TW201641504A - 1-胺基-2-環丁基乙酸衍生物 - Google Patents
1-胺基-2-環丁基乙酸衍生物 Download PDFInfo
- Publication number
- TW201641504A TW201641504A TW105105530A TW105105530A TW201641504A TW 201641504 A TW201641504 A TW 201641504A TW 105105530 A TW105105530 A TW 105105530A TW 105105530 A TW105105530 A TW 105105530A TW 201641504 A TW201641504 A TW 201641504A
- Authority
- TW
- Taiwan
- Prior art keywords
- substituted
- group
- aliphatic
- unsubstituted
- independently
- Prior art date
Links
- BCNMPHGGRXUKHU-UHFFFAOYSA-N (1-amino-2-cyclobutylethyl)boronic acid Chemical class OB(O)C(N)CC1CCC1 BCNMPHGGRXUKHU-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 135
- 239000000203 mixture Substances 0.000 claims abstract description 57
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 13
- 238000011282 treatment Methods 0.000 claims abstract description 7
- 239000002253 acid Substances 0.000 claims description 87
- 125000003118 aryl group Chemical group 0.000 claims description 86
- -1 tetrahydroquinolyl group Chemical group 0.000 claims description 76
- 125000001931 aliphatic group Chemical group 0.000 claims description 66
- 125000000217 alkyl group Chemical group 0.000 claims description 64
- 125000001072 heteroaryl group Chemical group 0.000 claims description 48
- 125000000623 heterocyclic group Chemical group 0.000 claims description 41
- 206010028980 Neoplasm Diseases 0.000 claims description 33
- 229910052757 nitrogen Inorganic materials 0.000 claims description 31
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 31
- 125000001424 substituent group Chemical group 0.000 claims description 31
- 229910052799 carbon Inorganic materials 0.000 claims description 28
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 25
- 125000004076 pyridyl group Chemical group 0.000 claims description 25
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 23
- 125000005842 heteroatom Chemical group 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 239000001257 hydrogen Substances 0.000 claims description 20
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 19
- 125000004432 carbon atom Chemical group C* 0.000 claims description 19
- 201000011510 cancer Diseases 0.000 claims description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
- 125000002950 monocyclic group Chemical group 0.000 claims description 18
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 150000008064 anhydrides Chemical class 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 14
- 229910052760 oxygen Inorganic materials 0.000 claims description 14
- 125000005843 halogen group Chemical group 0.000 claims description 13
- 229910052717 sulfur Inorganic materials 0.000 claims description 13
- 125000001624 naphthyl group Chemical group 0.000 claims description 12
- 229920006395 saturated elastomer Polymers 0.000 claims description 12
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 11
- 125000005434 dihydrobenzoxazinyl group Chemical group O1N(CCC2=C1C=CC=C2)* 0.000 claims description 10
- 125000005493 quinolyl group Chemical group 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 125000004122 cyclic group Chemical group 0.000 claims description 7
- 125000006162 fluoroaliphatic group Chemical group 0.000 claims description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 150000001412 amines Chemical class 0.000 claims description 6
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 5
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 125000004104 aryloxy group Chemical group 0.000 claims description 3
- 125000003709 fluoroalkyl group Chemical group 0.000 claims description 3
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 claims description 3
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 2
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims 1
- 150000008065 acid anhydrides Chemical class 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 17
- 229940079156 Proteasome inhibitor Drugs 0.000 abstract description 16
- 239000003207 proteasome inhibitor Substances 0.000 abstract description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 14
- 201000010099 disease Diseases 0.000 abstract description 10
- 108090000708 Proteasome Endopeptidase Complex Proteins 0.000 description 36
- 102000004245 Proteasome Endopeptidase Complex Human genes 0.000 description 36
- 210000004027 cell Anatomy 0.000 description 33
- 239000003795 chemical substances by application Substances 0.000 description 22
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 20
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 20
- 239000000243 solution Substances 0.000 description 19
- 230000000694 effects Effects 0.000 description 18
- 239000003112 inhibitor Substances 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 125000004429 atom Chemical group 0.000 description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
- 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 13
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 150000001721 carbon Chemical group 0.000 description 12
- 230000005764 inhibitory process Effects 0.000 description 12
- 239000002585 base Substances 0.000 description 11
- 125000002619 bicyclic group Chemical group 0.000 description 11
- 239000002552 dosage form Substances 0.000 description 11
- 150000002148 esters Chemical class 0.000 description 11
- 229940124597 therapeutic agent Drugs 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 125000000524 functional group Chemical group 0.000 description 10
- 239000008176 lyophilized powder Substances 0.000 description 10
- 108090000765 processed proteins & peptides Proteins 0.000 description 10
- 108090000623 proteins and genes Proteins 0.000 description 10
- 125000006413 ring segment Chemical group 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 235000010355 mannitol Nutrition 0.000 description 9
- 125000006239 protecting group Chemical group 0.000 description 9
- 102000004169 proteins and genes Human genes 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- 230000004663 cell proliferation Effects 0.000 description 8
- 238000010494 dissociation reaction Methods 0.000 description 8
- 230000005593 dissociations Effects 0.000 description 8
- 230000001404 mediated effect Effects 0.000 description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 8
- 210000001519 tissue Anatomy 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 7
- 235000019439 ethyl acetate Nutrition 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 235000000346 sugar Nutrition 0.000 description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 7
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 6
- 108010057466 NF-kappa B Proteins 0.000 description 6
- 102000003945 NF-kappa B Human genes 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 125000003342 alkenyl group Chemical group 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 229910052796 boron Inorganic materials 0.000 description 6
- 229960001467 bortezomib Drugs 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 239000008187 granular material Substances 0.000 description 6
- 230000012010 growth Effects 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 125000002971 oxazolyl group Chemical group 0.000 description 6
- 125000004430 oxygen atom Chemical group O* 0.000 description 6
- 239000000546 pharmaceutical excipient Substances 0.000 description 6
- 230000006663 ubiquitin-proteasome pathway Effects 0.000 description 6
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 229930195725 Mannitol Natural products 0.000 description 5
- 102000035195 Peptidases Human genes 0.000 description 5
- 108091005804 Peptidases Proteins 0.000 description 5
- 229930006000 Sucrose Natural products 0.000 description 5
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 5
- 239000002246 antineoplastic agent Substances 0.000 description 5
- 125000003710 aryl alkyl group Chemical group 0.000 description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
- 238000000576 coating method Methods 0.000 description 5
- 229940088598 enzyme Drugs 0.000 description 5
- 229930195733 hydrocarbon Natural products 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 239000008101 lactose Substances 0.000 description 5
- 125000005647 linker group Chemical group 0.000 description 5
- 239000007937 lozenge Substances 0.000 description 5
- 239000000594 mannitol Substances 0.000 description 5
- 125000006574 non-aromatic ring group Chemical group 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- 239000006187 pill Substances 0.000 description 5
- 229920001223 polyethylene glycol Polymers 0.000 description 5
- 102000004196 processed proteins & peptides Human genes 0.000 description 5
- 239000007909 solid dosage form Substances 0.000 description 5
- 239000005720 sucrose Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 4
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 4
- 239000004215 Carbon black (E152) Substances 0.000 description 4
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 4
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 4
- 206010035226 Plasma cell myeloma Diseases 0.000 description 4
- 208000009527 Refractory anemia Diseases 0.000 description 4
- 206010072684 Refractory cytopenia with unilineage dysplasia Diseases 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
- 239000012317 TBTU Substances 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- 235000010443 alginic acid Nutrition 0.000 description 4
- 229920000615 alginic acid Polymers 0.000 description 4
- 125000000304 alkynyl group Chemical group 0.000 description 4
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- 239000000945 filler Substances 0.000 description 4
- 235000019253 formic acid Nutrition 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 239000003701 inert diluent Substances 0.000 description 4
- 238000004895 liquid chromatography mass spectrometry Methods 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
- 239000002609 medium Substances 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- 210000000056 organ Anatomy 0.000 description 4
- 230000002062 proliferating effect Effects 0.000 description 4
- 125000002098 pyridazinyl group Chemical group 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 238000007920 subcutaneous administration Methods 0.000 description 4
- 239000011593 sulfur Substances 0.000 description 4
- 125000003396 thiol group Chemical group [H]S* 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- 239000001993 wax Substances 0.000 description 4
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 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 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 3
- 108020004414 DNA Proteins 0.000 description 3
- 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 3
- 241000124008 Mammalia Species 0.000 description 3
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 description 3
- 208000034578 Multiple myelomas Diseases 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- 206010060862 Prostate cancer Diseases 0.000 description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 125000002947 alkylene group Chemical group 0.000 description 3
- 239000012131 assay buffer Substances 0.000 description 3
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 3
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 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 3
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 230000022131 cell cycle Effects 0.000 description 3
- 230000010261 cell growth Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- GLNDAGDHSLMOKX-UHFFFAOYSA-N coumarin 120 Chemical compound C1=C(N)C=CC2=C1OC(=O)C=C2C GLNDAGDHSLMOKX-UHFFFAOYSA-N 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 229940127089 cytotoxic agent Drugs 0.000 description 3
