detailed description and specific examples, while indicating embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art. One skilled in the art, based upon the definitions herein, may utilize the present invention to its fullest extent. The following specific embodiments are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
Except as defined herein, all the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs.
Definitions
For the purpose of the disclosure, listed below are definitions of various terms used to describe the present invention. Unless otherwise indicated, these definitions apply to the terms as they are used throughout the specification and the appended claims, either individually or as part of a larger group. These definitions should not be interpreted in the literal sense. They are not general definitions, and are relevant only for this application.
The singular forms "a", "an" and "the" include plural references unless the context clearly indicates otherwise. . For instance, the terms "a", "an" and "the" refers to "one or more" when used in the subject specification, including the claims. Thus, for example, reference to "a compound" may include a plurality of such compounds.
Also, use of "(s)" as part of a term, includes reference to the term singly or in plurality, for example the term salt(s) indicates a single salt or more than one salt of the compound of formula I.
The term "or" is generally employed in its sense including "and/or" unless the content clearly dictates otherwise.
A symbol ( - ) is used to indicate a point of attachment to the atom, for example - COOH is attached through the carbon atom.
Unless indicated otherwise, the term "substitution" or "substituted by" or "substituted with" includes the implicit proviso that such substitution is in accordance with the permitted valence of the substituted atom and the substituent, as well as represents a stable compound, which does not readily undergo transformation such as by rearrangement, cyclization, elimination, etc.
As used herein, the term "halogen" refers to fluorine, chlorine, bromine or iodine atom.
As used herein, the term "(Ci-Cg)aikyl" or "alkyl" whether used alone or as part of a substituent group, refers to the radical of saturated aliphatic groups, including straight or branched-chain containing from 1 to 8 carbon atoms. Furthermore, unless stated otherwise, the term "alkyl" includes unsubstituted as well as substituted alkyl. When substituted, the alkyl group can be substituted with substituents selected from the group consisting of halogen, hydroxy, cyano, (Ci-Cg)-alkoxy, halo(Ci-Cg)alkyl and halo(Ci-Cg)aikoxy; preferably, alkyl is substituted with halogen or cyano. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, 1-methylbutyl, isopentyl, neopentyl, 2,2-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, sec-butyl, teri-butyl and the like. The "alkyl" group as defined above may be interrupted by oxygen or sulfur, means, any ether and thioether groups respectively containing from 1 to 8 carbon atoms are also included in the definition of "alkyl" group.
The term "aryl" as used herein refers to a monocyclic or polycyclic hydrocarbon group having up to 10 ring carbon atoms, preferably up to 6 ring carbon atoms in which at least one carbocyclic ring is present that has a conjugated π electron system. Accordingly, the term "aryl" refers to -C6-Cio aryl. Furthermore, unless stated otherwise, the term "aryl" includes unsubstituted as well as substituted aryl. Examples of aryl include but are not limited to phenyl, naphthyl and tetrahydronaphthyl. Aryl residues can be bonded via any desired position, and in substituted aryl residues, the substituents can be located in any desired position.
The term "heteroaryl" as used herein refers to an aromatic heterocyclic ring system containing 5 to 10 ring atoms, which can be monocyclic or bicyclic rings fused together or linked covalently. The "heteroaryl" is 5- to 10-membered heteroaryl. The rings can contain from 1 to 4 heteroatoms selected from N, O or S, wherein the N or S atom is optionally oxidized, or the N atom is optionally quaternized. Any suitable ring position of the heteroaryl moiety may be covalently linked to the defined chemical structure. Furthermore, unless stated otherwise, the term "heteroaryl" includes unsubstituted as well as substituted heteroaryl. When substituted, the heteroaryl group can be substituted with substituents selected from the group consisting of halogen, hydroxy, cyano, (Ci-Cg)-alkoxy, halo(Ci-Cg)alkyl and halo(Ci- Cg)alkoxy. Examples of heteroaryl include, but are not limited to, furan, thiophene, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, cinnolinyl, isoxazolyl, thiazolyl, isothiazolyl, lH-tetrazolyl,
oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, benzotriazinyl, phthalazinyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, purinyl, pteridinyl, indolizinyl, benzoisothiazolyl, benzoxazolyl, pyrrolopyridyl, furopyridinyl, purinyl, benzothiadiazolyl, benzooxadiazolyl, benzotriazolyl, benzodiazolyl, and the like.
The term "compound of formula I" as used herein encompasses the compound of formula IA and a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a polymorph or a solvate, thereof.
The term "pharmaceutically acceptable" refers to a compound or a carrier or an additive or a salt that is not biologically or otherwise undesirable. In other words a pharmaceutically acceptable compound or a salt must not cause any undesirable biological effects or interact in an undesirable manner with any of the other ingredients of the pharmaceutical composition in which it is contained.
The term "pharmaceutically acceptable salt(s)" as used herein refers to organic and inorganic salts of a compound of the invention. The compounds of the present invention represented by the general formula I, which contain acidic groups, can be converted into salts with pharmaceutically acceptable bases. Such salts include, for example, alkali metal salts, like lithium, sodium and potassium salts; alkaline earth metal salts like calcium and magnesium salts, ammonium salts, for example, tris(hydroxymethyl)aminomethane, trimethylamine salts and diethylamine salts; salts with organic amino acids such as lysine, arginine, guanidine and the like.
The term "stereoisomer" as used herein refers to all isomers of individual compounds that differ only in the orientation of their atoms in space. The term stereoisomer includes mirror image isomers (enantiomers), mixtures of mirror image isomers (racemates, racemic mixtures), geometric (cis/trans or syn/anti or E/Z) isomers, and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereoisomers). The compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures, individual diastereoisomers, or enantiomers, or may exist as geometric isomers, with all isomeric forms of said compounds being included in the present invention.
The term "tautomer" as used herein refers to the coexistence of two (or more) compounds that differ from each other only in the position of one (or more) mobile atoms and in electron distribution, for example, keto-enol and imine-enamine tautomers.
As used herein, the term "polymorph" or "polymorphic form" or "polymorphs" refers to crystals of the same compound that differs only in the arrangement and/or conformation of the molecule in the crystal lattice.
The polymorph of 'Compound A' which is encompassed in the "compound of formula I" or the "compound of formula IA" are part of this invention. The presence of polymorphs can be determined by infrared (IR) spectroscopy, solid probe nuclear magnetic resonance (NMR) spectroscopy, differential scanning calorimetry (DSC), powder X-ray diffraction (XRPD) or such other techniques.
The term "pharmaceutically acceptable solvate" or "solvate(s)" as used herein refers to a compound formed by the interaction of a solute (in this invention, a compound of formula I or compound of formula IA or Compound A or a salt thereof) and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Preferably the solvent used is a pharmaceutically acceptable solvent. Examples for suitable solvates are the mono- or di-hydrates including hemihydrates or alcoholates of the compounds of formula I or the compound of formula IA or Compound A.
The compounds of formula I, which contain one or more basic groups, i.e. groups which can be protonated, can form an addition salt with an inorganic or organic acid. Examples of suitable acid addition salts include: acetates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, cinnamates, citrates, ethanesulfonates, fumarates, glucuronates, glutamates, glycolates, hydrochlorides, hydrobromides, hydrofluorides, ketoglutarates, lactates, maleates, malonates, methanesulfonates, nitrates, oxalates, palmoates, perchlorates, phosphates, picrates, salicylates, succinates, sulfamate, sulfates, tartrates, toluenesulfonates and other acid addition salts known to the person skilled in the art.
The term "subject" as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. The term "mammal" as used herein is intended to encompass humans, as well as non-human mammals. Non-human mammals include, but are not limited to, domestic animals, such as cows, pigs, horses, dogs, cats, rabbits, rats and mice, and non-domestic animals. The term "subject" may be interchangeably used with the term "patient" in the context of the present invention.
The term "treat", "treating" or "treatment" as used herein includes (a) preventing the disease or disorder or condition (e.g. cancer) developing in a subject that may be afflicted
with or predisposed to the state, disorder or condition or accompanying symptoms; (b) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or accompanying symptoms or (c) relieving the disease, i.e., causing regression of the state, disorder or condition or accompanying symptoms.
The term "therapeutically active agent" as used herein is intended to encompass any known therapeutically active agent or investigational new drug that will produce a therapeutically beneficial pharmacological response when administered to a subject, both human and animal, in need thereof. Suitable known therapeutically active agent include, but are not limited to analgesics, immunosuppressants, anti-inflammatories, and anti-cancer agents, which can be useful in the treatment of diseases as described herein when used in combination with the polymorph. More than one therapeutically active agent may be used, if desired, in combination with the composition specified herein.
The term "therapeutically effective amount" as used herein, refers to the amount of a compound that, when administered to a subject for treating a state, disorder or condition, is sufficient to effect such treatment. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated.
The term "pharmaceutically acceptable excipient" as used herein means a non-toxic, inert solid, semi-solid, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable excipients are sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; malt; gelatin; talc; as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents; preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator which are well known to those skilled in the art.
The term "particle size distribution (PSD)" as used herein refers to the cumulative volume size distribution of equivalent spherical diameters as determined by laser diffraction in equipment. Typically, the Particle Size Distribution (PSD) is determined by laser diffraction in Malvern master Sizer 2000 equipment.
The term "about" as used herein in reference to a peak in a XRPD diffractogram, means the peak may vary by ±0.2 degrees of determined 2-theta value. The term "about" as
used herein in reference to a peak in a FTIR spectrum, means the peak may vary by ± 5 cm" of determined subject value.
The "solvent" as mentioned herein includes but is not limited to alcohols such as methanol, ethanol, tert-butyl alcohol, isobutyl alcohol, n-propyl alcohol, 2-propyl alcohol and the like; nitriles such as acetonitrile, propionitrile and the like; esters such as ethyl acetate, n- propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and the like; ketones such as methyl ethyl ketone, acetone and the like; ethers such as, methyl tert-butyl ether, dimethyl ether, diethyl ether, diisopropyl ether tetrahydrofuran and the like; halogenated solvents such as ethylene dichloride, methylene dichloride, chloroform, carbon tetrachloride and the like; hydrocarbon solvents such as, cyclohexane, isobutyl benzene, toluene, xylene, hexane and the like; aprotic polar solvents such as dimethyl sulfoxide, N,N-dimethylformamide, N,N- dimethylacetamide and the like or water. Any solvent or mixture of solvents or their combination with water can be used in the present invention.
