CN112996509A - 吡啶酮a2r拮抗剂 - Google Patents
吡啶酮a2r拮抗剂 Download PDFInfo
- Publication number
- CN112996509A CN112996509A CN201980064256.XA CN201980064256A CN112996509A CN 112996509 A CN112996509 A CN 112996509A CN 201980064256 A CN201980064256 A CN 201980064256A CN 112996509 A CN112996509 A CN 112996509A
- Authority
- CN
- China
- Prior art keywords
- cancer
- group
- alkyl
- compound
- disease
- 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
- 239000005557 antagonist Substances 0.000 title description 36
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 181
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 123
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 claims abstract description 116
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 105
- 239000000203 mixture Substances 0.000 claims abstract description 101
- 238000000034 method Methods 0.000 claims abstract description 88
- 201000010099 disease Diseases 0.000 claims abstract description 72
- 239000002126 C01EB10 - Adenosine Substances 0.000 claims abstract description 59
- 229960005305 adenosine Drugs 0.000 claims abstract description 58
- 208000035475 disorder Diseases 0.000 claims abstract description 50
- 230000001404 mediated effect Effects 0.000 claims abstract description 19
- 239000003814 drug Substances 0.000 claims description 100
- -1 -O-phenyl Chemical group 0.000 claims description 89
- 230000000694 effects Effects 0.000 claims description 46
- 201000011510 cancer Diseases 0.000 claims description 45
- 150000003839 salts Chemical class 0.000 claims description 40
- 125000001424 substituent group Chemical group 0.000 claims description 39
- 210000004027 cell Anatomy 0.000 claims description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 30
- 125000000217 alkyl group Chemical group 0.000 claims description 27
- 229940124597 therapeutic agent Drugs 0.000 claims description 27
- 229910052757 nitrogen Inorganic materials 0.000 claims description 26
- 230000001225 therapeutic effect Effects 0.000 claims description 26
- 239000008194 pharmaceutical composition Substances 0.000 claims description 25
- 238000006467 substitution reaction Methods 0.000 claims description 23
- 229910052736 halogen Inorganic materials 0.000 claims description 21
- 125000005842 heteroatom Chemical group 0.000 claims description 19
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
- 229910052717 sulfur Inorganic materials 0.000 claims description 18
- 150000002367 halogens Chemical class 0.000 claims description 17
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 17
- 229910052760 oxygen Inorganic materials 0.000 claims description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 15
- 239000012453 solvate Substances 0.000 claims description 15
- 239000002246 antineoplastic agent Substances 0.000 claims description 14
- 229940127089 cytotoxic agent Drugs 0.000 claims description 14
- 208000015181 infectious disease Diseases 0.000 claims description 14
- 108010021064 CTLA-4 Antigen Proteins 0.000 claims description 13
- 125000002947 alkylene group Chemical group 0.000 claims description 13
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
- 125000001072 heteroaryl group Chemical group 0.000 claims description 12
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 claims description 11
- 102000037984 Inhibitory immune checkpoint proteins Human genes 0.000 claims description 11
- 108091008026 Inhibitory immune checkpoint proteins Proteins 0.000 claims description 11
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 claims description 11
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 claims description 11
- 125000004043 oxo group Chemical group O=* 0.000 claims description 11
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 9
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 9
- 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 claims description 8
- 230000001506 immunosuppresive effect Effects 0.000 claims description 8
- 201000001441 melanoma Diseases 0.000 claims description 8
- 102100034458 Hepatitis A virus cellular receptor 2 Human genes 0.000 claims description 7
- 102100024834 T-cell immunoreceptor with Ig and ITIM domains Human genes 0.000 claims description 7
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 7
- 230000004054 inflammatory process Effects 0.000 claims description 7
- 208000032839 leukemia Diseases 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 206010006187 Breast cancer Diseases 0.000 claims description 6
- 208000026310 Breast neoplasm Diseases 0.000 claims description 6
- 201000009030 Carcinoma Diseases 0.000 claims description 6
- 101000831007 Homo sapiens T-cell immunoreceptor with Ig and ITIM domains Proteins 0.000 claims description 6
- 206010061218 Inflammation Diseases 0.000 claims description 6
- 102000017578 LAG3 Human genes 0.000 claims description 6
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 6
- 208000018737 Parkinson disease Diseases 0.000 claims description 6
- 239000004599 antimicrobial Substances 0.000 claims description 6
- 208000006673 asthma Diseases 0.000 claims description 6
- 201000005202 lung cancer Diseases 0.000 claims description 6
- 208000020816 lung neoplasm Diseases 0.000 claims description 6
- 208000024827 Alzheimer disease Diseases 0.000 claims description 5
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 5
- 206010009944 Colon cancer Diseases 0.000 claims description 5
- 101710083479 Hepatitis A virus cellular receptor 2 homolog Proteins 0.000 claims description 5
- 206010025323 Lymphomas Diseases 0.000 claims description 5
- 206010033128 Ovarian cancer Diseases 0.000 claims description 5
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 5
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 5
- 206010060862 Prostate cancer Diseases 0.000 claims description 5
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 5
- 201000004681 Psoriasis Diseases 0.000 claims description 5
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 5
- 201000006417 multiple sclerosis Diseases 0.000 claims description 5
- 201000002528 pancreatic cancer Diseases 0.000 claims description 5
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 5
- 230000002441 reversible effect Effects 0.000 claims description 5
- 206010005003 Bladder cancer Diseases 0.000 claims description 4
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 4
- 101001117317 Homo sapiens Programmed cell death 1 ligand 1 Proteins 0.000 claims description 4
- 208000001647 Renal Insufficiency Diseases 0.000 claims description 4
- 206010039491 Sarcoma Diseases 0.000 claims description 4
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 4
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 4
- 201000010881 cervical cancer Diseases 0.000 claims description 4
- 229960004679 doxorubicin Drugs 0.000 claims description 4
- 206010017758 gastric cancer Diseases 0.000 claims description 4
- 201000006370 kidney failure Diseases 0.000 claims description 4
- 230000005855 radiation Effects 0.000 claims description 4
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 4
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 3
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 3
- 208000011231 Crohn disease Diseases 0.000 claims description 3
- 206010014733 Endometrial cancer Diseases 0.000 claims description 3
- 206010014759 Endometrial neoplasm Diseases 0.000 claims description 3
- 206010019280 Heart failures Diseases 0.000 claims description 3
- 206010062016 Immunosuppression Diseases 0.000 claims description 3
- 208000007766 Kaposi sarcoma Diseases 0.000 claims description 3
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 3
- 206010038389 Renal cancer Diseases 0.000 claims description 3
- 208000006265 Renal cell carcinoma Diseases 0.000 claims description 3
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 3
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 3
- 208000006011 Stroke Diseases 0.000 claims description 3
- 229940126547 T-cell immunoglobulin mucin-3 Drugs 0.000 claims description 3
- 208000024313 Testicular Neoplasms Diseases 0.000 claims description 3
- 206010057644 Testis cancer Diseases 0.000 claims description 3
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 3
- 201000005188 adrenal gland cancer Diseases 0.000 claims description 3
- 208000024447 adrenal gland neoplasm Diseases 0.000 claims description 3
- 229960005475 antiinfective agent Drugs 0.000 claims description 3
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 claims description 3
- 229960004562 carboplatin Drugs 0.000 claims description 3
- 229960004316 cisplatin Drugs 0.000 claims description 3
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 3
- 208000029742 colonic neoplasm Diseases 0.000 claims description 3
- 208000005017 glioblastoma Diseases 0.000 claims description 3
- 201000010982 kidney cancer Diseases 0.000 claims description 3
- 201000007270 liver cancer Diseases 0.000 claims description 3
- 208000014018 liver neoplasm Diseases 0.000 claims description 3
- 208000026037 malignant tumor of neck Diseases 0.000 claims description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
- 201000000849 skin cancer Diseases 0.000 claims description 3
- 201000011549 stomach cancer Diseases 0.000 claims description 3
- 201000003120 testicular cancer Diseases 0.000 claims description 3
- 201000002510 thyroid cancer Diseases 0.000 claims description 3
- 206010003210 Arteriosclerosis Diseases 0.000 claims description 2
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 2
- 208000006332 Choriocarcinoma Diseases 0.000 claims description 2
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 2
- 201000004624 Dermatitis Diseases 0.000 claims description 2
- 206010012442 Dermatitis contact Diseases 0.000 claims description 2
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 2
- 208000001640 Fibromyalgia Diseases 0.000 claims description 2
- 206010016654 Fibrosis Diseases 0.000 claims description 2
- 206010020751 Hypersensitivity Diseases 0.000 claims description 2
- 206010027406 Mesothelioma Diseases 0.000 claims description 2
- 208000002231 Muscle Neoplasms Diseases 0.000 claims description 2
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 2
- 208000001132 Osteoporosis Diseases 0.000 claims description 2
- 206010033645 Pancreatitis Diseases 0.000 claims description 2
- 206010041067 Small cell lung cancer Diseases 0.000 claims description 2
- 201000009594 Systemic Scleroderma Diseases 0.000 claims description 2
- 206010042953 Systemic sclerosis Diseases 0.000 claims description 2
- 208000033133 Testicular seminomatous germ cell tumor Diseases 0.000 claims description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 2
- 208000002029 allergic contact dermatitis Diseases 0.000 claims description 2
- 208000026935 allergic disease Diseases 0.000 claims description 2
- 230000007815 allergy Effects 0.000 claims description 2
- 208000007502 anemia Diseases 0.000 claims description 2
- 206010002906 aortic stenosis Diseases 0.000 claims description 2
- 208000011775 arteriosclerosis disease Diseases 0.000 claims description 2
- 206010009887 colitis Diseases 0.000 claims description 2
- 201000010918 connective tissue cancer Diseases 0.000 claims description 2
- 201000004101 esophageal cancer Diseases 0.000 claims description 2
- 230000004761 fibrosis Effects 0.000 claims description 2
- 206010025135 lupus erythematosus Diseases 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 201000002077 muscle cancer Diseases 0.000 claims description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 2
- 229960001756 oxaliplatin Drugs 0.000 claims description 2
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 claims description 2
- 229960005079 pemetrexed Drugs 0.000 claims description 2
- 208000020352 skin basal cell carcinoma Diseases 0.000 claims description 2
- 208000000587 small cell lung carcinoma Diseases 0.000 claims description 2
- 208000024662 testicular seminoma Diseases 0.000 claims description 2
- 102100026882 Alpha-synuclein Human genes 0.000 claims 2
- 102100029822 B- and T-lymphocyte attenuator Human genes 0.000 claims 2
- 102000008203 CTLA-4 Antigen Human genes 0.000 claims 2
- 101000834898 Homo sapiens Alpha-synuclein Proteins 0.000 claims 2
- 101000864344 Homo sapiens B- and T-lymphocyte attenuator Proteins 0.000 claims 2
- 101001137987 Homo sapiens Lymphocyte activation gene 3 protein Proteins 0.000 claims 2
- 101000611936 Homo sapiens Programmed cell death protein 1 Proteins 0.000 claims 2
- 101000652359 Homo sapiens Spermatogenesis-associated protein 2 Proteins 0.000 claims 2
- 239000003529 anticholesteremic agent Substances 0.000 claims 2
- 206010005949 Bone cancer Diseases 0.000 claims 1
- 208000018084 Bone neoplasm Diseases 0.000 claims 1
- 206010062878 Gastrooesophageal cancer Diseases 0.000 claims 1
- 208000002030 Merkel cell carcinoma Diseases 0.000 claims 1
- 206010029266 Neuroendocrine carcinoma of the skin Diseases 0.000 claims 1
- 208000015634 Rectal Neoplasms Diseases 0.000 claims 1
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 claims 1
- 208000017763 cutaneous neuroendocrine carcinoma Diseases 0.000 claims 1
- 208000010749 gastric carcinoma Diseases 0.000 claims 1
- 201000006974 gastroesophageal cancer Diseases 0.000 claims 1
- 201000000459 head and neck squamous cell carcinoma Diseases 0.000 claims 1
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 claims 1
- 206010038038 rectal cancer Diseases 0.000 claims 1
- 201000001275 rectum cancer Diseases 0.000 claims 1
- 201000000498 stomach carcinoma Diseases 0.000 claims 1
- 238000011282 treatment Methods 0.000 abstract description 46
- 102000009346 Adenosine receptors Human genes 0.000 abstract description 19
- 108050000203 Adenosine receptors Proteins 0.000 abstract description 19
- 230000005764 inhibitory process Effects 0.000 abstract description 12
- 230000002194 synthesizing effect Effects 0.000 abstract description 4
- 239000003112 inhibitor Substances 0.000 description 117
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 84
- 239000003795 chemical substances by application Substances 0.000 description 77
- 229940079593 drug Drugs 0.000 description 67
- 229940002612 prodrug Drugs 0.000 description 54
- 239000000651 prodrug Substances 0.000 description 54
- 239000007787 solid Substances 0.000 description 46
- 238000005160 1H NMR spectroscopy Methods 0.000 description 43
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 43
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- 150000001540 azides Chemical class 0.000 description 39
- 150000001345 alkine derivatives Chemical class 0.000 description 38
- 239000000047 product Substances 0.000 description 37
- 102000005962 receptors Human genes 0.000 description 36
- 108020003175 receptors Proteins 0.000 description 36
- 108090000623 proteins and genes Proteins 0.000 description 35
- 239000003446 ligand Substances 0.000 description 34
- 239000000243 solution Substances 0.000 description 29
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 28
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
- 230000002401 inhibitory effect Effects 0.000 description 28
- 108090000765 processed proteins & peptides Proteins 0.000 description 28
- 238000003776 cleavage reaction Methods 0.000 description 26
- 230000007017 scission Effects 0.000 description 26
- 102000004169 proteins and genes Human genes 0.000 description 25
- 235000002639 sodium chloride Nutrition 0.000 description 25
- 229910001868 water Inorganic materials 0.000 description 25
- 235000018102 proteins Nutrition 0.000 description 24
- 210000001744 T-lymphocyte Anatomy 0.000 description 21
- 239000000556 agonist Substances 0.000 description 21
- 125000003118 aryl group Chemical group 0.000 description 21
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 20
- 102000004196 processed proteins & peptides Human genes 0.000 description 20
- 230000003213 activating effect Effects 0.000 description 19
- 230000004913 activation Effects 0.000 description 19
- 239000000427 antigen Substances 0.000 description 19
- 108091007433 antigens Proteins 0.000 description 19
- 102000036639 antigens Human genes 0.000 description 19
- 150000002148 esters Chemical class 0.000 description 19
- 238000009472 formulation Methods 0.000 description 19
- 239000002253 acid Substances 0.000 description 18
- 235000019439 ethyl acetate Nutrition 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 17
- 230000002829 reductive effect Effects 0.000 description 17
- 102000004127 Cytokines Human genes 0.000 description 16
- 108090000695 Cytokines Proteins 0.000 description 16
- 102100040678 Programmed cell death protein 1 Human genes 0.000 description 16
- 101710089372 Programmed cell death protein 1 Proteins 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 16
- 238000002648 combination therapy Methods 0.000 description 16
- 238000000746 purification Methods 0.000 description 16
- 108010016626 Dipeptides Proteins 0.000 description 15
- 150000001413 amino acids Chemical class 0.000 description 15
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 15
- 102000004190 Enzymes Human genes 0.000 description 14
- 108090000790 Enzymes Proteins 0.000 description 14
- 229940088598 enzyme Drugs 0.000 description 14
- 239000012634 fragment Substances 0.000 description 14
- 230000007246 mechanism Effects 0.000 description 14
- 239000000126 substance Substances 0.000 description 14
- 208000024891 symptom Diseases 0.000 description 14
- 229960005486 vaccine Drugs 0.000 description 14
- 238000009739 binding Methods 0.000 description 13
- 239000000460 chlorine Substances 0.000 description 13
- 150000003384 small molecules Chemical class 0.000 description 13
- 210000004881 tumor cell Anatomy 0.000 description 13
- 102000037982 Immune checkpoint proteins Human genes 0.000 description 12
- 108091008036 Immune checkpoint proteins Proteins 0.000 description 12
- 239000013543 active substance Substances 0.000 description 12
- 235000001014 amino acid Nutrition 0.000 description 12
- 125000003277 amino group Chemical group 0.000 description 12
- 230000027455 binding Effects 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 12
- 230000002255 enzymatic effect Effects 0.000 description 12
- 230000006870 function Effects 0.000 description 12
- 125000000524 functional group Chemical group 0.000 description 12
- 229920001223 polyethylene glycol Polymers 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 238000002560 therapeutic procedure Methods 0.000 description 12
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 description 11
- 238000013459 approach Methods 0.000 description 11
- 238000011161 development Methods 0.000 description 11
- 230000018109 developmental process Effects 0.000 description 11
- 239000010410 layer Substances 0.000 description 11
- 230000000873 masking effect Effects 0.000 description 11
- 239000003921 oil Substances 0.000 description 11