- 230000003111 delayed effect Effects 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 229930195729 fatty acid Natural products 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000005897 peptide coupling reaction Methods 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 3
- 125000003367 polycyclic group Chemical group 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 3
- 235000019833 protease Nutrition 0.000 description 3
- 230000017854 proteolysis Effects 0.000 description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 3
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 230000010076 replication Effects 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 3
- 239000008247 solid mixture Substances 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 2
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 2
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- NGEWQZIDQIYUNV-UHFFFAOYSA-N 2-hydroxy-3-methylbutyric acid Chemical compound CC(C)C(O)C(O)=O NGEWQZIDQIYUNV-UHFFFAOYSA-N 0.000 description 2
- BWLBGMIXKSTLSX-UHFFFAOYSA-N 2-hydroxyisobutyric acid Chemical compound CC(C)(O)C(O)=O BWLBGMIXKSTLSX-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- WHBMMWSBFZVSSR-UHFFFAOYSA-N 3-hydroxybutyric acid Chemical compound CC(O)CC(O)=O WHBMMWSBFZVSSR-UHFFFAOYSA-N 0.000 description 2
- 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 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- 239000005695 Ammonium acetate Substances 0.000 description 2
- 206010003571 Astrocytoma Diseases 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 208000003170 Bronchiolo-Alveolar Adenocarcinoma Diseases 0.000 description 2
- 206010058354 Bronchioloalveolar carcinoma 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
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical compound NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- 108010067225 Cell Adhesion Molecules Proteins 0.000 description 2
- 102000016289 Cell Adhesion Molecules Human genes 0.000 description 2
- 102100025064 Cellular tumor antigen p53 Human genes 0.000 description 2
- 108090000317 Chymotrypsin Proteins 0.000 description 2
- 229920000858 Cyclodextrin Polymers 0.000 description 2
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- 239000004705 High-molecular-weight polyethylene Substances 0.000 description 2
- 208000017604 Hodgkin disease Diseases 0.000 description 2
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 2
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- 102000008934 Muscle Proteins Human genes 0.000 description 2
- 108010074084 Muscle Proteins Proteins 0.000 description 2
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 2
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 235000019483 Peanut oil Nutrition 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
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 108090000631 Trypsin Proteins 0.000 description 2
- 102000004142 Trypsin Human genes 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- DZBUGLKDJFMEHC-UHFFFAOYSA-N acridine Chemical compound C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 2
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- 229940072056 alginate Drugs 0.000 description 2
- 239000000783 alginic acid Substances 0.000 description 2
- 229960001126 alginic acid Drugs 0.000 description 2
- 150000004781 alginic acids Chemical class 0.000 description 2
- 235000019257 ammonium acetate Nutrition 0.000 description 2
- 229940043376 ammonium acetate Drugs 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000003098 androgen Substances 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 2
- 125000005160 aryl oxy alkyl group Chemical group 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 2
- RROBIDXNTUAHFW-UHFFFAOYSA-N benzotriazol-1-yloxy-tris(dimethylamino)phosphanium Chemical compound C1=CC=C2N(O[P+](N(C)C)(N(C)C)N(C)C)N=NC2=C1 RROBIDXNTUAHFW-UHFFFAOYSA-N 0.000 description 2
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 239000008139 complexing agent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 235000005687 corn oil Nutrition 0.000 description 2
- 239000002285 corn oil Substances 0.000 description 2
- 235000012343 cottonseed oil Nutrition 0.000 description 2
- 239000002385 cottonseed oil Substances 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 229960004397 cyclophosphamide Drugs 0.000 description 2
- 230000003412 degenerative effect Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 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 2
- 150000002016 disaccharides Chemical class 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000001804 emulsifying effect Effects 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 239000002702 enteric coating Substances 0.000 description 2
- 238000009505 enteric coating Methods 0.000 description 2
- MMXKVMNBHPAILY-UHFFFAOYSA-N ethyl laurate Chemical compound CCCCCCCCCCCC(=O)OCC MMXKVMNBHPAILY-UHFFFAOYSA-N 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229960000390 fludarabine Drugs 0.000 description 2
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 2
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 2
- 150000002337 glycosamines Chemical class 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 125000004475 heteroaralkyl group Chemical group 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 2
- 229960002247 lomustine Drugs 0.000 description 2
- 208000016992 lung adenocarcinoma in situ Diseases 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 208000024191 minimally invasive lung adenocarcinoma Diseases 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Chemical group C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 150000002772 monosaccharides Chemical class 0.000 description 2
- 125000002757 morpholinyl group Chemical group 0.000 description 2
- 208000015122 neurodegenerative disease Diseases 0.000 description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 235000008390 olive oil Nutrition 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- 239000000312 peanut oil Substances 0.000 description 2
- 229950000688 phenothiazine Drugs 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 125000004193 piperazinyl group Chemical group 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- 239000004810 polytetrafluoroethylene Substances 0.000 description 2
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 150000004032 porphyrins Chemical class 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 238000012746 preparative thin layer chromatography Methods 0.000 description 2
- 230000000750 progressive effect Effects 0.000 description 2
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 2
- 150000003222 pyridines Chemical class 0.000 description 2
- 150000003230 pyrimidines Chemical group 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 239000008159 sesame oil Substances 0.000 description 2
- 235000011803 sesame oil Nutrition 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- UVFAEQZFLBGVRM-MSMWPWNWSA-N succinyl-Leu-Leu-Val-Tyr-7-amino-4-methylcoumarin Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)CCC(O)=O)CC(C)C)C(=O)NC=1C=C2OC(=O)C=C(C)C2=CC=1)C1=CC=C(O)C=C1 UVFAEQZFLBGVRM-MSMWPWNWSA-N 0.000 description 2
- 150000005846 sugar alcohols Chemical class 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 2
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000005809 transesterification reaction Methods 0.000 description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 150000003751 zinc Chemical class 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- LSPHULWDVZXLIL-UHFFFAOYSA-N (+/-)-Camphoric acid Chemical compound CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- LDDMACCNBZAMSG-BDVNFPICSA-N (2r,3r,4s,5r)-3,4,5,6-tetrahydroxy-2-(methylamino)hexanal Chemical compound CN[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO LDDMACCNBZAMSG-BDVNFPICSA-N 0.000 description 1
- ZYJPUMXJBDHSIF-NSHDSACASA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 ZYJPUMXJBDHSIF-NSHDSACASA-N 0.000 description 1
- MCODLPJUFHPVQP-LBPRGKRZSA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-4-phenylbutanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CCC1=CC=CC=C1 MCODLPJUFHPVQP-LBPRGKRZSA-N 0.000 description 1
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 1
- FOYHOBVZPWIGJM-KCHLEUMXSA-N (4s)-4-[[(2s)-4-methyl-2-[[(2s)-4-methyl-2-(phenylmethoxycarbonylamino)pentanoyl]amino]pentanoyl]amino]-5-[(4-methyl-2-oxochromen-7-yl)amino]-5-oxopentanoic acid Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)NC=1C=C2OC(=O)C=C(C)C2=CC=1)C(=O)OCC1=CC=CC=C1 FOYHOBVZPWIGJM-KCHLEUMXSA-N 0.000 description 1
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- 125000006039 1-hexenyl group Chemical group 0.000 description 1
- SJJCQDRGABAVBB-UHFFFAOYSA-N 1-hydroxy-2-naphthoic acid Chemical compound C1=CC=CC2=C(O)C(C(=O)O)=CC=C21 SJJCQDRGABAVBB-UHFFFAOYSA-N 0.000 description 1
- JZUMPNUYDJBTNO-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1.C1=CC=C2N(O)N=NC2=C1 JZUMPNUYDJBTNO-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- 125000006023 1-pentenyl group Chemical group 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Chemical group C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- XWIYUCRMWCHYJR-UHFFFAOYSA-N 1h-pyrrolo[3,2-b]pyridine Chemical compound C1=CC=C2NC=CC2=N1 XWIYUCRMWCHYJR-UHFFFAOYSA-N 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- QDKSGHXRHXVMPF-UHFFFAOYSA-N 2,2-dimethylundecane Chemical compound CCCCCCCCCC(C)(C)C QDKSGHXRHXVMPF-UHFFFAOYSA-N 0.000 description 1
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 1
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 1
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 1
- RRDPWAPIJGSANI-UHFFFAOYSA-N 2-cyclohexyl-2-hydroxyacetic acid Chemical compound OC(=O)C(O)C1CCCCC1 RRDPWAPIJGSANI-UHFFFAOYSA-N 0.000 description 1
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- FWVNWTNCNWRCOU-UHFFFAOYSA-N 2-hydroxy-3,3-dimethylbutanoic acid Chemical compound CC(C)(C)C(O)C(O)=O FWVNWTNCNWRCOU-UHFFFAOYSA-N 0.000 description 1
- LVRFTAZAXQPQHI-UHFFFAOYSA-N 2-hydroxy-4-methylvaleric acid Chemical compound CC(C)CC(O)C(O)=O LVRFTAZAXQPQHI-UHFFFAOYSA-N 0.000 description 1
- 229940080296 2-naphthalenesulfonate Drugs 0.000 description 1
- JBIJLHTVPXGSAM-UHFFFAOYSA-N 2-naphthylamine Chemical compound C1=CC=CC2=CC(N)=CC=C21 JBIJLHTVPXGSAM-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- ALKYHXVLJMQRLQ-UHFFFAOYSA-N 3-Hydroxy-2-naphthoate Chemical compound C1=CC=C2C=C(O)C(C(=O)O)=CC2=C1 ALKYHXVLJMQRLQ-UHFFFAOYSA-N 0.000 description 1
- UOQHWNPVNXSDDO-UHFFFAOYSA-N 3-bromoimidazo[1,2-a]pyridine-6-carbonitrile Chemical compound C1=CC(C#N)=CN2C(Br)=CN=C21 UOQHWNPVNXSDDO-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-M 3-phenylpropionate Chemical compound [O-]C(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-M 0.000 description 1
- BGNGWHSBYQYVRX-UHFFFAOYSA-N 4-(dimethylamino)benzaldehyde Chemical compound CN(C)C1=CC=C(C=O)C=C1 BGNGWHSBYQYVRX-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
- 125000006163 5-membered heteroaryl group Chemical group 0.000 description 1
- KDOPAZIWBAHVJB-UHFFFAOYSA-N 5h-pyrrolo[3,2-d]pyrimidine Chemical compound C1=NC=C2NC=CC2=N1 KDOPAZIWBAHVJB-UHFFFAOYSA-N 0.000 description 1
- WYWHKKSPHMUBEB-UHFFFAOYSA-N 6-Mercaptoguanine Natural products N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 108010022579 ATP dependent 26S protease Proteins 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000010444 Acidosis Diseases 0.000 description 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 1
