JP2021185208A - Ezh2阻害剤及びその使用 - Google Patents
Ezh2阻害剤及びその使用 Download PDFInfo
- Publication number
- JP2021185208A JP2021185208A JP2021149124A JP2021149124A JP2021185208A JP 2021185208 A JP2021185208 A JP 2021185208A JP 2021149124 A JP2021149124 A JP 2021149124A JP 2021149124 A JP2021149124 A JP 2021149124A JP 2021185208 A JP2021185208 A JP 2021185208A
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- group
- compound
- optionally substituted
- ezh2
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000003112 inhibitor Substances 0.000 title abstract description 68
- 150000001875 compounds Chemical class 0.000 claims abstract description 136
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 76
- 201000011510 cancer Diseases 0.000 claims abstract description 54
- 230000000694 effects Effects 0.000 claims abstract description 42
- 150000003839 salts Chemical class 0.000 claims abstract description 35
- 208000006994 Precancerous Conditions Diseases 0.000 claims abstract description 24
- 101000882127 Homo sapiens Histone-lysine N-methyltransferase EZH2 Proteins 0.000 claims abstract 8
- 102100038970 Histone-lysine N-methyltransferase EZH2 Human genes 0.000 claims abstract 6
- -1 pyridine-3-yl Chemical group 0.000 claims description 193
- 125000000217 alkyl group Chemical group 0.000 claims description 47
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 34
- 239000012453 solvate Substances 0.000 claims description 27
- 239000003814 drug Substances 0.000 claims description 25
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 25
- 239000008194 pharmaceutical composition Substances 0.000 claims description 21
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- 229940124597 therapeutic agent Drugs 0.000 claims description 16
- 238000011282 treatment Methods 0.000 claims description 16
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
- 125000001072 heteroaryl group Chemical group 0.000 claims description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 claims description 11
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 9
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 8
- 201000003444 follicular lymphoma Diseases 0.000 claims description 8
- 208000032839 leukemia Diseases 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
- 229940124530 sulfonamide Drugs 0.000 claims description 8
- 125000004429 atom Chemical group 0.000 claims description 7
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 7
- 125000001153 fluoro group Chemical group F* 0.000 claims description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- 125000002757 morpholinyl group Chemical group 0.000 claims description 7
- 125000004193 piperazinyl group Chemical group 0.000 claims description 7
- 125000005936 piperidyl group Chemical group 0.000 claims description 7
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims description 6
- 206010025323 Lymphomas Diseases 0.000 claims description 6
- 201000003793 Myelodysplastic syndrome Diseases 0.000 claims description 6
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 6
- 201000001441 melanoma Diseases 0.000 claims description 6
- 125000001064 morpholinomethyl group Chemical group [H]C([H])(*)N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 claims description 6
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 claims description 5
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims description 5
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 5
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
- WMSPXQIQBQAWLL-UHFFFAOYSA-N cyclopropanesulfonamide Chemical compound NS(=O)(=O)C1CC1 WMSPXQIQBQAWLL-UHFFFAOYSA-N 0.000 claims description 5
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 125000001544 thienyl group Chemical group 0.000 claims description 5
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 230000002401 inhibitory effect Effects 0.000 claims description 4
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 4
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- SJMCLWCCNYAWRQ-UHFFFAOYSA-N propane-2-sulfonamide Chemical compound CC(C)S(N)(=O)=O SJMCLWCCNYAWRQ-UHFFFAOYSA-N 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 239000011593 sulfur Substances 0.000 claims description 3
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 3
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Chemical group C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 claims description 2
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 claims description 2
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 2
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 2
- 125000001041 indolyl group Chemical group 0.000 claims description 2
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 2
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 2
- 125000002971 oxazolyl group Chemical group 0.000 claims description 2
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 claims description 2
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 claims description 2
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 claims description 2
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 2
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 2
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 2
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 125000001425 triazolyl group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 3
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims 2
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims 1
- 238000000034 method Methods 0.000 description 139
- 238000003786 synthesis reaction Methods 0.000 description 96
- 230000015572 biosynthetic process Effects 0.000 description 94
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 92
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 46
- 239000000203 mixture Substances 0.000 description 38
- KWUVPYOGESDCNX-UHFFFAOYSA-N n-ethylcyclopentanecarboxamide Chemical compound CCNC(=O)C1CCCC1 KWUVPYOGESDCNX-UHFFFAOYSA-N 0.000 description 35
- 210000004027 cell Anatomy 0.000 description 29
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 26
- 108010033040 Histones Proteins 0.000 description 23
- WLQCOYYCNXROKF-UHFFFAOYSA-N n-ethylcyclopropanecarboxamide Chemical compound CCNC(=O)C1CC1 WLQCOYYCNXROKF-UHFFFAOYSA-N 0.000 description 22
- 239000003795 chemical substances by application Substances 0.000 description 20
- 201000010099 disease Diseases 0.000 description 20
- 230000011987 methylation Effects 0.000 description 20
- 238000007069 methylation reaction Methods 0.000 description 20
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 19
- 125000003118 aryl group Chemical group 0.000 description 19
- 108090000623 proteins and genes Proteins 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 239000002207 metabolite Substances 0.000 description 17
- 102000011787 Histone Methyltransferases Human genes 0.000 description 16
- 108010036115 Histone Methyltransferases Proteins 0.000 description 16
- 229940002612 prodrug Drugs 0.000 description 16
- 239000000651 prodrug Substances 0.000 description 16
- 239000002253 acid Substances 0.000 description 15
- 230000014509 gene expression Effects 0.000 description 14
- 108020004414 DNA Proteins 0.000 description 12
- 238000003556 assay Methods 0.000 description 12
- 150000002148 esters Chemical class 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- 102000004190 Enzymes Human genes 0.000 description 11
- 108090000790 Enzymes Proteins 0.000 description 11
- 229940088598 enzyme Drugs 0.000 description 11
- 239000007924 injection Substances 0.000 description 11
- 238000002347 injection Methods 0.000 description 11
- 125000003282 alkyl amino group Chemical group 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 108010000597 Polycomb Repressive Complex 2 Proteins 0.000 description 9
- 102000002272 Polycomb Repressive Complex 2 Human genes 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 238000009472 formulation Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- FKSFKBQGSFSOSM-QFIPXVFZSA-N 1-[(2S)-butan-2-yl]-N-[(4,6-dimethyl-2-oxo-1H-pyridin-3-yl)methyl]-3-methyl-6-[6-(1-piperazinyl)-3-pyridinyl]-4-indolecarboxamide Chemical compound C1=C2N([C@@H](C)CC)C=C(C)C2=C(C(=O)NCC=2C(NC(C)=CC=2C)=O)C=C1C(C=N1)=CC=C1N1CCNCC1 FKSFKBQGSFSOSM-QFIPXVFZSA-N 0.000 description 8
- 102000000905 Cadherin Human genes 0.000 description 8
- 108050007957 Cadherin Proteins 0.000 description 8
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 8
- 125000003545 alkoxy group Chemical group 0.000 description 8
- 150000001408 amides Chemical class 0.000 description 8
- 125000004093 cyano group Chemical group *C#N 0.000 description 8
- 229960004397 cyclophosphamide Drugs 0.000 description 8
- 230000001225 therapeutic effect Effects 0.000 description 8
- 208000003174 Brain Neoplasms Diseases 0.000 description 7
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 7
- 206010018338 Glioma Diseases 0.000 description 7
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 229960002949 fluorouracil Drugs 0.000 description 7
- 125000005885 heterocycloalkylalkyl group Chemical group 0.000 description 7
- NSQSAUGJQHDYNO-UHFFFAOYSA-N n-[(4,6-dimethyl-2-oxo-1h-pyridin-3-yl)methyl]-3-[ethyl(oxan-4-yl)amino]-2-methyl-5-[4-(morpholin-4-ylmethyl)phenyl]benzamide Chemical compound C=1C(C=2C=CC(CN3CCOCC3)=CC=2)=CC(C(=O)NCC=2C(NC(C)=CC=2C)=O)=C(C)C=1N(CC)C1CCOCC1 NSQSAUGJQHDYNO-UHFFFAOYSA-N 0.000 description 7
- 235000018102 proteins Nutrition 0.000 description 7
- 102000004169 proteins and genes Human genes 0.000 description 7
- 230000004044 response Effects 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 108010077544 Chromatin Proteins 0.000 description 6
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 6
- 208000032612 Glial tumor Diseases 0.000 description 6
- 102000006947 Histones Human genes 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- WYNCHZVNFNFDNH-UHFFFAOYSA-N Oxazolidine Chemical compound C1COCN1 WYNCHZVNFNFDNH-UHFFFAOYSA-N 0.000 description 6
- 206010039491 Sarcoma Diseases 0.000 description 6
- 150000007513 acids Chemical class 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 230000002490 cerebral effect Effects 0.000 description 6
- 210000003483 chromatin Anatomy 0.000 description 6
- 208000035475 disorder Diseases 0.000 description 6
- 125000005843 halogen group Chemical group 0.000 description 6
- 230000004048 modification Effects 0.000 description 6
- 238000012986 modification Methods 0.000 description 6
- 239000013612 plasmid Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 230000001105 regulatory effect Effects 0.000 description 6
- 238000012216 screening Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 208000024891 symptom Diseases 0.000 description 6
- 101000584499 Homo sapiens Polycomb protein SUZ12 Proteins 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 102100030702 Polycomb protein SUZ12 Human genes 0.000 description 5
- 125000000266 alpha-aminoacyl group Chemical group 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 125000001589 carboacyl group Chemical group 0.000 description 5
- 230000010261 cell growth Effects 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 238000007796 conventional method Methods 0.000 description 5
- 125000000524 functional group Chemical group 0.000 description 5
- 230000003211 malignant effect Effects 0.000 description 5
- 230000036470 plasma concentration Effects 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 239000013598 vector Substances 0.000 description 5
- 241000255581 Drosophila <fruit fly, genus> Species 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 4
- 101000866766 Homo sapiens Polycomb protein EED Proteins 0.000 description 4
- 102000016397 Methyltransferase Human genes 0.000 description 4
- 108060004795 Methyltransferase Proteins 0.000 description 4
- 206010035226 Plasma cell myeloma Diseases 0.000 description 4
- 102100031338 Polycomb protein EED Human genes 0.000 description 4
- 208000000453 Skin Neoplasms Diseases 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 4
- 125000004104 aryloxy group Chemical group 0.000 description 4
- 230000004663 cell proliferation Effects 0.000 description 4
- 238000011260 co-administration Methods 0.000 description 4
- 239000008298 dragée Substances 0.000 description 4
- 230000001973 epigenetic effect Effects 0.000 description 4
- 239000012634 fragment Substances 0.000 description 4