- 235000019198 oils Nutrition 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 11
- 239000000741 silica gel Substances 0.000 description 11
- 229910002027 silica gel Inorganic materials 0.000 description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 10
- 239000007832 Na2SO4 Substances 0.000 description 10
- 108060008683 Tumor Necrosis Factor Receptor Proteins 0.000 description 10
- 230000009471 action Effects 0.000 description 10
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 10
- 230000028993 immune response Effects 0.000 description 10
- 229920001184 polypeptide Polymers 0.000 description 10
- 229910052938 sodium sulfate Inorganic materials 0.000 description 10
- 210000001519 tissue Anatomy 0.000 description 10
- 102000003298 tumor necrosis factor receptor Human genes 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000004480 active ingredient Substances 0.000 description 9
- 150000001412 amines Chemical class 0.000 description 9
- 239000000032 diagnostic agent Substances 0.000 description 9
- 238000010790 dilution Methods 0.000 description 9
- 239000012895 dilution Substances 0.000 description 9
- 125000005647 linker group Chemical group 0.000 description 9
- 230000004048 modification Effects 0.000 description 9
- 238000012986 modification Methods 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- 238000010898 silica gel chromatography Methods 0.000 description 9
- 230000004614 tumor growth Effects 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 8
- 208000036142 Viral infection Diseases 0.000 description 8
- 150000007513 acids Chemical class 0.000 description 8
- 108060000200 adenylate cyclase Proteins 0.000 description 8
- 102000030621 adenylate cyclase Human genes 0.000 description 8
- 238000003556 assay Methods 0.000 description 8
- 125000004429 atom Chemical group 0.000 description 8
- 239000013058 crude material Substances 0.000 description 8
- 229940039227 diagnostic agent Drugs 0.000 description 8
- 239000003085 diluting agent Substances 0.000 description 8
- 238000005755 formation reaction Methods 0.000 description 8
- 230000014509 gene expression Effects 0.000 description 8
- 239000002609 medium Substances 0.000 description 8
- 239000012528 membrane Substances 0.000 description 8
- 230000001105 regulatory effect Effects 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- 230000009385 viral infection Effects 0.000 description 8
- PJJGZPJJTHBVMX-UHFFFAOYSA-N 5,7-Dihydroxyisoflavone Chemical compound C=1C(O)=CC(O)=C(C2=O)C=1OC=C2C1=CC=CC=C1 PJJGZPJJTHBVMX-UHFFFAOYSA-N 0.000 description 7
- 230000001580 bacterial effect Effects 0.000 description 7
- 230000004071 biological effect Effects 0.000 description 7
- 239000000872 buffer Substances 0.000 description 7
- 125000000753 cycloalkyl group Chemical group 0.000 description 7
- 238000003818 flash chromatography Methods 0.000 description 7
- 230000007062 hydrolysis Effects 0.000 description 7
- 238000006460 hydrolysis reaction Methods 0.000 description 7
- 210000000987 immune system Anatomy 0.000 description 7
- 238000001727 in vivo Methods 0.000 description 7
- 229960003464 mefenamic acid Drugs 0.000 description 7
- 150000007523 nucleic acids Chemical group 0.000 description 7
- BXRNXXXXHLBUKK-UHFFFAOYSA-N piperazine-2,5-dione Chemical compound O=C1CNC(=O)CN1 BXRNXXXXHLBUKK-UHFFFAOYSA-N 0.000 description 7
- 229920000642 polymer Polymers 0.000 description 7
- 238000001959 radiotherapy Methods 0.000 description 7
- 230000001603 reducing effect Effects 0.000 description 7
- 210000003289 regulatory T cell Anatomy 0.000 description 7
- 230000004044 response Effects 0.000 description 7
- 230000004936 stimulating effect Effects 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 7
- 230000003612 virological effect Effects 0.000 description 7
- 108010074708 B7-H1 Antigen Proteins 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical group C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 229940045513 CTLA4 antagonist Drugs 0.000 description 6
- 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 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 101000611183 Homo sapiens Tumor necrosis factor Proteins 0.000 description 6
- 101100407308 Mus musculus Pdcd1lg2 gene Proteins 0.000 description 6
- FSVCELGFZIQNCK-UHFFFAOYSA-N N,N-bis(2-hydroxyethyl)glycine Chemical compound OCCN(CCO)CC(O)=O FSVCELGFZIQNCK-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 6
- 108700030875 Programmed Cell Death 1 Ligand 2 Proteins 0.000 description 6
- 102100024213 Programmed cell death 1 ligand 2 Human genes 0.000 description 6
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 102100040247 Tumor necrosis factor Human genes 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 6
- 239000012190 activator Substances 0.000 description 6
- 150000001408 amides Chemical class 0.000 description 6
- 230000033115 angiogenesis Effects 0.000 description 6
- 230000003042 antagnostic effect Effects 0.000 description 6
- 230000000259 anti-tumor effect Effects 0.000 description 6
- 230000008901 benefit Effects 0.000 description 6
- 239000000969 carrier Substances 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 108020001507 fusion proteins Proteins 0.000 description 6
- 102000037865 fusion proteins Human genes 0.000 description 6
- 230000001965 increasing effect Effects 0.000 description 6
- 230000002757 inflammatory effect Effects 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 230000037361 pathway Effects 0.000 description 6
- 230000001737 promoting effect Effects 0.000 description 6
- 230000011664 signaling Effects 0.000 description 6
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 6
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 6
- 238000011269 treatment regimen Methods 0.000 description 6
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 5
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 5
- 101150013553 CD40 gene Proteins 0.000 description 5
- 208000035473 Communicable disease Diseases 0.000 description 5
- 241000701022 Cytomegalovirus Species 0.000 description 5
- 108010008165 Etanercept Proteins 0.000 description 5
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 5
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 5
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 5
- 241000725303 Human immunodeficiency virus Species 0.000 description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 5
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 5
- 108091028043 Nucleic acid sequence Proteins 0.000 description 5
- 208000030852 Parasitic disease Diseases 0.000 description 5
- 230000006044 T cell activation Effects 0.000 description 5
- 230000005867 T cell response Effects 0.000 description 5
- 102100022153 Tumor necrosis factor receptor superfamily member 4 Human genes 0.000 description 5
- 101710165473 Tumor necrosis factor receptor superfamily member 4 Proteins 0.000 description 5
- 102100040245 Tumor necrosis factor receptor superfamily member 5 Human genes 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 210000003169 central nervous system Anatomy 0.000 description 5
- 229940107161 cholesterol Drugs 0.000 description 5
- 235000012000 cholesterol Nutrition 0.000 description 5
- 230000001684 chronic effect Effects 0.000 description 5
- 239000007859 condensation product Substances 0.000 description 5
- 229960000684 cytarabine Drugs 0.000 description 5
- 230000006378 damage Effects 0.000 description 5
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 5
- 210000004443 dendritic cell Anatomy 0.000 description 5
- 235000014113 dietary fatty acids Nutrition 0.000 description 5
- 239000002270 dispersing agent Substances 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 229930195729 fatty acid Natural products 0.000 description 5
- 239000000194 fatty acid Substances 0.000 description 5
- 150000004665 fatty acids Chemical class 0.000 description 5
- 150000002430 hydrocarbons Chemical group 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 230000002163 immunogen Effects 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 108091008042 inhibitory receptors Proteins 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 230000010534 mechanism of action Effects 0.000 description 5
- 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 5
- 108020004707 nucleic acids Proteins 0.000 description 5
- 102000039446 nucleic acids Human genes 0.000 description 5
- 230000036961 partial effect Effects 0.000 description 5
- 230000002265 prevention Effects 0.000 description 5
- 230000002062 proliferating effect Effects 0.000 description 5
- 230000002285 radioactive effect Effects 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 230000019491 signal transduction Effects 0.000 description 5
- 230000000638 stimulation Effects 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000000375 suspending agent Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 231100000331 toxic Toxicity 0.000 description 5
- 230000002588 toxic effect Effects 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- 208000035143 Bacterial infection Diseases 0.000 description 4
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 4
- 102100036842 C-C motif chemokine 19 Human genes 0.000 description 4
- 102100036846 C-C motif chemokine 21 Human genes 0.000 description 4
- 102100038078 CD276 antigen Human genes 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 4
- RBBWCVQDXDFISW-UHFFFAOYSA-N Feprazone Chemical compound O=C1C(CC=C(C)C)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 RBBWCVQDXDFISW-UHFFFAOYSA-N 0.000 description 4
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 4
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 4
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 4
- 241000711549 Hepacivirus C Species 0.000 description 4
- 101000713085 Homo sapiens C-C motif chemokine 21 Proteins 0.000 description 4
- 101000801234 Homo sapiens Tumor necrosis factor receptor superfamily member 18 Proteins 0.000 description 4
- 241000701806 Human papillomavirus Species 0.000 description 4
- 102100034980 ICOS ligand Human genes 0.000 description 4
- 102100040061 Indoleamine 2,3-dioxygenase 1 Human genes 0.000 description 4
- 102000003810 Interleukin-18 Human genes 0.000 description 4
- 108090000171 Interleukin-18 Proteins 0.000 description 4
- 102000002698 KIR Receptors Human genes 0.000 description 4
- 108010043610 KIR Receptors Proteins 0.000 description 4
- 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 4
- 101150030213 Lag3 gene Proteins 0.000 description 4
- 206010027476 Metastases Diseases 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- 108020004459 Small interfering RNA Proteins 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- 108091008874 T cell receptors Proteins 0.000 description 4
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 4
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 4
- 102100033728 Tumor necrosis factor receptor superfamily member 18 Human genes 0.000 description 4
- 230000002411 adverse Effects 0.000 description 4
- 230000001270 agonistic effect Effects 0.000 description 4
- 229960000473 altretamine Drugs 0.000 description 4
- 229960001830 amprenavir Drugs 0.000 description 4
- YMARZQAQMVYCKC-OEMFJLHTSA-N amprenavir Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 YMARZQAQMVYCKC-OEMFJLHTSA-N 0.000 description 4
- 239000003242 anti bacterial agent Substances 0.000 description 4
- 210000000612 antigen-presenting cell Anatomy 0.000 description 4
- 229940111133 antiinflammatory and antirheumatic drug oxicams Drugs 0.000 description 4
- 239000003443 antiviral agent Substances 0.000 description 4
- 239000007998 bicine buffer Substances 0.000 description 4
- 230000000903 blocking effect Effects 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 4
- 238000002512 chemotherapy Methods 0.000 description 4
- 230000000139 costimulatory effect Effects 0.000 description 4
- WHBIGIKBNXZKFE-UHFFFAOYSA-N delavirdine Chemical compound CC(C)NC1=CC=CN=C1N1CCN(C(=O)C=2NC3=CC=C(NS(C)(=O)=O)C=C3C=2)CC1 WHBIGIKBNXZKFE-UHFFFAOYSA-N 0.000 description 4
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 4
- NOPFSRXAKWQILS-UHFFFAOYSA-N docosan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCO NOPFSRXAKWQILS-UHFFFAOYSA-N 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 229950009791 durvalumab Drugs 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 230000002708 enhancing effect Effects 0.000 description 4
- 229960000489 feprazone Drugs 0.000 description 4
- 229960004369 flufenamic acid Drugs 0.000 description 4
- LPEPZBJOKDYZAD-UHFFFAOYSA-N flufenamic acid Chemical compound OC(=O)C1=CC=CC=C1NC1=CC=CC(C(F)(F)F)=C1 LPEPZBJOKDYZAD-UHFFFAOYSA-N 0.000 description 4
- 229960002949 fluorouracil Drugs 0.000 description 4
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 4
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[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 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 4
- 229960001101 ifosfamide Drugs 0.000 description 4
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 4
- 238000009169 immunotherapy Methods 0.000 description 4
- 230000001976 improved effect Effects 0.000 description 4
- 230000000155 isotopic effect Effects 0.000 description 4
- 229940043355 kinase inhibitor Drugs 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
- 239000012139 lysis buffer Substances 0.000 description 4
- 229920002521 macromolecule Polymers 0.000 description 4
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 4
- 108020004999 messenger RNA Proteins 0.000 description 4
- 230000002503 metabolic effect Effects 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 229960000485 methotrexate Drugs 0.000 description 4
- 229960001156 mitoxantrone Drugs 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- 235000001968 nicotinic acid Nutrition 0.000 description 4
- 239000011664 nicotinic acid Substances 0.000 description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 230000003000 nontoxic effect Effects 0.000 description 4
- 239000002773 nucleotide Chemical group 0.000 description 4
- 125000003729 nucleotide group Chemical group 0.000 description 4
- 210000000056 organ Anatomy 0.000 description 4
- 230000003285 pharmacodynamic effect Effects 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 239000002953 phosphate buffered saline Substances 0.000 description 4
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 4
- 230000000704 physical effect Effects 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 229960004618 prednisone Drugs 0.000 description 4
- 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 4
- 239000003755 preservative agent Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- 150000003431 steroids Chemical class 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- 230000014616 translation Effects 0.000 description 4
- 239000000080 wetting agent Substances 0.000 description 4
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 4
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 3
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 3
- SYCHUQUJURZQMO-UHFFFAOYSA-N 4-hydroxy-2-methyl-1,1-dioxo-n-(1,3-thiazol-2-yl)-1$l^{6},2-benzothiazine-3-carboxamide Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=CS1 SYCHUQUJURZQMO-UHFFFAOYSA-N 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
- 102100027207 CD27 antigen Human genes 0.000 description 3
- 102100025221 CD70 antigen Human genes 0.000 description 3
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 3
- 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 3
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 3
- 108020004414 DNA Proteins 0.000 description 3
- 108010092160 Dactinomycin Proteins 0.000 description 3
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 101000914511 Homo sapiens CD27 antigen Proteins 0.000 description 3
- 101001019455 Homo sapiens ICOS ligand Proteins 0.000 description 3
- 101000666896 Homo sapiens V-type immunoglobulin domain-containing suppressor of T-cell activation Proteins 0.000 description 3
- 206010021143 Hypoxia Diseases 0.000 description 3
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 3
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 3
- 108060003951 Immunoglobulin Proteins 0.000 description 3
- 102000003812 Interleukin-15 Human genes 0.000 description 3
- 108090000172 Interleukin-15 Proteins 0.000 description 3
- 108010002350 Interleukin-2 Proteins 0.000 description 3
- 102000000588 Interleukin-2 Human genes 0.000 description 3
- 241000222722 Leishmania <genus> Species 0.000 description 3
- 108010000817 Leuprolide Proteins 0.000 description 3
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 3
- SBDNJUWAMKYJOX-UHFFFAOYSA-N Meclofenamic Acid Chemical compound CC1=CC=C(Cl)C(NC=2C(=CC=CC=2)C(O)=O)=C1Cl SBDNJUWAMKYJOX-UHFFFAOYSA-N 0.000 description 3
- 208000031888 Mycoses Diseases 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 102000000574 RNA-Induced Silencing Complex Human genes 0.000 description 3
- 108010016790 RNA-Induced Silencing Complex Proteins 0.000 description 3
- XNKLLVCARDGLGL-JGVFFNPUSA-N Stavudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1C=C[C@@H](CO)O1 XNKLLVCARDGLGL-JGVFFNPUSA-N 0.000 description 3
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 3
- 102100038929 V-set domain-containing T-cell activation inhibitor 1 Human genes 0.000 description 3
- 102100038282 V-type immunoglobulin domain-containing suppressor of T-cell activation Human genes 0.000 description 3
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 3
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 3
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 3
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 238000011467 adoptive cell therapy Methods 0.000 description 3
- 229940100198 alkylating agent Drugs 0.000 description 3
- 239000002168 alkylating agent Substances 0.000 description 3
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 3
- 229960003805 amantadine Drugs 0.000 description 3
- 229960001220 amsacrine Drugs 0.000 description 3
- 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 3
- 239000002870 angiogenesis inducing agent Substances 0.000 description 3
- 230000000340 anti-metabolite Effects 0.000 description 3
- 230000005809 anti-tumor immunity Effects 0.000 description 3
- 230000000890 antigenic effect Effects 0.000 description 3
- 229940100197 antimetabolite Drugs 0.000 description 3
- 239000002256 antimetabolite Substances 0.000 description 3
- 239000007900 aqueous suspension Substances 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 208000022362 bacterial infectious disease Diseases 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 229960005243 carmustine Drugs 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 229960004630 chlorambucil Drugs 0.000 description 3
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 229910052681 coesite Inorganic materials 0.000 description 3
- 230000001609 comparable effect Effects 0.000 description 3
