KR101434841B1 - 2-치환-8-알킬-7-옥소-7,8-디하이드로피리도[2,3-ｄ] 피리미딘-6-카르보니트릴 및 이의 용도 - Google Patents
2-치환-8-알킬-7-옥소-7,8-디하이드로피리도[2,3-ｄ] 피리미딘-6-카르보니트릴 및 이의 용도 Download PDFInfo
- Publication number
- KR101434841B1 KR101434841B1 KR1020137004979A KR20137004979A KR101434841B1 KR 101434841 B1 KR101434841 B1 KR 101434841B1 KR 1020137004979 A KR1020137004979 A KR 1020137004979A KR 20137004979 A KR20137004979 A KR 20137004979A KR 101434841 B1 KR101434841 B1 KR 101434841B1
- Authority
- KR
- South Korea
- Prior art keywords
- compound
- cancer
- formula
- oxo
- amino
- 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.)
- Active
Links
- 150000001875 compounds Chemical class 0.000 claims abstract description 155
- 238000000034 method Methods 0.000 claims abstract description 58
- 150000003839 salts Chemical class 0.000 claims abstract description 43
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 50
- 206010028980 Neoplasm Diseases 0.000 claims description 45
- -1 4- (4-methylpiperazin-1-yl) anilinyl Chemical group 0.000 claims description 35
- 230000002062 proliferating effect Effects 0.000 claims description 35
- 201000011510 cancer Diseases 0.000 claims description 32
- 201000010099 disease Diseases 0.000 claims description 32
- 238000006243 chemical reaction Methods 0.000 claims description 29
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 21
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 19
- 238000011282 treatment Methods 0.000 claims description 19
- 208000035475 disorder Diseases 0.000 claims description 17
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 11
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 11
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 9
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 8
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 8
- MLIREBYILWEBDM-UHFFFAOYSA-N cyanoacetic acid Chemical compound OC(=O)CC#N MLIREBYILWEBDM-UHFFFAOYSA-N 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 7
- 239000007800 oxidant agent Substances 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- IIHQNAXFIODVDU-UHFFFAOYSA-N pyrimidine-2-carbonitrile Chemical compound N#CC1=NC=CC=N1 IIHQNAXFIODVDU-UHFFFAOYSA-N 0.000 claims description 7
- 206010009944 Colon cancer Diseases 0.000 claims description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 5
- DDLUGPZFSDJARE-UHFFFAOYSA-N 8-cyclopentyl-2-(3,5-dimethoxyanilino)-7-oxopyrido[2,3-d]pyrimidine-6-carbonitrile Chemical compound COC1=CC(OC)=CC(NC=2N=C3N(C4CCCC4)C(=O)C(C#N)=CC3=CN=2)=C1 DDLUGPZFSDJARE-UHFFFAOYSA-N 0.000 claims description 5
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 claims description 5
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 claims description 5
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 5
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 5
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 5
- 208000009905 Neurofibromatoses Diseases 0.000 claims description 5
- 206010033128 Ovarian cancer Diseases 0.000 claims description 5
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 5
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 claims description 5
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 5
- 206010038389 Renal cancer Diseases 0.000 claims description 5
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 5
- 201000010881 cervical cancer Diseases 0.000 claims description 5
- 208000029742 colonic neoplasm Diseases 0.000 claims description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
- 201000010982 kidney cancer Diseases 0.000 claims description 5
- 201000010260 leiomyoma Diseases 0.000 claims description 5
- 201000004931 neurofibromatosis Diseases 0.000 claims description 5
- XGTHJEPWJGOISN-UHFFFAOYSA-N 8-cyclopentyl-2-(4-morpholin-4-ylanilino)-7-oxopyrido[2,3-d]pyrimidine-6-carbonitrile Chemical compound N1=C2N(C3CCCC3)C(=O)C(C#N)=CC2=CN=C1NC(C=C1)=CC=C1N1CCOCC1 XGTHJEPWJGOISN-UHFFFAOYSA-N 0.000 claims description 4
- YNDJCUZGIVBCGR-UHFFFAOYSA-N 8-cyclopentyl-7-oxo-2-(3,4,5-trimethoxyanilino)pyrido[2,3-d]pyrimidine-6-carbonitrile Chemical compound COC1=C(OC)C(OC)=CC(NC=2N=C3N(C4CCCC4)C(=O)C(C#N)=CC3=CN=2)=C1 YNDJCUZGIVBCGR-UHFFFAOYSA-N 0.000 claims description 4
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims description 4
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 4
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims description 4
- 208000004362 Penile Induration Diseases 0.000 claims description 4
- 208000020758 Peyronie disease Diseases 0.000 claims description 4
- 208000002158 Proliferative Vitreoretinopathy Diseases 0.000 claims description 4
- 206010060862 Prostate cancer Diseases 0.000 claims description 4
- 208000004403 Prostatic Hyperplasia Diseases 0.000 claims description 4
- 206010038923 Retinopathy Diseases 0.000 claims description 4
- 206010038934 Retinopathy proliferative Diseases 0.000 claims description 4
- 208000024313 Testicular Neoplasms Diseases 0.000 claims description 4
- 206010057644 Testis cancer Diseases 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- 208000016738 bone Paget disease Diseases 0.000 claims description 4
- 230000001684 chronic effect Effects 0.000 claims description 4
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims description 4
- 208000007118 chronic progressive multiple sclerosis Diseases 0.000 claims description 4
- 208000011379 keloid formation Diseases 0.000 claims description 4
- 201000005202 lung cancer Diseases 0.000 claims description 4
- 208000020816 lung neoplasm Diseases 0.000 claims description 4
- 208000002780 macular degeneration Diseases 0.000 claims description 4
- 208000021971 neovascular inflammatory vitreoretinopathy Diseases 0.000 claims description 4
- 230000000750 progressive effect Effects 0.000 claims description 4
- 230000035755 proliferation Effects 0.000 claims description 4
- 230000006785 proliferative vitreoretinopathy Effects 0.000 claims description 4
- 208000037803 restenosis Diseases 0.000 claims description 4
- 201000008628 secondary progressive multiple sclerosis Diseases 0.000 claims description 4
- 201000003120 testicular cancer Diseases 0.000 claims description 4
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 3