- 208000022309 Alcoholic Liver disease Diseases 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 208000003950 B-cell lymphoma Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 208000004860 Blast Crisis Diseases 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 206010005949 Bone cancer Diseases 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 206010055113 Breast cancer metastatic Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- 108091007914 CDKs Proteins 0.000 description 1
- FVLVBPDQNARYJU-XAHDHGMMSA-N C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O Chemical compound C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O FVLVBPDQNARYJU-XAHDHGMMSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 1
- 206010058019 Cancer Pain Diseases 0.000 description 1
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 235000005979 Citrus limon Nutrition 0.000 description 1
- 244000131522 Citrus pyriformis Species 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 102000016736 Cyclin Human genes 0.000 description 1
- 108050006400 Cyclin Proteins 0.000 description 1
- 102100033270 Cyclin-dependent kinase inhibitor 1 Human genes 0.000 description 1
- 102100033233 Cyclin-dependent kinase inhibitor 1B Human genes 0.000 description 1
- 102000003903 Cyclin-dependent kinases Human genes 0.000 description 1
- 108090000266 Cyclin-dependent kinases Proteins 0.000 description 1
- 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 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- RGHNJXZEOKUKBD-MGCNEYSASA-N D-galactonic acid Chemical compound OC[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-MGCNEYSASA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 229940123780 DNA topoisomerase I inhibitor Drugs 0.000 description 1
- 229940124087 DNA topoisomerase II inhibitor Drugs 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010012689 Diabetic retinopathy Diseases 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- 102000015689 E-Selectin Human genes 0.000 description 1
- 108010024212 E-Selectin Proteins 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 241000206672 Gelidium Species 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- XYZZKVRWGOWVGO-UHFFFAOYSA-N Glycerol-phosphate Chemical compound OP(O)(O)=O.OCC(O)CO XYZZKVRWGOWVGO-UHFFFAOYSA-N 0.000 description 1
- 206010053759 Growth retardation Diseases 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000944361 Homo sapiens Cyclin-dependent kinase inhibitor 1B Proteins 0.000 description 1
- 101000979342 Homo sapiens Nuclear factor NF-kappa-B p105 subunit Proteins 0.000 description 1
- 101000705756 Homo sapiens Proteasome activator complex subunit 1 Proteins 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 1
- 102000001284 I-kappa-B kinase Human genes 0.000 description 1
- 108060006678 I-kappa-B kinase Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 108010064593 Intercellular Adhesion Molecule-1 Proteins 0.000 description 1
- 102000015271 Intercellular Adhesion Molecule-1 Human genes 0.000 description 1
- 102100037850 Interferon gamma Human genes 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- 102100027612 Kallikrein-11 Human genes 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 239000004166 Lanolin Substances 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 231100000002 MTT assay Toxicity 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- 206010050513 Metastatic renal cell carcinoma Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 208000026072 Motor neurone disease Diseases 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 208000028389 Nerve injury Diseases 0.000 description 1
- 206010052399 Neuroendocrine tumour Diseases 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical class OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- 102100023050 Nuclear factor NF-kappa-B p105 subunit Human genes 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 201000010133 Oligodendroglioma Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 229920002230 Pectic acid Polymers 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
- 208000026149 Primary peritoneal carcinoma Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical class CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 108090000783 Renin Proteins 0.000 description 1
- 102100028255 Renin Human genes 0.000 description 1
- 238000011579 SCID mouse model Methods 0.000 description 1
- 108091006627 SLC12A9 Proteins 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 208000021712 Soft tissue sarcoma Diseases 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 description 1
- SSZBUIDZHHWXNJ-UHFFFAOYSA-N Stearinsaeure-hexadecylester Natural products CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC SSZBUIDZHHWXNJ-UHFFFAOYSA-N 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 206010042971 T-cell lymphoma Diseases 0.000 description 1
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 1
- 239000000365 Topoisomerase I Inhibitor Substances 0.000 description 1
- 239000000317 Topoisomerase II Inhibitor Substances 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- 101710152431 Trypsin-like protease Proteins 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 102000044159 Ubiquitin Human genes 0.000 description 1
- 108090000848 Ubiquitin Proteins 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 108010000134 Vascular Cell Adhesion Molecule-1 Proteins 0.000 description 1
- 102100023543 Vascular cell adhesion protein 1 Human genes 0.000 description 1
- 231100000480 WST assay Toxicity 0.000 description 1
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 description 1
- 239000001089 [(2R)-oxolan-2-yl]methanol Substances 0.000 description 1
- BFPLMTPHDFFMTG-UHFFFAOYSA-N [1,3]oxazolo[5,4-b]pyridine Chemical compound C1=CN=C2OC=NC2=C1 BFPLMTPHDFFMTG-UHFFFAOYSA-N 0.000 description 1
- WFIHKLWVLPBMIQ-UHFFFAOYSA-N [1,3]thiazolo[5,4-b]pyridine Chemical compound C1=CN=C2SC=NC2=C1 WFIHKLWVLPBMIQ-UHFFFAOYSA-N 0.000 description 1
- VWUYKZDURVFNDW-UHFFFAOYSA-L [Mg+2].[Br-].[Br-].Br Chemical compound [Mg+2].[Br-].[Br-].Br VWUYKZDURVFNDW-UHFFFAOYSA-L 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000007950 acidosis Effects 0.000 description 1
- 208000026545 acidosis disease Diseases 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 208000030002 adult glioblastoma Diseases 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- AEMOLEFTQBMNLQ-BKBMJHBISA-N alpha-D-galacturonic acid Chemical compound O[C@H]1O[C@H](C(O)=O)[C@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-BKBMJHBISA-N 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 229940024545 aluminum hydroxide Drugs 0.000 description 1
- 229940063655 aluminum stearate Drugs 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000006909 anti-apoptosis Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- OGBUMNBNEWYMNJ-UHFFFAOYSA-N batilol Chemical class CCCCCCCCCCCCCCCCCCOCC(O)CO OGBUMNBNEWYMNJ-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 150000001555 benzenes Chemical group 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- UKXSKSHDVLQNKG-UHFFFAOYSA-N benzilic acid Chemical compound C=1C=CC=CC=1C(O)(C(=O)O)C1=CC=CC=C1 UKXSKSHDVLQNKG-UHFFFAOYSA-N 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- AXFYFNCPONWUHW-UHFFFAOYSA-N beta-hydroxy-beta-methyl butyric acid Natural products CC(C)(O)CC(O)=O AXFYFNCPONWUHW-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N beta-phenylpropanoic acid Natural products OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 229940127093 camptothecin Drugs 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- 229960004117 capecitabine Drugs 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 238000003570 cell viability assay Methods 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 229910000420 cerium oxide Inorganic materials 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 229960005395 cetuximab Drugs 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 230000026374 cyclin catabolic process Effects 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000522 cyclooctenyl group Chemical group C1(=CCCCCCC1)* 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- BALGDZWGNCXXES-UHFFFAOYSA-N cyclopentane;propanoic acid Chemical compound CCC(O)=O.C1CCCC1 BALGDZWGNCXXES-UHFFFAOYSA-N 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 230000009849 deactivation Effects 0.000 description 1
- INSRQEMEVAMETL-UHFFFAOYSA-N decane-1,1-diol Chemical compound CCCCCCCCCC(O)O INSRQEMEVAMETL-UHFFFAOYSA-N 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- RAABOESOVLLHRU-UHFFFAOYSA-O diazenium Chemical compound [NH2+]=N RAABOESOVLLHRU-UHFFFAOYSA-O 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
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 238000005906 dihydroxylation reaction Methods 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 125000005879 dioxolanyl group Chemical group 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 239000003221 ear drop Substances 0.000 description 1
- 229940047652 ear drops Drugs 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 210000002257 embryonic structure Anatomy 0.000 description 1
- 208000030172 endocrine system disease Diseases 0.000 description 1
- 210000003989 endothelium vascular Anatomy 0.000 description 1
- 230000006353 environmental stress Effects 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 208000030533 eye disease Diseases 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 201000003444 follicular lymphoma Diseases 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- 108091006104 gene-regulatory proteins Proteins 0.000 description 1
- 102000034356 gene-regulatory proteins Human genes 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 231100000001 growth retardation Toxicity 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 125000006161 haloaliphatic group Chemical group 0.000 description 1
- 125000000262 haloalkenyl group Chemical group 0.000 description 1
- 125000004438 haloalkoxy group Chemical group 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 201000000459 head and neck squamous cell carcinoma Diseases 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 201000011066 hemangioma Diseases 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 230000002489 hematologic effect Effects 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 1
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 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
- 102000057161 human PSME1 Human genes 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 229960001330 hydroxycarbamide Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- 229960003685 imatinib mesylate Drugs 0.000 description 1
- YLMAHDNUQAMNNX-UHFFFAOYSA-N imatinib methanesulfonate Chemical compound CS(O)(=O)=O.C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 YLMAHDNUQAMNNX-UHFFFAOYSA-N 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000003455 independent Effects 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 108091006086 inhibitor proteins Proteins 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007919 intrasynovial administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 208000037906 ischaemic injury Diseases 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 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
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 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
- 201000010982 kidney cancer Diseases 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229940099563 lactobionic acid Drugs 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 229960004942 lenalidomide Drugs 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 201000005249 lung adenocarcinoma Diseases 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 239000004337 magnesium citrate Substances 0.000 description 1
- 229960005336 magnesium citrate Drugs 0.000 description 1