- 230000000295 complement effect Effects 0.000 description 3
- 238000013270 controlled release Methods 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 229910052906 cristobalite Inorganic materials 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 229960004397 cyclophosphamide Drugs 0.000 description 3
- 229960003901 dacarbazine Drugs 0.000 description 3
- 229960000975 daunorubicin Drugs 0.000 description 3
- 229910052805 deuterium Inorganic materials 0.000 description 3
- 229960003957 dexamethasone Drugs 0.000 description 3
- 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 3
- 238000012377 drug delivery Methods 0.000 description 3
- 229940073621 enbrel Drugs 0.000 description 3
- 229960004396 famciclovir Drugs 0.000 description 3
- GGXKWVWZWMLJEH-UHFFFAOYSA-N famcyclovir Chemical compound N1=C(N)N=C2N(CCC(COC(=O)C)COC(C)=O)C=NC2=C1 GGXKWVWZWMLJEH-UHFFFAOYSA-N 0.000 description 3
- ZWJINEZUASEZBH-UHFFFAOYSA-N fenamic acid Chemical compound OC(=O)C1=CC=CC=C1NC1=CC=CC=C1 ZWJINEZUASEZBH-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 229940088597 hormone Drugs 0.000 description 3
- 239000005556 hormone Substances 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 230000007954 hypoxia Effects 0.000 description 3
- 229960000908 idarubicin Drugs 0.000 description 3
- 230000002519 immonomodulatory effect Effects 0.000 description 3
- 208000026278 immune system disease Diseases 0.000 description 3
- 230000036039 immunity Effects 0.000 description 3
- 102000018358 immunoglobulin Human genes 0.000 description 3
- 239000002955 immunomodulating agent Substances 0.000 description 3
- 229940121354 immunomodulator Drugs 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- 238000007918 intramuscular administration Methods 0.000 description 3
- 238000007912 intraperitoneal administration Methods 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 229960005386 ipilimumab Drugs 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- RGLRXNKKBLIBQS-XNHQSDQCSA-N leuprolide acetate Chemical compound CC(O)=O.CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 RGLRXNKKBLIBQS-XNHQSDQCSA-N 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 239000002502 liposome Substances 0.000 description 3
- 229940057995 liquid paraffin Drugs 0.000 description 3
- 229960002247 lomustine Drugs 0.000 description 3
- 210000004698 lymphocyte Anatomy 0.000 description 3
- 229960003803 meclofenamic acid Drugs 0.000 description 3
- 229960001428 mercaptopurine Drugs 0.000 description 3
- 230000009401 metastasis Effects 0.000 description 3
- 230000001394 metastastic effect Effects 0.000 description 3
- 206010061289 metastatic neoplasm Diseases 0.000 description 3
- 239000003094 microcapsule Substances 0.000 description 3
- 229960004857 mitomycin Drugs 0.000 description 3
- 229960000350 mitotane Drugs 0.000 description 3
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 3
- 210000000822 natural killer cell Anatomy 0.000 description 3
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 description 3
- 229960003512 nicotinic acid Drugs 0.000 description 3
- 229960003301 nivolumab Drugs 0.000 description 3
- 239000004006 olive oil Substances 0.000 description 3
- 235000008390 olive oil Nutrition 0.000 description 3
- 238000011275 oncology therapy Methods 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- AZQWKYJCGOJGHM-UHFFFAOYSA-N para-benzoquinone Natural products O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 3
- 229960002621 pembrolizumab Drugs 0.000 description 3
- 229960002340 pentostatin Drugs 0.000 description 3
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 3
- 230000004962 physiological condition Effects 0.000 description 3
- 108091033319 polynucleotide Proteins 0.000 description 3
- 102000040430 polynucleotide Human genes 0.000 description 3
- 239000002157 polynucleotide Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 230000000069 prophylactic effect Effects 0.000 description 3
- 150000003217 pyrazoles Chemical class 0.000 description 3
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 3
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 3
- 229960004622 raloxifene Drugs 0.000 description 3
- 108091006082 receptor inhibitors Proteins 0.000 description 3
- 229940116176 remicade Drugs 0.000 description 3
- 238000004007 reversed phase HPLC Methods 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 229910052682 stishovite Inorganic materials 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 229960002317 succinimide Drugs 0.000 description 3
- 229950005175 sudoxicam Drugs 0.000 description 3
- 238000013268 sustained release Methods 0.000 description 3
- 239000012730 sustained-release form Substances 0.000 description 3
- 230000002195 synergetic effect Effects 0.000 description 3
- 229960001603 tamoxifen Drugs 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- 229960002871 tenoxicam Drugs 0.000 description 3
- WZWYJBNHTWCXIM-UHFFFAOYSA-N tenoxicam Chemical compound O=C1C=2SC=CC=2S(=O)(=O)N(C)C1=C(O)NC1=CC=CC=N1 WZWYJBNHTWCXIM-UHFFFAOYSA-N 0.000 description 3
- 229960003087 tioguanine Drugs 0.000 description 3
- 230000001052 transient effect Effects 0.000 description 3
- 238000013519 translation Methods 0.000 description 3
- 150000003852 triazoles Chemical group 0.000 description 3
- 229910052905 tridymite Inorganic materials 0.000 description 3
- 229960003048 vinblastine Drugs 0.000 description 3
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 2
- GUHPRPJDBZHYCJ-SECBINFHSA-N (2s)-2-(5-benzoylthiophen-2-yl)propanoic acid Chemical compound S1C([C@H](C(O)=O)C)=CC=C1C(=O)C1=CC=CC=C1 GUHPRPJDBZHYCJ-SECBINFHSA-N 0.000 description 2
- CGMTUJFWROPELF-YPAAEMCBSA-N (3E,5S)-5-[(2S)-butan-2-yl]-3-(1-hydroxyethylidene)pyrrolidine-2,4-dione Chemical compound CC[C@H](C)[C@@H]1NC(=O)\C(=C(/C)O)C1=O CGMTUJFWROPELF-YPAAEMCBSA-N 0.000 description 2
- OQANPHBRHBJGNZ-FYJGNVAPSA-N (3e)-6-oxo-3-[[4-(pyridin-2-ylsulfamoyl)phenyl]hydrazinylidene]cyclohexa-1,4-diene-1-carboxylic acid Chemical compound C1=CC(=O)C(C(=O)O)=C\C1=N\NC1=CC=C(S(=O)(=O)NC=2N=CC=CC=2)C=C1 OQANPHBRHBJGNZ-FYJGNVAPSA-N 0.000 description 2
- XRBSKUSTLXISAB-XVVDYKMHSA-N (5r,6r,7r,8r)-8-hydroxy-7-(hydroxymethyl)-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydrobenzo[f][1,3]benzodioxole-6-carboxylic acid Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H](CO)[C@@H]2C(O)=O)=C1 XRBSKUSTLXISAB-XVVDYKMHSA-N 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- DCXHLPGLBYHNMU-UHFFFAOYSA-N 2-[1-(4-azidobenzoyl)-5-methoxy-2-methylindol-3-yl]acetic acid Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(N=[N+]=[N-])C=C1 DCXHLPGLBYHNMU-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- HNXQXTQTPAJEJL-UHFFFAOYSA-N 2-aminopteridin-4-ol Chemical compound C1=CN=C2NC(N)=NC(=O)C2=N1 HNXQXTQTPAJEJL-UHFFFAOYSA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- ZPSJGADGUYYRKE-UHFFFAOYSA-N 2H-pyran-2-one Chemical compound O=C1C=CC=CO1 ZPSJGADGUYYRKE-UHFFFAOYSA-N 0.000 description 2
- TZOYXRMEFDYWDQ-UHFFFAOYSA-N 3,4-dihydro-1h-quinolin-2-one Chemical compound C1=CC=C2NC(=O)CCC2=C1 TZOYXRMEFDYWDQ-UHFFFAOYSA-N 0.000 description 2
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- MVKDNXIKAWKCCS-UHFFFAOYSA-N 3-methyl-1h-pyridin-2-one Chemical compound CC1=CC=CN=C1O MVKDNXIKAWKCCS-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
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- 108010082808 4-1BB Ligand Proteins 0.000 description 2
- TVZGACDUOSZQKY-LBPRGKRZSA-N 4-aminofolic acid Chemical compound C1=NC2=NC(N)=NC(N)=C2N=C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 TVZGACDUOSZQKY-LBPRGKRZSA-N 0.000 description 2
- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-dimethylaminophenol Chemical compound CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-dimethylaminopyridine Substances CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- IDPUKCWIGUEADI-UHFFFAOYSA-N 5-[bis(2-chloroethyl)amino]uracil Chemical compound ClCCN(CCCl)C1=CNC(=O)NC1=O IDPUKCWIGUEADI-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
- BSYNRYMUTXBXSQ-FOQJRBATSA-N 59096-14-9 Chemical compound CC(=O)OC1=CC=CC=C1[14C](O)=O BSYNRYMUTXBXSQ-FOQJRBATSA-N 0.000 description 2
- 244000215068 Acacia senegal Species 0.000 description 2
- 235000006491 Acacia senegal Nutrition 0.000 description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- CEIZFXOZIQNICU-UHFFFAOYSA-N Alternaria alternata Crofton-weed toxin Natural products CCC(C)C1NC(=O)C(C(C)=O)=C1O CEIZFXOZIQNICU-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 235000003911 Arachis Nutrition 0.000 description 2
- 244000105624 Arachis hypogaea Species 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 2
- AXRYRYVKAWYZBR-UHFFFAOYSA-N Atazanavir Natural products C=1C=C(C=2N=CC=CC=2)C=CC=1CN(NC(=O)C(NC(=O)OC)C(C)(C)C)CC(O)C(NC(=O)C(NC(=O)OC)C(C)(C)C)CC1=CC=CC=C1 AXRYRYVKAWYZBR-UHFFFAOYSA-N 0.000 description 2
- 108010019625 Atazanavir Sulfate Proteins 0.000 description 2
- 208000023275 Autoimmune disease Diseases 0.000 description 2
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 2
- 101710112622 C-C motif chemokine 19 Proteins 0.000 description 2
- 102100021943 C-C motif chemokine 2 Human genes 0.000 description 2
- 101710155857 C-C motif chemokine 2 Proteins 0.000 description 2
- 101710185679 CD276 antigen Proteins 0.000 description 2
- QAGYKUNXZHXKMR-UHFFFAOYSA-N CPD000469186 Natural products CC1=C(O)C=CC=C1C(=O)NC(C(O)CN1C(CC2CCCCC2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 QAGYKUNXZHXKMR-UHFFFAOYSA-N 0.000 description 2
- 101100314454 Caenorhabditis elegans tra-1 gene Proteins 0.000 description 2
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 2
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 2
- 108010019670 Chimeric Antigen Receptors Proteins 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 229920001268 Cholestyramine Polymers 0.000 description 2
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 2
- VWFCHDSQECPREK-LURJTMIESA-N Cidofovir Chemical compound NC=1C=CN(C[C@@H](CO)OCP(O)(O)=O)C(=O)N=1 VWFCHDSQECPREK-LURJTMIESA-N 0.000 description 2
- UDMBCSSLTHHNCD-UHFFFAOYSA-N Coenzym Q(11) Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(O)=O)C(O)C1O UDMBCSSLTHHNCD-UHFFFAOYSA-N 0.000 description 2
- 108020004635 Complementary DNA Proteins 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- 241000709687 Coxsackievirus Species 0.000 description 2
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 2
- WEAHRLBPCANXCN-UHFFFAOYSA-N Daunomycin Natural products CCC1(O)CC(OC2CC(N)C(O)C(C)O2)c3cc4C(=O)c5c(OC)cccc5C(=O)c4c(O)c3C1 WEAHRLBPCANXCN-UHFFFAOYSA-N 0.000 description 2
- 206010012289 Dementia Diseases 0.000 description 2
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 2
- BXZVVICBKDXVGW-NKWVEPMBSA-N Didanosine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(NC=NC2=O)=C2N=C1 BXZVVICBKDXVGW-NKWVEPMBSA-N 0.000 description 2
- 102100031107 Disintegrin and metalloproteinase domain-containing protein 11 Human genes 0.000 description 2
- 101710121366 Disintegrin and metalloproteinase domain-containing protein 11 Proteins 0.000 description 2
- 206010058314 Dysplasia Diseases 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- XPOQHMRABVBWPR-UHFFFAOYSA-N Efavirenz Natural products O1C(=O)NC2=CC=C(Cl)C=C2C1(C(F)(F)F)C#CC1CC1 XPOQHMRABVBWPR-UHFFFAOYSA-N 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
- 229930189413 Esperamicin Natural products 0.000 description 2
- 208000027776 Extrapyramidal disease Diseases 0.000 description 2
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 108010069236 Goserelin Proteins 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- 101000713106 Homo sapiens C-C motif chemokine 19 Proteins 0.000 description 2
- 101000884279 Homo sapiens CD276 antigen Proteins 0.000 description 2
- 101000934356 Homo sapiens CD70 antigen Proteins 0.000 description 2
- 101001021491 Homo sapiens HERV-H LTR-associating protein 2 Proteins 0.000 description 2
- 101001068133 Homo sapiens Hepatitis A virus cellular receptor 2 Proteins 0.000 description 2
- 101001037256 Homo sapiens Indoleamine 2,3-dioxygenase 1 Proteins 0.000 description 2
- 101000610605 Homo sapiens Tumor necrosis factor receptor superfamily member 10A Proteins 0.000 description 2
- 101000610604 Homo sapiens Tumor necrosis factor receptor superfamily member 10B Proteins 0.000 description 2
- 241000701085 Human alphaherpesvirus 3 Species 0.000 description 2
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 2
- MPBVHIBUJCELCL-UHFFFAOYSA-N Ibandronate Chemical compound CCCCCN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O MPBVHIBUJCELCL-UHFFFAOYSA-N 0.000 description 2
- 102000037977 Immune checkpoint ligands Human genes 0.000 description 2
- 108091008029 Immune checkpoint ligands Proteins 0.000 description 2
- 102000037978 Immune checkpoint receptors Human genes 0.000 description 2
- 108091008028 Immune checkpoint receptors Proteins 0.000 description 2
- 208000029462 Immunodeficiency disease Diseases 0.000 description 2
- 101710120843 Indoleamine 2,3-dioxygenase 1 Proteins 0.000 description 2
- 102000000589 Interleukin-1 Human genes 0.000 description 2
- 108010002352 Interleukin-1 Proteins 0.000 description 2
- 102000051628 Interleukin-1 receptor antagonist Human genes 0.000 description 2
- 108700021006 Interleukin-1 receptor antagonist Proteins 0.000 description 2
- 108090000174 Interleukin-10 Proteins 0.000 description 2
- 108010065805 Interleukin-12 Proteins 0.000 description 2
- 102000013462 Interleukin-12 Human genes 0.000 description 2
- 102000003816 Interleukin-13 Human genes 0.000 description 2
- 108090000176 Interleukin-13 Proteins 0.000 description 2
- 108010002386 Interleukin-3 Proteins 0.000 description 2
- 102000000646 Interleukin-3 Human genes 0.000 description 2
- 108090000978 Interleukin-4 Proteins 0.000 description 2
- 102000004388 Interleukin-4 Human genes 0.000 description 2
- 108090001005 Interleukin-6 Proteins 0.000 description 2
- UETNIIAIRMUTSM-UHFFFAOYSA-N Jacareubin Natural products CC1(C)OC2=CC3Oc4c(O)c(O)ccc4C(=O)C3C(=C2C=C1)O UETNIIAIRMUTSM-UHFFFAOYSA-N 0.000 description 2
- KJHKTHWMRKYKJE-SUGCFTRWSA-N Kaletra Chemical compound N1([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=2C=CC=CC=2)NC(=O)COC=2C(=CC=CC=2C)C)CC=2C=CC=CC=2)CCCNC1=O KJHKTHWMRKYKJE-SUGCFTRWSA-N 0.000 description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 2
- 229920001491 Lentinan Polymers 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 description 2
- 102100028123 Macrophage colony-stimulating factor 1 Human genes 0.000 description 2
- 102100028198 Macrophage colony-stimulating factor 1 receptor Human genes 0.000 description 2
- 101710150918 Macrophage colony-stimulating factor 1 receptor Proteins 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- FQISKWAFAHGMGT-SGJOWKDISA-M Methylprednisolone sodium succinate Chemical compound [Na+].C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCC([O-])=O)CC[C@H]21 FQISKWAFAHGMGT-SGJOWKDISA-M 0.000 description 2
- VFKZTMPDYBFSTM-KVTDHHQDSA-N Mitobronitol Chemical compound BrC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CBr VFKZTMPDYBFSTM-KVTDHHQDSA-N 0.000 description 2
- 229930192392 Mitomycin Natural products 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
- 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
- 208000012902 Nervous system disease Diseases 0.000 description 2
- MITFXPHMIHQXPI-UHFFFAOYSA-N Oraflex Chemical compound N=1C2=CC(C(C(O)=O)C)=CC=C2OC=1C1=CC=C(Cl)C=C1 MITFXPHMIHQXPI-UHFFFAOYSA-N 0.000 description 2
- 229930012538 Paclitaxel Natural products 0.000 description 2
- JNTOCHDNEULJHD-UHFFFAOYSA-N Penciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(CO)CO)C=N2 JNTOCHDNEULJHD-UHFFFAOYSA-N 0.000 description 2
- 208000037581 Persistent Infection Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 208000006994 Precancerous Conditions Diseases 0.000 description 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 2
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- GIIWGCBLYNDKBO-UHFFFAOYSA-N Quinoline 1-oxide Chemical compound C1=CC=C2[N+]([O-])=CC=CC2=C1 GIIWGCBLYNDKBO-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 2
- 101710100968 Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 2
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 2
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 2
- 208000005793 Restless legs syndrome Diseases 0.000 description 2
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 2
- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 description 2
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 description 2
- 241000700584 Simplexvirus Species 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 description 2
- 238000006069 Suzuki reaction reaction Methods 0.000 description 2
- CGMTUJFWROPELF-UHFFFAOYSA-N Tenuazonic acid Natural products CCC(C)C1NC(=O)C(=C(C)/O)C1=O CGMTUJFWROPELF-UHFFFAOYSA-N 0.000 description 2
- SUJUHGSWHZTSEU-UHFFFAOYSA-N Tipranavir Natural products C1C(O)=C(C(CC)C=2C=C(NS(=O)(=O)C=3N=CC(=CC=3)C(F)(F)F)C=CC=2)C(=O)OC1(CCC)CCC1=CC=CC=C1 SUJUHGSWHZTSEU-UHFFFAOYSA-N 0.000 description 2
- 241000223996 Toxoplasma Species 0.000 description 2
- 229920001615 Tragacanth Polymers 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 102100024587 Tumor necrosis factor ligand superfamily member 15 Human genes 0.000 description 2
- 102100032101 Tumor necrosis factor ligand superfamily member 9 Human genes 0.000 description 2
- 102100040113 Tumor necrosis factor receptor superfamily member 10A Human genes 0.000 description 2
- 102100040112 Tumor necrosis factor receptor superfamily member 10B Human genes 0.000 description 2
- 102100022203 Tumor necrosis factor receptor superfamily member 25 Human genes 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 108010079206 V-Set Domain-Containing T-Cell Activation Inhibitor 1 Proteins 0.000 description 2
- HDOVUKNUBWVHOX-QMMMGPOBSA-N Valacyclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCOC(=O)[C@@H](N)C(C)C)C=N2 HDOVUKNUBWVHOX-QMMMGPOBSA-N 0.000 description 2
- OIRDTQYFTABQOQ-UHTZMRCNSA-N Vidarabine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O OIRDTQYFTABQOQ-UHTZMRCNSA-N 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- WREGKURFCTUGRC-POYBYMJQSA-N Zalcitabine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)CC1 WREGKURFCTUGRC-POYBYMJQSA-N 0.000 description 2
- DLGSOJOOYHWROO-WQLSENKSSA-N [(z)-(1-methyl-2-oxoindol-3-ylidene)amino]thiourea Chemical compound C1=CC=C2N(C)C(=O)\C(=N/NC(N)=S)C2=C1 DLGSOJOOYHWROO-WQLSENKSSA-N 0.000 description 2
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 description 2
- MCGSCOLBFJQGHM-SCZZXKLOSA-N abacavir Chemical compound C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 MCGSCOLBFJQGHM-SCZZXKLOSA-N 0.000 description 2
- 229960004748 abacavir Drugs 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 229960004150 aciclovir Drugs 0.000 description 2
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 229930183665 actinomycin Natural products 0.000 description 2
