TWI821180B - 使用三取代苯并三唑衍生物作為二氫乳清酸氧合酶抑制劑之方法 - Google Patents
使用三取代苯并三唑衍生物作為二氫乳清酸氧合酶抑制劑之方法 Download PDFInfo
- Publication number
- TWI821180B TWI821180B TW107113690A TW107113690A TWI821180B TW I821180 B TWI821180 B TW I821180B TW 107113690 A TW107113690 A TW 107113690A TW 107113690 A TW107113690 A TW 107113690A TW I821180 B TWI821180 B TW I821180B
- Authority
- TW
- Taiwan
- Prior art keywords
- compound
- cancer
- formula
- compounds
- pharmaceutically acceptable
- Prior art date
Links
- 238000000034 method Methods 0.000 title abstract description 56
- 125000003354 benzotriazolyl group Chemical class N1N=NC2=C1C=CC=C2* 0.000 title abstract 2
- 239000003650 oxygenase inhibitor Substances 0.000 title description 2
- UFIVEPVSAGBUSI-UHFFFAOYSA-N dihydroorotic acid Chemical compound OC(=O)C1CC(=O)NC(=O)N1 UFIVEPVSAGBUSI-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 129
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 76
- 201000011510 cancer Diseases 0.000 claims abstract description 40
- 150000003839 salts Chemical class 0.000 claims abstract description 37
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 claims description 20
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 claims description 20
- 238000002360 preparation method Methods 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 14
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 10
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 9
- 208000003721 Triple Negative Breast Neoplasms Diseases 0.000 claims description 7
- 208000022679 triple-negative breast carcinoma Diseases 0.000 claims description 7
- 206010073478 Anaplastic large-cell lymphoma Diseases 0.000 claims description 5
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 5
- 208000032004 Large-Cell Anaplastic Lymphoma Diseases 0.000 claims description 5
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 claims description 5
- 208000034578 Multiple myelomas Diseases 0.000 claims description 5
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 5
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 5
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 5
- 206010060862 Prostate cancer Diseases 0.000 claims description 5
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 5
- 201000004101 esophageal cancer Diseases 0.000 claims description 5
- 201000001441 melanoma Diseases 0.000 claims description 5
- 208000032568 B-cell prolymphocytic leukaemia Diseases 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 abstract description 17
- 230000000694 effects Effects 0.000 abstract description 15
- 230000004614 tumor growth Effects 0.000 abstract description 15
- 230000002401 inhibitory effect Effects 0.000 abstract description 11
- 102000004020 Oxygenases Human genes 0.000 abstract description 5
- 108090000417 Oxygenases Proteins 0.000 abstract description 5
- 206010027476 Metastases Diseases 0.000 abstract description 4
- 230000009401 metastasis Effects 0.000 abstract description 4
- 229940125904 compound 1 Drugs 0.000 description 62
- 239000000243 solution Substances 0.000 description 38
- 239000000203 mixture Substances 0.000 description 35
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 34
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 31
- 210000004027 cell Anatomy 0.000 description 31
- 235000002639 sodium chloride Nutrition 0.000 description 27
- 125000000217 alkyl group Chemical group 0.000 description 26
- 239000011541 reaction mixture Substances 0.000 description 25
- 230000012010 growth Effects 0.000 description 23
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 22
- 229910052757 nitrogen Inorganic materials 0.000 description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- 108010052167 Dihydroorotate Dehydrogenase Proteins 0.000 description 21
- 102100032823 Dihydroorotate dehydrogenase (quinone), mitochondrial Human genes 0.000 description 21
- 239000003981 vehicle Substances 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- 239000004480 active ingredient Substances 0.000 description 19
- 125000003118 aryl group Chemical group 0.000 description 18
- 230000035945 sensitivity Effects 0.000 description 18
- -1 isopropyl Aminomethyl Chemical group 0.000 description 17
- 230000005764 inhibitory process Effects 0.000 description 16
- 239000008194 pharmaceutical composition Substances 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 238000011579 SCID mouse model Methods 0.000 description 15
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical class O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 14
- UFIVEPVSAGBUSI-UHFFFAOYSA-M dihydroorotate Chemical compound [O-]C(=O)C1CC(=O)NC(=O)N1 UFIVEPVSAGBUSI-UHFFFAOYSA-M 0.000 description 14
- 239000000843 powder Substances 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 13
- 235000019439 ethyl acetate Nutrition 0.000 description 13
- 125000000623 heterocyclic group Chemical group 0.000 description 13
- 239000007787 solid Substances 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 11
- 238000005481 NMR spectroscopy Methods 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 11
- 238000009472 formulation Methods 0.000 description 11
- 125000001072 heteroaryl group Chemical group 0.000 description 11
- 229910052739 hydrogen Inorganic materials 0.000 description 11
- 239000001257 hydrogen Substances 0.000 description 11
- 239000002609 medium Substances 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 239000002585 base Substances 0.000 description 10
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 10
- 230000002829 reductive effect Effects 0.000 description 10
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 10
- 239000003826 tablet Substances 0.000 description 10
- 210000004881 tumor cell Anatomy 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000000872 buffer Substances 0.000 description 9
- 201000010099 disease Diseases 0.000 description 9
- 230000009036 growth inhibition Effects 0.000 description 9
- 150000003278 haem Chemical class 0.000 description 9
- 238000001727 in vivo Methods 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 9
- 229910052760 oxygen Inorganic materials 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 206010039073 rheumatoid arthritis Diseases 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 150000001565 benzotriazoles Chemical class 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 125000005842 heteroatom Chemical group 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- 239000007760 Iscove's Modified Dulbecco's Medium Substances 0.000 description 7
- 150000001412 amines Chemical class 0.000 description 7
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 229910052736 halogen Inorganic materials 0.000 description 7
- 150000002367 halogens Chemical group 0.000 description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 description 7
- 238000002953 preparative HPLC Methods 0.000 description 7
- 239000011550 stock solution Substances 0.000 description 7
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 7
- 229940045145 uridine Drugs 0.000 description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- 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 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 229910020008 S(O) Inorganic materials 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000001363 autoimmune Effects 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 125000000753 cycloalkyl group Chemical group 0.000 description 6
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 6
- 150000002431 hydrogen Chemical class 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 201000006417 multiple sclerosis Diseases 0.000 description 6
- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical compound OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 description 6
- 239000002953 phosphate buffered saline Substances 0.000 description 6
- 229910052717 sulfur Inorganic materials 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 206010025323 Lymphomas Diseases 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- 239000006071 cream Substances 0.000 description 5
- 238000003818 flash chromatography Methods 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 235000010288 sodium nitrite Nutrition 0.000 description 5
- 125000003107 substituted aryl group Chemical group 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 238000001665 trituration Methods 0.000 description 5
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 4
- 208000023275 Autoimmune disease Diseases 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 4
- 125000002619 bicyclic group Chemical group 0.000 description 4
- 239000011230 binding agent Substances 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 210000003169 central nervous system Anatomy 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 4
- 208000014829 head and neck neoplasm Diseases 0.000 description 4
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
- 208000032839 leukemia Diseases 0.000 description 4
- 239000000314 lubricant Substances 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
- 125000002950 monocyclic group Chemical group 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 4