- 201000001320 Atherosclerosis Diseases 0.000 claims description 3
- 208000001708 Dupuytren contracture Diseases 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 3
- 206010046798 Uterine leiomyoma Diseases 0.000 claims description 3
- 208000011803 breast fibrocystic disease Diseases 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 230000003647 oxidation Effects 0.000 claims description 3
- 238000007254 oxidation reaction Methods 0.000 claims description 3
- 208000035803 proliferative type breast fibrocystic change Diseases 0.000 claims description 3
- 238000002054 transplantation Methods 0.000 claims description 3
- MOZNZNKHRXRLLF-UHFFFAOYSA-N 4-(4-methylpiperazin-1-yl)aniline Chemical compound C1CN(C)CCN1C1=CC=C(N)C=C1 MOZNZNKHRXRLLF-UHFFFAOYSA-N 0.000 claims description 2
- PHNDZBFLOPIMSM-UHFFFAOYSA-N 4-morpholin-4-ylaniline Chemical compound C1=CC(N)=CC=C1N1CCOCC1 PHNDZBFLOPIMSM-UHFFFAOYSA-N 0.000 claims description 2
- 230000004770 neurodegeneration Effects 0.000 claims 2
- 208000015122 neurodegenerative disease Diseases 0.000 claims 2
- FUBDWXAVMGEMPP-UHFFFAOYSA-N 8-cyclopentyl-2-[4-(4-methylpiperazin-1-yl)anilino]pyrido[2,3-d]pyrimidin-7-one Chemical compound C1CN(C)CCN1C(C=C1)=CC=C1NC1=NC=C(C=CC(=O)N2C3CCCC3)C2=N1 FUBDWXAVMGEMPP-UHFFFAOYSA-N 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 18
- 238000003786 synthesis reaction Methods 0.000 abstract description 18
- 230000001028 anti-proliverative effect Effects 0.000 abstract description 2
- 229940043355 kinase inhibitor Drugs 0.000 abstract description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 36
- 239000000203 mixture Substances 0.000 description 31
- 239000002904 solvent Substances 0.000 description 25
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- 239000004480 active ingredient Substances 0.000 description 17
- 239000003814 drug Substances 0.000 description 15
- 238000013270 controlled release Methods 0.000 description 14
- 210000004881 tumor cell Anatomy 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 229940079593 drug Drugs 0.000 description 12
- 239000008194 pharmaceutical composition Substances 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 108091000080 Phosphotransferase Proteins 0.000 description 11
- 102000020233 phosphotransferase Human genes 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- 125000000524 functional group Chemical group 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- 230000008569 process Effects 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- 206010025323 Lymphomas Diseases 0.000 description 8
- 208000009956 adenocarcinoma Diseases 0.000 description 8
- 238000009472 formulation Methods 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- VADOZMZXXRBXNY-UHFFFAOYSA-N 8-cyclopentyl-2-[4-(4-methylpiperazin-1-yl)anilino]-7-oxopyrido[2,3-d]pyrimidine-6-carbonitrile Chemical compound C1CN(C)CCN1C(C=C1)=CC=C1NC1=NC=C(C=C(C#N)C(=O)N2C3CCCC3)C2=N1 VADOZMZXXRBXNY-UHFFFAOYSA-N 0.000 description 7
- 241000124008 Mammalia Species 0.000 description 7
- 230000006907 apoptotic process Effects 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- 102000001253 Protein Kinase Human genes 0.000 description 6
- 235000011054 acetic acid Nutrition 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
- 239000003153 chemical reaction reagent Substances 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
- 230000000052 comparative effect Effects 0.000 description 6
- 239000000499 gel Substances 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 108060006633 protein kinase Proteins 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- KCULUAOGWGVSGF-UHFFFAOYSA-N 8-cyclopentyl-2-methylsulfanyl-7-oxopyrido[2,3-d]pyrimidine-6-carbonitrile Chemical compound C1(CCCC1)N1C(C(=CC2=C1N=C(N=C2)SC)C#N)=O KCULUAOGWGVSGF-UHFFFAOYSA-N 0.000 description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 5
- 101000970023 Homo sapiens NUAK family SNF1-like kinase 1 Proteins 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 102100021732 NUAK family SNF1-like kinase 1 Human genes 0.000 description 5
- 206010039491 Sarcoma Diseases 0.000 description 5
- 125000003277 amino group Chemical group 0.000 description 5
- 230000001413 cellular effect Effects 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 230000001939 inductive effect Effects 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 5
- 238000007911 parenteral administration Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 206010041823 squamous cell carcinoma Diseases 0.000 description 5
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- 201000009030 Carcinoma Diseases 0.000 description 4
- 102000003903 Cyclin-dependent kinases Human genes 0.000 description 4
- 108090000266 Cyclin-dependent kinases Proteins 0.000 description 4
- 206010024612 Lipoma Diseases 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- AHJVXRBRJFXVEB-UHFFFAOYSA-N [4-(cyclopentylamino)-6-methylsulfanylpyridin-3-yl]methanol Chemical compound C1=NC(SC)=CC(NC2CCCC2)=C1CO AHJVXRBRJFXVEB-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- MYJQMHHJSZBXNK-UHFFFAOYSA-N ethyl 4-(cyclopentylamino)-2-methylsulfanylpyrimidine-5-carboxylate Chemical compound CCOC(=O)C1=CN=C(SC)N=C1NC1CCCC1 MYJQMHHJSZBXNK-UHFFFAOYSA-N 0.000 description 4
- 208000032839 leukemia Diseases 0.000 description 4
- 239000012280 lithium aluminium hydride Substances 0.000 description 4
- 239000011159 matrix material Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 0 *c1nc(N(*)C(C(C#N)=C2)=O)c2cn1 Chemical compound *c1nc(N(*)C(C(C#N)=C2)=O)c2cn1 0.000 description 3
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 3
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 3
- YXIXMOSBXGFPRA-UHFFFAOYSA-N C1(CCCC1)N1C(C(=CC2=C1N=C(N=C2)S(=O)C)C#N)=O Chemical compound C1(CCCC1)N1C(C(=CC2=C1N=C(N=C2)S(=O)C)C#N)=O YXIXMOSBXGFPRA-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 201000008808 Fibrosarcoma Diseases 0.000 description 3
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 206010043276 Teratoma Diseases 0.000 description 3
- 208000002495 Uterine Neoplasms Diseases 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 230000004663 cell proliferation Effects 0.000 description 3