- 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 2
- 230000001154 acute effect Effects 0.000 description 2
- 229960002964 adalimumab Drugs 0.000 description 2
- 230000033289 adaptive immune response Effects 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- UDMBCSSLTHHNCD-KQYNXXCUSA-N adenosine 5'-monophosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O UDMBCSSLTHHNCD-KQYNXXCUSA-N 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 229960003896 aminopterin Drugs 0.000 description 2
- 150000005010 aminoquinolines Chemical class 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000003098 androgen Substances 0.000 description 2
- 229940030486 androgens Drugs 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 229940045799 anthracyclines and related substance Drugs 0.000 description 2
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 2
- 230000002280 anti-androgenic effect Effects 0.000 description 2
- 239000000051 antiandrogen Substances 0.000 description 2
- 229940030495 antiandrogen sex hormone and modulator of the genital system Drugs 0.000 description 2
- 229940045719 antineoplastic alkylating agent nitrosoureas Drugs 0.000 description 2
- 239000003096 antiparasitic agent Substances 0.000 description 2
- 239000003435 antirheumatic agent Substances 0.000 description 2
- 125000004104 aryloxy group Chemical group 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 229960003277 atazanavir Drugs 0.000 description 2
- AXRYRYVKAWYZBR-GASGPIRDSA-N atazanavir Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)[C@@H](O)CN(CC=1C=CC(=CC=1)C=1N=CC=CC=1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C1=CC=CC=C1 AXRYRYVKAWYZBR-GASGPIRDSA-N 0.000 description 2
- 229960002756 azacitidine Drugs 0.000 description 2
- WOIIIUDZSOLAIW-NSHDSACASA-N azapropazone Chemical compound C1=C(C)C=C2N3C(=O)[C@H](CC=C)C(=O)N3C(N(C)C)=NC2=C1 WOIIIUDZSOLAIW-NSHDSACASA-N 0.000 description 2
- 229960001671 azapropazone Drugs 0.000 description 2
- 150000001541 aziridines Chemical class 0.000 description 2
- 210000003719 b-lymphocyte Anatomy 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 229940076134 benzene Drugs 0.000 description 2
- 229960002537 betamethasone Drugs 0.000 description 2
- 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 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 230000000975 bioactive effect Effects 0.000 description 2
- 238000002306 biochemical method Methods 0.000 description 2
- 230000003851 biochemical process Effects 0.000 description 2
- 239000013060 biological fluid Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 210000001185 bone marrow Anatomy 0.000 description 2
- 238000010322 bone marrow transplantation Methods 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 238000010804 cDNA synthesis Methods 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 229960004117 capecitabine Drugs 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 230000003915 cell function Effects 0.000 description 2
- 238000002659 cell therapy Methods 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000013043 chemical agent Substances 0.000 description 2
- 238000002144 chemical decomposition reaction Methods 0.000 description 2
- 208000037976 chronic inflammation Diseases 0.000 description 2
- 230000006020 chronic inflammation Effects 0.000 description 2
- 229960000724 cidofovir Drugs 0.000 description 2
- 238000010367 cloning Methods 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 230000021615 conjugation Effects 0.000 description 2
- 230000037011 constitutive activity Effects 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- JZCCFEFSEZPSOG-UHFFFAOYSA-L copper(II) sulfate pentahydrate Chemical compound O.O.O.O.O.[Cu+2].[O-]S([O-])(=O)=O JZCCFEFSEZPSOG-UHFFFAOYSA-L 0.000 description 2
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 2
- 108091008034 costimulatory receptors Proteins 0.000 description 2
- 238000006352 cycloaddition reaction Methods 0.000 description 2
- 230000016396 cytokine production Effects 0.000 description 2
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 2
- 229960002806 daclizumab Drugs 0.000 description 2
- 229960005107 darunavir Drugs 0.000 description 2
- CJBJHOAVZSMMDJ-HEXNFIEUSA-N darunavir Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1[C@@H]2CCO[C@@H]2OC1)C1=CC=CC=C1 CJBJHOAVZSMMDJ-HEXNFIEUSA-N 0.000 description 2
- 238000007405 data analysis Methods 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 229960005319 delavirdine Drugs 0.000 description 2
- 229960002656 didanosine Drugs 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 239000002988 disease modifying antirheumatic drug Substances 0.000 description 2
- 229960003668 docetaxel Drugs 0.000 description 2
- 229960000735 docosanol Drugs 0.000 description 2
- XPOQHMRABVBWPR-ZDUSSCGKSA-N efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 description 2
- 229960003804 efavirenz Drugs 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 239000012636 effector Substances 0.000 description 2
- VLCYCQAOQCDTCN-UHFFFAOYSA-N eflornithine Chemical compound NCCCC(N)(C(F)F)C(O)=O VLCYCQAOQCDTCN-UHFFFAOYSA-N 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 210000002889 endothelial cell Anatomy 0.000 description 2
- 239000002158 endotoxin Substances 0.000 description 2
- YJGVMLPVUAXIQN-UHFFFAOYSA-N epipodophyllotoxin Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YJGVMLPVUAXIQN-UHFFFAOYSA-N 0.000 description 2
- 229960001904 epirubicin Drugs 0.000 description 2
- 230000008029 eradication Effects 0.000 description 2
- FRPJXPJMRWBBIH-RBRWEJTLSA-N estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 description 2
- 229960001842 estramustine Drugs 0.000 description 2
- 229960000403 etanercept Drugs 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- OLNTVTPDXPETLC-XPWALMASSA-N ezetimibe Chemical compound N1([C@@H]([C@H](C1=O)CC[C@H](O)C=1C=CC(F)=CC=1)C=1C=CC(O)=CC=1)C1=CC=C(F)C=C1 OLNTVTPDXPETLC-XPWALMASSA-N 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 229960000961 floxuridine Drugs 0.000 description 2
- 238000002866 fluorescence resonance energy transfer Methods 0.000 description 2
- IJJVMEJXYNJXOJ-UHFFFAOYSA-N fluquinconazole Chemical compound C=1C=C(Cl)C=C(Cl)C=1N1C(=O)C2=CC(F)=CC=C2N=C1N1C=NC=N1 IJJVMEJXYNJXOJ-UHFFFAOYSA-N 0.000 description 2
- 229960002074 flutamide Drugs 0.000 description 2
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 2
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 238000002825 functional assay Methods 0.000 description 2
- 230000002538 fungal effect Effects 0.000 description 2
- CHPZKNULDCNCBW-UHFFFAOYSA-N gallium nitrate Chemical compound [Ga+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O CHPZKNULDCNCBW-UHFFFAOYSA-N 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 229960005277 gemcitabine Drugs 0.000 description 2
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 2
- 230000009368 gene silencing by RNA Effects 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 229940075507 glyceryl monostearate Drugs 0.000 description 2
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 2
- 230000013595 glycosylation Effects 0.000 description 2
- 238000006206 glycosylation reaction Methods 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 150000003840 hydrochlorides Chemical class 0.000 description 2
- 229960000890 hydrocortisone Drugs 0.000 description 2
- 239000000017 hydrogel Substances 0.000 description 2
- 229960001330 hydroxycarbamide Drugs 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 210000002865 immune cell Anatomy 0.000 description 2
- 239000007943 implant Substances 0.000 description 2
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 208000027866 inflammatory disease Diseases 0.000 description 2
- 229960000598 infliximab Drugs 0.000 description 2
- 229940102213 injectable suspension Drugs 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- GURKHSYORGJETM-WAQYZQTGSA-N irinotecan hydrochloride (anhydrous) Chemical compound Cl.C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 GURKHSYORGJETM-WAQYZQTGSA-N 0.000 description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- FMKOJHQHASLBPH-UHFFFAOYSA-N isopropyl iodide Chemical compound CC(C)I FMKOJHQHASLBPH-UHFFFAOYSA-N 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 2
- YYUAYBYLJSNDCX-UHFFFAOYSA-N isoxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC=1C=C(C)ON=1 YYUAYBYLJSNDCX-UHFFFAOYSA-N 0.000 description 2
- 229950002252 isoxicam Drugs 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229960001627 lamivudine Drugs 0.000 description 2
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 2
- 150000002605 large molecules Chemical class 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 229940115286 lentinan Drugs 0.000 description 2
- 229960004338 leuprorelin Drugs 0.000 description 2
- 229920006008 lipopolysaccharide Polymers 0.000 description 2
- 229960003538 lonidamine Drugs 0.000 description 2
- WDRYRZXSPDWGEB-UHFFFAOYSA-N lonidamine Chemical compound C12=CC=CC=C2C(C(=O)O)=NN1CC1=CC=C(Cl)C=C1Cl WDRYRZXSPDWGEB-UHFFFAOYSA-N 0.000 description 2
- 229960004525 lopinavir Drugs 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
- 238000007726 management method Methods 0.000 description 2
- 229960002510 mandelic acid Drugs 0.000 description 2
- MQXVYODZCMMZEM-ZYUZMQFOSA-N mannomustine Chemical compound ClCCNC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CNCCCl MQXVYODZCMMZEM-ZYUZMQFOSA-N 0.000 description 2
- 229950008612 mannomustine Drugs 0.000 description 2
- GSNHKUDZZFZSJB-QYOOZWMWSA-N maraviroc Chemical compound CC(C)C1=NN=C(C)N1[C@@H]1C[C@H](N2CC[C@H](NC(=O)C3CCC(F)(F)CC3)C=3C=CC=CC=3)CC[C@H]2C1 GSNHKUDZZFZSJB-QYOOZWMWSA-N 0.000 description 2
- 229960004710 maraviroc Drugs 0.000 description 2
- 239000003550 marker Substances 0.000 description 2
- 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 2
- 229960001924 melphalan Drugs 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 229960004584 methylprednisolone Drugs 0.000 description 2
- 229960003152 metisazone Drugs 0.000 description 2
- 239000000693 micelle Substances 0.000 description 2
- 239000011325 microbead Substances 0.000 description 2
- 239000004005 microsphere Substances 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 229960005485 mitobronitol Drugs 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 229960005285 mofebutazone Drugs 0.000 description 2
- REOJLIXKJWXUGB-UHFFFAOYSA-N mofebutazone Chemical compound O=C1C(CCCC)C(=O)NN1C1=CC=CC=C1 REOJLIXKJWXUGB-UHFFFAOYSA-N 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- FOYWNSCCNCUEPU-UHFFFAOYSA-N mopidamol Chemical compound C12=NC(N(CCO)CCO)=NC=C2N=C(N(CCO)CCO)N=C1N1CCCCC1 FOYWNSCCNCUEPU-UHFFFAOYSA-N 0.000 description 2
- 229950010718 mopidamol Drugs 0.000 description 2
- 230000014399 negative regulation of angiogenesis Effects 0.000 description 2
- QAGYKUNXZHXKMR-HKWSIXNMSA-N nelfinavir Chemical compound CC1=C(O)C=CC=C1C(=O)N[C@H]([C@H](O)CN1[C@@H](C[C@@H]2CCCC[C@@H]2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 QAGYKUNXZHXKMR-HKWSIXNMSA-N 0.000 description 2
- 229960000884 nelfinavir Drugs 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- 239000002777 nucleoside Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 229960003752 oseltamivir Drugs 0.000 description 2
- NENPYTRHICXVCS-YNEHKIRRSA-N oseltamivir acid Chemical compound CCC(CC)O[C@@H]1C=C(C(O)=O)C[C@H](N)[C@H]1NC(C)=O NENPYTRHICXVCS-YNEHKIRRSA-N 0.000 description 2
- 229960000649 oxyphenbutazone Drugs 0.000 description 2
- HFHZKZSRXITVMK-UHFFFAOYSA-N oxyphenbutazone Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=C(O)C=C1 HFHZKZSRXITVMK-UHFFFAOYSA-N 0.000 description 2
- 229960001592 paclitaxel Drugs 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 229960005489 paracetamol Drugs 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 229960001179 penciclovir Drugs 0.000 description 2
- 210000001428 peripheral nervous system Anatomy 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 229960002702 piroxicam Drugs 0.000 description 2
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- 229960001237 podophyllotoxin Drugs 0.000 description 2
- YJGVMLPVUAXIQN-XVVDYKMHSA-N podophyllotoxin Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-XVVDYKMHSA-N 0.000 description 2
- YVCVYCSAAZQOJI-UHFFFAOYSA-N podophyllotoxin Natural products COC1=C(O)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YVCVYCSAAZQOJI-UHFFFAOYSA-N 0.000 description 2
- 229960001109 policosanol Drugs 0.000 description 2
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 2
- 229920002401 polyacrylamide Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 230000032361 posttranscriptional gene silencing Effects 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 230000003389 potentiating effect Effects 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
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 2
- 229960004919 procaine Drugs 0.000 description 2
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 2
- 229960000624 procarbazine Drugs 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 239000003528 protein farnesyltransferase inhibitor Substances 0.000 description 2
- 239000003379 purinergic P1 receptor agonist Substances 0.000 description 2
- 150000003212 purines Chemical class 0.000 description 2
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 2
- 150000003230 pyrimidines Chemical class 0.000 description 2
- LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 description 2
- 239000000700 radioactive tracer Substances 0.000 description 2
- 238000009790 rate-determining step (RDS) Methods 0.000 description 2
- 230000008707 rearrangement Effects 0.000 description 2
- 210000000664 rectum Anatomy 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229960000329 ribavirin Drugs 0.000 description 2
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 2
- 125000006413 ring segment Chemical group 0.000 description 2
- 229960000311 ritonavir Drugs 0.000 description 2
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 description 2
- 150000003873 salicylate salts Chemical class 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- QWAXKHKRTORLEM-UGJKXSETSA-N saquinavir Chemical compound C([C@@H]([C@H](O)CN1C[C@H]2CCCC[C@H]2C[C@H]1C(=O)NC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)C=1N=C2C=CC=CC2=CC=1)C1=CC=CC=C1 QWAXKHKRTORLEM-UGJKXSETSA-N 0.000 description 2
- 229960001852 saquinavir Drugs 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 229960002855 simvastatin Drugs 0.000 description 2
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 2
- 235000010378 sodium ascorbate Nutrition 0.000 description 2
- 229960005055 sodium ascorbate Drugs 0.000 description 2
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 2
- 235000011069 sorbitan monooleate Nutrition 0.000 description 2
- 239000001593 sorbitan monooleate Substances 0.000 description 2
- 229940035049 sorbitan monooleate Drugs 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 206010041823 squamous cell carcinoma Diseases 0.000 description 2
- 229960001203 stavudine Drugs 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 229960001052 streptozocin Drugs 0.000 description 2
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 229960001940 sulfasalazine Drugs 0.000 description 2
- NCEXYHBECQHGNR-UHFFFAOYSA-N sulfasalazine Natural products C1=C(O)C(C(=O)O)=CC(N=NC=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-UHFFFAOYSA-N 0.000 description 2
- 229940124530 sulfonamide Drugs 0.000 description 2
- 150000003456 sulfonamides Chemical class 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 239000013589 supplement Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 2
- 229960002935 telaprevir Drugs 0.000 description 2
- 108010017101 telaprevir Proteins 0.000 description 2
- BBAWEDCPNXPBQM-GDEBMMAJSA-N telaprevir Chemical compound N([C@H](C(=O)N[C@H](C(=O)N1C[C@@H]2CCC[C@@H]2[C@H]1C(=O)N[C@@H](CCC)C(=O)C(=O)NC1CC1)C(C)(C)C)C1CCCCC1)C(=O)C1=CN=CC=N1 BBAWEDCPNXPBQM-GDEBMMAJSA-N 0.000 description 2
- 229960001278 teniposide Drugs 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
- 229960004556 tenofovir Drugs 0.000 description 2
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 229960003604 testosterone Drugs 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 2
- YAPQBXQYLJRXSA-UHFFFAOYSA-N theobromine Chemical compound CN1C(=O)NC(=O)C2=C1N=CN2C YAPQBXQYLJRXSA-UHFFFAOYSA-N 0.000 description 2
- 230000004797 therapeutic response Effects 0.000 description 2
- 229960001196 thiotepa Drugs 0.000 description 2
- 229960001312 tiaprofenic acid Drugs 0.000 description 2
- SUJUHGSWHZTSEU-FYBSXPHGSA-N tipranavir Chemical compound C([C@@]1(CCC)OC(=O)C([C@H](CC)C=2C=C(NS(=O)(=O)C=3N=CC(=CC=3)C(F)(F)F)C=CC=2)=C(O)C1)CC1=CC=CC=C1 SUJUHGSWHZTSEU-FYBSXPHGSA-N 0.000 description 2
- 229960000838 tipranavir Drugs 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 206010044412 transitional cell carcinoma Diseases 0.000 description 2
- 238000011277 treatment modality Methods 0.000 description 2
- 229950007217 tremelimumab Drugs 0.000 description 2
- 150000003626 triacylglycerols Chemical class 0.000 description 2
- 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 2
- 229960003962 trifluridine Drugs 0.000 description 2
- VSQQQLOSPVPRAZ-RRKCRQDMSA-N trifluridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C(F)(F)F)=C1 VSQQQLOSPVPRAZ-RRKCRQDMSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- NOYPYLRCIDNJJB-UHFFFAOYSA-N trimetrexate Chemical compound COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=NC(N)=NC3=CC=2)C)=C1 NOYPYLRCIDNJJB-UHFFFAOYSA-N 0.000 description 2
- 229960001099 trimetrexate Drugs 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 210000003171 tumor-infiltrating lymphocyte Anatomy 0.000 description 2
- KCFYEAOKVJSACF-UHFFFAOYSA-N umifenovir Chemical compound CN1C2=CC(Br)=C(O)C(CN(C)C)=C2C(C(=O)OCC)=C1CSC1=CC=CC=C1 KCFYEAOKVJSACF-UHFFFAOYSA-N 0.000 description 2
- 229960004626 umifenovir Drugs 0.000 description 2
- 229960001055 uracil mustard Drugs 0.000 description 2
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 2
- 229940093257 valacyclovir Drugs 0.000 description 2
- 230000024883 vasodilation Effects 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 229960003636 vidarabine Drugs 0.000 description 2
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 2
- 229960004528 vincristine Drugs 0.000 description 2
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 2
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 2
- 229960004355 vindesine Drugs 0.000 description 2
- GBABOYUKABKIAF-IELIFDKJSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-IELIFDKJSA-N 0.000 description 2
- 229960002066 vinorelbine Drugs 0.000 description 2
- 229940055760 yervoy Drugs 0.000 description 2
- ARAIBEBZBOPLMB-UFGQHTETSA-N zanamivir Chemical compound CC(=O)N[C@@H]1[C@@H](N=C(N)N)C=C(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO ARAIBEBZBOPLMB-UFGQHTETSA-N 0.000 description 2