The term "acid" as referred to herein includes but is not limited to acetic acid, methane sulfonic acid, para-toluene sulfonic acid, sulfuric acid or hydrochloric acid.
Base is selected from the group comprising alkali metal hydroxide, alkaline earth metal carbonate or bicarbonate. The example of the base as mentioned herein is selected from the group comprising NaOH, KOH, LiOH, NaHC03, KHCO3, Na2C03, K2C03, DIPEA or mixture thereof.
In an aspect, the present invention relates to a process for the preparation of the compound of formula I:
formula I
or a stereoisomer, a tautomer, a polymorph, a pharmaceutically acceptable salt or a solvate thereof;
wherein,
Ri is -(C6-Cio)aryl or heteroaryl;
R2 is -(Ci-C8) alkyl, which is unsubstituted or substituted with -CN;
R3 is -(C6-Cio)aryl or heteroaryl;
wherein each of -(Ce-Cio)aryl and heteroaryl is unsubstituted or substituted with one or more of Ra;
Ra at each occurrence is independently selected from the group consisting of halogen, -CN, - ORx, -SRX, -NRxRy or -(Ci-Cg)alkyl, wherein -(Ci-Cg)alkyl is unsubstituted or substituted with one or more of Rb; wherein Rx and Ry are independently selected from group consisting of hydrogen and -(Ci-Cg)alkyl, wherein -(Ci-Cg)alkyl is unsubstituted or substituted with Rb; and Rb is halogen or -CN.
In an embodiment, the present invention encompasses a compound of formula I, wherein Ri is selected from phenyl, pyridyl, quinolinyl and 2-morpholinoethyl, wherein each of phenyl, pyridyl, quinolinyl and 2-morpholinoethyl is unsubstituted or substituted with one or more groups Ra, wherein Ra is as defined above.
In an embodiment, the present invention encompasses a compound of formula I; Rj is pyridyl, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, -CN, -O-(Ci-Cg) alkyl and -Ci-Cg)alkyl, wherein -(Ci- Cg)alkyl is substituted with halogen or -CN;
R2 is -(C1-Cg)alkyl;
R3 is pyridyl which is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, -CN, -0-(Ci-Cg)alkyl, -NRxRy, and -(Q- Cg)alkyl, wherein -(Ci-Cg)alkyl is optionally substituted with halogen; and
Rx and Ry are independently hydrogen or -(Ci-Cg)alkyl.
In an embodiment, the compound of formula I encompass the compound of formula
I A as represented below;
Formula IA
or a stereoisomer, a tautomer, a polymorph, a pharmaceutically acceptable salt or a solvate thereof;
wherein, R2 is -CH3 and R3 is pyridyl which is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, -CN, -0-(Ci-Cg)alkyl, - NRxRy, and -(Ci-C8)alkyl, wherein -(Ci-Cg)alkyl is optionally substituted with halogen; and Rx and Ry are independently selected from hydrogen or -(Ci-Cg)alkyl.
In an embodiment, the compound of formula IA is N-(8-(6-amino-5- (trifluoromethyl)pyridin-3-yl)-l-(6-(2-cyanopropan-2-yl)pyridin-3-yl)-3-methyl-lH- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide (referred to herein as the 'Compound A').
In another aspect the present invention relates to a process for preparation of compound of formula I (as described above) which involves;
(3)
c) preparation of the intermediate compound (5);
d) preparation of the intermedi
(V) f) preparation of the compound of formula (8);
(8)
g) preparation of the compound of formula (9) and
> (wherein R2 is -CH3)
h) preparation of the compound of formula I.
In an aspect of the present invention the process for the preparation of the compoundormula I comprises the steps of:
a) methylating 5-nitro-2-pyridine acetonitrile (compound (1)) using methyl iodide in the presence of dimethylformamide (DMF) and sodium hydride to obtain the compound (2);
b) reducing the compound (2) using an iron catalyst to obtain the compound (3);
c) chlorinating 6-bromo-4-hydroxy-3-nitroquinoline (4) using phosphorus oxychloride(POCi3) in relatively lower volume in the presence of an organic solvent to obtain the compound (5);
d) reacting the compound (3) with the compound (5) in acetic acid medium to get intermediate compound (6);
e) reducing the compound (6) using iron catalyst to obtain compound (7);
f) cyclising the compound (7) with a reagent selected from diphenylcyanocarbonoimidate or dimethyl cyanocarbonimidodithioate in the presence of a base selected from diisopropylethylamine or cesium carbonate, to obtain the compound (8);
g) methylating the compound (8) using methyl iodide to obtain the compound (9);
h) treating the compound (9) with a compound of formula, Ι¾-Β(ΟΗ)3 wherein R3 is as defined above, to obtain the compound of formula I.
A representative compound of the formula Ι¾-Β(ΟΗ)3 is 5-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-amine, which can be procured from commercially available sources. Alternatively, the said compound can be prepared by the process described in PCT Application Publication No. WO2012/007926.
The compound 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3- 2-amine is represented as below:
In an embodiment, the present invention relates to a process for the preparation of the compound of formula IA; comprising the steps of;
a) preparation of the intermediate compound (2) as described above;
b) preparation of the intermediate compound (3) as described above;
c) preparation of intermediate compound (5) as described above;
d) preparation of an intermediate compound (6) comprising reaction of the compound (3) with the compound (5) in acetic acid medium to obtain intermediate compound
(6);
e) preparation of intermediate compound (7) comprising subjecting the compound (6) to reduction using iron catalyst to obtain the desired intermediate compound (7);
f) cyclisation of the compound (7) using diphenylcyanocarbonoimidate or dimethyl cyanocarbonimidodithioate in the presence of a base selected from diisopropylethylamine or cesium carbonate, to obtain the compound (8);
g) methylating the compound (8) using methyl iodide to obtain the compound (9);
h) treating the compound (9) with a compound of formula, Ι¾-Β(ΟΗ)3 wherein R3 is as defined above, to obtain the compound of formula IA.
In accordance with the present invention, the process for preparation of compound of formula IA is represented in the following Scheme II; wherein for each of reference each reactio
(9) F¾ is -CH3 formula IA
Scheme II
Each reaction step involved in the process for the preparation of compound of formula IA is further discussed below.
Step a: This step of the process for the preparation of the compound of formula IA involves preparation of 2-methyl-2-(5-nitropyridin-2-yl)propanenitrile (compound (2)) comprising reacting 2-(5-nitropyridin-2-yl)acetonitrile with methyl iodide in the presence of sodium hydride and DMF at a temperature ranging from -20°C to -10°C. Use of DMF is said
reaction step results in a cleaner and faster reaction. Moreover, the compound (2) can be used as such in the next step without any purification.
Step b: This step of the process for the preparation of the compound of formula IA involves preparation of 2-methyl-2-(5-aminopyridin-2-yl)propanenitrile (compound (3)) comprising subjecting the compound 2 to reduction using iron catalyst in the presence of ammonium chloride in an organic solvent selected from ethanol or tetrahydrofuran (THF) at a temperature ranging from 60 °C to 80 °C for 3 to 4 hours. After completion of reaction, the mixture was cooled to 25 °C to 30 °C and filtered. The solvent was distilled out from the reaction mixture and the compound (3) was isolated from the mixture.
Step c: This step of the process for the preparation of the compound of formula IA involves treating 6-bromo-4-hydroxy-3-nitroquinoline (compound (4)) is treated with lower volume of POCI3 in the presence of a base and an organic solvent at a temperature ranging from 65 °C to 75 °C for 2 to 3 hours. In particular, the reaction is carried out using one volume of POCI3 and acetonitrile as the organic solvent. After the completion of reaction, the mixture is cooled to 25 °C to 30 °C and the compound, 6-bromo-4-chloro-3-nitroquinoline (compound (5)) is isolated.
It was observed in the batch production of the compound (5) that when reaction was carried out using POCI3 in higher volumes, for instance, in 4 volumes, as described in the
PCT Publication No. WO2012/007926, the work up of the reaction becomes tedious and the product gets converted into the starting material. However, this problem is addressed by the process of the instant invention by which POCI3 is used in relatively lower volume, for instance it is used in 1 volume only.
Step d: This step of the process for the preparation of the compound of formula IA involves preparation of 2-(5-((6-bromo-3-nitroquinolin-4-yl)amino)pyridin-2-yl)-2- ethylpropanenitrile (compound (6)) comprising reaction of 2-methyl-2-(5-aminopyridin-2- yl)propanenitrile (compound (3)) with 6-bromo-4-chloro-3-nitroquinoline (compound (5)) in acetic acid medium to obtain intermediate, compound (6).
Step e: This step of the process for the preparation of the compound of formula IA involves preparation of 2-(5-((6-bromo-3-aminoquinolin-4-yl)amino)pyridin-2-yl)-2- ethylpropanenitrile (compound (7)) comprising reduction of 2-(5-((6-bromo-3-nitroquinolin-
4-yl)amino)pyridin-2-yl)-2-ethylpropanenitrile (compound (6)) using iron and ammonium chloride in an organic solvent selected from ethanol or THF at a temperature range from
60 °C to 80 °C for 2 to 3 hours to obtain the compound (7).
Step f: This step of the process for the preparation of the compound of formula IA involves reaction of compound (7) with a reagent selected from diphenylcyanocarbonoimidate or dimethyl cyanocarbonimidodithioate in the presence of a base selected from diisopropylethylamine or cesium carbonate, to obtain the compound (8). The resulting compound (8) is optionally purified with a solvent such as methanol, ethyl acetate or a mixture thereof.
Step g: This step of the process for the preparation of the compound of formula IA involves methylation of the compound (8) using methyl iodide in the presence of sodium hydride and an alcohol or DMF as solvent to obtain the compound (9).
Step h: This step of the process for the preparation of the compound of formula IA involves reaction of compound (9) in DMF with a compound of formula: Ι¾-Β(ΟΗ)3 (wherein R3 is as defined above) in the presence of dichlorbis(triphenylphosphine)- palladium(II) and sodium carbonate at a temperature ranging from 80 to 90°C. After the completion of the reaction, the resulting reaction mixture is treated with charcoal and filtered. The filtrate is treated with silica-thiol (Si-thiol) at a temperature ranging from 75 to 80 °C for 16 to 20 hours and the compound of formula IA is isolated. The advantage of treating the reaction mixture with Si-thiol is that it controls the palladium impurities in the final product which is isolated from the reaction mixture. It has been found that the level of palladium content gets reduced from about 500 ppm to about 1 ppm thereby making the process safer and commercially viable.
