CN104817559A - 氘代喹唑啉酮化合物以及包含该化合物的药物组合物 - Google Patents
氘代喹唑啉酮化合物以及包含该化合物的药物组合物 Download PDFInfo
- Publication number
- CN104817559A CN104817559A CN201410058184.7A CN201410058184A CN104817559A CN 104817559 A CN104817559 A CN 104817559A CN 201410058184 A CN201410058184 A CN 201410058184A CN 104817559 A CN104817559 A CN 104817559A
- Authority
- CN
- China
- Prior art keywords
- compound
- acid
- deuterium
- deuterated
- pharmaceutical composition
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 127
- 239000000203 mixture Substances 0.000 title abstract description 18
- 150000003839 salts Chemical class 0.000 claims abstract description 31
- 239000012453 solvate Substances 0.000 claims abstract description 12
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 11
- 201000010099 disease Diseases 0.000 claims abstract description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 11
- 239000013078 crystal Chemical group 0.000 claims abstract description 10
- 229910052805 deuterium Inorganic materials 0.000 claims description 36
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 31
- 239000008194 pharmaceutical composition Substances 0.000 claims description 23
- 239000003814 drug Substances 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 13
- AVRPFRMDMNDIDH-UHFFFAOYSA-N 1h-quinazolin-2-one Chemical class C1=CC=CC2=NC(O)=NC=C21 AVRPFRMDMNDIDH-UHFFFAOYSA-N 0.000 claims description 11
- 230000015572 biosynthetic process Effects 0.000 claims description 10
- 201000011510 cancer Diseases 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 7
- 208000035269 cancer or benign tumor Diseases 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 206010061218 Inflammation Diseases 0.000 claims description 6
- 208000026278 immune system disease Diseases 0.000 claims description 6
- 208000015181 infectious disease Diseases 0.000 claims description 6
- 230000004054 inflammatory process Effects 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 5
- 230000005764 inhibitory process Effects 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 2
- 241000700605 Viruses Species 0.000 claims description 2
- 208000016097 disease of metabolism Diseases 0.000 claims description 2
- 208000030159 metabolic disease Diseases 0.000 claims description 2
- 108091007960 PI3Ks Proteins 0.000 abstract description 23
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 abstract description 20
- 102000003993 Phosphatidylinositol 3-kinases Human genes 0.000 abstract 2
- 230000004663 cell proliferation Effects 0.000 abstract 1
- 239000002585 base Substances 0.000 description 30
- 235000002639 sodium chloride Nutrition 0.000 description 29
- -1 3-propyl Chemical group 0.000 description 24
- 102000038030 PI3Ks Human genes 0.000 description 21
- 238000000034 method Methods 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 230000000694 effects Effects 0.000 description 11
- 125000004429 atom Chemical group 0.000 description 10
- 229910052794 bromium Inorganic materials 0.000 description 9
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 230000000155 isotopic effect Effects 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 230000003285 pharmacodynamic effect Effects 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 229940024606 amino acid Drugs 0.000 description 6
- 235000001014 amino acid Nutrition 0.000 description 6
- 150000001413 amino acids Chemical class 0.000 description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 5
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- 239000006187 pill Substances 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 235000008504 concentrate Nutrition 0.000 description 4
- 208000032839 leukemia Diseases 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
- 239000003921 oil Substances 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 210000002381 plasma Anatomy 0.000 description 4
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 4
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 4
- 229960002930 sirolimus Drugs 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 239000000080 wetting agent Substances 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 3
- 206010025323 Lymphomas Diseases 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 108091008611 Protein Kinase B Proteins 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- TZBJGXHYKVUXJN-UHFFFAOYSA-N genistein Chemical compound C1=CC(O)=CC=C1C1=COC2=CC(O)=CC(O)=C2C1=O TZBJGXHYKVUXJN-UHFFFAOYSA-N 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 229940002612 prodrug Drugs 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 229960000575 trastuzumab Drugs 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- GQVRPSFDUVNMDA-UHFFFAOYSA-N 2-fluoro-6-nitro-n-phenylbenzamide Chemical compound [O-][N+](=O)C1=CC=CC(F)=C1C(=O)NC1=CC=CC=C1 GQVRPSFDUVNMDA-UHFFFAOYSA-N 0.000 description 2
- RJWUMFHQJJBBOD-UHFFFAOYSA-N 2-methylheptadecane Chemical compound CCCCCCCCCCCCCCCC(C)C RJWUMFHQJJBBOD-UHFFFAOYSA-N 0.000 description 2
- VVIAGPKUTFNRDU-UHFFFAOYSA-N 6S-folinic acid Natural products C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-UHFFFAOYSA-N 0.000 description 2
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 2
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- 208000003950 B-cell lymphoma Diseases 0.000 description 2
- OJRUSAPKCPIVBY-KQYNXXCUSA-N C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N Chemical compound C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N OJRUSAPKCPIVBY-KQYNXXCUSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 2
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 2
- 229940126657 Compound 17 Drugs 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- 108010092160 Dactinomycin Proteins 0.000 description 2
- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 description 2
- LTMHDMANZUZIPE-AMTYYWEZSA-N Digoxin Natural products O([C@H]1[C@H](C)O[C@H](O[C@@H]2C[C@@H]3[C@@](C)([C@@H]4[C@H]([C@]5(O)[C@](C)([C@H](O)C4)[C@H](C4=CC(=O)OC4)CC5)CC3)CC2)C[C@@H]1O)[C@H]1O[C@H](C)[C@@H](O[C@H]2O[C@@H](C)[C@H](O)[C@@H](O)C2)[C@@H](O)C1 LTMHDMANZUZIPE-AMTYYWEZSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- VWUXBMIQPBEWFH-WCCTWKNTSA-N Fulvestrant Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 2
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 2
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 2
- 239000002067 L01XE06 - Dasatinib Substances 0.000 description 2
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 208000034578 Multiple myelomas Diseases 0.000 description 2
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 229930012538 Paclitaxel Natural products 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 235000019483 Peanut oil Nutrition 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 description 2