- 235000002538 magnesium citrate Nutrition 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 229960000816 magnesium hydroxide Drugs 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 230000008774 maternal effect Effects 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 231100000682 maximum tolerated dose Toxicity 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 208000037819 metastatic cancer Diseases 0.000 description 1
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 108091005601 modified peptides Proteins 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 208000005264 motor neuron disease Diseases 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 230000002071 myeloproliferative effect Effects 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical group N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- DSWNRHCOGVRDOE-UHFFFAOYSA-N n,n-dimethylmethanimidamide Chemical compound CN(C)C=N DSWNRHCOGVRDOE-UHFFFAOYSA-N 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 230000008764 nerve damage Effects 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 201000002120 neuroendocrine carcinoma Diseases 0.000 description 1
- 208000016065 neuroendocrine neoplasm Diseases 0.000 description 1
- 201000011519 neuroendocrine tumor Diseases 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
- 150000002829 nitrogen Chemical class 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 238000006384 oligomerization reaction Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- BMMGVYCKOGBVEV-UHFFFAOYSA-N oxo(oxoceriooxy)cerium Chemical compound [Ce]=O.O=[Ce]=O BMMGVYCKOGBVEV-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-O oxonium Chemical compound [OH3+] XLYOFNOQVPJJNP-UHFFFAOYSA-O 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 1
- 229960002340 pentostatin Drugs 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000012026 peptide coupling reagents Substances 0.000 description 1
- 125000001151 peptidyl group Chemical group 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 229960005190 phenylalanine Drugs 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Chemical class 0.000 description 1
- 230000034190 positive regulation of NF-kappaB transcription factor activity Effects 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000019419 proteases Nutrition 0.000 description 1
- 230000004844 protein turnover Effects 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 229940024999 proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical compound [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- HAMAGKWXRRTWCJ-UHFFFAOYSA-N pyrido[2,3-b][1,4]oxazin-3-one Chemical compound C1=CN=C2OC(=O)C=NC2=C1 HAMAGKWXRRTWCJ-UHFFFAOYSA-N 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 1
- 230000003716 rejuvenation Effects 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 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 1
- 239000013557 residual solvent Substances 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 229960004641 rituximab Drugs 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 229960003440 semustine Drugs 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000003206 sterilizing agent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 238000012916 structural analysis Methods 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 229940097346 sulfobutylether-beta-cyclodextrin Drugs 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 229960003433 thalidomide Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 150000003567 thiocyanates Chemical class 0.000 description 1
- XDLNRRRJZOJTRW-UHFFFAOYSA-N thiohypochlorous acid Chemical compound ClS XDLNRRRJZOJTRW-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- MNRILEROXIRVNJ-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=NC=N[C]21 MNRILEROXIRVNJ-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 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
- 230000007704 transition Effects 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- OVCXRBARSPBVMC-UHFFFAOYSA-N triazolopyridine Chemical compound C=1N2C(C(C)C)=NN=C2C=CC=1C=1OC=NC=1C1=CC=C(F)C=C1 OVCXRBARSPBVMC-UHFFFAOYSA-N 0.000 description 1
- YWBFPKPWMSWWEA-UHFFFAOYSA-O triazolopyrimidine Chemical compound BrC1=CC=CC(C=2N=C3N=CN[N+]3=C(NCC=3C=CN=CC=3)C=2)=C1 YWBFPKPWMSWWEA-UHFFFAOYSA-O 0.000 description 1
- 125000006168 tricyclic group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- PLSARIKBYIPYPF-UHFFFAOYSA-H trimagnesium dicitrate Chemical compound [Mg+2].[Mg+2].[Mg+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O PLSARIKBYIPYPF-UHFFFAOYSA-H 0.000 description 1
- 239000013638 trimer Substances 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical class CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 229940099039 velcade Drugs 0.000 description 1
- JXLYSJRDGCGARV-CFWMRBGOSA-N vinblastine Chemical compound C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-CFWMRBGOSA-N 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- 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
- A61K31/69—Boron compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/04—Esters of boric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Pulmonology (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Epidemiology (AREA)
- Dermatology (AREA)
- Psychiatry (AREA)
- Diabetes (AREA)
- Ophthalmology & Optometry (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Immunology (AREA)
- Cardiology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Obesity (AREA)
- Heart & Thoracic Surgery (AREA)
- Hospice & Palliative Care (AREA)
Abstract
本發明提供適用作蛋白酶體抑制劑的新穎化合物。本發明亦提供包含本發明之化合物的醫藥組合物及使用該等組合物治療各種疾病的方法。
Description
本發明係關適用作蛋白酶體抑制劑的酸及酸酯化合物。本發明亦提供包含本發明化合物的醫藥組合物及使用該等組合物治療各種疾病的方法。
本申請案主張2008年9月29日申請之美國臨時專利申請案第61/194,614號之優先權,該案係以引用的方式全部併入本文中。
酸及酸酯化合物顯示了多種醫藥學上有用的生物活性。Shenvi等人之美國專利第4,499,082號(1985)揭示肽酸為某些蛋白水解酶之抑制劑。Kettner及Shenvi之美國專利第5,187,157號(1993)、美國專利第5,242,904號(1993)及美國專利第5,250,720號(1993)描述一類抑制胰蛋白酶樣蛋白酶之肽酸。Kleeman等人之美國專利第5,169,841號(1992)揭示抑制腎素作用之N末端經修飾的肽酸。Kinder等人之美國專利第5,106,948號(1992)揭示某些酸化合物抑制癌細胞生長。Bachovchin等人之WO 07/0005991揭示抑制纖維母細胞活化蛋白之肽酸化合物。
酸及酸酯化合物作為蛋白酶體(負責大部分細胞內蛋白質轉換之多催化蛋白酶)的抑制劑十分有前景。Adams等人之美國專利第5,780,454號(1998)描述適用作蛋白酶體抑制劑的肽酸酯及肽酸化
合物。此參考文獻亦描述酸酯及酸化合物降低肌肉蛋白質降解速率、降低細胞中NF-κB的活性、降低細胞中p53蛋白的降解速率、抑制細胞中細胞週期素的降解、抑制癌細胞生長及抑制NF-κB依賴性細胞黏著的用途。Furet等人之WO 02/096933、Chatterjee等人之WO 05/016859及Bernadini等人之WO 05/021558及WO 06/08660揭示其他據報導具有蛋白酶體抑制活性的酸酯及酸化合物。
Ciechanover,Cell,79:13-21(1994)揭示蛋白酶體為泛素蛋白酶體路徑之蛋白水解組份,其中蛋白質藉由與多個泛素分子結合而成為降解之目標。Ciechanover亦揭示泛素蛋白酶體路徑在多種重要生理學過程中起著關鍵作用。Rivett等人,Biochem.J.291:1(1993)揭示蛋白酶體顯示胰蛋白酶肽酶活性、胰凝乳蛋白酶肽酶活性及肽基麩胺醯基肽酶活性。20S蛋白酶體構成26S蛋白酶體之催化核心。McCormack等人,Biochemistry 37:7792(1998)教示包括Suc-Leu-Leu-Val-Tyr-AMC、Z-Leu-Leu-Arg-AMC及Z-Leu-Leu-Glu-2NA之多種肽受質受20S蛋白酶體裂解,其中Suc為N-琥珀醯基、AMC為7-胺基4-甲基香豆素而2NA為2-萘胺。
蛋白酶體抑制代表癌症治療之重要新策略。King等人,Science 274:1652-1659(1996)描述泛素蛋白酶體路徑在調節細胞週期、腫瘤生長及轉移中的重要作用。作者教示在細胞週期中泛素蛋白酶體路徑使多種包括細胞週期素及細胞週期素依賴性激酶p21及p27KIP1之關鍵調節蛋白按時序降解。細胞需要有序降解該等蛋白質以完全經歷細胞週期及進行有絲***。
此外,泛素蛋白酶體路徑亦為轉錄調節所需。Palombella等人,Cell,78:773(1994)教示轉錄因子NF-κB之活化受抑制劑蛋白質IκB之蛋白酶體介導之降解調節。NF-κB又在免疫及發炎性反應中所涉及之基因的調節中起重要作用。Read等人,Immunity 2:493-506(1995)教
示泛素蛋白酶體路徑為諸如E-選擇素(E-selectin)、ICAM-1及VCAM-1之細胞黏附分子之表現所需。Zetter,Seminars in Cancer Biology 4:219-229(1993)教示細胞黏附分子藉由引導腫瘤細胞黏附至及自血管滲出至體內之遠端組織部位而參與活體內腫瘤轉移及血管生成。此外,Beg及Baltimore,Science 274:782(1996)教示NF-κB為抗細胞凋亡控制因子,且抑制NF-κB活化使得細胞對環境壓力及細胞毒性劑更敏感。
蛋白酶體抑制劑VELCADE®(硼替佐米(bortezomib);N-2-吡嗪-羰基-L-***酸-L-白胺酸酸)為首個獲得官方批准的蛋白酶體抑制劑。Mitsiades等人,Current Drug Targets,7:1341(2006)回顧了促使批准硼替佐米用於治療事先已接受至少一種療法之多發性骨髓瘤患者的臨床研究。Fisher等人,J.Clin.Oncol.,30:4867描述了證實硼替佐米在患有復發或難治癒套細胞淋巴瘤之患者體內之活性的國際多中心第II期研究。Ishii等人,Anti-Cancer Agents in Medicinal Chemistry,7:359(2007)及Roccaro等人,Curr.Pharm.Biotech.,7:1341(2006)論述多種可能會有助於硼替佐米之抗腫瘤活性的分子機制。
由Voges等人,Annu.Rev.Biochem.,68:1015(1999)報導之結構分析揭示20S蛋白酶體包含28個次單位,其中催化次單位β1、β2及β5分別負責肽基麩胺醯基、胰蛋白酶及胰凝乳蛋白酶肽酶活性。Rivett等人,Curr.Protein Pept.Sci.,5:153(2004)揭示當蛋白酶體曝露於包括IFN-γ及TNF-α之某些細胞激素時,β1、β2及β5次單位經替代催化次單位β1i、β2i及β5i置換,形成稱為免疫蛋白酶體的蛋白酶體之變異體形式。
Orlowski,Hematology(Am.Soc.Hematol.Educ.Program)220(2005)揭示免疫蛋白酶體亦在一些來源於造血前驅細胞之細胞中組成性表現。作者表明對免疫蛋白酶體具有特異性之抑制劑可能允許針對
由血液學起源產生之癌症的靶向療法,從而可能使諸如胃腸及神經組織之正常組織免受副作用。
如上述參考文獻所證明,蛋白酶體代表治療性干預之重要目標。因此,對新穎及/或改良的蛋白酶體抑制劑仍持續存在需要。
本發明提供作為蛋白酶體之一或多種肽酶活性之有效抑制劑的化合物。該等化合物適用於活體外及活體內抑制蛋白酶體活性,且尤其適用於治療各種細胞增生性疾病。
本發明化合物具有通式(I):
或其醫藥學上可接受之鹽或酸酐,其中:A為0、1或2;P為氫或胺基封端部分;Ra1為C1-6脂族基、C1-6氟脂族基、-(CH2) m -CH2-RB、-(CH2) m -CH2-NHC(=NR4)NH-Y、-(CH2) m -CH2-CON(R4)2、-(CH2) m -CH2-N(R4)CON(R4)2、-(CH2) m -CH(R6)N(R4)2、-(CH2) m -CH(R5)-OR5或-(CH2) m -CH(R5)-SR5;各Ra2獨立地為氫、C1-6脂族基、C1-6氟脂族基、-(CH2) m -CH2-Rb、-(CH2) m -CH2-NHC(=NR4)NH-Y、-(CH2) m -CH2-CON(R4)2、-(CH2) m -CH2-N(R4)CON(R4)2、-(CH2) m -CH(R6)N(R4)2、-(CH2) m -CH(R5)-OR5或-(CH2) m -CH(R5)-SR5;各Y獨立地為氫、-CN、-NO2或-S(O)2-R10;各RB獨立地為經取代或未經取代之單環或雙環系統;
各R4獨立地為氫或經取代或未經取代之脂族基、芳基、雜芳基或雜環基;或同一氮原子上之兩個R4連同該氮原子一起形成經取代或未經取代之4至8員雜環基環,該環除該氮原子外還具有0至2個獨立地選自N、O及S之雜環原子;各R5獨立地為氫或經取代或未經取代之脂族基、芳基、雜芳基或雜環基;各R6獨立地為經取代或未經取代之脂族基、芳基或雜芳基;各R10獨立地為C1-6脂族基、C6-10芳基或-N(R4)2;m為0、1或2;Z1及Z2各自獨立地為羥基、烷氧基、芳氧基或芳烷氧基;或Z1及Z2一起形成衍生自酸錯合劑之部分。
除非另外明確聲明,否則術語「蛋白酶體」意指組成性蛋白酶體、免疫蛋白酶體或兩者。
如本文所用之術語「脂族」或「脂族基」意謂完全飽和或含有一或多個單位的不飽和度,但不為芳族之經取代或未經取代之直鏈、分支鏈或環狀C1-12烴。舉例而言,合適芳族基包括經取代或未經取代之直鏈、分支鏈或環狀烷基、烯基或炔基及其雜合物,諸如(環烷基)烷基、(環烯基)烷基或(環烷基)烯基。在各種實施例中,脂族基具有1至20、1至8、1至6、1至4或1至3個碳。
單獨或作為較大部分之一部分使用之術語「烷基」、「烯基」及「炔基」係指具有1至12個碳原子的直鏈或分支鏈脂族基。出於本發明之目的,當將脂族基連接至分子剩餘部分之碳原子為飽和碳原子時將使用術語「烷基」。然而,烷基可在其他碳原子處包括不飽和度。因此,烷基包括(但不限於)甲基、乙基、丙基、烯丙基、炔丙基、丁基、戊基及己基。
出於本發明之目的,當將脂族基連接至分子剩餘部分之碳原子形
成碳碳雙鍵之一部分時將使用術語「烯基」。烯基包括(但不限於)乙烯基、1-丙烯基、1-丁烯基、1-戊烯基及1-己烯基。
出於本發明之目的,當將脂族基連接至分子剩餘部分之碳原子形成碳碳參鍵的一部分時將使用術語「炔基」。炔基包括(但不限於)乙炔基、1-丙炔基、1-丁炔基、1-戊炔基及1-己炔基。
單獨或作為較大部分之一部分使用之術語「環脂族基」係指具有3至約14個成員之飽和或部分不飽和環狀脂族環系統,其中該脂族環系統視情況經取代。在一些實施例中,環脂族基為具有3-8或3-6個環碳原子的單環烴。非限制性實例包括環丙基、環丁基、環戊基、環戊烯基、環己基、環己烯基、環庚基、環庚烯基、環辛基、環辛烯基及環辛二烯基。在一些實施例中,環脂族基為具有6-12、6-10或6-8個環碳原子之橋聯或稠合雙環烴,其中雙環系統中之任何個別環具有3-8個成員。
在一些實施例中,環脂族環上兩個相鄰取代基連同其間之環原子一起形成具有0-3個選自由O、N及S組成之群之環雜原子的視情況經取代之稠合5至6員芳族環或3至8員非芳族環。因此,術語「環脂族基」包括與一或多個芳基、雜芳基或雜環基環稠合的脂族環。非限制性實例包括茚滿基、5,6,7,8-四氫喹喏啉基、十氫萘基或四氫萘基,其中基團或連接點在該脂族環上。
單獨或作為較大部分(例如「芳烷基」、「芳烷氧基」或「芳基氧基烷基」)之一部分使用之術語「芳基」及「芳」係指包含一至三個各自視情況經取代之環的C6至C14芳族烴。較佳地,芳基為C6-10芳基。芳基包括(但不限於)苯基、萘基及蒽基。在一些實施例中,芳基環上兩個相鄰取代基連同其間之環原子一起形成具有0-3個選自由O、N及S組成之群之環雜原子的視情況經取代之稠合5至6員芳族環或4至8員非芳族環。因此,如本文所用之術語「芳基」包括芳基環與一或
多個雜芳基、環脂族或雜環基環稠合的基團,其中基團或連接點在該芳族環上。該等稠合環系統之非限制性實例包括吲哚基、異吲哚基、苯并噻吩基、苯并呋喃基、二苯并呋喃基、吲唑基、苯并咪唑基、苯并噻唑基、喹啉基、異喹啉基、啉基、呔嗪基、喹唑啉基、喹喏啉基、咔唑基、吖啶基、啡嗪基、啡噻嗪基、啡噁嗪基、四氫喹啉基、四氫異喹啉基、茀基、茚滿基、啡啶基、四氫萘基、吲哚啉基、啡噁嗪基、苯并二噁烷基及苯并間二氧雜環戊烯基。芳基可為單環、雙環、三環或多環,較佳為單環、雙環或三環,更佳為單環或雙環。術語「芳基」可與術語「芳基」、「芳基部分」及「芳基環」互換使用。
「芳烷基」或「芳基烷基」包含與烷基共價連接之芳基,其中任一者均獨立地視情況經取代。較佳地,芳烷基為C6-10芳基(C1-6)烷基、C6-10芳基(C1-4)烷基或C6-10芳基(C1-3)烷基,包括(但不限於)苯甲基、苯乙基及萘甲基。
單獨或作為較大部分(例如雜芳烷基或「雜芳烷氧基」)之一部分使用之術語「雜芳基」及「雜芳」係指具有5至14個環原子,較佳具有5、6、9或10個環原子;具有6、10或14個於環陣列中共有之π電子;且除碳原子以外還具有一至四個雜原子之基團。術語「雜原子」係指氮、氧或硫且包括氮或硫之任何氧化形式及鹼性氮之任何四級銨化形式。因此,當關於雜芳基之環原子使用時,術語「氮」包括經氧化之氮(如在吡啶N-氧化物中)。如下文所進一步定義,5員雜芳基之某些氮原子亦可經取代。雜芳基包括(但不限於)衍生自噻吩、呋喃、吡咯、咪唑、吡唑、***、四唑、噁唑、異噁唑、噁二唑、噻唑、異噻唑、噻二唑、吡啶、噠嗪、嘧啶、吡嗪、吲嗪、啶、喋啶、吡咯并吡啶、咪唑并吡啶、噁唑并吡啶、噻唑并吡啶、***并吡啶、吡咯并嘧啶、嘌呤及***并嘧啶的基團。如本文所用之短語「衍生自......的基團」意謂藉由自母體雜芳族環系統移除一個氫基所產生的單價基
團。可在母體雜芳基環系統之任何環上之任何可取代位置處產生基團(亦即,雜芳基與分子剩餘部分之連接點)。
在一些實施例中,雜芳基上兩個相鄰取代基連同其間之環原子一起形成具有0-3個選自由O、N及S組成之群之環雜原子的視情況經取代之稠合5至6員芳族環或4至8員非芳族環。因此,如本文所用之術語「雜芳基」及「雜芳」亦包括一個雜芳族環與一或多個芳基、環脂族或雜環基環稠合的基團,其中基團或連接點在該芳族環上。非限制性實例包括吲哚基、異吲哚基、苯并噻吩基、苯并呋喃基、二苯并呋喃基、吲唑基、苯并咪唑基、苯并噻唑基、苯并噁唑基、喹啉基、異喹啉基、啉基、呔嗪基、喹唑啉基、喹喏啉基、4H-喹嗪基、咔唑基、吖啶基、啡嗪基、啡噻嗪基、啡噁嗪基、四氫喹啉基、四氫異喹啉基及吡啶并[2,3-b]-1,4-噁嗪-3(4H)-酮基。雜芳基可為單環、雙環、三環或多環,較佳為單環、雙環或三環,更佳為單環或雙環。術語「雜芳基」可與術語「雜芳基環」或「雜芳基」互換使用,該等術語中之任一者均包括視情況經取代之環。術語「雜芳烷基」係指經雜芳基取代的烷基,其中該烷基及雜芳基部分獨立地視情況經取代。
如本文所用之術語「芳族環」及「芳族環系統」係指具有0-6個、較佳0-4個環雜原子且具有6、10或14個於環陣列中共有之π電子的視情況經取代之單環、雙環或三環基團。因此,術語「芳族環」及「芳族環系統」涵蓋芳基及雜芳基兩者。
如本文所用之術語「雜環」、「雜環基」、「雜環基團」及「雜環狀環」可互換使用且係指穩定的3至7員單環或稠合7至10員或橋聯6至10員雙環雜環部分,其為飽和或部分不飽和部分且除碳原子以外還具有一或多個,較佳一至四個如上所定義之雜原子。當關於雜環之環原子使用時,術語「氮」包括經取代之氮。舉例而言,在具有1-3個選自氧、硫或氮之雜原子之雜環基環中,氮可為N(如在3,4-二氫-2H-吡咯