In an embodiment, the present invention relates to a process for the preparation of N- (8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-l-(6-(2-cyanopropan-2-yl)pyridin-3-yl)-3- methyl-lH-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide (Compound A) comprising the steps of;
a) methylating 2-(5-nitropyridin-2-yl)acetonitrile in the presence of sodium hydride and
DMF to obtain 2-methyl-2-(5-nitropyridin-2-yl)propanenitrile;
b) subjecting 2-methyl-2-(5-nitropyridin-2-yl)propanenitrile to reduction using iron as reducing catalyst in presence of ammonium chloride to obtain 2-methyl-2-(5- aminopyridin-2-yl)propanenitrile;
c) treating 6-bromo-3-nitroquinoline with 1 volume of POCI3 in presence of base to obtain 6-bromo-4-chloro-3-nitroquinoline;
d) subjecting 2-(5-((6-bromo-3-nitroquinolin-4-yl)amino)pyridin-2-yl)-2- ethylpropanenitrile to reduction using catalytic amount of iron as reducing catalyst in
presence of ammonium chloride to obtain 2-(5-((3-amino-6-bromoquinolin-4- yl)amino)pyridin-2-yl)-2-methylpropanenitrile;
e) treating 2-(5-((3-amino-6-bromoquinolin-4-yl)amino)pyridin-2-yl)-2- methylpropanenitrile with a reagent selected from diphenylcyanocarbonoimidate or dimethyl cyanocarbonimidodithioate in the presence of a base selected from diisopropylethylamine or cesium carbonate, to obtain N-(8-bromo-l-(6-(2- cyanopropan-2-yl)pyridin-3-yl)-lH-imidazo[4,5-c]quinolin-2(3H)- ylidene)cyanamide ;
f) methylating N-(8-bromo-l-(6-(2-cyanopropan-2-yl)pyridin-3-yl)-lH-imidazo[4,5- c]quinolin-2(3H)-ylidene)cyanamide using methyl iodide in the presence of sodium hydride to obtain N-(8-bromo-l-(6-(2-cyanopropan-2-yl)pyridin-3-yl)-3-methyl-lH- imidazo [4, 5 -c] quinolin-2(3H) -ylidene)cyanamide ;
g) optionally purifying N-(8-bromo-l-(6-(2-cyanopropan-2-yl)pyridin-3-yl)-3-methyl- lH-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide using an organic solvent;
h) treating N-(8-Bromo-l-(6-(2-cyanopropan-2-yl)pyridin-3-yl)-3-methyl-lH- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide with 5-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-amine at a temperature of 80-90 °C for about 1 to 2 hour to obtain N-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-l-(6- (2-cyanopropan-2-yl)pyridin-3-yl)-3-memyl-lH-imidazo[4,5-c]quinolin-2(3H)- ylidene)cyanamide (Compound A).
In an embodiment of the present invention, N-(8-(6-amino-5-(trifluoromethyl)pyridin- 3-yl)-l-(6-(2-cyanopropan-2-yl)pyridin-3-yl)-3-methyl-lH-imidazo[4,5-c]quinolin-2(3H)- ylidene)cyanamide (Compound A) is optionally purified to get the desired compound in good purity.
According to an embodiment, Compound A is treated with Si-thiol prior to purification to control the metal content, preferably palladium content in the said Compound A.
The process for the preparation of the compound of formula I or formula IA or of the Compound A according to the present invention is advantageous in that none of the intermediates formed in the process as well as the final compound was purified using column chromatography. Thus, avoiding column chromatography purification renders the process provided by present invention economically viable at commercial scale.
In an embodiment, the process for the purification of N-(8-(6-amino-5- (trifluoromethyl)pyridin-3-yl)-l-(6-(2-cyanopropan-2-yl)pyridin-3-yl)-3-methyl-lH- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide (Compound A) comprising the steps of; a) providing a slurry of the Compound A in a solvent;
b) heating the slurry obtained in step a) at a temperature ranging from 70 to 90°C; c) cooling the hot solution of step b) to a temperature of 25 of 35°C and
d) isolating pure Compound A.
In an embodiment, the solvent used in step (a) of the process for purification of N-(8- (6-amino-5-(trifluoromethyl)pyridin-3-yl)-l-(6-(2-cyanopropan-2-yl)pyridin-3-yl)-3-methyl- lH-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide (Compound A) is selected from the group consisting of methanol, ethanol, n-propanol, isopropyl alcohol (IPA), butanol, dichloromethane, ethylene dichloride, chloroform, acetic acid, acetinitrile, carbon tetrachloride, toluene, xylene, hexane, heptanes, dimethylformamide (DMF) and water or a mixture thereof.
In an embodiment, the solvent used in step (a) of the purification process is DMF, water or IPA.
In an embodiment, the solvent used in step (a) of the purification process is dimethylformamide.
In an embodiment, the solvent used in step (a) of the purification process is water. In an embodiment, the solvent used in step (a) of the purification process is isopropyl alcohol.
In an embodiment, the step b) is carried out at temperature of 70 to 90°C.
In an embodiment, the step b) is carried out under stirring for 2 to 4 hours.
In an embodiment, the step c) is carried out at temperature of 25 of 30°C.
In an embodiment, pure Compound A in step d) is isolated by filtering the compound obtained in step c) and washing it with suitable solvent used in step a) to get pure compound. In an embodiment, Compound A obtained in step d) can be purified with water to get the pure compound.
According to an embodiment the present invention relates to a process for purification of the Compound A which comprises isolating pure Compound A from a solution containing the Compound A and an organic solvent. The said organic solvent used for isolating pure Compound A is DMF.
According to an embodiment the present invention relates to a process for purification of the Compound A which comprises isolating pure Compound A from a solution containing the Compound A and an organic solvent. The said organic solvent used for isolating pure Compound A is water or IPA.
The process of the present invention, particularly the process for the purification according to the present invention provides N-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)- l-(6-(2-cyanopropan-2-yl)pyridin-3-yl)-3-methyl-lH-imidazo[4,5-c]quinolin-2(3H)- ylidene)cyanamide (Compound A) or pharmaceutically acceptable salt thereof, having a purity of at least 97%, preferably 98% by HPLC.
In an embodiment, the pure compound A can be converted to its pharmaceutically acceptable salts or hydrates or solvates by the processes known to the person skilled in the art.
In an embodiment, the present invention provides N-(8-(6-amino-5- (trifluoromethyl)pyridin-3-yl)-l-(6-(2-cyanopropan-2-yl)pyridin-3-yl)-3-methyl-lH- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide (Compound A) having particle size distribution such that 90 volume percent of the particles (D90) have particle size of less than about 250 microns, specifically less than about 100 microns, more specifically less than about 50 microns, still more specifically less than about 10 microns. The particles may be further micronized using conventional micronization techniques to get desired particle size.
In another embodiment, the particle size of the Compound A can be achieved by a mechanical process of reducing the size of particles which includes any one or more of cutting, crushing, milling, grinding, micronizing, spray drying or other particle size reduction methods known in the art. An appropriate mechanical process can be used to get the desired particle size range for the Compound A so as to impart on the compound good flowability, better dissolution and solubility thereby making it suitable for formulation.
Typically, the compound of formula I, particularly that of formula IA, more particularly Compound A obtained according to the process of the present invention can be micronized by jet milling method and the particle size is determined using a Malvern Mastersizer 2000 instrument, Scirocco 2000, which is commercially available from Malvern Instruments Ltd., United Kingdom.
Typically, the micronized Compound A (N-(8-(6-amino-5-(trifluoromethyl)pyridin-3- yl)-l-(6-(2-cyanopropan-2-yl)pyridin-3-yl)-3-methyl-lH-imidazo[4,5-c]quinolin-2(3H)- ylidene)cynamide) obtained according to the process of the present invention has particle size
distribution such that D90 is less than about 7-10 μ, Dso is less than about 2-5 μ and Djois less than about 0.5 - 1 μ.
It is a known fact that a chemical compound can possess multiple crystalline structures and this phenomenon is referred to as polymorphism, in drug discovery research, it has been demonstrated that certain specific polymorphs of a drug substance exhibit varying physical properties, however, obtaining proper polymorph of a drug substance is important to use the drug substance advantageously. Accordingly, a polymorph screening study was performed on the Compound A to obtain the desired polymorphs. Based on the polymorph screening study, it was found that compound A can exist in numerous polymorphic forms, however, only a few polymorphs of the said compound are found to be stable. One polymorphic form of the Compound A which is found to be the most stable form is designated herein as the Form A.
Accordingly, in an aspect, the present invention also relates to crystalline polymorphs of N-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-l-(6-(2-cyanopropan-2-yl)pyridin-3-yl)-3- methyl-lH-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide (Compound A) exhibiting an X-ray diffraction diagram as presented in the figures.
In another aspect, the present invention relates to a mixture of crystalline and amorphous form of N-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-l-(6-(2-cyanopropan-2- yl)pyridin-3-yl)-3-memyl-lH-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide (Compound A) exhibiting an X-ray diffraction diagram as presented in the figures.
According to an aspect, the present invention relates to a crystalline polymorph of N- (8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-l-(6-(2-cyanopropan-2-yl)pyridin-3-yl)-3- methyl-lH-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide (Compound A) referred to herein as Form A.
In an embodiment of the present invention, Form A of the Compound A exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2- theta values) of about 7.97, 11.38, 14.93, 15.95, 16.46, 17.40, 19.92, 20.98, 22.53, 22.84, 28.33, 29.05, 30.09 and 30.12 ± 0.2 degrees.
In an embodiment, of the present invention, Form A of the Compound A (exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2- theta values) of about 7.97, 11.38, 14.93, 15.95, 22.53 and 22.84 ± 0.2 degrees.
In another embodiment of the present invention, Form A of the Compound A exhibits at least the characteristic X-ray powder diffraction peaks shown in the following Table 1.