- 102000005765 Proto-Oncogene Proteins c-akt Human genes 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 190014017285 Satraplatin Chemical compound 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 239000004141 Sodium laurylsulphate Substances 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 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 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- NAVMQTYZDKMPEU-UHFFFAOYSA-N Targretin Chemical compound CC1=CC(C(CCC2(C)C)(C)C)=C2C=C1C(=C)C1=CC=C(C(O)=O)C=C1 NAVMQTYZDKMPEU-UHFFFAOYSA-N 0.000 description 2
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 229930183665 actinomycin Natural products 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 229940120638 avastin Drugs 0.000 description 2
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 229960002938 bexarotene Drugs 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- GMRQFYUYWCNGIN-NKMMMXOESA-N calcitriol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C GMRQFYUYWCNGIN-NKMMMXOESA-N 0.000 description 2
- 229960005084 calcitriol Drugs 0.000 description 2
- 235000020964 calcitriol Nutrition 0.000 description 2
- 239000011612 calcitriol Substances 0.000 description 2
- KVUAALJSMIVURS-ZEDZUCNESA-L calcium folinate Chemical compound [Ca+2].C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 KVUAALJSMIVURS-ZEDZUCNESA-L 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 229960004117 capecitabine Drugs 0.000 description 2
- 229960004562 carboplatin Drugs 0.000 description 2
- 229960000590 celecoxib Drugs 0.000 description 2
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 229960005395 cetuximab Drugs 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
- 229940126543 compound 14 Drugs 0.000 description 2
- 229940125758 compound 15 Drugs 0.000 description 2
- 229940126142 compound 16 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229960002448 dasatinib Drugs 0.000 description 2
- NIJJYAXOARWZEE-UHFFFAOYSA-N di-n-propyl-acetic acid Natural products CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 description 2
- LTMHDMANZUZIPE-PUGKRICDSA-N digoxin Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)[C@H](O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O LTMHDMANZUZIPE-PUGKRICDSA-N 0.000 description 2
- 229960005156 digoxin Drugs 0.000 description 2
- LTMHDMANZUZIPE-UHFFFAOYSA-N digoxine Natural products C1C(O)C(O)C(C)OC1OC1C(C)OC(OC2C(OC(OC3CC4C(C5C(C6(CCC(C6(C)C(O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)CC2O)C)CC1O LTMHDMANZUZIPE-UHFFFAOYSA-N 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229960001433 erlotinib Drugs 0.000 description 2
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 2
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 2
- 229960005420 etoposide Drugs 0.000 description 2
- 229960005167 everolimus Drugs 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 235000008191 folinic acid Nutrition 0.000 description 2
- 239000011672 folinic acid Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 229960002258 fulvestrant Drugs 0.000 description 2
- 229960002584 gefitinib Drugs 0.000 description 2
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 229960005277 gemcitabine Drugs 0.000 description 2
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 208000014951 hematologic disease Diseases 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- QQLKULDARVNMAL-UHFFFAOYSA-N icotinib Chemical compound C#CC1=CC=CC(NC=2C3=CC=4OCCOCCOCCOC=4C=C3N=CN=2)=C1 QQLKULDARVNMAL-UHFFFAOYSA-N 0.000 description 2
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 2
- 229960002411 imatinib Drugs 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229960004891 lapatinib Drugs 0.000 description 2
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 description 2
- 229960001320 lapatinib ditosylate Drugs 0.000 description 2
- 229960003881 letrozole Drugs 0.000 description 2
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 2
- 229960001691 leucovorin Drugs 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 230000003211 malignant effect Effects 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- AZBFJBJXUQUQLF-UHFFFAOYSA-N n-(1,5-dimethylpyrrolidin-3-yl)pyrrolidine-1-carboxamide Chemical compound C1N(C)C(C)CC1NC(=O)N1CCCC1 AZBFJBJXUQUQLF-UHFFFAOYSA-N 0.000 description 2
- LBWFXVZLPYTWQI-IPOVEDGCSA-N n-[2-(diethylamino)ethyl]-5-[(z)-(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C LBWFXVZLPYTWQI-IPOVEDGCSA-N 0.000 description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 210000004279 orbit Anatomy 0.000 description 2
- 229960001756 oxaliplatin Drugs 0.000 description 2
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 2
- 229960001592 paclitaxel Drugs 0.000 description 2
- 239000000312 peanut oil Substances 0.000 description 2
- 229960005079 pemetrexed Drugs 0.000 description 2
- WBXPDJSOTKVWSJ-ZDUSSCGKSA-L pemetrexed(2-) Chemical compound C=1NC=2NC(N)=NC(=O)C=2C=1CCC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 WBXPDJSOTKVWSJ-ZDUSSCGKSA-L 0.000 description 2
- 150000003905 phosphatidylinositols Chemical class 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229960004641 rituximab Drugs 0.000 description 2
- 229960005399 satraplatin Drugs 0.000 description 2
- 239000008159 sesame oil Substances 0.000 description 2
- 235000011803 sesame oil Nutrition 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 description 2
- 229960000894 sulindac Drugs 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 229940034785 sutent Drugs 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 2
- 229940063683 taxotere Drugs 0.000 description 2
- 229960000235 temsirolimus Drugs 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 2
- 229960000604 valproic acid Drugs 0.000 description 2
- NMDYYWFGPIMTKO-HBVLKOHWSA-N vinflunine Chemical compound C([C@@](C1=C(C2=CC=CC=C2N1)C1)(C2=C(OC)C=C3N(C)[C@@H]4[C@@]5(C3=C2)CCN2CC=C[C@]([C@@H]52)([C@H]([C@]4(O)C(=O)OC)OC(C)=O)CC)C(=O)OC)[C@H]2C[C@@H](C(C)(F)F)CN1C2 NMDYYWFGPIMTKO-HBVLKOHWSA-N 0.000 description 2
- 229960000922 vinflunine Drugs 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- MEIRRNXMZYDVDW-MQQKCMAXSA-N (2E,4E)-2,4-hexadien-1-ol Chemical compound C\C=C\C=C\CO MEIRRNXMZYDVDW-MQQKCMAXSA-N 0.000 description 1
- YXTKHLHCVFUPPT-YYFJYKOTSA-N (2s)-2-[[4-[(2-amino-5-formyl-4-oxo-1,6,7,8-tetrahydropteridin-6-yl)methylamino]benzoyl]amino]pentanedioic acid;(1r,2r)-1,2-dimethanidylcyclohexane;5-fluoro-1h-pyrimidine-2,4-dione;oxalic acid;platinum(2+) Chemical compound [Pt+2].OC(=O)C(O)=O.[CH2-][C@@H]1CCCC[C@H]1[CH2-].FC1=CNC(=O)NC1=O.C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 YXTKHLHCVFUPPT-YYFJYKOTSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- ZEMPKEQAKRGZGQ-AAKVHIHISA-N 2,3-bis[[(z)-12-hydroxyoctadec-9-enoyl]oxy]propyl (z)-12-hydroxyoctadec-9-enoate Chemical compound CCCCCCC(O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CC(O)CCCCCC)COC(=O)CCCCCCC\C=C/CC(O)CCCCCC ZEMPKEQAKRGZGQ-AAKVHIHISA-N 0.000 description 1