- 239000013641 positive control Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 239000007921 spray Substances 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 239000003643 water by type Substances 0.000 description 4
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 3
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- 208000017604 Hodgkin disease Diseases 0.000 description 3
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 3
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 3
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 3
- 201000004681 Psoriasis Diseases 0.000 description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- TZIHFWKZFHZASV-UHFFFAOYSA-N anhydrous methyl formate Natural products COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 230000010261 cell growth Effects 0.000 description 3
- 238000001516 cell proliferation assay Methods 0.000 description 3
- 230000003833 cell viability Effects 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- 229960000684 cytarabine Drugs 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 239000007884 disintegrant Substances 0.000 description 3
- 229960004679 doxorubicin Drugs 0.000 description 3
- 239000000975 dye Substances 0.000 description 3
- 230000001747 exhibiting effect Effects 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 235000013355 food flavoring agent Nutrition 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 230000003394 haemopoietic effect Effects 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 208000027866 inflammatory disease Diseases 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 230000002438 mitochondrial effect Effects 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 229960005010 orotic acid Drugs 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 210000003491 skin Anatomy 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 206010041823 squamous cell carcinoma Diseases 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000011593 sulfur Chemical group 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 229960000331 teriflunomide Drugs 0.000 description 3
- UTNUDOFZCWSZMS-YFHOEESVSA-N teriflunomide Chemical compound C\C(O)=C(/C#N)C(=O)NC1=CC=C(C(F)(F)F)C=C1 UTNUDOFZCWSZMS-YFHOEESVSA-N 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- 238000011200 topical administration Methods 0.000 description 3
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Substances C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 3
- 239000001993 wax Substances 0.000 description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 2
- UFIVEPVSAGBUSI-REOHCLBHSA-N (S)-dihydroorotic acid Chemical compound OC(=O)[C@@H]1CC(=O)NC(=O)N1 UFIVEPVSAGBUSI-REOHCLBHSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 2
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Chemical compound C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 2
- PAPNRQCYSFBWDI-UHFFFAOYSA-N 2,5-Dimethyl-1H-pyrrole Chemical compound CC1=CC=C(C)N1 PAPNRQCYSFBWDI-UHFFFAOYSA-N 0.000 description 2
- CCBICDLNWJRFPO-UHFFFAOYSA-N 2,6-dichloroindophenol Chemical compound C1=CC(O)=CC=C1N=C1C=C(Cl)C(=O)C(Cl)=C1 CCBICDLNWJRFPO-UHFFFAOYSA-N 0.000 description 2
- GSBZRCGZLMBSNY-UHFFFAOYSA-N 3-methyl-6-[4-(2-methylphenyl)phenyl]benzotriazole-4-carboxylic acid Chemical compound CC1=CC=CC=C1C1=CC=C(C=2C=C3N=NN(C)C3=C(C(O)=O)C=2)C=C1 GSBZRCGZLMBSNY-UHFFFAOYSA-N 0.000 description 2
- VMEGFMNVSYVVOM-UHFFFAOYSA-N 6-decylubiquinone Chemical compound CCCCCCCCCCC1=C(C)C(=O)C(OC)=C(OC)C1=O VMEGFMNVSYVVOM-UHFFFAOYSA-N 0.000 description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 2
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 2
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 2
- 206010004659 Biliary cirrhosis Diseases 0.000 description 2
- 206010005003 Bladder cancer Diseases 0.000 description 2
- 206010005949 Bone cancer Diseases 0.000 description 2
- 208000018084 Bone neoplasm Diseases 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 206010007953 Central nervous system lymphoma Diseases 0.000 description 2
- 206010008342 Cervix carcinoma Diseases 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 206010009900 Colitis ulcerative Diseases 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 208000011231 Crohn disease Diseases 0.000 description 2
- 101710088194 Dehydrogenase Proteins 0.000 description 2
- 102100034289 Deoxynucleoside triphosphate triphosphohydrolase SAMHD1 Human genes 0.000 description 2
- 206010012438 Dermatitis atopic Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 229940083266 Dihydroorotate dehydrogenase inhibitor Drugs 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- 201000003741 Gastrointestinal carcinoma Diseases 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 description 2
- 101000641031 Homo sapiens Deoxynucleoside triphosphate triphosphohydrolase SAMHD1 Proteins 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 2
- 208000007766 Kaposi sarcoma Diseases 0.000 description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 208000032271 Malignant tumor of penis Diseases 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 201000002481 Myositis Diseases 0.000 description 2
- 239000007832 Na2SO4 Substances 0.000 description 2
- 102000014160 PTEN Phosphohydrolase Human genes 0.000 description 2
- 108010011536 PTEN Phosphohydrolase Proteins 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- 208000000821 Parathyroid Neoplasms Diseases 0.000 description 2
- 206010034277 Pemphigoid Diseases 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- 208000002471 Penile Neoplasms Diseases 0.000 description 2
- 206010034299 Penile cancer Diseases 0.000 description 2
- 208000007913 Pituitary Neoplasms Diseases 0.000 description 2
- 201000005746 Pituitary adenoma Diseases 0.000 description 2
- 206010061538 Pituitary tumour benign Diseases 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 206010038389 Renal cancer Diseases 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- 208000000453 Skin Neoplasms Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 208000021712 Soft tissue sarcoma Diseases 0.000 description 2
- 206010042971 T-cell lymphoma Diseases 0.000 description 2
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 208000024770 Thyroid neoplasm Diseases 0.000 description 2
- 206010052779 Transplant rejections Diseases 0.000 description 2
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 description 2
- 208000023915 Ureteral Neoplasms Diseases 0.000 description 2
- 206010046392 Ureteric cancer Diseases 0.000 description 2
- 206010046431 Urethral cancer Diseases 0.000 description 2
- 206010046458 Urethral neoplasms Diseases 0.000 description 2
- DJJCXFVJDGTHFX-UHFFFAOYSA-N Uridinemonophosphate Natural products OC1C(O)C(COP(O)(O)=O)OC1N1C(=O)NC(=O)C=C1 DJJCXFVJDGTHFX-UHFFFAOYSA-N 0.000 description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 2
- 206010046851 Uveitis Diseases 0.000 description 2
- 206010047741 Vulval cancer Diseases 0.000 description 2
- 208000004354 Vulvar Neoplasms Diseases 0.000 description 2
- 230000005856 abnormality Effects 0.000 description 2
- 201000005188 adrenal gland cancer Diseases 0.000 description 2
- 208000024447 adrenal gland neoplasm Diseases 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 201000008937 atopic dermatitis Diseases 0.000 description 2
- 208000037979 autoimmune inflammatory disease Diseases 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000000440 bentonite Substances 0.000 description 2
- 229910000278 bentonite Inorganic materials 0.000 description 2
- 235000012216 bentonite Nutrition 0.000 description 2
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 2
- 239000000090 biomarker Substances 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- 239000004305 biphenyl Substances 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 229940098773 bovine serum albumin Drugs 0.000 description 2
- PHEZJEYUWHETKO-UHFFFAOYSA-N brequinar Chemical compound N1=C2C=CC(F)=CC2=C(C(O)=O)C(C)=C1C(C=C1)=CC=C1C1=CC=CC=C1F PHEZJEYUWHETKO-UHFFFAOYSA-N 0.000 description 2
- 208000000594 bullous pemphigoid Diseases 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 201000010881 cervical cancer Diseases 0.000 description 2
- 238000009104 chemotherapy regimen Methods 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 208000037976 chronic inflammation Diseases 0.000 description 2
- 208000037893 chronic inflammatory disorder Diseases 0.000 description 2
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 239000003363 dihydroorotate dehydrogenase inhibitor Substances 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 210000000750 endocrine system Anatomy 0.000 description 2
- 210000004696 endometrium Anatomy 0.000 description 2
- 208000037902 enteropathy Diseases 0.000 description 2
- 238000010931 ester hydrolysis Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 208000024711 extrinsic asthma Diseases 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 201000003444 follicular lymphoma Diseases 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 208000005017 glioblastoma Diseases 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 210000003128 head Anatomy 0.000 description 2