- 230000002496 gastric effect Effects 0.000 description 4
- 239000008273 gelatin Substances 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- 229940043355 kinase inhibitor Drugs 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000004949 mass spectrometry Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 230000001404 mediated effect Effects 0.000 description 4
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 230000035935 pregnancy Effects 0.000 description 4
- 238000012163 sequencing technique Methods 0.000 description 4
- 201000000849 skin cancer Diseases 0.000 description 4
- 150000003384 small molecules Chemical class 0.000 description 4
- 239000003381 stabilizer Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 125000000547 substituted alkyl group Chemical group 0.000 description 4
- 238000013268 sustained release Methods 0.000 description 4
- 239000012730 sustained-release form Substances 0.000 description 4
- 208000011580 syndromic disease Diseases 0.000 description 4
- 238000010189 synthetic method Methods 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 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 4
- 238000012360 testing method Methods 0.000 description 4
- 238000002877 time resolved fluorescence resonance energy transfer Methods 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- FSPIBFKGESGOLU-UHFFFAOYSA-N 4,6-dimethyl-1h-pyridin-2-one Chemical compound CC1=CC(C)=NC(O)=C1 FSPIBFKGESGOLU-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 206010006187 Breast cancer Diseases 0.000 description 3
- 208000026310 Breast neoplasm Diseases 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-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
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 101150090105 Ezh2 gene Proteins 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 3
- 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 3
- 108060001084 Luciferase Proteins 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 208000003445 Mouth Neoplasms Diseases 0.000 description 3
- 208000034578 Multiple myelomas Diseases 0.000 description 3
- 229930012538 Paclitaxel Natural products 0.000 description 3
- 102000002273 Polycomb Repressive Complex 1 Human genes 0.000 description 3
- 108010000598 Polycomb Repressive Complex 1 Proteins 0.000 description 3
- 102000012425 Polycomb-Group Proteins Human genes 0.000 description 3
- 108010022429 Polycomb-Group Proteins Proteins 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000002159 abnormal effect Effects 0.000 description 3
- 229940009456 adriamycin Drugs 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000027455 binding Effects 0.000 description 3
- 238000004166 bioassay Methods 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 239000000975 dye Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 239000003623 enhancer Substances 0.000 description 3
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 238000013537 high throughput screening Methods 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 230000002209 hydrophobic effect Effects 0.000 description 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 3
- 230000002267 hypothalamic effect Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 239000002502 liposome Substances 0.000 description 3
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 210000005036 nerve Anatomy 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 201000008968 osteosarcoma Diseases 0.000 description 3
- 229960001592 paclitaxel Drugs 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000002062 proliferating effect Effects 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 235000010356 sorbitol Nutrition 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 210000004500 stellate cell Anatomy 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- 239000007940 sugar coated tablet Substances 0.000 description 3
- 210000000115 thoracic cavity Anatomy 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- 238000013518 transcription Methods 0.000 description 3
- 230000035897 transcription Effects 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- 230000000007 visual effect Effects 0.000 description 3
- 238000001262 western blot Methods 0.000 description 3
- CIISBYKBBMFLEZ-UHFFFAOYSA-N 1,2-oxazolidine Chemical compound C1CNOC1 CIISBYKBBMFLEZ-UHFFFAOYSA-N 0.000 description 2
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 2
- FQUYSHZXSKYCSY-UHFFFAOYSA-N 1,4-diazepane Chemical compound C1CNCCNC1 FQUYSHZXSKYCSY-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin 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-VTZDEGQISA-N 0.000 description 2
- OIVLITBTBDPEFK-UHFFFAOYSA-N 5,6-dihydrouracil Chemical compound O=C1CCNC(=O)N1 OIVLITBTBDPEFK-UHFFFAOYSA-N 0.000 description 2
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 2
- 208000003200 Adenoma Diseases 0.000 description 2
- 108091023037 Aptamer Proteins 0.000 description 2
- 206010004593 Bile duct cancer 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
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 201000009030 Carcinoma Diseases 0.000 description 2
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 2
- 206010007953 Central nervous system lymphoma Diseases 0.000 description 2
- 206010008342 Cervix carcinoma Diseases 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
- 108010092160 Dactinomycin Proteins 0.000 description 2
- 206010014733 Endometrial cancer Diseases 0.000 description 2
- 206010014759 Endometrial neoplasm Diseases 0.000 description 2
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 2
- 208000006168 Ewing Sarcoma Diseases 0.000 description 2
- 206010053717 Fibrous histiocytoma Diseases 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 description 2
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 2
- 102000008157 Histone Demethylases Human genes 0.000 description 2
- 108010074870 Histone Demethylases Proteins 0.000 description 2
- 102100033636 Histone H3.2 Human genes 0.000 description 2
- 208000017604 Hodgkin disease Diseases 0.000 description 2
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 2
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 2
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 2
- 206010061252 Intraocular melanoma Diseases 0.000 description 2
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 2
- 240000000599 Lentinula edodes Species 0.000 description 2
- 235000001715 Lentinula edodes Nutrition 0.000 description 2
- 102000003960 Ligases Human genes 0.000 description 2
- 108090000364 Ligases Proteins 0.000 description 2
- 239000005089 Luciferase Substances 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 2
- 201000007224 Myeloproliferative neoplasm Diseases 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 108091008758 NR0A5 Proteins 0.000 description 2
- 208000010505 Nose Neoplasms Diseases 0.000 description 2
- 108010047956 Nucleosomes Proteins 0.000 description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 208000007541 Preleukemia Diseases 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- 208000015634 Rectal Neoplasms Diseases 0.000 description 2
- 108700008625 Reporter Genes Proteins 0.000 description 2
- 108010071034 Retinoblastoma-Binding Protein 4 Proteins 0.000 description 2
- 102000007508 Retinoblastoma-Binding Protein 4 Human genes 0.000 description 2
- MEFKEPWMEQBLKI-AIRLBKTGSA-N S-adenosyl-L-methioninate Chemical compound O[C@@H]1[C@H](O)[C@@H](C[S+](CC[C@H](N)C([O-])=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 MEFKEPWMEQBLKI-AIRLBKTGSA-N 0.000 description 2
- 102000051614 SET domains Human genes 0.000 description 2
- 108700039010 SET domains Proteins 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 208000021712 Soft tissue sarcoma Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 2
- 201000005969 Uveal melanoma Diseases 0.000 description 2
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 description 2
- 230000001594 aberrant effect Effects 0.000 description 2
- 150000001241 acetals Chemical class 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 208000009956 adenocarcinoma Diseases 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 210000001130 astrocyte Anatomy 0.000 description 2
- 125000000751 azo group Chemical group [*]N=N[*] 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 201000000053 blastoma Diseases 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 201000010881 cervical cancer Diseases 0.000 description 2
- WDDPHFBMKLOVOX-AYQXTPAHSA-N clofarabine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1F WDDPHFBMKLOVOX-AYQXTPAHSA-N 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 229940111134 coxibs Drugs 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 2
- AIMMVWOEOZMVMS-UHFFFAOYSA-N cyclopropanecarboxamide Chemical compound NC(=O)C1CC1 AIMMVWOEOZMVMS-UHFFFAOYSA-N 0.000 description 2
- 229960000640 dactinomycin Drugs 0.000 description 2
- 125000004663 dialkyl amino group Chemical group 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 201000008184 embryoma Diseases 0.000 description 2
- 238000005538 encapsulation Methods 0.000 description 2
- 230000006862 enzymatic digestion Effects 0.000 description 2
- 238000001952 enzyme assay Methods 0.000 description 2
- 229960001904 epirubicin Drugs 0.000 description 2
- 229960001433 erlotinib Drugs 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 201000008819 extrahepatic bile duct carcinoma Diseases 0.000 description 2
- 208000024519 eye neoplasm Diseases 0.000 description 2
- 239000010685 fatty oil Substances 0.000 description 2
- 239000011888 foil Substances 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 230000030279 gene silencing Effects 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 229930182470 glycoside Natural products 0.000 description 2
- 150000002338 glycosides Chemical class 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 201000000284 histiocytoma Diseases 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 2
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 2
- 238000010166 immunofluorescence Methods 0.000 description 2
- 238000003364 immunohistochemistry Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 238000004255 ion exchange chromatography Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 238000003670 luciferase enzyme activity assay Methods 0.000 description 2
- 201000000564 macroglobulinemia Diseases 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 2
- 210000001161 mammalian embryo Anatomy 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 229960001428 mercaptopurine Drugs 0.000 description 2
- 230000001394 metastastic effect Effects 0.000 description 2
- 206010061289 metastatic neoplasm Diseases 0.000 description 2
- 238000000386 microscopy Methods 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- TXXHDPDFNKHHGW-UHFFFAOYSA-N muconic acid Chemical compound OC(=O)C=CC=CC(O)=O TXXHDPDFNKHHGW-UHFFFAOYSA-N 0.000 description 2
- 208000037830 nasal cancer Diseases 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 210000001623 nucleosome Anatomy 0.000 description 2
- 201000008106 ocular cancer Diseases 0.000 description 2
- 201000002575 ocular melanoma Diseases 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 201000002528 pancreatic cancer Diseases 0.000 description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- 230000003285 pharmacodynamic effect Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 150000003014 phosphoric acid esters Chemical class 0.000 description 2
- RFIOZSIHFNEKFF-UHFFFAOYSA-M piperazine-1-carboxylate Chemical compound [O-]C(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-M 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 229960005205 prednisolone Drugs 0.000 description 2
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 2
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 2
- 208000016800 primary central nervous system lymphoma Diseases 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 2
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 2
- 206010038038 rectal cancer Diseases 0.000 description 2
- 201000001275 rectum cancer Diseases 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 208000037968 sinus cancer Diseases 0.000 description 2
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 2
- 229960002930 sirolimus Drugs 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 150000003462 sulfoxides Chemical class 0.000 description 2