- OFJRNBWSFXEHSA-UHFFFAOYSA-N 2-(3-amino-1,2-benzoxazol-5-yl)-n-[4-[2-[(dimethylamino)methyl]imidazol-1-yl]-2-fluorophenyl]-5-(trifluoromethyl)pyrazole-3-carboxamide Chemical compound CN(C)CC1=NC=CN1C(C=C1F)=CC=C1NC(=O)C1=CC(C(F)(F)F)=NN1C1=CC=C(ON=C2N)C2=C1 OFJRNBWSFXEHSA-UHFFFAOYSA-N 0.000 description 1
- AXRCEOKUDYDWLF-UHFFFAOYSA-N 3-(1-methyl-3-indolyl)-4-[1-[1-(2-pyridinylmethyl)-4-piperidinyl]-3-indolyl]pyrrole-2,5-dione Chemical compound C12=CC=CC=C2N(C)C=C1C(C(NC1=O)=O)=C1C(C1=CC=CC=C11)=CN1C(CC1)CCN1CC1=CC=CC=N1 AXRCEOKUDYDWLF-UHFFFAOYSA-N 0.000 description 1
- AFPHTEQTJZKQAQ-UHFFFAOYSA-N 3-nitrobenzoic acid Chemical compound OC(=O)C1=CC=CC([N+]([O-])=O)=C1 AFPHTEQTJZKQAQ-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 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
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 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
- 101150013553 CD40 gene Proteins 0.000 description 1
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 1
- 239000005461 Canertinib Substances 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-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
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 1
- 239000004278 EU approved seasoning Substances 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 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
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical class NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 229940123583 Factor Xa inhibitor Drugs 0.000 description 1
- MPJKWIXIYCLVCU-UHFFFAOYSA-N Folinic acid Natural products NC1=NC2=C(N(C=O)C(CNc3ccc(cc3)C(=O)NC(CCC(=O)O)CC(=O)O)CN2)C(=O)N1 MPJKWIXIYCLVCU-UHFFFAOYSA-N 0.000 description 1
- 201000003741 Gastrointestinal carcinoma Diseases 0.000 description 1
- 239000001828 Gelatine Substances 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
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 description 1
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 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
- 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
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 1
- 239000002146 L01XE16 - Crizotinib Substances 0.000 description 1
- 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 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia 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
- XUYPXLNMDZIRQH-LURJTMIESA-N N-acetyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC(C)=O XUYPXLNMDZIRQH-LURJTMIESA-N 0.000 description 1
- 102000003945 NF-kappa B Human genes 0.000 description 1
- 108010057466 NF-kappa B Proteins 0.000 description 1
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 240000007817 Olea europaea Species 0.000 description 1
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 1
- 239000012828 PI3K inhibitor Substances 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 102100033810 RAC-alpha serine/threonine-protein kinase Human genes 0.000 description 1
- 101710113459 RAC-alpha serine/threonine-protein kinase Proteins 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- 239000004012 Tofacitinib Substances 0.000 description 1
- 102100040245 Tumor necrosis factor receptor superfamily member 5 Human genes 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000016383 Zea mays subsp huehuetenangensis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- OUJTZYPIHDYQMC-LJQANCHMSA-N ambrisentan Chemical compound O([C@@H](C(OC)(C=1C=CC=CC=1)C=1C=CC=CC=1)C(O)=O)C1=NC(C)=CC(C)=N1 OUJTZYPIHDYQMC-LJQANCHMSA-N 0.000 description 1
- 229960002414 ambrisentan Drugs 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 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
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 229960001467 bortezomib Drugs 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- HXCHCVDVKSCDHU-LULTVBGHSA-N calicheamicin Chemical compound C1[C@H](OC)[C@@H](NCC)CO[C@H]1O[C@H]1[C@H](O[C@@H]2C\3=C(NC(=O)OC)C(=O)C[C@](C/3=C/CSSSC)(O)C#C\C=C/C#C2)O[C@H](C)[C@@H](NO[C@@H]2O[C@H](C)[C@@H](SC(=O)C=3C(=C(OC)C(O[C@H]4[C@@H]([C@H](OC)[C@@H](O)[C@H](C)O4)O)=C(I)C=3C)OC)[C@@H](O)C2)[C@@H]1O HXCHCVDVKSCDHU-LULTVBGHSA-N 0.000 description 1
- 229930195731 calicheamicin Natural products 0.000 description 1
- OMZCMEYTWSXEPZ-UHFFFAOYSA-N canertinib Chemical compound C1=C(Cl)C(F)=CC=C1NC1=NC=NC2=CC(OCCCN3CCOCC3)=C(NC(=O)C=C)C=C12 OMZCMEYTWSXEPZ-UHFFFAOYSA-N 0.000 description 1
- 229950002826 canertinib Drugs 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 201000010989 colorectal carcinoma Diseases 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229960005061 crizotinib Drugs 0.000 description 1
- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 150000005332 diethylamines Chemical class 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- MCWXGJITAZMZEV-UHFFFAOYSA-N dimethoate Chemical compound CNC(=O)CSP(=S)(OC)OC MCWXGJITAZMZEV-UHFFFAOYSA-N 0.000 description 1
- 150000004656 dimethylamines Chemical class 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 229950002189 enzastaurin Drugs 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 compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- 238000007046 ethoxylation reaction Methods 0.000 description 1
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- IDNUEBSJWINEMI-UHFFFAOYSA-N ethyl nitrate Chemical compound CCO[N+]([O-])=O IDNUEBSJWINEMI-UHFFFAOYSA-N 0.000 description 1
- 150000003947 ethylamines Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000004992 fission Effects 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 229940045109 genistein Drugs 0.000 description 1
- 235000006539 genistein Nutrition 0.000 description 1
- ZCOLJUOHXJRHDI-CMWLGVBASA-N genistein 7-O-beta-D-glucoside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=C2C(=O)C(C=3C=CC(O)=CC=3)=COC2=C1 ZCOLJUOHXJRHDI-CMWLGVBASA-N 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229930182478 glucoside Natural products 0.000 description 1
- 150000008131 glucosides Chemical class 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 239000000976 ink Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 201000002313 intestinal cancer Diseases 0.000 description 1
- 230000004068 intracellular signaling Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229960000201 isosorbide dinitrate Drugs 0.000 description 1
- MOYKHGMNXAOIAT-JGWLITMVSA-N isosorbide dinitrate Chemical compound [O-][N+](=O)O[C@H]1CO[C@@H]2[C@H](O[N+](=O)[O-])CO[C@@H]21 MOYKHGMNXAOIAT-JGWLITMVSA-N 0.000 description 1