- 238000006482 condensation reaction Methods 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- SNNHLSHDDGJVDM-UHFFFAOYSA-N ethyl 4-chloro-2-methylsulfanylpyrimidine-5-carboxylate Chemical compound CCOC(=O)C1=CN=C(SC)N=C1Cl SNNHLSHDDGJVDM-UHFFFAOYSA-N 0.000 description 3
- 229940093915 gynecological organic acid Drugs 0.000 description 3
- 201000011066 hemangioma Diseases 0.000 description 3
- 239000011859 microparticle Substances 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 235000005985 organic acids Nutrition 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- ZIEWSZYVEDTXGH-UHFFFAOYSA-N pyrimidine-4-carbonitrile Chemical compound N#CC1=CC=NC=N1 ZIEWSZYVEDTXGH-UHFFFAOYSA-N 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 2
- WHBMMWSBFZVSSR-UHFFFAOYSA-N 3-hydroxybutyric acid Chemical compound CC(O)CC(O)=O WHBMMWSBFZVSSR-UHFFFAOYSA-N 0.000 description 2
- 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 2
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 2
- WDHAAJIGSXNPFO-UHFFFAOYSA-N 8h-pyrido[2,3-d]pyrimidin-7-one Chemical compound N1=CN=C2NC(=O)C=CC2=C1 WDHAAJIGSXNPFO-UHFFFAOYSA-N 0.000 description 2
- 201000003076 Angiosarcoma Diseases 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 208000032612 Glial tumor Diseases 0.000 description 2
- 206010018338 Glioma Diseases 0.000 description 2
- DHCLVCXQIBBOPH-UHFFFAOYSA-N Glycerol 2-phosphate Chemical compound OCC(CO)OP(O)(O)=O DHCLVCXQIBBOPH-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 208000002927 Hamartoma Diseases 0.000 description 2
- 208000001258 Hemangiosarcoma Diseases 0.000 description 2
- 206010019695 Hepatic neoplasm Diseases 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- LELOWRISYMNNSU-UHFFFAOYSA-N Hydrocyanic acid Natural products N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 208000007766 Kaposi sarcoma Diseases 0.000 description 2
- 208000018142 Leiomyosarcoma Diseases 0.000 description 2
- 208000030289 Lymphoproliferative disease Diseases 0.000 description 2
- 208000034578 Multiple myelomas Diseases 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 206010029260 Neuroblastoma Diseases 0.000 description 2
- 201000004404 Neurofibroma Diseases 0.000 description 2
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical group CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 208000008383 Wilms tumor Diseases 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- IAJILQKETJEXLJ-RSJOWCBRSA-N aldehydo-D-galacturonic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-RSJOWCBRSA-N 0.000 description 2
- 208000000252 angiomatosis Diseases 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 238000011717 athymic nude mouse Methods 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 208000002458 carcinoid tumor Diseases 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 239000000356 contaminant Substances 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 239000012954 diazonium Substances 0.000 description 2
- 150000001989 diazonium salts Chemical group 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 206010016629 fibroma Diseases 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 238000011194 good manufacturing practice Methods 0.000 description 2
- 230000009036 growth inhibition Effects 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000006882 induction of apoptosis Effects 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 210000004698 lymphocyte Anatomy 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 206010027191 meningioma Diseases 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000004005 microsphere Substances 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000000269 nucleophilic effect Effects 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 201000008968 osteosarcoma Diseases 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N p-hydroxybenzoic acid methyl ester Natural products COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 239000003909 protein kinase inhibitor Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 208000029922 reticulum cell sarcoma Diseases 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000013207 serial dilution Methods 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- 239000007790 solid phase Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 206010046766 uterine cancer Diseases 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- XDIYNQZUNSSENW-UUBOPVPUSA-N (2R,3S,4R,5R)-2,3,4,5,6-pentahydroxyhexanal Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O XDIYNQZUNSSENW-UUBOPVPUSA-N 0.000 description 1
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 1
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- HQPWGXHTJVSDGR-UHFFFAOYSA-N 1,2-dihydropyrido[2,3-d]pyrimidine Chemical compound C1=CC=C2C=NCNC2=N1 HQPWGXHTJVSDGR-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- QKRVSWPBAOCWHY-UHFFFAOYSA-N 4-(cyclopentylamino)-2-methylsulfanylpyrimidine-5-carbaldehyde Chemical compound CSC1=NC=C(C=O)C(NC2CCCC2)=N1 QKRVSWPBAOCWHY-UHFFFAOYSA-N 0.000 description 1
- BNAIBNHYIGTKSM-UHFFFAOYSA-N 4-cyclopentyl-2-(3,5-dimethoxyanilino)-7-oxo-8H-pyrido[2,3-d]pyrimidine-6-carbonitrile Chemical compound C1(CCCC1)C=1C2=C(N=C(N=1)NC1=CC(=CC(=C1)OC)OC)NC(C(=C2)C#N)=O BNAIBNHYIGTKSM-UHFFFAOYSA-N 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- KBXQZLSWWXHNQI-UHFFFAOYSA-N 8-cyclobutyl-2-(3,5-dimethoxyanilino)-7-oxopyrido[2,3-d]pyrimidine-6-carbonitrile Chemical compound COC1=CC(OC)=CC(NC=2N=C3N(C4CCC4)C(=O)C(C#N)=CC3=CN=2)=C1 KBXQZLSWWXHNQI-UHFFFAOYSA-N 0.000 description 1
- UQTSLRFMNZMTTJ-UHFFFAOYSA-N 8-cyclobutyl-7-oxo-2-(3,4,5-trimethoxyanilino)pyrido[2,3-d]pyrimidine-6-carbonitrile Chemical compound COC1=C(OC)C(OC)=CC(NC=2N=C3N(C4CCC4)C(=O)C(C#N)=CC3=CN=2)=C1 UQTSLRFMNZMTTJ-UHFFFAOYSA-N 0.000 description 1
- LVYMZLSTOIDPIP-UHFFFAOYSA-N 8-cyclohexyl-2-(3,5-dimethoxyanilino)-7-oxopyrido[2,3-d]pyrimidine-6-carbonitrile Chemical compound COC1=CC(OC)=CC(NC=2N=C3N(C4CCCCC4)C(=O)C(C#N)=CC3=CN=2)=C1 LVYMZLSTOIDPIP-UHFFFAOYSA-N 0.000 description 1
- IRIWSIRFPLUOBD-UHFFFAOYSA-N 8-cyclohexyl-2-(4-morpholin-4-ylanilino)-7-oxopyrido[2,3-d]pyrimidine-6-carbonitrile Chemical compound N1=C2N(C3CCCCC3)C(=O)C(C#N)=CC2=CN=C1NC(C=C1)=CC=C1N1CCOCC1 IRIWSIRFPLUOBD-UHFFFAOYSA-N 0.000 description 1