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 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 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 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
- 230000007704 transition Effects 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 208000037965 uterine sarcoma Diseases 0.000 description 2
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 1
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 1
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 1
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 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
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- GCTFTMWXZFLTRR-GFCCVEGCSA-N (2r)-2-amino-n-[3-(difluoromethoxy)-4-(1,3-oxazol-5-yl)phenyl]-4-methylpentanamide Chemical compound FC(F)OC1=CC(NC(=O)[C@H](N)CC(C)C)=CC=C1C1=CN=CO1 GCTFTMWXZFLTRR-GFCCVEGCSA-N 0.000 description 1
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 1
- YJLIKUSWRSEPSM-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-phenylphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YJLIKUSWRSEPSM-WGQQHEPDSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- VIJSPAIQWVPKQZ-BLECARSGSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-4-methylpentanoyl]amino]-4,4-dimethylpentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(C)=O VIJSPAIQWVPKQZ-BLECARSGSA-N 0.000 description 1
- ITOFPJRDSCGOSA-KZLRUDJFSA-N (2s)-2-[[(4r)-4-[(3r,5r,8r,9s,10s,13r,14s,17r)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H](CC[C@]13C)[C@@H]2[C@@H]3CC[C@@H]1[C@H](C)CCC(=O)N[C@H](C(O)=O)CC1=CNC2=CC=CC=C12 ITOFPJRDSCGOSA-KZLRUDJFSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 1
- LABTWGUMFABVFG-ONEGZZNKSA-N (3E)-pent-3-en-2-one Chemical compound C\C=C\C(C)=O LABTWGUMFABVFG-ONEGZZNKSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- FNHHVPPSBFQMEL-KQHDFZBMSA-N (3S)-5-N-[(1S,5R)-3-hydroxy-6-bicyclo[3.1.0]hexanyl]-7-N,3-dimethyl-3-phenyl-2H-1-benzofuran-5,7-dicarboxamide Chemical compound CNC(=O)c1cc(cc2c1OC[C@@]2(C)c1ccccc1)C(=O)NC1[C@H]2CC(O)C[C@@H]12 FNHHVPPSBFQMEL-KQHDFZBMSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 description 1
- OOKAZRDERJMRCJ-KOUAFAAESA-N (3r)-7-[(1s,2s,4ar,6s,8s)-2,6-dimethyl-8-[(2s)-2-methylbutanoyl]oxy-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl]-3-hydroxy-5-oxoheptanoic acid Chemical compound C1=C[C@H](C)[C@H](CCC(=O)C[C@@H](O)CC(O)=O)C2[C@@H](OC(=O)[C@@H](C)CC)C[C@@H](C)C[C@@H]21 OOKAZRDERJMRCJ-KOUAFAAESA-N 0.000 description 1
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 1
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 1
- YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical compound CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 description 1
- MWWSFMDVAYGXBV-MYPASOLCSA-N (7r,9s)-7-[(2r,4s,5s,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydrochloride Chemical compound Cl.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 MWWSFMDVAYGXBV-MYPASOLCSA-N 0.000 description 1
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 1
- UVNPEUJXKZFWSJ-LMTQTHQJSA-N (R)-N-[(4S)-8-[6-amino-5-[(3,3-difluoro-2-oxo-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfanyl]pyrazin-2-yl]-2-oxa-8-azaspiro[4.5]decan-4-yl]-2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@@](=O)N[C@@H]1COCC11CCN(CC1)c1cnc(Sc2ccnc3NC(=O)C(F)(F)c23)c(N)n1 UVNPEUJXKZFWSJ-LMTQTHQJSA-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
- DEVSOMFAQLZNKR-RJRFIUFISA-N (z)-3-[3-[3,5-bis(trifluoromethyl)phenyl]-1,2,4-triazol-1-yl]-n'-pyrazin-2-ylprop-2-enehydrazide Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(C2=NN(\C=C/C(=O)NNC=3N=CC=NC=3)C=N2)=C1 DEVSOMFAQLZNKR-RJRFIUFISA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- DDMOUSALMHHKOS-UHFFFAOYSA-N 1,2-dichloro-1,1,2,2-tetrafluoroethane Chemical compound FC(F)(Cl)C(F)(F)Cl DDMOUSALMHHKOS-UHFFFAOYSA-N 0.000 description 1
- LKLLNYWECKEQIB-UHFFFAOYSA-N 1,3,5-triazinane Chemical compound C1NCNCN1 LKLLNYWECKEQIB-UHFFFAOYSA-N 0.000 description 1
- BGJSXRVXTHVRSN-UHFFFAOYSA-N 1,3,5-trioxane Chemical compound C1OCOCO1 BGJSXRVXTHVRSN-UHFFFAOYSA-N 0.000 description 1
- KKHFRAFPESRGGD-UHFFFAOYSA-N 1,3-dimethyl-7-[3-(n-methylanilino)propyl]purine-2,6-dione Chemical compound C1=NC=2N(C)C(=O)N(C)C(=O)C=2N1CCCN(C)C1=CC=CC=C1 KKHFRAFPESRGGD-UHFFFAOYSA-N 0.000 description 1
- VDFVNEFVBPFDSB-UHFFFAOYSA-N 1,3-dioxane Chemical compound C1COCOC1 VDFVNEFVBPFDSB-UHFFFAOYSA-N 0.000 description 1
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
- ABADUMLIAZCWJD-UHFFFAOYSA-N 1,3-dioxole Chemical compound C1OC=CO1 ABADUMLIAZCWJD-UHFFFAOYSA-N 0.000 description 1
- IMLSAISZLJGWPP-UHFFFAOYSA-N 1,3-dithiolane Chemical compound C1CSCS1 IMLSAISZLJGWPP-UHFFFAOYSA-N 0.000 description 1
- IVJFXSLMUSQZMC-UHFFFAOYSA-N 1,3-dithiole Chemical compound C1SC=CS1 IVJFXSLMUSQZMC-UHFFFAOYSA-N 0.000 description 1
- WJJSZTJGFCFNKI-UHFFFAOYSA-N 1,3-oxathiolane Chemical compound C1CSCO1 WJJSZTJGFCFNKI-UHFFFAOYSA-N 0.000 description 1
- KVGZZAHHUNAVKZ-UHFFFAOYSA-N 1,4-Dioxin Chemical compound O1C=COC=C1 KVGZZAHHUNAVKZ-UHFFFAOYSA-N 0.000 description 1
- MHSLDASSAFCCDO-UHFFFAOYSA-N 1-(5-tert-butyl-2-methylpyrazol-3-yl)-3-(4-pyridin-4-yloxyphenyl)urea Chemical compound CN1N=C(C(C)(C)C)C=C1NC(=O)NC(C=C1)=CC=C1OC1=CC=NC=C1 MHSLDASSAFCCDO-UHFFFAOYSA-N 0.000 description 1
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 1
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- 102100025573 1-alkyl-2-acetylglycerophosphocholine esterase Human genes 0.000 description 1
- JVCBVWTTXCNJBJ-UHFFFAOYSA-N 1-azabicyclo[2.2.1]heptane Chemical compound C1CC2CCN1C2 JVCBVWTTXCNJBJ-UHFFFAOYSA-N 0.000 description 1
- VCOZQFAYYZLGHV-UHFFFAOYSA-N 1-ethylcyclopropane-1-carboxamide Chemical compound CCC1(C(N)=O)CC1 VCOZQFAYYZLGHV-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- AMMPLVWPWSYRDR-UHFFFAOYSA-N 1-methylbicyclo[2.2.2]oct-2-ene-4-carboxylic acid Chemical compound C1CC2(C(O)=O)CCC1(C)C=C2 AMMPLVWPWSYRDR-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical group C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- UKHJNJFJCGBKSF-UHFFFAOYSA-N 2,5-diazabicyclo[2.2.1]heptane Chemical compound C1NC2CNC1C2 UKHJNJFJCGBKSF-UHFFFAOYSA-N 0.000 description 1
- ZHXUWDPHUQHFOV-UHFFFAOYSA-N 2,5-dibromopyridine Chemical compound BrC1=CC=C(Br)N=C1 ZHXUWDPHUQHFOV-UHFFFAOYSA-N 0.000 description 1
- WGFNXGPBPIJYLI-UHFFFAOYSA-N 2,6-difluoro-3-[(3-fluorophenyl)sulfonylamino]-n-(3-methoxy-1h-pyrazolo[3,4-b]pyridin-5-yl)benzamide Chemical compound C1=C2C(OC)=NNC2=NC=C1NC(=O)C(C=1F)=C(F)C=CC=1NS(=O)(=O)C1=CC=CC(F)=C1 WGFNXGPBPIJYLI-UHFFFAOYSA-N 0.000 description 1
- FQMZXMVHHKXGTM-UHFFFAOYSA-N 2-(1-adamantyl)-n-[2-[2-(2-hydroxyethylamino)ethylamino]quinolin-5-yl]acetamide Chemical compound C1C(C2)CC(C3)CC2CC13CC(=O)NC1=CC=CC2=NC(NCCNCCO)=CC=C21 FQMZXMVHHKXGTM-UHFFFAOYSA-N 0.000 description 1
- VCUXVXLUOHDHKK-UHFFFAOYSA-N 2-(2-aminopyrimidin-4-yl)-4-(2-chloro-4-methoxyphenyl)-1,3-thiazole-5-carboxamide Chemical compound ClC1=CC(OC)=CC=C1C1=C(C(N)=O)SC(C=2N=C(N)N=CC=2)=N1 VCUXVXLUOHDHKK-UHFFFAOYSA-N 0.000 description 1
- QEBYEVQKHRUYPE-UHFFFAOYSA-N 2-(2-chlorophenyl)-5-[(1-methylpyrazol-3-yl)methyl]-4-[[methyl(pyridin-3-ylmethyl)amino]methyl]-1h-pyrazolo[4,3-c]pyridine-3,6-dione Chemical compound C1=CN(C)N=C1CN1C(=O)C=C2NN(C=3C(=CC=CC=3)Cl)C(=O)C2=C1CN(C)CC1=CC=CN=C1 QEBYEVQKHRUYPE-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 1
- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 description 1
- RTQWWZBSTRGEAV-PKHIMPSTSA-N 2-[[(2s)-2-[bis(carboxymethyl)amino]-3-[4-(methylcarbamoylamino)phenyl]propyl]-[2-[bis(carboxymethyl)amino]propyl]amino]acetic acid Chemical compound CNC(=O)NC1=CC=C(C[C@@H](CN(CC(C)N(CC(O)=O)CC(O)=O)CC(O)=O)N(CC(O)=O)CC(O)=O)C=C1 RTQWWZBSTRGEAV-PKHIMPSTSA-N 0.000 description 1
- FMKGJQHNYMWDFJ-CVEARBPZSA-N 2-[[4-(2,2-difluoropropoxy)pyrimidin-5-yl]methylamino]-4-[[(1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl]amino]pyrimidine-5-carbonitrile Chemical compound FC(COC1=NC=NC=C1CNC1=NC=C(C(=N1)N[C@H]1CC([C@H](CC1)O)(C)C)C#N)(C)F FMKGJQHNYMWDFJ-CVEARBPZSA-N 0.000 description 1
- VVCMGAUPZIKYTH-VGHSCWAPSA-N 2-acetyloxybenzoic acid;[(2s,3r)-4-(dimethylamino)-3-methyl-1,2-diphenylbutan-2-yl] propanoate;1,3,7-trimethylpurine-2,6-dione Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O.CN1C(=O)N(C)C(=O)C2=C1N=CN2C.C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 VVCMGAUPZIKYTH-VGHSCWAPSA-N 0.000 description 1
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 1
- UPHOPMSGKZNELG-UHFFFAOYSA-N 2-hydroxynaphthalene-1-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=C(O)C=CC2=C1 UPHOPMSGKZNELG-UHFFFAOYSA-N 0.000 description 1
- HZLCGUXUOFWCCN-UHFFFAOYSA-N 2-hydroxynonadecane-1,2,3-tricarboxylic acid Chemical compound CCCCCCCCCCCCCCCCC(C(O)=O)C(O)(C(O)=O)CC(O)=O HZLCGUXUOFWCCN-UHFFFAOYSA-N 0.000 description 1
- LFOIDLOIBZFWDO-UHFFFAOYSA-N 2-methoxy-6-[6-methoxy-4-[(3-phenylmethoxyphenyl)methoxy]-1-benzofuran-2-yl]imidazo[2,1-b][1,3,4]thiadiazole Chemical compound N1=C2SC(OC)=NN2C=C1C(OC1=CC(OC)=C2)=CC1=C2OCC(C=1)=CC=CC=1OCC1=CC=CC=C1 LFOIDLOIBZFWDO-UHFFFAOYSA-N 0.000 description 1
- PFXXTYUSZRFQHC-UHFFFAOYSA-N 2-methylhept-5-enamide Chemical compound CC=CCCC(C)C(N)=O PFXXTYUSZRFQHC-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- RVBUGGBMJDPOST-UHFFFAOYSA-N 2-thiobarbituric acid Chemical compound O=C1CC(=O)NC(=S)N1 RVBUGGBMJDPOST-UHFFFAOYSA-N 0.000 description 1
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 1
- MLMQPDHYNJCQAO-UHFFFAOYSA-N 3,3-dimethylbutyric acid Chemical compound CC(C)(C)CC(O)=O MLMQPDHYNJCQAO-UHFFFAOYSA-N 0.000 description 1
- DFRAKBCRUYUFNT-UHFFFAOYSA-N 3,8-dicyclohexyl-2,4,7,9-tetrahydro-[1,3]oxazino[5,6-h][1,3]benzoxazine Chemical compound C1CCCCC1N1CC(C=CC2=C3OCN(C2)C2CCCCC2)=C3OC1 DFRAKBCRUYUFNT-UHFFFAOYSA-N 0.000 description 1
- XLZYKTYMLBOINK-UHFFFAOYSA-N 3-(4-hydroxybenzoyl)benzoic acid Chemical compound OC(=O)C1=CC=CC(C(=O)C=2C=CC(O)=CC=2)=C1 XLZYKTYMLBOINK-UHFFFAOYSA-N 0.000 description 1
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 1
- OGHQVXHJIWPXRF-UHFFFAOYSA-N 3-amino-5-bromo-2,4-dimethylbenzoic acid Chemical compound CC1=C(Br)C=C(C(O)=O)C(C)=C1N OGHQVXHJIWPXRF-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical compound OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 description 1
- OPXYNEYEDHAXOM-UHFFFAOYSA-N 3-oxobutanenitrile Chemical compound CC(=O)CC#N OPXYNEYEDHAXOM-UHFFFAOYSA-N 0.000 description 1
- MUGSKSNNEORSJG-UHFFFAOYSA-N 3174-74-1 Chemical compound C1CC=CCO1 MUGSKSNNEORSJG-UHFFFAOYSA-N 0.000 description 1
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 1
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 1
- OCYMJCILWYHKAU-UHFFFAOYSA-N 4,6-dimethyl-2-oxo-1h-pyridine-3-carbonitrile Chemical compound CC1=CC(C)=C(C#N)C(O)=N1 OCYMJCILWYHKAU-UHFFFAOYSA-N 0.000 description 1
- WYFCZWSWFGJODV-MIANJLSGSA-N 4-[[(1s)-2-[(e)-3-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]prop-2-enoyl]-5-(4-methyl-2-oxopiperazin-1-yl)-3,4-dihydro-1h-isoquinoline-1-carbonyl]amino]benzoic acid Chemical compound O=C1CN(C)CCN1C1=CC=CC2=C1CCN(C(=O)\C=C\C=1C(=CC=C(Cl)C=1F)N1N=NN=C1)[C@@H]2C(=O)NC1=CC=C(C(O)=O)C=C1 WYFCZWSWFGJODV-MIANJLSGSA-N 0.000 description 1
- DQAZPZIYEOGZAF-UHFFFAOYSA-N 4-ethyl-n-[4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl]piperazine-1-carboxamide Chemical compound C1CN(CC)CCN1C(=O)NC(C(=CC1=NC=N2)OC)=CC1=C2NC1=CC=CC(C#C)=C1 DQAZPZIYEOGZAF-UHFFFAOYSA-N 0.000 description 1
- XHPVOSNOIWGRQQ-UHFFFAOYSA-N 4-pyridin-2-ylmorpholine Chemical compound C1COCCN1C1=CC=CC=N1 XHPVOSNOIWGRQQ-UHFFFAOYSA-N 0.000 description 1
- MRUWJENAYHTDQG-UHFFFAOYSA-N 4H-pyran Chemical compound C1C=COC=C1 MRUWJENAYHTDQG-UHFFFAOYSA-N 0.000 description 1
- UCZQXJKDCHCTAI-UHFFFAOYSA-N 4h-1,3-dioxine Chemical compound C1OCC=CO1 UCZQXJKDCHCTAI-UHFFFAOYSA-N 0.000 description 1
- VKLKXFOZNHEBSW-UHFFFAOYSA-N 5-[[3-[(4-morpholin-4-ylbenzoyl)amino]phenyl]methoxy]pyridine-3-carboxamide Chemical compound O1CCN(CC1)C1=CC=C(C(=O)NC=2C=C(COC=3C=NC=C(C(=O)N)C=3)C=CC=2)C=C1 VKLKXFOZNHEBSW-UHFFFAOYSA-N 0.000 description 1
- DPKJOHPKAJISKW-UHFFFAOYSA-N 5-bromo-3-(ethylamino)-2,4-dimethylbenzoic acid Chemical compound CCNC1=C(C(=CC(=C1C)Br)C(=O)O)C DPKJOHPKAJISKW-UHFFFAOYSA-N 0.000 description 1
- XFJBGINZIMNZBW-CRAIPNDOSA-N 5-chloro-2-[4-[(1r,2s)-2-[2-(5-methylsulfonylpyridin-2-yl)oxyethyl]cyclopropyl]piperidin-1-yl]pyrimidine Chemical compound N1=CC(S(=O)(=O)C)=CC=C1OCC[C@H]1[C@@H](C2CCN(CC2)C=2N=CC(Cl)=CN=2)C1 XFJBGINZIMNZBW-CRAIPNDOSA-N 0.000 description 1