- 206010021198 ichthyosis Diseases 0.000 description 2
- 230000002519 immonomodulatory effect Effects 0.000 description 2
- 229940125721 immunosuppressive agent Drugs 0.000 description 2
- 239000003018 immunosuppressive agent Substances 0.000 description 2
- 238000000099 in vitro assay Methods 0.000 description 2
- 201000002313 intestinal cancer Diseases 0.000 description 2
- 208000028774 intestinal disease Diseases 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 201000010982 kidney cancer Diseases 0.000 description 2
- VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 description 2
- 229960000681 leflunomide Drugs 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 230000003211 malignant effect Effects 0.000 description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 2
- 208000026037 malignant tumor of neck Diseases 0.000 description 2
- 208000026045 malignant tumor of parathyroid gland Diseases 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- WBTZDZSHLVPNLU-UHFFFAOYSA-N methyl 6-bromo-2h-benzotriazole-4-carboxylate Chemical compound COC(=O)C1=CC(Br)=CC2=NNN=C12 WBTZDZSHLVPNLU-UHFFFAOYSA-N 0.000 description 2
- MOOITBAMMUMBBH-UHFFFAOYSA-N methyl 6-bromo-3-methylbenzotriazole-4-carboxylate Chemical compound COC(=O)C1=CC(Br)=CC2=C1N(C)N=N2 MOOITBAMMUMBBH-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 201000002528 pancreatic cancer Diseases 0.000 description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 239000008177 pharmaceutical agent Substances 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- 208000021310 pituitary gland adenoma Diseases 0.000 description 2
- 239000011505 plaster Substances 0.000 description 2
- 125000003367 polycyclic group Chemical group 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 235000011056 potassium acetate Nutrition 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 208000016800 primary central nervous system lymphoma Diseases 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 150000003230 pyrimidines Chemical class 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 201000000306 sarcoidosis Diseases 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 201000000849 skin cancer Diseases 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 208000037959 spinal tumor Diseases 0.000 description 2
- 229960005322 streptomycin Drugs 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 229920003051 synthetic elastomer Polymers 0.000 description 2
- 239000005061 synthetic rubber Substances 0.000 description 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 201000002510 thyroid cancer Diseases 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 230000005747 tumor angiogenesis Effects 0.000 description 2
- 201000011294 ureter cancer Diseases 0.000 description 2
- DJJCXFVJDGTHFX-XVFCMESISA-N uridine 5'-monophosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(O)=O)O[C@H]1N1C(=O)NC(=O)C=C1 DJJCXFVJDGTHFX-XVFCMESISA-N 0.000 description 2
- 201000005112 urinary bladder cancer Diseases 0.000 description 2
- 206010046885 vaginal cancer Diseases 0.000 description 2
- 208000013139 vaginal neoplasm Diseases 0.000 description 2
- 201000005102 vulva cancer Diseases 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- KTZQTRPPVKQPFO-UHFFFAOYSA-N 1,2-benzoxazole Chemical compound C1=CC=C2C=NOC2=C1 KTZQTRPPVKQPFO-UHFFFAOYSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- FKASFBLJDCHBNZ-UHFFFAOYSA-N 1,3,4-oxadiazole Chemical compound C1=NN=CO1 FKASFBLJDCHBNZ-UHFFFAOYSA-N 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- JPRPJUMQRZTTED-UHFFFAOYSA-N 1,3-dioxolanyl Chemical group [CH]1OCCO1 JPRPJUMQRZTTED-UHFFFAOYSA-N 0.000 description 1
- 125000005940 1,4-dioxanyl group Chemical group 0.000 description 1
- OXHNLMTVIGZXSG-UHFFFAOYSA-N 1-Methylpyrrole Chemical compound CN1C=CC=C1 OXHNLMTVIGZXSG-UHFFFAOYSA-N 0.000 description 1
- MWZDIEIXRBWPLG-UHFFFAOYSA-N 1-methyl-1,2,4-triazole Chemical compound CN1C=NC=N1 MWZDIEIXRBWPLG-UHFFFAOYSA-N 0.000 description 1
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- FGYADSCZTQOAFK-UHFFFAOYSA-N 1-methylbenzimidazole Chemical compound C1=CC=C2N(C)C=NC2=C1 FGYADSCZTQOAFK-UHFFFAOYSA-N 0.000 description 1
- OMAFFHIGWTVZOH-UHFFFAOYSA-N 1-methyltetrazole Chemical compound CN1C=NN=N1 OMAFFHIGWTVZOH-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- PKKDWPSOOQBWFB-UHFFFAOYSA-N 2,4-dichloro-6-[(3,5-dichloro-2-hydroxyphenyl)methyl]phenol Chemical compound OC1=C(Cl)C=C(Cl)C=C1CC1=CC(Cl)=CC(Cl)=C1O PKKDWPSOOQBWFB-UHFFFAOYSA-N 0.000 description 1
- HOLHYSJJBXSLMV-UHFFFAOYSA-N 2,6-dichlorophenol Chemical compound OC1=C(Cl)C=CC=C1Cl HOLHYSJJBXSLMV-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- BTOVVHWKPVSLBI-UHFFFAOYSA-N 2-methylprop-1-enylbenzene Chemical compound CC(C)=CC1=CC=CC=C1 BTOVVHWKPVSLBI-UHFFFAOYSA-N 0.000 description 1
- KFJDQPJLANOOOB-UHFFFAOYSA-N 2h-benzotriazole-4-carboxylic acid Chemical class OC(=O)C1=CC=CC2=NNN=C12 KFJDQPJLANOOOB-UHFFFAOYSA-N 0.000 description 1
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 description 1
- ISCMYZGMRHODRP-UHFFFAOYSA-N 3-(iminomethylideneamino)-n,n-dimethylpropan-1-amine Chemical compound CN(C)CCCN=C=N ISCMYZGMRHODRP-UHFFFAOYSA-N 0.000 description 1
- OGLAIXZTEPHYCS-UHFFFAOYSA-N 3-aminobenzoate 4-methoxy-5-[2-(2-methoxy-4-nitro-5-sulfophenyl)-1,3-dihydrotetrazol-3-ium-3-yl]-2-nitrobenzenesulfonic acid Chemical compound NC1=CC=CC(C([O-])=O)=C1.COC1=CC([N+]([O-])=O)=C(S(O)(=O)=O)C=C1N1[NH+](C=2C(=CC(=C(C=2)S(O)(=O)=O)[N+]([O-])=O)OC)N=CN1 OGLAIXZTEPHYCS-UHFFFAOYSA-N 0.000 description 1
- XCDNKYOCGWWHRR-UHFFFAOYSA-N 3-methyl-6-[4-(2-methylphenyl)phenyl]benzotriazole-4-carboxamide Chemical compound CC1=CC=CC=C1C1=CC=C(C=2C=C3N=NN(C)C3=C(C(N)=O)C=2)C=C1 XCDNKYOCGWWHRR-UHFFFAOYSA-N 0.000 description 1
- GAMYYCRTACQSBR-UHFFFAOYSA-N 4-azabenzimidazole Chemical compound C1=CC=C2NC=NC2=N1 GAMYYCRTACQSBR-UHFFFAOYSA-N 0.000 description 1
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 1
- PQGCEDQWHSBAJP-TXICZTDVSA-N 5-O-phosphono-alpha-D-ribofuranosyl diphosphate Chemical compound O[C@H]1[C@@H](O)[C@@H](O[P@](O)(=O)OP(O)(O)=O)O[C@@H]1COP(O)(O)=O PQGCEDQWHSBAJP-TXICZTDVSA-N 0.000 description 1
- RXGJTUSBYWCRBK-UHFFFAOYSA-M 5-methylphenazinium methyl sulfate Chemical compound COS([O-])(=O)=O.C1=CC=C2[N+](C)=C(C=CC=C3)C3=NC2=C1 RXGJTUSBYWCRBK-UHFFFAOYSA-M 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
- 239000005995 Aluminium silicate Substances 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- GUBGYTABKSRVRQ-DCSYEGIMSA-N Beta-Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-DCSYEGIMSA-N 0.000 description 1
- 206010006143 Brain stem glioma Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 description 1
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 description 1
- 125000005915 C6-C14 aryl group Chemical group 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- ACTIUHUUMQJHFO-UHFFFAOYSA-N Coenzym Q10 Natural products COC1=C(OC)C(=O)C(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-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-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
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 101710096246 Dihydroorotate dehydrogenase (fumarate) Proteins 0.000 description 1
- 101710175803 Dihydroorotate dehydrogenase (quinone) Proteins 0.000 description 1
- 101710084265 Dihydroorotate dehydrogenase (quinone), mitochondrial Proteins 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 206010060742 Endocrine ophthalmopathy Diseases 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 208000003084 Graves Ophthalmopathy Diseases 0.000 description 1
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 206010052178 Lymphocytic lymphoma Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229920000715 Mucilage Polymers 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 238000007126 N-alkylation reaction Methods 0.000 description 1
- UQFQONCQIQEYPJ-UHFFFAOYSA-N N-methylpyrazole Chemical compound CN1C=CC=N1 UQFQONCQIQEYPJ-UHFFFAOYSA-N 0.000 description 1
- REYJJPSVUYRZGE-UHFFFAOYSA-N Octadecylamine Chemical compound CCCCCCCCCCCCCCCCCCN REYJJPSVUYRZGE-UHFFFAOYSA-N 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- 230000006819 RNA synthesis Effects 0.000 description 1
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- AZFNGPAYDKGCRB-XCPIVNJJSA-M [(1s,2s)-2-amino-1,2-diphenylethyl]-(4-methylphenyl)sulfonylazanide;chlororuthenium(1+);1-methyl-4-propan-2-ylbenzene Chemical compound [Ru+]Cl.CC(C)C1=CC=C(C)C=C1.C1=CC(C)=CC=C1S(=O)(=O)[N-][C@@H](C=1C=CC=CC=1)[C@@H](N)C1=CC=CC=C1 AZFNGPAYDKGCRB-XCPIVNJJSA-M 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 239000000370 acceptor Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000013564 activation of immune response Effects 0.000 description 1
- 102000011759 adducin Human genes 0.000 description 1
- 108010076723 adducin Proteins 0.000 description 1
- TTWYZDPBDWHJOR-IDIVVRGQSA-L adenosine triphosphate disodium Chemical compound [Na+].[Na+].C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O TTWYZDPBDWHJOR-IDIVVRGQSA-L 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 235000012501 ammonium carbonate Nutrition 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000947 anti-immunosuppressive effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 239000008122 artificial sweetener Substances 0.000 description 1