- 229960001028 zanamivir Drugs 0.000 description 2
- 229950007802 zidometacin Drugs 0.000 description 2
- 229960002555 zidovudine Drugs 0.000 description 2
- NNJPGOLRFBJNIW-HNNXBMFYSA-N (-)-demecolcine Chemical compound C1=C(OC)C(=O)C=C2[C@@H](NC)CCC3=CC(OC)=C(OC)C(OC)=C3C2=C1 NNJPGOLRFBJNIW-HNNXBMFYSA-N 0.000 description 1
- MNULEGDCPYONBU-WMBHJXFZSA-N (1r,4s,5e,5'r,6'r,7e,10s,11r,12s,14r,15s,16s,18r,19s,20r,21e,25s,26r,27s,29s)-4-ethyl-11,12,15,19-tetrahydroxy-6'-[(2s)-2-hydroxypropyl]-5',10,12,14,16,18,20,26,29-nonamethylspiro[24,28-dioxabicyclo[23.3.1]nonacosa-5,7,21-triene-27,2'-oxane]-13,17,23-trio Polymers O([C@@H]1CC[C@@H](/C=C/C=C/C[C@H](C)[C@@H](O)[C@](C)(O)C(=O)[C@H](C)[C@@H](O)[C@H](C)C(=O)[C@H](C)[C@@H](O)[C@H](C)/C=C/C(=O)O[C@H]([C@H]2C)[C@H]1C)CC)[C@]12CC[C@@H](C)[C@@H](C[C@H](C)O)O1 MNULEGDCPYONBU-WMBHJXFZSA-N 0.000 description 1
- MNULEGDCPYONBU-DJRUDOHVSA-N (1s,4r,5z,5'r,6'r,7e,10s,11r,12s,14r,15s,18r,19r,20s,21e,26r,27s)-4-ethyl-11,12,15,19-tetrahydroxy-6'-(2-hydroxypropyl)-5',10,12,14,16,18,20,26,29-nonamethylspiro[24,28-dioxabicyclo[23.3.1]nonacosa-5,7,21-triene-27,2'-oxane]-13,17,23-trione Polymers O([C@H]1CC[C@H](\C=C/C=C/C[C@H](C)[C@@H](O)[C@](C)(O)C(=O)[C@H](C)[C@@H](O)C(C)C(=O)[C@H](C)[C@H](O)[C@@H](C)/C=C/C(=O)OC([C@H]2C)C1C)CC)[C@]12CC[C@@H](C)[C@@H](CC(C)O)O1 MNULEGDCPYONBU-DJRUDOHVSA-N 0.000 description 1
- QQWLGFMKQCGPGH-UHFFFAOYSA-N (2-aminohydrazinyl)benzene Chemical compound NNNC1=CC=CC=C1 QQWLGFMKQCGPGH-UHFFFAOYSA-N 0.000 description 1
- XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 description 1
- MQHLMHIZUIDKOO-OKZBNKHCSA-N (2R,6S)-2,6-dimethyl-4-[(2S)-2-methyl-3-[4-(2-methylbutan-2-yl)phenyl]propyl]morpholine Chemical compound C1=CC(C(C)(C)CC)=CC=C1C[C@H](C)CN1C[C@@H](C)O[C@@H](C)C1 MQHLMHIZUIDKOO-OKZBNKHCSA-N 0.000 description 1
- RJMIEHBSYVWVIN-LLVKDONJSA-N (2r)-2-[4-(3-oxo-1h-isoindol-2-yl)phenyl]propanoic acid Chemical compound C1=CC([C@H](C(O)=O)C)=CC=C1N1C(=O)C2=CC=CC=C2C1 RJMIEHBSYVWVIN-LLVKDONJSA-N 0.000 description 1
- WDQLRUYAYXDIFW-RWKIJVEZSA-N (2r,3r,4s,5r,6r)-4-[(2s,3r,4s,5r,6r)-3,5-dihydroxy-4-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-[[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxymethyl]oxan-2-yl]oxy-6-(hydroxymethyl)oxane-2,3,5-triol Chemical compound O[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)[C@H](O)[C@@H](CO[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)O1 WDQLRUYAYXDIFW-RWKIJVEZSA-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
- RDJGLLICXDHJDY-NSHDSACASA-N (2s)-2-(3-phenoxyphenyl)propanoic acid Chemical compound OC(=O)[C@@H](C)C1=CC=CC(OC=2C=CC=CC=2)=C1 RDJGLLICXDHJDY-NSHDSACASA-N 0.000 description 1
- MDKGKXOCJGEUJW-VIFPVBQESA-N (2s)-2-[4-(thiophene-2-carbonyl)phenyl]propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C(=O)C1=CC=CS1 MDKGKXOCJGEUJW-VIFPVBQESA-N 0.000 description 1
- JPSHPWJJSVEEAX-OWPBQMJCSA-N (2s)-2-amino-4-fluoranylpentanedioic acid Chemical compound OC(=O)[C@@H](N)CC([18F])C(O)=O JPSHPWJJSVEEAX-OWPBQMJCSA-N 0.000 description 1
- OJRHUICOVVSGSY-RXMQYKEDSA-N (2s)-2-chloro-3-methylbutan-1-ol Chemical compound CC(C)[C@H](Cl)CO OJRHUICOVVSGSY-RXMQYKEDSA-N 0.000 description 1
- KCEHUPIXDRDKQS-VKHMYHEASA-N (2s)-5-amino-2-hydrazinyl-5-oxopentanoic acid Chemical compound NN[C@H](C(O)=O)CCC(N)=O KCEHUPIXDRDKQS-VKHMYHEASA-N 0.000 description 1
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 1
- ZGGHKIMDNBDHJB-NRFPMOEYSA-M (3R,5S)-fluvastatin sodium Chemical compound [Na+].C12=CC=CC=C2N(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 ZGGHKIMDNBDHJB-NRFPMOEYSA-M 0.000 description 1
- MNULEGDCPYONBU-YNZHUHFTSA-N (4Z,18Z,20Z)-22-ethyl-7,11,14,15-tetrahydroxy-6'-(2-hydroxypropyl)-5',6,8,10,12,14,16,28,29-nonamethylspiro[2,26-dioxabicyclo[23.3.1]nonacosa-4,18,20-triene-27,2'-oxane]-3,9,13-trione Polymers CC1C(C2C)OC(=O)\C=C/C(C)C(O)C(C)C(=O)C(C)C(O)C(C)C(=O)C(C)(O)C(O)C(C)C\C=C/C=C\C(CC)CCC2OC21CCC(C)C(CC(C)O)O2 MNULEGDCPYONBU-YNZHUHFTSA-N 0.000 description 1
- ONKCBKDTKZIWHZ-MRWFHJSOSA-N (4r)-4-[[(2r)-6-amino-2-[[(2r)-2-[[4-(aminocarbamothioylamino)benzoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]hexanoyl]amino]-5-[[(2r)-1-amino-6-[bis[2-[[4-[2-(1h-imidazol-5-yl)ethylamino]-4-oxobutanoyl]amino]acetyl]amino]-1-oxohexan-2-yl]amino]-5-oxope Chemical compound C([C@H](C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CCCCN(C(=O)CNC(=O)CCC(=O)NCCC=1NC=NC=1)C(=O)CNC(=O)CCC(=O)NCCC=1NC=NC=1)C(N)=O)NC(=O)C=1C=CC(NC(=S)NN)=CC=1)C1=CC=C(O)C=C1 ONKCBKDTKZIWHZ-MRWFHJSOSA-N 0.000 description 1
- MNULEGDCPYONBU-VVXVDZGXSA-N (5e,5'r,7e,10s,11r,12s,14s,15r,16r,18r,19s,20r,21e,26r,29s)-4-ethyl-11,12,15,19-tetrahydroxy-6'-[(2s)-2-hydroxypropyl]-5',10,12,14,16,18,20,26,29-nonamethylspiro[24,28-dioxabicyclo[23.3.1]nonacosa-5,7,21-triene-27,2'-oxane]-13,17,23-trione Polymers C([C@H](C)[C@@H](O)[C@](C)(O)C(=O)[C@@H](C)[C@H](O)[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@H](C)/C=C/C(=O)OC([C@H]1C)[C@H]2C)\C=C\C=C\C(CC)CCC2OC21CC[C@@H](C)C(C[C@H](C)O)O2 MNULEGDCPYONBU-VVXVDZGXSA-N 0.000 description 1
- XRBSKUSTLXISAB-UHFFFAOYSA-N (7R,7'R,8R,8'R)-form-Podophyllic acid Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C(CO)C2C(O)=O)=C1 XRBSKUSTLXISAB-UHFFFAOYSA-N 0.000 description 1
- HMLGSIZOMSVISS-ONJSNURVSA-N (7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-(2,2-dimethylpropanoyloxymethoxyimino)acetyl]amino]-3-ethenyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound N([C@@H]1C(N2C(=C(C=C)CSC21)C(O)=O)=O)C(=O)\C(=N/OCOC(=O)C(C)(C)C)C1=CSC(N)=N1 HMLGSIZOMSVISS-ONJSNURVSA-N 0.000 description 1
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 description 1
- 125000006648 (C1-C8) haloalkyl group Chemical group 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 description 1
- XUBOMFCQGDBHNK-JTQLQIEISA-N (S)-gatifloxacin Chemical compound FC1=CC(C(C(C(O)=O)=CN2C3CC3)=O)=C2C(OC)=C1N1CCN[C@@H](C)C1 XUBOMFCQGDBHNK-JTQLQIEISA-N 0.000 description 1
- HOKKPVIRMVDYPB-UVTDQMKNSA-N (Z)-thiacloprid Chemical compound C1=NC(Cl)=CC=C1CN1C(=N/C#N)/SCC1 HOKKPVIRMVDYPB-UVTDQMKNSA-N 0.000 description 1
- AGNGYMCLFWQVGX-AGFFZDDWSA-N (e)-1-[(2s)-2-amino-2-carboxyethoxy]-2-diazonioethenolate Chemical compound OC(=O)[C@@H](N)CO\C([O-])=C\[N+]#N AGNGYMCLFWQVGX-AGFFZDDWSA-N 0.000 description 1
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 1
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
- YHIIJNLSGULWAA-UHFFFAOYSA-N 1,4-thiazinane 1-oxide Chemical compound O=S1CCNCC1 YHIIJNLSGULWAA-UHFFFAOYSA-N 0.000 description 1
- HJTAZXHBEBIQQX-UHFFFAOYSA-N 1,5-bis(chloromethyl)naphthalene Chemical compound C1=CC=C2C(CCl)=CC=CC2=C1CCl HJTAZXHBEBIQQX-UHFFFAOYSA-N 0.000 description 1
- VBEJJYHAOLANAA-UHFFFAOYSA-N 1,8-naphthyridine-2,3-dicarbaldehyde Chemical compound C1=CN=C2N=C(C=O)C(C=O)=CC2=C1 VBEJJYHAOLANAA-UHFFFAOYSA-N 0.000 description 1
- UBCHPRBFMUDMNC-UHFFFAOYSA-N 1-(1-adamantyl)ethanamine Chemical compound C1C(C2)CC3CC2CC1(C(N)C)C3 UBCHPRBFMUDMNC-UHFFFAOYSA-N 0.000 description 1
- MYBLAOJMRYYKMS-RTRLPJTCSA-N 1-(2-chloroethyl)-1-nitroso-3-[(3r,4r,5s,6r)-2,4,5-trihydroxy-6-(hydroxymethyl)oxan-3-yl]urea Chemical compound OC[C@H]1OC(O)[C@H](NC(=O)N(CCCl)N=O)[C@@H](O)[C@@H]1O MYBLAOJMRYYKMS-RTRLPJTCSA-N 0.000 description 1
- IDPURXSQCKYKIJ-UHFFFAOYSA-N 1-(4-methoxyphenyl)methanamine Chemical compound COC1=CC=C(CN)C=C1 IDPURXSQCKYKIJ-UHFFFAOYSA-N 0.000 description 1
- YYSLAWXDXHVRHU-UHFFFAOYSA-N 1-(oxan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole Chemical compound O1C(C)(C)C(C)(C)OB1C1=CN(C2OCCCC2)N=C1 YYSLAWXDXHVRHU-UHFFFAOYSA-N 0.000 description 1
- YZUPZGFPHUVJKC-UHFFFAOYSA-N 1-bromo-2-methoxyethane Chemical compound COCCBr YZUPZGFPHUVJKC-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
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- BFPYWIDHMRZLRN-UHFFFAOYSA-N 17alpha-ethynyl estradiol Natural products OC1=CC=C2C3CCC(C)(C(CC4)(O)C#C)C4C3CCC2=C1 BFPYWIDHMRZLRN-UHFFFAOYSA-N 0.000 description 1
- GCKMFJBGXUYNAG-UHFFFAOYSA-N 17alpha-methyltestosterone Natural products C1CC2=CC(=O)CCC2(C)C2C1C1CCC(C)(O)C1(C)CC2 GCKMFJBGXUYNAG-UHFFFAOYSA-N 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- BTOTXLJHDSNXMW-POYBYMJQSA-N 2,3-dideoxyuridine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(=O)NC(=O)C=C1 BTOTXLJHDSNXMW-POYBYMJQSA-N 0.000 description 1
- DZNPOCHJCGTGCP-UHFFFAOYSA-N 2,4-dichloro-8-methoxyquinazoline Chemical compound N1=C(Cl)N=C2C(OC)=CC=CC2=C1Cl DZNPOCHJCGTGCP-UHFFFAOYSA-N 0.000 description 1
- VTAKZNRDSPNOAU-UHFFFAOYSA-M 2-(chloromethyl)oxirane;hydron;prop-2-en-1-amine;n-prop-2-enyldecan-1-amine;trimethyl-[6-(prop-2-enylamino)hexyl]azanium;dichloride Chemical compound Cl.[Cl-].NCC=C.ClCC1CO1.CCCCCCCCCCNCC=C.C[N+](C)(C)CCCCCCNCC=C VTAKZNRDSPNOAU-UHFFFAOYSA-M 0.000 description 1
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- TYCOFFBAZNSQOJ-UHFFFAOYSA-N 2-[4-(3-fluorophenyl)phenyl]propanoic acid Chemical compound C1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC(F)=C1 TYCOFFBAZNSQOJ-UHFFFAOYSA-N 0.000 description 1
- JIEKMACRVQTPRC-UHFFFAOYSA-N 2-[4-(4-chlorophenyl)-2-phenyl-5-thiazolyl]acetic acid Chemical compound OC(=O)CC=1SC(C=2C=CC=CC=2)=NC=1C1=CC=C(Cl)C=C1 JIEKMACRVQTPRC-UHFFFAOYSA-N 0.000 description 1
- BGFTWECWAICPDG-UHFFFAOYSA-N 2-[bis(4-chlorophenyl)methyl]-4-n-[3-[bis(4-chlorophenyl)methyl]-4-(dimethylamino)phenyl]-1-n,1-n-dimethylbenzene-1,4-diamine Chemical compound C1=C(C(C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)C(N(C)C)=CC=C1NC(C=1)=CC=C(N(C)C)C=1C(C=1C=CC(Cl)=CC=1)C1=CC=C(Cl)C=C1 BGFTWECWAICPDG-UHFFFAOYSA-N 0.000 description 1
- FSVJFNAIGNNGKK-UHFFFAOYSA-N 2-[cyclohexyl(oxo)methyl]-3,6,7,11b-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4-one Chemical compound C1C(C2=CC=CC=C2CC2)N2C(=O)CN1C(=O)C1CCCCC1 FSVJFNAIGNNGKK-UHFFFAOYSA-N 0.000 description 1
- XKSAJZSJKURQRX-UHFFFAOYSA-N 2-acetyloxy-5-(4-fluorophenyl)benzoic acid Chemical compound C1=C(C(O)=O)C(OC(=O)C)=CC=C1C1=CC=C(F)C=C1 XKSAJZSJKURQRX-UHFFFAOYSA-N 0.000 description 1
- QCXJFISCRQIYID-IAEPZHFASA-N 2-amino-1-n-[(3s,6s,7r,10s,16s)-3-[(2s)-butan-2-yl]-7,11,14-trimethyl-2,5,9,12,15-pentaoxo-10-propan-2-yl-8-oxa-1,4,11,14-tetrazabicyclo[14.3.0]nonadecan-6-yl]-4,6-dimethyl-3-oxo-9-n-[(3s,6s,7r,10s,16s)-7,11,14-trimethyl-2,5,9,12,15-pentaoxo-3,10-di(propa 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=C2C(C(=O)N[C@@H]3C(=O)N[C@H](C(N4CCC[C@H]4C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]3C)=O)[C@@H](C)CC)=C(N)C(=O)C(C)=C2O2)C2=C(C)C=C1 QCXJFISCRQIYID-IAEPZHFASA-N 0.000 description 1
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 1
- RFWQNKSTYMEPOO-UHFFFAOYSA-N 2-chloro-n,n-diphenylaniline Chemical compound ClC1=CC=CC=C1N(C=1C=CC=CC=1)C1=CC=CC=C1 RFWQNKSTYMEPOO-UHFFFAOYSA-N 0.000 description 1
- XGBMQBPLWXTEPM-UHFFFAOYSA-N 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound O1C(C)(C)C(C)(C)OB1C1CC1 XGBMQBPLWXTEPM-UHFFFAOYSA-N 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- 229940013085 2-diethylaminoethanol Drugs 0.000 description 1
- NLEPLDKPYLYCSY-UHFFFAOYSA-N 2-fluoroquinoline Chemical compound C1=CC=CC2=NC(F)=CC=C21 NLEPLDKPYLYCSY-UHFFFAOYSA-N 0.000 description 1
- CESUXLKAADQNTB-SSDOTTSWSA-N 2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@](N)=O CESUXLKAADQNTB-SSDOTTSWSA-N 0.000 description 1
- CESUXLKAADQNTB-ZETCQYMHSA-N 2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@@](N)=O CESUXLKAADQNTB-ZETCQYMHSA-N 0.000 description 1
- IXUYISWDRMQAKU-UHFFFAOYSA-N 2-morpholin-4-ylguanidine Chemical compound NC(=N)NN1CCOCC1 IXUYISWDRMQAKU-UHFFFAOYSA-N 0.000 description 1
- LGEXGKUJMFHVSY-UHFFFAOYSA-N 2-n,4-n,6-n-trimethyl-1,3,5-triazine-2,4,6-triamine Chemical compound CNC1=NC(NC)=NC(NC)=N1 LGEXGKUJMFHVSY-UHFFFAOYSA-N 0.000 description 1
- CTRPRMNBTVRDFH-UHFFFAOYSA-N 2-n-methyl-1,3,5-triazine-2,4,6-triamine Chemical compound CNC1=NC(N)=NC(N)=N1 CTRPRMNBTVRDFH-UHFFFAOYSA-N 0.000 description 1
- YZEUHQHUFTYLPH-UHFFFAOYSA-N 2-nitroimidazole Chemical compound [O-][N+](=O)C1=NC=CN1 YZEUHQHUFTYLPH-UHFFFAOYSA-N 0.000 description 1
- DNTYEVWEOFZXFE-UHFFFAOYSA-N 2-oxo-1h-pyridine-3-carbaldehyde Chemical compound O=CC1=CC=CNC1=O DNTYEVWEOFZXFE-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- AZSNMRSAGSSBNP-UHFFFAOYSA-N 22,23-dihydroavermectin B1a Natural products C1CC(C)C(C(C)CC)OC21OC(CC=C(C)C(OC1OC(C)C(OC3OC(C)C(O)C(OC)C3)C(OC)C1)C(C)C=CC=C1C3(C(C(=O)O4)C=C(C)C(O)C3OC1)O)CC4C2 AZSNMRSAGSSBNP-UHFFFAOYSA-N 0.000 description 1
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 1
- UBYSCQRRRZBHDK-UHFFFAOYSA-N 3-(2-hydroxyphenyl)-2,2-dimethylpropanoic acid Chemical class OC(=O)C(C)(C)CC1=CC=CC=C1O UBYSCQRRRZBHDK-UHFFFAOYSA-N 0.000 description 1
- PWMYMKOUNYTVQN-UHFFFAOYSA-N 3-(8,8-diethyl-2-aza-8-germaspiro[4.5]decan-2-yl)-n,n-dimethylpropan-1-amine Chemical compound C1C[Ge](CC)(CC)CCC11CN(CCCN(C)C)CC1 PWMYMKOUNYTVQN-UHFFFAOYSA-N 0.000 description 1
- ATSJWUGDFIQDCG-CQSZACIVSA-N 3-[[4-(2-amino-6-fluoro-8-methoxyquinazolin-4-yl)triazol-1-yl]methyl]-1-[(1R)-1-(oxan-4-yl)ethyl]pyridin-2-one Chemical compound C1(=C2C(=NC(=N1)N)C(OC)=CC(F)=C2)C=1N=NN(C=1)CC=1C(=O)N(C=CC=1)[C@@H](C1CCOCC1)C ATSJWUGDFIQDCG-CQSZACIVSA-N 0.000 description 1
- FYDUACLZEGJDFV-LBPRGKRZSA-N 3-[[4-(2-amino-6-fluoro-8-methoxyquinazolin-4-yl)triazol-1-yl]methyl]-1-[(2S)-3-hydroxy-3-methylbutan-2-yl]pyridin-2-one Chemical compound C1=C(C=C(C2=C1C(C=1N=NN(C=1)CC=1C(=O)N(C=CC=1)[C@@H](C)C(O)(C)C)=NC(=N2)N)OC)F FYDUACLZEGJDFV-LBPRGKRZSA-N 0.000 description 1
- LHXJBKUKGGSMCZ-UHFFFAOYSA-N 3-[[4-(2-amino-6-fluoro-8-methoxyquinazolin-4-yl)triazol-1-yl]methyl]-1-propan-2-ylpyridin-2-one Chemical compound C1(=C2C(=NC(=N1)N)C(OC)=CC(F)=C2)C=1N=NN(C=1)CC=1C(=O)N(C=CC=1)C(C)C LHXJBKUKGGSMCZ-UHFFFAOYSA-N 0.000 description 1
- INLAMMKSOHGWQA-UHFFFAOYSA-N 3-[[4-(2-amino-7-fluoro-8-methoxyquinazolin-4-yl)triazol-1-yl]methyl]-1-propan-2-ylpyridin-2-one Chemical compound C1(=C2C(=NC(=N1)N)C(OC)=C(F)C=C2)C=1N=NN(C=1)CC=1C(=O)N(C=CC=1)C(C)C INLAMMKSOHGWQA-UHFFFAOYSA-N 0.000 description 1
- KMXJCRWAHDECHJ-UHFFFAOYSA-N 3-[[4-(2-amino-7-methoxyquinazolin-4-yl)triazol-1-yl]methyl]-1-propan-2-ylpyridin-2-one Chemical compound C1=2C=CC(=CC=2N=C(N=C1C=1N=NN(C=1)CC=1C(=O)N(C=CC=1)C(C)C)N)OC KMXJCRWAHDECHJ-UHFFFAOYSA-N 0.000 description 1
- UOAFFDPARLELEA-UHFFFAOYSA-N 3-[[4-(2-amino-8-chloroquinazolin-4-yl)triazol-1-yl]methyl]-1-propan-2-ylpyridin-2-one Chemical compound C1(=C2C(=NC(=N1)N)C(Cl)=CC=C2)C=1N=NN(C=1)CC=1C(=O)N(C=CC=1)C(C)C UOAFFDPARLELEA-UHFFFAOYSA-N 0.000 description 1
- PLMHKJRIWUKDHY-UHFFFAOYSA-N 3-[[4-(2-amino-8-ethoxyquinazolin-4-yl)triazol-1-yl]methyl]-1-propan-2-ylpyridin-2-one Chemical compound C1(=C2C(=NC(=N1)N)C(OCC)=CC=C2)C=1N=NN(C=1)CC=1C(=O)N(C=CC=1)C(C)C PLMHKJRIWUKDHY-UHFFFAOYSA-N 0.000 description 1
- ZUQZWHPNOMWYKY-UHFFFAOYSA-N 3-[[4-(2-amino-8-fluoroquinazolin-4-yl)triazol-1-yl]methyl]-1-propan-2-ylpyridin-2-one Chemical compound C1=2C=CC=C(C=2N=C(N=C1C=1N=NN(C=1)CC=1C(=O)N(C=CC=1)C(C)C)N)F ZUQZWHPNOMWYKY-UHFFFAOYSA-N 0.000 description 1
- JFIAEKZSRKOMHG-UHFFFAOYSA-N 3-[[4-(2-amino-8-fluoroquinolin-4-yl)triazol-1-yl]methyl]-1-propan-2-ylpyridin-2-one Chemical compound NC1=NC2=C(C=CC=C2C(=C1)C=1N=NN(C=1)CC=1C(N(C=CC=1)C(C)C)=O)F JFIAEKZSRKOMHG-UHFFFAOYSA-N 0.000 description 1
- LQKLBMWNYIMQMR-MRXNPFEDSA-N 3-[[4-(2-amino-8-methoxyquinazolin-4-yl)pyrazol-1-yl]methyl]-1-[(1R)-1-(oxan-4-yl)ethyl]pyridin-2-one Chemical compound C1(=C2C(=NC(=N1)N)C(OC)=CC=C2)C=1C=NN(C=1)CC=1C(=O)N(C=CC=1)[C@@H](C1CCOCC1)C LQKLBMWNYIMQMR-MRXNPFEDSA-N 0.000 description 1
- MOGXVSDUMNMPST-UHFFFAOYSA-N 3-[[4-(2-amino-8-methoxyquinazolin-4-yl)pyrazol-1-yl]methyl]-1-cyclopropylpyridin-2-one Chemical compound C1=2C=CC=C(C=2N=C(N=C1C=1C=NN(C=1)CC=1C(=O)N(C=CC=1)C1CC1)N)OC MOGXVSDUMNMPST-UHFFFAOYSA-N 0.000 description 1
- VEAQPTADDJRRSO-UHFFFAOYSA-N 3-[[4-(2-amino-8-methoxyquinazolin-4-yl)pyrazol-1-yl]methyl]-1-ethylpyridin-2-one Chemical compound C1=C2C(C=3C=NN(C=3)CC=3C(=O)N(C=CC=3)CC)=NC(=NC2=C(OC)C=C1)N VEAQPTADDJRRSO-UHFFFAOYSA-N 0.000 description 1
- BJWMPTPRWHKXNC-UHFFFAOYSA-N 3-[[4-(2-amino-8-methoxyquinazolin-4-yl)pyrazol-1-yl]methyl]-1-propan-2-ylpyridin-2-one Chemical compound C1=C2C(C=3C=NN(C=3)CC=3C(=O)N(C=CC=3)C(C)C)=NC(=NC2=C(OC)C=C1)N BJWMPTPRWHKXNC-UHFFFAOYSA-N 0.000 description 1
- NQJXEDOCKOJDPW-UHFFFAOYSA-N 3-[[4-(2-amino-8-methoxyquinazolin-4-yl)triazol-1-yl]methyl]-1-(1-methoxypropan-2-yl)pyridin-2-one Chemical compound C1(=C2C(=NC(=N1)N)C(OC)=CC=C2)C=1N=NN(C=1)CC=1C(=O)N(C=CC=1)C(COC)C NQJXEDOCKOJDPW-UHFFFAOYSA-N 0.000 description 1
- YIMHKEXGHLPTDN-UHFFFAOYSA-N 3-[[4-(2-amino-8-methoxyquinazolin-4-yl)triazol-1-yl]methyl]-1-(2-hydroxy-2-methylpropyl)pyridin-2-one Chemical compound C1(=C2C(=NC(=N1)N)C(OC)=CC=C2)C=1N=NN(C=1)CC=1C(=O)N(C=CC=1)CC(O)(C)C YIMHKEXGHLPTDN-UHFFFAOYSA-N 0.000 description 1
- UPFGKMQVHOFVKO-UHFFFAOYSA-N 3-[[4-(2-amino-8-methoxyquinazolin-4-yl)triazol-1-yl]methyl]-1-(2-methoxyethyl)pyridin-2-one Chemical compound C1=2C=CC=C(C=2N=C(N=C1C=1N=NN(C=1)CC=1C(=O)N(C=CC=1)CCOC)N)OC UPFGKMQVHOFVKO-UHFFFAOYSA-N 0.000 description 1
- CRYIVUSMCQPDBJ-UHFFFAOYSA-N 3-[[4-(2-amino-8-methoxyquinazolin-4-yl)triazol-1-yl]methyl]-1-(3-hydroxy-3-methylbutan-2-yl)pyridin-2-one Chemical compound C1=2C=CC=C(C=2N=C(N=C1C=1N=NN(C=1)CC=1C(=O)N(C=CC=1)C(C)C(O)(C)C)N)OC CRYIVUSMCQPDBJ-UHFFFAOYSA-N 0.000 description 1
- UFAWEDHWUKTJGF-UHFFFAOYSA-N 3-[[4-(2-amino-8-methoxyquinazolin-4-yl)triazol-1-yl]methyl]-1-(cyclopropylmethyl)pyridin-2-one Chemical compound C1(=C2C(=NC(=N1)N)C(OC)=CC=C2)C=1N=NN(C=1)CC=1C(=O)N(C=CC=1)CC1CC1 UFAWEDHWUKTJGF-UHFFFAOYSA-N 0.000 description 1
- SSPVIFPYDDXBEB-UHFFFAOYSA-N 3-[[4-(2-amino-8-methoxyquinazolin-4-yl)triazol-1-yl]methyl]-1-(oxan-4-yl)pyridin-2-one Chemical compound NC1=NC2=C(C=CC=C2C(=N1)C=1N=NN(C=1)CC=1C(N(C=CC=1)C1CCOCC1)=O)OC SSPVIFPYDDXBEB-UHFFFAOYSA-N 0.000 description 1
- AZQSAIXSAGLAJN-UHFFFAOYSA-N 3-[[4-(2-amino-8-methoxyquinazolin-4-yl)triazol-1-yl]methyl]-1-(oxan-4-ylmethyl)pyridin-2-one Chemical compound C1(=C2C(=NC(=N1)N)C(OC)=CC=C2)C=1N=NN(C=1)CC=1C(=O)N(C=CC=1)CC1CCOCC1 AZQSAIXSAGLAJN-UHFFFAOYSA-N 0.000 description 1
- XCESAGYOJDLZRF-OAHLLOKOSA-N 3-[[4-(2-amino-8-methoxyquinazolin-4-yl)triazol-1-yl]methyl]-1-[(1R)-1-(oxan-4-yl)ethyl]pyridin-2-one Chemical compound O1CCC(CC1)[C@@H](C)N1C(C(=CC=C1)CN1N=NC(=C1)C1=NC(=NC2=C(C=CC=C12)OC)N)=O XCESAGYOJDLZRF-OAHLLOKOSA-N 0.000 description 1
- OQEWQPFSPXJVEZ-ZDUSSCGKSA-N 3-[[4-(2-amino-8-methoxyquinazolin-4-yl)triazol-1-yl]methyl]-1-[(1S)-1-(1-hydroxycyclopropyl)ethyl]pyridin-2-one Chemical compound C1=C2C(C=3N=NN(C=3)CC=3C(=O)N(C=CC=3)[C@H](C3(O)CC3)C)=NC(=NC2=C(OC)C=C1)N OQEWQPFSPXJVEZ-ZDUSSCGKSA-N 0.000 description 1
- XCESAGYOJDLZRF-HNNXBMFYSA-N 3-[[4-(2-amino-8-methoxyquinazolin-4-yl)triazol-1-yl]methyl]-1-[(1S)-1-(oxan-4-yl)ethyl]pyridin-2-one Chemical compound C1(=C2C(=NC(=N1)N)C(OC)=CC=C2)C=1N=NN(C=1)CC=1C(=O)N(C=CC=1)[C@H](C1CCOCC1)C XCESAGYOJDLZRF-HNNXBMFYSA-N 0.000 description 1
- UBVMOZUJHKKPDI-ZDUSSCGKSA-N 3-[[4-(2-amino-8-methoxyquinazolin-4-yl)triazol-1-yl]methyl]-1-[(1S)-1-cyclopropylethyl]pyridin-2-one Chemical compound C1(=C2C(=NC(=N1)N)C(OC)=CC=C2)C=1N=NN(C=1)CC=1C(=O)N(C=CC=1)[C@H](C1CC1)C UBVMOZUJHKKPDI-ZDUSSCGKSA-N 0.000 description 1