- RSIWALKZYXPAGW-NSHDSACASA-N 6-(3-fluorophenyl)-3-methyl-7-[(1s)-1-(7h-purin-6-ylamino)ethyl]-[1,3]thiazolo[3,2-a]pyrimidin-5-one Chemical compound C=1([C@@H](NC=2C=3N=CNC=3N=CN=2)C)N=C2SC=C(C)N2C(=O)C=1C1=CC=CC(F)=C1 RSIWALKZYXPAGW-NSHDSACASA-N 0.000 description 1
- GDUANFXPOZTYKS-UHFFFAOYSA-N 6-bromo-8-[(2,6-difluoro-4-methoxybenzoyl)amino]-4-oxochromene-2-carboxylic acid Chemical compound FC1=CC(OC)=CC(F)=C1C(=O)NC1=CC(Br)=CC2=C1OC(C(O)=O)=CC2=O GDUANFXPOZTYKS-UHFFFAOYSA-N 0.000 description 1
- HCCNBKFJYUWLEX-UHFFFAOYSA-N 7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)-3-(pyrazin-2-ylmethylamino)pyrido[3,4-b]pyrazin-2-one Chemical compound O=C1N(CCOCCC)C2=CC(C=3C=NC(OC)=CC=3)=NC=C2N=C1NCC1=CN=CC=N1 HCCNBKFJYUWLEX-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- XASOHFCUIQARJT-UHFFFAOYSA-N 8-methoxy-6-[7-(2-morpholin-4-ylethoxy)imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one Chemical compound C(N1C(=O)C2=C(OC)C=C(C=3N4C(=NC=3)C=C(C=C4)OCCN3CCOCC3)C=C2CC1)C(F)(F)F XASOHFCUIQARJT-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 208000002008 AIDS-Related Lymphoma Diseases 0.000 description 1
- 206010069754 Acquired gene mutation Diseases 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- 206010001233 Adenoma benign Diseases 0.000 description 1
- 208000006468 Adrenal Cortex Neoplasms Diseases 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 108010012934 Albumin-Bound Paclitaxel Proteins 0.000 description 1
- PQSUYGKTWSAVDQ-ZVIOFETBSA-N Aldosterone Chemical compound C([C@@]1([C@@H](C(=O)CO)CC[C@H]1[C@@H]1CC2)C=O)[C@H](O)[C@@H]1[C@]1(C)C2=CC(=O)CC1 PQSUYGKTWSAVDQ-ZVIOFETBSA-N 0.000 description 1
- PQSUYGKTWSAVDQ-UHFFFAOYSA-N Aldosterone Natural products C1CC2C3CCC(C(=O)CO)C3(C=O)CC(O)C2C2(C)C1=CC(=O)CC2 PQSUYGKTWSAVDQ-UHFFFAOYSA-N 0.000 description 1
- 108700028369 Alleles Proteins 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical class N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 206010061424 Anal cancer Diseases 0.000 description 1
- 208000007860 Anus Neoplasms Diseases 0.000 description 1
- 108010024976 Asparaginase Proteins 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 208000003950 B-cell lymphoma Diseases 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- 206010061692 Benign muscle neoplasm Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 206010005949 Bone cancer Diseases 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- 208000006274 Brain Stem Neoplasms Diseases 0.000 description 1
- JQUCWIWWWKZNCS-LESHARBVSA-N C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F Chemical compound C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F JQUCWIWWWKZNCS-LESHARBVSA-N 0.000 description 1
- ISMDILRWKSYCOD-GNKBHMEESA-N C(C1=CC=CC=C1)[C@@H]1NC(OCCCCCCCCCCCNC([C@@H](NC(C[C@@H]1O)=O)C(C)C)=O)=O Chemical compound C(C1=CC=CC=C1)[C@@H]1NC(OCCCCCCCCCCCNC([C@@H](NC(C[C@@H]1O)=O)C(C)C)=O)=O ISMDILRWKSYCOD-GNKBHMEESA-N 0.000 description 1
- 0 CC(N1)=CC(*)=C(CNC(c2c(C)c(N(*)C(*)=O)cc(*)c2)=O)C1=O Chemical compound CC(N1)=CC(*)=C(CNC(c2c(C)c(N(*)C(*)=O)cc(*)c2)=O)C1=O 0.000 description 1
- RLPOAVQXUPWDMS-UHFFFAOYSA-N CCCC(C=C(C)N1)=C(CNC(c2c(C)c(N(CC)C(C3CCCC3)=O)cc(-c3ccnc(N4CCN(CC5CC5)CC4)c3)c2)=O)C1=O Chemical compound CCCC(C=C(C)N1)=C(CNC(c2c(C)c(N(CC)C(C3CCCC3)=O)cc(-c3ccnc(N4CCN(CC5CC5)CC4)c3)c2)=O)C1=O RLPOAVQXUPWDMS-UHFFFAOYSA-N 0.000 description 1
- AJJOUDBFKJIYJE-UHFFFAOYSA-N CCN(C(C1CC1)=O)c1cc(-c(cc2)c(C)cc2OCCN2CCOCC2)cc(C(NCC2=C(C)C=C(C)NC2=O)=O)c1C Chemical compound CCN(C(C1CC1)=O)c1cc(-c(cc2)c(C)cc2OCCN2CCOCC2)cc(C(NCC2=C(C)C=C(C)NC2=O)=O)c1C AJJOUDBFKJIYJE-UHFFFAOYSA-N 0.000 description 1
- QEWYETMHHYUIGK-UHFFFAOYSA-N CCN(C(C1CC1)=O)c1cc(-c(cc2)c(C)nc2N)cc(C(NCC2=C(C)C=C(C)NC2=O)=O)c1C Chemical compound CCN(C(C1CC1)=O)c1cc(-c(cc2)c(C)nc2N)cc(C(NCC2=C(C)C=C(C)NC2=O)=O)c1C QEWYETMHHYUIGK-UHFFFAOYSA-N 0.000 description 1
- ULSALLQRJMLIIM-UHFFFAOYSA-N CCN(C(C1CC1)=O)c1cc(-c(ccc(OCCN2CCOCC2)c2)c2Cl)cc(C(NCC2=C(C)C=C(C)NC2=O)=O)c1C Chemical compound CCN(C(C1CC1)=O)c1cc(-c(ccc(OCCN2CCOCC2)c2)c2Cl)cc(C(NCC2=C(C)C=C(C)NC2=O)=O)c1C ULSALLQRJMLIIM-UHFFFAOYSA-N 0.000 description 1
- JQCUCBHCNVNQRL-UHFFFAOYSA-N CCN(C(C1CCCC1)=O)c1cc(-c(cc2)c(C)cc2OCCCN2CCOCC2)cc(C(NCC2=C(C)C=C(C)NC2=O)=O)c1C Chemical compound CCN(C(C1CCCC1)=O)c1cc(-c(cc2)c(C)cc2OCCCN2CCOCC2)cc(C(NCC2=C(C)C=C(C)NC2=O)=O)c1C JQCUCBHCNVNQRL-UHFFFAOYSA-N 0.000 description 1
- LSVMYHJYABKESH-UHFFFAOYSA-N CCN(C(C1CCCC1)=O)c1cc(-c(cc2)c(C)cc2OCCN2CCOCC2)cc(C(NCC2=C(C)C=C(C)NC2=O)=O)c1C Chemical compound CCN(C(C1CCCC1)=O)c1cc(-c(cc2)c(C)cc2OCCN2CCOCC2)cc(C(NCC2=C(C)C=C(C)NC2=O)=O)c1C LSVMYHJYABKESH-UHFFFAOYSA-N 0.000 description 1
- HCJYHCJWCILNHO-UHFFFAOYSA-N CCN(C(C1CCCC1)=O)c1cc(-c(cc2)cnc2N(CC2)CCN2C(OC(C)(C)C)=O)cc(C(NCC2=C(C)C=C(C)NC2=O)=O)c1C Chemical compound CCN(C(C1CCCC1)=O)c1cc(-c(cc2)cnc2N(CC2)CCN2C(OC(C)(C)C)=O)cc(C(NCC2=C(C)C=C(C)NC2=O)=O)c1C HCJYHCJWCILNHO-UHFFFAOYSA-N 0.000 description 1
- BYSZYQBTXDIPOU-UHFFFAOYSA-N CCN(C(C1CCCC1)=O)c1cc(-c2ccc(CN3CCNCC3)cc2)cc(C(NCC2=C(C)C=C(C)NC2=O)=O)c1C Chemical compound CCN(C(C1CCCC1)=O)c1cc(-c2ccc(CN3CCNCC3)cc2)cc(C(NCC2=C(C)C=C(C)NC2=O)=O)c1C BYSZYQBTXDIPOU-UHFFFAOYSA-N 0.000 description 1
- BQXUPNKLZNSUMC-YUQWMIPFSA-N CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 Chemical compound CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 BQXUPNKLZNSUMC-YUQWMIPFSA-N 0.000 description 1
- PKMUHQIDVVOXHQ-HXUWFJFHSA-N C[C@H](C1=CC(C2=CC=C(CNC3CCCC3)S2)=CC=C1)NC(C1=C(C)C=CC(NC2CNC2)=C1)=O Chemical compound C[C@H](C1=CC(C2=CC=C(CNC3CCCC3)S2)=CC=C1)NC(C1=C(C)C=CC(NC2CNC2)=C1)=O PKMUHQIDVVOXHQ-HXUWFJFHSA-N 0.000 description 1
- 101100314454 Caenorhabditis elegans tra-1 gene Proteins 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
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 229940126639 Compound 33 Drugs 0.000 description 1
- 229940127007 Compound 39 Drugs 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- ITRJWOMZKQRYTA-RFZYENFJSA-N Cortisone acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)CC2=O ITRJWOMZKQRYTA-RFZYENFJSA-N 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 229930105110 Cyclosporin A Natural products 0.000 description 1
- 108010036949 Cyclosporine 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
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 1
- 102000003849 Cytochrome P450 Human genes 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 230000007067 DNA methylation Effects 0.000 description 1
- 230000033616 DNA repair Effects 0.000 description 1
- VPGRYOFKCNULNK-ACXQXYJUSA-N Deoxycorticosterone acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)COC(=O)C)[C@@]1(C)CC2 VPGRYOFKCNULNK-ACXQXYJUSA-N 0.000 description 1
- 229920002307 Dextran Polymers 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
- 239000004338 Dichlorodifluoromethane Substances 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- 241000257465 Echinoidea Species 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 201000003741 Gastrointestinal carcinoma Diseases 0.000 description 1
- 208000034826 Genetic Predisposition to Disease Diseases 0.000 description 1
- 102000016354 Glucuronosyltransferase Human genes 0.000 description 1
- 108010092364 Glucuronosyltransferase Proteins 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 description 1
- 108010069236 Goserelin Proteins 0.000 description 1
- 108010043121 Green Fluorescent Proteins Proteins 0.000 description 1
- 102000004144 Green Fluorescent Proteins Human genes 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 239000012981 Hank's balanced salt solution Substances 0.000 description 1
- 108010016918 Histone-Lysine N-Methyltransferase Proteins 0.000 description 1
- 102000000581 Histone-lysine N-methyltransferase Human genes 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000963360 Homo sapiens Histone-lysine N-methyltransferase, H3 lysine-79 specific Proteins 0.000 description 1
- 101000833157 Homo sapiens Zinc finger protein AEBP2 Proteins 0.000 description 1
- 206010021042 Hypopharyngeal cancer Diseases 0.000 description 1
- 206010056305 Hypopharyngeal neoplasm Diseases 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
- 102000000588 Interleukin-2 Human genes 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- SRBFZHDQGSBBOR-HWQSCIPKSA-N L-arabinopyranose Chemical compound O[C@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-HWQSCIPKSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 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
- 239000002146 L01XE16 - Crizotinib Substances 0.000 description 1
- 206010023825 Laryngeal cancer Diseases 0.000 description 1
- 206010061523 Lip and/or oral cavity cancer Diseases 0.000 description 1
- 206010062038 Lip neoplasm Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- 206010025312 Lymphoma AIDS related Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 1
- 208000006644 Malignant Fibrous Histiocytoma Diseases 0.000 description 1
- 206010025997 Malignant neoplasm of islets of Langerhans Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-N Metaphosphoric acid Chemical compound OP(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-N 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 1
- TXXHDPDFNKHHGW-CCAGOZQPSA-N Muconic acid Natural products OC(=O)\C=C/C=C\C(O)=O TXXHDPDFNKHHGW-CCAGOZQPSA-N 0.000 description 1
- 102000007474 Multiprotein Complexes Human genes 0.000 description 1
- 108010085220 Multiprotein Complexes Proteins 0.000 description 1
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 1
- 206010028570 Myelopathy Diseases 0.000 description 1
- 201000004458 Myoma Diseases 0.000 description 1
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 1
- NUGPIZCTELGDOS-QHCPKHFHSA-N N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclopentanecarboxamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CC[C@@H](C=1C=NC=CC=1)NC(=O)C1CCCC1)C NUGPIZCTELGDOS-QHCPKHFHSA-N 0.000 description 1
- LVDRREOUMKACNJ-BKMJKUGQSA-N N-[(2R,3S)-2-(4-chlorophenyl)-1-(1,4-dimethyl-2-oxoquinolin-7-yl)-6-oxopiperidin-3-yl]-2-methylpropane-1-sulfonamide Chemical compound CC(C)CS(=O)(=O)N[C@H]1CCC(=O)N([C@@H]1c1ccc(Cl)cc1)c1ccc2c(C)cc(=O)n(C)c2c1 LVDRREOUMKACNJ-BKMJKUGQSA-N 0.000 description 1
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
- AVYVHIKSFXVDBG-UHFFFAOYSA-N N-benzyl-N-hydroxy-2,2-dimethylbutanamide Chemical compound C(C1=CC=CC=C1)N(C(C(CC)(C)C)=O)O AVYVHIKSFXVDBG-UHFFFAOYSA-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
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- QOVYHDHLFPKQQG-NDEPHWFRSA-N N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O Chemical compound N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O QOVYHDHLFPKQQG-NDEPHWFRSA-N 0.000 description 1
- 208000001894 Nasopharyngeal Neoplasms Diseases 0.000 description 1
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- KYRVNWMVYQXFEU-UHFFFAOYSA-N Nocodazole Chemical compound C1=C2NC(NC(=O)OC)=NC2=CC=C1C(=O)C1=CC=CS1 KYRVNWMVYQXFEU-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 208000012868 Overgrowth Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000000821 Parathyroid Neoplasms Diseases 0.000 description 1
- 208000002471 Penile Neoplasms Diseases 0.000 description 1
- 206010034299 Penile cancer Diseases 0.000 description 1
- CXOFVDLJLONNDW-UHFFFAOYSA-N Phenytoin Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 description 1
- 235000008331 Pinus X rigitaeda Nutrition 0.000 description 1
- 235000011613 Pinus brutia Nutrition 0.000 description 1
- 241000018646 Pinus brutia Species 0.000 description 1
- 208000007913 Pituitary Neoplasms Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- 201000008183 Pulmonary blastoma Diseases 0.000 description 1
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 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
- 238000001530 Raman microscopy Methods 0.000 description 1
- 238000001069 Raman spectroscopy Methods 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 239000012891 Ringer solution Substances 0.000 description 1
- 108010041897 SU(VAR)3-9 Proteins 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 208000031673 T-Cell Cutaneous 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
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 208000015778 Undifferentiated pleomorphic sarcoma Diseases 0.000 description 1
- XCCTYIAWTASOJW-XVFCMESISA-N Uridine-5'-Diphosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(O)=O)O[C@H]1N1C(=O)NC(=O)C=C1 XCCTYIAWTASOJW-XVFCMESISA-N 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000006593 Urologic Neoplasms Diseases 0.000 description 1