Table 1: X-ray powder diffraction peaks of Form A of the Compound A
In another embodiment of the present invention, Form A of Compound A exhibits an X-ray powder diffraction pattern as shown in Figure 1.
In yet another embodiment of the present invention, Form A of the Compound A represents Differential Scanning calorimetry (DSC) onset of 295.98°C ± 2.0°C as shown in Figure 2.
In yet another embodiment of the present invention, Form A of the Compound A is characterized by an infra-red (IR) spectrum showing bands at about 3593, 3501, 3438, 3335, 3204, 2180, 1847, 1626, and 499 cm"1 as shown in Figure 3.
In an aspect, the present invention provides a process for the preparation of crystalline polymorph of the compound A i.e. the Form A of compound A (N-(8-(6-amino-5- (trifluoromethyl)pyridin-3-yl)-l-(6-(2-cyanopropan-2-yl)pyridin-3-yl)-3-methyl-lH- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide) comprising the steps of;
a) forming a slurry of the Compound A in a solvent;
b) heating the slurry as obtained in step (a) at a temperature ranging from about 75 °C to 80°C;
c) cooling the solution obtained in the above step (b) to a temperature of about 25 °C to 35°C; and
d) isolating the Form A of the Compound A
Suitable solvents used for the preparation of crystalline polymorph of Compound A i.e. the Form A include, but are not limited to, an alcoholic solvent aromatic hydrocarbon solvent, water and/or mixtures thereof.
In an embodiment, an alcoholic solvent is used for the preparation of crystalline polymorph of compound A; which is selected from the group consisting of methanol, ethanol, isopropanol and butanol or a mixture thereof.
In an embodiment, an aromatic hydrocarbon is used for the preparation of crystalline polymorph of Compound A; which is selected from isobutyl benzene, toluene or xylene or a mixture thereof.
In an embodiment, Form A of the Compound A is prepared by suspending the
Compound A in a solvent selected from the group consisting of water, IPA, toluene, xylene, isobutyl benzene and heating the suspension at temperature 60 to 80 °C for 2 to 3 hours. The hot solution is then cooled to 25 to 30 °C to obtain the crystalline Form A.
In an embodiment, Form A of the Compound A is prepared by suspending the Compound A in IPA and heating the suspension at temperature ranging from 60 to 80 °C for 2 to 3 hours. The hot solution is then cooled to 25 to 35 °C to obtain the crystalline Form A.
In an embodiment, Form A of the Compound A is prepared by suspending the Compound A in water and heating the suspension at temperature ranging from 60 to 80 °C for 2 to 3 hours. The hot solution is then cooled to 25 to 35 °C to obtain the crystalline Form A.
The Form A of the Compound A is a substantially crystalline Form A of the
Compound A and refers to at least 80% of the crystalline Form A of the Compound A.
In an embodiment, the Form A of the Compound A is at least 90% of the crystalline Form A of the Compound A.
In an embodiment, the Form A of compound is at least 95% of the crystalline Form A of the Compound A.
In another aspect, the present invention relates to Form B of the Compound A (N-(8- (6-amino-5-(trifluoromethyl)pyridin-3-yl)-l-(6-(2-cyanopropan-2-yl)pyridin-3-yl)-3-methyl- lH-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide).
In an aspect of the present invention, Form B of the Compound A is obtained in a crystalline form which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2-theta values) of about: 10.15, 14.33, 17.35, 19.26, 19.66, 21.90, 23.62, 25.91 and 26.06 ± 0.2 degrees.
In an embodiment of the present invention, Form B of the Compound A is obtained in a crystalline form which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2-theta values) of about: 19.26, 19.66, 21.90, 25.91 and 26.06 ± 0.2 degrees.
In an embodiment of the present invention, Form B of the Compound A exhibits at least the characteristic X-ray powder diffraction peaks shown in the following Table 2.
Table 2: X-ray powder diffraction peaks of Form B of the Compound A
19.26 4.60 32.44 2.75
19.66 4.51 32.90 2.71
19.94 4.44 33.73 2.65
20.36 4.35 33.91 2.64
21.34 4.15 34.45 2.60
21.62 4.10 34.77 2.57
21.90 4.05 35.55 2.52
22.40 3.96 36.44 2.46
22.80 3.89 37.21 2.41
23.09 3.84 38.39 2.34
23.62 3.76 38.67 2.32
24.27 3.66
39.06 2.30
25.59 3.47
In an embodiment of the present invention, Form B of the Compound A exhibits an X-ray powder diffraction pattern as shown in the Figure 4.
In yet another embodiment of the present invention, Form B of the compound A represents Differential Scanning Calorimetry (DSC) onset of 195.48±2.0°C and 296.22±2.0°C as shown in the Figure 5.
In an embodiment of the present invention, Form B of the Compound A is characterized by an infra-red (IR) spectrum showing bands at about 3458, 3328, 3189, 2180, 1965, 1711, 1618 and 1498 cm"1 as shown in the Figure 6.
In an aspect, the present invention provides a process for the preparation of Form B of the Compound A (N-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-l-(6-(2-cyanopropan-2- yl)pyridin-3-yl)-3-memyl-lH-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide) comprising the steps of;
a) forming a slurry of the Compound A in an organic solvent;
b) heating the slurry of step a) at a temperature ranging from 60°C to 80°C;
c) cooling the obtained solution to a temperature of about 25 °C to 35°C and
d) isolating the crystalline Form B.
Suitable solvents include, but are not limited to, methyl ethyl ketone, acetone and/or mixtures thereof.
In an embodiment, Form B of the Compound A is prepared by suspending the Compound A in methyl ethyl ketone and heating the resulting mixture at a temperature ranging from 60 to 80 °C for 2-3 hours. The hot solution is then cooled to a temperature of about 25 to 30 °C to obtain the crystalline polymorph of Compound A i.e. the Form B.
In another embodiment, Form B of the Compound A is prepared by suspending the
Compound A in acetone and heating the resulting mixture at temperature ranging from 60 to 80 °C for 2-3 hours. The hot solution is then cooled to a temperature of about 25 to 35 °C to obtain the crystalline Form B.
The Form B of the Compound A is a substantially crystalline Form B of the Compound A and refers to at least 80% of the crystalline Form B of the Compound A.
In an embodiment, the Form B of the Compound A is at least 90% of the crystalline Form B of the Compound A.
In an embodiment, the Form B of Compound A is at least 95% of the crystalline Form B of the Compound A.
In another aspect, the present invention provides a mixture of crystalline and amorphous form of the Compound A (N-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-l-(6- (2-cyanopropan-2-yl)pyridin-3-yl)-3-methyl-lH-imidazo[4,5-c]quinolin-2(3H)- ylidene)cy anamide) .
In an embodiment of the present invention, a mixture of crystalline and amorphous form of the Compound A exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2-theta values) of about: 5.06, 5.24, 7.72, 8.28, 10.23, 12.78, 13.43, 14.19, 14.47, 15.16, 15.95, 16.48, 17.51, 17.86, 18.37, 19.20, 19.89, 20.95, 21.52, 22.56, 23.28, 25.05, 25.55, 26.40, 26.71, 27.65, 29.06 and 30.32 ± 0.2 degrees.
In an embodiment of the present invention, a mixture of crystalline and amorphous form of the Compound A exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2-theta values) of about: 5.06, 5.24, 15.95, 17.51, 17.86, 18.37, 25.05, 25.55 and 26.40 ± 0.2 degrees.
In another embodiment of the present invention, a mixture of crystalline and amorphous form of the Compound A exhibits at least the characteristic X-ray powder diffraction peaks shown in the following Table 3.
Table 3: X-ray powder diffraction peaks of a mixture of crystalline and amorphous form of the Compound A
2 theta values in d spacing values 2 theta values in d spacing values Degrees in Angstrom Degrees in Angstrom
4.63 19.06 17.86 4.96
5.06 17.43 18.37 4.82
5.24 16.82 19.20 4.61
6.83 12.91 19.89 4.45
7.72 11.43 20.95 4.23
8.28 10.66 21.52 4.12
9.13 9.67 22.56 3.93
10.23 8.63 23.28 3.81
12.21 7.23 25.05 3.55
12.78 6.91 25.55 3.48
13.43 6.58 26.40 3.37
14.19 6.23 26.71 3.33
14.47 6.11 27.65 3.22
15.16 5.83 29.06 3.06
15.95 5.55 30.32 2.94
16.48 5.37 35.27 2.54
17.51 5.05 38.51 2.33
A mixture of crystalline and amorphous form of the compound A according to the present invention is characterized by an X-ray powder diffraction pattern as that shown in the Figure 7.
In another embodiment of the present invention, a mixture of crystalline and amorphous form of the compound A shows DSC onsets of 295.88°C ±2.0°C as shown in the Figure 8.
In yet another embodiment of the present invention, a mixture of crystalline and amorphous form of N-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-l-(6-(2-cyanopropan-2- yl)pyridin-3-yl)-3-memyl-lH-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide is characterized by an infra-red (IR) spectrum showing bands at about 3478, 3328, 3197, 2185, 1618 and 1499 cm"1 as shown in the Figure 9.
In an aspect, the present invention provides a process for the preparation of a mixture of crystalline and amorphous form of the Compound A (N-(8-(6-amino-5-
(trifluoromethyl)pyridin-3-yl)-l-(6-(2-cyanopropan-2-yl)pyridin-3-yl)-3-methyl-lH- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide) comprising the steps of;
a) providing a slurry of the Compound A in an organic solvent;
b) heating the solution obtained in step a) at temperature ranging from 60 to 80°C;
c) cooling the solution to a temperature of about 25 to 35°C and
d) isolating the mixture of crystalline and amorphous form of the Compound A.
The organic solvent used in step a) is dimethylformamide (DMF).
In an embodiment, the mixture of crystalline and amorphous form of the Compound A is prepared by suspending the Compound A in DMF and heating the suspension at temperature ranging from 60 to 80 °C for 2 to 3 hours. The hot solution is then cooled to a temperature of about 25 to 30 °C to obtain the mixture of crystalline and amorphous form of the Compound A.