基中)、NH(如在吡咯啶基中)或+NR(如在N-經取代之吡咯啶基中)。雜環可以任何產生穩定結構之雜原子或碳原子與其側基連接,且該等環原子中之任一者均可視情況經取代。該等飽和或部分不飽和雜環基的實例包括(但不限於)四氫呋喃基、四氫噻吩基、吡咯啶基、吡咯啶酮基、哌啶基、吡咯啉基、四氫喹啉基、四氫異喹啉基、十氫喹啉基、噁唑啶基、哌嗪基、二噁烷基、二氧戊環基、二氮呯基、噁氮呯基、噻氮呯基、嗎啉基及啶基。
在一些實施例中,雜環上兩個相鄰取代基連同其間之環原子一起形成具有0-3個選自由O、N及S組成之群之環雜原子的視情況經取代之稠合5至6員芳族環或3至8員非芳族環。因此,術語「雜環」、「雜環基」、「雜環基環」、「雜環基」、「雜環部分」及「雜環基團」在本文中可互換使用,且包括一個雜環基環與一或多個芳基、雜芳基或環脂族環稠合的基團,諸如吲哚啉基、3H-吲哚基、烷基、啡啶基或四氫喹啉基,其中基團或連接點在該雜環基環上。雜環基可為單環、雙環、三環或多環,較佳為單環、雙環或三環,更佳為單環或雙環。術語「雜環基烷基」指經雜環基取代的烷基,其中烷基及雜環基部分獨立地視情況經取代。
如本文所用之術語「部分不飽和」係指在環原子之間包括至少一個雙鍵或三鍵的環部分。術語「部分不飽和」意欲涵蓋具有多個位點之不飽和度的環,但不欲包括如本文所定義之芳基或雜芳基部分。
術語「鹵脂族基」、「鹵烷基」、「鹵烯基」及「鹵烷氧基」係指視情況經一或多個鹵素原子取代之脂族基、烷基、烯基或烷氧基。如本文所用之術語「鹵素」或「鹵基」意謂F、Cl、Br或I。術語「氟脂族基」係指鹵素為氟的鹵脂族基,包括全氟脂族基。氟脂族基之實例包括(但不限於)氟甲基、二氟甲基、三氟甲基、2-氟乙酯、2,2,2-三氟乙基、1,1,2-三氟乙基、1,2,2-三氟乙基及五氟乙基。
術語「連接基」或「連接子」意謂連接化合物之兩個部分之有機部分。連接子通常包含諸如氧或硫之原子、諸如-NH-、-CH2-、-C(O)、-C(O)NH-之單元或諸如伸烷基鏈之原子鏈。連接子之分子質量通常在約14至200之範圍內,較佳在14至96之範圍內,長度為至多約6個原子。在一些實施例中,連接子為C1-6伸烷基鏈。
術語「伸烷基」係指二價烷基。「伸烷基鏈」為聚亞甲基,亦即-(CH2)x-,其中x為正整數,較佳為1至6、1至4、1至3、1至2或2至3。經取代伸烷基鏈為一或多個亞甲基氫原子經取代基置換的聚亞甲基。合適取代基包括以下關於經取代脂族基描述之彼等取代基。伸烷基鏈亦可於一或多個位置經脂族基或經取代脂族基取代。
伸烷基鏈亦可視情況雜有官能基。當內部亞甲基單元經官能基置換時,伸烷基鏈「雜有」官能基。合適「雜入官能基」之非限制性實例包括-C(R*)=C(R*)-、-C≡C-、-O-、-S-、-S(O)-、-S(O)2-、-S(O)2N(R+)-、-N(R*)-、-N(R+)CO-、-N(R+)C(O)N(R+)-、-N(R+)C(=NR+)-N(R+)-、-N(R+)-C(=NR+)-、-N(R+)CO2-、-N(R+)SO2-、-N(R+)SO2N(R+)-、-OC(O)-、-OC(O)O-、-OC(O)N(R+)-、-C(O)-、-CO2-、-C(O)N(R+)-、-C(O)-C(O)-、-C(=NR+)-N(R+)-、-C(NR+)=N-、-C(=NR+)-O-、-C(OR*)=N-、-C(Ro)=N-O-或-N(R+)-N(R+)-。各R+獨立為氫或視情況經取代之脂族基、芳基、雜芳基或雜環基,或同一氮原子上之兩個R+連同該氮原子一起形成除該氮原子以外還具有0-2個選自N、O及S之環雜原子的5-8員芳族環或非芳族環。各R*獨立地為氫或視情況經取代之脂族基、芳基、雜芳基或雜環基。
「雜有」-O-之C3-6伸烷基鏈之實例包括例如-CH2OCH2-、-CH2O(CH2)2-、-CH2O(CH2)3-、-CH2O(CH2)4-、-(CH2)2OCH2-、-(CH2)2O(CH2)2-、-(CH2)2O(CH2)3-、-(CH2)3O(CH2)-、-(CH2)3O(CH2)2-及-(CH2)4O(CH2)-。「雜有」官能基之伸烷基鏈之實例包括-CH2ZCH2-
、-CH2Z(CH2)2-、-CH2Z(CH2)3-、-CH2Z(CH2)4-、-(CH2)2ZCH2-、-(CH2)2Z(CH2)2-、-(CH2)2Z(CH2)3-、-(CH2)3Z(CH2)-、-(CH2)3Z(CH2)2-及-(CH2)4Z(CH2)-,其中Z為上文所列之「雜入」官能基之一。
一般技術者將認識到,當具有雜入基團之伸烷基鏈連接於官能基時,某些組合對於醫藥用途而言將不夠穩定。類似地,T1與R2c或T2與R2d之某些組合對於醫藥用途而言將不夠穩定。僅穩定或化學上可行之化合物在本發明之範疇內。穩定或化學上可行之化合物為維持其完整性足夠久以適用於對患者進行治療性或預防性投藥者。較佳地,當在低於-70℃、低於-50℃、低於-20℃、低於0℃或低於20℃之溫度下,在不存在水分或其他化學反應性條件之情況下保存至少一週時,化學結構實質上無改變。
如本文所用之「經取代」意謂所指定部分之氫基經指定取代基置換,限制條件為該取代產生穩定或化學上可行之化合物。當關於所指定原子使用時,術語「可取代」意謂可經合適取代基置換之氫基連接於該原子。
如本文所用之短語「一或多個取代基」係指等於一至基於可用鍵結位點之數目可能的取代基之最大數目的取代基數目,限制條件為符合上述穩定性及化學可行性的條件。除非另有說明,否則視情況經取代之基團可在基團之各可取代位置具有取代基,且該等取代基可相同或不同。
如本文所用之術語「獨立地選自」意謂在單一化合物中可對指定代號之多個實例選擇相同或不同值。
芳基(包括芳烷基、芳烷氧基、芳基氧基烷基及其類似基團之芳基部分)或雜芳基(包括雜芳烷基及雜芳烷氧基及其類似基團之雜芳基部分)可含有一或多個取代基。芳基或雜芳基之不飽和碳原子上之合適取代基的非限制性實例包括鹵基、-NO2、-CN、-R*、-
C(R*)=C(R*)2、-C≡C-R*、-OR*、-SRo、-S(O)Ro、-SO2Ro、-SO3R*、-SO2N(R+)2、-N(R+)2、-NR+C(O)R*、-NR+C(O)N(R+)2、-N(R+)C(=NR+)-N(R+)2、-N(R+)C(=NR+)-Ro、-NR+CO2Ro、-NR+SO2Ro、-NR+SO2N(R+)2、-O-C(O)R*、-O-CO2R*、-OC(O)N(R+)2、-C(O)R*、-CO2R*、-C(O)-C(O)R*、-C(O)N(R+)2、-C(O)N(R+)-OR*、-C(O)N(R+)C(=NR+)-N(R+)2、-N(R+)C(=NR+)-N(R+)-C(O)R*、-C(=NR+)-N(R+)2、-C(=NR+)-OR*、-N(R+)-N(R+)2、-C(=NR+)-N(R+)-OR*、-C(Ro)=N-OR*、-P(O)(R*)2、-P(O)(OR*)2、-O-P(O)-OR*及-P(O)(NR+)-N(R+)2,其中Ro為視情況經取代之脂族基、芳基或雜芳基,且R+及R*係如上文所定義,或兩個相鄰取代基連同其間之原子一起形成具有0-3個選自由N、O及S組成之群之環原子的5至6員不飽和或部分不飽和環。
脂族基或非芳族雜環可經一或多個取代基取代。脂族基或非芳族雜環之飽和碳上之合適取代基的實例包括(但不限於)上文關於芳基或雜芳基之不飽和碳所列出者及以下:=O、=S、=C(R*)2、=N-N(R*)2、=N-OR*、=N-NHC(O)R*、=N-NHCO2Ro、=N-NHSO2Ro或=N-R*,其中R*及Ro各自係如上文所定義。
雜芳基或非芳族雜環之可取代氮原子上之合適取代基包括(但不限於)-R*、-N(R*)2、-C(O)R*、-CO2R*、-C(O)-C(O)R*、-C(O)CH2C(O)R*、-SO2R*、-SO2N(R*)2、-C(=S)N(R*)2、-C(=NH)-N(R*)2及-NR*SO2R*;其中各R*係如上文所定義。雜芳基或非芳族雜環之環氮原子亦可經氧化以形成相應N-羥基或N-氧化物化合物。該種具有氧化環氮原子之雜芳基之一非限制性實例為N-伸氧吡啶基。
本文中使用之術語「約」意謂大約、在範圍內、大致或左右。當結合數值範圍使用術語「約」時,其藉由使所闡明數值之界限上下擴展來修訂該範圍。一般而言,本文中使用術語「約」來修訂數值至所
述數值上方及下方10%的偏差。
如本文所用之術語「包含」意謂「包括(但不限於)」。
熟習此項技術者將明瞭,本發明之某些化合物可以互變異構體形式存在,化合物之所有該等互變異構形式均在本發明之範疇內。除非另有說明,否則本文所述之結構亦意欲包括所有幾何(或構形)異構體,亦即(Z)及(E)雙鍵異構體及(Z)及(E)構形異構體,以及結構之所有立體化學形式;亦即各不對稱中心的R及S構型。因此,本發明化合物之單一立體化學異構體以及對映異構及非對映異構混合物均在本發明之範疇內。當混合物中相對於另一立體異構體富含一種立體異構體時,該混合物可含有例如至少50%、75%、90%、99%或99.5%之對映異構體過量。
除非另有說明,否則本文所述之結構亦意欲包括僅因存在一或多個同位素富集原子而不同之化合物。舉例而言,除氫經氘或氚置換,或碳原子經13C-或14C-富集碳置換以外,具有本發明結構之化合物均在本發明之範疇內。
在式(I)化合物中,代號P為氫或胺基封端部分。胺基封端部分之非限制性實例可見於P.G.M.Wuts及T.W.Greene,Greene's Protective Groups in Organic Synthesis(第四版)John Wiley & Sons,NJ(2007)中,且包括例如醯基、磺醯基、氧醯基及胺醯基。
在一些實施例中,P為Rc-C(O)-、Rc-O-C(O)-、Rc-N(R4c)-C(O)-、Rc-S(O)2-或Rc-N(R4c)-S(O)2-,其中Rc係選自由C1-6脂族基、C1-6氟脂族基、-RD、-T1-RD及-T1-R2c組成之群,且代號T1、RD、R2c及R4c具有下文描述之值。
代號R4c為氫、C1-4烷基、C1-4氟烷基或C6-10芳(C1-4烷基,其芳基部分經取代或未經取代。在一些實施例中,R4c為氫或C1-4烷基。在某些特定實施例中,R4c為氫。
代號T1為經0-2個獨立選擇之R3a或R3b取代的C1-6伸烷基鏈,其中伸烷基鏈視情況雜有-C(R5)=C(R5)-、-C≡C-或-O-。各R3a獨立地選自由以下組成之群:-F、-OH、-O(C1-4烷基)、-CN、-N(R4)2、-C(O)(C1-4烷基)、-CO2H、-CO2(C1-4烷基)、-C(O)NH2及-C(O)-NH(C1-4烷基)。各R3b獨立地為視情況經R3a或R7取代之C1-3脂族基。各R7為經取代或未經取代之芳族基。在一些實施例中,T1為C1-4伸烷基鏈。
代號R2c為鹵基、-OR5、-SR6、-S(O)R6、-SO2R6、-SO2N(R4)2、-N(R4)2、-NR4C(O)R5、-NR4C(O)N(R4)2、-NR4CO2R6、-N(R4)SO2R6、-N(R4)SO2N(R4)2、-O-C(O)R5、-OC(O)N(R4)2、-C(O)R5、-CO2R5或-C(O)N(R4)2,其中:各R4獨立地為氫或視情況經取代之脂族基、芳基、雜芳基或雜環基;或同一氮原子上之兩個R4連同氮原子一起形成除該氮原子以外還具有0-2個獨立地選自N、O及S之環雜原子的視情況經取代之4至8員雜環基環;各R5獨立地為氫或視情況經取代之脂族基、芳基、雜芳基或雜環基;且各R6獨立地為視情況經取代之脂族基、芳基或雜芳基。
代號RD為經取代或未經取代之芳族環、雜環基環或環脂族環,其中任一者視情況與經取代或未經取代之芳族環、雜環基環或環脂族環稠合。RD中之各飽和環碳原子未經取代,或經=O、Rd或R8d取代。RD中之各不飽和環碳原子未經取代,或經Rd或R8d取代。RD中之各可取代環氮原子未經取代或經以下取代:-C(O)R5、-C(O)N(R4)2、-CO2R6、-SO2R6、-SO2N(R4)2、C1-4脂族基、經取代或未經取代之C6-10芳基或C6-10芳(C1-4)烷基,其芳基部分經取代或未經取代。
在一些實施例中,RD中之一或兩個飽和環碳原子係經=O取代;RD中之剩餘可取代之環碳原子經0-2個Rd及0-2個R8d取代;且RD中之
各可取代環氮原子未經取代或經以下取代:-C(O)R5、-C(O)N(R4)2、-CO2R6、-SO2R6、-SO2N(R4)2、C1-4脂族基、經取代或未經取代之C6-10芳基或C6-10芳(C1-4)烷基,其芳基部分經取代或未經取代。各Rd係獨立地選自由以下組成之群:C1-6脂族基、C1-6氟脂族基、鹵基、-R1d、-R2d、-T2-R1d及-T2-R2d,其中代號T2、R1d、R2d及R8d具有下文描述之值。
T2為經0-2個獨立選擇之R3a或R3b取代的C1-6伸烷基鏈,其中該伸烷基鏈視情況雜有-C(R5)=C(R5)-、-C≡C-或-O-。代號R3a及R3b具有上文所述之值。
各R1d獨立地為經取代或未經取代之芳基、雜芳基、雜環基或環脂族環。
各R2d獨立地為-NO2、-CN、-C(R5)=C(R5)2、-C≡C-R5、-OR5、-SR6、-S(O)R6、-SO2R6、-SO2N(R4)2、-N(R4)2、-NR4C(O)R5、-NR4C(O)N(R4)2、-N(R4)C(=NR4)-N(R4)2、-N(R4)C(=NR4)-R6、-NR4CO2R6、-N(R4)SO2R6、-N(R4)SO2N(R4)2、-O-C(O)R5、-OC(O)N(R4)2、-C(O)R5、-CO2R5、-C(O)N(R4)2、-C(O)N(R4)-OR5、-C(O)N(R4)C(=NR4)-N(R4)2、-N(R4)C(=NR4)-N(R4)-C(O)R5或-C(=NR4)-N(R4)2。
各R8d係獨立地選自由以下組成之群:C1-4脂族基、C1-4氟脂族基、鹵基、-OH、-O(C1-4脂族基)、-NH2、-NH(C1-4脂族基)及-N(C1-4脂族基)2。
在一些實施例中,RD為選自由以下組成之群之經取代或未經取代之單環或雙環系統:呋喃基、噻吩基、吡咯基、異噁唑基、噁唑基、噻唑基、異噻唑基、咪唑基、吡唑基、噁二唑基、噻二唑基、苯基、吡啶基、噠嗪基、嘧啶基、吡嗪基、苯并呋喃基、苯并噻吩基、吲哚基、苯并噁唑基、苯并異噁唑基、苯并咪唑基、吲唑基、嘌呤基、萘
基、喹啉基、異喹啉基、啉基、喹唑啉基、喹喏啉基、呔嗪基、啶基、四氫喹啉基、四氫異喹啉基、四氫喹喏啉基及二氫苯并噁嗪基。在一些實施例中,RD為選自由以下組成之群之經取代或未經取代之單環或雙環系統:苯基、吡啶基、嘧啶基、吡嗪基、萘基、苯并咪唑基、喹啉基、異喹啉基、喹喏啉基、四氫喹啉基、四氫異喹啉基、四氫喹喏啉基及二氫苯并噁嗪基。
在一些實施例中,RD中之一或兩個飽和環碳原子經=O取代,且RD中之剩餘可取代環碳原子經0-1個Rd及0-2個R8d取代,其中:各Rd係獨立地選自由以下組成之群:C1-6脂族基、C1-6氟脂族基、鹵基、-R1d、-R2d、-T2-R1d及-T2-R2d;T2為未經取代或經R3a或R3b取代之C1-3伸烷基鏈;各R1d獨立地為經取代或未經取代之芳基、雜芳基、雜環基或環脂族環;且各R2d獨立地為-OR5、-SR6、-S(O)R6、-SO2R6、-SO2N(R4)2、-N(R4)2、-NR4C(O)R5、-NR4C(O)N(R4)2、-O-C(O)R5、-OC(O)N(R4)2、-C(O)R5、-CO2R5或-C(O)N(R4)2。
在一些實施例中,代號Rd具有式-Q-RE,其中Q為-O-、-NH-或-CH2-,且RE為經取代或未經取代之芳基、雜芳基、雜環基或環脂族環。在一些實施例中,RE為經取代或未經取代之苯基、吡啶基、嘧啶基、吡嗪基、哌啶基、哌嗪基或嗎啉基環。
在一些實施例中,P具有式Rc-C(O)-,其中Rc為C1-4烷基、C1-4氟烷基或C6-10芳(C1-4)烷基,其芳基部分經取代或未經取代。在某些該等實施例中,P係選自由乙醯基、三氟乙醯基及苯乙醯基組成之群。
在一些實施例中,P具有式RD-C(O)-,其中RD為經取代或未經取代之苯基、吡啶基、吡嗪基、嘧啶基、喹啉基或喹喏啉基。在某些實施例中,P具有式RD-C(O)-,其中RD為經0-1個Rd及0-2個R8d取代之苯
基、吡啶基、吡嗪基、嘧啶基、萘基、喹啉基、喹喏啉基、苯并咪唑基或二氫苯并噁嗪基。在某些特定實施例中,P具有式RD-C(O)-,其中RD為經式-O-RE之取代基取代之吡啶基、吡嗪基或嘧啶基,且RE為經取代或未經取代之苯基。在某些其他特定實施例中,P具有式RD-C(O)-,其中RD為經式-O-RE之取代基取代之苯基,且RE為經取代或未經取代之吡啶基、吡嗪基或嘧啶基。
在一些其他實施例中,P具有式Rc-SO2-,其中Rc為-RD或-T1-RD,其中T1為C1-4伸烷基且RD為經0-1個Rd及0-2個R8d取代之苯基、吡啶基、吡嗪基、嘧啶基、萘基、喹啉基、喹喏啉基、苯并咪唑基或二氫苯并噁嗪基。在一些實施例中,P具有式RD-SO2-,其中RD為經取代或未經取代之苯基、吡啶基、吡嗪基、嘧啶基、喹啉基或喹喏啉基。在某些實施例中,P具有式RD-SO2-,其中RD為經0-1個Rd及0-2個R8d取代之苯基、吡啶基、吡嗪基、嘧啶基、萘基、喹啉基、喹喏啉基、苯并咪唑基或二氫苯并噁嗪基。在某些特定實施例中,P具有式RD-SO2-,其中RD為經式-O-RE之取代基取代之吡啶基、吡嗪基或嘧啶基,且RE為經取代或未經取代之苯基。在某些其他特定實施例中,P具有式RD-SO2-,其中RD為經式-O-RE之取代基取代之苯基,且RE為經取代或未經取代之吡啶基、吡嗪基或嘧啶基。
代號Ra1及各代號Ra2獨立地為C1-6脂族基、C1-6氟脂族基、-(CH2) m -CH2-RB、-(CH2) m -CH2-NHC(=NR4)NH-Y、-(CH2) m -CH2-CON(R4)2、-(CH2) m -CH2-N(R4)CON(R4)2、-(CH2) m -CH(R6)N(R4)2、-(CH2) m -CH(R5)-OR5或-(CH2) m -CH(R5)-SR5,其中代號R4、R5及R6具有上文所述之值,且代號RB及m具有下文描述之值。
各RB獨立地為經取代或未經取代之單雙或雙環系統。在一些實施例中,各RB獨立地為經取代或未經取代之苯基、吡啶基、吲哚基、苯并咪唑基、萘基、喹啉基、喹喏啉基或異喹啉基環。在某些實施例
中,RB為經取代或未經取代之苯基環。
代號m為0、1或2。在一些實施例中,m為0或1。
在一些實施例中,Ra1及Ra2各自獨立地為C1-6脂族基、C1-6氟脂族基或-(CH2) m -CH2-RB,且m為0或1。在一些該等實施例中,RB為經取代或未經取代之苯基。
在一些實施例中,Ra1為C1-6脂族基、-(CH2) m -CH2RB或-(CH2) m -CH(C1-4烷基)-OH。在某些實施例中,Ra1為苯甲基。在其他某些實施例中,Ra1為-CH2-CH(CH3)-OH。
在一些實施例中,Ra2為C1-6脂族基或-(CH2) m -CH2RB。在某些實施例中,Ra2為異丙基、苯甲基或苯乙基。
代號A為0、1或2。在一些實施例中,A為0或1。在某些實施例中,A為0。
在一些實施例中,本發明係關於特徵為式(I-A)之式(I)化合物:
或其醫藥學上可接受之鹽或酸酐,其中各代號P、Ra1、Ra2、A、Z1及Z2具有上文針對式(I)描述之值及較佳值。
在某些實施例中,本發明係關於特徵為式(I-B)之式(I)之化合物:
或其醫藥學上可接受之鹽或酸酐,其中各代號P、Ra1、Ra2、A、Z1及Z2具有上文針對式(I)描述之值及較佳值。
在某些特定實施例中,本發明係關於特徵為式(II)之式(I)化合物:
或其醫藥學上可接受之鹽或酸酐,其中各代號P、Z1及Z2具有上文針對式(I)描述之值及較佳值。
在一些實施例中,本發明係關於式(II)化合物,其中P具有式RD-C(O)-,其中RD為經取代或未經取代之苯基、吡啶基、吡嗪基、嘧啶基、喹啉基或喹喏啉基。在某些實施例中,P具有式RD-C(O)-,其中RD為經0-1個Rd及0-2個R8d取代的苯基、吡啶基、吡嗪基、嘧啶基、萘基、喹啉基、喹喏啉基、苯并咪唑基或二氫苯并噁嗪基。在某些特定實施例中,P具有式RD-C(O)-,其中RD為經式-O-RE之取代基取代之吡啶基、吡嗪基或嘧啶基,且RE為經取代或未經取代之苯基。在某些其他特定實施例中,P具有式RD-C(O)-,其中RD為經式-O-RE之取代基取代之苯基,且RE為經取代或未經取代之吡啶基、吡嗪基或嘧啶基。
在一些其它實施例中,本發明係關於式(II)化合物,其中P具有式Rc-SO2-,其中Rc為-RD或-T1-RD,其中T1為C1-4伸烷基且RD為經0-1個Rd及0-2個R8d取代的苯基、吡啶基、吡嗪基、嘧啶基、萘基、喹啉基、喹喏啉基、苯并咪唑基或二氫苯并噁嗪基。在一些實施例中,P具有式RD-SO2-,其中RD為經取代或未經取代之苯基、吡啶基、吡嗪基、嘧啶基、喹啉基或喹喏啉基。在某些實施例中,P具有式RD-SO2-
,其中RD為經0-1個Rd及0-2個R8d取代的苯基、吡啶基、吡嗪基、嘧啶基、萘基、喹啉基、喹喏啉基、苯并咪唑基或二氫苯并噁嗪基。在某些特定實施例中,P具有式RD-SO2-,其中RD為經式-O-RE之取代基取代之吡啶基、吡嗪基或嘧啶基,且RE為經取代或未經取代之苯基。在某些其他特定實施例中,P具有式RD-SO2-,其中RD為經式-O-RE之取代基取代之苯基,且RE為經取代或未經取代之吡啶基、吡嗪基或嘧啶基。
式(I)化合物之代表性實例展示於表1中。
上表1中之化合物亦可由以下化學名稱鑑別:
如本文所用之術語「酸」係指含有-B(OH)2部分之化合物。在一些實施例中,酸化合物可藉由酸部分之脫水作用形成寡聚酸
酐。舉例而言,Snyder等人,J.Am.Chem.Soc.80:3611(1958)報導寡聚芳基酸。
如本文所用之術語「酸酐」係指藉由兩個或兩個以上酸化合物分子失去一或多個水分子而組合形成的化合物。當與水混合時,酸酐化合物水合釋放游離酸化合物。在各種實施例中,酸酐可包含兩個、三個、四個或更多個酸單元,且可具有環狀或線性構型。本發明肽酸化合物之寡聚酸酐之非限制性實例說明如下:
在式(1)及(2)中,代號n為0至約10之整數,較佳為0、1、2、3或4。在一些實施例中,酸酐化合物包含式(2)之環狀三聚體(「烷基硼氧烷」),其中n為1。代號W具有式(3):
其中代號P、Ra1及Ra2具有上文針對式(I)所述之值及較佳值。
在一些實施例中,酸酐化合物中所存在酸之至少80%以單一寡聚酸酐形式存在。在一些實施例中,酸酐化合物中所存在酸之至少85%、90%、95%或99%以單一寡聚酸酐形式存在。在某些較佳實施例中,酸酐化合物由具有式(3)之烷基硼氧烷組成,或基本上由具有式(3)之烷基硼氧烷組成。
酸酐化合物較佳可由相應酸藉由曝露於脫水條件(包括但不限於再結晶、冷凍乾燥)、曝露於熱及/或曝露於乾燥劑來製備。合適再結晶溶劑之非限制性實例包括乙酸乙酯、二氯甲烷、己烷、***、乙腈、乙醇及其混合物。
在一些實施例中、Z1及Z2一起形成衍生自酸錯合劑之部分。出於本發明之目的,術語「酸錯合劑」係指具有至少兩個官能基,且各官能基可與硼形成共價鍵之任何化合物。合適官能基之非限制性實例包括胺基、羥基及羧基。在一些實施例中,至少一個官能基為羥基。術語「衍生自酸錯合劑之部分」係指藉由自酸錯合劑之兩個官能基移除氫原子所形成的部分。
如本文所用之術語「酸酯(boronate ester)」及「酸酯(boronic ester)」可互換使用且係指含有-B(Z1)(Z2)部分之化合物,其中Z1或Z2中之至少一者為烷氧基、芳烷氧基或芳氧基;或Z1及Z2一起形成衍生自具有至少一個羥基之酸錯合劑的部分。
在式(I)、(I-A)、(I-B)及(II)之化合物中,Z1及Z2各自獨立地為羥基、烷氧基、芳氧基或芳烷氧基;或Z1及Z2一起形成衍生自酸錯合劑的部分。在一些實施例中,Z1及Z2各自為羥基。在一些其他實施例中,Z1及Z2一起形成衍生自鏈或環中具有至少兩個由至少兩個連接原子隔開之羥基之化合物的部分,該鏈或環包含碳原子且視情況包含一或多個可為N、S或O之雜原子,其中在各狀況下與硼連接之原子為氧原子。
如本文所用之術語「具有至少兩個羥基之化合物」係指具有兩個或兩個以上羥基之任何化合物。出於本發明之目的,兩個羥基較佳由至少兩個連接原子,較佳約2至約5個連接原子,更佳2或3個連接原子隔開。為方便起見,術語「二羥基化合物」可用於指代如上文所定義之具有至少兩個羥基的化合物。因此,如本文所用之術語「二羥基化
合物」不欲限於僅具有兩個羥基的化合物。衍生自具有至少兩個羥基之化合物的部分可藉由其中任意兩個羥基之氧原子與硼連接。較佳地,硼原子、與硼連接之氧原子及連接該兩個氧原子之原子一起形成5或6員環。
出於本發明之目的,酸錯合劑較佳為醫藥學上可接受的,亦即合適投與人類。在一些較佳實施例中,酸錯合劑為糖,如例如Plamondon等人之WO 02/059131及Gupta等人之WO 02/059130中所描述。術語「糖」包括任何多羥基碳水化物部分,包括單醣、雙醣、多醣、糖醇及胺基糖。在一些實施例中,糖為單醣、雙醣、糖醇或胺基糖。合適糖之非限制性實例包括葡萄糖、蔗糖、果糖、海藻糖、甘露糖醇、山梨糖醇、葡糖胺及N-甲基葡糖胺。在某些實施例中,糖為甘露糖醇或山梨糖醇。因此,在糖為甘露糖醇或山梨糖醇之實施例中,Z1及Z2一起形成式C6H12O6之部分,其中兩個去質子化羥基之氧原子與硼形成共價連接以形成酸酯化合物。在某些特定實施例中,Z1及Z2一起形成衍生自D-甘露糖醇之部分。
在一些其它較佳實施例中,如例如Elliott等人於2009年6月16日申請之U.S.12/485,344中所述,酸錯合劑為α-羥基羧酸或β-羥基羧酸。在一些該等實施例中,酸錯合劑係選自由以下組成之群:乙醇酸、蘋果酸、六氫扁桃酸、檸檬酸、2-羥基異丁酸、3-羥基丁酸、扁桃酸、乳酸、2-羥基-3,3-二甲基丁酸、2-羥基-3-甲基丁酸、2-羥基異己酸、β-羥基異戊酸、水楊酸、酒石酸、二苯基乙醇酸、葡糖庚酸、葡萄糖酸、乳糖酸、半乳糖二酸、亞甲基雙羥萘酸、1-羥基-2-萘甲酸及3-羥基-2-萘甲酸。在某些該等實施例中,酸錯合劑為檸檬酸。
通用合成方法
式(I)之化合物可藉由一般技術者已知之方法製備。參見例如Adams等人之美國專利第5,780,454號;Pickersgill等人之國際專利公
開案WO 2005/097809。本發明N-醯基-肽基酸化合物(P=Rc-C(O)-)之一例示性合成路徑闡述於下文流程1中。
使化合物i與N-經保護之胺基酸(ii)偶合,隨後脫除N末端之保護基,形成化合物iii。合適保護基(PG)的實例包括(但不限於):醯基保護基,例如甲醯基、乙醯基(Ac)、琥珀醯基(Suc)及甲氧基琥珀醯基;及胺基甲酸酯保護基,例如第三丁氧羰基(Boc)、苯甲氧羰基(Cbz)及茀基甲氧羰基(Fmoc)。肽偶合反應可藉由先將化合物ii之羧酸部分轉化為活化酯(例如O-(N-羥基琥珀醯亞胺)酯),隨後以化合物i處理來進行。或者,可藉由使羧酸與肽偶合試劑接觸來現場產生活化酯。合適肽偶合試劑的實例包括(但不限於):碳化二亞胺試劑,例如二環己基碳化二亞胺(DCC)或1-(3-二甲胺基丙基)-3-乙基碳化二亞胺(EDC);鏻試劑,例如六氟磷酸苯并***-1-基氧基三(二甲胺基)鏻(BOP);及試劑,例如四氟酸O-(1H-苯并***-1-基)-N,N,N',N'-四甲基(TBTU)。
隨後使化合物iii與羧酸(RcCO2H)偶合得到化合物iv。上述用於化合物i與化合物ii之偶合之肽偶合條件亦適用於偶合化合物iii與RcCO2H。隨後,脫除酸部分之保護基得到化合物v。較佳藉由在包
含酸酯化合物iv、有機酸受體、低碳烷醇、C5-8烴溶劑及無機酸水溶液之兩相混合物中進行酯基轉移反應完成保護基脫除步驟。
或者,如流程2所示,逆轉偶合反應之順序。因此,首先使O-經保護之甘胺酸(vi)與經取代之苯甲酸(ArCO2H)偶合,隨後進行酯水解以形成化合物vii。隨後,如上文關於流程1所述完成與化合物i之偶合及酸保護基脫除以得到化合物v。