- 235000021311 artificial sweeteners Nutrition 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 150000001499 aryl bromides Chemical class 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- 239000010425 asbestos Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- 239000000022 bacteriostatic agent Substances 0.000 description 1
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 description 1
- 150000001556 benzimidazoles Chemical class 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical class C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 239000012964 benzotriazole Substances 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
- 230000033228 biological regulation Effects 0.000 description 1
- 230000001851 biosynthetic effect Effects 0.000 description 1
- 230000006696 biosynthetic metabolic pathway Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 1
- 210000000133 brain stem Anatomy 0.000 description 1
- 229950010231 brequinar Drugs 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 238000011095 buffer preparation Methods 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000002701 cell growth assay Methods 0.000 description 1
- 230000022534 cell killing Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000012054 celltiter-glo Methods 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 235000017471 coenzyme Q10 Nutrition 0.000 description 1
- ACTIUHUUMQJHFO-UPTCCGCDSA-N coenzyme Q10 Chemical compound COC1=C(OC)C(=O)C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UPTCCGCDSA-N 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- JCWIWBWXCVGEAN-UHFFFAOYSA-L cyclopentyl(diphenyl)phosphane;dichloropalladium;iron Chemical compound [Fe].Cl[Pd]Cl.[CH]1[CH][CH][CH][C]1P(C=1C=CC=CC=1)C1=CC=CC=C1.[CH]1[CH][CH][CH][C]1P(C=1C=CC=CC=1)C1=CC=CC=C1 JCWIWBWXCVGEAN-UHFFFAOYSA-L 0.000 description 1
- 210000000172 cytosol Anatomy 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 238000002784 cytotoxicity assay Methods 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 235000011850 desserts Nutrition 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- ZOCHARZZJNPSEU-UHFFFAOYSA-N diboron Chemical compound B#B ZOCHARZZJNPSEU-UHFFFAOYSA-N 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
- 230000004069 differentiation Effects 0.000 description 1
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Substances CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940079360 enema for constipation Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 238000001952 enzyme assay Methods 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 239000005454 flavour additive Substances 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 125000004438 haloalkoxy group Chemical group 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 125000004446 heteroarylalkyl group Chemical group 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
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000008309 hydrophilic cream Substances 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 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
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 150000002545 isoxazoles Chemical class 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
- 230000000670 limiting effect Effects 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 238000005461 lubrication Methods 0.000 description 1
- 201000011649 lymphoblastic lymphoma Diseases 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 208000020984 malignant renal pelvis neoplasm Diseases 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
- 230000010534 mechanism of action Effects 0.000 description 1
- 238000011177 media preparation Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000001525 mentha piperita l. herb oil Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- FZXQUCUWEZQIHL-UHFFFAOYSA-N methyl 2h-triazole-4-carboxylate Chemical compound COC(=O)C=1C=NNN=1 FZXQUCUWEZQIHL-UHFFFAOYSA-N 0.000 description 1
- RMZHRGOYCCXXNK-UHFFFAOYSA-N methyl 6-bromo-2-methylbenzotriazole-4-carboxylate Chemical compound BrC=1C=C(C=2C(=NN(N=2)C)C=1)C(=O)OC RMZHRGOYCCXXNK-UHFFFAOYSA-N 0.000 description 1
- 125000006533 methyl amino methyl group Chemical group [H]N(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 239000002324 mouth wash Substances 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 235000021096 natural sweeteners Nutrition 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
- 210000005036 nerve Anatomy 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 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
- 238000005457 optimization Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000011236 particulate material Substances 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 235000019477 peppermint oil Nutrition 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 239000004304 potassium nitrite Substances 0.000 description 1
- 235000010289 potassium nitrite Nutrition 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011241 protective layer Substances 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical group C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 239000002719 pyrimidine nucleotide Substances 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- NPCOQXAVBJJZBQ-UHFFFAOYSA-N reduced coenzyme Q9 Natural products COC1=C(O)C(C)=C(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)C(O)=C1OC NPCOQXAVBJJZBQ-UHFFFAOYSA-N 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 201000007444 renal pelvis carcinoma Diseases 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229910052895 riebeckite Inorganic materials 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 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
- 239000012748 slip agent Substances 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 208000017572 squamous cell neoplasm Diseases 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000000101 thioether group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 229940035936 ubiquinone Drugs 0.000 description 1
- 239000002691 unilamellar liposome Substances 0.000 description 1
- 201000000360 urethra cancer Diseases 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 229930195724 β-lactose Natural products 0.000 description 1
Classifications
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4192—1,2,3-Triazoles
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本發明提供用於在個體中治療癌症及用於抑制腫瘤或癌症細胞之腫瘤生長、轉移或二氫乳清酸氧合酶活性之方法。將至少一種具有式(I)之三取代苯并三唑衍生物投與該個體或與該癌細胞接觸。式(I)化合物及其醫藥學上可接受之鹽具有取代基R1
、R2
及R3
,該等取代基具有說明書中所給出之意義。
Description
本發明係關於新穎的式(I)之三取代苯并三唑衍生物,其為二氫乳清酸去氫酶之抑制劑。詳言之,本發明係關於抑制DHODH酶活性之新穎化合物;用於製造其等之方法及含有其等之醫藥組合物;以及其等用於治療及預防疾病或病症之用途,尤其在抑制DHODH方面存在優勢之疾病或病症中之用途。
DHODH為一種蛋白質,其可催化嘧啶核苷酸重新生物合成路徑中之一個步驟。(Greene等人 Biochem Pharmacol 1995, 50:861-7;Davis J.P等人 FASEB J 1996, 10(6): Abst C23)。其催化該路徑中唯一的氧化/還原反應,該反應為藉助於黃素輔因子及電子受體將DHO (二氫乳清酸)轉化成乳清酸之步驟。已發現二氫乳清酸去氫酶抑制劑具有作為化學治療劑之更廣泛應用。(Kensler等人 1989 於:Design of Enzyme Inhibitors as Drugs中;Sandler, M., 及Smith, H. J.編, 第379-401頁 Oxford Univ Press, 英國牛津(Oxford England);Cody等人 Am. J. Clin. Oncol. 16, 526-528 (1993))。 作為DHODH抑制劑之實例,喹啉衍生物布喹那(Brequinar) (6-氟-2-(2'-氟[1,1'-聯苯]-4-基)-3-甲基-4-喹啉羧酸)展現針對L1210鼠白血病之抗癌活性(Andreson LW.等人 Cancer Commun. 1989;1(6), 381-7;Chen SF.等人 Cancer Res. 1986 Oct;46(10): 5014-9)。亦展示布喹那藉由尿苷核苷酸池之組織特異性調節在鼠模型結腸38腫瘤中增強5-氟尿嘧啶抗腫瘤活性。(G Pizzorno等人 Cancer Res. 1992年4月1日;52:1660-5)。 DHODH抑制劑亦可用於治療病毒介導之疾病(參見US 6,841,561)。此外,已知抑制DHODH係治療移植排斥反應、類風濕性關節炎、牛皮癬以及自體免疫疾病之有前景的靶標(Kovarik, J. M.等人 Expert Opin. Emerg. Drugs 2003, 8, 47;Allison, A.C. Transplantation Proc. (1993) 25(3) 增刊2, 8-18);Makowka, L., Immunolog Rev. (1993) 136, 51-70;Davis J.P等人 Biochemistry 1996, 35: 1270-3)。 熟知的DHODH抑制劑來氟米特(Leflunomide)為目前市售之合成藥物,其為異噁唑類之低分子量藥物(參見EP0527736、JP1993506425、JP1999322700、JP1999343285、US5494911、US5532259、WO19991017748)且用於治療類風濕性關節炎,且亦在接受評估以用於治療發炎性腸病及慢性同種異體移植排斥反應。 來氟米特在活體內快速地轉化成其活性代謝物特立氟胺(Teriflunomide),特立氟胺經由未完全瞭解之機制發揮其抗發炎、抗增生及免疫抑制作用。特立氟胺不僅係活體內蛋白酪胺酸激酶之潛在抑制劑,而且係針對DHODH之強100-1,000倍的抑制劑(Davis J.P等人 FASEB J 1996, 10(6): Abst C23;Davis J.P等人 Biochemistry 1996, 35:1270-3)。 隨著患有自體免疫及相關疾病之患者數目上升,對於可更有效治療此類疾病之新藥物存在著未滿足的需求。仍然亟需可進一步用於廣泛多種自體免疫及慢性發炎疾病的免疫抑制劑,該等疾病包括全身性紅斑性狼瘡症、慢性類風濕性關節炎、多發性硬化症、I型糖尿病、發炎性腸病、膽汁性肝硬化、葡萄膜炎及其它病症,諸如克羅恩氏病、潰瘍性結腸炎、大皰性類天疱瘡、類肉瘤病、牛皮癬、自體免疫肌炎、韋格納氏肉芽腫病(Wegener's granulomatosis)、魚鱗癬、格雷夫斯眼病(Graves ophthalmopathy)、異位性皮膚炎及哮喘。該等免疫抑制劑亦可用作化學治療方案之部分,用於單獨或與熟習此項技術者熟知之抗腫瘤化合物組合治療癌症、淋巴瘤及白血病。
本發明係針對用於在需要此類治療之個體中治療癌症之方法。在一個實施例中,癌症選自:急性骨髓白血病、多發性骨髓瘤、B-前淋巴球性白血病、急性淋巴母細胞白血病、慢性淋巴球性白血病、霍奇金氏病、非霍奇金氏淋巴瘤、濾泡性淋巴瘤、彌漫性大B細胞淋巴瘤、間變性大細胞淋巴瘤、套細胞淋巴瘤、肺癌、乳癌、三陰性乳癌、黑色素瘤、神經膠母細胞瘤、前列腺癌、結腸癌、胰臟癌、骨癌、頭部或頸部癌症、皮膚癌、皮膚或眼內惡性子宮內膜、子宮頸癌、陰道癌、外陰癌、食道癌、小腸癌、內分泌系統癌、甲狀腺癌、副甲狀腺癌、腎上腺癌、軟組織肉瘤、尿道癌、陰莖癌、兒童實體腫瘤、淋巴球性淋巴瘤、膀胱癌、腎臟或輸尿管癌、腎盂癌瘤、中樞神經系統(CNS)腫瘤、原發性CNS淋巴瘤、腫瘤血管生成、脊軸腫瘤、腦幹神經膠質瘤、垂體腺瘤、卡波西氏肉瘤、表皮樣癌、鱗狀細胞癌、T細胞淋巴瘤、環境誘導之癌症及PTEN突變癌症。在另一實施例中,癌症選自急性骨髓白血病、多發性骨髓瘤、B-前淋巴球性白血病、非霍奇金氏淋巴瘤、彌漫性大B細胞淋巴瘤、間變性大細胞淋巴瘤、套細胞淋巴瘤、三陰性乳癌、黑色素瘤、前列腺癌及食道癌。方法包含以下步驟:一或多次向個體投與治療有效量之至少一種式(I)之化合物:或其醫藥學上可接受之鹽。在該結構中,環內的虛線[....]表示能夠以任何穩定組合存在之視情況選用之鍵。R1
可為氫及烷基。R2