- 244000047670 Viola x wittrockiana Species 0.000 description 1
- 235000004031 Viola x wittrockiana Nutrition 0.000 description 1
- 208000008383 Wilms tumor Diseases 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 238000000441 X-ray spectroscopy Methods 0.000 description 1
- 102100024389 Zinc finger protein AEBP2 Human genes 0.000 description 1
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 1
- SPXSEZMVRJLHQG-XMMPIXPASA-N [(2R)-1-[[4-[(3-phenylmethoxyphenoxy)methyl]phenyl]methyl]pyrrolidin-2-yl]methanol Chemical compound C(C1=CC=CC=C1)OC=1C=C(OCC2=CC=C(CN3[C@H](CCC3)CO)C=C2)C=CC=1 SPXSEZMVRJLHQG-XMMPIXPASA-N 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- PSLUFJFHTBIXMW-WYEYVKMPSA-N [(3r,4ar,5s,6s,6as,10s,10ar,10bs)-3-ethenyl-10,10b-dihydroxy-3,4a,7,7,10a-pentamethyl-1-oxo-6-(2-pyridin-2-ylethylcarbamoyloxy)-5,6,6a,8,9,10-hexahydro-2h-benzo[f]chromen-5-yl] acetate Chemical compound O([C@@H]1[C@@H]([C@]2(O[C@](C)(CC(=O)[C@]2(O)[C@@]2(C)[C@@H](O)CCC(C)(C)[C@@H]21)C=C)C)OC(=O)C)C(=O)NCCC1=CC=CC=N1 PSLUFJFHTBIXMW-WYEYVKMPSA-N 0.000 description 1
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 1
- AIWRTTMUVOZGPW-HSPKUQOVSA-N abarelix Chemical compound C([C@@H](C(=O)N[C@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCNC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)N(C)C(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 AIWRTTMUVOZGPW-HSPKUQOVSA-N 0.000 description 1
- 108010023617 abarelix Proteins 0.000 description 1
- 229960002184 abarelix Drugs 0.000 description 1
- 229940028652 abraxane Drugs 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 201000002454 adrenal cortex cancer Diseases 0.000 description 1
- 238000005273 aeration Methods 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 229940040563 agaric acid Drugs 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical class O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 229960002478 aldosterone Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000004422 alkyl sulphonamide group Chemical group 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 1
- 230000000172 allergic effect Effects 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
- 229960000473 altretamine Drugs 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 description 1
- 229960001220 amsacrine Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 201000011165 anus cancer Diseases 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
- 150000001491 aromatic compounds Chemical group 0.000 description 1
- 125000001769 aryl amino group Chemical group 0.000 description 1
- 125000000732 arylene group Chemical group 0.000 description 1
- FIVPIPIDMRVLAY-UHFFFAOYSA-N aspergillin Natural products C1C2=CC=CC(O)C2N2C1(SS1)C(=O)N(C)C1(CO)C2=O FIVPIPIDMRVLAY-UHFFFAOYSA-N 0.000 description 1
- 238000003149 assay kit Methods 0.000 description 1
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 238000001479 atomic absorption spectroscopy Methods 0.000 description 1
- 238000001593 atomic mass spectrometry Methods 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 229960002756 azacitidine Drugs 0.000 description 1
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 229940125388 beta agonist Drugs 0.000 description 1
- 229960002537 betamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000000133 brain stem Anatomy 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 201000002143 bronchus adenoma Diseases 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 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
- 229940127093 camptothecin Drugs 0.000 description 1
- 238000005251 capillar electrophoresis Methods 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 229960004424 carbon dioxide Drugs 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 231100000357 carcinogen Toxicity 0.000 description 1
- 239000003183 carcinogenic agent Substances 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 230000033077 cellular process Effects 0.000 description 1
- 201000006612 cervical squamous cell carcinoma Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000013626 chemical specie Substances 0.000 description 1
- 201000002687 childhood acute myeloid leukemia Diseases 0.000 description 1
- 208000011654 childhood malignant neoplasm Diseases 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 210000004252 chorionic villi Anatomy 0.000 description 1
- 230000002759 chromosomal effect Effects 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- 229960000928 clofarabine Drugs 0.000 description 1
- 229940103380 clolar Drugs 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
- 229940125961 compound 24 Drugs 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 229940127204 compound 29 Drugs 0.000 description 1
- 229940125877 compound 31 Drugs 0.000 description 1
- 229940125878 compound 36 Drugs 0.000 description 1
- 229940125807 compound 37 Drugs 0.000 description 1
- 229940127573 compound 38 Drugs 0.000 description 1
- 229940126540 compound 41 Drugs 0.000 description 1
- 229940125936 compound 42 Drugs 0.000 description 1
- 229940125844 compound 46 Drugs 0.000 description 1
- 229940127271 compound 49 Drugs 0.000 description 1
- 229940126545 compound 53 Drugs 0.000 description 1
- 229940127113 compound 57 Drugs 0.000 description 1
- 229940125900 compound 59 Drugs 0.000 description 1
- 229940126179 compound 72 Drugs 0.000 description 1
- 108091036078 conserved sequence Proteins 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 229960003290 cortisone acetate Drugs 0.000 description 1
- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 description 1
- 229960005061 crizotinib Drugs 0.000 description 1
- 201000007241 cutaneous T cell lymphoma Diseases 0.000 description 1
- 125000002993 cycloalkylene group Chemical group 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
- 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
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- ZOOSILUVXHVRJE-UHFFFAOYSA-N cyclopropanecarbonyl chloride Chemical compound ClC(=O)C1CC1 ZOOSILUVXHVRJE-UHFFFAOYSA-N 0.000 description 1
- 229930182912 cyclosporin Natural products 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 229960004486 desoxycorticosterone acetate Drugs 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- VQODGRNSFPNSQE-CXSFZGCWSA-N dexamethasone phosphate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)COP(O)(O)=O)(O)[C@@]1(C)C[C@@H]2O VQODGRNSFPNSQE-CXSFZGCWSA-N 0.000 description 1
- 229960004833 dexamethasone phosphate Drugs 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 125000004986 diarylamino group Chemical group 0.000 description 1
- ZOCHARZZJNPSEU-UHFFFAOYSA-N diboron Chemical compound B#B ZOCHARZZJNPSEU-UHFFFAOYSA-N 0.000 description 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 1
- 229940042935 dichlorodifluoromethane Drugs 0.000 description 1
- 229940087091 dichlorotetrafluoroethane Drugs 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000004821 distillation 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
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000008482 dysregulation Effects 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 210000002308 embryonic cell Anatomy 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940079360 enema for constipation Drugs 0.000 description 1
- BJXYHBKEQFQVES-NWDGAFQWSA-N enpatoran Chemical compound N[C@H]1CN(C[C@H](C1)C(F)(F)F)C1=C2C=CC=NC2=C(C=C1)C#N BJXYHBKEQFQVES-NWDGAFQWSA-N 0.000 description 1
- 210000002336 epiblast cell Anatomy 0.000 description 1
- 230000004049 epigenetic modification Effects 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- GWNFQAKCJYEJEW-UHFFFAOYSA-N ethyl 3-[8-[[4-methyl-5-[(3-methyl-4-oxophthalazin-1-yl)methyl]-1,2,4-triazol-3-yl]sulfanyl]octanoylamino]benzoate Chemical compound CCOC(=O)C1=CC(NC(=O)CCCCCCCSC2=NN=C(CC3=NN(C)C(=O)C4=CC=CC=C34)N2C)=CC=C1 GWNFQAKCJYEJEW-UHFFFAOYSA-N 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
- 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
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 229960000556 fingolimod Drugs 0.000 description 1
- KKGQTZUTZRNORY-UHFFFAOYSA-N fingolimod Chemical compound CCCCCCCCC1=CC=C(CCC(N)(CO)CO)C=C1 KKGQTZUTZRNORY-UHFFFAOYSA-N 0.000 description 1
- SYWHXTATXSMDSB-GSLJADNHSA-N fludrocortisone acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O SYWHXTATXSMDSB-GSLJADNHSA-N 0.000 description 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- 229960003336 fluorocortisol acetate Drugs 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 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
- 229940020967 gemzar Drugs 0.000 description 1
- 238000012226 gene silencing method Methods 0.000 description 1
- 210000004392 genitalia Anatomy 0.000 description 1
- 210000001280 germinal center Anatomy 0.000 description 1
- 229940080856 gleevec Drugs 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229950006191 gluconic acid Drugs 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000005090 green fluorescent protein Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 229920000591 gum Polymers 0.000 description 1
- 210000002768 hair cell Anatomy 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 229940022353 herceptin Drugs 0.000 description 1
- 150000002390 heteroarenes Chemical group 0.000 description 1
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 1
- 125000005549 heteroarylene group Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000006588 heterocycloalkylene group Chemical group 0.000 description 1
- 230000000423 heterosexual effect Effects 0.000 description 1
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-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
- 238000012203 high throughput assay Methods 0.000 description 1
- 229940121372 histone deacetylase inhibitor Drugs 0.000 description 1
- 239000003276 histone deacetylase inhibitor Substances 0.000 description 1
- 238000001794 hormone therapy Methods 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229920001600 hydrophobic polymer Polymers 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 230000006607 hypermethylation Effects 0.000 description 1
- 230000003463 hyperproliferative effect Effects 0.000 description 1
- 201000006866 hypopharynx cancer Diseases 0.000 description 1
- 210000003016 hypothalamus Anatomy 0.000 description 1
- 229960001001 ibritumomab tiuxetan Drugs 0.000 description 1
- 229960002411 imatinib Drugs 0.000 description 1
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- LPAGFVYQRIESJQ-UHFFFAOYSA-N indoline Chemical compound C1=CC=C2NCCC2=C1 LPAGFVYQRIESJQ-UHFFFAOYSA-N 0.000 description 1
- 238000009616 inductively coupled plasma Methods 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 201000002313 intestinal cancer Diseases 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 210000004153 islets of langerhan Anatomy 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- GWVMLCQWXVFZCN-UHFFFAOYSA-N isoindoline Chemical compound C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 210000000244 kidney pelvis Anatomy 0.000 description 1
- 239000004922 lacquer Substances 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 206010023841 laryngeal neoplasm Diseases 0.000 description 1
- 201000006721 lip cancer Diseases 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- RENRQMCACQEWFC-UGKGYDQZSA-N lnp023 Chemical compound C1([C@H]2N(CC=3C=4C=CNC=4C(C)=CC=3OC)CC[C@@H](C2)OCC)=CC=C(C(O)=O)C=C1 RENRQMCACQEWFC-UGKGYDQZSA-N 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 238000012792 lyophilization process Methods 0.000 description 1
- 229940100029 lysodren Drugs 0.000 description 1
- 229940124302 mTOR inhibitor Drugs 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 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
- 208000025854 malignant tumor of adrenal cortex Diseases 0.000 description 1
- 208000026045 malignant tumor of parathyroid gland Diseases 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- 229960004961 mechlorethamine Drugs 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
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229940110254 minocin Drugs 0.000 description 1
- GLMUAFMGXXHGLU-VQAITOIOSA-N minocycline hydrochloride Chemical compound [H+].[Cl-].C([C@H]1C2)C3=C(N(C)C)C=CC(O)=C3C(=O)C1=C(O)[C@@]1(O)[C@@H]2[C@H](N(C)C)C(O)=C(C(N)=O)C1=O GLMUAFMGXXHGLU-VQAITOIOSA-N 0.000 description 1