- 230000005445 isotope effect Effects 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 235000009973 maize Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 229950008001 matuzumab Drugs 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 150000003956 methylamines Chemical class 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- ZUXWMZPBQLGDDY-UHFFFAOYSA-N n,n-dihydroxyethanamine Chemical class CCN(O)O ZUXWMZPBQLGDDY-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- AHJRHEGDXFFMBM-UHFFFAOYSA-N palbociclib Chemical compound N1=C2N(C3CCCC3)C(=O)C(C(=O)C)=C(C)C2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 AHJRHEGDXFFMBM-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229960001972 panitumumab Drugs 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 229940067626 phosphatidylinositols Drugs 0.000 description 1
- 229940043441 phosphoinositide 3-kinase inhibitor Drugs 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical class CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 229950010535 razaxaban Drugs 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000000979 retarding effect Effects 0.000 description 1
- KGFYHTZWPPHNLQ-AWEZNQCLSA-N rivaroxaban Chemical compound S1C(Cl)=CC=C1C(=O)NC[C@@H]1OC(=O)N(C=2C=CC(=CC=2)N2C(COCC2)=O)C1 KGFYHTZWPPHNLQ-AWEZNQCLSA-N 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011257 shell material Substances 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 229960003787 sorafenib Drugs 0.000 description 1
- 239000002594 sorbent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 235000014347 soups Nutrition 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 201000000498 stomach carcinoma Diseases 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 1
- 229960001796 sunitinib Drugs 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229940061353 temodar Drugs 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- QFJCIRLUMZQUOT-UHFFFAOYSA-N temsirolimus Natural products C1CC(O)C(OC)CC1CC(C)C1OC(=O)C2CCCCN2C(=O)C(=O)C(O)(O2)C(C)CCC2CC(OC)C(C)=CC=CC=CC(C)CC(C)C(=O)C(OC)C(O)C(C)=CC(C)C(=O)C1 QFJCIRLUMZQUOT-UHFFFAOYSA-N 0.000 description 1
- MFPWEWYKQYMWRO-UHFFFAOYSA-N tert-butyl carboxy carbonate Chemical compound CC(C)(C)OC(=O)OC(O)=O MFPWEWYKQYMWRO-UHFFFAOYSA-N 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical class CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- 229940098465 tincture Drugs 0.000 description 1
- PLHJCIYEEKOWNM-HHHXNRCGSA-N tipifarnib Chemical compound CN1C=NC=C1[C@](N)(C=1C=C2C(C=3C=C(Cl)C=CC=3)=CC(=O)N(C)C2=CC=1)C1=CC=C(Cl)C=C1 PLHJCIYEEKOWNM-HHHXNRCGSA-N 0.000 description 1
- 229950009158 tipifarnib Drugs 0.000 description 1
- UJLAWZDWDVHWOW-YPMHNXCESA-N tofacitinib Chemical compound C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)C1=NC=NC2=C1C=CN2 UJLAWZDWDVHWOW-YPMHNXCESA-N 0.000 description 1
- 229960001350 tofacitinib Drugs 0.000 description 1
- 229940100411 torisel Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 229940086542 triethylamine Drugs 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 229940038773 trisodium citrate Drugs 0.000 description 1
- 230000005747 tumor angiogenesis Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004862 vasculogenesis Effects 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 229940099039 velcade Drugs 0.000 description 1
- 229950001212 volociximab Drugs 0.000 description 1
- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 description 1
- 229960000237 vorinostat Drugs 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 229940055725 xarelto Drugs 0.000 description 1
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 1
- 229960000641 zorubicin Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
- C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Virology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Cardiology (AREA)
- Vascular Medicine (AREA)
- Molecular Biology (AREA)
- Diabetes (AREA)
- Transplantation (AREA)
- Obesity (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明涉及氘代的喹唑啉酮化合物以及包含该化合物的药物组合物。具体地,本发明公开了式(I)所示的氘代的喹唑啉酮化合物以及含有该化合物、或其晶型、药学上可接受的盐、水合物或溶剂合物的药物组合物。本发明的化合物可用于治疗和/或预防磷脂酰肌醇3-激酶(PI3K)相关性疾病,例如癌症、细胞增殖性疾病等。
Description
技术领域
本发明属于医药领域。具体地,本发明涉及新型的氘代喹唑啉酮化合物以及含该化合物的药物组合物。
背景技术
磷脂酰肌醇-3-激酶(phosphoinositide3-kinases,PI3Ks)是一类特异性催化磷脂酰肌醇(phosphatidylinositol,PI)及其衍生物的3位羟基磷酸化并产生具有第二信使作用的磷脂酰肌醇-3-磷酸(phosphatidylinositol-3,4,5-triphosphate,PI3P)的酶。PI3Ks介导的信号传导参与细胞分裂、分化、凋亡、代谢以及血管生成等多种细胞功能的调节,对多种细胞生物功能的活化起到重要作用。近年来研究表明,PI3Ks和下游分子蛋白激酶B(protein kinase B,PKB或Akt)所组成的信号通路与肿瘤的发生、发展密切相关,调节肿瘤细胞的增殖、凋亡,促进肿瘤血管形成等。
喹唑啉酮化合物及衍生物是一类磷脂酰肌醇3-激酶的抑制剂。在专利WO03035075和WO2005113556中公开了系列喹唑啉酮衍生物,其中,化合物GS-1101是选择性的PI3K抑制剂,化学名为(S)-2-(1-(9H-嘌呤-6-基氨基)丙基)-5-氟-3-苯基喹唑啉-4(3H)-酮,具有治疗癌症和细胞增殖性疾病以及其它相关疾病中的用途,目前该化合物正处于治疗慢性淋巴白血病(chroniclymphocytic leukemia)和非霍奇金淋巴瘤(non-Hodgkin lymphomas)的临床三期研究中。
虽然磷脂酰肌醇-3-激酶(PI3K)是抗肿瘤新药研发的重要靶点之一,然而除了雷帕霉素(rapamycin)及同系物以外,抑制PI3K信号传导通路的研究进展相对缓慢,特别是特异性抑制PI3K亚型(如I型PI3K包括p110α,p110β,p110δ等)的抑制剂的开发还具有很大的挑战性。
因此,本领域仍需要开发具有对磷脂酰肌醇3-激酶具有很好抑制活性或更好药效学/药代动力学性能的化合物。
发明内容
本发明的目的是提供一类新型的具有磷脂酰肌醇3-激酶抑制活性和更好药效学/药代动力学性能的化合物及其用途。
在本发明的第一方面中,提供了一种式(I)所示的氘代的喹唑啉酮化合物、或其晶型、药学上可接受的盐、水合物或溶剂合物:
式中:
R1、R2各自独立地为氢、氘或卤素;
R3选自氢、氘、CH3、CH2D、CHD2、CD3、CH2CH3、CD2CH3、CH2CD3和CD2CD3;
R4、R5、R6、R7、R8、R9、R10、R11、R12和R13各自独立地为氢或氘;
附加条件是R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12或R13中至少一个是氘代的或氘。
在另一优选例中,氘在氘取代位置的氘同位素含量至少是大于天然氘同位素含量(0.015%),较佳地大于30%,更佳地大于50%,更佳地大于75%,更佳地大于95%,更佳地大于99%。
在另一优选例中,式(I)化合物至少含有1个氘原子,更佳地3个氘原子,更佳地4个氘原子,更佳地6个氘原子。
在另一优选例中,式(I)化合物的对映体过量值(e.e.值)大于95%,更佳地大于98%,更佳地大于99%。
在另一优选例中,R1为氟和/或R2为氢。
在另一优选例中,R4为氢或氘。
在另一优选例中,R5、R6、R7、R8、R9、R10、R11、R12和R13各自独立地为氢或氘。
在另一优选例中,R1为卤素,如氟、氯、溴、碘。
在另一优选例中,R1是氟。
在另一优选例中,R3是CH3、CH2D、CHD2、CD3、CH2CH3、CD2CH3、CH2CD3或CD2CD3。
在另一优选例中,R4是氘。
在另一优选例中,R12为氘和/或R13为氘。
在另一优选例中,R12是氘。
在另一优选例中,R13是氘。
在另一优选例中,所述化合物是选自下组的化合物或其药学上可接受的盐:
在另一优选例中,所述化合物是选自下组的化合物或其药学上可接受的盐:
(S)-2-(1-(9H-嘌呤-6-基氨基)-(1-d-丙基))-5-氟-3-苯基喹唑啉-4(3H)-酮;
(S)-2-(1-(9H-嘌呤-6-基氨基)-(1,2,2-d3-丙基))-5-氟-3-苯基喹唑啉-4(3H)-酮;
(S)-2-(1-(9H-嘌呤-6-基氨基)-(1,2,2,3,3,3-d6-丙基))-5-氟-3-苯基喹唑啉-4(3H)-酮;
(S)-2-(1-(9H-嘌呤-6-基氨基)-(1,3,3,3-d4-丙基))-5-氟-3-苯基喹唑啉-4(3H)-酮;
(S)-2-(1-(9H-嘌呤-6-基氨基)-(2,2,3,3,3-d5-丙基))-5-氟-3-苯基喹唑啉-4(3H)-酮;
(S)-2-(1-(9H-嘌呤-6-基氨基)-(3,3,3-d3-丙基))-5-氟-3-苯基喹唑啉-4(3H)-酮;
(S)-2-(1-(9H-嘌呤-6-基氨基)-(2,2-d2-丙基))-5-氟-3-苯基喹唑啉-4(3H)-酮;
(S)-2-(1-(9H-嘌呤-6-基氨基)-(1-d-乙基))-6-氟-3-苯基喹唑啉-4(3H)-酮;
(S)-2-(1-(9H-嘌呤-6-基氨基)-(1,2,2,2-d4-乙基))-6-氟-3-苯基喹唑啉-4(3H)-酮;
(S)-2-(1-(9H-嘌呤-6-基氨基)-(2,2,2-d3-乙基))-6-氟-3-苯基喹唑啉-4(3H)-酮;
(S)-2-(1-(9H-嘌呤-8-d-6-基氨基)-(1-d-丙基))-5-氟-3-苯基喹唑啉-4(3H)-酮
(S)-2-(1-(9H-嘌呤-2,8-d2-6-基氨基)-(1-d-丙基))-5-氟-3-苯基喹唑啉-4(3H)-酮
在另一优选例中,所述的化合物为其具有如下特征:MS计算值:416;MS测量值:417(M+H)+,439(M+Na)+。
在另一优选例中,所述的化合物为其具有如下特征:MS计算值:421;MS测量值:422(M+H)+,444(M+Na)+。
在另一优选例中,所述的化合物为其具有如下特征:MS计算值:419;MS测量值:420(M+H)+,442(M+Na)+。
在另一优选例中,所述的化合物为其具有如下特征:MS计算值:405;MS测量值:406(M+H)+,428(M+Na)+。
在另一优选例中,所述的化合物为其具有如下特征:MS计算值:417;MS测量值:418(M+H)+,440(M+Na)+。
在另一优选例中,所述的化合物为其具有如下特征:MS计算值:418;MS测量值:419(M+H)+,441(M+Na)+。
在另一优选例中,所述的化合物不包括非氘代的化合物。
在另一优选例中,所述的非氘代的化合物为(S)-2-(1-(9H-嘌呤-6-基氨基)丙基)-5-氟-3-苯基喹唑啉-4(3H)-酮。
在另一优选例中,所述的化合物由实施例1-12所述的方法制备的。
在本发明的第二方面中,提供了一种制备药物组合物的方法,包括步骤:将药学上可接受的载体与本发明第一方面中所述的化合物,或其晶型、药学上可接受的盐、水合物或溶剂合物进行混合,从而形成药物组合物。
在本发明的第三方面中,提供了一种药物组合物,它含有药学上可接受的载体和本发明第一方面中所述的化合物,或其晶型、药学上可接受的盐、水合物或溶剂合物。