製備本發明之N-磺醯基-肽基酸化合物(P=Rc-S(O)2-)之一例示性合成路徑闡述於下文流程3中:流程3:
在鹼(諸如二異丙基乙胺)存在下用磺醯氯處理如上文關於流程1所述製備之化合物iii以得到化合物vi。隨後,如上文關於流程1所述完成酸部分之保護基脫除以得到化合物vii。亦可以類似於流程2之方式逆轉製備化合物vii之反應順序。
用途、調配物及投藥
本發明提供作為蛋白酶體之有效抑制劑的化合物。可在活體外或活體內檢定該等化合物抑制蛋白酶體介導之肽水解或蛋白質降解的能力。
因此,在另一態樣中,本發明提供一種抑制細胞中蛋白酶體之一或多種肽酶活性的方法,其包含使需要蛋白酶體抑制之細胞與本文所述之化合物或其醫藥學上可接受之鹽、酸酯或酸酐相接觸。
本發明亦提供一種抑制細胞增殖的方法,其包含使需要此抑制之細胞與本文所述之化合物相接觸。短語「抑制細胞增殖」用來表示與未接觸抑制劑之細胞相比,本發明化合物抑制接觸細胞之細胞數目及細胞生長的能力。可藉由使用細胞計數器計數細胞或藉由細胞生存力檢定(例如MTT或WST檢定)來評估細胞增殖。當細胞處於實體生長(例如實體腫瘤或器官)中時,可藉由例如以測徑規量測生長,並比較接觸細胞與未接觸細胞之生長尺寸來進行細胞增殖之該種評估。
較佳地,與未接觸細胞的生長相比,與抑制劑接觸之細胞的生長延緩至少約50%。在各種實施例中,與未接觸細胞相比,接觸細胞之細胞增殖受抑制達至少約75%、至少約90%或至少約95%。在一些實施例中,短語「抑制細胞增殖」包括與未接觸細胞相比,接觸細胞之數目減少。因此,抑制接觸細胞之細胞增殖的蛋白酶體抑制劑可誘導接觸細胞經歷生長延緩、經歷生長停滯、經歷漸進式細胞死亡(亦即凋亡)或經歷壞死性細胞死亡。
在另一態樣中,本發明提供一種醫藥組合物,其包含式(I)化合物或其醫藥學上可接受之鹽或酸酐,及醫藥學上可接受之載劑。
若在該等組合物中使用本發明化合物之醫藥學上可接受之鹽,則該鹽較佳衍生自無機或有機酸或鹼。關於合適鹽之回顧,參見例如Berge等人,J.Pharm.Sci.66:1-19(1977)及Remington:The Science and Practice of Pharmacy,第20版,A.Gennaro編,Lippincott Williams & Wilkins,2000。
合適酸加成鹽之非限制性實例包括以下:乙酸鹽、己二酸鹽、海藻酸鹽、天冬胺酸鹽、苯甲酸鹽、苯磺酸鹽、硫酸氫鹽、丁酸鹽、檸檬酸鹽、樟腦酸鹽、樟腦磺酸鹽、環戊烷丙酸鹽、二葡萄糖酸鹽、月桂基硫酸鹽、乙烷磺酸鹽、反丁烯二酸鹽、葡糖庚酸鹽(lucoheptanoate)、甘油磷酸鹽、半硫酸鹽、庚酸鹽、己酸鹽、鹽酸鹽、氫溴酸鹽、氫碘酸鹽、2-羥基乙烷磺酸鹽、乳酸鹽、順丁烯二酸、甲烷磺酸鹽、2-萘磺酸鹽、菸鹼酸鹽、草酸鹽、雙羥萘酸鹽、果膠酸鹽、過硫酸鹽、3-苯基-丙酸鹽、苦酸鹽、特戊酸鹽、丙酸鹽、琥珀酸鹽、酒石酸鹽、硫氰酸鹽、甲苯磺酸鹽及十一烷酸鹽。
合適鹼加成鹽包括(但不限於):銨鹽;鹼金屬鹽,諸如鋰鹽、鈉鹽及鉀鹽;鹼土金屬鹽,諸如鈣鹽及鎂鹽;其他多價金屬鹽,諸如鋅鹽;與諸如二環己胺、N-甲基-D-葡糖胺、第三丁胺、乙二胺、乙醇
胺及膽鹼之有機鹼形成之鹽;以及與諸如精胺酸、離胺酸之胺基酸形成之鹽,等等。在一些實施例中,醫藥學上可接受之鹽為式(I)之酸化合物的鹼加成鹽,其中Z1及Z2均為羥基。
如本文所用之術語「醫藥學上可接受之載劑」係指與接受個體(較佳為哺乳動物,更佳為人類)相容且合適向目標部位傳遞活性劑而不終止藥劑活性的物質。與載劑相關之毒性或不良作用(若存在)較佳與合理的活性劑預定用途之風險/效益比相稱。
術語「載劑」、「助劑」或「媒劑」在本文中可互換使用,且包括合適於特定所要劑型之任何及所有溶劑、稀釋劑及其他液體媒劑、分散劑或分散助劑、表面活性劑、pH值調節劑、等張劑、增稠劑或乳化劑、防腐劑、固體黏合劑、潤滑劑及其類似物。Remington:The Science and Practice of Pharmacy,第20版,A.Gennaro編,Lippincott Williams & Wilkins,2000揭示了用於調配醫藥學上可接受之組合物之各種載劑及其已知製備技術。除非任何習知載劑介質均不與本發明化合物相容,諸如因產生任何不合意生物作用,或另外與醫藥學上可接受之組合物的任何其他組份以有害方式相互作用,否則預期其使用在本發明之範疇內。可充當醫藥學上可接受之載劑之物質的一些實例包括(但不限於):離子交換劑;氧化鋁;硬脂酸鋁;卵磷脂;血清蛋白質,諸如人類血清白蛋白;緩衝物質,諸如磷酸鹽、碳酸鹽、氫氧化鎂及氫氧化鋁、甘胺酸、山梨酸或山梨酸鉀;飽和植物脂肪酸之偏甘油酯混合物;水;無熱原質水;鹽或電解質,諸如硫酸魚精蛋白、磷酸氫二鈉、磷酸氫鉀、氯化鈉及鋅鹽;膠態二氧化矽;三矽酸鎂;聚乙烯吡咯啶酮;聚丙烯酸酯;蠟;聚乙烯-聚氧丙烯封端聚合物;羊毛脂;糖,諸如乳糖、葡萄糖、蔗糖及甘露糖醇;澱粉,諸如玉米澱粉及馬鈴薯澱粉;纖維素及其衍生物,諸如羧甲基纖維素鈉、乙基纖維素及乙酸纖維素;粉狀黃芪膠;麥芽;明膠;滑石粉;賦形劑,諸
如可可脂及栓劑蠟;油,諸如花生油、棉籽油、紅花油、芝麻油、橄欖油、玉米油及大豆油;二醇,諸如丙二醇及聚乙二醇;酯,諸如油酸乙酯及月桂酸乙酯;瓊脂;褐藻酸;等張鹽水;任氏溶液(Ringer's solution);醇,諸如乙醇、異丙醇、十六烷醇及甘油;環糊精,諸如羥丙基-β-環糊精及磺丁基醚-β-環糊精;潤滑劑,諸如月桂基硫酸鈉及硬脂酸鎂;石油烴,諸如礦物油及石蠟脂。著色劑、釋放劑、塗布劑、甜味劑、調味劑及芳香劑、防腐劑及抗氧化劑亦可根據調配者之判斷存在於組合物中。
本發明之醫藥組合物可藉由此項技術中熟知之方法製造,尤其諸如習知粒化、混合、溶解、囊封、凍乾或乳化方法。組合物可以各種形式產生,包括顆粒、沈澱物或微粒、粉末(包括凍乾粉末、旋轉乾燥粉末或噴霧乾燥粉末)、非晶形粉末、錠劑、膠囊、糖漿、栓劑、注射劑、乳液、酏劑、懸浮液或溶液。
根據一較佳實施例,本發明組合物經調配以供醫藥投與至哺乳動物,較佳人類。本發明之該等醫藥組合物可經口、非經腸、藉由吸入噴霧、局部、直腸、經鼻、經頰、***或經由植入式貯器投與。如本文所用之術語「非經腸」包括皮下、靜脈內、肌肉內、關節內、滑膜內、胸骨內、鞘內、肝內、病灶內及顱內注射或輸注技術。較佳地,該等組合物係經口、靜脈內或皮下投與。本發明調配物可設計為短效、快速釋放或長效調配物。更進一步,化合物可以局部而非全身方式投與,諸如在腫瘤部位(例如藉由注射)投與。
用於經口投藥之液體劑型包括(但不限於)醫藥學上可接受之乳液、微乳液、溶液、懸浮液、糖漿及酏劑。除活性化合物外,液體劑型還可含有此項技術中常用之惰性稀釋劑,諸如水或其他溶劑;增溶劑及乳化劑,諸如乙醇、異丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苯甲酯、丙二醇、1,3-丁二醇、環糊精、二甲基甲醯胺;油(尤其
為棉籽油、落花生油、玉米油、胚芽油、橄欖油、蓖麻油及芝麻油);甘油;四氫糠醇;聚乙二醇及脫水山梨糖醇之脂肪酸酯,及其混合物。除惰性稀釋劑外,經口組合物亦可包括佐劑,諸如潤濕劑、乳化劑及懸浮劑、甜味劑、調味劑及芳香劑。
可根據已知技術使用合適分散劑或潤濕劑及懸浮劑來調配注射製劑,例如無菌注射水溶液或油性懸浮液。無菌注射製劑亦可為非經腸可接受之無毒稀釋劑或溶劑中之無菌注射溶液、懸浮液或乳液,例如為1,3-丁二醇中之溶液。可使用之可接受媒劑及溶劑為水、任氏溶液、U.S.P.及等張氯化鈉溶液。此外,通常使用無菌不揮發性油作為溶劑或懸浮介質。為此目的,可使用任何溫和不揮發性油,包括合成單酸甘油酯或二酸甘油酯。此外,在注射劑製備中使用脂肪酸,諸如油酸。可對注射調配物進行滅菌,例如藉由經由留菌過濾器過濾,或藉由併入呈無菌固體組合物形式之滅菌劑,其可在使用前溶解或分散於無菌水或其他無菌注射介質中。調配供非經腸投藥之組合物可藉由快速注射或定時推注注射,或可藉由連續輸注投與。
供經口投藥之固體劑型包括膠囊、錠劑、丸劑、散劑及顆粒。在該等固體劑型中,活性化合物與至少一種以下混合:醫藥學上可接受之惰性賦形劑或載劑,諸如檸檬酸鈉或磷酸二鈣;及/或a)填充劑或增量劑,諸如澱粉、乳糖、蔗糖、葡萄糖、甘露糖醇及矽酸;b)黏合劑,諸如羧甲基纖維素、海藻酸鹽、明膠、聚乙烯吡咯啶酮、蔗糖及***膠;c)保濕劑,諸如甘油;d)崩解劑,諸如瓊脂-瓊脂、碳酸鈣、馬鈴薯或木薯澱粉、海藻酸、某些矽酸鹽及碳酸鈉;e)溶解延遲劑,諸如石蠟;f)吸收促進劑,諸如四級銨化合物;g)潤濕劑,諸如十六烷醇及單硬脂酸甘油酯;h)吸收劑,諸如高嶺土及膨潤土;及i)潤滑劑,諸如滑石粉、硬脂酸鈣、硬脂酸鎂、固態聚乙二醇、月桂基硫酸鈉及其混合物。在膠囊、錠劑及丸劑之情況下,劑型亦可包含緩
衝劑,諸如磷酸鹽或碳酸鹽。
亦可使用相似類型之固體組合物作為使用諸如乳糖(lactose或milk sugar)以及高分子量聚乙二醇及其類似物之賦形劑之軟質及硬質填充明膠膠囊中的填充劑。可用諸如腸溶衣及醫藥調配技術中熟知之其他包衣之包衣及殼來製備錠劑、糖衣藥丸、膠囊、丸劑及顆粒的固體劑型。其可視情況含有遮光劑,且亦可具有僅在或優先在腸道某一部分釋放或視情況以延遲方式釋放活性成份的組成。可使用之包埋組合物的實例包括聚合物及蠟。亦可使用相似類型之固體組合物作為使用諸如乳糖(lactose或milk sugar)以及高分子量聚乙二醇及其類似物之賦形劑之軟質及硬質填充明膠膠囊中的填充劑。
活性化合物亦可用一或多種上述賦形劑製備為微囊封形式。可用諸如腸溶衣、釋放控制包衣及醫藥調配技術中熟知之其他包衣之包衣及殼來製備錠劑、糖衣藥丸、膠囊、丸劑及顆粒的固體劑型。在該等固體劑型中,活性化合物可與至少一種諸如蔗糖、乳糖或澱粉之惰性稀釋劑混合。正常實施時,該等劑型亦可包含除惰性稀釋劑之外的其他物質,例如壓片潤滑劑以及其他壓片助劑,諸如硬脂酸鎂及微晶纖維素。在膠囊、錠劑及丸劑之情況下,該等劑型亦可包含緩衝劑。其可視情況含有遮光劑,且亦可具有僅在或優先在腸道某一部分釋放或視情況以延遲方式釋放活性成份的組成。可使用之包埋組合物的實例包括聚合物及蠟。
供局部或經皮投與本發明化合物之劑型包括軟膏、糊劑、乳霜、洗劑、凝膠、散劑、溶液、噴霧、吸入劑或貼片。在無菌條件下將活性組份與醫藥學上可接受之載劑及任何所需防腐劑或緩衝劑按要求混合。亦預期眼用調配物、滴耳劑及滴眼劑處於本發明之範疇內。此外,本發明涵蓋使用經皮貼片,其具有提供化合物向身體之控制傳遞的額外優點。該等劑型可藉由將化合物溶解或分散於適當介質中來製
備。亦可使用吸收增進劑來增加化合物穿過皮膚之流量。速率可藉由提供速率控制膜或將化合物分散於聚合物基質或凝膠中來控制。
在一些實施例中,式(I)化合物係經靜脈內投與。在一些該等實施例中,如全文以引用的方式併入本文中之Plamondon等人之WO 02/059131中所述,Z1及Z2一起形成衍生自酸錯合劑之部分的式(I)化合物可以凍乾粉末形式製備。在一些實施例中,凍乾粉末亦包含游離酸錯合劑。較佳地,游離酸錯合劑及式(I)化合物係以約0.5:1至約100:1、更佳約5:1至約100:1範圍內之莫耳比存在於混合物中。在各種實施例中,凍乾粉末包含莫耳比在約10:1至約100:1、約20:1至約100:1或約40:1至100:1範圍內之游離酸錯合劑與相應酸酯。
在一些實施例中,凍乾粉末包含酸錯合劑及式(I)化合物,實質上不含其他組份。然而,組合物可進一步包含一或多種其他醫藥學上可接受之賦形劑、載劑、稀釋劑、填充劑、鹽、緩衝劑、增積劑、穩定劑、增溶劑及此項技術中熟知之其他物質。含有該等物質之醫藥學上可接受之調配物的製備描述於例如Remington:The Science and Practice of Pharmacy,第20版,A.Gennaro編,Lippincott Williams & Wilkins,2000或最新版本中。在一些實施例中,醫藥組合物包含式(I)化合物、增積劑及緩衝劑。
包含式(I)化合物之凍乾粉末可根據描述於Plamondon等人之WO 02/059131中之程序製備。因此,在一些實施例中,製備凍乾粉末之方法包含:(a)製備包含式(I)酸化合物(其中Z1及Z2各自為羥基)及酸錯合劑之水性混合物;及(b)將該混合物凍乾。
凍乾粉末較佳藉由添加適於醫藥投藥之水性溶劑復原。合適復原溶劑之實例包括(但不限於)水、鹽水及磷酸鹽緩衝鹽水(PBS)。較佳地,以生理(0.9%)鹽水復原凍乾粉末。復原後,在酸酯化合物與相應游離酸化合物之間建立平衡。在一些實施例中,平衡在添加水性
介質後例如10-15分鐘之內快速達成。平衡時存在之酸酯及酸的相對濃度視諸如溶液pH值、溫度、酸錯合劑之性質及凍乾粉末中存在之酸錯合劑與酸酯化合物之比率的參數而定。
本發明之醫藥組合物較佳經調配用於向患有蛋白酶體介導之病症或有發展該病症之風險或經歷該病症之復發的患者投藥。如本文所用之術語「患者」意謂動物,較佳為哺乳動物,更佳為人類。本發明之較佳醫藥組合物為調配用於經口、靜脈內或皮下投藥之醫藥組合物。然而,含有治療有效量之本發明化合物的任何上述劑型均完全在常規試驗之範圍內,且因此亦完全在本發明之範疇內。在一些實施例中,本發明之醫藥組合物可進一步包含另一治療劑。在一些實施例中,該另一治療劑為通常投與患有所治療疾病或病狀之患者的治療劑。
「治療有效量」意謂足以引起蛋白酶體活性或蛋白酶體介導之病症之嚴重程度之可偵測降低的量。所需蛋白酶體抑制劑的量將視抑制劑對於指定細胞類型之有效性及治療該病症所需之時間長度而定。亦應瞭解,用於任何特定患者之特定劑量及治療方案將視多種因素而定,該等因素包括所用特定化合物之活性、患者之年齡、體重、一般健康狀況、性別及飲食、投藥時間、***率、藥物組合及治療醫師之判斷,及所治療之特定疾病之嚴重程度。本發明組合物中存在之額外治療劑的量通常將不超過僅包含該治療劑作為唯一活性劑的組合物中通常投與之量。較佳地,額外治療劑之量將在通常存在於包含該藥劑作為唯一治療活性劑之組合物中之量的約50%至約100%範圍內。
在另一態樣中,本發明提供一種治療患有蛋白酶體介導之病症或有發展該病症之風險或經歷該病症復發之患者的方法。如本文所用之術語「蛋白酶體介導之病症」包括由蛋白酶體表現或活性增加所導致或以蛋白酶體表現或活性增加為特徵,或需要蛋白酶體活性的任何病症、疾病或病狀。術語「蛋白酶體介導之病症」亦包括抑制蛋白酶體
活性有益之任何病症、疾病或病狀。
舉例而言,本發明之化合物及醫藥組合物適用於治療經由受蛋白酶體活性調節之蛋白質(例如NFκB、p27Kip、p21WAF/CIP1、p53)介導之病症。相關病症包括發炎性病症(例如類風濕性關節炎、發炎性腸病、哮喘、慢性阻塞性肺病(COPD)、骨關節炎、皮膚病(例如異位性皮膚炎、牛皮癬))、血管增生性病症(例如動脈粥樣硬化、再狹窄)、增生性眼病(例如糖尿病性視網膜病)、良性增生性病症(例如血管瘤)、自體免疫疾病(例如多發性硬化症、組織及器官排斥反應)以及感染相關性炎症(例如免疫反應)、神經退化性病症(例如阿爾茨海默氏病(Alzheimer's disease)、帕金森氏病(Parkinson's disease)、運動神經元疾病、神經性疼痛、三核苷酸重複病症、星形細胞瘤及酒精性肝病導致的神經退化)、缺血性損傷(例如中風)及惡質症(例如伴隨各種生理及病理病況的肌肉蛋白質分解加速(例如神經損傷、禁食、發燒、酸中毒、HIV感染、癌症痛苦及某些內分泌病))。
本發明之化合物及醫藥組合物尤其適用於治療癌症。如本文所用之術語「癌症」係指一種細胞性病症,其特徵為細胞增殖失控或不受調節、細胞分化減少、具有侵入周圍組織之不當能力及/或能夠在異位建立新生長。術語「癌症」包括(但不限於)實體腫瘤及血液腫瘤。術語「癌症」涵蓋皮膚、組織、器官、骨、軟骨、血液及血管之疾病。術語「癌症」還涵蓋原發性及轉移性癌症。
各種蛋白酶體抑制劑之間的酶動力學(亦即解離半衰期)之差異可導致各種抑制劑之組織分布的差異,該差異可導致安全性及功效概況之差異。舉例而言,使用緩慢可逆及不可逆抑制劑之情況下,相當大比例之分子可與紅血球、血管內皮及諸如肝之充分灌注器官中之蛋白酶體(亦即最近隔室中之最「可立即利用之」蛋白酶體)結合。該等部位可有效充當該等藥劑迅速結合分子且影響實體腫瘤中之分布的「接
收器(sink)」。
不希望受理論束縛,本發明者相信更迅速與蛋白酶體解離之化合物會更有效分布至腫瘤,從而產生改良之抗腫瘤活性。在一些實施例中,本發明係關於一種治療患有癌症之患者的方法,其包含向患者投與式( I )、( I-A )、( I-B )或( II )中任一者之化合物,其中該化合物展現小於60分鐘之解離半衰期。在一些實施例中,該化合物展現小於10分鐘之解離半衰期。
可用所揭示蛋白酶體抑制劑治療之實體腫瘤的非限制性實例包括:胰腺癌;膀胱癌;結腸直腸癌;乳癌,包括轉移性乳癌;***癌,包括雄激素依賴性***癌及不依賴雄激素之***癌;腎癌,包括例如轉移性腎細胞癌;肝細胞癌;肺癌,包括例如非小細胞肺癌(NSCLC)、細支氣管肺泡癌(BAC)及肺腺癌;卵巢癌,包括例如進行性上皮性或原發性腹膜性癌;子宮頸癌;胃癌;食道癌;頭頸癌,包括例如頭頸部之鱗狀細胞癌;黑色素瘤;神經內分泌癌,包括轉移性神經內分泌腫瘤;腦腫瘤,包括例如神經膠質瘤、退行性寡樹突神經膠細胞瘤、成人多形性膠質母細胞瘤及成人退行性星形細胞瘤;骨癌;及軟組織肉瘤。
可用所揭示蛋白酶體抑制劑治療之血液科惡性疾病的非限制性實例包括:急性骨髓白血病(AML);慢性骨髓性白血病(CML),包括加速CML及CML急變期(CML-BP);急性淋巴母細胞性白血病(ALL);慢性淋巴母細胞性白血病(CLL);霍奇金病(Hodgkin's disease,HD);非霍奇金淋巴瘤(non-Hodgkin's lymphoma,NHL),包括濾泡性淋巴瘤及套細胞淋巴瘤;B細胞淋巴瘤;T細胞淋巴瘤;多發性骨髓瘤(MM);瓦爾登斯特倫巨球蛋白血症(Waldenstrom's macroglobulinemia);骨髓發育不良症候群(MDS),包括難治性貧血(RA)、難治性貧血伴有環形含鐵胚血球(RARS)、難治性貧血伴有胚
細胞增多(RAEB)及轉化中之RAEB(RAEB-T);及骨髓增生症候群。
在一些實施例中,使用本發明之化合物或組合物來治療患有選自由多發性骨髓瘤及套細胞淋巴瘤組成之群的癌症或有發展該癌症之風險或經歷該癌症之復發的患者。
在一些實施例中,本發明之蛋白酶體抑制劑可結合另一治療劑投與。另一治療劑亦可抑制蛋白酶體,或可藉由不同機制起作用。在一些實施例中,另一治療劑為通常向患有所治療疾病或病狀之患者投與的治療劑。本發明之蛋白酶體抑制劑可與另一治療劑以單一劑型或以單獨劑型投與。當以單獨劑型投與時,另一劑型可在投與本發明之蛋白酶體抑制劑之前、同時或之後投與。
在一些實施例中,式(I)之蛋白酶體抑制劑結合抗癌劑投與。如本文所用之術語「抗癌劑」係指出於治療癌症之目的投與患有癌症之個體的任何藥劑。
損傷DNA之化學療劑之非限制性實例包括:拓撲異構酶I抑制劑(例如伊立替康(irinotecan)、拓朴替康(topotecan)、喜樹鹼(camptothecin)及其類似物或代謝產物,及阿黴素(doxorubicin));拓撲異構酶II抑制劑(例如依託泊苷(etoposide)、替尼泊甙(teniposide)及道諾黴素(daunorubicin));烷化劑(例如美法侖(melphalan)、苯丁酸氮芥(chlorambucil)、白消安(busulfan)、硫替派(thiotepa)、異環磷醯胺(ifosfamide)、亞硝脲氮芥(carmustine)、洛莫司汀(lomustine)、司莫司汀(semustine)、鏈脲黴素(streptozocin)、達卡巴仁(decarbazine)、甲胺蝶呤(methotrexate)、絲裂黴素C(mitomycin C)及環磷醯胺(cyclophosphamide));DNA***劑(例如順鉑(cisplatin)、奧賽力鉑(oxaliplatin)及卡鉑(carboplatin));DNA***劑及自由基產生劑,諸如博萊黴素(bleomycin);及核苷模擬劑(例如5-氟尿嘧啶(5-fluorouracil)、截瘤達(capecitibine)、吉西他濱(gemcitabine)、氟達拉
賓(fludarabine)、阿糖胞苷(cytarabine)、巰基嘌呤(mercaptopurine)、硫鳥嘌呤(thioguanine)、噴司他汀(pentostatin)及羥基脲(hydroxyurea))。
中斷細胞複製之化學療劑包括:太平洋紫杉醇(paclitaxel)、多烯紫杉醇(docetaxel)及相關類似物;長春新鹼(vincristine)、長春鹼(vinblastin)及相關類似物;沙立度胺(thalidomide)、來那度胺(lenalidomide)及相關類似物(例如CC-5013及CC-4047);蛋白質酪胺酸激酶抑制劑(例如甲磺酸伊瑪替尼(imatinib mesylate)及吉非替尼(gefitinib));蛋白酶體抑制劑(例如硼替左米(bortezomib));NF-κB抑制劑,包括IκB激酶之抑制劑;與癌症中過度表現之蛋白質結合且從而向下調節細胞複製之抗體(例如曲妥珠單抗(trastuzumab)、利妥昔單抗(rituximab)、西妥昔單抗(cetuximab)及貝伐單抗(bevacizumab));及已知在癌症中向上調節、過度表現或活化之蛋白質或酶的其他抑制劑,其中抑制該等蛋白質或酶向下調節細胞複製。
為更充分理解本發明,闡述以下製備及測試實例。該等實例說明如何製備或測試特定化合物,而不欲以任何方式理解為限制本發明之範疇。
實例
定義
ACN 乙腈
BOC 第三丁氧羰基
DCM 二氯甲烷
DIBAL 二異丁基氫化鋁
DIEA 二異丙基乙胺
DMF 二甲基甲醯胺
EDCI N-(3-二甲胺基丙基)-N'-乙基碳化二亞胺鹽酸鹽
EtOAc 乙酸乙酯
h 小時
HOBt 1-羥基苯并***水合物
homophe-OH 高***酸
HPLC 高效液相層析法
LC/MS 液相層析質譜
LiHMDS 雙(三甲基矽烷)胺基鋰
min 分鐘
NMM 4-甲基嗎啉
Rt 自二極體陣列光譜之滯留時間
TBTU 四氟酸O-苯并***-1-基-N,N,N',N'-四甲基
THF 四氫呋喃
TLC 薄層層析法
分析型LC-MS方法
LCMS條件
以Waters Symmetry 3.5μm C18 6×100mm ID管柱使用以下梯度對酸進行分析:
溶劑A:1%乙腈,99%水,0.1%甲酸
溶劑B:95%乙腈,5%水,0.1%甲酸
中間物之光譜係以Hewlett-Packard HP1100使用以下條件進行:甲酸:Phenominex Luna 5μm C18 50×4.6mm管柱,流速2.5mL/min,梯度為3分鐘內於H2O中之含有0至100% 0.1%甲酸之ACN。
乙酸銨:Phenominex Luna 5μm C18 50×4.6mm管柱,流速2.6mL/min,梯度為3分鐘內於H2O中之含有0至100% 10mM乙酸銨之ACN。
實例1:(1R)-2-環丁基-1-[(3aS,4S,6S)-3a,5,5-三甲基六氫-4,6-甲橋-1,3,2-苯并二氧硼-2-基]乙胺‧C2HO2F3(中間物4)
步驟1:(3aS,4S,6S)-2-(二氯甲基)-3a,5,5-三甲基六氫-4,6-甲橋-1,3,2-苯并二氧硼
(中間物1)
在N2下,在-80℃至-90℃下向CH2Cl2(80mL,1.2mol)於THF(800mL)中之溶液中添加正丁基鋰(於己烷中2.5M,480mL,1.2mol),且在-80℃下攪拌反應混合物1.5h。以單份添加B(OEt)3(200mL,1.2mol),且在-45℃至-30℃下攪拌混合物1h。隨後在低於-20℃之溫度下逐滴添加HCl水溶液(5M,240mL,1.2mol),且在-20℃下攪拌所得混合物4h。分離有機層且以Et2O(100mL×2)萃取水層。合併之有機層經無水Na2SO4乾燥且濃縮以得到中間物。將中間物再溶解於Et2O(800mL)中,且向該溶液中添加蒎烷二醇(188g,1.1mol)。在室溫下攪拌反應混合物隔夜且隨後在真空中濃縮。藉由管柱層析(石油醚:乙酸乙酯=10:1至1:1)純化殘餘物得到中間物1(190g,60%產
率)。
步驟2:(3aS,4S,6S)-2-[(1S)-1-氯-2-環丁基乙基]-3a,5,5-三甲基六氫-4,6-甲橋-1,3,2-苯并二氧硼
(中間物2)
在N2下,向於THF(650mL)中之Mg(13.60g,560mmol)中添加DIBAL(於甲苯中1M,9.1mL,9.1mmol),且在室溫下攪拌混合物30分鐘。隨後在低於40℃下逐滴添加中間物2(40.6mL,360mmol),且在室溫下攪拌反應混合物2.5h。冷卻至-78℃後,在N2保護下在-78℃下將溶液轉移至中間物1(70g,0.267mol)於THF(400mL)中之溶液中,且攪拌所得混合物45分鐘。隨後以單份添加ZnCl2(於Et2O中1M,750mL,750mmol),使混合物升溫至室溫並攪拌隔夜。向反應混合物中添加乙酸乙酯(800mL)及飽和NH4Cl(350mL),攪拌混合物1h且以水(300mL)、鹽水(300mL)洗滌有機層,經無水Na2SO4乾燥並濃縮。藉由管柱層析(石油醚:乙酸乙酯=20:1至2:1)純化殘餘物得到呈無色油狀之中間物2(65g,82%產率)。
步驟3:N-{(1R)-2-環丁基-1-[(3aS,4S,6S)-3a,5,5-三甲基六氫-4,6-甲橋-1,3,2-苯并二氧硼
-2-基]乙基}-1,1,1-三甲基-N-(三甲基矽烷基)矽烷胺(中間物3)
在N2保護下,在-78℃下向LiHMDS(於THF中1M,500mL,0.5mol)於THF(500mL)中之溶液中添加中間物2(130g,0.438mol)於THF(700mL)中之溶液。使反應混合物升溫至室溫並攪拌隔夜。藉由旋轉蒸發移除溶劑且以1.0L Et2O/Hex(1:1)溶解殘餘物。經由矽膠(300g)墊過濾溶液並以500mL Et2O/Hex(1:1)洗滌。濃縮溶液得到呈無色油狀之中間物3(166g,90%)。
步驟4:(1R)-2-環丁基-1-[(3aS,4S,6S)-3a,5,5-三甲基六氫-4,6-甲橋-1,3,2-苯并二氧硼
-2-基]乙胺‧C
2
HO
2
F
3
(中間物4)
在-45℃下,向中間物3(166g,0.39mol)於Et2O(1.5L)中之溶液
中添加TFA(92mL,1.2mol)於Et2O(500mL)中之溶液。使混合物升溫至室溫且攪拌1h。藉由過濾收集沈澱物且以Et2O(200mL×3)洗滌得到呈白色固體狀之中間物4(103g,71%產率)。
實例2:{(1R)-1-[((2S)-2-{[(2S)-2-(乙醯胺基)-4-苯基丁醯基]胺基}-3-苯基丙醯基)胺基]-2-環丁基乙基}
酸(22)
步驟1:[(1S)-1-苯甲基-2-({(1R)-2-環丁基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氫-4,6-甲橋-1,3,2-苯并二氧硼
-2-基]乙基}胺基)-2-側氧基乙基]胺基甲酸第三丁酯
向單頸圓底燒瓶中添加中間物4(496mg,1.26mmol)N-(第三丁氧羰基)-L-***酸(0.362g,1.36mmol)、TBTU(0.640g,1.99mmol)及N,N-二甲基甲醯胺(10.0mL,0.129mol)。隨後在-45℃下逐滴添加N,N-二異丙基乙胺(1.12mL,6.40mmol)。20分鐘後移除冷卻槽,且在室溫下攪拌混合物隔夜。使反應混合物分配於乙酸乙酯與水之間,隨後以3×100mL水及3×100mL鹽水洗滌有機層。有機層經硫酸鈉乾燥且在真空中移除溶劑。藉由40% EA/hex中之管柱層析純化所得殘餘物得到0.55g(84%產率)呈灰白色固體狀之產物。