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 1
- 229960001156 mitoxantrone Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- UXOUKMQIEVGVLY-UHFFFAOYSA-N morin Natural products OC1=CC(O)=CC(C2=C(C(=O)C3=C(O)C=C(O)C=C3O2)O)=C1 UXOUKMQIEVGVLY-UHFFFAOYSA-N 0.000 description 1
- 206010051747 multiple endocrine neoplasia Diseases 0.000 description 1
- 229940014456 mycophenolate Drugs 0.000 description 1
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 description 1
- 201000005962 mycosis fungoides Diseases 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- NXFDPMAUXFRFLK-UHFFFAOYSA-N n,2-diethylbutan-1-amine Chemical compound CCNCC(CC)CC NXFDPMAUXFRFLK-UHFFFAOYSA-N 0.000 description 1
- YFJAIURZMRJPDB-UHFFFAOYSA-N n,n-dimethylpiperidin-4-amine Chemical compound CN(C)C1CCNCC1 YFJAIURZMRJPDB-UHFFFAOYSA-N 0.000 description 1
- NZSQUUYVDDKADD-UHFFFAOYSA-N n-(cyclopropylmethyl)cyclopentanecarboxamide Chemical compound C1CCCC1C(=O)NCC1CC1 NZSQUUYVDDKADD-UHFFFAOYSA-N 0.000 description 1
- VMFMUJZRXZXYAH-UHFFFAOYSA-N n-[5-[[5-chloro-4-[2-[2-(dimethylamino)-2-oxoacetyl]anilino]pyrimidin-2-yl]amino]-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl]prop-2-enamide Chemical compound C=CC(=O)NC=1C=C(NC=2N=C(NC=3C(=CC=CC=3)C(=O)C(=O)N(C)C)C(Cl)=CN=2)C(OC)=CC=1N1CCN(C)CC1 VMFMUJZRXZXYAH-UHFFFAOYSA-N 0.000 description 1
- YGBMCLDVRUGXOV-UHFFFAOYSA-N n-[6-[6-chloro-5-[(4-fluorophenyl)sulfonylamino]pyridin-3-yl]-1,3-benzothiazol-2-yl]acetamide Chemical compound C1=C2SC(NC(=O)C)=NC2=CC=C1C(C=1)=CN=C(Cl)C=1NS(=O)(=O)C1=CC=C(F)C=C1 YGBMCLDVRUGXOV-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- SBRBPFHRQPLPLX-UHFFFAOYSA-N n-ethyl-2,2-dimethylbutan-1-amine Chemical compound CCNCC(C)(C)CC SBRBPFHRQPLPLX-UHFFFAOYSA-N 0.000 description 1
- WQLQCNJDXCGKIL-UHFFFAOYSA-N n-ethyl-2-methylpropanamide Chemical compound CCNC(=O)C(C)C WQLQCNJDXCGKIL-UHFFFAOYSA-N 0.000 description 1
- HLSPSIVLFJLIAT-UHFFFAOYSA-N n-ethyl-3,3-dimethylbutan-1-amine Chemical compound CCNCCC(C)(C)C HLSPSIVLFJLIAT-UHFFFAOYSA-N 0.000 description 1
- QLPRAXXGCFGXLJ-UHFFFAOYSA-N n-ethyl-4-methylbenzamide Chemical compound CCNC(=O)C1=CC=C(C)C=C1 QLPRAXXGCFGXLJ-UHFFFAOYSA-N 0.000 description 1
- AXDLTLIKVSAPPJ-UHFFFAOYSA-N n-ethylcyclobutanecarboxamide Chemical compound CCNC(=O)C1CCC1 AXDLTLIKVSAPPJ-UHFFFAOYSA-N 0.000 description 1
- ZCSFJAQXKNVTTF-UHFFFAOYSA-N n-ethylcyclohexanecarboxamide Chemical compound CCNC(=O)C1CCCCC1 ZCSFJAQXKNVTTF-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 201000008026 nephroblastoma Diseases 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229950006344 nocodazole Drugs 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000008183 oral pharmaceutical preparation Substances 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003791 organic solvent mixture Substances 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 201000008033 ovary epithelial cancer Diseases 0.000 description 1
- ZVDQRORIRBQUIG-UHFFFAOYSA-N oxane;pyrrolidine Chemical compound C1CCNC1.C1CCOCC1 ZVDQRORIRBQUIG-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 230000009996 pancreatic endocrine effect Effects 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
- 230000001575 pathological effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 238000009521 phase II clinical trial Methods 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- IVXQBCUBSIPQGU-UHFFFAOYSA-N piperazine-1-carboxamide Chemical compound NC(=O)N1CCNCC1 IVXQBCUBSIPQGU-UHFFFAOYSA-N 0.000 description 1
- JTHRRMFZHSDGNJ-UHFFFAOYSA-N piperazine-2,3-dione Chemical compound O=C1NCCNC1=O JTHRRMFZHSDGNJ-UHFFFAOYSA-N 0.000 description 1
- 208000010916 pituitary tumor Diseases 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 208000010626 plasma cell neoplasm Diseases 0.000 description 1
- 210000004180 plasmocyte Anatomy 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 208000025638 primary cutaneous T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 230000019639 protein methylation Effects 0.000 description 1
- 230000029983 protein stabilization Effects 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000012217 radiopharmaceutical Substances 0.000 description 1
- 229940121896 radiopharmaceutical Drugs 0.000 description 1
- 230000002799 radiopharmaceutical effect Effects 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000014493 regulation of gene expression Effects 0.000 description 1
- 230000021448 regulation of histone methylation Effects 0.000 description 1
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 1
- 230000002207 retinal effect Effects 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 229940100486 rice starch Drugs 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 239000005060 rubber Substances 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 229960004029 silicic acid Drugs 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 230000037439 somatic mutation Effects 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000012306 spectroscopic technique Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 229940120982 tarceva Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940063683 taxotere Drugs 0.000 description 1
- 229950004774 tazemetostat Drugs 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000002076 thermal analysis method Methods 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- ANRHNWWPFJCPAZ-UHFFFAOYSA-M thionine Chemical compound [Cl-].C1=CC(N)=CC2=[S+]C3=CC(N)=CC=C3N=C21 ANRHNWWPFJCPAZ-UHFFFAOYSA-M 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 230000034512 ubiquitination Effects 0.000 description 1
- 238000010798 ubiquitination Methods 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 229940065658 vidaza Drugs 0.000 description 1
- HOFQVRTUGATRFI-XQKSVPLYSA-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=C1N=C1[C]2C=CC=C1 HOFQVRTUGATRFI-XQKSVPLYSA-N 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000001238 wet grinding Methods 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
- 238000003963 x-ray microscopy Methods 0.000 description 1
- 229940033942 zoladex Drugs 0.000 description 1
Classifications
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
Yはシアノ、アミノアシル、1つのR4で任意に置換されたアルキルアミノ、1つ〜3つの独立したR4で任意に置換されたアリール、1つ〜3つの独立したR4で任意に置換されたヘテロアリール及び1つ〜3つの独立したR4で任意に置換されたヘテロシクロアルキルアルキルアミノからなる群から選択され、
R1はアルキルであり、
R2は水素、アルキル及びシクロアルキルアルキルからなる群から選択され、
R3はアルキル、シクロアルキル、ヘテロシクロアルキル、ヘテロアリール、アルキルアリール及びビシクロ[2.2.1]ヘプタ−2−エニルからなる群から選択され、
R4は独立して水素、ハロ、アミノ、シアノ、アルキル、アルコキシ、アルカノイル、1つのR5で任意に置換されたアルキルアミノ、1つのR5で任意に置換されたアルキルスルホンアミド、1つのR5で任意に置換されたシクロアルキルスルホンアミド、1つ〜3つの独立したR5で任意に置換されたヘテロシクロアルキル、1つ〜3つの独立したR5で任意に置換されたヘテロシクロアルキルカルボニル、1つ〜3つの独立したR5で任意に置換されたヘテロシクロアルキルアルキル、1つ〜3つの独立したR5で任意に置換されたヘテロシクロアルキルアルコキシ、1つ〜3つの独立したR5で任意に置換されたヘテロシクロアルキルカルボニルアルキル及び1つ〜3つの独立したR5で任意に置換されたアリールオキシからなる群から選択され、
R5は独立してアミノ、アルキル、アルカノイル、アルキルアミノ、ヒドロキシアルキル、シクロアルキル、シクロアルキルアルキル、ヘテロシクロアルキル及びアミノ保護基からなる群から選択される)の化合物、又はその薬学的に許容可能な塩、溶媒和物、異性体、エステル、酸、代謝産物若しくはプロドラッグを含む。
他に規定のない限り、本明細書で使用される全ての技術用語及び科学用語は、本発明が属する技術分野の当業者によって一般に理解されるものと同じ意味を有する。本明細書において、文脈上明らかに他の指示がない限り単数形は複数形も含む。本明細書で言及される全ての刊行物、特許出願、特許及び他の参照文献は引用することにより本明細書の一部をなす。矛盾する場合は、定義を含む本明細書が優先される。加えて、材料、方法及び例は一例にすぎず、限定を意図するものではない。
本発明の様々な態様は、
式(I):
Yはシアノ、アミノアシル、1つのR4で任意に置換されたアルキルアミノ、1つ〜3つの独立したR4で任意に置換されたアリール、1つ〜3つの独立したR4で任意に置換されたヘテロアリール及び1つ〜3つの独立したR4で任意に置換されたヘテロシクロアルキルアルキルアミノからなる群から選択され、
R1はアルキルであり、
R2は水素、アルキル及びシクロアルキルアルキルからなる群から選択され、
R3はアルキル、シクロアルキル、ヘテロシクロアルキル、ヘテロアリール、アルキルアリール及びビシクロ[2.2.1]ヘプタ−2−エニルからなる群から選択され、
R4は独立して水素、ハロ、アミノ、シアノ、アルキル、アルコキシ、アルカノイル、1つのR5で任意に置換されたアルキルアミノ、1つのR5で任意に置換されたアルキルスルホンアミド、1つのR5で任意に置換されたシクロアルキルスルホンアミド、1つ〜3つの独立したR5で任意に置換されたヘテロシクロアルキル、1つ〜3つの独立したR5で任意に置換されたヘテロシクロアルキルカルボニル、1つ〜3つの独立したR5で任意に置換されたヘテロシクロアルキルアルキル、1つ〜3つの独立したR5で任意に置換されたヘテロシクロアルキルアルコキシ、1つ〜3つの独立したR5で任意に置換されたヘテロシクロアルキルカルボニルアルキル及び1つ〜3つの独立したR5で任意に置換されたアリールオキシからなる群から選択され、
R5は独立してアミノ、アルキル、アルカノイル、アルキルアミノ、ヒドロキシアルキル、シクロアルキル、シクロアルキルアルキル、ヘテロシクロアルキル及びアミノ保護基からなる群から選択される)の化合物、又はその薬学的に許容可能な塩、溶媒和物、エステル、酸、代謝産物若しくはプロドラッグを含む、EZH2キナーゼの阻害剤に関する。
R4は独立してフルオロ、クロロ、シアノ、メチル、メトキシ、アセチル、(2−(ジメチルアミノ)エチル)アミノ、(2−(ジメチルアミノ)エチル)(メチル)アミノ、イソプロピルスルホンアミド、シクロプロピルスルホンアミド、ピペリジル、ピペラジニル、モルホリニル、ホモピペラジニル、モルホリン−4−カルボニル、モルホリノメチル、ピペリジルメチル、ピペラジニルメチル、モルホリノエトキシル、モルホリノプロポキシ、モルホリン−4−カルボニルメチル及びフェノキシからなる群から選択され、ここで、ピペリジル、ピペラジニル、モルホリニル、ホモピペラジニル、モルホリン−4−カルボニル、モルホリノメチル、ピペリジルメチル、ピペラジニルメチル、モルホリノエトキシル、モルホリノプロポキシ、モルホリン−4−カルボニルメチル及びフェノキシは、1つ〜3つの独立したR5で任意に置換され、
R5は独立してアミノ、メチル、エチル、イソプロピル、アセチル、ジメチルアミノ、ヒドロキシメチル、シクロプロピル、シクロプロピルメチル、ピロリル及びtert−ブトキシカルボニルからなる群から選択される。
本発明の1つ以上のEZH2阻害剤は、個別に又は医薬組成物の形態でヒト患者に投与することができ、医薬組成物中でEZH2阻害剤は、本明細書に記載の疾患又は病態を治療又は回復する投与量で、好適な担体又は1つ以上の賦形剤と混合される。これらのEZH2阻害剤の混合物はまた、単純混合物として又は好適な配合医薬組成物で患者に投与することができる。例えば、本発明の一態様は、治療有効投与量のEZH2阻害剤、又はその薬学的に許容可能な塩、溶媒和物、異性体、エステル、酸、代謝産物若しくはプロドラッグと、薬学的に許容可能な担体又は賦形剤と、他の治療剤とを含む医薬組成物に関する。
ヒストン又は他のタンパク質のメチル化状態を調節することによって経過に影響を与えることができる癌及び前癌状態等の病態及び疾患を治療、予防又は緩和する方法が本明細書で提供され、上記メチル化状態は、EZH2の活性によって少なくとも部分的に媒介される。ヒストンのメチル化状態の調節は次に、メチル化によって活性化される標的遺伝子及び/又はメチル化によって抑制される標的遺伝子の発現レベルに影響を与え得る。
本発明の一態様では、EZH2阻害剤又はその薬学的に許容可能な塩は、癌等の疾患を治療するために、別の治療剤と組み合わせて使用することができる。例えば、付加的な作用物質は、本発明の化合物によって治療される疾患又は病態の治療に有用であるとして当該技術分野で認識されている治療剤であり得る。
本明細書で使用される場合、「治療有効量」又は「治療有効用量」は、病態の進行を完全若しくは部分的に阻害するか、又は病態の1つ以上の症状を少なくとも部分的に緩和する、EZH2阻害剤又は2つ以上のかかる化合物の組合せの量である。治療有効量は、予防上有効な量でもあり得る。治療上有効な量は、患者の体格及び性別、治療すべき病態、病態の重症度、並びに求められる結果によって決まる。一実施形態では、治療有効用量は、患者における症状の回復をもたらすEZH2阻害剤の量を指す。所与の患者については、治療有効量は、当業者に既知の方法によって決定することができる。
EZH2阻害剤は、必要に応じて、EZH2阻害剤を含有する1つ以上の単位剤形を含み得るキット(例えば、パック又はディスペンサーデバイス)内で与えることができる。パックは、金属箔又は例えばブリスターパック等のプラスチック箔を含み得る。パック又はディスペンサーデバイスには、投与の説明書を添付することができる。適合した医薬担体中で配合された本発明のEZH2阻害剤を含む組成物も調製し、適切な容器に入れ、指定の病態の治療についてラベルを付けることができる。使用説明書を提供することもできる。
本発明の化合物は、当業者に既知の標準合成法を用いるか又は本明細書に記載の方法と組み合わせた当該技術分野で既知の方法を用いて合成することができる。加えて、本明細書に提示される溶媒、温度及び他の反応条件は、当業者によって変化し得る。更なる指針として、以下の合成方法を利用することもできる。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(6−(4−(ジメチルアミノ)ピペリジン−1−イル)ピリジン−3−イル)−3−(N−エチルシクロプロパンカルボキサミド)−2−メチル−ベンズアミド1
化合物a:3−アミノ−5−ブロモ−2−メチルメチルベンゾエート(5g、1.0当量)及び酢酸(3.51ml、3.0当量)をメタノール(30ml)に添加し、アセトアルデヒド(1.26ml、1.1当量)を氷浴下で添加した。室温で2時間撹拌した後、シアノ水素化ホウ素ナトリウム(2.57g、2.0当量)を氷浴下で添加した。1時間の撹拌後に、飽和重炭酸ナトリウムを気泡が発生しなくなるまで添加した。生成物(resultant)を濃縮、並びに酢酸エチル及び水による希釈に供した。有機層を水(3×30ml)及び飽和食塩水(30ml)による洗浄に続けて供した後、無水硫酸ナトリウムで乾燥させ、濃縮及びカラムクロマトグラフィーに供して、固体b(3.8g)を得た。
化合物b:5−ブロモ−3−(エチルアミノ)−2−メチルメチルベンゾエート(3g、1.0当量)及びトリエチルアミン(12ml、8.0当量)をジクロロメタン(30ml)に添加した。シクロプロパンカルボニルクロリド(4ml、4.0当量)を氷浴下で添加し、混合物を室温で10分間撹拌した。飽和重炭酸ナトリウムを添加することによってクエンチを行い、生成物を直接抽出に供し、有機層を飽和重炭酸ナトリウム(3×30ml)及び飽和食塩水(30ml)による洗浄に供した後、無水硫酸ナトリウムで乾燥させ、濃縮及びカラムクロマトグラフィーに供して、固体c(3.1g)を得た。
化合物c:5−ブロモ−3−(N−エチルシクロプロパンカルボキサミド)−2−メチルメチルベンゾエート(3g、1.0当量)、ビス(ピナコラート)ジボロン(4.5g、2.0)、酢酸カリウム(2.4g、2.5当量)及びPd(dppf)Cl2(0.36g、0.05当量)を混合し、1,4−ジオキサン(20ml)に添加し、混合物を窒素保護下にて100℃で一晩撹拌した後、濃縮及びカラムクロマトグラフィーに供して、固体d(2.7g)を得た。
化合物2,5−ジブロモピリジン(200mg、1.0当量)、N,N−ジメチルピペリジン−4−アミン(160mg、1.1当量)及び炭酸カリウム(470mg、3.0当量)を混合し、DMSO(10ml)に添加し、混合物を窒素保護下にて100℃で一晩撹拌した後、水で希釈し、酢酸エチルで抽出した。得られた有機相を3回の水による洗浄及び飽和食塩水による洗浄、並びに無水硫酸ナトリウムによる乾燥に供して、固体i(300mg)を得たが、これについては更なる精製は必要でない。
化合物d:3−(N−エチルシクロプロパンカルボキサミド)−2−メチル−5−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)メチルベンゾエート(100mg、1当量)、化合物i 1−(5−ブロモピリジン−2−イル)−N,N−ジメチルピペリジン−4−アミン(73mg、1.0当量)、Pd(PPh3)4(15mg、0.05当量)及び炭酸カリウム(53mg、1.5当量)を混合し、1,4−ジオキサン/水(5ml/0.5ml)に添加し、混合物を窒素保護下にて110℃で一晩撹拌した後、濃縮及びカラムクロマトグラフィーに供して、固体e(85mg)を得た。
化合物e 5−(6−(4−(ジメチルアミノ)ピペリジン−1−イル)ピリジン−3−イル)−3−(N−エチルシクロプロパンカルボキサミド)−2−メチルメチルベンゾエート(80mg、1.0当量)及びリチウム水和物(39mg、10当量)を混合し、メタノール/水(10ml/3ml)に溶解し、1M HClでpHを6に調整して、混合物を室温で2時間撹拌し、濃縮した後、水の添加によって希釈し、n−ブタノールで2回抽出し、乾燥させ、濃縮して産物f(60mg)を得たが、これについては更なる精製は必要でない。
3−オキソ−ブチロニトリル(5.04、1.05当量)及びカリウムtert−ブトキシド(7g、1.05当量)を混合し、DMSO(80ml)に添加し、混合物を室温で10分間撹拌した後、(E)−3−ペンテン−2−オン(5g、1当量)を添加した。混合物を室温で30分間撹拌し、カリウムtert−ブトキシド(7g、1.05当量)を再度添加し、1時間後に、通気しながら一晩撹拌した。反応液を0℃まで冷却し、20mlの水の添加によって希釈し、4N HCl(15ml)を滴加し、15分間撹拌した後、濾過して固体を得て、これを100mlの水による洗浄に供し、産物g(3.8g)を得たが、これについては更なる精製は必要でない。
化合物g:4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−ニトリル(3g、1.0当量)及び好適な量のラネーニッケルをメタノール(50ml)に添加した後、飽和アンモニア(25ml)を添加した。混合物を、水素を含む雰囲気下で24時間反応させた後、濾過し、濃縮し、結晶化させて2.0gの産物hを得た。
化合物f:5−(6−(4−(ジメチルアミノ)ピペリジン−1−イル)ピリジン−3−イル)−3−(N−エチルシクロプロパンカルボキサミド)−2−メチル安息香酸(25mg、1.0当量)をDMF(3ml)に溶解し、混合物にDIPEA(0.029ml、3当量)、HATU(32mg、1.5当量)、化合物h 3−(アミノメチル)−4,6−ジメチルピリジン−2(1H)−オン(9.3mg、1.1当量)を続けて添加し、混合物を室温で1時間撹拌し、水の添加によって希釈し、酢酸エチルで抽出した。抽出した有機相を3回の水による洗浄及び飽和食塩水による洗浄、次いで無水硫酸ナトリウムによる乾燥、更には濃縮及びカラムクロマトグラフィーに供して、固体産物1(15mg)を得た。
質量分析データ:LC−MS(ESI,m/z):585.3542[M+H]+。
5−(6−(4−(ジメチルアミノ)ピペリジン−1−イル)ピリジン−3−イル)−3−(N−エチルシクロプロパンカルボキサミド)−2−メチル−N−((6−メチル−2−オキソ−4−プロピル−1,2−ジヒドロピリジン−3−イル)メチル)ベンズアミド2