The crystalline forms of the Compound A according to present invention can exist in both unsolvated and solvated forms. The term 'solvate' as used herein refers to a molecular complex comprising the Compound A and an amount of one or more pharmaceutically acceptable solvent selected from tetrahydrofuran, chloroform, acetone, 1,4-dioxane, 1,2- ethanediol, N-methyl-2-pyrrolidone, formamide, ethanol, dimethylsulfoxide, dichloromethane, acetonitrile or ethanol.
According to the present invention the Form A of the Compound A and/or the Form B of the Compound A and/or the mixture of the crystalline and amorphous form of the Compound A is/are referred to as polymorphic crystalline form of the Compound A.
In an aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of the polymorphic crystalline form of the compound A and at least one pharmaceutically acceptable excipient; wherein said polymorphic crystalline form is selected from the Form A of the Compound A, the Form B of the compound A or a mixture of the crystalline and amorphous form of the Compound A.
In an embodiment, the pharmaceutical composition comprises a therapeutically effective amount of the Form A of the Compound A and at least one pharmaceutically acceptable excipient.
In another embodiment, the pharmaceutical composition comprises a therapeutically effective amount of the Form B of the Compound A and at least one pharmaceutically acceptable excipient.
In an embodiment, the pharmaceutical composition comprises a therapeutically effective amount of a mixture of the crystalline and amorphous form of the Compound A and at least one pharmaceutically acceptable excipient.
Pharmaceutically acceptable excipient(s), carrier(s), adjuvant(s) and vehicle(s) that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose- based substances, polyethylene glycol, sodium carboxymethylcellulose, poly aery lates, waxes, polyethylene-polyoxypropylene-block polymers and polyethylene glycol.
The administration route of the pharmaceutical composition of the present invention is not particularly limited. In one embodiment, the active ingredients (Compound A in crystalline and/or a mixture of crystalline and amorphous form or pharmaceutically acceptable salts thereof as described herein) comprised in the composition may have to be administered by different routes either orally or parenterally depending on the dosage form. The dosage form suitable for oral administration may be a tablet or capsule, forms of parenteral administration include intravenous injection, intravenous infusion, subcutaneous injection, transdermal injection, intraperitoneal injection and so on. In the case of tablets for oral use, carriers which are commonly used include lactose, corn starch, magnesium carbonate, talc, and sugar, and lubricating agents such as magnesium stearate are commonly added. For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are usually employed, and the pH of the solutions should be suitably adjusted and buffered.
In practice, oral preparations for oral administration may be produced by adding to the active ingredients the fillers, and if necessary, binders, disintegrants, lubricants, coloring agents, flavoring agents, etc. and formulating the resultant mixture according to conventional procedures into tablets, coated tablets, granules, subtle granules, powders, capsules or the like. Resultant tablets and granules may be appropriately coated with, for example, sugar or gelatin according to necessity.
The polymorphic forms of the Compound A (as described herein) can be administered as pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to
90%) of active ingredient in combination with a pharmaceutically acceptable carrier. The ultimate dose will depend on the condition being treated, severity of symptom, the route of administration, the age, sex, body weight, condition of the patient, sensitivity difference of the patient, the mode, time, interval and duration of administration, the nature, formulation and type of the preparation, the type of the active ingredient, etc.
In one aspect, the polymorphic crystalline form of the Compound A (as described herein) is provided for use in the treatment of a disease or disorder mediated by kinases selected from a group consisting of PI3K (phosphoinositide 3 -kinases), mTOR (mammalian target of rapamycin), DNA-PK (DNA-dependent protein kinase) and ALK1 (activin receptor- like kinase 1) or a combination thereof; wherein said polymorphic crystalline form is selected from the Form A of the Compound A, the Form B of the Compound A or a mixture of the crystalline and amorphous form of the Compound A.
In one aspect, the invention relates to N-(8-(6-amino-5-(trifluoromethyl)pyridin-3- yl)-l-(6-(2-cyanopropan-2-yl)pyridin-3-yl)-3-methyl-lH-imidazo[4,5-c]quinolin-2(3H)- ylidene)cyanamide (Compound A) in a mixture of crystalline and amorphous form for use in the treatment of diseases or disorders mediated by one or more kinases, particularly proliferative diseases or disorders such as cancer.
In an embodiment, the disease or disorder mediated by one or more kinases (as described herein) is a proliferative disease or disorder, an inflammatory disorder or an angiogenesis related disorder.
In an embodiment, the proliferative disease or disorder is cancer.
Accordingly, in an embodiment of the present invention, the polymorphic crystalline form of the Compound A is provided for use in the treatment of cancer; wherein said polymorphic crystalline form is selected from the Form A of the Compound A, the Form B of the Compound A or a mixture of the crystalline and amorphous form of the Compound A.
In another embodiment of the present invention, there is provided a method for the treatment of cancer in a subject; comprising administering to the subject a therapeutically effective amount of the polymorphic crystalline form of the Compound A selected from the Form A of the Compound A, the Form B of the Compound A or a mixture of the crystalline and amorphous form of the Compound A.
In an embodiment of the present invention, there is provided use of the polymorphic crystalline form of the Compound A for the manufacture of a medicament for use in the treatment of cancer; wherein said polymorphic crystalline form is selected from the Form A
of the Compound A, the Form B of the Compound A or a mixture of the crystalline and amorphous form of the Compound A.
In an embodiment, the cancer is selected from the group consisting of leukemia such as acute lymphocytic leukemia; acute myeloid leukemia; adult acute myeloid leukemia; acute lymphoblastic leukemia; chronic lymphocytic leukemia; chronic myeloid leukemia; hairy cell leukemia, lung cancer including non-small-cell lung cancer and small-cell lung cancer, brain tumors such as brain stem glioma; glioblastoma; astrocytoma including cerebellar astrocytoma and cerebral astrocytoma, visual pathway and hypothalamic glioma; supratentorial primitive neuroectodermal and pineal tumors; medulloblastoma, lymphoma such as primary central nervous system lymphoma; non-Hodgkin's lymphoma particularly mantle cell lymphoma, Hodgkin's disease, liver cancer such as hepatocellular carcinoma, kidney cancer such as renal cell carcinoma and Wilms' tumor, sarcoma such as Ewing's sarcoma family of tumors; osteosarcoma; rhabdomyosarcoma; soft tissue sarcomas, mesothelioma, bladder cancer, breast cancer, endometrial cancer, head and neck cancer, melanoma, cervical cancer, thyroid cancer, gastric cancer, germ cell tumor, cholangiocarcinoma, extracranial cancer, malignant fibrous histiocytoma of bone, retinoblastoma, esophageal cancer, multiple myeloma, oral cancer, pancreatic cancer, ependymoma, neuroblastoma, skin cancer, ovarian cancer, recurrent ovarian cancer, prostate cancer, testicular cancer, colorectal cancer, lymphoproliferative disease, refractory multiple myeloma, resistant multiple myeloma and myeloproliferative disorder.
In an embodiment, the present invention relates to use of the polymorphic crystalline form of the Compound A; in combination with a further therapeutically active agent, in the treatment of a disease or a condition mediated by one or more kinases (as described herein); wherein said polymorphic crystalline form is selected from the Form A of the Compound A, the Form B of the Compound A or a mixture of the crystalline and amorphous form of the Compound A. The therapeutically active agents include, but are not limited to, known analgesics, immunosuppressants, anti-inflammatory agents and anti-cancer agents.
It is understood that modifications that do not substantially affect the activity of the various embodiments of this invention are included within scope of the invention disclosed herein. Accordingly, the following examples are intended to illustrate but not to limit scope of the present invention.
General Experimental Conditions:
X-ray Powder Diffraction (XRPD):
X-ray powder diffraction pattern were obtained on Bruker D8 Advance (Bragg Brentano geometry) using Copper Ka radiation with scanning range between 3 to 40 degree 2 [theta] at scanning speed of 0.25 steps/sec.
Differential Scanning Calorimeter (DSC):
Differential Scanning Calorimetry was performed on Diamond DSC of Perkin Elmer instrument. The experiments were performed at a heating rate of 20°C/minute over a temperature range of 40°C-320°C purging with nitrogen at a flow rate of 25ml/min.
Fourier Transform Infrared (FTIR) spectra:
The FT-IR spectra were obtained on Perkin Elmer instrument in the range of 450-4000 cm"1 with a resolution of 4 cm"1.
Unless otherwise stated all temperatures are in degree Celsius. Also, in the examples described below and throughout the specification, abbreviations have the following meanings:
Abbreviations:
Examples:
Example 1
Preparation of the compound A (N-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-l-(6-(2- cyanopropan-2-yl)pyridin-3-yl)-3-methyl-lH-imidazo[4,5-c]quinolin-2(3H)- ylidene)cyanamide)
Step 1 : Synthesis of 2-methyl-2-(5-nitropyridin-2-yl)-propanenitrile (Compound 2)
A solution of 2-(5-nitropyridin-2-yl)acetonitrile (250 g) in DMF (750 mL) was added drop wise to a mixture of sodium hydride (126.44 g) and dimethylformamide (2000 mL) and the mass was cooled to a temperature ranging from -15 to -10°C over a period of 1 h at -15 to
-10°C. Methyl iodide (656.6 g) was added to the reaction mass and stirred for 25 to 30 min. The temperature was raised to 20-25 °C over a period of 1 h and the reaction mass was maintained for 2 h at the same temperature. The reaction mass was cooled to temperature of - 15 to -10°C and quenched with methanol (250 mL) and followed by 20% ammonium chloride solution (1500 mL) to attain pH of reaction mixture to 6.0 to 6.5. The reaction mass was diluted with water (4750 mL). Mass was filtered and washed the bed with water (250 mL) followed by w-heptane (500 mL). The resulting compound was dried below 40°C to get title compound (250 g). Yield: 83% g,
Purity: 96.6%.
JH NMR (300 MHz, DMSO-d6): δ 9.43 (d, 1H, J=2.7Hz), 8.55 (dd, 1H, J=8.7Hz, 2.4Hz), 7.86 (d, 1H, J=8.7Hz), 1.82 (s, 6H).