步驟2:(2S)-2-胺基-N-{(1R)-2-環丁基-1-[(3aS,4S,6S,7aR)-3s,5,5-三甲基六氫-4,6-甲橋-1,3,2-苯并二氧硼
-2-基]乙基}-3-苯基丙醯胺‧HCl
向單頸圓底燒瓶中添加[(1S)-1-苯甲基-2-({(1R)-2-環丁基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氫-4,6-甲橋-1,3,2-苯并二氧硼-2-基]乙基}胺基)-2-側氧基乙基]胺基甲酸第三丁酯(0.550g,1.05mmol)、二氯甲烷(6.00mL,0.0936mol)及於1,4-二噁烷中之4.0M鹽酸(6.00mL,0.024mol)。在室溫下攪拌混合物30分鐘。在真空中移除溶劑及HCl得到0.517g(99%產率)呈白色固體狀之所要產物。
步驟3:[(1S)-1-({[(1S)-1-苯甲基-2-({(1R)-2-環丁基-1-
[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氫-4,6-甲橋-1,3,2-苯并二氧硼
-2-基]乙基}胺基)-2-側氧基乙基]胺基}羰基)-3-苯基丙基]胺基甲酸第三丁酯
在室溫下向單頸圓底燒瓶中相繼逐滴添加(2S)-2-胺基-N-{(1R)-2-環丁基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氫-4,6-甲橋-1,3,2-苯并二氧硼-2-基]乙基}-3-苯基丙醯胺(217mg,0.511mmol)、Boc-homophe-OH(171mg,0.614mmol)、TBTU(246mg,0.767mmol)及N,N-二甲基甲醯胺(14.5mL,0.187mol),隨後添加N,N-二異丙基乙胺(0.187mL,1.07mmol)。在室溫下攪拌混合物隔夜。在真空下自反應混合物移除DMF,且將所得殘餘物藉由製備型TLC於40% EtOAc/己烷中純化得到298mg(85%產率)呈白色固體狀之所要產物。
步驟4:(2S)-2-胺基-N-[(1S)-1-苯甲基-2-({(1R)-2-環丁基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氫-4,6-甲橋-1,3,2-苯并二氧硼
-2-基]乙基}胺基)-2-側氧基乙基]-4-苯基丁醯胺‧HCl
向單頸圓底燒瓶中相繼添加[(1S)-1-({[(1S)-1-苯甲基-2-({(1R)-2-環丁基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氫-4,6-甲橋-1,3,2-苯并二氧硼-2-基]乙基}胺基)-2-側氧基乙基]胺基}羰基)-3-苯基丙基]胺基甲酸第三丁酯(298mg,0.000434mol)、二氯甲烷(3.0mL,0.047mol)及於1,4-二噁烷中之4.0M鹽酸(3.0mL,0.012mol)。在室溫下攪拌混合物30分鐘,隨後在真空中移除溶劑得到0.243g(90%產率)所要產物。
步驟5:(2S)-2-(乙醯胺基)-N-[(1S)-1-苯甲基-2-({(1R)-2-環丁基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氫-4,6-甲橋-1,3,2-苯并二氧硼
-2-基]乙基}胺基)-2-側氧基乙基]-4-苯基丁醯胺
向20mL閃爍瓶中添加(2S)-2-胺基-N-[(1S)-1-苯甲基-2-({(1R)-2-環丁基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氫-4,6-甲橋-1,3,2-苯并二氧硼-2-基]乙基}胺基)-2-側氧基乙基]-4-苯基丁醯胺‧HCl(52.0mg,
0.0836mmol)、乙腈(5.20mL,0.0996mol)、乙酸酐(8.68μL,0.092mmol)、N,N-二異丙基乙胺(36.4μL,0.209mmol)及N,N-二甲基胺基吡啶(0.0005g,0.004mmol)。攪拌混合物隔夜,並過濾沈澱物且以Et2O洗滌得到0.028g(53%產率)呈白色固體狀之產物。
步驟6:{(1R)-1-[((2S)-2-{[(2S)-2-(乙醯胺基)-4-苯基丁醯基]胺基}-3-苯基丙醯基)胺基]-2-環丁基乙基}
酸
向單頸圓底燒瓶中添加(2S)-2-(乙醯胺基)-N-[(1S)-1-苯甲基-2-({(1R)-2-環丁基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氫-4,6-甲橋-1,3,2-苯并二氧硼-2-基]乙基}胺基)-2-側氧基乙基]-4-苯基丁醯胺(24.8mg,0.0395mmol)、甲醇(0.237mL,5.86mmol)、己烷(0.237mL,1.81mmol)、鹽酸(0.0889mmol,0.0889mmol)及2-甲基丙基酸(8.65mg,0.0849mmol)。在室溫下攪拌混合物隔夜。藉由製備型TLC於10% MeOH/CH2Cl2中純化反應混合物得到9.90mg(51%產率)呈白色固體狀之所要產物。1H NMR(CD3OD,300MHz,δ):7.32-7.12(m,10H);4.74(t,J=7.94Hz,1H);4.26(dd,J=5.49,8.55Hz,1H);3.14-3.05(m,2H);2.66-2.55(m,2H);2.48-2.41(m,1H);2.19-2.05(m,1H);2.04-1.89(m,8H);1.89-1.69(m,3H);1.58-1.36(m,3H);1.33-1.22(m,1H)。
實例3:{(1R)-1-[((2S)-2-{[(2S)-2-(乙醯胺基)-4-苯基丁醯基]胺基}-3-苯基丙醯基)胺基]-2-環丁基乙基}
酸之D-甘露糖醇酯
向上述產物{(1R)-1-[((2S)-2-{[(2S)-2-(乙醯胺基)-4-苯基丁醯基]胺基}-3-苯基丙醯基)胺基]-2-環丁基乙基}酸(9.90mg,0.0201mmol)中添加第三丁醇(1.21mL,0.0127mol)、水(1.21mL,0.0672mol)及D-甘露糖醇(72.0mg,0.395mmol)。將溶液在-78℃下冷凍,並置於冷凍乾燥機上40h得到80.1mg(97%產率)白色粉末。
實例4:其他N-醯基-肽基
酸化合物
藉由類似於上文實例1-2中描述之程序製備下列酸化合物。如
實例3中所述將所有化合物亦轉化為相應D-甘露糖醇酯。
實例5:{(1R)-2-環丁基-1-[((2S)-2-{[(6-苯氧基吡啶-3-基)磺醯基]胺基}-3-苯基丙醯基)胺基]乙基}
酸(11)
步驟1:(2S)-N-{(1R)-2-環丁基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氫-4,6-甲橋-1,3,2-苯并二氧硼
-2-基]乙基}-2-{[(6-苯氧基吡啶-3-基)磺醯基]胺基}-3-苯基丙醯胺
向20mL小瓶中添加(2S)-2-胺基-N-{(1R)-2-環丁基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氫-4,6-甲橋-1,3,2-苯并二氧硼-2-基]乙基}-3-苯基丙醯胺‧HCl(46.3mg,0.109mmol)(如實例中所述製備)、THF(1.47mL)、N,N-二異丙基乙胺(47.5μL)及6-苯氧基-3-吡啶磺醯氯(32.4mg)。在室溫下攪拌混合物隔夜。藉由製備型TLC於矽石板上利用於己烷中之50%乙酸乙酯純化產物得到35mg呈白色固體狀之所要產物。
步驟2:{(1R)-2-環丁基-1-[((2S)-2-{[(6-苯氧基吡啶-3-基)磺醯基]胺基}-3-苯基丙醯基)胺基]乙基}
酸
向20mL小瓶中添加(2S)-N-{(1R)-2-環丁基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氫-4,6-甲橋-1,3,2-苯并二氧硼-2-基]乙基}-2-{[(6-苯氧基吡啶-3-基)磺醯基]胺基}-3-苯基丙醯胺(31.2mg,0.047mmol)、(2-甲基丙基)酸(10.4mg)、1N鹽酸(0.107mmol)、甲醇(0.285mL)及己烷(0.285mL)。在室溫下攪拌混合物隔夜,隨後分離己烷層並丟棄。在真空中移除殘餘溶劑,並藉由製備型TLC於矽石板上利用於CH2Cl2中之10% MeOH純化產物得到18.4mg(74%產率)呈白色固體狀之所要產物。1H NMR(CD3OD,300MHz,δ):8.36(s,1H);7.95-7.84(m,1H);7.52-7.39(m,2H);7.33-7.06(m,10H);6.95-6.83(m,1H);4.25-4.13(m,1H);3.09-2.94(m,1H);2.93-2.78(m,1H);2.46-2.32(m,1H);2.26-1.93(m,3H);1.92-1.71(m,2H);1.64-1.37(m,3H);1.37-1.22(m,1H)。
實例6:{(1R)-2-環丁基-1-[((2S)-2-{[(6-苯氧基吡啶-3-基)磺醯基]胺基}-3-苯基丙醯基)胺基]乙基}
酸之D-甘露糖醇酯
向上述產物{(1R)-2-環丁基-1-[((2S)-2-{[(6-苯氧基吡啶-3-基)磺醯基]胺基}-3-苯基丙醯基)胺基]乙基}酸(18.4mg,0.0352mmol)中添加第三丁醇(2.12mL,0.0222mol)、水(2.12mL,0.118mol)及甘露糖醇-D(127mg,0.697mmol)。將溶液在-78℃下冷凍,並置於冷凍乾燥機上40h。獲得142.6mg(97%產率)呈白色粉末狀之所得{(1R)-2-環丁基-1-[((2S)-2-{[(6-苯氧基吡啶-3-基)磺醯基]胺基}-3-苯基丙醯基)胺基]乙基}酸‧20[C6H14O6]。
實例7:其他N-磺醯基-肽基
酸化合物
藉由類似於上文實例5中描述之程序製備下列化合物。將所有化合物亦轉化為相應D-甘露糖醇酯。
實例8:20S蛋白酶體檢定
向384孔黑色微孔滴定板中之1μL溶解於DMSO中之測試化合物中添加25μL含有人類PA28活化劑(Boston Biochem,最終12nM)與Ac-WLA-AMC(β5選擇性受質)(最終15μM)的37℃檢定緩衝液,隨後添加25μL含有人類20S蛋白酶體(Boston Biochem,最終0.25nM)的37℃檢定緩衝液。檢定緩衝液包含20mM HEPES、0.5mM EDTA及0.01% BSA(pH7.4)。隨後將反應置於BMG Galaxy板讀取器(37℃,激發380nm,發射460nm,增益20)上。相對於0%抑制(DMSO)及100%抑制(10μM硼替左米)對照組計算出抑制百分比。
在此檢定中測試化合物1-24及29-32及化合物34-48。在此檢定中,化合物1-9、11-14、16-32、34-41、43-45及48展現小於50nM之IC50值。在此檢定中,化合物10、15、42、46及47展現大於50nM且小於150nM之IC50值。
實例9:蛋白酶體抑制動力學
包括解離常數及半衰期之酶動力參數藉由如下對酶進展曲線之分析測定:藉由監測位點特異性經螢光7-醯胺基-4-甲基香豆素(AMC)-標記
之肽受質(β5,Suc-LLVY-AMC;β2,Z-VLR-AMC,及β1,Z-LLE-AMC)在不同抑制劑濃度下水解之個別進展曲線獲得蛋白酶體去活量測值。根據460nm(λex=360nm)下螢光發射之變化連續監測螢光肽之裂解並作為時間之函數繪圖。所有檢定係在37±0.2℃下在具有2mL之50mM HEPES(pH 7.5)、0.5mM EDTA之光析管中進行,並伴隨連續攪拌。受質濃度自10至25μM(<1/2 K M)不等。人類20S蛋白酶體之濃度為0.25nM且以0.01% SDS活化。描述自初始速度至穩態速度之轉變的速率常數k obs係藉由非線性最小二乘回歸法利用時間相關性或緩慢結合抑制之等式分析個別進展曲線來估算:
其中F為螢光,v i及v s為抑制劑存在下反應之初始及穩態速度,且t為時間。由線性擬合數據之斜率獲得與[I]相關之k obs之曲線圖以獲得k on。表觀解離常數K app i係藉由與[I]相關之分數速度vs/vo之非線性最小擬合測定,其中vs為由隨時間相關性或緩慢結合等式獲得之穩態值且vo為不存在抑制劑情況下的初始速度:
解離常數Ki係由表觀Ki利用以下表達式計算:
解離速率koff係由上述測定參數利用以下關係式以數學方法計算:
隨後由koff值利用以下關係式測定半衰期:
利用此方案,測定化合物1、2、6、17、20、35、36、41、43及45之解離半衰期。化合物1、20、35、36、41、43及45展現小於10分鐘之T1/2。化合物2、6及17展現大於10分鐘且小於60分鐘之T1/2。
實例10:抗增殖檢定
將於100μL補充有10%胎牛血清(Invitrogen)之適當細胞培養基(對於HCT-116為McCoy's 5A,Invitrogen)中之HCT-116(1000)或其他腫瘤細胞接種於96孔細胞培養板之孔中,並在37℃下培育過夜。添加測試化合物至孔中並將板在37℃下培育96小時。向各孔中添加MTT或WST試劑(10μL,Roche),並按製造商所述在37℃下培育4小時。對於MTT,根據製造商說明書(Roche)將經代謝之染料溶解過夜。使用分光光度計(Molecular Devices)在595nm(主波長)及690nm(參比波長)下(對於MTT)及在450nm下(對於WST)讀取每孔之光學密度。對於MTT,自主波長之值中減去參比光學密度值。使用設定為100%之DMSO對照組之值來計算抑制百分比。
實例11:活體內腫瘤功效模型
使用1mL 26 3/8號針(Becton Dickinson Ref #309625)將於100μL RPMI-1640培養基(Sigma-Aldrich)中之新解離的HCT-116(2-5×106)、WSU-DLCL2(2-5×106)或其他腫瘤細胞無菌注射至雌性CD-1裸小鼠(5-8週齡,Charles River)右背側的皮下間隙內。或者,一些異種移植模型(例如CWR22)需要腫瘤片段連續繼代。在此情況下,將腫瘤組織之較小片段(約1mm3)經由13號套針(Popper & Sons 7927)植入經麻醉(3-
5%異氟烷(isoflourane)/氧混合物)C.B-17/SCID小鼠(5-8週齡,Charles River)之右背側皮下。在接種腫瘤之後第7天開始利用游標測徑規一週兩次量測。利用標準程序(0.5×(長度×寬度2))計算腫瘤體積。當腫瘤達到約200mm3之體積時,將小鼠隨機分成治療組並開始接受藥物治療。基於先前自藥物動力學/藥效學及最大耐受劑量研究獲得之結果確定每次實驗的劑量及時程。對照組將接受不含任何藥物的媒劑。通常,以不同劑量及時程經由靜脈內(27號針)、經口(20號管飼針)或皮下(27號針)途徑投與測試化合物(100-200μL)。每週兩次量測腫瘤尺寸及體重,且當對照腫瘤達到約2000mm3時結束研究。
儘管前文已出於清晰性及理解之目以一定詳細程度描述了本發明,但認為該等特定實施例僅具說明性而非限制性。熟習此項技術者閱讀本揭示案後將瞭解,可在不脫離本發明真實範疇之情況下對形式及細節作出各種改變,該真實範疇將由附隨申請專利範圍而非特定實施例界定。
本文參考之專利及科技文獻確定熟習此項技術者可獲得之知識。除非另有定義,否則如本文所用之所有技術及科學術語具有與普通熟習本發明所屬技術者所通常瞭解相同之含義。本文引用之頒予專利、申請案及參考文獻係以引用之方式併入本文中,程度仿佛指出各自以引用之方式具體且個別地併入一般。在矛盾的情況下,將以本揭示案(包括定義)為主。
Claims (16)
- 一種式(I)化合物:
- 如請求項1之化合物,其中P為Rc-C(O)-、Rc-O-C(O)-、Rc-N(R4c)-C(O)-、Rc-S(O)2-或Rc-N(R4c)-S(O)2-;Rc係選自由C1-6脂族基、C1-6氟脂族基、-RD、-T1-RD及-T1-R2c組成之群;T1為經0-2個獨立選擇之R3a或R3b取代的C1-6伸烷基鏈,其中該伸烷基鏈視情況雜有-C(R5)=C(R5)-、-C≡C-或-O-;RD為經取代或未經取代之單環或雙環系統;R2c為鹵基、-OR5、-SR6、-S(O)R6、-SO2R6、-SO2N(R4)2、-N(R4)2、-NR4C(O)R5、-NR4C(O)N(R4)2、-NR4CO2R6、-N(R4)SO2R6、-N(R4)SO2N(R4)2、-O-C(O)R5、-OC(O)N(R4)2、-C(O)R5、-CO2R5或-C(O)N(R4)2;各R3a獨立地選自由以下組成之群:-F、-OH、-O(C1-4烷基)、-CN、-N(R4)2、-C(O)(C1-4烷基)、-CO2H、-CO2(C1-4烷基)、-C(O)NH2及-C(O)-NH(C1-4烷基);各R3b獨立地為經R3a或R7取代或未經取代之C1-3脂族基;各R7為經取代或未經取代之芳族基;且R4c為氫、C1-4烷基、C1-4氟烷基或C6-10芳(C1-4烷基),其中該芳基部分經取代或未經取代。
- 如請求項2之化合物,其特徵為式(I-B):
- 如請求項3之化合物,其中A為0。
- 如請求項3之化合物,其中Ra1及Ra2各自獨立地為C1-6脂族基、C1-6氟脂族基或-(CH2)m-CH2-RB,且m為0或1。
- 如請求項5之化合物,其中RB為經取代或未經取代之苯基。
- 如請求項6之化合物,其中Ra1為-CH2-RB,且RB為苯基。
- 如請求項3之化合物,其中Ra1為-(CH2)m-CH(C1-4烷基)-OH。
- 如請求項3之化合物,其中RD在可取代環碳原子上經0-2個Rd及0-2個R8d取代;各Rd係獨立地選自由以下組成之群:C1-6脂族基、C1-6氟脂族基、鹵基、-R1d、-R2d、-T2-R1d及-T2-R2d,T2為經0-2個獨立選擇之R3a或R3b取代的C1-6伸烷基鏈,其中該伸烷基鏈視情況雜有-C(R5)=C(R5)-、-C≡C-或-O-;各R1d獨立地為經取代或未經取代之芳基、雜芳基、雜環基或環脂族環;各R2d獨立地為-NO2、-CN、-C(R5)=C(R5)2、-C≡C-R5、-OR5、-SR6、-S(O)R6、-SO2R6、-SO2N(R4)2、-N(R4)2、-NR4C(O)R5、-NR4C(O)N(R4)2、-N(R4)C(=NR4)-N(R4)2、-N(R4)C(=NR4)-R6、-NR4CO2R6、-N(R4)SO2R6、-N(R4)SO2N(R4)2、-O-C(O)R5、-OC(O)N(R4)2、-C(O)R5、-CO2R5、-C(O)N(R4)2、-C(O)N(R4)-OR5、-C(O)N(R4)C(=NR4)-N(R4)2、-N(R4)C(=NR4)-N(R4)-C(O)R5或-C(=NR4)-N(R4)2; 各R3a係獨立地選自由以下組成之群:-F、-OH、-O(C1-4烷基)、-CN、-N(R4)2、-C(O)(C1-4烷基)、-CO2H、-CO2(C1-4烷基)、-C(O)NH2及-C(O)NH(C1-4烷基);各R3b獨立地為經R3a或R7取代或未經取代之C1-3脂族基,或同一個碳原子上之兩個取代基R3b連同其所連接之該碳原子一起形成3至6員環脂族環;各R7獨立地為經取代或未經取代之芳基或雜芳基環;各R8d係獨立地選自由以下組成之群:C1-4脂族基、C1-4氟脂族基、鹵基、-OH、-O(C1-4脂族基)、-NH2、-NH(C1-4脂族基)及-N(C1-4脂族基)2;且RD中之各可取代環氮原子係未經取代或經以下取代:-C(O)R5、-C(O)N(R4)2、-CO2R6、-SO2R6、-SO2N(R4)2、C1-4脂族基、經取代或未經取代之C6-10芳基或C6-10芳(C1-4)烷基,其中該芳基部分經取代或未經取代。
- 如請求項3之化合物,其中:RD中之各飽和環碳原子係未經取代或經=O、Rd或R8d取代;RD中之各不飽和環碳原子係未經取代或經Rd或R8d取代;各Rd係獨立地選自由以下組成之群:C1-6脂族基、C1-6氟脂族基、鹵基、-R1d、-R2d、-T2-R1d、-T2-R2d,T2為經0-2個獨立選擇之R3a或R3b取代的C1-6伸烷基鏈,其中該伸烷基鏈視情況雜有-C(R5)=C(R5)-、-C≡C-或-O-;各R1d獨立地為經取代或未經取代之芳基、雜芳基、雜環基或環脂族環;各R2d獨立地為-NO2、-CN、-C(R5)=C(R5)2、-C≡C-R5、-OR5、-SR6、-S(O)R6、-SO2R6、-SO2N(R4)2、-N(R4)2、-NR4C(O)R5、-NR4C(O)N(R4)2、-N(R4)C(=NR4)-N(R4)2、- N(R4)C(=NR4)-R6、-NR4CO2R6、-N(R4)SO2R6、-N(R4)SO2N(R4)2、-O-C(O)R5、-OC(O)N(R4)2、-C(O)R5、-CO2R5、-C(O)N(R4)2、-C(O)N(R4)-OR5、-C(O)N(R4)C(=NR4)-N(R4)2、-N(R4)C(=NR4)-N(R4)-C(O)R5或-C(=NR4)-N(R4)2;各R3a係獨立地選自由以下組成之群:-F、-OH、-O(C1-4烷基)、-CN、-N(R4)2、-C(O)(C1-4烷基)、-CO2H、-CO2(C1-4烷基)、-C(O)NH2及-C(O)NH(C1-4烷基);各R3b獨立地為經R3a或R7取代或未經取代之C1-3脂族基,或同一個碳原子上之兩個取代基R3b連同其所連接之該碳原子一起形成3至6員環脂族環;各R7獨立地為經取代或未經取代之芳基或雜芳基環;各R8d係獨立地選自由以下組成之群:C1-4脂族基、C1-4氟脂族基、鹵基、-OH、-O(C1-4脂族基)、-NH2、-NH(C1-4脂族基)及-N(C1-4脂族基)2;且RD中之各可取代環氮原子係未經取代或經以下取代:-C(O)R5、-C(O)N(R4)2、-CO2R6、-SO2R6、-SO2N(R4)2、C1-4脂族基、經取代或未經取代之C6-10芳基或C6-10芳(C1-4)烷基,其中該芳基部分經取代或未經取代。
- 如請求項7之化合物,其中RD為選自由以下組成之群之經取代或未經取代之單環或雙環系統:苯基、吡啶基、嘧啶基、吡嗪基、萘基、苯并咪唑基、喹啉基、異喹啉基、喹喏啉基、四氫喹啉基、四氫異喹啉基、四氫喹喏啉基及二氫苯并噁嗪基。
- 如請求項7之化合物d,其特徵為式(II):
- 如請求項12之化合物,其中Rd具有式-Q-RE;Q為-O-、-NH-或-CH2-;且 RE為經取代或未經取代之芳基、雜芳基、雜環基或環脂族環。
- 如請求項12之化合物,其中RD為經式-O-RE之取代基取代之苯基、吡啶基、吡嗪基或嘧啶基,且RE為經取代或未經取代之苯基、吡啶基、吡嗪基或嘧啶基。
- 一種醫藥組合物,其包含如請求項1之化合物及醫藥學上可接受之載劑。
- 一種如請求項1至14中任一項之化合物的用途,其係用於製造治療癌症之藥物。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US19461408P | 2008-09-29 | 2008-09-29 | |
US12/586,650 US8664200B2 (en) | 2008-09-29 | 2009-09-25 | Derivatives of 1-amino-2-cyclobutylethylboronic acid |
Publications (2)
Publication Number | Publication Date |
---|---|
TW201641504A true TW201641504A (zh) | 2016-12-01 |
TWI598352B TWI598352B (zh) | 2017-09-11 |
Family
ID=41426361
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW098133005A TW201024313A (en) | 2008-09-29 | 2009-09-29 | Derivatives of 1-amino-2-cyclobutylethylboronic acid |
TW105105530A TWI598352B (zh) | 2008-09-29 | 2009-09-29 | 1-胺基-2-環丁基乙酸衍生物 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW098133005A TW201024313A (en) | 2008-09-29 | 2009-09-29 | Derivatives of 1-amino-2-cyclobutylethylboronic acid |
Country Status (25)
Country | Link |
---|---|
US (3) | US8664200B2 (zh) |
EP (1) | EP2346882B1 (zh) |
JP (3) | JP5736314B2 (zh) |
KR (1) | KR101739470B1 (zh) |
CN (2) | CN102203103A (zh) |
AR (1) | AR075090A1 (zh) |
AU (1) | AU2009297113B2 (zh) |
BR (1) | BRPI0919447B8 (zh) |
CA (1) | CA2739375C (zh) |
CL (1) | CL2011000653A1 (zh) |
CO (1) | CO6362015A2 (zh) |
CR (2) | CR20160475A (zh) |
DO (1) | DOP2011000086A (zh) |
EA (1) | EA030539B1 (zh) |
EC (1) | ECSP11011011A (zh) |
IL (1) | IL211983A0 (zh) |
MA (1) | MA32729B1 (zh) |
MX (1) | MX2011003317A (zh) |
MY (1) | MY166653A (zh) |
NZ (2) | NZ592497A (zh) |
SG (1) | SG194388A1 (zh) |
TW (2) | TW201024313A (zh) |
UA (1) | UA105503C2 (zh) |
WO (1) | WO2010036357A1 (zh) |
ZA (1) | ZA201203615B (zh) |
Families Citing this family (31)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NZ595196A (en) | 2005-11-09 | 2013-03-28 | Proteolix Inc | Peptide-based compounds for enzyme inhibition |
PL2041158T3 (pl) | 2006-06-19 | 2013-08-30 | Onyx Therapeutics Inc | Peptydowe epoksyketony do hamowania proteasomu |
PL2207791T5 (pl) | 2007-10-04 | 2020-07-27 | Onyx Therapeutics, Inc. | Krystaliczne peptydo- epoksy ketonowe inhibitory proteazy i synteza keto-epoksydów Aminokwasowych |