可為-A-R4
。A可為伸芳基或四取代之伸芳基,其中取代基為鹵素。R3
可為羥基及胺基。R4
可為視情況經取代之芳基及視情況經取代之雜芳基。視情況選用之取代基可為一或多個R5
。R5
可為烷基及-(CH2
)n
N(Ra
)Rb
。Ra
及Rb
可獨立地為氫、烷基及-C(O)烷基,或替代地Ra
及Rb
可藉由其所連接之氮原子結合在一起以形成視情況經取代之4至6員雜環基,該雜環基含有0-2個獨立地選自O及N之另外的雜原子,其中視情況選用之取代基為烷基且『n』可為整數0及1。 本發明亦針對用於在個體中抑制腫瘤細胞之生長及/或轉移之方法。方法包含以下步驟:一或多次向個體投與治療有效量之至少一種式(I)之化合物:或其醫藥學上可接受之鹽。在該結構中,環內的虛線[....]表示能夠以任何穩定組合存在之視情況選用之鍵。R1
可為氫及烷基。R2
可為-A-R4
。A可為伸芳基或四取代之伸芳基,其中取代基為鹵素。R3
可為羥基及胺基。R4
可為視情況經取代之芳基及視情況經取代之雜芳基。視情況選用之取代基可為一或多個R5
。R5
可為烷基及-(CH2
)n
N(Ra
)Rb
。Ra
及Rb
可獨立地為氫、烷基及-C(O)烷基,或替代地Ra
及Rb
可藉由其所連接之氮原子結合在一起以形成視情況經取代之4至6員雜環基,該雜環基含有0-2個獨立地選自O及N之另外的雜原子,其中視情況選用之取代基為烷基且『n』可為整數0及1。 本發明進一步針對用於抑制腫瘤細胞中二氫乳清酸氧合酶活性之方法。該方法包含以下步驟:使腫瘤細胞與治療有效量之至少一種式(I)之化合物接觸一或多次:或其醫藥學上可接受之鹽。在該結構中,環內的虛線[....]表示能夠以任何穩定組合存在之視情況選用之鍵。R1
可為氫及烷基。R2
可為-A-R4
。A可為伸芳基或四取代之伸芳基,其中取代基為鹵素。R3
可為羥基及胺基。R4
可為視情況經取代之芳基及視情況經取代之雜芳基。視情況選用之取代基可為一或多個R5
。R5
可為烷基及-(CH2
)n
N(Ra
)Rb
。Ra
及Rb
可獨立地為氫、烷基及-C(O)烷基,或替代地Ra
及Rb
可藉由其所連接之氮原子結合在一起以形成視情況經取代之4至6員雜環基,該雜環基含有0-2個獨立地選自O及N之另外的雜原子,其中視情況選用之取代基為烷基且『n』可為整數0及1。
相關申請案之交叉參考
本申請案主張申請於2018年2月20日之美國專利申請案第15/899,707號及申請於2017年4月24日且現為美國專利第9,937,155號之美國專利申請案第15/494,820號的優先權,其皆以全文引用的方式併入本文中。在一個實施例中,本發明提供作為二氫乳清酸氧合酶抑制劑之三取代苯并三唑衍生物。 此等衍生物可作為藥劑適用於治療自體免疫及發炎性病症(諸如多發性硬化症、類風濕性關節炎)以及如癌症之疾病。 在一特定實施例中,本發明提供式(I)化合物,或其醫藥學上可接受之鹽,以及其醫藥學上可接受之區位異構物, 其中; 環內的虛線[....]代表可以任何穩定組合存在之視情況選用之鍵; R1
選自氫及烷基; R2
為-A-R4
; A為伸芳基或四取代之伸芳基;其中取代基為鹵素; R3
選自羥基及胺基; R4
選自視情況經取代之芳基及視情況經取代之雜芳基;其中視情況選用之取代基選自一或多個R5
; R5
選自烷基及-(CH2
)n
N(Ra
)Rb
; Ra
及Rb
獨立地選自氫、烷基及-C(O)烷基; 或者Ra
及Rb
可與其所連接之氮原子結合在一起以形成視情況經取代之4至6員雜環基,該雜環基含有0-2個獨立地選自O及N之另外的雜原子;其中視情況選用之取代基為烷基;且 『n』為選自0及1之整數。 以下實施例說明本發明且不意欲將申請專利範圍限制於所例示的具體實施例。 根據一個實施例,具體而言提供式(I)化合物,其中R1
為烷基;詳言之烷基為甲基。 根據另一實施例,具體提供式(I)化合物,其中R2
為-A-R4
;其中-A-選自伸芳基及四取代之伸芳基。 根據前述實施例,具體提供式(I)化合物,其中R2
選自。 根據前述實施例中之一者,具體提供式(I)化合物,其中R4
選自視情況經取代之苯基;其中視情況選用之取代基選自甲基、乙醯胺基、異丙基胺基甲基、甲胺基甲基、二甲胺基甲基、 。 根據前述實施例中之一者,具體提供式(I)化合物,其中R4
選自2,5-二甲基-1H-吡咯; 根據又一實施例,具體提供式(I)化合物,其中R3
為-OH及-NH2
。 根據又一具體實施例,式(I)化合物為式(Ia)化合物其中,虛線[---]、R1
、R3
及R4
與式(I)中所描述相同。 根據又一具體實施例,式(I)化合物為式(Ib)化合物其中,虛線[---]、R1
、R3
及R4
與式(I)中所描述相同。 在本發明之另一實施例中,提供用於製備式(I)之三取代苯并三唑衍生物的方法。 用於式(I)化合物之程序在本文中逐步地詳述於以下說明書中,其包括根據本發明製造化合物之方法有關的各種中間產物之通用合成。 更具體而言,本發明提供式(I)化合物或其醫藥學上可接受之鹽或區位異構物(包括其以所有比率之混合物)作為藥劑之用途,其用於藉由抑制二氫乳清酸氧合酶活性治療如多發性硬化症之病症及其他疾病,諸如發炎性病症、類風濕性關節炎及癌症。 本發明之式(I)之三取代苯并三唑衍生物具有抑制二氫乳清酸去氫酶(DHODH或DHOD)之治療性作用。式(I)化合物可用於治療及/或預防(但不限於)自體免疫及慢性發炎疾病,包括全身性紅斑性狼瘡症、慢性類風濕性關節炎、多發性硬化症、I型糖尿病、發炎性腸病、膽汁性肝硬化、葡萄膜炎及其它病症,諸如克羅恩氏病、潰瘍性結腸炎、大皰性類天疱瘡、類肉瘤病、牛皮癬、自體免疫肌炎、韋格納氏肉芽腫病、魚鱗癬、格雷夫斯眼病、異位性皮膚炎及哮喘。式(I)化合物及相關式亦可適用作化學治療方案之部分,用於單獨或與熟習此項技術者熟知之典型抗腫瘤化合物組合治療癌症、淋巴瘤及白血病。 在不限制本發明之範疇情況下,提供以下定義以便輔助熟習此項技術者理解本發明之實施方式。 「烷基」係指可為直鏈或分支鏈之含有指定碳原子數的烴鏈,例如C1
-C6
烷基在其中可具有1至6 (包括端點)個碳原子。C1
-C4
及C1
-C6
烷基之實例包括但不限於甲基、乙基、丙基、丁基、戊基、己基、異丙基、異丁基、第二丁基、第三丁基、異戊基、新戊基及異己基。烷基可為未經取代或經一或多個合適的基團取代。 「胺基」係指-N-基團,該基團之氮原子連接至氫、烷基、環烷基、芳基、雜環基或任何合適的基團。胺基之代表性實例包括但不限於-NH2
、-NHCH3
及-NH-環丙基。胺基可為未經取代或經一或多個合適的基團取代。 「芳基」係指視情況約6至14個碳原子之經取代之單環、雙環或多環芳族碳環系統。C6
-C14
芳基之實例包括但不限於苯基、萘基、聯二苯、蒽基、四氫萘基、茀基、茚滿基、伸聯苯基及苊基。芳基可為未經取代或經一或多個合適的基團取代。 「伸芳基」指示具有6至14個碳原子之二價單環或雙環、飽和、不飽和或芳族碳環,其可為未經取代或經一或多個合適的基團取代。 「鹵素」或「鹵基」包括氟、氯、溴或碘。 「羥基」係指-OH基團。 術語「雜環基」包括「雜環烷基」及「雜芳基」之定義。術語「雜環烷基」係指非芳族、飽和或部分飽和、單環或多環之3至10員環系統,其具有選自以下之至少一個雜原子或雜基團:O、N、S、S(O)、S(O)2
、NH及C(O)。例示性雜環烷基包括哌啶基、哌嗪基、嗎啉基、硫代嗎啉基、1,3-二氧戊環基、1,4-二氧雜環己烷基及類似者。雜環烷基可為未經取代或經一或多個合適的基團取代。 「雜芳基」係指含有選自氧、硫及氮之至少一個雜原子的不飽和、單環、雙環或多環芳環系統。C5
-C10
雜芳基之實例包括呋喃、噻吩、吲哚、氮雜吲哚、噁唑、噻唑、噻二唑、異噁唑、異噻唑、咪唑、N-甲基咪唑、吡啶、嘧啶、吡嗪、吡咯、N-甲基吡咯、吡唑、N-甲基吡唑、1,3,4-噁二唑、1,2,4-三唑、1-甲基-1,2,4-三唑、1H-四唑、1-甲基四唑、苯并噁唑、苯并噻唑、苯并呋喃、苯并異噁唑、苯并咪唑、N-甲基苯并咪唑、氮雜苯并咪唑、吲唑、喹唑啉、喹啉及異喹啉。雙環雜芳基包括其中苯基、吡啶、嘧啶或噠嗪環與5或6員單環雜環基環稠合之彼等基團,其具有環中一或兩個氮原子、一個氮原子連同環中一個氧或硫原子、或一個O或S環原子。雜芳基可為未經取代或經一或多個合適的基團取代。 「雜原子」係指硫、氮或氧原子。 如本文中所用,「視情況經取代或經取代」意指視情況經取代之基團之至少一個氫原子經合適的取代基取代,取代基如以下所例示但不限於:鹵素、硝基、氰基、羥基、側氧基(=O)、硫基(=S)、-N(C1
-C3
烷基)C(O)(C1
-C6
烷基)、-NHC(O)(C1
-C6
烷基)、-NHC(O)(環烷基)、-NHC(O)(芳基)、-NHC(O)(雜環基)、-NHC(O)(雜芳基)、-NHC(O)H、-C(O)NH2
、-C(O)NH(C1
-C6
烷基)、-C(O)NH(環烷基)、-C(O)NH(雜環基)、 -C(O)NH(雜芳基)、-C(O)N(C1
-C6
烷基)(C1
-C6
烷基)、-S(O)NH(C1
-C6
烷基)、-S(O)2
NH(C1
-C6
烷基)、-S(O)NH(環烷基), -S(O)2
NH(環烷基)、羧基、-C(O)O(C1
-C6
烷基)、-C(O)(C1
-C6
烷基)、=N-OH、經取代或未經取代之烷基、經取代或未經取代之鹵代烷基、經取代或未經取代之烷氧基、經取代或未經取代之鹵代烷氧基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之芳基、經取代或未經取代之芳烷基、經取代或未經取代之環烷基、經取代或未經取代之環烯基烷基、經取代或未經取代之環烯基、經取代或未經取代之胺基、經取代或未經取代之雜芳基、經取代或未經取代之雜環基、經取代或未經取代之雜芳基烷基、經取代或未經取代之雜環。 在不背離根據式(I)化合物所給出定義之範疇的情況下,本發明具體之化合物及源於式(I)之特定化合物概述於下文表中,其涵蓋在式(I)化合物內的化合物之全部範疇。
或其醫藥學上可接受之鹽或其醫藥學上可接受之區位異構物。 在又一實施例中本發明係關於用於治療發炎性病症及自體免疫疾病或過度活化免疫反應之式(I)化合物。更佳地,本發明係關於式(I)化合物用於治療多發性硬化症、類風濕性關節炎及移植排斥反應之用途。 本發明之其他實施例包括式(I)化合物或其醫藥學上可接受之衍生物、鹽及區位異構物(包括其以所有比率之混合物)作為藥劑之用途。 如上所述之化合物及其醫藥學上可用之衍生物、鹽及區位異構物(包括其以所有比率之混合物)用於製備供治療及/或預防二氫乳清酸去氫酶相關病症用之藥物的用途。 如上所述之化合物之用途,其中二氫乳清酸去氫酶相關病症為與過度活化免疫反應相關之自體免疫病症或病狀。 如上所述之化合物及其醫藥學上可用之衍生物、鹽及區位異構物(包括其以所有比率之混合物)用於製備供治療及/或預防免疫調節異常用之藥物的用途。 如上所述之化合物之用途,其中免疫調節異常為多發性硬化症或類風濕性關節炎。 如上所述之化合物用於製備供治療及防治癌症疾病、發炎性腸病或類風濕性關節炎用之藥物的用途。 在另一實施例中本發明係關於包含至少一種式(I)化合物及/或其醫藥學上可用之衍生物、鹽及區位異構物(包括其以所有比率之混合物),以及至少一種其他活性成分的醫藥調配物。 本發明進一步提供一種醫藥組合物,其包含至少一種式(I)化合物及/或其醫藥學上可用之衍生物、鹽及區位異構物(包括其以所有比率之混合物)、最終另一活性成分及賦形劑。 術語「醫藥學上可接受之鹽」或「醫藥學上可接受之衍生物」意謂包含呈其之一種鹽形式之式(I)化合物的活性成分,尤其在相較於活性成分之游離形式或活性成分先前所用之任何其他鹽形式,此種鹽形式賦予活性成分改良的藥物動力學性質的情況下。活性成分之醫藥學上可接受之鹽形式亦可使此活性成分首次具有其先前沒有的所需藥物動力學性質,且可甚至就其體內治療功效而論對此活性成分之藥物效應動力學具有積極影響。 術語「區位異構物(regioisomer/regioisomers)」係指位置異構物,其為結構異構物之一種類別,其中位置或取代基改變母結構上之位置。本文中術語區位異構物在不背離式(I)化合物本身之範疇的情況下,包括呈純區位異構物形式或其兩種或更多種區位異構物之混合物形式的所有區位異構物。由於本發明化合物之區位異構物之醫藥上活性可能不同,因此可能需要使用區位異構物。在此等情況下區位異構物可藉由熟習此項技術者熟知之方法在任何可能的階段中作為中間產物或作為終產物分離或甚至原樣用於合成中。式(I)化合物之區位異構物係指以下結構。 醫藥調配物可適用於經由任何所需合適方法投與,例如藉由經口(包括頰內或舌下)、經直腸、經鼻、局部(包括頰內、舌下或經皮)、經陰道或非經腸(包括皮下、肌肉內、靜脈內或皮內)方法。此類調配物可使用醫藥學領域已知之所有製程來製備,例如藉由將活性成分與一或多種賦形劑或佐劑組合來製備。 適用於經口投與之醫藥調配物可以離散單元投與,諸如膠囊或錠劑;粉末或顆粒;水性或非水性液體中之溶液或懸浮液;可食用發泡體或乳油甜點;或水包油液體乳液或油包水液體乳液。 舉例而言,在以錠劑或膠囊形式經口投與之情況下,活性成分組分可與經口、無毒且醫藥學上可接受之惰性賦形劑組合,諸如乙醇、甘油、水及類似者。粉劑藉由將化合物粉碎至合適的精細尺寸且將其與以類似方式粉碎之醫藥賦形劑(諸如可食用碳水化合物,諸如澱粉或甘露醇)混合來製備。調味劑、防腐劑、分散劑及染料同樣可存在。 膠囊由製備如上文所述之粉末混合物且用其充填成形的明膠外殼來製造。可將助滑劑及潤滑劑,諸如呈固體形式之高度分散矽酸、滑石、硬脂酸鎂、硬脂酸鈣或聚乙二醇,在填充操作之前添加至粉末混合物中。亦可添加崩解劑或增溶劑,諸如瓊脂、碳酸鈣或碳酸鈉,以便在已獲得膠囊之後改良藥劑之可用性。 此外,視需要或必要,亦可將合適的黏合劑、潤滑劑及崩解劑以及染料併入至混合物中。合適的黏合劑包括澱粉、明膠、天然糖(諸如葡萄糖或β-乳糖)、由玉米製備之甜味劑、天然合成橡膠合成橡膠(諸如阿拉伯膠、黃蓍或褐藻酸鈉)、羧甲基纖維素、聚乙二醇、蠟及類似者。用於此等劑型之潤滑劑包括油酸鈉、硬脂酸鈉、硬脂酸鎂、苯甲酸鈉、乙酸鈉、氯化鈉及其類似物。崩解劑包括而不限制於澱粉、甲基纖維素、瓊脂、膨潤土、黃原膠及類似者。錠劑藉由以下調配:例如製備粉末混合物,粒化或乾式壓製該混合物,添加潤滑劑及崩解劑且壓製整個混合物以得到錠劑。粉末混合物藉由以合適的方式將粉碎之化合物與以下混合來製備:如上文所述之稀釋劑或鹼、及視情況黏合劑(諸如羧甲基纖維素、海藻酸鹽、明膠或聚乙烯吡咯啶酮)、溶解阻滯劑(諸如石蠟)、吸收促進劑(諸如四級鹽)及/或吸收劑(諸如膨潤土、高嶺土磷酸二鈣)。粉末混合物可藉由用黏合劑(諸如糖漿、澱粉糊、阿卡迪亞膠(acadia mucilage)或纖維素之溶液或聚合物材料)使其潤濕且將其壓製通過篩來粒化。作為粒化之替代方案,可使粉末混合物穿過壓錠機,得到不均勻形狀之團塊,將其粉碎以形成顆粒。可藉助於添加硬脂酸、硬脂酸鹽、滑石或礦物油潤滑以防止顆粒黏著於造錠模具。潤滑之混合物隨後經壓製得到錠劑。活性成分亦可與自由流動之惰性賦形劑組合,且隨後直接壓製得到錠劑,而無需進行粒化或乾式壓製步驟。可存在由蟲膠密封層、糖或聚合物材料層及蠟之光澤層組成食物透明或不透明的保護層。可將染料添加至此等塗層中以便能夠區分不同的劑量單元。 經口液體,諸如溶液、糖漿及酏劑可呈劑量單元之形式製備,使得給定的數量包含預定量之化合物。糖漿可藉由使化合物與合適的調味劑溶解於水溶液中來製備,同時酏劑使用無毒醇性媒劑製備。懸浮液可藉由將化合物分散於無毒媒劑中調配。亦可添加增溶劑及乳化劑(諸如乙氧基化異硬脂醇及聚氧乙烯山梨醇醚)、防腐劑、調味添加劑(諸如薄荷油或天然甜味劑或糖精,或其他人工甜味劑)及類似者。 用於經口投與之劑量單元可視需要囊封在微膠囊中。調配物亦可以使得延長或延遲釋放之方式製備,諸如藉由聚合物、蠟及類似者塗佈或包埋粒狀材料。 新的式(I)之三取代苯并三唑衍生物及其醫藥學上可接受之鹽及其生理學上功能衍生物及另一活性成分亦可以脂質體遞送系統形式投與,諸如小型單層囊泡、大型單層囊泡及多層囊泡。脂質體可由合適的脂質或磷脂或兩者形成,諸如膽固醇、硬脂胺或磷脂醯膽鹼或類似者。 適用於經皮投與之醫藥調配物可以獨立硬膏劑形式投與,用於與接受者之表皮層延長、密切的接觸。因此,舉例而言,可將活性成分藉由離子電滲法自硬膏劑遞送,如以通用術語於Pharmaceutical Research, 3(6), 318 (1986)中所描述的。 適用於局部投與之醫藥化合物可調配為軟膏、乳膏、懸浮液、洗劑、散劑、溶液、糊劑、凝膠、噴霧劑、氣霧劑或油劑。 對於眼睛或其他外部組織,例如口腔及皮膚之處理,調配物較佳以局部軟膏或乳膏形式施用。在調配為軟膏之情況下,活性成分可與石蠟或水可混溶性乳膏基劑一起採用。或者,活性成分可藉由水包油乳膏基劑或油包水基劑調配以得到乳膏。 適用於局部施用至眼睛之醫藥調配物包括滴眼劑,其中活性成分溶解或懸浮於適合之載劑、尤其水性溶劑中。 適用於局部施用於口中之醫藥調配物涵蓋口含錠、片劑及漱口劑。 適用於直腸投與之醫藥調配物可以栓劑或灌腸劑形式投與。 其中載劑物質為固體的適用於經鼻投與之醫藥調配物包含粒徑例如在20-500微米範圍內之粗粉末,其以鼻吸之方式投與,亦即自靠近鼻部之含有粉末的容器經由鼻腔通道快速吸入。用於與作為載劑物質之液體以鼻用噴霧或鼻滴劑形式投與之合適的調配物涵蓋活性成分於水或油中之溶液。 適用於藉由吸入投與之醫藥調配物涵蓋精細粒子粉塵或噴霧,其可由具有噴霧器、霧化器或吹入器的各種類型之加壓分配器產生。 適用於經陰道投與之醫藥調配物可以子宮托、棉塞、乳膏、凝膠、漿料、發泡體或噴霧調配物形式投與。適用於非經腸投與之醫藥調配物包括水性及非水性無菌注射溶液,該等溶液包含抗氧化劑、緩衝液、抑菌劑及溶解物,調配物藉助於其呈現與待治療接受者之血液等滲;及水性及非水性無菌懸浮液,其可包含懸浮介質及增稠劑。調配物可以單次劑量或多次劑量容器形式(例如密封安瓿及小瓶)投與,且儲存在冷凍乾燥(凍乾)狀態,使得僅必需在使用之前立即添加無菌載劑液體(例如注射用水)。 根據配方製備之注射溶液及懸浮液可由無菌粉劑、顆粒及錠劑來製備。 不言而喻,除了以上特別提及之組分以外,根據調配物之具體類型,調配物亦可包含本領域中常用之其他藥劑;因此,例如適用於經口投與之調配物可包含調味劑。 式(I)化合物及另一活性成分之治療有效量視多種因素而定,包括例如動物之年齡及體重、需要治療之確切疾病情況及其嚴重程度、調配物之性質及投與方法,且最終由治療醫生或獸醫來確定。然而,有效量之化合物一般在每天0.1至100 mg/kg接受者(哺乳動物)體重之範圍內且尤其通常在每天1至10 mg/kg體重範圍內。因此,每天用於重量為70 kg之成人哺乳動物的實際量通常在70與700 mg之間,其中此量可每天以單獨劑量形式投與,或通常每天以一系列部分劑量(諸如兩次、三次、四次、五次或六次)投與,使得總日劑量相同。有效量之鹽或溶劑合物或其生理學上功能衍生物可作為化合物本身有效量之分數來確定。 在又一實施例中,本發明係關於用於在需要此類治療之個體中治療癌症之方法,其包含以下步驟:一或多次向個體投與治療有效量之本文所揭示夫人至少一種化合物或其醫藥學上可接受之鹽。 在又一實施例中,本發明係關於用於抑制個體中腫瘤細胞之生長及/或轉移之方法,其包含以下步驟:一或多次向個體投與治療有效量之如本文所揭示的至少一種化合物或其醫藥學上可接受之鹽。 在又一實施例中,本發明係關於用於抑制腫瘤細胞中二氫乳清酸氧合酶活性之方法,其包含以下步驟:使腫瘤細胞一或多次與治療有效量之如本文所揭示的至少一種化合物或其醫藥學上可接受之鹽接觸。在此實施例中,在體內、離體或體外接觸腫瘤細胞。 本文所揭示之化合物、其醫藥學上可接受之鹽及醫藥調配物及組合物可用於在需要此類治療之個體中治療癌症。同時,可抑制其中之腫瘤細胞生長及/或轉移或二氫乳清酸氧合酶活性。可一或多次投與化合物及醫藥組合物以達成治療效果。如本領域中已知,熟習此項技術者能夠很好地取決於待治療之病症及需要治療之個體來確定劑量、給藥方案及投與途徑。癌症之代表性實例包括血液惡性病,諸如但不限於急性骨髓白血病、多發性骨髓瘤、B-前淋巴球性白血病、急性淋巴母細胞白血病及慢性淋巴球性白血病。癌症之代表性實例包括淋巴瘤,諸如但不限於霍奇金氏病、非霍奇金氏淋巴瘤、濾泡性淋巴瘤、彌漫性大B細胞淋巴瘤、間變性大細胞淋巴瘤及套細胞淋巴瘤。癌症之代表性實例包括固體癌症,諸如但不限於肺癌、乳癌、三陰性乳癌、黑色素瘤、神經膠母細胞瘤、前列腺癌、結腸癌、胰臟癌、骨癌、頭部或頸部癌症、皮膚癌、皮膚或眼內惡性子宮內膜、子宮頸癌、陰道癌、外陰癌、食道癌、小腸癌、內分泌系統癌、甲狀腺癌、副甲狀腺癌、腎上腺癌、軟組織肉瘤、尿道癌、陰莖癌、兒童之實體腫瘤、淋巴球性淋巴瘤、膀胱癌、腎臟或輸尿管癌症、腎盂癌瘤、中樞神經系統(CNS)腫瘤、原發性CNS淋巴瘤、腫瘤血管生成、脊軸腫瘤、腦幹神經膠質瘤、垂體腺瘤、卡波西氏肉瘤、表皮樣癌症、鱗狀細胞癌症、T細胞淋巴瘤、環境誘導之癌症(包括由石棉誘導之彼等癌症)及PTEN突變癌症。 在另一態樣中,本發明係關於用於製備式(I)之三取代苯并三唑衍生物的製程。 根據式(I)之二氫乳清酸去氫酶抑制劑可由容易獲得的起始物質使用以下通用方法及程序來製備。應瞭解,在給定典型或較佳之實驗條件(亦即反應溫度、時間、試劑之莫耳、溶劑等)情況下,除非另外說明,否則亦可使用其他實驗條件。雖然最佳反應條件可隨所用特定反應物或溶劑而變化,但該等條件可由熟習此項技術者使用常規最佳化程序來確定。此外,藉由利用詳細描述之程序,一般熟習此項技術者可製備本文中所主張之另外的本發明化合物。除非另外指出,否則所有溫度為攝氏度(℃)。 在另一態樣中,本發明化合物亦可在構成此類化合物之一或多個原子處含有非天然比例之原子同位素。舉例而言,本發明亦涵蓋經同位素標記之本發明之變型,其與本文中列舉之彼等一致,除了化合物之一或多個原子由原子質量或質量數與自然界中通常存在之原子的主要原子質量或質量數不同的原子置換。指定之任何特定原子或元素之所有同位素均涵蓋於本發明化合物之範疇及其用途內。可併入本發明化合物中之例示性同位素包括氫、碳、氮、氧、磷、硫、氟、氯及碘之同位素,諸如2