- NQJXEDOCKOJDPW-CYBMUJFWSA-N 3-[[4-(2-amino-8-methoxyquinazolin-4-yl)triazol-1-yl]methyl]-1-[(2R)-1-methoxypropan-2-yl]pyridin-2-one Chemical compound C1=2C=CC=C(C=2N=C(N=C1C=1N=NN(C=1)CC=1C(=O)N(C=CC=1)[C@@H](COC)C)N)OC NQJXEDOCKOJDPW-CYBMUJFWSA-N 0.000 description 1
- CRYIVUSMCQPDBJ-CYBMUJFWSA-N 3-[[4-(2-amino-8-methoxyquinazolin-4-yl)triazol-1-yl]methyl]-1-[(2R)-3-hydroxy-3-methylbutan-2-yl]pyridin-2-one Chemical compound C1(=C2C(=NC(=N1)N)C(OC)=CC=C2)C=1N=NN(C=1)CC=1C(=O)N(C=CC=1)[C@@H](C(O)(C)C)C CRYIVUSMCQPDBJ-CYBMUJFWSA-N 0.000 description 1
- NQJXEDOCKOJDPW-ZDUSSCGKSA-N 3-[[4-(2-amino-8-methoxyquinazolin-4-yl)triazol-1-yl]methyl]-1-[(2S)-1-methoxypropan-2-yl]pyridin-2-one Chemical compound C1=C2C(C=3N=NN(C=3)CC=3C(=O)N(C=CC=3)[C@H](COC)C)=NC(=NC2=C(OC)C=C1)N NQJXEDOCKOJDPW-ZDUSSCGKSA-N 0.000 description 1
- CRYIVUSMCQPDBJ-ZDUSSCGKSA-N 3-[[4-(2-amino-8-methoxyquinazolin-4-yl)triazol-1-yl]methyl]-1-[(2S)-3-hydroxy-3-methylbutan-2-yl]pyridin-2-one Chemical compound C1=C2C(C=3N=NN(C=3)CC=3C(=O)N(C=CC=3)[C@H](C(O)(C)C)C)=NC(=NC2=C(OC)C=C1)N CRYIVUSMCQPDBJ-ZDUSSCGKSA-N 0.000 description 1
- OXICWGLHTJPYID-MRXNPFEDSA-N 3-[[4-(2-amino-8-methoxyquinazolin-4-yl)triazol-1-yl]methyl]-1-[(3R)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]pyridin-2-one Chemical compound C1=2C=CC=C(C=2N=C(N=C1C=1N=NN(C=1)CC=1C(=O)N(C=CC=1)[C@@H]1CCN(C(=O)C(O)(C)C)C1)N)OC OXICWGLHTJPYID-MRXNPFEDSA-N 0.000 description 1
- DWJCANAHMXSFBD-OAHLLOKOSA-N 3-[[4-(2-amino-8-methoxyquinazolin-4-yl)triazol-1-yl]methyl]-1-[(3R)-oxan-3-yl]pyridin-2-one Chemical compound C1=2C=CC=C(C=2N=C(N=C1C=1N=NN(C=1)CC=1C(=O)N(C=CC=1)[C@@H]1CCCOC1)N)OC DWJCANAHMXSFBD-OAHLLOKOSA-N 0.000 description 1
- SMFZIOMPYAAVIN-CQSZACIVSA-N 3-[[4-(2-amino-8-methoxyquinazolin-4-yl)triazol-1-yl]methyl]-1-[(3R)-oxolan-3-yl]pyridin-2-one Chemical compound C1=2C=CC=C(C=2N=C(N=C1C=1N=NN(C=1)CC=1C(=O)N(C=CC=1)[C@@H]1CCOC1)N)OC SMFZIOMPYAAVIN-CQSZACIVSA-N 0.000 description 1
- OXICWGLHTJPYID-INIZCTEOSA-N 3-[[4-(2-amino-8-methoxyquinazolin-4-yl)triazol-1-yl]methyl]-1-[(3S)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]pyridin-2-one Chemical compound C1(=C2C(=NC(=N1)N)C(OC)=CC=C2)C=1N=NN(C=1)CC=1C(=O)N(C=CC=1)[C@@H]1CN(C(=O)C(O)(C)C)CC1 OXICWGLHTJPYID-INIZCTEOSA-N 0.000 description 1
- DWJCANAHMXSFBD-HNNXBMFYSA-N 3-[[4-(2-amino-8-methoxyquinazolin-4-yl)triazol-1-yl]methyl]-1-[(3S)-oxan-3-yl]pyridin-2-one Chemical compound C1=2C=CC=C(C=2N=C(N=C1C=1N=NN(C=1)CC=1C(=O)N(C=CC=1)[C@H]1CCCOC1)N)OC DWJCANAHMXSFBD-HNNXBMFYSA-N 0.000 description 1
- SMFZIOMPYAAVIN-AWEZNQCLSA-N 3-[[4-(2-amino-8-methoxyquinazolin-4-yl)triazol-1-yl]methyl]-1-[(3S)-oxolan-3-yl]pyridin-2-one Chemical compound C1=C2C(C=3N=NN(C=3)CC=3C(=O)N(C=CC=3)[C@H]3CCOC3)=NC(=NC2=C(OC)C=C1)N SMFZIOMPYAAVIN-AWEZNQCLSA-N 0.000 description 1
- BILBBHMYDIMZOP-UHFFFAOYSA-N 3-[[4-(2-amino-8-methoxyquinazolin-4-yl)triazol-1-yl]methyl]-1-cyclopentylpyridin-2-one Chemical compound C1(=C2C(=NC(=N1)N)C(OC)=CC=C2)C=1N=NN(C=1)CC=1C(=O)N(C=CC=1)C1CCCC1 BILBBHMYDIMZOP-UHFFFAOYSA-N 0.000 description 1
- IHOWJLSTZPOIIS-UHFFFAOYSA-N 3-[[4-(2-amino-8-methoxyquinazolin-4-yl)triazol-1-yl]methyl]-1-cyclopropylpyridin-2-one Chemical compound NC1=NC2=C(C=CC=C2C(=N1)C=1N=NN(C=1)CC=1C(N(C=CC=1)C1CC1)=O)OC IHOWJLSTZPOIIS-UHFFFAOYSA-N 0.000 description 1
- ZNIJLCUNOANHMA-UHFFFAOYSA-N 3-[[4-(2-amino-8-methoxyquinazolin-4-yl)triazol-1-yl]methyl]-1-ethylpyridin-2-one Chemical compound C1=2C=CC=C(C=2N=C(N=C1C=1N=NN(C=1)CC=1C(=O)N(C=CC=1)CC)N)OC ZNIJLCUNOANHMA-UHFFFAOYSA-N 0.000 description 1
- ZYWGDFGPSAGPOU-UHFFFAOYSA-N 3-[[4-(2-amino-8-methoxyquinazolin-4-yl)triazol-1-yl]methyl]-1-methylpyridin-2-one Chemical compound C1=C2C(C=3N=NN(C=3)CC=3C(=O)N(C=CC=3)C)=NC(=NC2=C(OC)C=C1)N ZYWGDFGPSAGPOU-UHFFFAOYSA-N 0.000 description 1
- TZFQBJQCXGLVJX-UHFFFAOYSA-N 3-[[4-(2-amino-8-methoxyquinazolin-4-yl)triazol-1-yl]methyl]-1-propan-2-ylpyridin-2-one Chemical compound NC1=NC2=C(C=CC=C2C(=N1)C=1N=NN(C=1)CC=1C(N(C=CC=1)C(C)C)=O)OC TZFQBJQCXGLVJX-UHFFFAOYSA-N 0.000 description 1
- JAKOYDCRCIUULU-UHFFFAOYSA-N 3-[[4-(2-amino-8-methoxyquinolin-4-yl)triazol-1-yl]methyl]-1-propan-2-ylpyridin-2-one Chemical compound C1=2C=CC=C(C=2N=C(C=C1C=1N=NN(C=1)CC=1C(=O)N(C=CC=1)C(C)C)N)OC JAKOYDCRCIUULU-UHFFFAOYSA-N 0.000 description 1
- JMZUUWSTAOPMDV-UHFFFAOYSA-N 3-[[4-(2-amino-8-methylquinazolin-4-yl)triazol-1-yl]methyl]-1-propan-2-ylpyridin-2-one Chemical compound C1(=C2C(=NC(=N1)N)C(C)=CC=C2)C=1N=NN(C=1)CC=1C(=O)N(C=CC=1)C(C)C JMZUUWSTAOPMDV-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- JVQIKJMSUIMUDI-UHFFFAOYSA-N 3-pyrroline Chemical compound C1NCC=C1 JVQIKJMSUIMUDI-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- NHQAUSOKYWFWHO-UHFFFAOYSA-N 4-aminobutane-2-sulfonic acid Chemical compound OS(=O)(=O)C(C)CCN NHQAUSOKYWFWHO-UHFFFAOYSA-N 0.000 description 1
- GAMYYCRTACQSBR-UHFFFAOYSA-N 4-azabenzimidazole Chemical group C1=CC=C2NC=NC2=N1 GAMYYCRTACQSBR-UHFFFAOYSA-N 0.000 description 1
- MNULEGDCPYONBU-UHFFFAOYSA-N 4-ethyl-11,12,15,19-tetrahydroxy-6'-(2-hydroxypropyl)-5',10,12,14,16,18,20,26,29-nonamethylspiro[24,28-dioxabicyclo[23.3.1]nonacosa-5,7,21-triene-27,2'-oxane]-13,17,23-trione Polymers CC1C(C2C)OC(=O)C=CC(C)C(O)C(C)C(=O)C(C)C(O)C(C)C(=O)C(C)(O)C(O)C(C)CC=CC=CC(CC)CCC2OC21CCC(C)C(CC(C)O)O2 MNULEGDCPYONBU-UHFFFAOYSA-N 0.000 description 1
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- WYXSYVWAUAUWLD-SHUUEZRQSA-N 6-azauridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=N1 WYXSYVWAUAUWLD-SHUUEZRQSA-N 0.000 description 1
- YCWQAMGASJSUIP-YFKPBYRVSA-N 6-diazo-5-oxo-L-norleucine Chemical compound OC(=O)[C@@H](N)CCC(=O)C=[N+]=[N-] YCWQAMGASJSUIP-YFKPBYRVSA-N 0.000 description 1
- 229960005538 6-diazo-5-oxo-L-norleucine Drugs 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [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
- ZGXJTSGNIOSYLO-UHFFFAOYSA-N 88755TAZ87 Chemical compound NCC(=O)CCC(O)=O ZGXJTSGNIOSYLO-UHFFFAOYSA-N 0.000 description 1
- SPBDXSGPUHCETR-JFUDTMANSA-N 8883yp2r6d Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](OC)C[C@H](O[C@@H]2C(=C/C[C@@H]3C[C@@H](C[C@@]4(O[C@@H]([C@@H](C)CC4)C(C)C)O3)OC(=O)[C@@H]3C=C(C)[C@@H](O)[C@H]4OC\C([C@@]34O)=C/C=C/[C@@H]2C)/C)O[C@H]1C.C1C[C@H](C)[C@@H]([C@@H](C)CC)O[C@@]21O[C@H](C\C=C(C)\[C@@H](O[C@@H]1O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C1)[C@@H](C)\C=C\C=C/1[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\1)O)C[C@H]4C2 SPBDXSGPUHCETR-JFUDTMANSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- 230000035502 ADME Effects 0.000 description 1
- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 description 1
- 235000007173 Abies balsamea Nutrition 0.000 description 1
- 229930024421 Adenine Natural products 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- 102100035990 Adenosine receptor A2a Human genes 0.000 description 1
- 102100035984 Adenosine receptor A2b Human genes 0.000 description 1
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 1
- 102100031934 Adhesion G-protein coupled receptor G1 Human genes 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 206010001540 Akathisia Diseases 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 240000002234 Allium sativum Species 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 108090000531 Amidohydrolases Proteins 0.000 description 1
- 102000004092 Amidohydrolases Human genes 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 229930183010 Amphotericin Natural products 0.000 description 1
- QGGFZZLFKABGNL-UHFFFAOYSA-N Amphotericin A Natural products OC1C(N)C(O)C(C)OC1OC1C=CC=CC=CC=CCCC=CC=CC(C)C(O)C(C)C(C)OC(=O)CC(O)CC(O)CCC(O)C(O)CC(O)CC(O)(CC(O)C2C(O)=O)OC2C1 QGGFZZLFKABGNL-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 208000003017 Aortic Valve Stenosis Diseases 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 102100029361 Aromatase Human genes 0.000 description 1
- 108010078554 Aromatase Proteins 0.000 description 1
- 102000015790 Asparaginase Human genes 0.000 description 1
- 108010024976 Asparaginase Proteins 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 description 1
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 description 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- 108010008014 B-Cell Maturation Antigen Proteins 0.000 description 1
- 102000006942 B-Cell Maturation Antigen Human genes 0.000 description 1
- 229940125565 BMS-986016 Drugs 0.000 description 1
- 229940125557 BMS-986207 Drugs 0.000 description 1
- 241000193738 Bacillus anthracis Species 0.000 description 1
- 239000004857 Balsam Substances 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- CULUWZNBISUWAS-UHFFFAOYSA-N Benznidazole Chemical compound [O-][N+](=O)C1=NC=CN1CC(=O)NCC1=CC=CC=C1 CULUWZNBISUWAS-UHFFFAOYSA-N 0.000 description 1
- 239000004342 Benzoyl peroxide Substances 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- VGGGPCQERPFHOB-MCIONIFRSA-N Bestatin Chemical compound CC(C)C[C@H](C(O)=O)NC(=O)[C@@H](O)[C@H](N)CC1=CC=CC=C1 VGGGPCQERPFHOB-MCIONIFRSA-N 0.000 description 1
- 102100039705 Beta-2 adrenergic receptor Human genes 0.000 description 1
- ZBJJDYGJCNTNTH-UHFFFAOYSA-N Betahistine mesilate Chemical compound CS(O)(=O)=O.CS(O)(=O)=O.CNCCC1=CC=CC=N1 ZBJJDYGJCNTNTH-UHFFFAOYSA-N 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- 208000014644 Brain disease Diseases 0.000 description 1
- 244000056139 Brassica cretica Species 0.000 description 1
- 235000003351 Brassica cretica Nutrition 0.000 description 1
- 235000003343 Brassica rupestris Nutrition 0.000 description 1
- 102000003930 C-Type Lectins Human genes 0.000 description 1
- 108090000342 C-Type Lectins Proteins 0.000 description 1
- LTKHPMDRMUCUEB-IBGZPJMESA-N CB3717 Chemical compound C=1C=C2NC(N)=NC(=O)C2=CC=1CN(CC#C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 LTKHPMDRMUCUEB-IBGZPJMESA-N 0.000 description 1
- 108010046080 CD27 Ligand Proteins 0.000 description 1
- 229940121697 CD27 agonist Drugs 0.000 description 1
- 108010029697 CD40 Ligand Proteins 0.000 description 1
- 229940123189 CD40 agonist Drugs 0.000 description 1
- 229940122551 CD40 antagonist Drugs 0.000 description 1
- 102100032937 CD40 ligand Human genes 0.000 description 1
- 102100036008 CD48 antigen Human genes 0.000 description 1
- 210000005236 CD8+ effector T cell Anatomy 0.000 description 1
- 210000001266 CD8-positive T-lymphocyte Anatomy 0.000 description 1
- 206010006895 Cachexia Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000222122 Candida albicans Species 0.000 description 1
- KXLUWEYBZBGJRZ-POEOZHCLSA-N Canin Chemical compound O([C@H]12)[C@]1([C@](CC[C@H]1C(=C)C(=O)O[C@@H]11)(C)O)[C@@H]1[C@@]1(C)[C@@H]2O1 KXLUWEYBZBGJRZ-POEOZHCLSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical group NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- OKTJSMMVPCPJKN-OUBTZVSYSA-N Carbon-13 Chemical compound [13C] OKTJSMMVPCPJKN-OUBTZVSYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- SHHKQEUPHAENFK-UHFFFAOYSA-N Carboquone Chemical compound O=C1C(C)=C(N2CC2)C(=O)C(C(COC(N)=O)OC)=C1N1CC1 SHHKQEUPHAENFK-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- AOCCBINRVIKJHY-UHFFFAOYSA-N Carmofur Chemical compound CCCCCCNC(=O)N1C=C(F)C(=O)NC1=O AOCCBINRVIKJHY-UHFFFAOYSA-N 0.000 description 1
- 108090000426 Caspase-1 Proteins 0.000 description 1
- 102000053642 Catalytic RNA Human genes 0.000 description 1
- 108090000994 Catalytic RNA Proteins 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- GPFVKTQSZOQXLY-UHFFFAOYSA-N Chrysartemin A Natural products CC1(O)C2OC2C34OC3(C)CC5C(CC14)OC(=O)C5=C GPFVKTQSZOQXLY-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 229920002905 Colesevelam Polymers 0.000 description 1
- 229920002911 Colestipol Polymers 0.000 description 1
- 240000003890 Commiphora wightii Species 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 101710095468 Cyclase Proteins 0.000 description 1
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 1
- 101710093674 Cyclic nucleotide-gated cation channel beta-1 Proteins 0.000 description 1
- 108010037462 Cyclooxygenase 2 Proteins 0.000 description 1
- 239000012626 DNA minor groove binder Substances 0.000 description 1
- 229940124087 DNA topoisomerase II inhibitor Drugs 0.000 description 1
- NNJPGOLRFBJNIW-UHFFFAOYSA-N Demecolcine Natural products C1=C(OC)C(=O)C=C2C(NC)CCC3=CC(OC)=C(OC)C(OC)=C3C2=C1 NNJPGOLRFBJNIW-UHFFFAOYSA-N 0.000 description 1
- 101000802894 Dendroaspis angusticeps Fasciculin-2 Proteins 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010012689 Diabetic retinopathy Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- ZMJOVJSTYLQINE-UHFFFAOYSA-N Dichloroacetylene Chemical compound ClC#CCl ZMJOVJSTYLQINE-UHFFFAOYSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 208000014094 Dystonic disease Diseases 0.000 description 1
- 102100025137 Early activation antigen CD69 Human genes 0.000 description 1
- 102100037354 Ectodysplasin-A Human genes 0.000 description 1
- XQSPYNMVSIKCOC-NTSWFWBYSA-N Emtricitabine Chemical compound C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)SC1 XQSPYNMVSIKCOC-NTSWFWBYSA-N 0.000 description 1
- 102400000792 Endothelial monocyte-activating polypeptide 2 Human genes 0.000 description 1
- 108010032976 Enfuvirtide Proteins 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- BFPYWIDHMRZLRN-SLHNCBLASA-N Ethinyl estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 BFPYWIDHMRZLRN-SLHNCBLASA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 101150021185 FGF gene Proteins 0.000 description 1
- 108010087819 Fc receptors Proteins 0.000 description 1
- 102000009109 Fc receptors Human genes 0.000 description 1
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 108091006027 G proteins Proteins 0.000 description 1
- 102100025101 GATA-type zinc finger protein 1 Human genes 0.000 description 1
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 description 1
- 102000030782 GTP binding Human genes 0.000 description 1
- 108091000058 GTP-Binding Proteins 0.000 description 1
- 108010001498 Galectin 1 Proteins 0.000 description 1
- 102100021736 Galectin-1 Human genes 0.000 description 1
- 102100031351 Galectin-9 Human genes 0.000 description 1
- 101710121810 Galectin-9 Proteins 0.000 description 1
- 208000022072 Gallbladder Neoplasms Diseases 0.000 description 1
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 1
- 241000224466 Giardia Species 0.000 description 1
- 108010072051 Glatiramer Acetate Proteins 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 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
- 235000010469 Glycine max Nutrition 0.000 description 1
- 239000000579 Gonadotropin-Releasing Hormone Substances 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
- 239000007995 HEPES buffer Substances 0.000 description 1
- 102100035943 HERV-H LTR-associating protein 2 Human genes 0.000 description 1
- 229940033330 HIV vaccine Drugs 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 208000016988 Hemorrhagic Stroke Diseases 0.000 description 1
- 108010007712 Hepatitis A Virus Cellular Receptor 1 Proteins 0.000 description 1
- 102100034459 Hepatitis A virus cellular receptor 1 Human genes 0.000 description 1
- 241000700721 Hepatitis B virus Species 0.000 description 1
- 101000783751 Homo sapiens Adenosine receptor A2a Proteins 0.000 description 1
- 101000783756 Homo sapiens Adenosine receptor A2b Proteins 0.000 description 1
- 101000775042 Homo sapiens Adhesion G-protein coupled receptor G1 Proteins 0.000 description 1
- 101000716130 Homo sapiens CD48 antigen Proteins 0.000 description 1
- 101000934374 Homo sapiens Early activation antigen CD69 Proteins 0.000 description 1
- 101000880080 Homo sapiens Ectodysplasin-A Proteins 0.000 description 1
- 101001138062 Homo sapiens Leukocyte-associated immunoglobulin-like receptor 1 Proteins 0.000 description 1
- 101001023712 Homo sapiens Nectin-3 Proteins 0.000 description 1
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 1
- 101000830596 Homo sapiens Tumor necrosis factor ligand superfamily member 15 Proteins 0.000 description 1
- 101000764263 Homo sapiens Tumor necrosis factor ligand superfamily member 4 Proteins 0.000 description 1
- 101000610602 Homo sapiens Tumor necrosis factor receptor superfamily member 10C Proteins 0.000 description 1
- 101000610609 Homo sapiens Tumor necrosis factor receptor superfamily member 10D Proteins 0.000 description 1
- 101000798130 Homo sapiens Tumor necrosis factor receptor superfamily member 11B Proteins 0.000 description 1
- 101000795167 Homo sapiens Tumor necrosis factor receptor superfamily member 13B Proteins 0.000 description 1
- 101000795169 Homo sapiens Tumor necrosis factor receptor superfamily member 13C Proteins 0.000 description 1
- 101000679903 Homo sapiens Tumor necrosis factor receptor superfamily member 25 Proteins 0.000 description 1
- 101000679907 Homo sapiens Tumor necrosis factor receptor superfamily member 27 Proteins 0.000 description 1
- 101000597785 Homo sapiens Tumor necrosis factor receptor superfamily member 6B Proteins 0.000 description 1
- 101000851376 Homo sapiens Tumor necrosis factor receptor superfamily member 8 Proteins 0.000 description 1
- 101000920026 Homo sapiens Tumor necrosis factor receptor superfamily member EDAR Proteins 0.000 description 1
- 238000006736 Huisgen cycloaddition reaction Methods 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DOMWKUIIPQCAJU-LJHIYBGHSA-N Hydroxyprogesterone caproate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)CCCCC)[C@@]1(C)CC2 DOMWKUIIPQCAJU-LJHIYBGHSA-N 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 101710093458 ICOS ligand Proteins 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 1
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 1
- 244000018716 Impatiens biflora Species 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 238000012695 Interfacial polymerization Methods 0.000 description 1
- 108010005716 Interferon beta-1a Proteins 0.000 description 1
- 108010005714 Interferon beta-1b Proteins 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108090000177 Interleukin-11 Proteins 0.000 description 1
- 102000003815 Interleukin-11 Human genes 0.000 description 1
- 102000004559 Interleukin-13 Receptors Human genes 0.000 description 1
- 108010017511 Interleukin-13 Receptors Proteins 0.000 description 1
- 101800003050 Interleukin-16 Proteins 0.000 description 1
- 108010002586 Interleukin-7 Proteins 0.000 description 1
- 108090001007 Interleukin-8 Proteins 0.000 description 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 1
- 238000008214 LDL Cholesterol Methods 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241000222738 Leishmania aethiopica Species 0.000 description 1
- 241000222732 Leishmania major Species 0.000 description 1
- 241000222734 Leishmania mexicana Species 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 102100020943 Leukocyte-associated immunoglobulin-like receptor 1 Human genes 0.000 description 1