EP2730579A1 (en) | 2008-06-17 | 2014-05-14 | Millennium Pharmaceuticals, Inc. | Boronate ester compounds and pharmaceutical compositions thereof |
AP2011005690A0 (en) | 2008-10-21 | 2011-06-30 | Onyx Therapeutics Inc | Combination therapy with peptide epoxyketones. |
TWI504598B (zh) | 2009-03-20 | 2015-10-21 | Onyx Therapeutics Inc | 結晶性三肽環氧酮蛋白酶抑制劑 |
JP5919196B2 (ja) | 2009-11-13 | 2016-05-18 | オニキス セラピューティクス, インク.Onyx Therapeutics, Inc. | 転移抑制のためのペプチドエポキシケトンの使用 |
BR112012022060A2 (pt) * | 2010-03-01 | 2018-05-08 | Onyx Therapeutics Inc | composto para a inibição de imunoproteassoma |
JP5933523B2 (ja) | 2010-03-31 | 2016-06-08 | ミレニアム ファーマシューティカルズ, インコーポレイテッドMillennium Pharmaceuticals, Inc. | 1−アミノ−2−シクロプロピルエチルボロン酸の誘導体 |
US9920373B2 (en) | 2011-11-11 | 2018-03-20 | Millennium Pharmaceuticals, Inc. | Biomarkers of response to proteasome inhibitors |
WO2013071163A2 (en) | 2011-11-11 | 2013-05-16 | Millennium Pharamaceuticals, Inc. | Biomarkers of response to proteasome inhibitors |
CA2860142C (en) | 2011-12-22 | 2020-10-27 | Ares Trading S.A. | Alpha-amino boronic acid derivatives, selective immunoproteasome inhibitors |
WO2013112601A1 (en) | 2012-01-24 | 2013-08-01 | Millennium Pharmaceuticals, Inc. | Methods of treatment of cancer |
JP2015524394A (ja) | 2012-07-09 | 2015-08-24 | オニキス セラピューティクス, インク.Onyx Therapeutics, Inc. | ペプチドエポキシケトンプロテアーゼ阻害剤のプロドラッグ |
JP6018319B2 (ja) * | 2012-12-03 | 2016-11-02 | エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft | 置換トリアゾールボロン酸化合物 |
MX2016003979A (es) | 2013-10-03 | 2016-06-15 | Millennium Pharm Inc | Metodo para profilaxis o tratamiento de lupus eritematoso sistemico y/o nefritis lupica. |
USRE49816E1 (en) | 2014-01-10 | 2024-01-30 | Cornell University | Dipeptides as inhibitors of human immunoproteasomes |
KR102481856B1 (ko) | 2014-05-20 | 2022-12-26 | 밀레니엄 파머슈티컬스 인코퍼레이티드 | 일차 암 치료법 후 사용하기 위한 붕소-함유 프로테아좀 저해제 |
WO2016022955A1 (en) | 2014-08-07 | 2016-02-11 | Mayo Foundation For Medical Education And Research | Compounds and methods for treating cancer |
US11202817B2 (en) | 2014-08-18 | 2021-12-21 | Cornell University | Dipeptidomimetics as inhibitors of human immunoproteasomes |
RU2017115193A (ru) * | 2014-10-01 | 2018-11-06 | Мерк Патент Гмбх | Производные бороновой кислоты |
BR112017006622A2 (pt) * | 2014-10-01 | 2018-07-03 | Merck Patent Gmbh | derivados de ácido borônico |
MX2017004043A (es) * | 2014-10-01 | 2017-07-04 | Merck Patent Gmbh | Derivados de acido boronico. |
AU2015327346B2 (en) * | 2014-10-01 | 2019-12-05 | Merck Patent Gmbh | Boronic acid derivatives |
EP3362754B1 (en) | 2015-10-15 | 2021-12-22 | Cornell University | Proteasome inhibitors and uses thereof |
JP7164521B2 (ja) | 2016-06-21 | 2022-11-01 | オリオン・オフサルモロジー・エルエルシー | 炭素環式プロリンアミド誘導体 |
CN114685453A (zh) | 2016-06-21 | 2022-07-01 | 奥瑞恩眼科有限责任公司 | 杂环脯氨酰胺衍生物 |
CA3054572A1 (en) | 2017-02-28 | 2018-09-07 | Mayo Foundation For Medical Education And Research | Compounds and methods for treating cancer |
WO2019075252A1 (en) | 2017-10-11 | 2019-04-18 | Cornell University | PEPTIDOMIMETIC INHIBITORS OF PROTEASOME |
US11243207B2 (en) | 2018-03-29 | 2022-02-08 | Mayo Foundation For Medical Education And Research | Assessing and treating cancer |
WO2020210649A1 (en) | 2019-04-12 | 2020-10-15 | Riboscience Llc | Bicyclic heteroaryl derivatives as ectonucleotide pyrophosphatase phosphodiesterase 1 inhibitors |
Family Cites Families (42)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NZ203706A (en) | 1982-04-22 | 1986-03-14 | Squibb & Sons Inc | Occlusive multi-layer wound dressing and hydrocolloidal granules for wound treatment |
US4499082A (en) * | 1983-12-05 | 1985-02-12 | E. I. Du Pont De Nemours And Company | α-Aminoboronic acid peptides |
US5187157A (en) | 1987-06-05 | 1993-02-16 | Du Pont Merck Pharmaceutical Company | Peptide boronic acid inhibitors of trypsin-like proteases |
US5250720A (en) | 1987-06-05 | 1993-10-05 | The Dupont Merck Pharmaceutical Company | Intermediates for preparing peptide boronic acid inhibitors of trypsin-like proteases |
US5242904A (en) | 1987-06-05 | 1993-09-07 | The Dupont Merck Pharmaceutical Company | Peptide boronic acid inhibitors of trypsin-like proteases |
EP0315574A3 (de) | 1987-11-05 | 1990-08-22 | Hoechst Aktiengesellschaft | Renin-Inhibitoren |
US5159060A (en) | 1988-05-27 | 1992-10-27 | Mayo Foundation For Medical Education And Research | Cytotoxic boronic acid peptide analogs |
US5106948A (en) | 1988-05-27 | 1992-04-21 | Mao Foundation For Medical Education And Research | Cytotoxic boronic acid peptide analogs |
DE3827340A1 (de) * | 1988-08-12 | 1990-02-15 | Hoechst Ag | Verwendung von (alpha)-aminoboronsaeure-derivaten zur prophylaxe und behandlung von viruserkrankungen |
ATE149563T1 (de) | 1992-08-14 | 1997-03-15 | Procter & Gamble | Alpha-aminoborsäurehaltige flüssige waschmittel |
US5492900A (en) | 1993-09-10 | 1996-02-20 | Neutron Technology Corporation | Method for enhancing the solubility of the boron delivery drug, boronophenylalanine (BPA) |
US5935944A (en) | 1993-09-10 | 1999-08-10 | Neutron Technology Corporation | Formulation for I.V. administration of the boron delivery drug, boronophenylalanine (BPA) |
US6060462A (en) | 1993-10-20 | 2000-05-09 | Dupont Pharmaceuticals Company | Electrophilic peptide analogs as inhibitors of trypsin-like enzymes |
US5574017A (en) | 1994-07-05 | 1996-11-12 | Gutheil; William G. | Antibacterial agents |
US6083903A (en) | 1994-10-28 | 2000-07-04 | Leukosite, Inc. | Boronic ester and acid compounds, synthesis and uses |
US5614649A (en) | 1994-11-14 | 1997-03-25 | Cephalon, Inc. | Multicatalytic protease inhibitors |
EP0979096B1 (en) | 1997-02-15 | 2003-05-14 | Millennium Pharmaceuticals, Inc. | Treatment of infarcts through inhibition of nf-kappab |
WO1999015183A1 (en) | 1997-09-25 | 1999-04-01 | Proscript Inc. | PROTEASOME INHIBITORS, UBIQUITIN PATHWAY INHIBITORS OR AGENTS THAT INTERFERE WITH THE ACTIVATION OF NF-λB VIA THE UBIQUITIN PROTEASOME PATHWAY TO TREAT INFLAMMATORY AND AUTOIMMUNE DISEASES |
US20010012854A1 (en) | 1997-12-16 | 2001-08-09 | Robert Siman | Multicatalytic protease inhibitors for use as anti-tumor agents |
US6169076B1 (en) | 1999-03-31 | 2001-01-02 | Glcosyn Pharmaceuticals, Inc. | P-Boronophenylalanine complexes with fructose and related carbohydrates and polyols |
AU5788800A (en) | 1999-07-07 | 2001-01-22 | Du Pont Pharmaceuticals Company | Peptide boronic acid inhibitors of hepatitis c virus protease |
US6846806B2 (en) * | 2000-10-23 | 2005-01-25 | Bristol-Myers Squibb Company | Peptide inhibitors of Hepatitis C virus NS3 protein |
EP1360189A1 (en) | 2001-01-25 | 2003-11-12 | Millennium Pharmaceuticals, Inc. | Formulation of boronic acid compounds |
CN100415770C (zh) | 2001-05-30 | 2008-09-03 | 诺瓦提斯公司 | 2-{[n-(2-氨基-3-(杂芳基或芳基)丙酰基)-氨基酰基]-氨基}-烷基硼酸衍生物 |
WO2003033507A1 (fr) | 2001-10-12 | 2003-04-24 | Kyorin Pharmaceutical Co., Ltd. | Derives d'acide benzylmalonique et inhibiteurs de proteasomes les contenant |
EP1463719A2 (en) | 2002-01-08 | 2004-10-06 | Eisai Co., Ltd | Eponemycin and epoxomicin analogs and uses thereof |
AU2003223930A1 (en) | 2002-06-14 | 2003-12-31 | Novo Nordisk A/S | Pharmaceutical use of boronic acids and esters thereof |
US20060084592A1 (en) * | 2002-09-09 | 2006-04-20 | Trigen Limited | Peptide boronic acid inhibitors |
TW200418791A (en) | 2003-01-23 | 2004-10-01 | Bristol Myers Squibb Co | Pharmaceutical compositions for inhibiting proteasome |
US7576206B2 (en) * | 2003-08-14 | 2009-08-18 | Cephalon, Inc. | Proteasome inhibitors and methods of using the same |
US7223745B2 (en) | 2003-08-14 | 2007-05-29 | Cephalon, Inc. | Proteasome inhibitors and methods of using the same |
MY162518A (en) * | 2003-08-14 | 2017-06-15 | Cephalon Inc | Proteasome inhibitors and methods of using the same |
GB0405267D0 (en) | 2004-03-09 | 2004-04-21 | Trigen Ltd | Compounds |
RS51983B (en) | 2004-03-30 | 2012-02-29 | Millennium Pharmaceuticals Inc. | SYNTHESIS OF ORGANOBORIC ACID AND ORGANOBORIC ACID COMPOUNDS |
US7468383B2 (en) | 2005-02-11 | 2008-12-23 | Cephalon, Inc. | Proteasome inhibitors and methods of using the same |
MX2008000318A (es) | 2005-07-05 | 2008-03-11 | Tufts College | Inhibidores de la proteina alfa de activacion del fibroblasto. |
US20090304631A1 (en) | 2006-01-27 | 2009-12-10 | David Alan Campbell | Hepatitis c serine protease inhibitors and uses therefor |
WO2009006473A2 (en) | 2007-07-05 | 2009-01-08 | Trustees Of Tufts College | Pro-soft polypeptide proteasome inhibitors, and methods of use thereof |
WO2009020448A1 (en) | 2007-08-06 | 2009-02-12 | Millennium Pharmaceuticals, Inc. | Proteasome inhibitors |
US7442830B1 (en) | 2007-08-06 | 2008-10-28 | Millenium Pharmaceuticals, Inc. | Proteasome inhibitors |
EP2730579A1 (en) | 2008-06-17 | 2014-05-14 | Millennium Pharmaceuticals, Inc. | Boronate ester compounds and pharmaceutical compositions thereof |
JP5933523B2 (ja) * | 2010-03-31 | 2016-06-08 | ミレニアム ファーマシューティカルズ, インコーポレイテッドMillennium Pharmaceuticals, Inc. | 1−アミノ−2−シクロプロピルエチルボロン酸の誘導体 |
-
2009
- 2009-09-12 AR ARP090103760A patent/AR075090A1/es not_active Application Discontinuation
- 2009-09-25 NZ NZ592497A patent/NZ592497A/xx not_active IP Right Cessation
- 2009-09-25 CN CN200980144074XA patent/CN102203103A/zh active Pending
- 2009-09-25 JP JP2011529021A patent/JP5736314B2/ja active Active
- 2009-09-25 CA CA2739375A patent/CA2739375C/en active Active
- 2009-09-25 UA UAA201105450A patent/UA105503C2/uk unknown
- 2009-09-25 NZ NZ606001A patent/NZ606001A/en not_active IP Right Cessation
- 2009-09-25 MY MYPI2011001392A patent/MY166653A/en unknown
- 2009-09-25 AU AU2009297113A patent/AU2009297113B2/en not_active Ceased
- 2009-09-25 WO PCT/US2009/005324 patent/WO2010036357A1/en active Application Filing
- 2009-09-25 CN CN201310475757.1A patent/CN103554143B/zh active Active
- 2009-09-25 EP EP09789372.1A patent/EP2346882B1/en active Active
- 2009-09-25 MX MX2011003317A patent/MX2011003317A/es active IP Right Grant
- 2009-09-25 SG SG2013073267A patent/SG194388A1/en unknown
- 2009-09-25 CR CR20160475A patent/CR20160475A/es unknown
- 2009-09-25 US US12/586,650 patent/US8664200B2/en active Active
- 2009-09-25 KR KR1020117009732A patent/KR101739470B1/ko active IP Right Grant
- 2009-09-25 BR BRPI0919447A patent/BRPI0919447B8/pt active IP Right Grant
- 2009-09-25 EA EA201170508A patent/EA030539B1/ru not_active IP Right Cessation
- 2009-09-29 TW TW098133005A patent/TW201024313A/zh unknown
- 2009-09-29 TW TW105105530A patent/TWI598352B/zh not_active IP Right Cessation
-
2011
- 2011-03-25 CL CL2011000653A patent/CL2011000653A1/es unknown
- 2011-03-28 IL IL211983A patent/IL211983A0/en unknown
- 2011-03-28 DO DO2011000086A patent/DOP2011000086A/es unknown
- 2011-04-26 CR CR20110216A patent/CR20110216A/es unknown
- 2011-04-26 MA MA33796A patent/MA32729B1/fr unknown
- 2011-04-27 CO CO11051428A patent/CO6362015A2/es active IP Right Grant
- 2011-04-28 EC EC2011011011A patent/ECSP11011011A/es unknown
-
2012
- 2012-05-17 ZA ZA2012/03615A patent/ZA201203615B/en unknown
-
2014
- 2014-01-13 US US14/153,752 patent/US9771381B2/en active Active
-
2015
- 2015-04-20 JP JP2015085803A patent/JP2015143264A/ja active Pending
-
2016
- 2016-10-11 JP JP2016199804A patent/JP2017025091A/ja active Pending
-
2017
- 2017-08-18 US US15/680,514 patent/US10035811B2/en active Active
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI598352B (zh) | 1-胺基-2-環丁基乙酸衍生物 | |
TWI498333B (zh) | 酸酯化合物及其醫藥組合物 | |
JP5933523B2 (ja) | 1−アミノ−2−シクロプロピルエチルボロン酸の誘導体 | |
JP5600595B2 (ja) | プロテアソーム阻害剤 | |
AU2013204874B2 (en) | Derivatives of 1-amino-2-cyclobutylethylboronic acid | |
AU2013204868B2 (en) | Derivatives of 1-amino-2-cyclopropylethylboronic acid | |
JP2013177455A (ja) | プロテアソーム阻害剤 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MM4A | Annulment or lapse of patent due to non-payment of fees |