- ZQCPOGHWQZWOQO-UHFFFAOYSA-N 8-cyclohexyl-7-oxo-2-(3,4,5-trimethoxyanilino)pyrido[2,3-d]pyrimidine-6-carbonitrile Chemical compound COC1=C(OC)C(OC)=CC(NC=2N=C3N(C4CCCCC4)C(=O)C(C#N)=CC3=CN=2)=C1 ZQCPOGHWQZWOQO-UHFFFAOYSA-N 0.000 description 1
- AIVYSWYSVUTUJL-UHFFFAOYSA-N 8-cyclopentyl-2-[4-(4-methylpiperazin-1-yl)anilino]-7-oxopyrido[2,3-d]pyrimidine-6-carbonitrile;hydrochloride Chemical compound Cl.C1CN(C)CCN1C(C=C1)=CC=C1NC1=NC=C(C=C(C#N)C(=O)N2C3CCCC3)C2=N1 AIVYSWYSVUTUJL-UHFFFAOYSA-N 0.000 description 1
- WYIGQMOLCGTYOZ-UHFFFAOYSA-N 8-cyclopropyl-2-(3,5-dimethoxyanilino)-7-oxopyrido[2,3-d]pyrimidine-6-carbonitrile Chemical compound COC1=CC(OC)=CC(NC=2N=C3N(C4CC4)C(=O)C(C#N)=CC3=CN=2)=C1 WYIGQMOLCGTYOZ-UHFFFAOYSA-N 0.000 description 1
- QTLZMQKYPJOJEW-UHFFFAOYSA-N 8-cyclopropyl-2-(4-morpholin-4-ylanilino)-7-oxopyrido[2,3-d]pyrimidine-6-carbonitrile Chemical compound N1=C2N(C3CC3)C(=O)C(C#N)=CC2=CN=C1NC(C=C1)=CC=C1N1CCOCC1 QTLZMQKYPJOJEW-UHFFFAOYSA-N 0.000 description 1
- KJXVJURWGMUVPR-UHFFFAOYSA-N 8-cyclopropyl-7-oxo-2-(3,4,5-trimethoxyanilino)pyrido[2,3-d]pyrimidine-6-carbonitrile Chemical compound COC1=C(OC)C(OC)=CC(NC=2N=C3N(C4CC4)C(=O)C(C#N)=CC3=CN=2)=C1 KJXVJURWGMUVPR-UHFFFAOYSA-N 0.000 description 1
- MBXYMSJPYCKCNM-UHFFFAOYSA-N 8h-quinolin-2-one Chemical compound C1=CCC2=NC(=O)C=CC2=C1 MBXYMSJPYCKCNM-UHFFFAOYSA-N 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 206010003571 Astrocytoma Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 206010073106 Bone giant cell tumour malignant Diseases 0.000 description 1
- 206010006253 Breast fibrosis Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- KTZQUIVIRZTXKR-UHFFFAOYSA-N C1(CCCC1)C=1C2=C(N=C(N1)NC1=CC(=C(C(=C1)OC)OC)OC)NC(C(=C2)C#N)=O Chemical compound C1(CCCC1)C=1C2=C(N=C(N1)NC1=CC(=C(C(=C1)OC)OC)OC)NC(C(=C2)C#N)=O KTZQUIVIRZTXKR-UHFFFAOYSA-N 0.000 description 1
- KVBVKDYWUYZLMX-UHFFFAOYSA-N C1(CCCC1)N1C(C=CC2=C1N=C(N=C2)NC2=CC(=CC(=C2)OC)OC)=O Chemical compound C1(CCCC1)N1C(C=CC2=C1N=C(N=C2)NC2=CC(=CC(=C2)OC)OC)=O KVBVKDYWUYZLMX-UHFFFAOYSA-N 0.000 description 1
- QLJGDDCKWAMPRU-UHFFFAOYSA-N CC1=CC=C(C=C1)NC=1C2=C(N=CN1)NC(C(=C2)C#N)=O Chemical compound CC1=CC=C(C=C1)NC=1C2=C(N=CN1)NC(C(=C2)C#N)=O QLJGDDCKWAMPRU-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 206010007275 Carcinoid tumour Diseases 0.000 description 1
- 208000009458 Carcinoma in Situ Diseases 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 206010008263 Cervical dysplasia Diseases 0.000 description 1
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- 201000005262 Chondroma Diseases 0.000 description 1
- 208000005243 Chondrosarcoma Diseases 0.000 description 1
- 201000009047 Chordoma Diseases 0.000 description 1
- 208000006332 Choriocarcinoma Diseases 0.000 description 1
- 206010048832 Colon adenoma Diseases 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- 241000195493 Cryptophyta Species 0.000 description 1
- 102000006311 Cyclin D1 Human genes 0.000 description 1
- 108010058546 Cyclin D1 Proteins 0.000 description 1
- 102000013701 Cyclin-Dependent Kinase 4 Human genes 0.000 description 1
- 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 description 1
- 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 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-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
- 206010012689 Diabetic retinopathy Diseases 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 208000007033 Dysgerminoma Diseases 0.000 description 1
- 208000000471 Dysplastic Nevus Syndrome Diseases 0.000 description 1
- 201000009051 Embryonal Carcinoma Diseases 0.000 description 1
- 206010014967 Ependymoma Diseases 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 208000006168 Ewing Sarcoma Diseases 0.000 description 1
- 208000000571 Fibrocystic breast disease Diseases 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 206010053717 Fibrous histiocytoma Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- DSLZVSRJTYRBFB-UHFFFAOYSA-N Galactaric acid Natural products OC(=O)C(O)C(O)C(O)C(O)C(O)=O DSLZVSRJTYRBFB-UHFFFAOYSA-N 0.000 description 1
- 208000003098 Ganglion Cysts Diseases 0.000 description 1
- 201000003741 Gastrointestinal carcinoma Diseases 0.000 description 1
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 1
- 208000000527 Germinoma Diseases 0.000 description 1
- 208000007569 Giant Cell Tumors Diseases 0.000 description 1
- 206010018341 Gliosis Diseases 0.000 description 1
- 206010018404 Glucagonoma Diseases 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 206010018691 Granuloma Diseases 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 1
- 206010019629 Hepatic adenoma Diseases 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 241001272567 Hominoidea Species 0.000 description 1
- 101000650863 Homo sapiens SH2 domain-containing protein 1A Proteins 0.000 description 1
- 208000005045 Interdigitating dendritic cell sarcoma Diseases 0.000 description 1
- 208000002260 Keloid Diseases 0.000 description 1
- 206010023330 Keloid scar Diseases 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
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 201000004462 Leydig Cell Tumor Diseases 0.000 description 1
- 208000002404 Liver Cell Adenoma Diseases 0.000 description 1
- 208000006644 Malignant Fibrous Histiocytoma Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 208000000172 Medulloblastoma Diseases 0.000 description 1
- 208000015021 Meningeal Neoplasms Diseases 0.000 description 1
- 206010027406 Mesothelioma Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 208000019022 Mood disease Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 201000010133 Oligodendroglioma Diseases 0.000 description 1
- 208000010191 Osteitis Deformans Diseases 0.000 description 1
- 208000000035 Osteochondroma Diseases 0.000 description 1
- 208000027067 Paget disease of bone Diseases 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 description 1
- 208000007641 Pinealoma Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 201000000582 Retinoblastoma Diseases 0.000 description 1
- 208000005678 Rhabdomyoma Diseases 0.000 description 1
- 230000018199 S phase Effects 0.000 description 1
- 102100027720 SH2 domain-containing protein 1A Human genes 0.000 description 1