Mass Spectrum (MS): m/z 192 (M+l)
Step 2: Synthesis of 2-(5-aminopyridin-2-yl)-2-methylpropanenitrile (Compound 3)
2-Methyl-2-(5-nitropyridin-2-yl)propanenitrile (compound 2) (280 g), iron (163.5 g) and ammonium chloride (232.1 g) were added to a mixture of ethanol (1568 mL), THF (700 mL), water (350 mL) and heated the reaction mass to a temperature ranging from 70 to 75°C for 3 to 4 h. The reaction mass was cooled to 25 to 30°C, filtered through celite bed and washed the bed with ethanol (1400 mL). The filtrate was distilled out completely below 50°C. The resulting residue after the distillation was dissolved in ethyl acetate (4200 mL) and washed with water (1400 mL). The organic layer was separated and washed with 10% sodium chloride solution (1400 mL). Organic layer was dried over anhydrous sodium sulphate and filtered. The filtrate was distilled out under vacuum until 280 mL of reaction mass volume. The residue was chased below 40°C with w-heptane (560 mL) and suspended in w-heptane (560 mL). The mass was cooled to 25-30°C, filtered and washed with w-heptane (280 mL). The compound was dried at 45-50°C to get title compound (140 g). Yield: 59% Purity: 96.12%
JH NMR (300 MHz, DMSO-de): δ 7.89 (d, 1H, /=2.7Hz), 7.13 (d, 1H, /=8.7Hz), 6.93 (dd, 1H, /=2.7Hz, 8.7Hz), 5.38 (s, 2H), 1.57 (s, 6H).
MS: m/z 162 (M+l)
Step 3: Synthesis of 5-bromo-3-(trifluoromethyl)pyridin-2-amine
3-(Trifluoromethyl)-2-pyridinamine (150 g) was added to acetic acid (1500 mL) and stirred the mass for 10 to 15 min. Bromine (47.54 mL) was added to the mixture over a
period of 45-60 min at 25-30°C. The reaction mass was maintained under stirring at 25-30°C for 2-3 h. After completion of the reaction, the mass was cooled to 10 to 15°C and diluted with water (2500 mL) subsequently neutralized the mass with solid sodium carbonate (420 g). The reaction mass was filtered and bed was washed with water (300 mL) and dried at 25 to 30°C for 12 h. The dried mass was dissolved in ethyl acetate (2250 mL) and washed with 5% sodium bicarbonate solution (750 mL). The separated organic layer was washed with 10% sodium chloride solution (750 mL). Clean organic layer was distilled out completely to obtain the title compound (183 g). Yield: 82%
Purity: 99.52%
JH NMR (300 MHz, DMSO-<¾): δ 8.25 (s, 1H), 7.89 (s, 1H), 6.7 (bs, 2H).
MS: m/z 242 (M+l)
Step 4: Synthesis of 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3- (trifluoromethyl)pyridin-2-amine
A mixture of 5-bromo-3-(trifluoromethyl)pyridin-2-amine (180 g) and 1,4-dioxane
(3600 mL) was stirred in a flask. Bis(pinacolato)diboron (284.47 g), potassium acetate (109.95 g) and l,l-bis(diphenylphosphino)ferrocene dichloropalladium (II) DCM complex (18 g), were then added under stirring at a temperature of about 25 to 30°C. Reaction mass was heated to 95 to 100°C and maintained for 15-16 hr. After the completion of reaction, the mass was cooled to 25 to 30°C, filtered through celite bed and the bed was washed with ethyl acetate (1800 mL). The filtrate was distilled out completely under vacuum to get crude title compound (450 g).
Purification
The crude title compound was dissolved in methanol (1800 mL) in a round bottom flask. Charcoal (45 g) and silica gel (60-120 mesh size, 450 g) were added to the mass and maintained under stirring at a temperature of about 25 to 30°C for 1 h. The mass was filtered through celite bed and washed the bed with methanol (450 mL). The filtrate was added into a flask containing cold water (6750 mL) at 0-5°C, over a period of 1 h. The precipitated solid was filtered out, washed with cold water (900 mL). The wet compound was unloaded and dried at 45 to 50°C to obtain the title compound (209 g). Yield: 97.47%
Purity: 98.43%
JH NMR (300 MHz, DMSO-d6): δ 8.38 (s, 1H), 7.80 (s, 1H), 6.92 (s, 2H), 1.27 (s, 12H). MS: m/z 289.1 (M+l)
Step 5: Synthesis of 6-bromo-4-chloro-3-nitroquinoline (Compound 5)
6-Bromo-3-nitroquinolin-4-ol (50 g) and N,N-diisopropylethylamine (60 mL) were added to acetonitrile (500 mL) and stirred for 10 to 15 min under nitrogen atmosphere. The reaction mass was cooled to a temperature of about 0-5 °C and phosphorusoxychloride (50 mL) was added dropwise to the cooled solution while maintaining the temperature below 10°C. The reaction mass was heated to 70 to 75 °C for 2 to 3 h. After completion of the reaction, the mass was cooled to 25 to 30°C. The cooled reaction mass was added dropwise into a mixture of ice-water (1.25 Kg) and sodium chloride (50 g) maintaining the temperature below 0°C. The mixture was stirred for 15 to 30 min. The compound obtained was filtered and washed with ice-cold water (250 mL). The wet compound was dissolved in MDC (750 mL) and filtered through celite bed. The bed was washed with MDC (250 mL). The combined organic layer from the filtrate was separated and washed with ice cold water (500 mL). The separated organic layer was dried over anhydrous sodium sulphate and subjected to distillation below 35°C under vacuum to obtain the title compound (55 g). This compound was dissolved in 500 mL of acetic acid and used for the next step without isolation. Yield: 93.5%
Step 6: Synthesis of 2-(5-((6-bromo-3-nitroquinolin-4-yl)amino)pyridin-2-yl)-2- methylpropanenitrile (Compound 6)
2-(5-Aminopyridin-2-yl)-2-methylpropanenitrile (28 g) was added to a solution of 6- bromo-4-chloro-3-nitroquinoline (55 g) in acetic acid (500 mL) under stirring. The reaction mass was maintained for 12 to 16 h at a temperature of about 25 to 30°C. After the completion of reaction, the precipitated compound was filtered. The bed was washed with acetic acid (100 mL) followed by water (250 mL). The wet solid was stirred in water (250 mL) and filtered. The wet solid was then stirred again in water (250 mL) and adjusted the pH of water to 7 with 100 mL of 5% solution of sodium bicarbonate solution and filtered. The bed was washed with water (500 mL) and unloaded the compound in a tray. Compound was subjected to drying at 50 to 55 °C to obtain the title compound. Yield: 59%
Purity: 95%
JH NMR (300 MHz, DMSO-<¾): δ 10.19 (bs, 1H), 9.09 (s, 1H), 8.70 (d, 1H, /=1.5Hz), 8.41 (s, 1H), 8.01 (d, 1H, /=5.1Hz), 7.95 (d, 1H, /=5.1Hz), 7.50 (s, 2H), 1.68 (s, 6H).
MS: m/z 412 (M+l)
Step 7: Synthesis of 2-(5-((3-amino-6-bromoquinolin-4-yl)amino)pyridin-2-yl)-2- methylpropanenitrile (Compound 7)
Ammonium chloride (45 g), iron (56 g; 100 mesh electrolytic) and 2-(5-((6-bromo-3- nitroquinolin-4-yl)amino)pyridin-2-yl)-2-methylpropanenitrile (100 g) were added to a mixture of ethanol (560 mL), THF (280 mL), water (140 mL) and heated to a temperature of about 70 to 75°C for 2 to 3 h. The reaction mass was cooled to a temperature of about 25- 30°C and filtered through celite bed. The filtrate was subjected to distillation until it reaches volume of -300 mL inside the flask. The mixture was charged into a mixture of ice-water (1.5 Kg) maintaining the temperature below 10°C. The mass was stirred for 30 to 45 min. The solid obtained was filtered, washed with water (500 mL) and dried to obtain the title compound (87 g). Yield: 93%
Purity: 95.6%
JH NMR (300 MHz, DMSO-d6): δ 8.60 (s, 1H), 8.15 (s, 1H), 8.01 (d, 1H, J=2.1Hz), 7.86 (s, 1H), 7.77 (d, 1H, J=9Hz), 7.47 (d, 1H, 8.7Hz), 7.30 (d, 1H, J=8.4Hz), 6.67 (dd, 1H, J=2.4Hz, 8.4Hz), 5.57 (s, 2H), 1.61 (s, 6H).
MS: m/z 384.1 (M+l)
Step 8: Synthesis of N-(8-bromo-l-(6-(2-cyanopropan-2-yl)pyridin-3-yl)-lH-imidazo[4,5- c]quinolin-2(3H)-ylidene)cyanamide (Compound 8)
2-(5-((3-amino-6-bromoquinolin-4-yl)amino)pyridin-2-yl)-2-methylpropanenitrile (163.5 g), cesium carbonate (209 g) and dimethyl cyanodithioimino carbonate (156.4 g) in DMF (820 mL) were taken in a round bottom flask and heated to 60 to 65 °C for 24 to 25 h under stirring. After completion of the reaction, the mass was cooled to 25 to 30°C. The cooled reaction mass was added to a solution of ammonium chloride (30%, 3270 mL) while maintaining the temperature below 0-5°C. The pH of the reaction mass was adjusted in the range of 4 to 5 with IN hydrochloric acid (~ 817.5 mL). The temperature of the reaction mass was raised to 25 to 30°C and stirred for 15 to 30 min. The precipitated compound was filtered and washed twice with water (816 mL) and dried at 50 to 55 °C. The dried compound was added to a mixture of methanol (1400 mL) and ethyl acetate (600 mL) then the mixture was heated to 50 to 55°C for 1 to 1.15 h. The mass was then cooled to 25 to 30°C. The solid obtained was filtered, washed with a mixture of 30% methanol in ethyl acetate (200 mL) and dried at 45 to 50°C to get title compound (122 g). Yield: 74.7%
Purity: 98%
H NMR (300 MHz, DMSO-d6): δ 8.82 (s, 1H), 8.73 (d, 1H, J=2.1Hz), 8.09 (dd, 1H, J=2.4Hz, 8.4Hz), 7.88 (d, 2H, J=8.7Hz), 7.49 (dd, 1H, J=1.8Hz, 8.7Hz), 6.91 (d, 1H, J=2.1Hz), 1.80 (s, 6H).