H (「D」)、3
H、11
C、13
C、14
C、13
N、15
N、15
O、17
O、18
O、32
P、33
P、35
S、18
F、36
Cl、123
I及125
I。經同位素標記之本發明化合物一般可藉由遵循與下文流程及/或實例中所揭示者類似的程序,藉由用經同位素標記之試劑取代未經同位素標記之試劑來製備。 以下縮寫對應地指以下定義: AcOH (乙酸)、ACN (乙腈)、ATP (腺苷三磷酸)、BSA (牛血清白蛋白)、CHCl3
(氯仿)、Cs2
CO3
(碳酸銫)、DCM (二氯甲烷)、DIPEA (二異丙基乙胺)、DMSO (二甲亞碸)、DMF (N, N-二甲基甲醯胺)、EDCI.HCl (鹽酸1-乙基-3-(3-二甲胺基丙基)碳化二亞胺)、Et3
N (三乙胺)、EtOAc (乙酸乙酯)、EtOH (乙醇)、HOBT (羥基苯并三唑)、HCl (鹽酸)、K2
CO3
(碳酸鉀)、KOAc (乙酸鉀)、min (分鐘)、MeOH (甲醇)、MeI (碘甲烷)、MgSO4
(硫酸鎂)、NH4
Cl (氯化銨)、NH4
(CO3
)2
(碳酸銨)、Pd(dppf)2
Cl2
([1,1-雙(二苯膦基)-二茂鐵]二氯鈀(II))、NaH (氫化鈉)、NaNO2
(亞硝酸鈉)、NaHCO3
(碳酸氫鈉)、PetEther (石油醚)、PBS (磷酸鹽緩衝鹽水)、RT-室溫(25℃-35℃)、TEA (三乙胺)、TFA (三氟乙酸)、THF (四氫呋喃)、t-BuOK
(第三丁醇鉀)、TMSI (三甲基矽烷基碘)、TLC (薄層層析法)、H2
O-水;mL-毫升、hr/h-小時;N-當量濃度;M-莫耳濃度;s-單峰;d-二重峰;t-三重峰;m-多重峰;1
HNMR-質子核磁共振;MS-質譜法;LC-液相層析;HPLC-高效液相層析法,J
-耦合常數;1
H-質子;MHz-兆赫茲(頻率);Hz-赫茲;ppm-百萬分之一;bs-寬單峰;ES-電子噴霧;濃(Conc.)-濃縮;g-克;mmol或mM-毫莫耳;μM-微莫耳;nM-毫微莫耳;UV-紫外線;℃-攝氏度,M+
-分子態離子,%-百分比;μ-微米;及δ-差量(Delta);anh.-無水;pH-酸鹼度(potential of Hydrogen); 提供可用於製造式(I)化合物之方法的本發明之另一實施例闡述於以下實例中且概括於流程-I中。熟習此項技術者應認識到流程I可用於製造根據本發明之式(I)化合物及式(I)化合物的醫藥學上可接受之鹽。除非另外說明,否則其中所有符號/變量如前文所定義。方法由流程-I表示:本發明之化合物可使用流程I中說明之合成轉化作用製備。起始物質為市售的,可藉由本文所描述之程序、藉由文獻程序或藉由熟習有機化學技術者將熟知之程序製備。起始物質5-經取代甲基2,3-二胺-苯甲酸酯藉由WO 2010115736A2中所描述之程序製備。 步驟-a:使化合物-i與亞硝酸鈉在酸性介質中使用通用程序-A反應,獲得化合物-ii。 步驟-b:化合物-ii進一步使用碘甲烷在諸如通用程序-B中所描述之彼等鹼性條件下經歷N-烷化,獲得式-iii化合物。 步驟-c:使式-iii化合物與雙頻哪醇二硼(bispinacolate diboran)在鹼性條件下在合適的鈀催化劑存在下使用通用程序-C反應,獲得式-iv化合物。 步驟-d:將式-iv化合物用經取代芳基鹵化物在合適的鈀催化劑存在下使用諸如通用程序-D中所描述之彼等條件處理,獲得式-v化合物。 步驟-e:或者,式-v化合物可由式-iii化合物藉由使用適當的硼酸,在諸如通用程序-D中所描述之彼等合適的條件下製備。 步驟-f:所得式-v化合物在諸如通用程序-F中所描述之彼等鹼性條件下經歷酯水解,獲得式(I)化合物(其中R3
=OH)。 步驟-g:將式(I)之羧酸用氯化銨使用通用程序-G中所描述之條件處理,獲得對應的式(I)化合物(其中R3
=NH2
)。 若以上通用合成方法之集合不適用於獲得根據式(I)之化合物及/或用於合成式(I)化合物之必需中間產物,則應使用熟習此項技術者已知的合適製備方法。大體而言,任何單獨式(I)化合物之合成路徑將取決於各分子之具體取代基以及取決於必需中間產物之易獲得性;同樣,此類因素為一般技術者所瞭解的。 與溶劑分子結合之本發明化合物可藉由自合適溶劑蒸發之結晶來分離。含有鹼性中心的式(I)化合物之醫藥學上可接受之酸加成鹽可以習知方式製備。舉例而言,可將游離鹼之溶液用合適的酸(純酸或以合適的溶液形式)處理,且所得鹽藉由過濾或藉由在真空中蒸發反應溶劑來分離。醫藥學上可接受之鹼加成鹽可為以類似方式藉由用合適的鹼處理式(I)化合物之溶液來獲得。兩種類型之皆可使用離子交換樹脂技術形成或互相轉化。 雖然本發明藉由某些以下實施例來說明,但不應理解為藉此受到限制;相反地,本發明涵蓋如上文所揭示之通用領域。可在不背離其精神及範疇之情況下進行各種修改及具體實例。實例 概要 :
如下獲得下文所述之實例中提供的MS資料:質譜:LC/MS Waters ZMD (ESI)或Waters Acquity SQD (ESI)。 下文所述之實例中所提供的NMR資料如下獲得:1
H-NMR:Bruker DPX-300MHz或Bruker DPX 400 MHz。 下文所述之實例中所提供的HPLC資料如下獲得。 條件A:柱Waters XbridgeTM
C8
50 mm x 4.6 mm,流量為2 mL/min;8 min梯度自含0.1%TFA之H2
O至含0.07%TFA之CH3
CN。 條件B:C18 BDS (4.6X250) mm,SC\244流量為0.7 mL/min;10 min梯度自含0.1% TFA之H2
O至CH3
CN。 製備型HPLC條件:柱-Zorbax Eclipse XDB C18 PrepHT (150 X 21.2mm, 5µ);移動相:(A) 0.01%TFA或0.1%TFA;(B) ACN或ACN: MeOH (1:1);流量:20 ml/min。 除非另外報導,否則使用來自Waters且裝備有Sunfire Prep C18 OBD管柱19 × 100 mm 5 µm的質量引導之自動純化Fractionlynx進行製備型HPLC純化。所有HPLC純化藉由ACN/H2
O或ACN/H2
O/HCOOH (0.1%)之梯度進行。 本發明之化合物已根據來自「Advanced Chemistry Development Inc.,ACD/實驗室(7.00發佈」的程式ACD/Name Batch中所使用之標準來命名。產品版本:7.10 構建:2003年9月15日。 式(I)化合物之程序詳述於下文通用程序,包括與製造根據本發明化合物之製程有關的各種中間產物之通用合成。通用程序 -A : 製備經取代 [1,2,3] 苯并三唑
向含有於乙酸中之6-經取代二胺酯或經取代二胺酯(1-3當量)攪拌10-20分鐘,較佳10分鐘,隨後添加於水中之(亞硝酸鈉、亞硝酸鉀,較佳亞硝酸鈉) (2.5至3.5當量,較佳2.5當量)。在室溫下將反應混合物攪拌1至2小時、較佳1小時。分離之固體藉由過濾採集且在真空下乾燥,獲得目標產物。通用程序 -A 之 說明性實例: 製備編號 A.1 : 6- 溴 -1H- 苯并 [d][1,2,3] 三唑 -4- 甲酸甲酯之合成 : 將2,3-二胺-5-溴苯甲酸甲酯(1.0 g,4.08 mmol)於乙酸(15 mL)中之溶液(參考:WO2010/115736 A2)在室溫下攪拌10分鐘。添加於水(2 mL)中之亞硝酸鈉(0.309 g,4.48 mmol)且在室溫下攪拌反應混合物約30分鐘。沈澱固體經過濾,用水洗滌且在真空下乾燥,獲得所需產物(0.8 g,77%);1
H NMR (400 MHz, DMSO-d6):δ 16.19 (s, 1H), 8.70 (s, 1H), 8.14 (s, 1H), 3.99 (s, 3H)且LC-MS m/z: 258 (M+H)+
。通用程序 -B :經取代苯并三唑之 N- 烷化
向經取代苯并三唑-甲酸酯衍生物(1當量)於有機溶劑(諸如DMF、THF、二噁烷,較佳DMF)之攪拌溶液中添加合適的鹼(諸如K2
CO3
、CS2
CO3
、NaH等,較佳K2
CO3
,2至5當量,較佳2當量),隨後添加烷基鹵化物(2至5當量,較佳3當量)。室溫攪拌反應混合物約1至10小時 (較佳3小時)。將反應混合物倒入至冰冷的水中且分離之固體藉由過濾採集且在真空下乾燥。區位異構物由管柱層析法分離,獲得所需產物。通用程序 -B 之 說明性實例 : 製備編號 B.1 : 5- 溴 -1- 甲基 -1H- 苯并 [d][1,2,3] 三唑 -7- 甲酸甲酯、 6- 溴 -2- 甲基 -2H- 苯并 [d][1,2,3] 三唑 -4- 甲酸甲酯及 6- 溴 -1- 甲基 -1H- 苯并 [d][1,2,3] 三唑 -4- 甲酸甲酯之合成 向6-溴-1H-苯并[d][1,2,3]三唑-4-甲酸甲酯(4.5 g,17.5 mmol,製備編號A.1)於DMF (25 mL)中之攪拌溶液中添加碳酸鉀(4.85 g,35.15 mmol),隨後添加碘甲烷(7.48 g,52.73 mmol)。在室溫下將反應混合物攪拌1小時。將反應混合物用冰冷的水(100 mL)淬滅且分離之固體藉由過濾採集,在真空下乾燥。所獲得之粗化合物藉由管柱層析法經矽膠(100-200篩目)使用含於己烷中之10%乙酸乙酯純化,得到異構物-I(B.1.a) (1.9 g);1
H NMR(400 MHz,CDCl3
) δ 8.40 (s, 1H), 8.22 (s, 1H), 4.57 (s, 3H), 4.01 (s, 3H)且LC-MS m/z: 272 (M+2)+
;用含於己烷中之15-20%乙酸乙酯純化得到異構物-II (B.1.b) (1.4 g);1
H NMR (400 MHz, CDCl3
) δ 8.26 (s, 1H), 8.23 (s, 1H), 4.58 (s, 3H), 4.04 (s, 3H)且LC-MS m/z: 272.0 (M+2)+
;用含於己烷中之20-25%乙酸乙酯純化,得到異構物-III (B.1.c) (1.0 g):1
H NMR (400 MHz, DMSO-d6
): δ 8.67 (s, 1H), 8.13 (s, 1H), 4.45 (s, 3H), 3.96 (s, 3H)且LC-MS m/z: 272.0 (M+2)+
。通用程序 -C : 製備硼酸酯
將芳基鹵基衍生物(1.0至3.0當量,較佳1.0當量)、合適的無機鹼(諸如KOAC或Na2
CO3
或K2
CO3
或Cs2
CO3
,較佳KOAC)、雙頻哪醇二硼烷(1.0至3.0當量,較佳1.1當量)於二噁烷中之混合物用氮脫氣約10至15分鐘且添加[1,1-雙(二苯膦基)-二茂鐵]二氯鈀(II) (0.001至0.010當量,較佳0.05當量)。將反應混合物在回流溫度下在氮氣下攪拌約3小時至12小時 (較佳約6小時)。使反應混合物冷卻至室溫且在減壓下蒸發至乾燥。將所獲得殘留物再溶解於EtOAc中,接連用水及鹽水溶液洗滌。有機溶液經Na2
SO4
乾燥,過濾且減壓濃縮。產物藉由結晶或自一或多種合適溶劑研磨或藉由製備型HPLC急驟層析法來純化。通用程序 -C 之說明性實例: 製備編號 C.1 : 1- 甲基 -5-(4,4,5,5- 四甲基 -1,3,2- 二氧硼㖦 -2- 基 )-1H- 苯并 [d][1,2,3] 三唑 -7- 甲酸甲酯之合成 將5-溴-1-甲基-1H-苯并[d][1,2,3]三唑-7-甲酸甲酯(1.0 g,3.7 mmol,製備編號B.1.a)、乙酸鉀(0.627 g,5.92 mmol)、雙頻那醇二硼烷(0.93 g,3.7 mmol)於二噁烷(60 mL)中之混合物用氮脫氣約15分鐘且添加[1,1-雙(二苯膦基)-二茂鐵]二氯鈀(II) (0.151 g,0.018 mmol)。在回流溫度下在氮氣下攪拌反應混合物6小時。使反應混合物冷卻至室溫且在減壓下蒸發至乾燥。將所獲得殘留物再溶解於EtOAc中,接連用水及鹽水溶液洗滌且濃縮。所獲得之粗化合物藉由管柱層析法經矽膠(60-120篩目)使用於己烷中之30%乙酸乙酯純化,得到所需產物(0.9 g,77%);1
H NMR (400 MHz, DMSO-d6): δ 8.46 (s, 1H), 8.31 (s, 1H), 4.59 (s, 3H), 3.94 (s, 3H), 1.35 (s, 12H)且LC-MS m/z = 318.2 (M+H)+
。 使用通用程序C合成之其他化合物描述於表C.1中通用程序 -D : 鈴木反應 (Suzuki Reaction)
將乙腈及水(8:2)之混合物用氮氣脫氣約10至15分鐘,隨後添加合適的鹼(諸如Na2
CO3
或K2
CO3
或Cs2
CO3
,較佳Na2
CO3
),隨後添加芳基溴基衍生物(1.0至3.0當量,較佳1.0當量)及適當的硼酸(1.0至3.0當量,較佳1.5當量)。再次將反應混合物脫氣15分鐘且最終添加[1,1-雙(二苯膦基)-二茂鐵]二氯鈀(II)(添加0.001至0.010當量,較佳0.05當量)。將反應混合物在回流溫度下在氮氣下攪拌約3小時至12小時(較佳約4小時)。使反應混合物冷卻至室溫且在減壓下蒸發至乾燥。將所獲得殘留物再溶解於EtOAc中,接連用水及鹽水溶液洗滌。有機溶液經Na2
SO4
乾燥,過濾且減壓濃縮。產物藉由結晶或自一或多種合適溶劑研磨或藉由製備型HPLC急驟層析法來純化。通用程序 -D 之說明性實例 : 製備編號 D.1 : 1- 甲基 -5-(2'- 甲基 -[1,1'- 聯苯 ]-4- 基 )-1H- 苯并 [d][1,2,3] 三唑 -7- 甲酸甲酯之合成 將乙腈(80 mL)及水(15 mL)之混合物用氮氣脫氣10分鐘。添加碳酸鈉(2.74 g,25.9 mmol),隨後添加5-溴-1-甲基-1H-苯并[d][1,2,3]三唑-7-甲酸甲酯(3.5 g,12.9 mmol)及4,4,5,5-四甲基-2-(2'-甲基-[1,1'-聯苯]-4-基)-1,3,2-二氧硼㖦(3.81 g,12.0 mmol) (C.1.5)。再次將反應混合物脫氣15分鐘。最終添加[1,1-雙(二苯膦基)-二茂鐵]二氯鈀(II) (0.526 g,0.64 mmol)。在回流溫度下在氮氣下攪拌反應混合物5小時。使反應混合物冷卻至室溫且在減壓下蒸發至乾燥。將所獲得殘留物再溶解於EtOAc中,接連用水及鹽水溶液洗滌且濃縮。所獲得之粗化合物藉由管柱層析法經矽膠(60-120篩目)使用於己烷中之30%乙酸乙酯純化,得到所需產物(3.6 g,77%);1
H NMR (400 MHz, CDCl3
): δ 8.52 (s, 1H), 8.31 (s, 1H), 7.76-7.74 (d, J=8.0 Hz, 2H), 7.48-7.46 (d, J=7.6, 2H), 7.31-7.28 (m, 4H), 4.63 (s, 3H), 4.08 (s, 3H), 2.34 (s, 3H)且LC-MS m/z = 358.2 (M+H)+
。 使用通用程序D合成之其他化合物描述於表D.1中。通用程序 -E : 還原胺化
將適當的醛及胺於有機溶劑(諸如DCM、THF、ACN、DMF、DCE或二噁烷)之混合物在室溫下攪拌30分鐘至4小時。使所得反應混合物冷卻至0℃且以小份添加還原劑(諸如三乙醯氧基硼氫化鈉),隨後添加催化量之乙酸。在室溫下攪拌所得反應混合物2-4小時。藉由TLC監測反應進展,且用碳酸氫鈉水溶液淬滅反應混合物。其進一步用乙酸乙酯萃取,將經合併之有機層經硫酸鈉乾燥且在真空下濃縮,獲得目標化合物。視情況,目標化合物可藉由結晶或自一或多種合適溶劑研磨、或藉由製備型HPLC或急驟層析法來純化通用程序 -E 之說明性實例 : 製備編號 E.1 : 1- 甲基 -5-(2'-((N- 嗎啉基 ) 甲基 )-[1,1'- 聯苯 ]-4- 基 )-1H- 苯并 [d] [1,2,3] 三唑 -7- 甲酸甲酯之合成 將5-(2'-甲醯基-[1,1'-聯苯]-4-基)-1-甲基-1H-苯并[d][1,2,3]三唑-7-甲酸甲酯(0.300 g,0.8 mmol,D.1.8)及嗎啉(0.070 g,0.8 mmol)於DCE (15 mL)中之溶液在室溫下攪拌30分鐘。使反應混合物冷卻至0℃,添加三乙醯氧基硼氫化鈉(0.342 g,1.6 mmol),隨後添加乙酸(0.2 mL)。反應混合物在室溫下攪拌2小時。將反應混合物用碳酸氫鈉水溶液淬滅(50 mL)。其用乙酸乙酯萃取(3 × 50 mL),經合併之有機層經硫酸鈉乾燥且在減壓下濃縮。所獲得之粗產物不經純化即用於下一步驟(0.200 g);1
H NMR (400 MHz, DMSO-d6
): δ 8.69 (s, 1H), 8.696 (s, 1H), 8.424-8.422 (d, J=8 Hz, 2H), 7.912-7.891 (d, J=8 Hz, 2H), 7.607 (m, 1H), 7.531-7.324 (m, 3H), 4.50 (s, 3H), 4.0 (s, 3H), 3.560 (m, 4H), 3.55 (s, 2H), 3.308 (m, 4H)且LC-MS m/z = 443.3 (M+H)+
。通用程序 -F : 酯水解
向含有含於水性有機溶劑(諸如THF或甲醇、1,4二噁烷,較佳1,4二噁烷)之適當烷基酯之燒瓶中添加1.5當量氫氧化鈉水溶液且使反應混合物回流1至8小時 (較佳4小時)。藉由TLC監測反應之完成。將過量溶劑在真空下移除且用10% HCl溶液酸化溶液。分離之固體藉由過濾採集且在真空下乾燥,獲得目標羧酸衍生物。視情況,目標化合物可藉由結晶或自一或多種合適溶劑研磨、或藉由製備型HPLC或急驟層析法來純化通用程序 -F 之說明性實例 : 實例編號 1 : 1- 甲基 -5-(2'- 甲基 - [1,1'- 聯苯 ]-4- 基 )-1H- 苯并 [d] [1,2,3] 三唑 -7- 羧酸 ( 化合物 -1) 之合成 向1-甲基-5-(2'-甲基-[1,1'-聯苯]-4-基)-1H-苯并[d][1,2,3]三唑-7-甲酸甲酯(1.2 g,3.361 mmol,D.1)於1,4二噁烷(15 mL)之攪拌溶液中添加2 N NaOH水溶液(15 mL)。使反應混合物回流持續4小時。在反應完成之後,使反應混合物冷卻至室溫,減壓移除過量溶劑且溶液用10% HCl溶液(pH約2)酸化。分離之固體藉由過濾採集且在真空下乾燥,得到呈灰白色固體之標題化合物(1.1 g,95%);1
H NMR (400 MHz, DMSO-d6): δ 13.35 (bs, 1H), 8.52 (s, 1H), 8.38 (s, 1H), 7.89-7.87 (d, J=8.0 Hz, 2H), 7.51-7.49 (d, J=8.4 Hz, 2H), 7.32-7.25 (m, 4H), 4.58 (s, 3H) 2.30 (s, 3H)且LC-MS m/z = 344.1 (M+H)+
。通用程序 -G :醯胺化反應
向含有含於有機溶劑(諸如DMF、THF或CH2
Cl2
)中之適當羧酸衍生物(1.0當量)的燒瓶中添加EDCI.HCl (1.5當量)、HOBT (1.5當量)及N-
乙基-N
-異丙基丙-2-胺(3當量)。在大致25℃下攪拌約10分鐘之後,添加適當的胺(1.5當量)且另外攪拌反應物8至12小時(較佳12小時)。分離之固體在添加水之後藉由過濾採集且在真空下乾燥,獲得目標醯胺衍生物。視情況,所獲得化合物可藉由結晶或自一或多種合適溶劑研磨、或藉由製備型HPLC或急驟層析法來純化通用程序 -G 之說明性實例 : 實例編號 2 : 1- 甲基 -5-(2'- 甲基 -[1,1'- 聯苯 ]-4- 基 )-1H- 苯并 [d][1,2,3] 三唑 -7- 甲醯胺 ( 化合物 -2) 之合成 向含有含於DMF (3 mL)中之1-甲基-5-(2'-甲基-[1,1'-聯苯]-4-基)-1H-苯并[d][1,2,3]三唑-7-羧酸(0.150 g,0.43 mmol,化合物-1)的燒瓶中添加EDCI.HCl (0.100 g,0.52 mmol)、HOBT (0.070 g,0.52 mmol)及N-
乙基-N-異丙基丙-2-胺(0.168 g,1.31 mmol)。混合物在約25℃下攪拌大致10分鐘且添加氯化銨(0.070 g,1.31 mmol)。隨後再攪拌反應物約12小時且用水(50 mL)淬滅。分離之固體藉由過濾採集且在真空下乾燥,得到呈灰白色固體之所需化合物(0.08 g,53%);1
H NMR (400 MHz, DMSO-d6): δ 8.47 (s, 1H), 8.37 (s, 1H), 8.05 (s, 1H), 8.00 (s, 1H), 7.90-7.88 (d, J=8.0 Hz, 2H), 7.51-7.49 (d, J=7.6 Hz, 2H), 7.35-7.27 (m, 4H), 4.61 (s, 3H), 2.30 (s, 3H)且LC-MS m/z = 343.2 (M+H)+
。 以下中間產物藉由與通用程序-C中所描述者類似的程序製備,其中反應物、試劑之數量及反應條件適當變化。化合物之生理化學特徵概述於下文表C.1中。 表C.1.