- 201000010208 Seminoma Diseases 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- 208000005400 Synovial Cyst Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 1
- 208000015778 Undifferentiated pleomorphic sarcoma Diseases 0.000 description 1
- 206010046458 Urethral neoplasms Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000009311 VIPoma Diseases 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 description 1
- 208000033779 X-linked lymphoproliferative disease Diseases 0.000 description 1
- 206010068348 X-linked lymphoproliferative syndrome Diseases 0.000 description 1
- 206010048214 Xanthoma Diseases 0.000 description 1
- 206010048215 Xanthomatosis Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229940112258 acular Drugs 0.000 description 1
- 208000002718 adenomatoid tumor Diseases 0.000 description 1
- 210000004100 adrenal gland Anatomy 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 230000000954 anitussive effect Effects 0.000 description 1
- 230000002141 anti-parasite Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 description 1
- 239000003096 antiparasitic agent Substances 0.000 description 1
- 229940124584 antitussives Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000007080 aromatic substitution reaction Methods 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 210000004666 bacterial spore Anatomy 0.000 description 1
- 208000001119 benign fibrous histiocytoma Diseases 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 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
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-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
- 239000011230 binding agent Substances 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 1
- 201000009480 botryoid rhabdomyosarcoma Diseases 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 208000003362 bronchogenic carcinoma Diseases 0.000 description 1
- 201000002143 bronchus adenoma Diseases 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 208000006990 cholangiocarcinoma Diseases 0.000 description 1
- 201000005217 chondroblastoma Diseases 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 208000009060 clear cell adenocarcinoma Diseases 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 201000010305 cutaneous fibrous histiocytoma Diseases 0.000 description 1
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 1
- NISGSNTVMOOSJQ-UHFFFAOYSA-N cyclopentanamine Chemical compound NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 230000001672 cytoproliferative effect Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 201000009409 embryonal rhabdomyosarcoma Diseases 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 208000023965 endometrium neoplasm Diseases 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- HKSZLNNOFSGOKW-UHFFFAOYSA-N ent-staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(C)O1 HKSZLNNOFSGOKW-UHFFFAOYSA-N 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- WSYVIAQNTFPTBI-UHFFFAOYSA-N ethyl 3-[2-[(2-methoxyphenoxy)methyl]-1,3-thiazolidin-3-yl]-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)N1CCSC1COC1=CC=CC=C1OC WSYVIAQNTFPTBI-UHFFFAOYSA-N 0.000 description 1
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 201000009968 fibrosclerosis of breast Diseases 0.000 description 1
- 230000003176 fibrotic effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- DSLZVSRJTYRBFB-DUHBMQHGSA-N galactaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O DSLZVSRJTYRBFB-DUHBMQHGSA-N 0.000 description 1
- 229930182830 galactose Natural products 0.000 description 1
- 210000000232 gallbladder Anatomy 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 208000015419 gastrin-producing neuroendocrine tumor Diseases 0.000 description 1
- 201000000052 gastrinoma Diseases 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 201000003115 germ cell cancer Diseases 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 230000007387 gliosis Effects 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 201000010235 heart cancer Diseases 0.000 description 1
- 208000024348 heart neoplasm Diseases 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 229910052595 hematite Inorganic materials 0.000 description 1
- 239000011019 hematite Substances 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- 208000006359 hepatoblastoma Diseases 0.000 description 1
- 201000002735 hepatocellular adenoma Diseases 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000003463 hyperproliferative effect Effects 0.000 description 1
- 201000004933 in situ carcinoma Diseases 0.000 description 1
- 239000005414 inactive ingredient Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 206010022498 insulinoma Diseases 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 210000002570 interstitial cell Anatomy 0.000 description 1
- 201000002313 intestinal cancer Diseases 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 201000010985 invasive ductal carcinoma Diseases 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- LIKBJVNGSGBSGK-UHFFFAOYSA-N iron(3+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Fe+3].[Fe+3] LIKBJVNGSGBSGK-UHFFFAOYSA-N 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 210000001117 keloid Anatomy 0.000 description 1
- BWHLPLXXIDYSNW-UHFFFAOYSA-N ketorolac tromethamine Chemical compound OCC(N)(CO)CO.OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 BWHLPLXXIDYSNW-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 208000022013 kidney Wilms tumor Diseases 0.000 description 1
- 238000000021 kinase assay Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 206010024627 liposarcoma Diseases 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 238000000622 liquid--liquid extraction Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 230000001589 lymphoproliferative effect Effects 0.000 description 1
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical group CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 201000004593 malignant giant cell tumor Diseases 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 201000000289 malignant teratoma Diseases 0.000 description 1