在另一优选例中,所述的药物组合物为注射剂、囊剂、片剂、丸剂、散剂或颗粒剂。
在另一优选例中,所述的药物组合物还含有另外的治疗药物,所述的另外的治疗药物为癌症、心血管疾病、炎症、感染、免疫性疾病、细胞增殖性疾病、病毒性疾病、代谢性疾病、或器官移植的药物。
更佳地,所述的另外的治疗药物包括(但并不限于):5-氟尿嘧啶、FOLFOX、阿瓦斯丁TM(avastin,bevacizumab)、贝沙罗汀(bexarotene)、硼替佐米(bortezomib)、骨化三醇(calcitriol)、卡奈替尼(canertinib)、卡培他滨(capecitabine)、吉西他滨(gemcitabine)、碳铂(carboplatin)、塞来考昔(celecoxib)、西妥昔单抗(cetuximab)、顺铂(cisplatin)、达沙替尼(dasatinib)、地高辛(digoxin)、enzastaurin、埃罗替尼(Erlotinib)、依托泊甙(etoposide)、依维莫司(everolimus)、氟维司群(fulvestrant)、吉非替尼(gefitinib)、金雀异黄素(genistein)、伊马替尼(imatinib)、依立替康(irinotecan)、拉帕替尼(lapatinib)、来那度胺(lenalidomide)、来曲唑(letrozole)、亚叶酸(leucovorin)、马妥珠单抗(matuzumab)、奥沙利铂(oxaliplatin)、紫杉醇(paclitaxel)、多西他赛(doxetaxel)、帕尼单抗(panitumumab)、PEG化的粒细胞集落刺激因子(pegfilgrastin)、PEG化的α-干扰素(peglated alfa-interferon)、培美曲塞(pemetrexed)、E、沙铂(satraplatin)、西罗莫司(sirolimus)、舒尼替尼(sutent,sunitinib)、舒林酸(sulindac)、泰索帝(taxotere)、替莫唑胺(temodar、temozomolomide)、驮瑞塞尔(Torisel)、替西罗莫司(temsirolimus)、替吡法尼(tipifarnib)、曲妥单抗(trastuzumab)、丙戊酸(valproic acid)、长春氟宁(vinflunine)、Volociximab、Vorinostat、索拉非尼(Sorafenib)、克唑替尼(Crizotinib)、埃克替尼(Lcotinib)、拉帕替尼(Lapatinib)、托法替尼(Tofacitinib)、PD-0332991(Palbociclib)、安贝生坦(ambrisentan)、多柔比星、甲氨蝶呤、泼尼松、利妥昔单抗(rituximab)、CD40和/或CD154特异性抗体、融合蛋白、NF-kB抑制剂、非甾体抗炎药、凝血因子FXa抑制剂(如利伐沙班等)、抗-TNF抗体、抗生素药物如刺孢霉素(calicheamicin)、放线菌素(actinomycin)、阿霉素(doxorubicin)等。
在本发明的第四方面中,提供了本发明第一方面中所述的化合物,或其晶型、药学上可接受的盐、水合物或溶剂合物本发明第三方面所述的药物组合物的用途,它们被用于制备抑制磷脂酰肌醇3-激酶的药物组合物。
在另一优选例中,所述的药物组合物用于制备治疗和预防以下疾病的药物:癌症、细胞增殖性疾病、炎症、感染或免疫性疾病。
在另一优选例中,所述的癌症包括(但并不限于):肺癌、乳腺癌、前列腺癌、食道癌、直肠癌、结肠癌、血癌(或恶性血液病)、骨癌、肾癌、胃癌、肝癌或大肠癌。
在另一优选例中,所述的血癌(或恶性血液病)为白血病、淋巴瘤。
在另一优选例中,所述的淋巴瘤是指非霍奇金淋巴瘤(non-Hodgkinlymphomas)、B细胞淋巴瘤(B-cell lymphoma)、套细胞淋巴瘤(mantle celllymphoma)。
在另一优选例中,所述的白血病是指慢性淋巴白血病(chronic lymphocyticleukemia)、急性淋巴白血病(acute lymphocytic leukemia)、急性骨髓性白血病(acute myeloid leukemia)、多发性骨髓瘤(multiple myeloma)、慢性骨髓性白血病(chronic myeloid leukemia)。
在本发明的第五方面中,提供了一种抑制磷脂酰肌醇3-激酶的方法或一种疾病(如癌症、细胞增殖性疾病、炎症、感染、免疫性疾病)的治疗方法,它包括步骤:给需要治疗的对象施用本发明第一方面中所述的化合物,或其晶型、药学上可接受的盐、水合物或溶剂合物,或施用本发明第三方面中所述的药物组合物。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
具体实施方式
本发明人经过研究,意外地发现,本发明的氘代的喹唑啉酮化合物及其药学上可接受的盐与未氘代的化合物相比,具有明显更优异的药物动力学和/或药效学性能,因此更适合作为抑制磷脂酰肌醇3-激酶的化合物,进而更适用制备治疗癌症以及磷脂酰肌醇3-激酶相关疾病的药物。在此基础上完成了本发明。
定义
如本文所用,“卤素”指F、Cl、Br、和I。更佳地,卤原子选自F、Cl和Br。
如本文所用,“更优异的药物动力学和/或药效学性能”是指更长的药物半衰期(t1/2),或者更高的药物暴露量(AUC),或者更高的最大药物浓度(Cmax),或者更低的药物清除率
如本文所用,“氘代”指化合物或基团中的一个或多个氢被氘所取代。氘代可以是一取代、二取代、多取代或全取代。术语“一个或多个氘代的”与“一次或多次氘代”可互换使用。
如本文所用,“非氘代的化合物”是指含氘原子比例不高于天然氘同位素含量(0.015%)的化合物。
在另一优选例中,氘在氘取代位置的氘同位素含量是大于天然氘同位素含量(0.015%),更佳地大于50%,更佳地大于75%,更佳地大于95%,更佳地大于97%,更佳地大于99%,更佳地大于99.5%。
在另一优选例中,式(I)化合物至少含有1个氘原子,更佳地2个氘原子、3个氘原子,更佳地4个氘原子,更佳地6个氘原子。
优选地,式(I)化合物中,N为14N和/或O为16O。
在另一优选例中,所述化合物中,14N在氮原子所在位置的同位素含量≥95%,更佳地≥99%。
在另一优选例中,所述化合物中,16O在氧原子所在位置的同位素含量≥95%,更佳地≥99%。
活性成分
如本文所用,术语“本发明化合物”指式(I)所示的化合物。该术语还包括及式(I)化合物的各种晶型形式、药学上可接受的盐、水合物或溶剂合物。
其中,术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于:盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸;甲酸、乙酸、三氟乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、乙磺酸、甲苯磺酸、苯磺酸、萘磺酸等有机酸;以及脯氨酸、苯丙氨酸、天冬氨酸、谷氨酸等氨基酸。另一类优选的盐是本发明化合物与碱形成的盐,例如碱金属盐(例如钠盐或钾盐)、碱土金属盐(例如镁盐或钙盐)、铵盐(如低级的烷醇铵盐以及其它药学上可接受的胺盐),例如甲胺盐、乙胺盐、丙胺盐、二甲基胺盐、三甲基胺盐、二乙基胺盐、三乙基胺盐、叔丁基胺盐、乙二胺盐、羟乙胺盐、二羟乙胺盐、三羟乙胺盐,以及分别由吗啉、哌嗪、赖氨酸形成的胺盐。
术语“溶剂合物”指本发明化合物与溶剂分子配位形成特定比例的配合物。“水合物”是指本发明化合物与水进行配位形成的配合物。
此外,本发明化合物还包括式(I)所示的喹唑啉酮化合物的手性对映异构体、或消旋体。
此外,本发明化合物还包括式(I)所示的喹唑啉酮化合物的前药。术语“前药”包括其本身可以是具有生物学活性的或非活性的,当用适当的方法服用后,其在人体内进行代谢或化学反应而转变成式(I)的一类化合物,或式(I)的一个化合物所组成的盐或溶液。所述的前药包括(但不局限于)所述化合物的羧酸酯、碳酸酯、磷酸酯、硝酸酯、硫酸酯、砜酯、亚砜酯、氨基化合物、氨基甲酸盐、偶氮化合物、磷酰胺、葡萄糖苷、醚、乙缩醛等形式。
制备方法
下面更具体地描述本发明式(I)结构化合物的制备方法,但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得,这样的组合可由本发明所属领域的技术人员容易地进行。
本发明使用的未氘代的喹唑啉酮化合物及其生理上相容的盐的制备方法是已知的。对应氘代的喹唑啉酮化合物的制备可以用相应的氘代起始化合物为原料,用同样的路线合成。例如,本发明式(I)化合物可按WO03035075中所述的制备方法制备,不同点在于在反应中用氘代的原料代替非氘代的原料。
通常,在制备流程中,各反应通常在惰性溶剂中,在室温至回流温度(如0℃~200℃,优选0℃~100℃)下进行。反应时间通常为0.1小时-60小时,较佳地为0.5-48小时。
下面的通用制备路线可以用于合成本发明式(I)结构的化合物。
其中:R2、R1选自H、D、F、Cl、Br、I;R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13的定义同前。
如合成路线一所示,取代的间硝基苯甲酸化合物II经草酰氯酰化后与取代的苯胺III在碱性条件下反应生成化合物IV;IV在氯化亚砜作用下酰胺氢被氯代,再与相关Boc保护氘代氨基酸V作用形成化合物VI,VI结构中的芳硝基经化学还原条件如锌粉/醋酸、氯化亚锡、还原铁粉或如钯、铂、雷尼镍等催化氢化条件得到芳胺,关环得到喹唑啉酮结构VII;化合物VII在三氟乙酸/二氯甲烷、盐酸/二氧六环等条件下脱Boc再经碱游离得到化合物VIII,最后与6-溴嘌呤或6-溴氘代嘌呤在碱作用下于醇(如乙醇,正丁醇,叔丁醇)或四氢呋喃等溶剂中煮沸即可得到本发明化合物I。上述反应在惰性溶剂,如二氯甲烷、二氯乙烷、乙腈、正己烷、甲苯、四氢呋喃、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲基亚砜、乙酸、丁醇、丙醇等中,温度0~200℃下进行。
氘代化合物V的制备方法如下面合成路线所示:
其中R3、R4的定义同前。
如合成路线二所示,氘代氨基酸IX和二碳酸二叔丁酯(Boc2O)在碱性条件下和惰性溶剂中反应生成N-Boc保护氨基酸V。一些氘代氨基酸IX可通过常规氘代方法制得。另一些氘代氨基酸IX可以商业化购买到,如:(2S)-2-氨基-4,4,4-d3-丁酸、(2S)-2-氨基-3,3-d2-丁酸、(2S)-2-氨基-2-d-丁酸和(2S)-2-氨基-2,3,3-d3-丁酸等。
药物组合物和施用方法
由于本发明化合物具有优异的对磷脂酰肌醇3-激酶的抑制活性,因此本发明化合物及其各种晶型,药学上可接受的无机或有机盐,水合物或溶剂合物,以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解由对磷脂酰肌醇3-激酶介导的疾病。根据现有技术,本发明化合物可用于治疗以下疾病:癌症、细胞增殖性疾病、炎症、感染、免疫性疾病等。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是:化合物的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物含有1-2000mg本发明化合物/剂,更佳地,含有10-1000mg本发明化合物/剂。较佳地,所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和,而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药,或者与其他药学上可接受的化合物联合给药。
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常为1~2000mg,优选50~1000mg。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
本发明的化合物与现有技术中已知的非氘代化合物相比,具有一系列优点。本发明的主要优点包括:
(1)本发明化合物对磷脂酰肌醇3-激酶(PI3K)具有优异的抑制性。
(2)通过氘化这一技术改变化合物在生物体中的代谢,使化合物具有更好的药代动力学参数特性。在这种情况下,可以改变剂量并形成长效制剂,改善适用性。
(3)用氘取代化合物中的氢原子,由于其氘同位素效应,能够提高化合物在动物体内的药物浓度,以提高药物疗效。
(4)用氘取代化合物中的氢原子,由于某些代谢产物被抑制,可能提高化合物的安全性。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则份数和百分比为重量份和重量百分比。
实施例1制备(S)-2-(1-(9H-嘌呤-6-基氨基)-(1-d-丙基))-5-氟-3-苯基喹唑啉-4(3H)-酮(化合物6)
1、制备2-氟-6-硝基-N-苯基苯甲酰胺(化合物2)
向烧瓶中加入化合物2-氟-6-硝基苯甲酸(5.0g,0.027mol)和N,N-二甲基甲酰胺(0.5ml),加入二氯甲烷(20ml)溶解,再缓慢滴加草酰氯(5.1g,0.04mol,1.5eq)。室温搅拌2小时后,浓缩。浆状物溶于二氧六环(10ml)并冷却到5℃,将该溶液缓慢滴入到苯胺(5ml,0.027mol,1eq)及碳酸氢钠(4.5g,0.054mol,2eq)的二氧六环和水(1:1,v:v,30ml)的混合体系中。滴加完后升温至室温搅拌60分钟。加入纯水,析出大量固体,抽滤,滤饼用水洗涤,抽干,50℃下高真空干燥24h,得到类白色固体目标产物(6.0g,85%)。1H NMR(300MHz,DMSO-d6)δ10.82(s,1H),8.12(d,J=7.7Hz,1H),7.91-7.77(m,2H),7.64(d,J=7.7Hz,2H),7.38(t,J=7.9Hz,2H),7.15(t,J=7.4Hz,1H);ESI-MS m/z261(M+H)+。
2、制备(S)-[1-(2-氟-6-硝基-苯甲酰基)-苯基-氨甲酰基]-(1-d-丙基)-氨基甲酸叔丁酯(化合物3)
向烧瓶中一次加入2-氟-6-硝基-N-苯基苯甲酰胺(7.8g,0.03mol)、N,N-二甲基甲酰胺(0.5ml)和氯化亚砜(17.8g,0.15mol,5eq),升温到85℃并搅拌5小时。样品浓缩得棕色稠状物。稠状物用二氯甲烷(20ml)溶解后,10℃下缓慢滴加到(S)-2-(叔丁氧羰酰胺)-2-d-丁酸(6.7g,0.033mol,1.1eq),三乙胺(3.4g,0.033mol,1.1eq)的二氯甲烷(50ml)溶液中。室温搅拌3小时后,过滤除去固体,滤液分别用纯水、饱和碳酸氢钠、纯水、5%柠檬酸及饱和食盐水洗涤。有机相用无水硫酸镁干燥,浓缩得红色稠状物。稠状物经硅胶柱层析(10%-25%正己烷/乙酸乙酯)得到类白色的目标化合物3(8.0g,60%)。ESI-MS m/z447(M+H)+。
3、制备(S)-[1-(5-氟-4-氧-3-苯基-3,4-二羟基-喹唑啉-2-基)-(1-d-丙基)]-氨基甲酸叔丁酯(化合物4)
向烧瓶中加入(S)-[1-(2-氟-6-硝基-苯甲酰基)-苯基-氨甲酰基]-(1-d-丙基)-氨基甲酸叔丁酯(4.5g,0.01mol,1eq)和醋酸(50ml),搅拌。控制温度低于20℃,分三批加入锌粉(48.4g,740mmol,6eq)。室温下搅拌2小时。抽滤并用醋酸洗涤滤饼,滤液浓缩后溶于乙酸乙酯,依次用纯水、饱和碳酸氢钠水溶液及食盐水洗涤,无水硫酸镁干燥,浓缩得残余物。残余物经硅胶柱层析(10%-25%正己烷/乙酸乙酯)得到类白色的泡状固体(2.5g,63%)。1H NMR(400MHz,DMSO-d6)δ7.80(s,1H),7.62-7.44(m,5H),7.38(d,J=7.6Hz,1H),7.30(m,1H),7.23(d,J=7.6Hz,1H),1.76-1.68(m,1H),1.60-1.46(m,1H),1.31(s,9H),0.62(t,J=7.2Hz,3H).ESI-MS m/z399(M+H)+.