以下中間產物藉由與通用程序-D中所描述者類似的程序製備,其中反應物、試劑之數量及反應條件適當變化。化合物之生理化學特徵概述於下文表-D.1中。 表D.1.
以下化合物藉由與通用程序-E、F及G中所描述者類似的程序製備,其中反應物、試劑之數量及反應條件適當變化。化合物之生理化學特徵概述於下文表中。 藥理學活性 DHODH 抑制酶活性之量測 ( 體外分析 )
DHODH活性分析為結合酶分析,其中DHO之氧化及泛醌之隨後還原在化學計量上等效於DCIP (2,6-二氯苯酚)之還原。DCIP之還原伴隨著610 nm下之吸收損失。 製備溶液/試劑: 緩衝液製備:50 mM tris HCl,150 mM KCl,以及pH 8.0,0.8%特立通(triton)。 於緩衝液中之20 mM L-二氫乳清酸儲備溶液。 於緩衝液中之20 mM 2,6-二氫乳清酸鈉鹽水合物儲備溶液。 於緩衝液中之20 mM癸基泛醌儲備溶液。 DMSO用作媒劑。程序
將含5 µL二甲亞碸或式(I)化合物之DMSO溶液添加至96孔板之孔中。式(I)化合物量測處於10 µM。 添加蛋白以及緩衝液,使得包括DMSO之總體積為87 µL。在混合之後將化合物及蛋白在室溫下培育半小時。5 µL之20 mM L-二氫乳清酸溶液、5 µL之2 mM癸基泛醌溶液及3 µL之2 mM 2,6-二氯酚靛鈉鹽水合物溶液添加至以上溶液(總分析體積100 µL)。將混合物攪拌2分鐘且每10分鐘記錄610奈米下之吸收。 按以下計算抑制百分比:
含有化合物之反應具有化合物、緩衝液、酶及受質 陽性對照含有DMSO、緩衝液、酶及受質 無酶反應含有DMSO、緩衝液及受質IC50 測定
製備待檢驗的所選擇之本發明三取代苯并咪唑及式(I)之苯并三唑衍生物之2 mM DMSO儲備溶液。隨後製得1/3稀釋液。 5 µL式(I)化合物之各儲備液用於各100 µL分析。因此,在由緩衝液、蛋白及受質製造時,5 µL之2 mM儲備液提供100 µL之100 µM式(I)化合物溶液。亦參見:Ulrich 等人 (2001) Eur. J. Biochem.268, 1861-1868
。 所選擇之本發明化合物的IC50
值提供於以下表中,展現IC50
值 ≤ 0.1 µM之化合物分組為『a』,展現IC50
值在0.101 µM至1.0 µM範圍內之化合物分組為『b』且展現IC50
值 > 1.0 µM之化合物分組為『c』。 表:所選擇化合物之DHODH抑制活性。 基於細胞之活性 拉莫斯 (Ramos) 增殖分析 ( 體外分析 )
細胞增殖分析為用於在細胞毒性或增殖分析中定量活細胞之敏感方法。XTT (2,3-雙[2-甲氧基-4-硝基-5-磺基苯基]-2H-四唑鎓-5-羧基苯胺內鹽)系統為經由粒線體脫氫酶量測活細胞之活性的方法。活細胞之粒線體脫氫酶分解XTT之四唑鎓環,產生可溶於水性溶液之橙色甲臢(formazan)晶體。XTT溶液藉由將電子偶合劑(吩嗪硫酸甲酯(PMS))添加至反應來增強。所得橙色以分光光度法量測處於450 nm。細胞數目之增加或降低導致所形成甲臢之量的相應變化,指示由測試材料造成之細胞毒性程度。製備溶液 / 試劑 介質製備
將17.7 g IMDM (伊斯科夫氏(Iscove's)改質杜爾貝科氏(Dulbecco's)培養基)粉末、1.5 g 碳酸氫鈉pH 7.2-7.4溶解於1 L MiliQ水中,添加1%青黴素/鏈黴素及10% FBS。 將10.6 g漢姆氏(Ham's) F12粉末、1.5 g碳酸氫鈉pH 7.2-7.4溶解於1L MiliQ水中,添加1%青黴素/鏈黴素。 DMSO用作媒劑。 1×PBS (磷酸鹽緩衝鹽水):將5個PBS錠劑(西格瑪(Sigma):目錄號P4417)溶解於1L MiliQ水中。程序
(IC50 測定
)使拉莫斯細胞再懸浮於完整IMDM培養基中至1x105
個細胞/毫升之密度。將95 µL此細胞懸浮液添加至96孔板以接種約每孔10,000個細胞。在添加化合物之前,板在37℃下在5%CO2
之潮濕氛圍下培育約1小時。 將測試化合物(參考表1)溶解於100% DMSO中,產生2/6/10/20 mM儲備溶液。在DMSO中製備所需最終濃度之200倍濃度。隨後將10 µL之各濃度(200倍)稀釋於90 µL無血清漢姆氏F12培養基中以在培養基中得到20倍之中間產物濃度。在此步驟中DMSO濃度為10% (中間產物稀釋液)。隨後將5 µL之各中間產物稀釋液一式三份添加至此前經接種之96孔板中。實驗孔中最終DMSO濃度為0.5%。經0.5% DMSO處理之細胞充當陽性對照。100 µL之完整IMDM培養基充當用於資料分析之培養基空白組。將200 µL之1×PBS添加至分析板之所有拐角孔中。隨後將板在具有5% CO2
之保溫箱中在37℃下培育72小時。 在終止日,將100 µl之XTT溶液(補充有25 µM PMS於漢姆氏F12培養基中之1 mg/ml XTT)添加至各孔。將板培育2小時。所產生甲臢之量藉由使用VICTOR X5多標記板讀取器在450 nm波長下讀取板之吸光度來測定。IC50
值以細胞存活率減少50%之濃度確定且曲線藉由GraphPad Prism 6.0繪製。 按以下計算抑制百分比: 抑制百分比(%)藉由將DMSO對照值標準化至100%使用下式來計算: %抑制= 100% - (Abs450測試化合物 - 空白組
) / (Abs450陽性對照 - 空白組
)×100 測試化合物含有細胞、測試化合物、IMDM培養基及0.5% DMSO 陽性對照含有細胞、IMDM培養基及0.5% DMSO 空白組含有IMDM培養基 多個人類癌細胞株藉由化合物 1 之體外生長抑制
進行腫瘤細胞株小組篩檢,其旨在鑑別對藉由化合物1之DHODH抑制尤其敏感之腫瘤細胞亞群。化合物1由以下結構式表示之化合物:此等細胞株經化合物1處理總計72小時。 如圖1及表1中所示,72小時處理後對腫瘤生長速率之評估揭示對化合物1敏感的細胞株之不同亞群(藉由圖1中之灰色點所繪示)。對化合物1展現高靈敏度之大部分細胞株為造血來源,但是一些實體腫瘤亦展現高靈敏度(表1)。出於產生圖1之目的,敏感細胞株所定義為展現≥75%最大生長抑制且GI50
值為<1.5 µM。表1為針對化合物1之敏感細胞株中之一些以及GI50
值及最大生長反應的列表。最大抑制為100表示完全生長抑制;最大抑制值>100表示細胞殺滅。 後續篩檢對於血紅素譜系之細胞株之擴展小組在4日生長分析中進行。生長藉由第0天及第4天之Cell-Titer Glo測量來評估。如圖2中所示,所篩檢之25%血紅素株系(20/80)展現對化合物1之敏感度,其中彌漫性大B細胞淋巴瘤(DLBCL)株系尤其敏感(8/11或73%)。對化合物1中度敏感(定義為>50%且<75%增長率抑制)或不敏感(定義為<50%增長率抑制)血紅素株系之亞群在此後續篩檢中經歷延長生長分析以評估增加治療時間是否調節其敏感度量變曲線。具體而言,此等血紅素株系藉由化合物1以指定濃度預處理三天且隨後再接種於新鮮培養基/藥物中金瓶梅該用於標準4日生長分析。在用化合物1處理7天之後,絕大部分再經測試之血紅素株系展現對化合物1之強敏感度(表2)。 表1。經化合物1處理之不同細胞株之GI50
及最大生長抑制
表2.經化合物1處理之不同血紅素細胞株之4天及7天敏感度 藉由化合物 1 之癌細胞生長抑制歸因於 DHODH 抑制
DHODH催化嘧啶重新生物合成中之第四步驟,在粒線體內膜中使二氫乳清酸氧化成乳清酸。乳清酸隨後與磷酸核糖焦磷酸(PRPP)組合以形成乳清酸核苷-5'-單磷酸(OMP)。最終由OMP在細胞胞液質中產生尿苷單磷酸(UMP),其中尿苷單磷酸用於RNA/DNA生物合成以製造嘧啶以及用於其他重要生物合成功能,諸如用於膜生物合成之蛋白/脂質糖基化及磷脂生成。 為了證實化合物1削弱細胞生長/存活力之作用係歸因於DHODH之特異性抑制,在將不同量之尿苷補充至培養基的情況下進行細胞生長分析。其中尿苷濃度接近生理(5 µM)之補充培養基部分地挽救化合物1之作用,而超生理濃度(25 µM及100 µM)完全挽救高達10 µM 化合物1對生長之作用。此等結果指示針對化合物1對生長之作用(圖3)。化合物 1 敏感度量變曲線相對於阿糖胞苷及阿黴素敏感度曲線之比較
針對血紅素株系之亞類將化合物1之敏感度量變曲線與用作血紅素惡性病之標準護理(SOC)的其他藥劑的敏感度量變曲線相比。根據其不同的作用機制,化合物1顯示與阿糖胞苷(圖4B)及阿黴素(圖4C)敏感度量變曲線不同之敏感度量變曲線(圖4A)。化合物 1 在體內有效抑制 DHODH 且在 AML 異種移植模型中阻斷腫瘤生長
進行對化合物1之體內功效研究以評估對阻斷DHODH及腫瘤細胞生長抑制之作用的體外至體內轉變。將1 × 106
個MOLM-13細胞皮下植入至CB17 SCID小鼠中。一旦腫瘤達到約150 mm3
之平均值,小鼠(n = 15隻/組)經媒劑或化合物1以100 mg/kg每天兩次經口處理。在研究結束時,在最後一次給藥後指定時間點處收集組織用於藥物動力學(PK)及路徑生物標記分析。 以100 mg/kg每天兩次投與化合物1具有良好耐受性且引起MOLM-13急性骨髓白血病(AML)異種移植模型之幾乎完全腫瘤生長抑制(TGI) (圖5A)。血漿及腫瘤中所量測之藥物動力學特徵顯示藥物濃度在12小時時下降,支持每天兩次給藥方案(圖5B)。藉由腫瘤中二氫乳清酸(DHO)、DHODH受質(圖5C)之水準顯著增加觀測到目標結合之明確證據。基線DHO水準低於可定量限值(BQL < 120 ng/g)。取決於所評估時間點,腫瘤尿苷池同時減少了約60% (圖5D)。化合物 1 在體內有效抑制 DHODH 且在來源於 患者之 AML 及 DLBCL 異種移植模型中阻斷腫瘤生長
隨後使用小數量之小鼠/組進行篩檢以評估化合物1在AML及DLBCL來源於患者之異種移植模型中之功效。攜帶腫瘤之小鼠(n = 3隻/組)經媒劑或化合物1以100 mg/kg每天兩次經口處理。 如圖6A-6E及7A-7B中所示,在所有經測試模型中觀測到化合物1之抗腫瘤活性,其中在五個AML模型中之兩個(亦即AML_2及AML_5)及兩個DLBCL模型中之一個(DLBCL_1) TGI>60%。DLBCL_1模型表徵為三重打擊DLBCL模型。雙重打擊彌漫性大 B 細胞淋巴瘤人類癌細胞株藉由化合物 1 之體外生長抑制
分類為雙重打擊DLBCL的三個來源於患者之DBLCL淋巴瘤細胞株,亦即OCILY18、SC-1及CARNAVAL,被認為在96小時生長分析(圖8)中對藉由化合物1之抑制為高度敏感的。化合物 1 在來源於患者之 DLBCL 異種移植模型中有效阻斷腫瘤生長
在OCILY-19彌漫性大B細胞淋巴瘤(DLBCL)異種移植模型中對於化合物1觀測到體內腫瘤生長之強阻斷。將7 × 106
個OCILY-19細胞皮下植入至CB17 SCID小鼠中。一旦腫瘤達到約150 mm3
之平均值,小鼠(n = 15-18隻/組)經媒劑或化合物1以指定劑量/頻率處理。在最後一次給藥後指定時間點處收集組織用於PK及生物標記分析。 路徑調節及腫瘤生長抑制之程度展示為劑量及計劃依賴性(圖9A)。100 mg/kg每天兩次給藥方案與10及30 mg/kg每天兩次劑量組相比產生優異的功效,且此與腫瘤DHO之較大增加(圖9C)以及總腫瘤尿苷池之降低(圖9D)相關。200 mg/kg每天一次方案與100 mg/kg每天兩次給藥方案相比不太有效,因為化合物1在小鼠中之短半衰期導致在每天一次給藥之情況下谷值藥物濃度較低(參見圖9B)。多個人類三陰性乳癌細胞株藉由化合物 1 之體外生長抑制
一組三陰性癌細胞株(TNBC)經篩檢以評估TNBC之亞類是否可潛在地受益於用化合物1作為單一藥劑處理。用化合物1處理96小時使DU4475中之細胞存活率/細胞生長穩健地減弱至與血紅素來源之細胞株中所觀測到的可比較的程度(參見圖10),而四個其他TNBC株系(HCC1143、HCC38、BTS49及HCC1806)在測試條件下不敏感。
圖1顯示一組約400種生血細胞來源及非生血細胞來源之人類癌症株系對本發明化合物1之生長抑制的敏感度。灰色圓圈代表作為敏感度之細胞株評分(展現≥75%最大生長抑制且GI50值<1.5µM。 圖2展示另外一組血紅素譜系之人類癌症株系對本發明化合物1之生長抑制的敏感度。 圖3顯示生理(5 μM)及超生理(25 μM,100 μM)濃度之外源尿苷對於指定癌症株系挽救10 μM化合物之細胞毒性作用的能力。 圖4A顯示MV411、Kasumi-1、THP-1、DB、Toledo及WSU-DLCL2細胞株對不同濃度之化合物1的相對增長率對比濃度靈敏度曲線。 圖4B顯示MV411、Kasumi-1、THP-1、DB、Toledo及WSU-DLCL2細胞株對不同濃度之阿糖胞苷的相對增長率對比濃度靈敏度曲線。 圖4C顯示MV411、Kasumi-1、THP-1、DB、Toledo及WSU-DLCL2細胞株對不同濃度之阿黴素的相對增長率對比濃度靈敏度曲線。 圖5A顯示歷經14天之時程所量測,CB17 SCID小鼠中在未經處理(媒劑)或每天兩次用100 mg/kg 化合物1處理時MOLM-13腫瘤生長曲線。 圖5B顯示在研究結束時最後一次給藥之後的指定時間點下,在CB17 SCID小鼠之血漿中以及植入的MOLM-13腫瘤中的化合物1(劑量= 100 mg/kg,每天兩次)之藥物動力學曲線。 圖5C顯示在研究結束時最後一次給藥之後歷經12小時之時程所量測,在未經處理之(媒劑) MOLM-13腫瘤及用化合物1處理之腫瘤中的DHO水準。 圖5D顯示在研究結束時在最後一次給藥之後歷經12小時所量測,在未經處理之(媒劑) MOLM-13腫瘤及用化合物1處理之腫瘤中的尿苷水準。 圖6A顯示在未經處理(媒劑)或每天兩次用100 mg/kg 化合物1處理時,在CB17 SCID小鼠中來源於患者之AML_1腫瘤生長曲線。 圖6B顯示在未經處理(媒劑)或每天兩次用100 mg/kg 化合物1處理時,在CB17 SCID小鼠中來源於患者之AML_2腫瘤生長曲線。 圖6C顯示在未經處理(媒劑)或每天兩次用100 mg/kg 化合物1處理時,在CB17 SCID小鼠中來源於患者之AML_3腫瘤生長曲線。 圖6D顯示在未經處理(媒劑)或每天兩次用100 mg/kg 化合物1處理時,在CB17 SCID小鼠中來源於患者之AML_4腫瘤生長曲線。 圖6E顯示在未經處理(媒劑)或每天兩次用100 mg/kg 化合物1處理時,在CB17 SCID小鼠中來源於患者之AML_5腫瘤生長曲線。 圖7A顯示在未經處理(媒劑)或每天兩次用100 mg/kg 化合物1處理時,在CB17 SCID小鼠中來源於患者之DLBCL_1(三重打擊模型(triple hit model))腫瘤生長曲線。 圖7B顯示在未經處理(媒劑)或每天兩次用100 mg/kg 化合物1處理時,在CB17 SCID小鼠中來源於患者之DLBCL_2腫瘤生長曲線。 圖8為顯示OCILY18、SC-1及CARNAVAL雙重打擊彌漫性大B細胞淋巴瘤(double hit diffuse large B cell lymphoma)(DLBCL)細胞株用不同濃度之化合物1處理96小時之相對增長率的曲線。 圖9A顯示在未經處理(媒劑)或每天兩次用10 mg/kg化合物1處理;每天兩次用30 mg/kg 化合物1處理;每天兩次用100 mg/kg 化合物1處理;以及每天一次用200 mg/kg 化合物1處理時CB17 SCID小鼠中OCILY-19雙重打擊彌漫性大B細胞淋巴瘤(DLBCL)腫瘤生長曲線,其全部歷經14天之時程量測。 圖9B顯示以對圖9A所描述之劑量所投與,在CB17 SCID小鼠之血漿中在研究結束時最後一次給藥之後的指定時間點處,化合物1之藥代動力學曲線。 圖9C顯示在研究結束時最後一次給藥之後歷經12小時之時程所量測,未經處理之(媒劑) OCILY-19腫瘤及用指定劑量之化合物1處理的腫瘤中的DHO水準。 圖9D顯示在研究結束時最後一次給藥之後歷經12小時之時程所量測,未經處理之(媒劑) OCILY-19腫瘤及用指定劑量之化合物1處理的腫瘤中的尿苷水準。 圖10為顯示DU4475三陰性乳癌株系用不同濃度之化合物1處理96小時之相對增長率的曲線。