- 208000022006 malignant tumor of meninges Diseases 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 208000037843 metastatic solid tumor Diseases 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 229950009623 moguisteine Drugs 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 208000010492 mucinous cystadenocarcinoma Diseases 0.000 description 1
- 208000009091 myxoma Diseases 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 230000007524 negative regulation of DNA replication Effects 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 201000008026 nephroblastoma Diseases 0.000 description 1
- 208000007538 neurilemmoma Diseases 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 208000004649 neutrophil actin dysfunction Diseases 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical group 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 230000000683 nonmetastatic effect Effects 0.000 description 1
- 238000004305 normal phase HPLC Methods 0.000 description 1
- 238000002414 normal-phase solid-phase extraction Methods 0.000 description 1
- 238000007344 nucleophilic reaction Methods 0.000 description 1
- 235000015097 nutrients Nutrition 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
- 239000006186 oral dosage form Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 208000003388 osteoid osteoma Diseases 0.000 description 1
- 208000008798 osteoma Diseases 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 230000010765 pachytene Effects 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 208000021255 pancreatic insulinoma Diseases 0.000 description 1
- 229940055726 pantothenic acid Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical class OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 206010034674 peritonitis Diseases 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 208000024724 pineal body neoplasm Diseases 0.000 description 1
- 201000004123 pineal gland cancer Diseases 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 208000017805 post-transplant lymphoproliferative disease Diseases 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 230000001012 protector Effects 0.000 description 1
- 230000009822 protein phosphorylation Effects 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- BWESROVQGZSBRX-UHFFFAOYSA-N pyrido[3,2-d]pyrimidine Chemical compound C1=NC=NC2=CC=CN=C21 BWESROVQGZSBRX-UHFFFAOYSA-N 0.000 description 1
- 229940107700 pyruvic acid Drugs 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
- 238000007347 radical substitution reaction Methods 0.000 description 1
- 150000003254 radicals Chemical group 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000002207 retinal effect Effects 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 206010039667 schwannoma Diseases 0.000 description 1
- 238000003345 scintillation counting Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 208000004548 serous cystadenocarcinoma Diseases 0.000 description 1
- 208000012201 sexual and gender identity disease Diseases 0.000 description 1
- 208000015891 sexual disease Diseases 0.000 description 1
- 239000003079 shale oil Substances 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 201000001839 skull cancer Diseases 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 201000011096 spinal cancer Diseases 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 208000014618 spinal cord cancer Diseases 0.000 description 1
- 210000004215 spore Anatomy 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- HKSZLNNOFSGOKW-FYTWVXJKSA-N staurosporine Chemical compound C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1[C@H]1C[C@@H](NC)[C@@H](OC)[C@]4(C)O1 HKSZLNNOFSGOKW-FYTWVXJKSA-N 0.000 description 1
- CGPUWJWCVCFERF-UHFFFAOYSA-N staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(OC)O1 CGPUWJWCVCFERF-UHFFFAOYSA-N 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000011289 tar acid Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 208000001608 teratocarcinoma Diseases 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- IXZDIALLLMRYOU-UHFFFAOYSA-N tert-butyl hypochlorite Chemical compound CC(C)(C)OCl IXZDIALLLMRYOU-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 230000002381 testicular Effects 0.000 description 1
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 231100000440 toxicity profile Toxicity 0.000 description 1
- 206010044412 transitional cell carcinoma Diseases 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 208000022271 tubular adenoma Diseases 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 208000013139 vaginal neoplasm Diseases 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 208000009540 villous adenoma Diseases 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 210000003905 vulva Anatomy 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physical Education & Sports Medicine (AREA)
- Urology & Nephrology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Vascular Medicine (AREA)
- Hematology (AREA)
- Ophthalmology & Optometry (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Oncology (AREA)
- Rheumatology (AREA)
- Dermatology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US37094610P | 2010-08-05 | 2010-08-05 | |
| US61/370,946 | 2010-08-05 | ||
| PCT/US2011/044807 WO2012018540A1 (en) | 2010-08-05 | 2011-07-21 | 2-substituted-8-alkyl-7-oxo-7,8-dihydropyrido[2,3-d] pyrimidine-6-carbonitriles and uses thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR20130098314A KR20130098314A (ko) | 2013-09-04 |
| KR101434841B1 true KR101434841B1 (ko) | 2014-08-29 |
Family
ID=45559737
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020137004979A Active KR101434841B1 (ko) | 2010-08-05 | 2011-07-21 | 2-치환-8-알킬-7-옥소-7,8-디하이드로피리도[2,3-ｄ] 피리미딘-6-카르보니트릴 및 이의 용도 |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US8987267B2 (https=) |
| EP (1) | EP2600719B1 (https=) |
| JP (1) | JP5512894B2 (https=) |
| KR (1) | KR101434841B1 (https=) |
| CN (1) | CN103200822B (https=) |
| AU (1) | AU2011286282B2 (https=) |
| BR (1) | BR112013002375B1 (https=) |
| CA (1) | CA2807498C (https=) |
| DK (1) | DK2600719T3 (https=) |
| EA (1) | EA022527B1 (https=) |
| ES (1) | ES2525866T3 (https=) |
| IL (1) | IL224555A (https=) |
| MX (1) | MX2013001427A (https=) |
| NZ (1) | NZ606281A (https=) |
| PL (1) | PL2600719T3 (https=) |
| PT (1) | PT2600719E (https=) |