4、制备(S)-2-(1-氨基-1-d-丙基)-5-氟-3-苯基喹唑啉-4(3H)-酮(化合物5)
向烧瓶中依次加入(S)-[1-(5-氟-4-氧-3-苯基-3,4-二羟基-喹唑啉-2-基)-(1-d-丙基)]-氨基甲酸叔丁酯(1.99g,5mmol)和二氯甲烷(6ml),搅拌,加入三氟乙酸(6ml)。室温下搅拌1小时。高真空浓缩,残留物溶于二氯甲烷,加入10%碳酸钾水溶液直至pH约为9,分层,水相再用二氯甲烷萃取,合并有机相依次用纯水及食盐水洗涤,无水硫酸镁干燥,浓缩得到类白色固体目标产物(1.4g,93%)。1H NMR(400MHz,CDCl3)δ7.74-7.66(m,1H),7.62-7.50(m,4H),7.30-7.20(m,2H),7.12-7.06(m,1H),1.88-1.72(m,1H),1.58-1.41(m,1H),0.78(t,J=7.2Hz,3H).ESI-MS m/z299.1(M+H)+。
5、制备(S)-2-(1-(9H-嘌呤-6-基氨基)-1-d-丙基)-5-氟-3-苯基喹唑啉-4(3H)-酮(化合物6)
向反应瓶中依次加入(S)-2-(1-氨基-1-d-丙基)-5-氟-3-苯基喹唑啉-4(3H)-酮(1.2g,4mmol,1eq)、6-溴嘌呤(0.88g,4.4mmol,1.1eq)和二异丙基乙胺(1.04g,8mmol,2eq)和叔丁醇(8ml)。混合物在80℃下搅拌30小时。样品浓缩得到固体粗品,经硅胶柱层析(4%甲醇/二氯甲烷)分离纯化得到淡黄色固体产物(1.0g,60%)。1H NMR(400MHz,DMSO-d6)δ12.70(s,1H),8.12(s,1H),8.02(s,1H),7.82-7.74(m,1H),7.62-7.40(m,6H),7.26-7.15(m,2H),2.03-1.75(m,2H),0.78(t,J=7.2Hz,3H).ESI-MS m/z417(M+H)+。
实施例2制备(S)-2-(1-(9H-嘌呤-6-基氨基)-1,2,2-d3-丙基)-5-氟-3-苯基喹唑啉-4(3H)-酮(化合物7)
按实施例1中所述的方法,不同点在于:用(S)-2-(叔丁氧羰酰胺)-2,3,3-d3-丁酸替换(S)-2-(叔丁氧羰酰胺)-2-d-丁酸,从而制得目标化合物7。ESI-MS m/z419(M+H)+。
实施例3制备(S)-2-(1-(9H-嘌呤-6-基氨基)-1,2,2,3,3,3-d6-丙基)-5-氟-3-苯基喹唑啉-4(3H)-酮(化合物8)
按实施例1中所述的方法,不同点在于:用(S)-2-(叔丁氧羰酰胺)-2,3,3,4,4,4-d6-丁酸替换(S)-2-(叔丁氧羰酰胺)-2-d-丁酸,从而制得目标化合物8。ESI-MS m/z422(M+H)+。
实施例4制备(S)-2-(1-(9H-嘌呤-6-基氨基)-1,3,3,3-d4-丙基)-5-氟-3-苯基喹唑啉-4(3H)-酮(化合物9)
按实施例1中所述的方法,不同点在于:用(S)-2-(叔丁氧羰酰胺)-2,4,4,4-d4-丁酸替换(S)-2-(叔丁氧羰酰胺)-2-d-丁酸,从而制得目标化合物9。ESI-MS m/z420(M+H)+。
实施例5制备(S)-2-(1-(9H-嘌呤-6-基氨基)-2,2,3,3,3-d5-丙基)-5-氟-3-苯基喹唑啉-4(3H)-酮(化合物10)
按实施例1中所述的方法,不同点在于:用(S)-2-(叔丁氧羰酰胺)-3,3,4,4,4-d5-丁酸替换(S)-2-(叔丁氧羰酰胺)-2-d-丁酸,从而制得目标化合物10。ESI-MS m/z421(M+H)+。
实施例6制备(S)-2-(1-(9H-嘌呤-6-基氨基)-3,3,3-d3-丙基)-5-氟-3-苯基喹唑啉-4(3H)-酮(化合物11)
按实施例1中所述的方法,不同点在于:用(S)-2-(叔丁氧羰酰胺)-4,4,4-d3-丁酸替换(S)-2-(叔丁氧羰酰胺)-2-d-丁酸,从而制得目标化合物11。ESI-MS m/z419(M+H)+。
实施例7制备(S)-2-(1-(9H-嘌呤-6-基氨基)-2,2-d2-丙基)-5-氟-3-苯基喹唑啉-4(3H)-酮(化合物12)
按实施例1中所述的方法,不同点在于:用(S)-2-(叔丁氧羰酰胺)-3,3-d2-丁酸替换(S)-2-(叔丁氧羰酰胺)-2-d-丁酸,从而制得目标化合物12。ESI-MS m/z418(M+H)+。
实施例8制备(S)-2-(1-(9H-嘌呤-6-基氨基)-1-d-乙基)-6-氟-3-苯基喹唑啉-4(3H)-酮(化合物13)
按实施例1中所述的方法,不同点在于:用3-氟-6-硝基苯甲酸替换2-氟-6-硝基苯甲酸、(S)-2-(叔丁氧羰酰胺)-2-d-丙酸替换(S)-2-(叔丁氧羰酰胺)-2-d-丁酸,从而制得目标化合物13。ESI-MS m/z403(M+H)+。
实施例9制备(S)-2-(1-(9H-嘌呤-6-基氨基)-1,2,2,2-d4-乙基)-6-氟-3-苯基喹唑啉-4(3H)-酮(化合物14)
按实施例1中所述的方法,不同点在于:用3-氟-6-硝基苯甲酸替换2-氟-6-硝基苯甲酸、(S)-2-(叔丁氧羰酰胺)-2,3,3,3-d4-丙酸替换(S)-2-(叔丁氧羰酰胺)-2-d-丁酸,从而制得目标化合物14。ESI-MS m/z406(M+H)+。
实施例10制备(S)-2-(1-(9H-嘌呤-6-基氨基)-2,2,2-d3-乙基)-6-氟-3-苯基喹唑啉-4(3H)-酮(化合物15)
按实施例1中所述的方法,不同点在于:用3-氟-6-硝基苯甲酸替换2-氟-6-硝基苯甲酸、(S)-2-(叔丁氧羰酰胺)-3,3,3-d3-丙酸替换(S)-2-(叔丁氧羰酰胺)-2-d-丁酸,从而制得目标化合物15。ESI-MS m/z405(M+H)+。
实施例11制备(S)-2-(1-(9H-嘌呤-8-d-6-基氨基)-(1-d-丙基))-5-氟-3-苯基喹唑啉-4(3H)-酮(化合物16)
按实施例1中所述的方法,不同点在于:用6-溴-8-d-嘌呤替换6-溴嘌呤从而制得目标化合物16。ESI-MS m/z418(M+H)+。
实施例12制备(S)-2-(1-(9H-嘌呤-2,8-d2-6-基氨基)-(1-d-丙基))-5-氟-3-苯基喹唑啉-4(3H)-酮(化合物17)
按实施例1中所述的方法,不同点在于:用6-溴-2,8-d2-嘌呤替换6-溴嘌呤从而制得目标化合物17。ESI-MS m/z419(M+H)+。
实施例13:大鼠中的药代动力学评价
4只雄性Sprague-Dawley大鼠,7-8周龄,体重约210g,单次联合口服给予3mg/kg剂量的(a)对照组:(S)-2-(1-(9H-嘌呤-6-基氨基)丙基)-5-氟-3-苯基喹唑啉-4(3H)-酮和(b)试验组:实施例1~12制备的一些化合物,比较其药代动力学差异。
大鼠采用标准饲料饲养,给予水。试验前16小时开始禁食。药物用PEG400和二甲亚砜溶解。眼眶采血,采血的时间点为给药后0.25小时、0.5小时、1小时、2小时、4小时、6小时、8小时、12小时、24小时和36小时。
大鼠吸入乙醚后短暂麻醉,眼眶采集300μL血样于试管。试管内有30μL1%肝素盐溶液。使用前,试管于60℃烘干过夜。在随后一个时间点血样采集完成之后,大鼠乙醚麻醉后处死。
血样采集后,立即温和地颠倒试管至少5次,保证混合充分后放置于冰上。血样在4℃5000rpm离心5分钟,将血浆与红细胞分离。用移液器吸出100μL血浆到干净的塑料离心管中,表明化合物的名称和时间点。血浆在进行分析前保存在-80℃。用LC-MS/MS测定血浆中本发明化合物的浓度。药代动力学参数基于每只动物在不同时间点的血药浓度进行计算。
从结果看出,相对于对照化合物,本发明化合物在动物体内具有更好的药物动力学性质,因而具有更好的药效学和治疗效果。
实施例14:本发明化合物对磷脂酰肌醇3-激酶的体外药效学评价
本发明化合物的体外药效学评价试验方案参照文献J.Med.Chem.2013,56,1922?1939。
实验结果如表1所示。可见,本发明所述的化合物对磷脂酰肌醇3-激酶具有优异的抑制活性。
表1
化合物 | 对PI3Kδ抑制活性(IC50) |
实施例1 | <20nM |
实施例2 | <20nM |
实施例3 | <20nM |
实施例4 | <20nM |
实施例5 | <20nM |
实施例6 | <20nM |
实施例7 | <20nM |
实施例8 | <20nM |
实施例9 | <20nM |
实施例10 | <20nM |
实施例11 | <20nM |
实施例12 | <20nM |
实施例15药物组合物
化合物(实施例1-12) 100g
淀粉 130g
微晶纤维素 60g
按常规方法,将上述物质混合均匀后,装入普通明胶胶囊,得到1000颗胶囊。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (11)
1.一种式(I)所示的氘代的喹唑啉酮化合物、或其晶型、药学上可接受的盐、水合物或溶剂合物:
其中:
R1、R2各自独立地为氢、氘或卤素;
R3选自氢、氘、CH3、CH2D、CHD2、CD3、CH2CH3、CD2CH3、CH2CD3和CD2CD3;
R4、R5、R6、R7、R8、R9、R10、R11、R12和R13各自独立地为氢或氘;
附加条件是R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12或R13中至少一个是氘代的或氘。
2.如权利要求1所述的化合物,其特征在于,R1为氟和/或R2为氢。
3.如权利要求1所述的化合物,其特征在于,R3为CH3、CH2D、CHD2、CD3、CH2CH3、CD2CH3、CH2CD3或CD2CD3。
4.如权利要求1中所述的化合物,其特征在于,R4为氘或氢。
5.如权利要求1-4中任一所述的化合物,其特征在于,R12为氘和/或R13为氘。
6.如权利要求1所述的化合物,其特征在于,所述化合物是选自下组的化合物或其药学上可接受的盐:
7.如权利要求1所述的化合物,其特征在于,所述的化合物不包括非氘代的化合物。
8.一种药物组合物,其特征在于,它含有药学上可接受的载体和权利要求1所述的化合物,或其晶型、药学上可接受的盐、水合物或溶剂合物。
9.如权利要求8所述的药物组合物,其特征在于,它还含有另外的治疗药物,所述的另外的治疗药物为癌症、细胞增殖性疾病、心血管疾病、炎症、感染、免疫性疾病、病毒性疾病、或代谢性疾病的药物。
10.一种权利要求1所述的化合物,或其晶型、药学上可接受的盐、水合物或溶剂合物或如权利要求8所述的药物组合物的用途,其特征在于,用于制备抑制磷脂酰肌醇3-激酶(PI3K)的药物组合物。
11.如权利要求10所述的用途,其特征在于,所述的药物组合物用于制备用于治疗和预防以下疾病的药物:癌症、细胞增殖性疾病、炎症、感染或免疫性疾病。
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201410058184.7A CN104817559B (zh) | 2014-01-30 | 2014-02-20 | 氘代喹唑啉酮化合物以及包含该化合物的药物组合物 |
CN201580006716.5A CN106232602B (zh) | 2014-01-30 | 2015-01-30 | 氘代喹唑啉酮化合物以及包含该化合物的药物组合物 |
US15/115,316 US10414767B2 (en) | 2014-01-30 | 2015-01-30 | Deuterated quinazolinone compound and pharmaceutical composition comprising same |
JP2016549229A JP6606806B2 (ja) | 2014-01-30 | 2015-01-30 | 重水素化キナゾリノン化合物及び該化合物を含む薬物組成物 |
RU2016135192A RU2656485C2 (ru) | 2014-01-30 | 2015-01-30 | Дейтерированные соединения хиназолинона и содержащие их фармацевтические композиции |
CA2956773A CA2956773C (en) | 2014-01-30 | 2015-01-30 | Deuterated quinazolinone compounds and pharmaceutical compositions comprising same |
EP15743414.3A EP3101020B1 (en) | 2014-01-30 | 2015-01-30 | Deuterated quinazolinone compound and pharmaceutical composition comprising same |
PCT/CN2015/071996 WO2015113521A1 (zh) | 2014-01-30 | 2015-01-30 | 氘代喹唑啉酮化合物以及包含该化合物的药物组合物 |
BR112016017628-6A BR112016017628A2 (pt) | 2014-01-30 | 2015-01-30 | compostos de quinazolinona deuterados e composições farmacêuticas que compreendem os mesmos |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2014100446205 | 2014-01-30 | ||
CN201410044620 | 2014-01-30 | ||
CN201410058184.7A CN104817559B (zh) | 2014-01-30 | 2014-02-20 | 氘代喹唑啉酮化合物以及包含该化合物的药物组合物 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN104817559A true CN104817559A (zh) | 2015-08-05 |
CN104817559B CN104817559B (zh) | 2021-05-25 |
Family
ID=53728059
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201410058184.7A Active CN104817559B (zh) | 2014-01-30 | 2014-02-20 | 氘代喹唑啉酮化合物以及包含该化合物的药物组合物 |
CN201580006716.5A Active CN106232602B (zh) | 2014-01-30 | 2015-01-30 | 氘代喹唑啉酮化合物以及包含该化合物的药物组合物 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201580006716.5A Active CN106232602B (zh) | 2014-01-30 | 2015-01-30 | 氘代喹唑啉酮化合物以及包含该化合物的药物组合物 |
Country Status (8)
Country | Link |
---|---|
US (1) | US10414767B2 (zh) |
EP (1) | EP3101020B1 (zh) |
JP (1) | JP6606806B2 (zh) |
CN (2) | CN104817559B (zh) |
BR (1) | BR112016017628A2 (zh) |
CA (1) | CA2956773C (zh) |
RU (1) | RU2656485C2 (zh) |
WO (1) | WO2015113521A1 (zh) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106232602A (zh) * | 2014-01-30 | 2016-12-14 | 苏州泽璟生物制药有限公司 | 氘代喹唑啉酮化合物以及包含该化合物的药物组合物 |
CN108137592A (zh) * | 2015-11-03 | 2018-06-08 | 纽弗姆制药有限公司 | 用于治疗血癌的氘代化合物以及其组合物和方法 |
CN108699061A (zh) * | 2015-11-16 | 2018-10-23 | 纽弗姆制药有限公司 | 用于治疗血液恶性肿瘤、炎症和自身免疫性疾病的氘代化合物 |
CN113603713A (zh) * | 2017-12-05 | 2021-11-05 | 深圳市塔吉瑞生物医药有限公司 | 一种取代的硼酸酯化合物的制备方法及其晶型 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1606444A (zh) * | 2001-10-19 | 2005-04-13 | 艾科斯有限公司 | 人磷脂酰肌醇3-激酶δ抑制剂 |
CN101031569A (zh) * | 2004-05-13 | 2007-09-05 | 艾科斯有限公司 | 作为人磷脂酰肌醇3-激酶δ抑制剂的喹唑啉酮 |
CN102458410A (zh) * | 2009-04-20 | 2012-05-16 | 吉联亚·卡利斯托加有限责任公司 | 治疗实体瘤的方法 |
CN102647987A (zh) * | 2009-07-21 | 2012-08-22 | 吉里德卡利斯托加公司 | 使用pi3k抑制剂治疗肝脏障碍 |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2193921T3 (es) * | 1999-12-03 | 2003-11-16 | Pfizer Prod Inc | Compuestos de sulfamoilheteroaril-pirazol como agentes antinflamatorios/analgesicos. |
JP5869222B2 (ja) * | 2008-01-04 | 2016-02-24 | インテリカイン, エルエルシー | 特定の化学的実体、組成物および方法 |
US8193182B2 (en) * | 2008-01-04 | 2012-06-05 | Intellikine, Inc. | Substituted isoquinolin-1(2H)-ones, and methods of use thereof |
CA2824197C (en) | 2011-01-10 | 2020-02-25 | Michael Martin | Processes for preparing isoquinolinones and solid forms of isoquinolinones |
WO2013082540A1 (en) * | 2011-12-02 | 2013-06-06 | Gilead Calistoga Llc | Compositions and methods of treating a proliferative disease with a quinazolinone derivative |
CN104817559B (zh) * | 2014-01-30 | 2021-05-25 | 苏州泽璟生物制药股份有限公司 | 氘代喹唑啉酮化合物以及包含该化合物的药物组合物 |
WO2015179772A1 (en) | 2014-05-23 | 2015-11-26 | Concert Pharmaceuticals, Inc. | Deuterated phenylquinazolinone and phenylisoquinolinone compounds |