Claims (18)
- 如請求項1之用途,其中該癌症為急性骨髓白血病。
- 如請求項1之用途,其中該癌症為多發性骨髓瘤。
- 如請求項1之用途,其中該癌症為B-前淋巴球性白血病。
- 如請求項1之用途,其中該癌症為非霍奇金氏淋巴瘤。
- 如請求項1之用途,其中該癌症為彌漫性大B細胞淋巴瘤。
- 如請求項1之用途,其中該癌症為間變性大細胞淋巴瘤。
- 如請求項1之用途,其中該癌症為套細胞淋巴瘤。
- 如請求項1之用途,其中該癌症為三陰性乳癌。
- 如請求項1之用途,其中該癌症為黑色素瘤。
- 如請求項1之用途,其中該癌症為前列腺癌。
- 如請求項1之用途,其中該癌症為食道癌。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US15/494,820 | 2017-04-24 | ||
US15/494,820 US9937155B2 (en) | 2013-02-25 | 2017-04-24 | Methods of use for trisubstituted benzotriazole derivatives as dihydroorotate oxygenase inhibitors |
US15/899,707 US20180369206A1 (en) | 2017-04-24 | 2018-02-20 | Methods of Use for Trisubstituted Benzotriazole Derivatives as Dihydroorotate Oxygenase Inhibitors |
US15/899,707 | 2018-02-20 |
Publications (2)
Publication Number | Publication Date |
---|---|
TW201902880A TW201902880A (zh) | 2019-01-16 |
TWI821180B true TWI821180B (zh) | 2023-11-11 |
Family
ID=65803213
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW107113690A TWI821180B (zh) | 2017-04-24 | 2018-04-23 | 使用三取代苯并三唑衍生物作為二氫乳清酸氧合酶抑制劑之方法 |
Country Status (26)
Country | Link |
---|---|
US (1) | US20220241246A1 (zh) |
EP (2) | EP3915557A1 (zh) |
JP (2) | JP7225114B2 (zh) |
KR (1) | KR20190140005A (zh) |
CN (1) | CN110662539B (zh) |
AU (1) | AU2018260390B2 (zh) |
BR (1) | BR112019022331A2 (zh) |
CA (1) | CA3060390A1 (zh) |
CY (1) | CY1124702T1 (zh) |
DK (1) | DK3615027T3 (zh) |
EA (1) | EA201992528A1 (zh) |
ES (1) | ES2889100T3 (zh) |
HR (1) | HRP20211462T1 (zh) |
HU (1) | HUE056485T2 (zh) |
IL (1) | IL270066B2 (zh) |
LT (1) | LT3615027T (zh) |
MA (1) | MA48459B1 (zh) |
MD (1) | MD3615027T2 (zh) |
MX (1) | MX2019012640A (zh) |
PH (1) | PH12019502402A1 (zh) |
PL (1) | PL3615027T3 (zh) |
PT (1) | PT3615027T (zh) |
RS (1) | RS62519B1 (zh) |
SG (1) | SG11201909718QA (zh) |
SI (1) | SI3615027T1 (zh) |
TW (1) | TWI821180B (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BR112020016929A8 (pt) * | 2018-02-20 | 2022-06-28 | Agios Pharmaceuticals Inc | Métodos de uso para derivados de benzotriazol trissubstituídos |
KR102514860B1 (ko) * | 2020-12-01 | 2023-03-29 | 한국과학기술연구원 | 5-ht7 세로토닌 수용체 활성 저해용 바이페닐 피롤리딘 및 바이페닐 다이하이드로이미다졸 유도체 및 이를 유효성분으로 포함하는 약학 조성물 |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5494911A (en) | 1990-05-18 | 1996-02-27 | Hoechst Aktiengesellschaft | Isoxazole-4-carboxamides and hydroxyalkylidenecyanoacetamides, pharmaceuticals containing these compounds and their use |
US5904937A (en) | 1997-10-03 | 1999-05-18 | Fmc Corporation | Taste masked pharmaceutical compositions |
US6841561B1 (en) | 1999-10-01 | 2005-01-11 | Institute Of Molecular And Cell Biology | Dihydroorotate dehydrogenase inhibitors for the treatment of viral-mediated diseases |
ES2882797T3 (es) | 2009-04-02 | 2021-12-02 | Merck Serono Sa | Inhibidores de dihidroorotato deshidrogenasa |
PT3019482T (pt) * | 2013-02-25 | 2018-11-28 | Aurigene Discovery Tech Ltd | Derivados de benzotriazole trissubstituídos enquanto inibidores de di-hidro-orotato-oxigenase |
-
2018
- 2018-04-19 LT LTEPPCT/IB2018/052710T patent/LT3615027T/lt unknown
- 2018-04-19 RS RS20211150A patent/RS62519B1/sr unknown
- 2018-04-19 EP EP21184786.8A patent/EP3915557A1/en active Pending
- 2018-04-19 CA CA3060390A patent/CA3060390A1/en active Pending
- 2018-04-19 KR KR1020197034384A patent/KR20190140005A/ko active IP Right Grant
- 2018-04-19 HU HUE18723602A patent/HUE056485T2/hu unknown
- 2018-04-19 EP EP18723602.1A patent/EP3615027B1/en active Active
- 2018-04-19 SI SI201830423T patent/SI3615027T1/sl unknown
- 2018-04-19 HR HRP20211462TT patent/HRP20211462T1/hr unknown
- 2018-04-19 ES ES18723602T patent/ES2889100T3/es active Active
- 2018-04-19 IL IL270066A patent/IL270066B2/en unknown
- 2018-04-19 PL PL18723602T patent/PL3615027T3/pl unknown
- 2018-04-19 MX MX2019012640A patent/MX2019012640A/es unknown
- 2018-04-19 JP JP2019557358A patent/JP7225114B2/ja active Active
- 2018-04-19 AU AU2018260390A patent/AU2018260390B2/en active Active
- 2018-04-19 PT PT187236021T patent/PT3615027T/pt unknown
- 2018-04-19 CN CN201880027155.0A patent/CN110662539B/zh active Active
- 2018-04-19 BR BR112019022331-2A patent/BR112019022331A2/pt unknown
- 2018-04-19 DK DK18723602.1T patent/DK3615027T3/da active
- 2018-04-19 SG SG11201909718Q patent/SG11201909718QA/en unknown
- 2018-04-19 MD MDE20200226T patent/MD3615027T2/ro unknown
- 2018-04-19 MA MA48459A patent/MA48459B1/fr unknown
- 2018-04-19 EA EA201992528A patent/EA201992528A1/ru unknown
- 2018-04-23 TW TW107113690A patent/TWI821180B/zh active
-
2019
- 2019-10-23 PH PH12019502402A patent/PH12019502402A1/en unknown
-
2021
- 2021-10-04 CY CY20211100855T patent/CY1124702T1/el unknown
- 2021-10-14 US US17/501,701 patent/US20220241246A1/en active Pending
-
2022
- 2022-12-02 JP JP2022193406A patent/JP2023022252A/ja active Pending
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US9937155B2 (en) | Methods of use for trisubstituted benzotriazole derivatives as dihydroorotate oxygenase inhibitors | |
AU2019202922B2 (en) | Compositions and methods of using the same for treatment of neurodegenerative and mitochondrial disease | |
US20180170929A1 (en) | Pyrimidine-2,4-diamine derivatives for treatment of cancer | |
US11147801B2 (en) | Methods of use for trisubstituted benzotriazole derivatives as dihydroorotate oxygenase inhibitors | |
RU2415850C2 (ru) | Новые антраниламидопиридинмочевины в качестве ингибиторов киназы рецептора vegf | |
JP2023022252A (ja) | ジヒドロオロト酸オキシゲナーゼの阻害剤としての三置換ベンゾトリアゾール誘導体の使用方法 | |
TW201300360A (zh) | 做為jak激酶調節劑之菸鹼醯胺 | |
CN108299420B (zh) | 作为选择性雌激素受体下调剂的五环类化合物及其应用 | |
WO2015166398A1 (en) | 3h-imidazo[4,5-b]pyridine derivatives as dihydroorotate dehydrogenase inhibitors | |
KR20230141799A (ko) | Cd38의 억제제로서의 퀴놀린 및 아자퀴놀린 | |
US20090143375A1 (en) | Tricyclic Lactam Derivatives, Their Manufacture and Use as Pharmaceutical Agents | |
EA041464B1 (ru) | Способ лечения рака при помощи тризамещенного производного бензотриазола | |
TW201713631A (zh) | 作為trpm8拮抗劑之咪唑啉酮衍生物 |