- 241000186779 Listeria monocytogenes Species 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- 102000009151 Luteinizing Hormone Human genes 0.000 description 1
- 108010073521 Luteinizing Hormone Proteins 0.000 description 1
- 102000043136 MAP kinase family Human genes 0.000 description 1
- 108091054455 MAP kinase family Proteins 0.000 description 1
- 239000007993 MOPS buffer Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- JCYZMTMYPZHVBF-UHFFFAOYSA-N Melarsoprol Chemical compound NC1=NC(N)=NC(NC=2C=CC(=CC=2)[As]2SC(CO)CS2)=N1 JCYZMTMYPZHVBF-UHFFFAOYSA-N 0.000 description 1
- 108010061593 Member 14 Tumor Necrosis Factor Receptors Proteins 0.000 description 1
- GCKMFJBGXUYNAG-HLXURNFRSA-N Methyltestosterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)CC2 GCKMFJBGXUYNAG-HLXURNFRSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 1
- 101100046559 Mus musculus Tnfrsf12a gene Proteins 0.000 description 1
- 101000597780 Mus musculus Tumor necrosis factor ligand superfamily member 18 Proteins 0.000 description 1
- 206010062207 Mycobacterial infection Diseases 0.000 description 1
- 241000186362 Mycobacterium leprae Species 0.000 description 1
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 1
- 108010083674 Myelin Proteins Proteins 0.000 description 1
- 102000006386 Myelin Proteins Human genes 0.000 description 1
- KJHOZAZQWVKILO-UHFFFAOYSA-N N-(diaminomethylidene)-4-morpholinecarboximidamide Chemical compound NC(N)=NC(=N)N1CCOCC1 KJHOZAZQWVKILO-UHFFFAOYSA-N 0.000 description 1
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 1
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 1
- JADDQZYHOWSFJD-FLNNQWSLSA-N N-ethyl-5'-carboxamidoadenosine Chemical compound O[C@@H]1[C@H](O)[C@@H](C(=O)NCC)O[C@H]1N1C2=NC=NC(N)=C2N=C1 JADDQZYHOWSFJD-FLNNQWSLSA-N 0.000 description 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-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
- RFWFFGNSNTULJN-IYBDPMFKSA-N NC1=NC2=C(C=CC=C2C(=N1)C=1N=NN(C=1)CC=1C(N(C=CC=1)[C@@H]1CC[C@@H](CC1)O)=O)OC Chemical compound NC1=NC2=C(C=CC=C2C(=N1)C=1N=NN(C=1)CC=1C(N(C=CC=1)[C@@H]1CC[C@@H](CC1)O)=O)OC RFWFFGNSNTULJN-IYBDPMFKSA-N 0.000 description 1
- RFWFFGNSNTULJN-WKILWMFISA-N NC1=NC2=C(C=CC=C2C(=N1)C=1N=NN(C=1)CC=1C(N(C=CC=1)[C@@H]1CC[C@H](CC1)O)=O)OC Chemical compound NC1=NC2=C(C=CC=C2C(=N1)C=1N=NN(C=1)CC=1C(N(C=CC=1)[C@@H]1CC[C@H](CC1)O)=O)OC RFWFFGNSNTULJN-WKILWMFISA-N 0.000 description 1
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 1
- 102100035488 Nectin-2 Human genes 0.000 description 1
- 102100035487 Nectin-3 Human genes 0.000 description 1
- 229930193140 Neomycin Natural products 0.000 description 1
- 206010029113 Neovascularisation Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 1
- ARFHIAQFJWUCFH-IZZDOVSWSA-N Nifurtimox Chemical compound CC1CS(=O)(=O)CCN1\N=C\C1=CC=C([N+]([O-])=O)O1 ARFHIAQFJWUCFH-IZZDOVSWSA-N 0.000 description 1
- 108700001237 Nucleic Acid-Based Vaccines Proteins 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 208000001388 Opportunistic Infections Diseases 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- 102000008212 P-Selectin Human genes 0.000 description 1
- 108010035766 P-Selectin Proteins 0.000 description 1
- 229940124060 PD-1 antagonist Drugs 0.000 description 1
- 229940123751 PD-L1 antagonist Drugs 0.000 description 1
- 241001631646 Papillomaviridae Species 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 229940123354 Phosphatidylinositol kinase inhibitor Drugs 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- NCXMLFZGDNKEPB-UHFFFAOYSA-N Pimaricin Natural products OC1C(N)C(O)C(C)OC1OC1C=CC=CC=CC=CCC(C)OC(=O)C=CC2OC2CC(O)CC(O)(CC(O)C2C(O)=O)OC2C1 NCXMLFZGDNKEPB-UHFFFAOYSA-N 0.000 description 1
- KMSKQZKKOZQFFG-HSUXVGOQSA-N Pirarubicin Chemical compound O([C@H]1[C@@H](N)C[C@@H](O[C@H]1C)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]1CCCCO1 KMSKQZKKOZQFFG-HSUXVGOQSA-N 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 241000224016 Plasmodium Species 0.000 description 1
- 241000223960 Plasmodium falciparum Species 0.000 description 1
- 241001505293 Plasmodium ovale Species 0.000 description 1
- 241000223810 Plasmodium vivax Species 0.000 description 1
- 102100029740 Poliovirus receptor Human genes 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920002732 Polyanhydride Polymers 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- 108010040201 Polymyxins Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- TVQZAMVBTVNYLA-UHFFFAOYSA-N Pranoprofen Chemical compound C1=CC=C2CC3=CC(C(C(O)=O)C)=CC=C3OC2=N1 TVQZAMVBTVNYLA-UHFFFAOYSA-N 0.000 description 1
- HFVNWDWLWUCIHC-GUPDPFMOSA-N Prednimustine Chemical compound O=C([C@@]1(O)CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)[C@@H](O)C[C@@]21C)COC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 HFVNWDWLWUCIHC-GUPDPFMOSA-N 0.000 description 1
- 101710094000 Programmed cell death 1 ligand 1 Proteins 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 description 1
- 102000007327 Protamines Human genes 0.000 description 1
- 108010007568 Protamines Proteins 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 1
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 1
- 208000001431 Psychomotor Agitation Diseases 0.000 description 1
- 238000012228 RNA interference-mediated gene silencing Methods 0.000 description 1
- 108091030071 RNAI Proteins 0.000 description 1
- AHHFEZNOXOZZQA-ZEBDFXRSSA-N Ranimustine Chemical compound CO[C@H]1O[C@H](CNC(=O)N(CCCl)N=O)[C@@H](O)[C@H](O)[C@H]1O AHHFEZNOXOZZQA-ZEBDFXRSSA-N 0.000 description 1
- 230000010799 Receptor Interactions Effects 0.000 description 1
- 102000004389 Ribonucleoproteins Human genes 0.000 description 1
- 108010081734 Ribonucleoproteins Proteins 0.000 description 1
- 108091028664 Ribonucleotide Proteins 0.000 description 1
- 229940127395 Ribonucleotide Reductase Inhibitors Drugs 0.000 description 1
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 1
- URWAJWIAIPFPJE-UHFFFAOYSA-N Rickamicin Natural products O1CC(O)(C)C(NC)C(O)C1OC1C(O)C(OC2C(CC=C(CN)O2)N)C(N)CC1N URWAJWIAIPFPJE-UHFFFAOYSA-N 0.000 description 1
- 229930189077 Rifamycin Natural products 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 208000004337 Salivary Gland Neoplasms Diseases 0.000 description 1
- 206010061934 Salivary gland cancer Diseases 0.000 description 1
- 102000003800 Selectins Human genes 0.000 description 1
- 108090000184 Selectins Proteins 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- CSPPKDPQLUUTND-NBVRZTHBSA-N Sethoxydim Chemical compound CCO\N=C(/CCC)C1=C(O)CC(CC(C)SCC)CC1=O CSPPKDPQLUUTND-NBVRZTHBSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 229930192786 Sisomicin Natural products 0.000 description 1
- 229920000519 Sizofiran Polymers 0.000 description 1
- 101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 description 1
- 206010041925 Staphylococcal infections Diseases 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 206010061372 Streptococcal infection Diseases 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 208000032851 Subarachnoid Hemorrhage Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 208000003734 Supraventricular Tachycardia Diseases 0.000 description 1
- 108700005078 Synthetic Genes Proteins 0.000 description 1
- 230000024932 T cell mediated immunity Effects 0.000 description 1
- 102100039367 T-cell immunoglobulin and mucin domain-containing protein 4 Human genes 0.000 description 1
- 101710174757 T-cell immunoglobulin and mucin domain-containing protein 4 Proteins 0.000 description 1
- 101710090983 T-cell immunoreceptor with Ig and ITIM domains Proteins 0.000 description 1
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 1
- 108700012920 TNF Proteins 0.000 description 1
- 108010014401 TWEAK Receptor Proteins 0.000 description 1
- 102000016946 TWEAK Receptor Human genes 0.000 description 1
- 208000001871 Tachycardia Diseases 0.000 description 1
- 206010043118 Tardive Dyskinesia 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
- 206010043276 Teratoma Diseases 0.000 description 1
- PDMMFKSKQVNJMI-BLQWBTBKSA-N Testosterone propionate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CC)[C@@]1(C)CC2 PDMMFKSKQVNJMI-BLQWBTBKSA-N 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- 239000005940 Thiacloprid Substances 0.000 description 1
- 102000003978 Tissue Plasminogen Activator Human genes 0.000 description 1
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 1
- 239000000365 Topoisomerase I Inhibitor Substances 0.000 description 1
- 239000000317 Topoisomerase II Inhibitor Substances 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 102100025946 Transforming growth factor beta activator LRRC32 Human genes 0.000 description 1
- 101710169732 Transforming growth factor beta activator LRRC32 Proteins 0.000 description 1
- 208000030886 Traumatic Brain injury Diseases 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 241000224526 Trichomonas Species 0.000 description 1
- UMILHIMHKXVDGH-UHFFFAOYSA-N Triethylene glycol diglycidyl ether Chemical compound C1OC1COCCOCCOCCOCC1CO1 UMILHIMHKXVDGH-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- FYAMXEPQQLNQDM-UHFFFAOYSA-N Tris(1-aziridinyl)phosphine oxide Chemical compound C1CN1P(N1CC1)(=O)N1CC1 FYAMXEPQQLNQDM-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 102000004243 Tubulin Human genes 0.000 description 1
- 108090000704 Tubulin Proteins 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102100024584 Tumor necrosis factor ligand superfamily member 12 Human genes 0.000 description 1
- 101710097155 Tumor necrosis factor ligand superfamily member 12 Proteins 0.000 description 1
- 108090000138 Tumor necrosis factor ligand superfamily member 15 Proteins 0.000 description 1
- 102100035283 Tumor necrosis factor ligand superfamily member 18 Human genes 0.000 description 1
- 102100026890 Tumor necrosis factor ligand superfamily member 4 Human genes 0.000 description 1
- 102100040115 Tumor necrosis factor receptor superfamily member 10C Human genes 0.000 description 1
- 102100040110 Tumor necrosis factor receptor superfamily member 10D Human genes 0.000 description 1
- 102100032236 Tumor necrosis factor receptor superfamily member 11B Human genes 0.000 description 1
- 102100029675 Tumor necrosis factor receptor superfamily member 13B Human genes 0.000 description 1
- 102100029690 Tumor necrosis factor receptor superfamily member 13C Human genes 0.000 description 1
- 102100028785 Tumor necrosis factor receptor superfamily member 14 Human genes 0.000 description 1
- 102100022202 Tumor necrosis factor receptor superfamily member 27 Human genes 0.000 description 1
- 102100035284 Tumor necrosis factor receptor superfamily member 6B Human genes 0.000 description 1
- 102100036857 Tumor necrosis factor receptor superfamily member 8 Human genes 0.000 description 1
- 102100030810 Tumor necrosis factor receptor superfamily member EDAR Human genes 0.000 description 1
- 206010053613 Type IV hypersensitivity reaction Diseases 0.000 description 1
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 1
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- WPVFJKSGQUFQAP-GKAPJAKFSA-N Valcyte Chemical compound N1C(N)=NC(=O)C2=C1N(COC(CO)COC(=O)[C@@H](N)C(C)C)C=N2 WPVFJKSGQUFQAP-GKAPJAKFSA-N 0.000 description 1
- 108020005202 Viral DNA Proteins 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- WERKSKAQRVDLDW-ANOHMWSOSA-N [(2s,3r,4r,5r)-2,3,4,5,6-pentahydroxyhexyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO WERKSKAQRVDLDW-ANOHMWSOSA-N 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- IAEOJPMHMNCKAZ-UHFFFAOYSA-N [N-]=[N+]=[N-].N1C(C=CC=C1)=O Chemical class [N-]=[N+]=[N-].N1C(C=CC=C1)=O IAEOJPMHMNCKAZ-UHFFFAOYSA-N 0.000 description 1
- GLWHPRRGGYLLRV-XLPZGREQSA-N [[(2s,3s,5r)-3-azido-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](N=[N+]=[N-])C1 GLWHPRRGGYLLRV-XLPZGREQSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 229960004892 acemetacin Drugs 0.000 description 1
- FSQKKOOTNAMONP-UHFFFAOYSA-N acemetacin Chemical compound CC1=C(CC(=O)OCC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 FSQKKOOTNAMONP-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 229930188522 aclacinomycin Natural products 0.000 description 1
- USZYSDMBJDPRIF-SVEJIMAYSA-N aclacinomycin A Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1CCC(=O)[C@H](C)O1 USZYSDMBJDPRIF-SVEJIMAYSA-N 0.000 description 1
- 229960004176 aclarubicin Drugs 0.000 description 1
- 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 1
- 239000011149 active material Substances 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 229960001997 adefovir Drugs 0.000 description 1
- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 description 1
- 229960000643 adenine Drugs 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- LNQVTSROQXJCDD-UHFFFAOYSA-N adenosine monophosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(CO)C(OP(O)(O)=O)C1O LNQVTSROQXJCDD-UHFFFAOYSA-N 0.000 description 1
- 229950006790 adenosine phosphate Drugs 0.000 description 1
- 230000001780 adrenocortical effect Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- HXHWSAZORRCQMX-UHFFFAOYSA-N albendazole Chemical compound CCCSC1=CC=C2NC(NC(=O)OC)=NC2=C1 HXHWSAZORRCQMX-UHFFFAOYSA-N 0.000 description 1
- 229960002669 albendazole Drugs 0.000 description 1
- 229960005142 alclofenac Drugs 0.000 description 1
- ARHWPKZXBHOEEE-UHFFFAOYSA-N alclofenac Chemical compound OC(=O)CC1=CC=C(OCC=C)C(Cl)=C1 ARHWPKZXBHOEEE-UHFFFAOYSA-N 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- IAJILQKETJEXLJ-RSJOWCBRSA-N aldehydo-D-galacturonic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-RSJOWCBRSA-N 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 229960002459 alefacept 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
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 229940045714 alkyl sulfonate alkylating agent Drugs 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 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
- 230000000735 allogeneic effect Effects 0.000 description 1
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 1
- CJCSPKMFHVPWAR-JTQLQIEISA-N alpha-methyl-L-dopa Chemical compound OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1 CJCSPKMFHVPWAR-JTQLQIEISA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- BIIVYFLTOXDAOV-YVEFUNNKSA-N alvocidib Chemical compound O[C@@H]1CN(C)CC[C@@H]1C1=C(O)C=C(O)C2=C1OC(C=1C(=CC=CC=1)Cl)=CC2=O BIIVYFLTOXDAOV-YVEFUNNKSA-N 0.000 description 1
- 229950010817 alvocidib Drugs 0.000 description 1
- 238000006470 amide elimination reaction Methods 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- 229960003437 aminoglutethimide Drugs 0.000 description 1
- ROBVIMPUHSLWNV-UHFFFAOYSA-N aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 description 1
- 229940126575 aminoglycoside Drugs 0.000 description 1
- 229960002749 aminolevulinic acid Drugs 0.000 description 1
- 229960003204 amorolfine Drugs 0.000 description 1
- 229940009444 amphotericin Drugs 0.000 description 1
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 229960004238 anakinra Drugs 0.000 description 1
- 229940051880 analgesics and antipyretics pyrazolones Drugs 0.000 description 1
- 239000012491 analyte Substances 0.000 description 1
- BBDAGFIXKZCXAH-CCXZUQQUSA-N ancitabine Chemical compound N=C1C=CN2[C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3OC2=N1 BBDAGFIXKZCXAH-CCXZUQQUSA-N 0.000 description 1
- 229950000242 ancitabine Drugs 0.000 description 1
- 230000002491 angiogenic effect Effects 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940124650 anti-cancer therapies Drugs 0.000 description 1
- 229940046836 anti-estrogen Drugs 0.000 description 1
- 230000001833 anti-estrogenic effect Effects 0.000 description 1
- 230000036436 anti-hiv Effects 0.000 description 1
- 230000003388 anti-hormonal effect Effects 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000002141 anti-parasite Effects 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 238000011319 anticancer therapy Methods 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 239000013059 antihormonal agent Substances 0.000 description 1
- 229940111131 antiinflammatory and antirheumatic product propionic acid derivative Drugs 0.000 description 1
- 229940045687 antimetabolites folic acid analogs Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 229940125687 antiparasitic agent Drugs 0.000 description 1
- 229940124522 antiretrovirals Drugs 0.000 description 1
- 239000003903 antiretrovirus agent Substances 0.000 description 1
- 229940111121 antirheumatic drug quinolines Drugs 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 150000008209 arabinosides Chemical class 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229960003121 arginine Drugs 0.000 description 1
- 150000001483 arginine derivatives Chemical class 0.000 description 1
- GOLCXWYRSKYTSP-UHFFFAOYSA-N arsenic trioxide Inorganic materials O1[As]2O[As]1O2 GOLCXWYRSKYTSP-UHFFFAOYSA-N 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 125000004350 aryl cycloalkyl group Chemical group 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 229960003852 atezolizumab Drugs 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- FQCKMBLVYCEXJB-MNSAWQCASA-L atorvastatin calcium Chemical compound [Ca+2].C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1.C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 FQCKMBLVYCEXJB-MNSAWQCASA-L 0.000 description 1
- 229960001770 atorvastatin calcium Drugs 0.000 description 1
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 description 1
- 229940090047 auto-injector Drugs 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 230000005784 autoimmunity Effects 0.000 description 1
- 229940003504 avonex Drugs 0.000 description 1
- 229950011321 azaserine Drugs 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- 229940065181 bacillus anthracis Drugs 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 229960005430 benoxaprofen Drugs 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 229960004001 benznidazole Drugs 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- 235000019400 benzoyl peroxide Nutrition 0.000 description 1
- 108010014499 beta-2 Adrenergic Receptors Proteins 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 229960003237 betaine Drugs 0.000 description 1
- 229940021459 betaseron Drugs 0.000 description 1
- 229960000997 bicalutamide Drugs 0.000 description 1
- GPRLTFBKWDERLU-UHFFFAOYSA-N bicyclo[2.2.2]octane Chemical compound C1CC2CCC1CC2 GPRLTFBKWDERLU-UHFFFAOYSA-N 0.000 description 1
- 239000003613 bile acid Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000012867 bioactive agent Substances 0.000 description 1
- 238000006065 biodegradation reaction Methods 0.000 description 1
- 230000009875 biological transport Effects 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 239000012455 biphasic mixture Substances 0.000 description 1
- 239000004305 biphenyl Chemical group 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- QKSKPIVNLNLAAV-UHFFFAOYSA-N bis(2-chloroethyl) sulfide Chemical compound ClCCSCCCl QKSKPIVNLNLAAV-UHFFFAOYSA-N 0.000 description 1