質量分析データ:LC−MS(ESI,m/z):613.3854[M+H]+。
5−(6−(4−(シクロプロピルメチル)ピペラジン−1−イル)ピリジン−3−イル)−N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−(N−エチルシクロプロパンカルボキサミド)−2−メチルベンズアミド3
質量分析データ:LC−MS(ESI,m/z):597.3545[M+H]+。
5−(6−(4−(シクロプロピルメチル)ピペラジン−1−イル)ピリジン−3−イル)−3−(N−エチルシクロプロパンカルボキサミド)−2−メチル−N−((6−メチル−2−オキソ−4−プロピル−1,2−ジヒドロピリジン−3−イル)メチル)ベンズアミド4
質量分析データ:LC−MS(ESI,m/z):625.3849[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(N−エチルシクロプロパンカルボキサミド)−4−メチル−4’−(モルホリノメチル)−[1,1’−ジフェニル]−3−カルボキサミド5
質量分析データ:LC−MS(ESI,m/z):557.3132[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(N−エチルシクロプロパンカルボキサミド)−4−メチル−4’−モルホリニル−[1,1’−ジフェニル]−3−カルボキサミド6
質量分析データ:LC−MS(ESI,m/z):543.2960[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−(N−エチルシクロプロパンカルボキサミド)−2−メチル−5−(6−モルホリノピリジン−3−イル)ベンズアミド7
質量分析データ:LC−MS(ESI,m/z):544.2910[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(N−エチルシクロプロパンカルボキサミド)−4’−(4−エチルピペラジン−1−イル)−4−メチル−[1,1’−ジフェニル]−3−カルボキサミド8
質量分析データ:LC−MS(ESI,m/z):570.3422[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−(N−エチルシクロプロパンカルボキサミド)−2−メチル−5−(6−(4−メチルピペラジン−1−イル)ピリジン−3−イル)ベンズアミド9
質量分析データ:LC−MS(ESI,m/z):557.3251[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−(N−エチルシクロプロパンカルボキサミド)−5−(6−(4−イソプロピルピペラジン−1−イル)ピリジン−3−イル)−2−メチルベンズアミド10
質量分析データ:LC−MS(ESI,m/z):585.3542[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−4’−((4−(ジメチルアミノ)ピペリジン−1−イル)メチル)−5−(N−エチルシクロプロパンカルボキサミド)−4−メチル−[1,1’−ジフェニル]−3−カルボキサミド11
質量分析データ:LC−MS(ESI,m/z):598.3772[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(6−((2−(ジメチルアミノ)エチル)(メチル)アミノ)ピリジン−3−イル)−3−(N−エチルシクロプロパンカルボキサミド)−2−メチルベンズアミド12
質量分析データ:LC−MS(ESI,m/z):559.3390[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−(N−エチルシクロプロパンカルボキサミド)−2−メチル−5−((2−モルホリノエチル)アミノ)−ベンズアミド13
質量分析データ:LC−MS(ESI,m/z):510.3058[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(6−(4−(ジメチルアミノ)ピペリジン−1−イル)ピリジン−3−イル)−3−(N−エチルシクロペンタンカルボキサミド)−2−メチルベンズアミド14
質量分析データ:LC−MS(ESI,m/z):613.3864[M+H]+。
5−(6−(4−(シクロプロピルメチル)ピペラジン−1−イル)ピリジン−3−イル)−N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−(N−エチルシクロペンタンカルボキサミド)−2−メチルベンズアミド15
質量分析データ:LC−MS(ESI,m/z):625.3862[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(N−エチルシクロペンタンカルボキサミド)−4−メチル−4’−(モルホリノメチル)−[1,1’−ジフェニル]−3−カルボキサミド16
質量分析データ:LC−MS(ESI,m/z):585.3430[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−(N−エチルシクロペンタンカルボキサミド)−2−メチル−5−(2−(4−メチルピペラジン−1−イル)ピリジン−4−イル)ベンズアミド17
質量分析データ:LC−MS(ESI,m/z):585.3550[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−(N−エチルシクロペンタンカルボキサミド)−5−(6−(4−イソプロピルピペラジン−1−イル)ピリジン−3−イル)−2−メチルベンズアミド18
質量分析データ:LC−MS(ESI,m/z):613.3860[M+H]+。
4’−シアノ−N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(N−エチルシクロペンタンカルボキサミド)−3’−フルオロ−4−メチル−[1,1’−ジフェニル]−3−カルボキサミド19
質量分析データ:LC−MS(ESI,m/z):529.2605[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(N−エチルシクロペンタンカルボキサミド)−4−メチル−4’−(モルホリン−4−カルボニル)−[1,1’−ジフェニル]−3−カルボキサミド20
質量分析データ:LC−MS(ESI,m/z):599.3240[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(N−エチルシクロペンタンカルボキサミド)−4−メチル−4’−モルホリニル−[1,1’−ジフェニル]−3−カルボキサミド21
質量分析データ:LC−MS(ESI,m/z):571.3275[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(N−エチルシクロペンタンカルボキサミド)−4−メチル−4’−(2−モルホリニル−2−オキソエチル)−[1,1’−ジフェニル]−3−カルボキサミド22
質量分析データ:LC−MS(ESI,m/z):613.3375[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(N−エチルシクロペンタンカルボキサミド)−4’−((4−エチルピペラジン−1−イル)メチル)−4−メチル−[1,1’−ジフェニル]−3−カルボキサミド23
質量分析データ:LC−MS(ESI,m/z):612.3901[M+H]+。
tert−ブチル−4−((3’−(((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)カルバモイル)−5’−(N−エチルシクロペンタンカルボキサミド)−4’−メチル−[1,1’−ジフェニル]−4−イル)メチル)ピペラジン−1−カルボキシレート24
質量分析データ:LC−MS(ESI,m/z):684.4105[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(N−エチルシクロペンタンカルボキサミド)−4−メチル−4’−((4−ピペラジン−1−イル)メチル)−4−メチル−[1,1’−ジフェニル]−3−カルボキサミド25
質量分析データ:LC−MS(ESI,m/z):584.3601[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(N−エチルシクロペンタンカルボキサミド)−4−メチル−4’−(プロパ−2−イルスルホンアミド)−[1,1’−ジフェニル]−3−カルボキサミド26
質量分析データ:LC−MS(ESI,m/z):607.2960[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(N−エチルシクロペンタンカルボキサミド)−4’−(4−エチルピペラジン−1−イル)−4−メチル−[1,1’−ジフェニル]−3−カルボキサミド27
質量分析データ:LC−MS(ESI,m/z):598.3750[M+H]+。
4’−(シクロプロパンスルホンアミド)−N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(N−エチルシクロペンタンカルボキサミド)−4−メチル−[1,1’−ジフェニル]−3−カルボキサミド28
質量分析データ:LC−MS(ESI,m/z):605.2801[M+H]+。
tertブチル−4−(5−(3−(((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)カルバモイル)−5−(N−エチルシクロペンタンカルボキサミド)−4−メチルフェニル)ピリジン−2−イル)ピペラジン−1−カルボキシレート29
質量分析データ:LC−MS(ESI,m/z):671.3911[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(N−エチルシクロペンタンカルボキサミド)−4−メチル−4’−(3−モルホリノプロポキシ)−[1,1’−ジフェニル]−3−カルボキサミド30
質量分析データ:LC−MS(ESI,m/z):629.3720[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(N−エチルシクロペンタンカルボキサミド)−4−メチル−4’−(ピペラジン−1−イル)−[1,1’−ジフェニル]−3−カルボキサミド31
質量分析データ:LC−MS(ESI,m/z):570.3438[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−(N−エチルシクロペンタンカルボキサミド)−2−メチル−5−(6−(ピペラジン−1−イル)ピリジン−3−イル)−ベンズアミド32
質量分析データ:LC−MS(ESI,m/z):571.3405[M+H]+。
5−シアノ−N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−(N−エチルシクロペンタンカルボキサミド)−2−メチルベンズアミド33
質量分析データ:LC−MS(ESI,m/z):435.2388[M+H]+。
N1−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(N−エチルシクロペンタンカルボキサミド)−6−メチル−イソフタルアミド34
質量分析データ:LC−MS(ESI,m/z):453.2511[M+H]+。
(S)−N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(N−エチルシクロペンタンカルボキサミド)−4’−((2−ヒドロキシメチル)ピペラジン−1−イル)メチル)−4−メチル−[1,1’−ジフェニル]−3−カルボキサミド35
質量分析データ:LC−MS(ESI,m/z):614.3702[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−(N−エチルシクロペンタンカルボキサミド)−2−メチル−5−(6−(4−メチルピペラジン−1−イル)ピリジン−3−イル)ベンズアミド36
質量分析データ:LC−MS(ESI,m/z):585.3541[M+H]+。
5−(6−(4−アミノピペリジン−1−イル)ピリジン−3−イル)−N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−(N−エチルシクロペンタンカルボキサミド)−2−メチルベンズアミド37
質量分析データ:LC−MS(ESI,m/z):585.3540[M+H]+。
5−(2−(4−(シクロプロピルメチル)ピペラジン−1−イル)ピリジン−4−イル)−N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−(N−エチルシクロペンタンカルボキサミド)−2−メチルベンズアミド38
質量分析データ:LC−MS(ESI,m/z):625.3859[M+H]+。
5−(2−(4−(シクロプロピルメチル)ピペラジン−1−イル)ピリジン−4−イル)−3−(N−エチルシクロペンタンカルボキサミド)−2−メチル−N−((6−メチル−2−オキソ−4−プロピル−1,2−ジヒドロピリジン−3−イル)メチル)ベンズアミド39
質量分析データ:LC−MS(ESI,m/z):653.4165[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(N−エチルシクロペンタンカルボキサミド)−4−メチル−4’−(2−モルホリノエトキシル)−[1,1’−ジフェニル]−3−カルボキサミド40
質量分析データ:LC−MS(ESI,m/z):615.3550[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(N−エチルシクロペンタンカルボキサミド)−4−メチル−4’−フェノキシ−[1,1’−ジフェニル]−3−カルボキサミド41
質量分析データ:LC−MS(ESI,m/z):578.3008[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(N−エチルシクロペンタンカルボキサミド)−3’−フルオロ−4−メチル−4’−(3−モルホリノプロポキシ)−[1,1’−ジフェニル]−3−カルボキサミド42
質量分析データ:LC−MS(ESI,m/z):647.3601[M+H]+。
5−(5−アセチルチオフェン−2−イル)−N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−(N−エチルシクロペンタンカルボキサミド)−2−メチルベンズアミド43
質量分析データ:LC−MS(ESI,m/z):534.2415[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(N−エチルシクロペンタンカルボキサミド)−2’−フルオロ−4−メチル−4’−(3−モルホリノプロポキシ)−[1,1’−ジフェニル]−3−カルボキサミド44
質量分析データ:LC−MS(ESI,m/z):647.3602[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(N−エチルシクロペンタンカルボキサミド)−2’,4−メチル−4’−(3−モルホリノプロポキシ)−[1,1’−ジフェニル]−3−カルボキサミド45
質量分析データ:LC−MS(ESI,m/z):643.3855[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(N−エチルシクロペンタンカルボキサミド)−3’,4−メチル−4’−(3−モルホリノプロポキシ)−[1,1’−ジフェニル]−3−カルボキサミド46
質量分析データ:LC−MS(ESI,m/z):643.3854[M+H]+。
3’−シアノ−N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(N−エチルシクロペンタンカルボキサミド)−4−メチル−4’−(2−モルホリノエトキシル)−[1,1’−ジフェニル]−3−カルボキサミド47
質量分析データ:LC−MS(ESI,m/z):640.3503[M+H]+。
2’−クロロ−N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(N−エチルシクロペンタンカルボキサミド)−4−メチル−4’−(2−モルホリノエトキシル)−[1,1’−ジフェニル]−3−カルボキサミド48
質量分析データ:LC−MS(ESI,m/z):649.3172[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(N−エチルシクロペンタンカルボキサミド)−3’−メトキシ−4−メチル−4’−(2−モルホリノエトキシル)−[1,1’−ジフェニル]−3−カルボキサミド49
質量分析データ:LC−MS(ESI,m/z):645.3661[M+H]+。
3−(N−(シクロプロピルメチル)シクロペンタンカルボキサミド)−N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(6−(4−(ジメチルアミノ)ピペリジン−1−イル)ピリジン−3−イル)−2−メチルベンズアミド50
質量分析データ:LC−MS(ESI,m/z):639.4018[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(N−エチルシクロペンタンカルボキサミド)−2’−フルオロ−4−メチル−4’−(2−モルホリノエトキシル)−[1,1’−ジフェニル]−3−カルボキサミド51
質量分析データ:LC−MS(ESI,m/z):633.3432[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(N−エチルシクロペンタンカルボキサミド)−3’−フルオロ−4−メチル−4’−(2−モルホリノエトキシル)−[1,1’−ジフェニル]−3−カルボキサミド52
質量分析データ:LC−MS(ESI,m/z):633.3435[M+H]+。
N−(5−(((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)カルバモイル−4−メチル−4’−(モルホリノメチル)−[1,1’−ジフェニル]−N−エチルテトラヒドロ−2H−ピラン−4−カルボキサミド53
質量分析データ:LC−MS(ESI,m/z):601.3388[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(N−エチル−3,3−ジメチルブチルアミド)−4−メチル−4’−(モルホリノメチル)−[1,1’−ジフェニル]−3−カルボキサミド54
質量分析データ:LC−MS(ESI,m/z):587.3601[M+H]+。
N−(5−(((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)カルバモイル−4−メチル−4’−(モルホリノメチル)−[1,1’−ジフェニル]−N−エチルフラン−4−カルボキサミド55
質量分析データ:LC−MS(ESI,m/z):583.2909[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(N−エチルシクロヘキシルカルボキサミド)−4−メチル−4’−(モルホリノメチル)−[1,1’−ジフェニル]−3−カルボキサミド56
質量分析データ:LC−MS(ESI,m/z):599.3599[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(N−エチル−4−メチルベンズアミド)−4−メチル−4’−(モルホリノメチル)−[1,1’−ジフェニル]−3−カルボキサミド57
質量分析データ:LC−MS(ESI,m/z):607.3271[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(N−エチル−2,2−ジメチルブチルアミド)−4−メチル−4’−(モルホリノメチル)−[1,1’−ジフェニル]−3−カルボキサミド58
質量分析データ:LC−MS(ESI,m/z):587.3597[M+H]+。
5−(N,2−ジエチルブチルアミド)−N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−4−メチル−4’−(モルホリノメチル)−[1,1’−ジフェニル]−3−カルボキサミド59
質量分析データ:LC−MS(ESI,m/z):587.3600[M+H]+。
(1R,4R)−N−(5−(((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)カルバモイル−4−メチル−4’−(モルホリノメチル)−[1,1’−ジフェニル]−3−イル)−N−エチルビシクロ[2.2.1]ヘプタ−5−エン−2−カルボキサミド60
質量分析データ:LC−MS(ESI,m/z):609.3429[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(N−エチルシクロブタンカルボキサミド)−4−メチル−4’−(モルホリノメチル)−[1,1’−ジフェニル]−3−カルボキサミド61
質量分析データ:LC−MS(ESI,m/z):571.3295[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(N−エチルイソブチルアミド)−4−メチル−4’−(モルホリノメチル)−[1,1’−ジフェニル]−3−カルボキサミド62
質量分析データ:LC−MS(ESI,m/z):559.3291[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(N−エチルシクロペンタンカルボキサミド)−2’,4−ジメチル−4’−(2−モルホリノエトキシル)−[1,1’−ジフェニル]−3−カルボキサミド63
質量分析データ:LC−MS(ESI,m/z):629.3700[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(N−エチルシクロプロパンカルボキサミド)−2’,4−ジメチル−4’−(3−モルホリノプロポキシ)−[1,1’−ジフェニル]−3−カルボキサミド64
質量分析データ:LC−MS(ESI,m/z):615.3441[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(N−エチルシクロプロパンカルボキサミド)−3’−フルオロ−4−メチル−4’−(3−モルホリノプロポキシ)−[1,1’−ジフェニル]−3−カルボキサミド65
質量分析データ:LC−MS(ESI,m/z):619.3301[M+H]+
3−(シクロプロパンカルボキサミド)−N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(6−(4−(ジメチルアミノ)ピペリジン−1−イル)ピリジン−3−イル)−2−メチルベンズアミド66
質量分析データ:LC−MS(ESI,m/z):557.3236[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(6−(2−(ジメチルアミノ)エチルアミノ)ピリジン−3−イル)−3−(N−エチルシクロプロパンカルボキサミド)−2−メチルベンズアミド67
質量分析データ:LC−MS(ESI,m/z):545.3245[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−(N−エチルシクロプロパンカルボキサミド)−2−メチル−5−(6−(4−(ピロール−1−イル)ピペリジン−1−イル)ピリジン−3−イル)ベンズアミド68
質量分析データ:LC−MS(ESI,m/z):611.3712[M+H]+。
5−(6−(4−(シクロプロピルメチル)ピペラジン−1−イル)−2−メチルピリジン−3−イル)−N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−(N−エチルシクロプロパンカルボキサミド)−2−メチルベンズアミド69
質量分析データ:LC−MS(ESI,m/z):611.3709[M+H]+。
5−(6−(4−(シクロプロピルメチル)ピペラジン−1−イル)−5−メチルピリジン−3−イル)−N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−(N−エチルシクロプロパンカルボキサミド)−2−メチルベンズアミド70
質量分析データ:LC−MS(ESI,m/z):611.3711[M+H]+。
5−(6−(4−(シクロプロピルメチル)ピペラジン−1−イル)−4−メチルピリジン−3−イル)−N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−(N−エチルシクロプロパンカルボキサミド)−2−メチルベンズアミド71
質量分析データ:LC−MS(ESI,m/z):611.3710[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(N−エチルシクロプロパンカルボキサミド)−3’,4−ジメチル−4’−(3−モルホリノプロポキシ)−[1,1’−ジフェニル]−3−カルボキサミド72
質量分析データ:LC−MS(ESI,m/z):615.3440[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(N−エチルシクロプロパンカルボキサミド)−2’−クロロ−4−メチル−4’−(2−モルホリノエトキシル)−[1,1’−ジフェニル]−3−カルボキサミド73
質量分析データ:LC−MS(ESI,m/z):621.2806[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(N−エチルシクロプロパンカルボキサミド)−3’−フルオロ−4−メチル−4’−(2−モルホリノエトキシル)−[1,1’−ジフェニル]−3−カルボキサミド74
質量分析データ:LC−MS(ESI,m/z):605.3050[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(N−エチルシクロプロパンカルボキサミド)−2’,4−ジメチル−4’−(2−モルホリノエトキシル)−[1,1’−ジフェニル]−3−カルボキサミド75
質量分析データ:LC−MS(ESI,m/z):601.3333[M+H]+。
5−(6−(4−(シクロプロピルピペラジン−1−イル)ピリジン−3−イル)−N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−(N−エチルシクロプロパンカルボキサミド)−2−メチルベンズアミド76
質量分析データ:LC−MS(ESI,m/z):583.3323[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−(N−エチルシクロプロパンカルボキサミド)−2−メチル−5−(6−(4−メチルホモピペラジン−1−イル)ピリジン−3−イル)ベンズアミド77
質量分析データ:LC−MS(ESI,m/z):571.3347[M+H]+。
5−(6−(4−アセチルピペラジン−1−イル)ピリジン−3−イル)−N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−(N−エチルシクロプロパンカルボキサミド)−2−メチルベンズアミド78
質量分析データ:LC−MS(ESI,m/z):585.3123[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−(N−エチルシクロプロパンカルボキサミド)−2−メチル−5−(3−モルホリニルプロピルアミノ)ベンズアミド79
質量分析データ:LC−MS(ESI,m/z):524.3173[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−((2−(ジメチルアミノ)エチル)(メチル)アミノ)−3−(N−エチルシクロプロパンカルボキサミド)−2−メチルベンズアミド80