| WO (1) | WO2012018540A1 (https=) |
Families Citing this family (27)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2525866T3 (es) * | 2010-08-05 | 2014-12-30 | Temple University - Of The Commonwealth System Of Higher Education | 8-alquil-7-oxo-7,8-dihidropirido [2,3-d]pirimidina-6-carbonitrilos sustituidos en 2 y usos de los mismos |
| WO2014031571A1 (en) * | 2012-08-21 | 2014-02-27 | Icahn School Of Medicine At Mount Sinai | Treatment of viral infections |
| US9815847B2 (en) | 2013-03-14 | 2017-11-14 | Icahn School Of Medicine At Mount Sinai | Pyrimidine compounds as kinase inhibitors |
| SG11201608303QA (en) | 2014-04-04 | 2016-11-29 | Del Mar Pharmaceuticals | Use of dianhydrogalactitol and analogs or derivatives thereof to treat non-small-cell carcinoma of the lung and ovarian cancer |
| CN105294682B (zh) | 2014-07-26 | 2017-07-07 | 广东东阳光药业有限公司 | Cdk类小分子抑制剂的化合物及其用途 |
| CN104447739B (zh) * | 2014-11-07 | 2016-02-17 | 郑州泰基鸿诺药物科技有限公司 | 一种氘代Palbociclib衍生物、制备方法及应用 |
| CN104496983B (zh) | 2014-11-26 | 2016-06-08 | 苏州明锐医药科技有限公司 | 一种帕博西尼的制备方法 |
| CN104447743B (zh) | 2014-11-26 | 2016-03-02 | 苏州明锐医药科技有限公司 | 帕博西尼的制备方法 |
| CN104478874B (zh) * | 2014-12-08 | 2016-03-02 | 新发药业有限公司 | 一种帕博赛布的制备方法 |
| CN104610254B (zh) * | 2015-01-26 | 2017-02-01 | 新发药业有限公司 | 一种帕博赛布的低成本制备方法 |
| CN105111205B (zh) * | 2015-09-12 | 2017-01-04 | 山东罗欣药业集团股份有限公司 | 一种帕博西尼的制备方法 |
| TWI749126B (zh) | 2016-12-16 | 2021-12-11 | 大陸商基石藥業（蘇州）有限公司 | Cdk4/6抑制劑 |
| JP2021514359A (ja) | 2018-02-15 | 2021-06-10 | ニューベイション・バイオ・インコーポレイテッドＮｕｖａｔｉｏｎ Ｂｉｏ Ｉｎｃ． | キナーゼ阻害剤としての複素環式化合物 |
| KR102286701B1 (ko) * | 2018-09-28 | 2021-08-06 | 재단법인 대구경북첨단의료산업진흥재단 | 피리도[2,3-d]피리미딘 유도체, 이의 제조방법 및 이를 유효성분으로 포함하는 암의 예방 또는 치료용 약학적 조성물 |
| TWI818930B (zh) * | 2018-11-12 | 2023-10-21 | 美商昂可諾法治療股份有限公司 | 8-環戊基-7-側氧基-2-(4-哌嗪-1-基-苯基胺基)-7,8-二氫-吡啶[2,3-d]嘧啶-6-氰基及其用於治療增生性疾病的用途 |
| JP7378167B2 (ja) * | 2018-11-12 | 2023-11-13 | オンコノバ セラピューティクス インコーポレイテッド | ８‐シクロペンチル‐７‐オキソ‐２‐（４‐ピペラジン‐１‐イル‐フェニルアミノ）‐７，８‐ジヒドロ‐ピリド［２，３‐ｄ］ピリミジン‐６‐カルボニトリル及び同化合物の増殖性障害の治療における使用 |
| CA3124574A1 (en) * | 2018-12-28 | 2020-07-02 | Spv Therapeutics Inc. | Cyclin-dependent kinase inhibitors |
| WO2020140053A1 (en) * | 2018-12-28 | 2020-07-02 | Spv Therapeutics Inc. | Cyclin-dependent kinase inhibitors |
| CA3145821A1 (en) * | 2019-07-02 | 2021-01-07 | Nuvation Bio Inc. | Heterocyclic compounds as kinase inhibitors |
| US11697648B2 (en) | 2019-11-26 | 2023-07-11 | Theravance Biopharma R&D Ip, Llc | Fused pyrimidine pyridinone compounds as JAK inhibitors |
| WO2021242770A1 (en) * | 2020-05-28 | 2021-12-02 | University Of Washington | Drug-like molecules and methods for the therapeutic targeting of viral rna structures |
| AU2022379973A1 (en) | 2021-11-08 | 2024-06-27 | Progentos Therapeutics, Inc. | Platelet-derived growth factor receptor (pdgfr) alpha inhibitors and uses thereof |
| WO2023092104A1 (en) * | 2021-11-18 | 2023-05-25 | Onconova Therapeutics, Inc. | Methods and compositions for treating cancer |
| IL312846A (en) * | 2021-11-18 | 2024-07-01 | Onconova Therapeutics Inc | Methods and preparations for the treatment of cancer |
| WO2023230288A1 (en) * | 2022-05-25 | 2023-11-30 | Onconova Therapeutics, Inc. | Methods and compositions for treating cancer |
| WO2024107730A1 (en) * | 2022-11-14 | 2024-05-23 | Onconova Therapeutics, Inc. | Methods and compositions for treating cancer |
| EP4618992A1 (en) * | 2022-11-17 | 2025-09-24 | Onconova Therapeutics, Inc. | Methods and compositions for treating cancer |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080004285A1 (en) | 2004-12-30 | 2008-01-03 | De Jonghe Steven C A | Pyrido(3,2-d)pyrimidines and pharmaceutical compositions useful for medical treatment |
| US20090062274A1 (en) | 2005-10-07 | 2009-03-05 | Exelixis, Inc | Pyridopyrimidinone inhibitors of pi3kalpha |
Family Cites Families (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5620981A (en) | 1995-05-03 | 1997-04-15 | Warner-Lambert Company | Pyrido [2,3-D]pyrimidines for inhibiting protein tyrosine kinase mediated cellular proliferation |
| US6498163B1 (en) * | 1997-02-05 | 2002-12-24 | Warner-Lambert Company | Pyrido[2,3-D]pyrimidines and 4-aminopyrimidines as inhibitors of cellular proliferation |
| TR200003429T2 (tr) * | 1998-05-26 | 2001-07-23 | Warner-Lambert Company | Hücresel çoğalma inhibitörleri olarak bisiklik pirimidinler ve bisiklik 3,4-dihidropirimidinler. |
| JP2003523358A (ja) * | 2000-01-27 | 2003-08-05 | ワーナー−ランバート・カンパニー、リミテッド、ライアビリティ、カンパニー | 神経変性疾患の治療のためのピリドピリミジノン誘導体 |
| WO2001062233A2 (en) * | 2000-02-25 | 2001-08-30 | F. Hoffmann La Roche Ag | Adenosine receptor modulators |
| AP2002002643A0 (en) | 2000-03-06 | 2002-12-31 | Warner Lambert Co | 5-alkylpyrido[2,3-d]pyrimidines tyrosine kinase inhibitors |
| MXPA04005939A (es) | 2002-01-22 | 2005-01-25 | Warner Lambert Co | 2-(piridin-2-ilamino)-pirido[2,3-d]pirimidin-7-onas. |
| BRPI0507852A (pt) | 2004-02-18 | 2007-07-10 | Warner Lambert Co | 2-(piridin-3-ilamino)-pirido[2,3-d]pirimidin-7-onas |
| WO2005105097A2 (en) | 2004-04-28 | 2005-11-10 | Gpc Biotech Ag | Pyridopyrimidines for treating inflammatory and other diseases |
| US20060142312A1 (en) | 2004-12-23 | 2006-06-29 | Pfizer Inc | C6-aryl and heteroaryl substituted pyrido[2,3-D] pyrimidin-7-ones |
| JP2008526704A (ja) * | 2004-12-30 | 2008-07-24 | ４・アー・ゼット・アー・アイ・ピー・ナムローゼ・フエンノートシャップ | ピリド（３，２−ｄ）ピリミジンおよび医療処置に有用な医薬組成物 |
| AU2006261607A1 (en) * | 2005-06-24 | 2006-12-28 | Gilead Sciences, Inc. | Pyrido(3,2-d)pyrimidines and pharmaceutical compositions useful for treating hepatitis C. |
| EA016945B1 (ru) * | 2005-10-07 | 2012-08-30 | Экселиксис, Инк. | ПИРИДОПИРИМИДИНОНОВЫЕ ИНГИБИТОРЫ PI3Kα |
| EP2046322A4 (en) | 2006-08-02 | 2010-10-06 | Univ Temple | ARYL-VINYL-SULFIDE, -SULFONE, -SULFOXIDE AND -SULFONAMIDES, DERIVATIVES THEREOF AND THERAPEUTIC APPLICATIONS THEREOF |
| WO2008047307A1 (en) | 2006-10-16 | 2008-04-24 | Gpc Biotech Inc. | Pyrido [2, 3-d] pyrimidines and their use as kinase inhibitors |
| WO2008150260A1 (en) | 2007-06-06 | 2008-12-11 | Gpc Biotech, Inc. | 8-oxy-2-aminopyrido (2, 3-d) pyrimidin-7-one derivatives as kinase inhibitors and anticancer agents |
| JP5797664B2 (ja) | 2009-12-18 | 2015-10-21 | テンプル・ユニバーシティ−オブ・ザ・コモンウェルス・システム・オブ・ハイアー・エデュケイションＴｅｍｐｌｅ Ｕｎｉｖｅｒｓｉｔｙ−Ｏｆ Ｔｈｅ Ｃｏｍｍｏｎｗｅａｌｔｈ Ｓｙｓｔｅｍ Ｏｆ Ｈｉｇｈｅｒ Ｅｄｕｃａｔｉｏｎ | 置換ピリド［２，３−ｄ］ピリミジン−７（８Ｈ）−オン及びそれらの治療用の使用 |