MS: m/z 434 (M+l)
Step 9: Synthesis of N-(8-bromo-l-(6-(2-cyanopropan-2-yl)pyridin-3-yl)-3-methyl-lH- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide (Compound 9)
Sodium hydride (30.84 g) was added in DMF (2200 mL) and cooled the mass to a temperature of about -5 to 0°C. N-(8-bromo-l-(6-(2-cyanopropan-2-yl)pyridin-3-yl)-lH- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide (220 g) was added to the cooled mixture at -5 to 0°C. Methyl iodide (180.57 g) was added dropwise to the reaction mass and temperature of the mixture was raised to 25 to 30°C and maintained for 2 to 3 h. After completion of the reaction, the reaction mass was cooled to -10 to -5 °C and quenched with methanol (110 mL) followed by ammonium chloride solution (20%, 440 mL). Reaction mass was diluted with water (3300 mL) and the mixture was stirred for 30 min. The precipitated compound was filtered, washed with water (440 mL) followed by w-heptane (440 mL). Compound was unloaded in a tray and dried at 50 to 55°C to get crude compound (250 g).
Purification 1:
The crude compound was added to MDC (5000 mL) and stirred for 60 min. The mass was filtered. The layer of the bed was suspended in MDC (5000 mL), stirred for 30 to 45 min and filtered. The combined filtrate was subjected to distillation under vacuum until residue. The obtained mass was stirred with w-heptane (500 mL) as slurry and stirred for 30 to 45 min. The compound obtained was filtered, washed the bed with w-heptane (100 mL). Compound was unloaded and dried at 45 to 50°C to get partially purified compound (150 g).
Purification 2:
The partially purified compound (150 g) was charged in a mixture of methanol (1050 mL): ethyl acetate (450 mL) and heated to 50 to 55°C for 1 to 1.15 h. The solution was cooled to a temperature of about 25 to 30°C and filtered the compound. Bed was washed with a mixture of 30% methanol in ethyl acetate (150 mL). Compound was unloaded in a tray and dried at 45 to 50°C to get the title compound (116 g). Yield: 57.7%,
Purity: 94%
H NMR (300 MHz, DMSO-d6): δ 9.27 (s, 1H), 9.03 (d, 1H, J=2.1Hz), 8.40 (dd, 1H, J=2.4Hz, 8.4Hz), 8.06 (d, 2H, J=9.3Hz), 7.78 (dd, 1H, J=1.8Hz, 9Hz), 6.70 (d, 1H, J=2.1Hz), 3.88 (s, 3H), 1.81 (s, 6H).
MS: m/z 446.1 (M+l)
Step 10
Synthesis of N-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-l-(6-(2-cyanopropan-2- yl)pyridin-3-yl)-3-memyl-lH-inndazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide (Compound A)
N-(8-Bromo-l-(6-(2-cyanopropan-2-yl)pyridin-3-yl)-3-methyl-lH-imidazo[4,5- c]quinolin-2(3H)-ylidene)cyanamide (lOg) and 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-3-(trifluoromethyl)pyridin-2-amine (12.9 g) were added in DMF (100 mL) in a round bottom flask. The reaction mass was purged with nitrogen for 15 min and added sodium carbonate (5.9 g), purified water (5 mL) and dichlorobis(triphenylphosphine)palladium (II) (0.95 g). The reaction mixture was then heated to a temperature of about 85 to 90°C for 0.5 to 1 h. After completion of the reaction, activated charcoal (0.1 g) was added into it and stirred for 15 to 30 min. The reaction mass was filtered through celite bed and washed the bed with hot DMF (10 mL). The filtrate was treated with Si-thiol (7.5 g) at 75 to 80°C for 16 to 20 h. The solid mass was filtered through celite bed and washed bed with hot DMF (10 mL). The filtrate obtained was cooled to 0 to 5°C over a period of 2 to 3 h. The solid obtained was filtered and washed with cold DMF (10 mL).
Purification:
The wet compound (15 g) as obtained above was added to water (100 mL) and heated to a temperature of about 80 to 85°C with stirring for 2 h. The mass was cooled to a temperature of about 25 to 30°C, filtered and washed with water (30 mL) to get the solid (12 g)-
The wet compound (12 g) was added to IPA (100 mL) and heated to a temperature of about 80 to 85°C for 2 h. The mass was cooled to 25 to 30°C. The solid obtained was filtered and washed with IPA (30 mL). Compound was unloaded in a tray and dried at 45 to 50°C to obtain the title compound (8 g)
Yield: 67.8%
Purity: 98%.
H NMR (300 MHz, DMSO-d6): δ 9.23 (s, IH), 9.07 (d, IH, J=2.1Hz), 8.50 (m, IH), 8.19 (d, 2H, J=9Hz), 8.01 (d, 2H, J=7.8Hz), 7.75 (s, IH), 6.90 (d, IH, J=1.8Hz), 6.75 (s, 2H), 3.92 (s, 3H), 1.80 (s, 6H).
MS: m/z 528.2 (M+l)
Example 2
Polymorph screening for the Compound A:
The polymorph screening of Compound A involves two crystallization methods: slurry conversion and evaporative experiments.
Slurry Experiments:
The experiments were carried out by stirring a mixture of the compound (Compound A) in a solvent at a controlled temperature. The solvent can be selected from the group consisting of tetrahydrofuran (THF), chloroform, acetone, 1,4-dioxane, 1 ,2-ethanediol, dimethylformamide (DMF), acetonitrile, ethanol, dimethyl sulfoxide (DMSO), dichloromethane (DCM), N-methyl-2-pyrrolidone (NMP), isopropanol (IP A) and water. Following completion of the slurry experiments, the solids were separated from the solutions by centrifugation, harvested wet and dried and samples were analyzed by XRPD and digital imaging. The clear solutions were evaporated under mild vacuum. Following this, all the solids were exposed to accelerated aging conditions and reanalysed by XRPD and digital imaging.
Based on the screening of all the samples, the Form A of the Compound A is physically stable under applied accelerated stress conditions.
Polymorphs of the Compound A:
Form A of the Compound A:
Example 3
Compound A (1 g) was suspended in water (10 mL) and heated at a temperature of about 75 to 80°C. The suspension was maintained at this temperature for 2 to 3 h. The obtained hot solution was cooled to 25 to 30°C. The solid obtained was filtered, washed with water (1 mL) and dried at a temperature of about 50 to 55°C to obtain Form A of Compound A.
Yield: 90%
Purity: 98%
Example 4
Compound A (1 g) was suspended in IPA (10 ml) and heated at a temperature of about 75 to 80°C. The suspension was maintained at this temperature for 2 to 3 h. The obtained hot solution was cooled to a temperature of about 25 to 30°C. The solid obtained was filtered, washed with IPA (1 mL) and dried at a temperature of about 50 to 55°C to obtain Form A of Compound A.
Yield: 90%
Purity: 98%
Example 5
Compound A (1 g) was suspended in toluene (10 mL) and heated at a temperature of about 75 to 80°C. The suspension was maintained at this temperature for 2 to 3 h. The obtained hot solution was cooled to a temperature of about 25 to 30°C. The solid obtained was filtered, washed with toluene (1 mL) and dried at 50 to 55°C to obtain Form A of compound A.
Yield: 90%
Purity: 98%
Example 6
Compound A (1 g) was suspended in xylene (10 mL) and heated at a temperature of about 75 to 80°C. The suspension was maintained at this temperature for 2 to 3 h. The obtained hot solution was cooled to a temperature of about 25 to 30°C. The solid obtained was filtered, washed with xylene (1 mL) and dried at 50 to 55°C to obtain Form A of the Compound A.
Yield: 90%
Purity: 98% Example 7
Compound 1 (1 g) was suspended in isobutyl benzene (10 mL) and heated at a temperature of about 75 to 80°C. The suspension was maintained at this temperature for 2 to 3 h. The obtained hot solution was cooled to a temperature of about 25 to 30°C. The solid obtained was filtered, washed with isobutyl benzene (1 mL) and dried at a temperature of about 50 to 55°C to obtain Form A of Compound A.
Yield: 90%
Purity: 98%
Form B of the Compound A:
Example 8
Compound A (1 g) was suspended in acetone (10 ml) and heated at a temperature of about 50 to 55°C. The suspension was maintained at this temperature for 2 to 3 h. The obtained hot solution was cooled to a temperature of about 25 to 30°C for 30 to 45 min. The solid obtained was filtered, washed with acetone (1 mL) and dried at 50 to 55°C to obtain Form B of the Compound A.
Yield: 70%
Purity: 98%
Example 9
Compound A (1 g) was suspended in methyl ethyl ketone (10 ml) and heated at a temperature of about 75 to 80°C. The suspension was maintained at this temperature for 2 to 3 h. The obtained hot solution was cooled to a temperature of about 25 to 30°C. The solid obtained was filtered, washed with methyl ethyl ketone (1 mL) and dried at 50 to 55°C to obtain Form
B of Compound A.
Yield: 70%
Purity: 98%
Example 10
A mixture of crystalline and amorphous form of the Compound A:
Compound A (1 g) was dissolved in DMF (10 ml) at a temperature of about 75 to 80°C. The solution was maintained at this temperature for 1 to 2 h. The hot solution was cooled to 25 to 30°C. The solid obtained was filtered, washed with DMF (1 mL) and dried at 50 to 55°C to get mixture of crystalline and amorphous Form of the Compound A.
Yield: 70%, Purity: 98%
Pharmacology:
The efficacy of the compounds particularly the polymorphic forms of the Compound A (the test compounds) can be determined by a number of pharmacological assays well known in the art, such as described below. The exemplified pharmacological assays, which follow herein, are carried out with the test compounds.
Example 10: Protocol for kinase assay (PI3Ka)
PI 10a radioactive lipid kinase assay
The assay is designed as in the reference, Journal of Biomolecular Screening, 2002,
Vol. 7, No. 5, 441 -450, the disclosure of which is incorporated by reference for the teaching of the assay.