質量分析データ:LC−MS(ESI,m/z):482.3061[M+H]+。
3’−クロロ−N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(N−エチルシクロペンタンカルボキサミド)−4−メチル−4’−(2−モルホリノエトキシル)−[1,1’−ビフェニル]−3−カルボキサミド
質量分析データ:LC−MS(ESI,m/z):621.2765[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(N−エチルシクロペンタンカルボキサミド)−3’,4−ジメチル−4’−(2−モルホリノエチル)−[1,1’−ビフェニル]−3−カルボキサミド
質量分析データ:LC−MS(ESI,m/z):601.3312[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(N−エチルシクロペンタンカルボキサミド)−3’−メトキシ−4−メチル−4’−(2−モルホリノエトキシル)−[1,1’−ビフェニル]−3−カルボキサミド
質量分析データ:LC−MS(ESI,m/z):617.3261[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−(N−エチルシクロプロパンカルボキサミド)−2−メチル−5−(2−メチルピリジン−3−イル)ベンズアミド
質量分析データ:LC−MS(ESI,m/z):473.2474[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−(N−エチルシクロペンタンカルボキサミド)−2−メチル−5−(2−メチル−6−モルホリノピリジン−3−イル)ベンズアミド
質量分析データ:LC−MS(ESI,m/z):473.2474[M+H]+。
tert−ブチル(5−(3−(((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)カルバモイル)−5−(N−エチルシクロプロパンカルボキサミド)−4−メチルフェニル)−6−メチルピリジン−2−イル)ピペラジン−1−カルボキサミド
質量分析データ:LC−MS(ESI,m/z):657.3686[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−(N−エチルシクロペンタンカルボキサミド)−2−メチル−5−(2−メチル−6−(ピペラジン−1−イル)ピリジン−3−イル)ベンズアミド
質量分析データ:LC−MS(ESI,m/z):557.3162[M+H]+。
(6−アミノ−2−メチルピリジン−3−イル)−N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−(N−エチルシクロペンタンカルボキサミド)−2−メチルベンズアミド
質量分析データ:LC−MS(ESI,m/z):488.2583[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(6−(ジメチルアミノ)−2−メチルピリジン−3−イル)−3−(N−エチルシクロプロパンカルボキサミド)−2−メチルベンズアミド
質量分析データ:LC−MS(ESI,m/z):516.2896[M+H]+。
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−(N−エチルシクロプロパンカルボキサミド)−2−メチル−5−(2−メチル−6−メチルアミノ)ピリジン−3−イル)ベンズアミド
質量分析データ:LC−MS(ESI,m/z):502.2740[M+H]+。
5−(2−(4−(シクロプロピルメチル)ピペラジン−1−イル)ピリジン−4−イル)−N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−(N−エチルシクロプロパンカルボキサミド)−2−メチルベンズアミド
質量分析データ:LC−MS(ESI,m/z):597.3475[M+H]+。
3−(シクロプロパンカルボキサミド)−5−(6−(4−(シクロプロピルメチル)ピペラジン−1−イル)−2−メチルピリジン−3−イル)−N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロ−2−ジヒドロピリジン−3−イル)メチル)−2−メチルベンズアミド
質量分析データ:LC−MS(ESI,m/z):583.3318[M+H]+。
EZH2の小分子をスクリーニングする系
EZH2は、下流のE−カドヘリンの発現を抑制し、EZH2の抑制時にE−カドヘリンの発現は増大する。かかる原理に基づいて、レポーター遺伝子発現ベクターを、ルシフェラーゼを用いて構築した。
ゲノムDNAを、抽出キットとしてDNeasy Blood & Tissue Kit(米国のQiagenから購入)を用いて、細胞数が約106である293T細胞(米国のATCCから購入)から抽出し、抽出したゲノムDNAを、下記に示す配列を有するプライマーを用いてE−カドヘリンのプロモーター配列を増幅するための鋳型として用いた。PCR後の増幅フラグメント及びPGL4.1ベクター(日本のタカラバイオ株式会社から購入)を、それぞれSacI及びBglII(日本のタカラバイオ株式会社から購入)による酵素消化に供した後、PCRクリーンアップキット(Axygen PCRクリーンアップキット)を用いて精製した。続いて、精製及び酵素消化したPCR産物を、精製及び酵素消化したPGL4.1ベクターにリガーゼ溶液I(DNA Ligation Kit Ver.2.1、日本のタカラバイオ株式会社から購入)を用いてライゲートし、形質転換に供した。次いで、単一クローンをスクリーニングし(screened out)、シークエンシングに供し、Eカドヘリンのプロモーターフラグメントを含有する得られた陽性プラスミドをE−カドヘリンRE−PGL4.1と命名した。
GGCGAGCTCCTGATCATTATTCCCATTAGGAGGGTG
GGCAGATCTGGCTGGCCGGGGACGCCGAGCGAG
GGCGGTACCGTTGACATTGATTATTGACTAGTTATTAATA
GGCCTCGAGGAGCTCTGCTTATATAGACCTCCCA
EZH2酵素活性アッセイ系
酵素活性アッセイを、Cisbio社のEZH2(Y641F) TR−FRETアッセイキットを用い、一次スクリーニングにおいて活性であることが示された化合物に対して行い、GSK126(Shanghai Haoyuan Chemexpress Co., Ltd.から購入)及びEPZ6438(CAS番号1403254−99−8、Shanghai Haoyuan Chemexpress Co., Ltd.から購入)を対照として用いた。
Claims (14)
- 式(I):
Yは1つ〜3つの独立したR4で任意に置換されたフェニル、1つ〜3つの独立したR4で任意に置換されたピリジン−3−イル及び1つ〜3つの独立したR4で任意に置換されたピリジン−4−イルからなる群から選択され、
R1はメチル、エチル及びプロピルからなる群から選択され、
R2は水素、メチル、エチル、プロピル、シクロプロピルメチル、シクロプロピルエチル、シクロブチルメチル、シクロブチルエチル、シクロペンチルメチル及びシクロヘキシルメチルからなる群から選択され、
R3は1個〜8個の炭素原子を有するアルキル、3個〜8個の炭素原子を有するシクロアルキル、窒素、酸素及び硫黄からなる群から選択される1つ以上の原子を含む3個〜8個の原子で形成されるヘテロシクロアルキル、ピリジニル、イミダゾリル、ピリミジニル、ピラゾリル、トリアゾリル、ピラジニル、テトラゾリル、フリル、チエニル、イソオキサゾリル、チアゾリル、オキサゾリル、イソチアゾリル、ピロリル、キノリニル、イソキノリニル、インドリル、ベンズイミダゾリル、ベンゾフリル、インダゾリル、インドリジニル、フタラジニル、ピリダジニル、イソインドリル、プテリジニル、プリニル、オキサジアゾリル、チアジアゾリル、フリル、ベンゾフリル、ベンゾチオフェニル、ベンゾチアゾリル、ベンゾオキサゾリル、キナゾリニル、ナフチリジニル及びフロピリジニルからなる群から選択されるヘテロアリール、1個〜8個の炭素原子を有するアルキルで置換されているフェニル、ナフタレニル、フェナントレニル、アントラセニル、フルオレニル及びインデニルからなる群から選択されるアルキルアリール及びビシクロ[2.2.1]ヘプタ−2−エニルからなる群から選択され、
R4は独立して水素、フルオロ、クロロ、アミノ、シアノ、メチル、メトキシ、アセチル、(2−(ジメチルアミノ)エチル)アミノ、(2−(ジメチルアミノ)エチル)(メチル)アミノ、イソプロピルスルホンアミド、シクロプロピルスルホンアミド、ピペリジル、ピペラジニル、モルホリニル、ホモピペラジニル、モルホリン−4−カルボニル、モルホリノメチル、ピペリジルメチル、ピペラジニルメチル、モルホリノエトキシル、モルホリノプロポキシ、モルホリン−4−カルボニルメチル及びフェノキシからなる群から選択され、ここで、イソプロピルスルホンアミド及びシクロプロピルスルホンアミドは、1つのR5で任意に置換され、ピペリジル、ピペラジニル、モルホリニル、ホモピペラジニル、モルホリン−4−カルボニル、モルホリノメチル、ピペリジルメチル、ピペラジニルメチル、モルホリノエトキシル、モルホリノプロポキシ、モルホリン−4−カルボニルメチル及びフェノキシは、1つ〜3つの独立したR5で任意に置換され、
R5は独立してアミノ、メチル、エチル、イソプロピル、アセチル、ジメチルアミノ、ヒドロキシメチル、シクロプロピル、シクロプロピルメチル、ピロリル及びt−ブチルオキシカルボニルからなる群から選択される)の化合物、又はその薬学的に許容可能な塩若しくは溶媒和物。 - R2がメチル、エチル、プロピル及びシクロプロピルメチルからなる群から選択され、R3がイソプロピル、ネオペンチル、tert−ペンチル、ペンタ−3−イル、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、テトラヒドロピラニル、フリル、メチルフェニル及びビシクロ[2.2.1]ヘプタ−2−エニルからなる群から選択される、請求項1に記載の化合物、又はその薬学的に許容可能な塩若しくは溶媒和物。
- YがR4で置換されたフェニル、ピリジン−3−イル又はピリジン−4−イルであり、
R4はフルオロ、メチル、4−(シクロプロピルメチル)ピペラジン−1−イル、モルホリノエトキシル、モルホリノプロポキシ、モルホリノメチル、又はN原子がアミノ保護基で任意に置換されたピペラジニルメチルからなる群から選択され、
R1がメチルであり、
R2がエチルであり、
R3がシクロプロピル又はシクロペンチルである、請求項1に記載の化合物、又はその薬学的に許容可能な塩若しくは溶媒和物。 - XがCHであり、
R1がメチルであり、
R2がエチルであり、
R3がイソプロピル、ネオペンチル、tert−ペンチル、ペンタ−3−イル、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、テトラヒドロピラン−4−イル、フラン−2−イル、p−メチルフェニル及びビシクロ[2.2.1]ヘプタ−2−エニルからなる群から選択され、
R4が各々独立して水素、フルオロ、メチル、1つのR5で任意に置換されたイソプロピルスルホンアミド、1つのR5で任意に置換されたシクロプロピルスルホンアミド、1つ〜3つの独立したR5で任意に置換されたピペリジル、1つ〜3つの独立したR5で任意に置換されたピペラジニル、1つ〜3つの独立したR5で任意に置換されたモルホリニル、1つ〜3つの独立したR5で任意に置換されたモルホリン−4−カルボニル、1つ〜3つの独立したR5で任意に置換されたモルホリノメチル、1つ〜3つの独立したR5で任意に置換されたピペリジルメチル、1つ〜3つの独立したR5で任意に置換されたピペラジニルメチル、1つ〜3つの独立したR5で任意に置換されたモルホリノエトキシル、1つ〜3つの独立したR5で任意に置換されたモルホリノプロポキシ、1つ〜3つの独立したR5で任意に置換されたモルホリン−4−カルボニルメチル及び1つ〜3つの独立したR5で任意に置換されたフェノキシからなる群から選択され、
R5は独立してエチル、シクロプロピルメチル、ジメチルアミノ、ヒドロキシメチル及びt−ブチルオキシカルボニルからなる群から選択される、請求項4に記載の化合物、又はその薬学的に許容可能な塩若しくは溶媒和物。 - 請求項1〜6のいずれか一項に記載の化合物、又はその薬学的に許容可能な塩若しくは溶媒和物と、薬学的に許容可能な担体又は賦形剤と、任意に他の治療剤とを含む医薬組成物。
- 請求項1〜6のいずれか一項に記載の化合物、又はその薬学的に許容可能な塩若しくは溶媒和物を含み、EZH2の活性の阻害に使用される、医薬組成物。
- 前記EZH2が野生型EZH2及び/又はY641F突然変異体EZH2である、請求項8に記載の医薬組成物。
- 請求項1〜6のいずれか一項に記載の化合物、又はその薬学的に許容可能な塩若しくは溶媒和物を含み、EZH2活性と関連する癌又は前癌状態の治療に使用される、医薬組成物。
- 前記癌がリンパ腫、白血病及び黒色腫からなる群から選択される、請求項10に記載の医薬組成物。
- 前記リンパ腫が非ホジキンリンパ腫、濾胞性リンパ腫及びびまん性大細胞型B細胞リンパ腫からなる群から選択される、請求項11に記載医薬組成物。
- 前記白血病が慢性骨髄性白血病である、請求項11に記載の医薬組成物。
- 前記前癌状態が骨髄異形成症候群である、請求項10に記載の医薬組成物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710045099.0 | 2017-01-17 | ||
CN201710045099.0A CN108314677B (zh) | 2017-01-17 | 2017-01-17 | 一种ezh2抑制剂及其用途 |
JP2019559154A JP7320263B2 (ja) | 2017-01-17 | 2018-01-17 | Ezh2阻害剤及びその使用 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2019559154A Division JP7320263B2 (ja) | 2017-01-17 | 2018-01-17 | Ezh2阻害剤及びその使用 |
Publications (1)
Publication Number | Publication Date |
---|---|
JP2021185208A true JP2021185208A (ja) | 2021-12-09 |
Family
ID=62892481
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2019559154A Active JP7320263B2 (ja) | 2017-01-17 | 2018-01-17 | Ezh2阻害剤及びその使用 |
JP2021149124A Pending JP2021185208A (ja) | 2017-01-17 | 2021-09-14 | Ezh2阻害剤及びその使用 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2019559154A Active JP7320263B2 (ja) | 2017-01-17 | 2018-01-17 | Ezh2阻害剤及びその使用 |
Country Status (6)
Country | Link |
---|---|
US (1) | US10647700B2 (ja) |
EP (1) | EP3572400B1 (ja) |
JP (2) | JP7320263B2 (ja) |
CN (1) | CN108314677B (ja) |
ES (1) | ES2963590T3 (ja) |
WO (1) | WO2018133795A1 (ja) |
Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108314677B (zh) * | 2017-01-17 | 2020-06-30 | 安徽中科拓苒药物科学研究有限公司 | 一种ezh2抑制剂及其用途 |
US11919912B2 (en) | 2018-05-21 | 2024-03-05 | Constellation Pharmaceuticals, Inc. | Modulators of methyl modifying enzymes, compositions and uses thereof |
JP7411256B2 (ja) * | 2018-07-27 | 2024-01-11 | エボポイント、バイオサイエンシズ、カンパニー、リミテッド | 多置換ベンゼン環化合物、製造方法及びその用途 |
CN110828564B (zh) * | 2018-08-13 | 2022-04-08 | 香港科技大学 | 具有半导体性栅极的场效应晶体管 |
US20220024941A1 (en) * | 2019-03-25 | 2022-01-27 | Shanghai Synergy Pharmaceutical Sciences Co., Ltd. | Preparation Method for Amide Compounds and Use Thereof in Medical Field |
BR112022001154A2 (pt) * | 2019-07-24 | 2022-06-07 | Constellation Pharmaceuticals Inc | Terapias de inibição de ezh2 para o tratamento de cânceres |
CN112920176B (zh) * | 2020-05-25 | 2022-11-04 | 四川大学华西医院 | 可诱导prc2蛋白复合物核心亚基降解的双功能化合物和药物组合物及应用 |
AU2021359475A1 (en) * | 2020-10-13 | 2023-06-15 | Evopoint Biosciences Co., Ltd. | Crystal form of multi-substituted benzene ring compound maleate, and preparation method therefor and use thereof |
CN113248481B (zh) * | 2021-04-19 | 2023-03-24 | 中山大学 | Ezh2共价不可逆抑制剂、制备方法及其用途 |
CN113440511B (zh) * | 2021-07-07 | 2023-04-07 | 天津医科大学总医院 | Hotair-prc2阻断剂及其复合制剂在制备治疗子宫内膜癌药物中的用途 |
CN115364231B (zh) * | 2021-10-15 | 2023-11-17 | 北京大学第三医院(北京大学第三临床医学院) | 一种增强ezh2抑制剂抗肿瘤作用的药物组合物及其用途 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2014513084A (ja) * | 2011-04-13 | 2014-05-29 | エピザイム,インコーポレイティド | 置換されたベンゼン化合物 |
JP2020514406A (ja) * | 2017-01-17 | 2020-05-21 | タラピューティクス サイエンス インコーポレイテッド | Ezh2阻害剤及びその使用 |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5763263A (en) | 1995-11-27 | 1998-06-09 | Dehlinger; Peter J. | Method and apparatus for producing position addressable combinatorial libraries |
DE602005017781D1 (de) | 2004-06-01 | 2009-12-31 | Univ North Carolina | Rekonstituierter histon-methyltransferase-komplex und verfahren zur identifizierung von modulatoren dafür |
JO3438B1 (ar) * | 2011-04-13 | 2019-10-20 | Epizyme Inc | مركبات بنزين مستبدلة بأريل أو أريل غير متجانس |
JP5571113B2 (ja) | 2012-03-16 | 2014-08-13 | 株式会社東芝 | 液体処理システム、制御方法及び制御プログラム |
RU2699546C2 (ru) * | 2012-04-13 | 2019-09-06 | Эпизайм, Инк. | Комбинированная терапия для лечения рака |
CA2887243C (en) | 2012-10-15 | 2024-04-09 | Epizyme, Inc. | Methods of treating cancer |
WO2017139404A1 (en) * | 2016-02-08 | 2017-08-17 | Epizyme, Inc. | Methods of treating cancer |
CA3018270A1 (en) | 2016-04-22 | 2017-10-26 | Dana-Farber Cancer Institute, Inc. | Ezh2 inhibitors and uses thereof |
-
2017
- 2017-01-17 CN CN201710045099.0A patent/CN108314677B/zh active Active
-
2018
- 2018-01-17 US US16/478,277 patent/US10647700B2/en active Active
- 2018-01-17 WO PCT/CN2018/073002 patent/WO2018133795A1/zh unknown
- 2018-01-17 JP JP2019559154A patent/JP7320263B2/ja active Active
- 2018-01-17 ES ES18741236T patent/ES2963590T3/es active Active
- 2018-01-17 EP EP18741236.6A patent/EP3572400B1/en active Active
-
2021
- 2021-09-14 JP JP2021149124A patent/JP2021185208A/ja active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2014513084A (ja) * | 2011-04-13 | 2014-05-29 | エピザイム,インコーポレイティド | 置換されたベンゼン化合物 |
JP2020514406A (ja) * | 2017-01-17 | 2020-05-21 | タラピューティクス サイエンス インコーポレイテッド | Ezh2阻害剤及びその使用 |
Non-Patent Citations (1)
Title |
---|
MOLECULAR CANCER THERAPEUTICS, vol. 13, no. 4, JPN6020035449, 2014, pages 842 - 854, ISSN: 0005034196 * |
Also Published As
Publication number | Publication date |
---|---|
CN108314677A (zh) | 2018-07-24 |
JP2020514406A (ja) | 2020-05-21 |
US10647700B2 (en) | 2020-05-12 |
ES2963590T3 (es) | 2024-04-01 |
US20190367482A1 (en) | 2019-12-05 |
EP3572400B1 (en) | 2023-10-04 |
EP3572400C0 (en) | 2023-10-04 |
JP7320263B2 (ja) | 2023-08-03 |
WO2018133795A1 (zh) | 2018-07-26 |
EP3572400A1 (en) | 2019-11-27 |
CN108314677B (zh) | 2020-06-30 |
EP3572400A4 (en) | 2020-12-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP2021185208A (ja) | Ezh2阻害剤及びその使用 | |
AU2016312011B2 (en) | Process for preparing Parp inhibitor, crystalline forms, and uses thereof | |
US20180243315A1 (en) | Inhibitors of human ezh2, and methods of use thereof | |
JP2020011971A (ja) | ガンの治療方法 | |
ES2423851T3 (es) | Compuesto de aciltiourea o sal del mismo y uso del mismo | |
TW201141480A (en) | Reverse amide compounds as protein deacetylase inhibitors and methods of use thereof | |
EP2949647A1 (en) | Deuterated phenyl amino pyrimidine compound and pharmaceutical composition containing same | |
TW202019880A (zh) | 作為神經激肽-1受體拮抗劑的化合物及其用途 | |
CN111093658B (zh) | 用于治疗皮肤疾病的稠合杂芳环-苯胺化合物 | |
CN107428762B (zh) | 酞嗪酮衍生物、其制备方法及用途 | |
TWI546304B (zh) | Protein tyrosine kinase inhibitors and their use | |
WO2023030335A1 (zh) | 作为tyk2/jak1假激酶结构域抑制剂的化合物及合成和使用方法 | |
JP2023536634A (ja) | 自己免疫疾患および癌の処置のための小分子 | |
EP3632912B1 (en) | Pyridoquinazoline derivatives useful as protein kinase inhibitors | |
CN110759891A (zh) | Set8赖氨酸甲基转移酶抑制剂及其中间体、制备方法和用途 | |
WO2021092892A1 (zh) | 喹啉或喹唑啉类化合物在制备抗肿瘤药物中的应用 | |
WO2023131677A1 (en) | Compounds containing a hydroxyphenyl moiety and their use | |
CN117295523A (zh) | 靶向pxr的双官能protac型化合物、其制备方法及其治疗用途 | |
WO2017148318A1 (zh) | 一种取代的丙烯酰胺化合物及其药物组合物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20210914 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20220415 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20221004 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20221228 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20230411 |