-
2014
- 2014-02-20 CN CN201410058184.7A patent/CN104817559B/zh active Active
-
2015
- 2015-01-30 EP EP15743414.3A patent/EP3101020B1/en active Active
- 2015-01-30 US US15/115,316 patent/US10414767B2/en active Active
- 2015-01-30 BR BR112016017628-6A patent/BR112016017628A2/pt not_active Application Discontinuation
- 2015-01-30 CA CA2956773A patent/CA2956773C/en active Active
- 2015-01-30 RU RU2016135192A patent/RU2656485C2/ru active
- 2015-01-30 WO PCT/CN2015/071996 patent/WO2015113521A1/zh active Application Filing
- 2015-01-30 JP JP2016549229A patent/JP6606806B2/ja active Active
- 2015-01-30 CN CN201580006716.5A patent/CN106232602B/zh active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1606444A (zh) * | 2001-10-19 | 2005-04-13 | 艾科斯有限公司 | 人磷脂酰肌醇3-激酶δ抑制剂 |
CN101031569A (zh) * | 2004-05-13 | 2007-09-05 | 艾科斯有限公司 | 作为人磷脂酰肌醇3-激酶δ抑制剂的喹唑啉酮 |
CN102458410A (zh) * | 2009-04-20 | 2012-05-16 | 吉联亚·卡利斯托加有限责任公司 | 治疗实体瘤的方法 |
CN102647987A (zh) * | 2009-07-21 | 2012-08-22 | 吉里德卡利斯托加公司 | 使用pi3k抑制剂治疗肝脏障碍 |
Non-Patent Citations (2)
Title |
---|
DAVID G. WINKLER ET AL.: "PI3K-d and PI3K-g Inhibition by IPI-145 Abrogates Immune Responses and Suppresses Activity in Autoimmune and Inflammatory Disease Models", 《CHEMISTRY & BIOLOGY》 * |
王世真: "《分子核医学》", 30 April 2004, 中国协和医科大学出版社 * |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106232602A (zh) * | 2014-01-30 | 2016-12-14 | 苏州泽璟生物制药有限公司 | 氘代喹唑啉酮化合物以及包含该化合物的药物组合物 |
CN106232602B (zh) * | 2014-01-30 | 2021-06-18 | 苏州泽璟生物制药股份有限公司 | 氘代喹唑啉酮化合物以及包含该化合物的药物组合物 |
CN108137592A (zh) * | 2015-11-03 | 2018-06-08 | 纽弗姆制药有限公司 | 用于治疗血癌的氘代化合物以及其组合物和方法 |
CN108137592B (zh) * | 2015-11-03 | 2021-03-05 | 纽弗姆制药有限公司 | 用于治疗血癌的氘代化合物以及其组合物和方法 |
CN108699061A (zh) * | 2015-11-16 | 2018-10-23 | 纽弗姆制药有限公司 | 用于治疗血液恶性肿瘤、炎症和自身免疫性疾病的氘代化合物 |
CN108699061B (zh) * | 2015-11-16 | 2022-07-05 | 纽弗姆制药有限公司 | 用于治疗血液恶性肿瘤、炎症和自身免疫性疾病的氘代化合物 |
CN113603713A (zh) * | 2017-12-05 | 2021-11-05 | 深圳市塔吉瑞生物医药有限公司 | 一种取代的硼酸酯化合物的制备方法及其晶型 |
Also Published As
Publication number | Publication date |
---|---|
CA2956773A1 (en) | 2015-08-06 |
CN106232602B (zh) | 2021-06-18 |
WO2015113521A1 (zh) | 2015-08-06 |
US20170305911A1 (en) | 2017-10-26 |
EP3101020A1 (en) | 2016-12-07 |
US10414767B2 (en) | 2019-09-17 |
CN106232602A (zh) | 2016-12-14 |
BR112016017628A2 (pt) | 2020-10-27 |
CA2956773C (en) | 2019-04-30 |
EP3101020B1 (en) | 2020-03-11 |
RU2016135192A3 (zh) | 2018-03-05 |
RU2016135192A (ru) | 2018-03-05 |
JP6606806B2 (ja) | 2019-11-20 |
RU2656485C2 (ru) | 2018-06-06 |
JP2017504638A (ja) | 2017-02-09 |
CN104817559B (zh) | 2021-05-25 |
EP3101020A4 (en) | 2017-06-14 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5719770B2 (ja) | 塩酸イコチニブ、合成物、結晶学的形態、併用薬及びその用途 | |
ES2818620T3 (es) | Derivados de azabencimidazol como inhibidores de pi3k beta | |
CN103619820B (zh) | 可用作溴区结构域抑制剂的四氢喹啉衍生物 | |
CN103874689B (zh) | Akt抑制剂化合物和威罗菲尼的组合及使用方法 | |
CN104109149A (zh) | 氘代的二氨基嘧啶化合物以及包含该化合物的药物组合物 | |
CN103965114B (zh) | 氘代的苯基氨基嘧啶化合物以及包含该化合物的药物组合物 | |
CA2990145A1 (en) | Brk inhibitory compound | |
CN113980032B (zh) | 稠合四环类衍生物、其制备方法及其在医药上的应用 | |
JP7047772B2 (ja) | Brk阻害化合物 | |
CN114728945B (zh) | 3,5-二取代吡唑化合物作为激酶抑制剂及其应用 | |
CN104817559A (zh) | 氘代喹唑啉酮化合物以及包含该化合物的药物组合物 | |
WO2022109577A1 (en) | Fgfr inhibitors and methods of making and using the same | |
CN104557913B (zh) | 吡啶并嘧啶类化合物,其制备方法和用途 | |
CA2967551A1 (en) | Imidazopyridazine derivatives as pi3k.beta. inhibitors | |
CN103965175A (zh) | 4-(取代苯氨基)喹唑啉类化合物、其制备方法及应用 | |
TWI529174B (zh) | 埃克替尼的晶型及其應用 | |
WO2022171018A1 (zh) | 取代苯并或吡啶并嘧啶胺类抑制剂及其制备方法和应用 | |
CN104557955B (zh) | 作为PI3K/mTOR抑制剂的三环类化合物,其制备方法和用途 | |
WO2016153394A1 (ru) | Применение новых химических соединений (варианты) в качестве ингибиторов nuak1 киназы для лечения онкологических заболеваний |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
CB02 | Change of applicant information |
Address after: 215300 Chenfeng Road 209, Yushan Town, Kunshan City, Suzhou City, Jiangsu Province Applicant after: Suzhou Zehuang Biopharmaceutical Co., Ltd. Address before: 215300 Chenfeng Road 209, Kunshan City, Suzhou City, Jiangsu Province Applicant before: Suzhou Zelgen Biopharmaceuticals Co., Ltd. |
|
CB02 | Change of applicant information | ||
GR01 | Patent grant | ||
GR01 | Patent grant |