The pi 10α biochemical assay is performed using a radioactive assay measuring the
32
incorporation of P into the pi 10a substrate, phosphatidylinsoitol (PI). For the generation of IC50 curves, the reaction is performed in a 96-well MaxiSorp plates. Plates are pre -coated with 4μg/well of a 1 : 1 ratio of phosphatidylinositol (PI: Avanti #840042C) and phosphatidylserine (PS: Avanti #840032C) diluted in CHCI3. Equal amount of p 110a (Upstate Millipore) protein was added to each well, containing reaction buffer (50 mM MOPSO pH7.0, 100 mM NaCl, 4 mM MgCl2, 0.1% (w/v) BSA) whereas, for negative control, only reaction buffer is added. Test compounds are dissolved in DMSO are treated at nine -point dose responses. Reactions are initiated by the addition of 25 μΜ ATP solution containing 50 μ(Ιϋ/πι1[γ-32Ρ]-ΑΤΡ and incubated at RT for 2 h with gentle shaking. Reactions are finally terminated by the addition of 50 mM EDTA stock solution. Plates are washed 3 times with TBS buffer. The plates are air dried, Microscint 0 (Perkin Elmer) is added to each well and the plates are sealed. The radioactivity incorporated into the immobilized PI substrate is determined with Top Count (Perkin Elmer). Inhibition is calculated using the following equation:
% inhibition = (Dcpm - Tcpm)/(Dcpm)X100
32
Tcpm = P-cpm in presence of test compounds
32
Dcpm = P-cpm in DMSO control (enzyme control deducted) Example 11 : Angiogenesis assay
Tube formation assay
Human umbilical vein endothelial cells (HUVECs) are grown in endothelial medium (Promocell), supplemented with 20% fetal bovine serum (FBS), 100 units/ml penicillin, 100μg/ml streptomycin, 3ng/ml basic fibroblast growth factor, and 5 units/ml heparin at 37°C under a humidified 95% -5% (v/v) mixture of air and C(¾.
For the assay, 250μ1 of growth factor-reduced Matrigel (BD Biosciences) is pipetted into a 24 well tissue culture plate and polymerized for 30 min at 37°C. HUVECs incubated in endothelial media containing 1% FBS for 6 h are harvested after trypsin treatment and suspended in endothelial medium containing 1 % FBS. Cells are plated onto matrigel layer at a density of 2xl04 cells/well. These cells are treated with test compounds for 30 min at RT followed by the addition of 40 ng/ml VEGF. After 18 h, the cultures are photographed and inhibition is recorded.
Claims
We Claim:
A crystalline polymorph of N-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-l-(6-(2- cyanopropan-2-yl)pyridin-3-yl)-3-methyl-lH-imidazo[4,5-c]quinolin-2(3H)- ylidene)cyanamide (Compound A) or a pharmaceutically acceptable salt or a solvate thereof.
The crystalline form of Compound A according to claim 1 is Form A.
The crystalline form of Compound A according to claim 2, wherein said crystalline form is characterized by X-Ray diffraction peaks (expressed in degrees 2-theta values) of about 7.97, 11.38, 14.93, 15.95, 22.53 and 22.84 ± 0.2 degrees.
The crystalline form of Compound A according to claim 1 is Form B.
The crystalline form of Compound A according to claim 4, wherein said crystalline form is characterized by X-Ray diffraction peaks (expressed in degrees 2-theta values) of about: 19.26, 19.66, 21.90, 25.91 and 26.06 ± 0.2 degrees.
A mixture of crystalline and amorphous forms of N-(8-(6-amino-5-
(trifluoromethyl)pyridin-3-yl)-l-(6-(2-cyanopropan-2-yl)pyridin-3-yl)-3-methyl-lH- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide (Compound A) or a pharmaceutically acceptable salt or a solvate thereof.
A process for the
Compound A
or a stereoisomer, a tautomer, a polymorph, a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate thereof;
comprising the steps of:
(2)
b) reducing the compound (2) using an iron catalyst in the presence of
(3)
c) chlorinating 6-bromo-4-hydroxy-3-nitroquinoline
(4) using phosphorus oxy chloride (POCI3) in relatively lower volume in the presence of an organic solvent to obtain the compound (5);
d) reacting the compound (3) with the compound
(5) in acetic acid medium to get intermediate compound (6);
(6)
e) reducing the compound (6) using iron catalyst to obtain compound (7);
f) cyclising the compound
(8) using methyl iodide to obtain the compound (9);
(9)
(10)
to obtain the compound A.
The process according to claim 7 wherein the organic solvent used in step (b) is selected from ethanol and tetrahydrofuran (THF).
The process according to claim 7 wherein the solvent used in step (e) is selected from ethanol and tetrahydrofuran (THF).
10. The process according to claim 7 wherein the base used in step (f), is selected from diisopropylethylamine and cesium carbonate.
11. The process according to claim 7, wherein compound A is further treated with Si-thiol to reduce metal content.
12. A process for the purification of N-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-l-(6- (2-cyanopropan-2-yl)pyridin-3-yl)-3-methyl-lH-imidazo[4,5-c]quinolin-2(3H)- ylidene)cyanamide (Compound A) comprising the steps of:
a) providing a slurry of the Compound A in a solvent;
b) heating the slurry obtained in step a) at a temperature ranging from 70°C to 90°C; c) cooling the hot solution of step b) to a temperature of 25 °C of 35°C and
d) isolating pure Compound A.
The process according to claim 12 wherein the solvent used in step (a) is selected from methanol, ethanol, n-propanol, isopropyl alcohol (IPA), butanol, dichloromethane, ethylene dichloride, chloroform, acetic acid, acetonitrile, carbon tetrachloride, toluene, xylene, hexane, heptanes, dimethylformamide (DMF) and water or a mixture thereof.
The process according to claim 13 wherein the solvent used in step (a) is selected from dimethylformamide (DMF), water and isopropyl alcohol (IPA).
Use of Form A of the Compound A or pharmaceutically acceptable salts thereof for the treatment of cancer.
Use of Form B of Compound A or pharmaceutically acceptable salts thereof for the treatment of cancer.
Use of mixture of crystalline and amorphous form of Compound A or pharmaceutically acceptable salts thereof for the treatment of cancer.
A pharmaceutical composition comprising therapeutically effective amount of at least one polymorphic form of the Compound A as claimed in claim 1 and claim 6 and a pharmaceutically acceptable excipient.
A use of a therapeutically effective amount of at least one polymorphic form of the Compound A as claimed in claim 1, for the manufacture of a medicament for the treatment of cancers.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN1077/MUM/2014 | 2014-03-27 | ||
IN1077MU2014 | 2014-03-27 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2015145369A1 true WO2015145369A1 (en) | 2015-10-01 |
Family
ID=54194054
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB2015/052194 WO2015145369A1 (en) | 2014-03-27 | 2015-03-25 | Process for the preparation of substituted imidazo[4,5-c]quinoline compounds, intermediates and polymorphs thereof |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2015145369A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2019170543A1 (en) | 2018-03-07 | 2019-09-12 | Bayer Aktiengesellschaft | Identification and use of erk5 inhibitors |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012007926A1 (en) * | 2010-07-16 | 2012-01-19 | Piramal Life Sciences Limited | Substituted imidazoquinoline derivatives as kinase inhibitors |
WO2014177915A1 (en) * | 2013-05-01 | 2014-11-06 | Piramal Enterprises Limited | Cancer combination therapy using imidazo[4,5-c]quinoline derivatives |
-
2015
- 2015-03-25 WO PCT/IB2015/052194 patent/WO2015145369A1/en active Application Filing
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012007926A1 (en) * | 2010-07-16 | 2012-01-19 | Piramal Life Sciences Limited | Substituted imidazoquinoline derivatives as kinase inhibitors |
WO2014177915A1 (en) * | 2013-05-01 | 2014-11-06 | Piramal Enterprises Limited | Cancer combination therapy using imidazo[4,5-c]quinoline derivatives |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2019170543A1 (en) | 2018-03-07 | 2019-09-12 | Bayer Aktiengesellschaft | Identification and use of erk5 inhibitors |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2011277935B2 (en) | Substituted imidazoquinoline derivatives as kinase inhibitors | |
AU2019279951A1 (en) | Diaryl macrocycles as modulators of protein kinases | |
US10022374B2 (en) | Certain protein kinase inhibitors | |
JP5350277B2 (en) | Pyrrolopyrimidine derivatives as PI3K inhibitors and uses thereof | |
JP2018519343A (en) | Chiral diaryl macrocycles as modulators of protein kinases | |
TW202019913A (en) | Necroptosis inhibitors, and preparation and use of the same | |
CA2830367A1 (en) | Novel imidazo-oxazine compound or salt thereof | |
AU2018391833A1 (en) | Compound functioning as bromodomain protein inhibitor, and composition | |
US20130310374A1 (en) | Substituted Imidazoquinoline Derivatives | |
TW200936141A (en) | Substituted heteroarylamide oxazepinopyrimidone derivatives | |
EP3694330A1 (en) | Indazolyl-spiro[2.2]pentane-carbonitrile derivatives as lrrk2 inhibitors, pharmaceutical compositions, and uses thereof | |
EP3741752A1 (en) | Tam family kinase /and csf1r kinase inhibitor and use thereof | |
EP3967696A1 (en) | Compound used as kinase inhibitor and application thereof | |
AU2014340249A1 (en) | Substituted pyrimidine compounds and their use as SYK inhibitors | |
WO2018233526A9 (en) | Csf1r inhibitor, and manufacturing method therefor and application thereof | |
WO2015145369A1 (en) | Process for the preparation of substituted imidazo[4,5-c]quinoline compounds, intermediates and polymorphs thereof | |
CN114126614A (en) | Heterocyclic compounds as PRMT5 inhibitors | |
US7547706B2 (en) | 1H-pyrimido[4,5-b]indole derivatives, their preparation and therapeutic use | |
WO2019154329A1 (en) | Compound having bet inhibitory activity and preparation method and use therefor | |
AU2013252944B2 (en) | Highly pure pyrroloquinolinyl-pyrrole-2,5-dione and pyrroloquinolinyl-pyrrolidine-2,5-dione and methods of preparing same | |
WO2023109918A1 (en) | Nitrogenous heterocyclic compound, and preparation method therefor and use thereof | |
WO2020083089A1 (en) | Compound of 5- or 6-membered heterocyclic pyrimidines and use thereof | |
WO2024046370A1 (en) | Heterocyclic compounds as kras inhibitors, and preparation and therapeutic use thereof | |
WO2014141118A1 (en) | Imidazo[4,5-c]quinoline derivatives and uses thereof | |
CN116375712A (en) | Dimorpholine-substituted heterocyclic compound and medical application thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 15769344 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 15769344 Country of ref document: EP Kind code of ref document: A1 |