| ES2525866T3 (es) * | 2010-08-05 | 2014-12-30 | Temple University - Of The Commonwealth System Of Higher Education | 8-alquil-7-oxo-7,8-dihidropirido [2,3-d]pirimidina-6-carbonitrilos sustituidos en 2 y usos de los mismos |
-
2011
- 2011-07-21 ES ES11815012.7T patent/ES2525866T3/es active Active
- 2011-07-21 KR KR1020137004979A patent/KR101434841B1/ko active Active
- 2011-07-21 EA EA201390199A patent/EA022527B1/ru not_active IP Right Cessation
- 2011-07-21 CN CN201180038325.3A patent/CN103200822B/zh active Active
- 2011-07-21 CA CA2807498A patent/CA2807498C/en active Active
- 2011-07-21 DK DK11815012.7T patent/DK2600719T3/da active
- 2011-07-21 EP EP11815012.7A patent/EP2600719B1/en active Active
- 2011-07-21 BR BR112013002375-9A patent/BR112013002375B1/pt active IP Right Grant
- 2011-07-21 PT PT118150127T patent/PT2600719E/pt unknown
- 2011-07-21 US US13/813,023 patent/US8987267B2/en active Active
- 2011-07-21 MX MX2013001427A patent/MX2013001427A/es active IP Right Grant
- 2011-07-21 JP JP2013523185A patent/JP5512894B2/ja not_active Expired - Fee Related
- 2011-07-21 NZ NZ606281A patent/NZ606281A/en unknown
- 2011-07-21 WO PCT/US2011/044807 patent/WO2012018540A1/en not_active Ceased
- 2011-07-21 AU AU2011286282A patent/AU2011286282B2/en not_active Ceased
- 2011-07-21 PL PL11815012T patent/PL2600719T3/pl unknown
-
2013
- 2013-02-03 IL IL224555A patent/IL224555A/en active IP Right Grant
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080004285A1 (en) | 2004-12-30 | 2008-01-03 | De Jonghe Steven C A | Pyrido(3,2-d)pyrimidines and pharmaceutical compositions useful for medical treatment |
| US20090062274A1 (en) | 2005-10-07 | 2009-03-05 | Exelixis, Inc | Pyridopyrimidinone inhibitors of pi3kalpha |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2013538196A (ja) | 2013-10-10 |
| CN103200822B (zh) | 2014-12-24 |
| JP5512894B2 (ja) | 2014-06-04 |
| EP2600719A4 (en) | 2014-01-01 |
| EA201390199A1 (ru) | 2013-07-30 |
| AU2011286282A1 (en) | 2013-02-14 |
| EA022527B1 (ru) | 2016-01-29 |
| IL224555A (en) | 2016-03-31 |
| US20130131058A1 (en) | 2013-05-23 |
| MX2013001427A (es) | 2013-06-13 |
| NZ606281A (en) | 2014-09-26 |
| CA2807498A1 (en) | 2012-02-09 |
| BR112013002375A2 (pt) | 2016-05-24 |
| CN103200822A (zh) | 2013-07-10 |
| WO2012018540A1 (en) | 2012-02-09 |
| EP2600719A1 (en) | 2013-06-12 |
| US8987267B2 (en) | 2015-03-24 |
| PT2600719E (pt) | 2014-12-22 |
| ES2525866T3 (es) | 2014-12-30 |
| AU2011286282B2 (en) | 2014-08-21 |
| CA2807498C (en) | 2017-02-07 |
| KR20130098314A (ko) | 2013-09-04 |
| DK2600719T3 (da) | 2014-12-15 |
| EP2600719B1 (en) | 2014-10-08 |
| BR112013002375B1 (pt) | 2020-05-12 |
| PL2600719T3 (pl) | 2015-03-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR101434841B1 (ko) | 2-치환-8-알킬-7-옥소-7,8-디하이드로피리도[2,3-ｄ] 피리미딘-6-카르보니트릴 및 이의 용도 | |
| US8765755B2 (en) | N-containing heterocyclic compounds | |
| JP2013502404A (ja) | ホスホイノシチド３−キナーゼ阻害剤としての三環式複素環化合物 | |
| KR20190104632A (ko) | 트라이사이클릭 자이라제 억제제 | |
| EP1325009B1 (en) | Amino-substituted tetracyclic compounds useful as anti-inflammatory agents and pharmaceutical compositions comprising same | |
| AU2002211827A1 (en) | Amino-substituted tetracyclic compounds useful as anti-inflammatory agents and pharmaceutical compositions comprising same | |
| CN116528871A (zh) | 一种吡唑并喹唑啉类化合物、其制备方法及应用 | |
| CN111868060B (zh) | 二氢吡啶并酞嗪酮衍生物、其制备方法及应用 | |
| KR101754664B1 (ko) | 치환된 피리도〔2,3-ｄ〕피리미딘-7(8ｈ)-온스 및 이의 치료 용도 | |
| ES2747423T3 (es) | Compuesto de quinoxalina | |
| CA2994036A1 (en) | Novel fused pyrimidinone and triazinone derivatives, their process of preparation and their therapeutic uses as antifungal and/or antiparasitic agents | |
| CN111825694A (zh) | 稠环化合物、其制备方法及用途 | |
| CN108912095B (zh) | 苯并咪唑类化合物及其制备方法和应用 | |
| CN114230557B (zh) | 喹唑啉取代的1,2,3-三氮唑衍生物及其药物组合物、制备方法和用途 | |
| AU2010330863B2 (en) | Substituted pyrido[2,3-d]pyrimidin-7(8H)-ones and therapeutic uses thereof | |
| WO2013142010A1 (en) | 3-AMINOTHIENO[3,2-c]QUINOLINE DERIVATIVES, METHODS OF PREPARATION AND USES |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PA0105 | International application |
Patent event date: 20130227 Patent event code: PA01051R01D Comment text: International Patent Application |
|
| PG1501 | Laying open of application | ||
| A201 | Request for examination | ||
| A302 | Request for accelerated examination | ||
| PA0201 | Request for examination |
Patent event code: PA02012R01D Patent event date: 20140226 Comment text: Request for Examination of Application |
|
| PA0302 | Request for accelerated examination |
Patent event date: 20140226 Patent event code: PA03022R01D Comment text: Request for Accelerated Examination |
|
| E701 | Decision to grant or registration of patent right | ||
| PE0701 | Decision of registration |
Patent event code: PE07011S01D Comment text: Decision to Grant Registration Patent event date: 20140708 |
|
| GRNT | Written decision to grant | ||
| PR0701 | Registration of establishment |
Comment text: Registration of Establishment Patent event date: 20140821 Patent event code: PR07011E01D |
|
| PR1002 | Payment of registration fee |
Payment date: 20140822 End annual number: 3 Start annual number: 1 |
|
| PG1601 | Publication of registration | ||
| FPAY | Annual fee payment |
Payment date: 20170810 Year of fee payment: 4 |
|
| PR1001 | Payment of annual fee |
Payment date: 20170810 Start annual number: 4 End annual number: 4 |
|
| FPAY | Annual fee payment |
Payment date: 20180808 Year of fee payment: 5 |
|
| PR1001 | Payment of annual fee |
Payment date: 20180808 Start annual number: 5 End annual number: 5 |
|
| FPAY | Annual fee payment |
Payment date: 20190808 Year of fee payment: 6 |
|
| PR1001 | Payment of annual fee |
Payment date: 20190808 Start annual number: 6 End annual number: 6 |
|
| PR1001 | Payment of annual fee |
Payment date: 20200812 Start annual number: 7 End annual number: 7 |
|
| PR1001 | Payment of annual fee |
Payment date: 20210811 Start annual number: 8 End annual number: 8 |
|
| PR1001 | Payment of annual fee |
Payment date: 20220805 Start annual number: 9 End annual number: 9 |
|
| PR1001 | Payment of annual fee |
Payment date: 20230808 Start annual number: 10 End annual number: 10 |