- 229950008548 bisantrene Drugs 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 201000006491 bone marrow cancer Diseases 0.000 description 1
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000007975 buffered saline Substances 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- DQXBYHZEEUGOBF-UHFFFAOYSA-N but-3-enoic acid;ethene Chemical compound C=C.OC(=O)CC=C DQXBYHZEEUGOBF-UHFFFAOYSA-N 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 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
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 108700002839 cactinomycin Proteins 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- HXCHCVDVKSCDHU-LULTVBGHSA-N calicheamicin Chemical compound C1[C@H](OC)[C@@H](NCC)CO[C@H]1O[C@H]1[C@H](O[C@@H]2C\3=C(NC(=O)OC)C(=O)C[C@](C/3=C/CSSSC)(O)C#C\C=C/C#C2)O[C@H](C)[C@@H](NO[C@@H]2O[C@H](C)[C@@H](SC(=O)C=3C(=C(OC)C(O[C@H]4[C@@H]([C@H](OC)[C@@H](O)[C@H](C)O4)O)=C(I)C=3C)OC)[C@@H](O)C2)[C@@H]1O HXCHCVDVKSCDHU-LULTVBGHSA-N 0.000 description 1
- 229930195731 calicheamicin Natural products 0.000 description 1
- 230000009702 cancer cell proliferation Effects 0.000 description 1
- 238000002619 cancer immunotherapy Methods 0.000 description 1
- 229940022399 cancer vaccine Drugs 0.000 description 1
- 229940095731 candida albicans Drugs 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 229960002115 carboquone Drugs 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- XREUEWVEMYWFFA-CSKJXFQVSA-N carminomycin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=C(O)C=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XREUEWVEMYWFFA-CSKJXFQVSA-N 0.000 description 1
- 229930188550 carminomycin Natural products 0.000 description 1
- XREUEWVEMYWFFA-UHFFFAOYSA-N carminomycin I Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=C(O)C=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XREUEWVEMYWFFA-UHFFFAOYSA-N 0.000 description 1
- 229960003261 carmofur Drugs 0.000 description 1
- 229960003184 carprofen Drugs 0.000 description 1
- IVUMCTKHWDRRMH-UHFFFAOYSA-N carprofen Chemical compound C1=CC(Cl)=C[C]2C3=CC=C(C(C(O)=O)C)C=C3N=C21 IVUMCTKHWDRRMH-UHFFFAOYSA-N 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 229950001725 carubicin Drugs 0.000 description 1
- 108010047060 carzinophilin Proteins 0.000 description 1
- 238000000423 cell based assay Methods 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000011748 cell maturation Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000010307 cell transformation Effects 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 229960003115 certolizumab pegol Drugs 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- JQXXHWHPUNPDRT-BQVAUQFYSA-N chembl1523493 Chemical compound O([C@](C1=O)(C)O\C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)/C=C\C=C(C)/C(=O)NC=2C(O)=C3C(O)=C4C)C)OC)C4=C1C3=C(O)C=2C=NN1CCN(C)CC1 JQXXHWHPUNPDRT-BQVAUQFYSA-N 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000009104 chemotherapy regimen Methods 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 208000013056 classic Hodgkin lymphoma Diseases 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 238000005354 coacervation Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- 229940097479 colestid Drugs 0.000 description 1
- 238000001246 colloidal dispersion Methods 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 229940014461 combivir Drugs 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000004590 computer program Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 229940035811 conjugated estrogen Drugs 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229940038717 copaxone Drugs 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000007819 coupling partner Substances 0.000 description 1
- 229940066901 crestor Drugs 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000011461 current therapy Methods 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000007872 degassing Methods 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 229960005052 demecolcine Drugs 0.000 description 1
- 239000005547 deoxyribonucleotide Substances 0.000 description 1
- 125000002637 deoxyribonucleotide group Chemical group 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000000779 depleting effect Effects 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical compound ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- RGLYKWWBQGJZGM-ISLYRVAYSA-N diethylstilbestrol Chemical compound C=1C=C(O)C=CC=1C(/CC)=C(\CC)C1=CC=C(O)C=C1 RGLYKWWBQGJZGM-ISLYRVAYSA-N 0.000 description 1
- 229960000452 diethylstilbestrol Drugs 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- HUPFGZXOMWLGNK-UHFFFAOYSA-N diflunisal Chemical compound C1=C(O)C(C(=O)O)=CC(C=2C(=CC(F)=CC=2)F)=C1 HUPFGZXOMWLGNK-UHFFFAOYSA-N 0.000 description 1
- 229960000616 diflunisal Drugs 0.000 description 1
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 1
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical class COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 description 1
- GWZCCUDJHOGOSO-UHFFFAOYSA-N diphenic acid Chemical class OC(=O)C1=CC=CC=C1C1=CC=CC=C1C(O)=O GWZCCUDJHOGOSO-UHFFFAOYSA-N 0.000 description 1
- 229940042397 direct acting antivirals cyclic amines Drugs 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- 238000003182 dose-response assay Methods 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 230000036267 drug metabolism Effects 0.000 description 1
- 208000010118 dystonia Diseases 0.000 description 1
- 229960000284 efalizumab Drugs 0.000 description 1
- 210000003162 effector t lymphocyte Anatomy 0.000 description 1
- 229960002759 eflornithine Drugs 0.000 description 1
- 229940056913 eftilagimod alfa Drugs 0.000 description 1
- 239000012039 electrophile Substances 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000008393 encapsulating agent Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- PEASPLKKXBYDKL-FXEVSJAOSA-N enfuvirtide Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(C)=O)[C@@H](C)O)[C@@H](C)CC)C1=CN=CN1 PEASPLKKXBYDKL-FXEVSJAOSA-N 0.000 description 1
- 229960002062 enfuvirtide Drugs 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000007071 enzymatic hydrolysis Effects 0.000 description 1
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 description 1
- 230000009144 enzymatic modification Effects 0.000 description 1
- 230000009483 enzymatic pathway Effects 0.000 description 1
- 230000008995 epigenetic change Effects 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 150000003883 epothilone derivatives Chemical class 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- ITSGNOIFAJAQHJ-BMFNZSJVSA-N esorubicin 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[C@H](C)O1 ITSGNOIFAJAQHJ-BMFNZSJVSA-N 0.000 description 1
- 229950002017 esorubicin Drugs 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 239000000328 estrogen antagonist Substances 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 229960002568 ethinylestradiol Drugs 0.000 description 1
- 239000005038 ethylene vinyl acetate Substances 0.000 description 1
- WHRIKZCFRVTHJH-UHFFFAOYSA-N ethylhydrazine Chemical compound CCNN WHRIKZCFRVTHJH-UHFFFAOYSA-N 0.000 description 1
- 229960005237 etoglucid Drugs 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- ZPAKPRAICRBAOD-UHFFFAOYSA-N fenbufen Chemical compound C1=CC(C(=O)CCC(=O)O)=CC=C1C1=CC=CC=C1 ZPAKPRAICRBAOD-UHFFFAOYSA-N 0.000 description 1
- 229960001395 fenbufen Drugs 0.000 description 1
- 229950006236 fenclofenac Drugs 0.000 description 1
- IDKAXRLETRCXKS-UHFFFAOYSA-N fenclofenac Chemical compound OC(=O)CC1=CC=CC=C1OC1=CC=C(Cl)C=C1Cl IDKAXRLETRCXKS-UHFFFAOYSA-N 0.000 description 1
- YMTINGFKWWXKFG-UHFFFAOYSA-N fenofibrate Chemical compound C1=CC(OC(C)(C)C(=O)OC(C)C)=CC=C1C(=O)C1=CC=C(Cl)C=C1 YMTINGFKWWXKFG-UHFFFAOYSA-N 0.000 description 1
- 229960001419 fenoprofen Drugs 0.000 description 1
- 229960002679 fentiazac Drugs 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 108700014844 flt3 ligand Proteins 0.000 description 1
- 229960004884 fluconazole Drugs 0.000 description 1
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 1
- XRECTZIEBJDKEO-UHFFFAOYSA-N flucytosine Chemical compound NC1=NC(=O)NC=C1F XRECTZIEBJDKEO-UHFFFAOYSA-N 0.000 description 1
- 229960004413 flucytosine Drugs 0.000 description 1
- 229960000390 fludarabine Drugs 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- 229950007979 flufenisal Drugs 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- YLRFCQOZQXIBAB-RBZZARIASA-N fluoxymesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)C[C@@H]2O YLRFCQOZQXIBAB-RBZZARIASA-N 0.000 description 1
- 229960001751 fluoxymesterone Drugs 0.000 description 1
- 229950001284 fluprofen Drugs 0.000 description 1
- 229960002390 flurbiprofen Drugs 0.000 description 1
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 239000004052 folic acid antagonist Substances 0.000 description 1
- 150000002224 folic acids Chemical class 0.000 description 1
- XCWFZHPEARLXJI-UHFFFAOYSA-N fomivirsen Chemical compound C1C(N2C3=C(C(NC(N)=N3)=O)N=C2)OC(CO)C1OP(O)(=S)OCC1OC(N(C)C(=O)\N=C(\N)C=C)CC1OP(O)(=S)OCC1OC(N2C3=C(C(NC(N)=N3)=O)N=C2)CC1OP(O)(=S)OCC1OC(N2C(NC(=O)C(C)=C2)=O)CC1OP(O)(=S)OCC1OC(N2C(NC(=O)C(C)=C2)=O)CC1OP(O)(=S)OCC1OC(N2C(NC(=O)C(C)=C2)=O)CC1OP(O)(=S)OCC1OC(N2C3=C(C(NC(N)=N3)=O)N=C2)CC1OP(O)(=S)OCC1OC(N2C(N=C(N)C=C2)=O)CC1OP(O)(=S)OCC(C(C1)OP(S)(=O)OCC2C(CC(O2)N2C(N=C(N)C=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(N=C(N)C=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(N=C(N)C=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=S)OCC2C(CC(O2)N2C(N=C(N)C=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C3=C(C(NC(N)=N3)=O)N=C2)O)OC1N1C=C(C)C(=O)NC1=O XCWFZHPEARLXJI-UHFFFAOYSA-N 0.000 description 1
- 229960001447 fomivirsen Drugs 0.000 description 1
- 230000022244 formylation Effects 0.000 description 1
- 238000006170 formylation reaction Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 201000010175 gallbladder cancer Diseases 0.000 description 1
- 229940044658 gallium nitrate Drugs 0.000 description 1
- 229960002963 ganciclovir Drugs 0.000 description 1
- IRSCQMHQWWYFCW-UHFFFAOYSA-N ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 description 1
- 229940083124 ganglion-blocking antiadrenergic secondary and tertiary amines Drugs 0.000 description 1
- 230000000574 ganglionic effect Effects 0.000 description 1
- 235000004611 garlic Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 229960003923 gatifloxacin Drugs 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 229910052732 germanium Inorganic materials 0.000 description 1
- GNPVGFCGXDBREM-UHFFFAOYSA-N germanium atom Chemical compound [Ge] GNPVGFCGXDBREM-UHFFFAOYSA-N 0.000 description 1
- 229940080856 gleevec Drugs 0.000 description 1
- 238000003881 globally optimized alternating phase rectangular pulse Methods 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 229940075529 glyceryl stearate Drugs 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 0.000 description 1
- 229940035638 gonadotropin-releasing hormone Drugs 0.000 description 1
- 229960002913 goserelin Drugs 0.000 description 1
- 229960003690 goserelin acetate Drugs 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 201000010235 heart cancer Diseases 0.000 description 1
- 208000024348 heart neoplasm Diseases 0.000 description 1
- 210000005003 heart tissue Anatomy 0.000 description 1
- 210000002443 helper t lymphocyte Anatomy 0.000 description 1
- 210000000777 hematopoietic system Anatomy 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 235000008216 herbs Nutrition 0.000 description 1
- 229940022353 herceptin Drugs 0.000 description 1
- FBPFZTCFMRRESA-UHFFFAOYSA-N hexane-1,2,3,4,5,6-hexol Chemical compound OCC(O)C(O)C(O)C(O)CO FBPFZTCFMRRESA-UHFFFAOYSA-N 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 229940125697 hormonal agent Drugs 0.000 description 1
- 102000057041 human TNF Human genes 0.000 description 1
- 229940048921 humira Drugs 0.000 description 1
- WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 description 1
- 229940091173 hydantoin Drugs 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- RCCPEORTSYDPMB-UHFFFAOYSA-N hydroxy benzenecarboximidothioate Chemical compound OSC(=N)C1=CC=CC=C1 RCCPEORTSYDPMB-UHFFFAOYSA-N 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 229950000801 hydroxyprogesterone caproate Drugs 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 230000000642 iatrogenic effect Effects 0.000 description 1
- 229940015872 ibandronate Drugs 0.000 description 1
- 229960005236 ibandronic acid Drugs 0.000 description 1
- CYWFCPPBTWOZSF-UHFFFAOYSA-N ibufenac Chemical compound CC(C)CC1=CC=C(CC(O)=O)C=C1 CYWFCPPBTWOZSF-UHFFFAOYSA-N 0.000 description 1
- 229950009183 ibufenac Drugs 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 239000012216 imaging agent Substances 0.000 description 1
- YLMAHDNUQAMNNX-UHFFFAOYSA-N imatinib methanesulfonate Chemical compound CS(O)(=O)=O.C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 YLMAHDNUQAMNNX-UHFFFAOYSA-N 0.000 description 1
- YAMHXTCMCPHKLN-UHFFFAOYSA-N imidazolidin-2-one Chemical compound O=C1NCCN1 YAMHXTCMCPHKLN-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000005934 immune activation Effects 0.000 description 1
- 239000012642 immune effector Substances 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 102000027596 immune receptors Human genes 0.000 description 1
- 108091008915 immune receptors Proteins 0.000 description 1
- 230000006058 immune tolerance Effects 0.000 description 1
- 230000007813 immunodeficiency Effects 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 238000003364 immunohistochemistry Methods 0.000 description 1
- 238000001114 immunoprecipitation Methods 0.000 description 1
- 230000003308 immunostimulating effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 229940125721 immunosuppressive agent Drugs 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- DBIGHPPNXATHOF-UHFFFAOYSA-N improsulfan Chemical compound CS(=O)(=O)OCCCNCCCOS(C)(=O)=O DBIGHPPNXATHOF-UHFFFAOYSA-N 0.000 description 1
- 229950008097 improsulfan Drugs 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 208000035231 inattentive type attention deficit hyperactivity disease Diseases 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 229960004187 indoprofen Drugs 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000003960 inflammatory cascade Effects 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 229940074383 interleukin-11 Drugs 0.000 description 1
- 230000031146 intracellular signal transduction Effects 0.000 description 1
- 208000020658 intracerebral hemorrhage Diseases 0.000 description 1
- 238000000185 intracerebroventricular administration Methods 0.000 description 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
- XMBWDFGMSWQBCA-YPZZEJLDSA-M iodine-125(1-) Chemical compound [125I-] XMBWDFGMSWQBCA-YPZZEJLDSA-M 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 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
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- QFGMXJOBTNZHEL-UHFFFAOYSA-N isoxepac Chemical compound O1CC2=CC=CC=C2C(=O)C2=CC(CC(=O)O)=CC=C21 QFGMXJOBTNZHEL-UHFFFAOYSA-N 0.000 description 1
- 229950011455 isoxepac Drugs 0.000 description 1
- 229960004130 itraconazole Drugs 0.000 description 1
- 229960002418 ivermectin Drugs 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 229960004125 ketoconazole Drugs 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 229940054136 kineret Drugs 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 description 1
- 238000007273 lactonization reaction Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- 229950007278 lenercept Drugs 0.000 description 1
- 229940095570 lescol Drugs 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 229940002661 lipitor Drugs 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 1
- CJPLEFFCVDQQFZ-UHFFFAOYSA-N loviride Chemical compound CC(=O)C1=CC=C(C)C=C1NC(C(N)=O)C1=C(Cl)C=CC=C1Cl CJPLEFFCVDQQFZ-UHFFFAOYSA-N 0.000 description 1
- 229950006243 loviride Drugs 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229950004563 lucatumumab Drugs 0.000 description 1
- 210000004924 lung microvascular endothelial cell Anatomy 0.000 description 1
- 229940087857 lupron Drugs 0.000 description 1
- 229940040129 luteinizing hormone Drugs 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 229940041033 macrolides Drugs 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- FSQQTNAZHBEJLS-UPHRSURJSA-N maleamic acid Chemical compound NC(=O)\C=C/C(O)=O FSQQTNAZHBEJLS-UPHRSURJSA-N 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 231100000682 maximum tolerated dose Toxicity 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229960003439 mebendazole Drugs 0.000 description 1
- BAXLBXFAUKGCDY-UHFFFAOYSA-N mebendazole Chemical compound [CH]1C2=NC(NC(=O)OC)=NC2=CC=C1C(=O)C1=CC=CC=C1 BAXLBXFAUKGCDY-UHFFFAOYSA-N 0.000 description 1
- QZIQJVCYUQZDIR-UHFFFAOYSA-N mechlorethamine hydrochloride Chemical compound Cl.ClCCN(C)CCCl QZIQJVCYUQZDIR-UHFFFAOYSA-N 0.000 description 1
- 229960002868 mechlorethamine hydrochloride Drugs 0.000 description 1
- 229960004616 medroxyprogesterone Drugs 0.000 description 1
- FRQMUZJSZHZSGN-HBNHAYAOSA-N medroxyprogesterone Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](O)(C(C)=O)CC[C@H]21 FRQMUZJSZHZSGN-HBNHAYAOSA-N 0.000 description 1
- 229960001728 melarsoprol Drugs 0.000 description 1
- 108010000525 member 1 small inducible cytokine subfamily E Proteins 0.000 description 1
- 102000006240 membrane receptors Human genes 0.000 description 1
- 108020004084 membrane receptors Proteins 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 229960001810 meprednisone Drugs 0.000 description 1
- PIDANAQULIKBQS-RNUIGHNZSA-N meprednisone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)CC2=O PIDANAQULIKBQS-RNUIGHNZSA-N 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 229960001566 methyltestosterone Drugs 0.000 description 1
- 229940099246 mevacor Drugs 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
- 230000000813 microbial effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 210000004925 microvascular endothelial cell Anatomy 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- OJGQFYYLKNCIJD-UHFFFAOYSA-N miroprofen Chemical compound C1=CC(C(C(O)=O)C)=CC=C1C1=CN(C=CC=C2)C2=N1 OJGQFYYLKNCIJD-UHFFFAOYSA-N 0.000 description 1
- 229950006616 miroprofen Drugs 0.000 description 1
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 238000000302 molecular modelling Methods 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 125000006682 monohaloalkyl group Chemical group 0.000 description 1
- 229960005389 moroxydine Drugs 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 150000002780 morpholines Chemical class 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 235000010460 mustard Nutrition 0.000 description 1
- 238000002703 mutagenesis Methods 0.000 description 1
- 231100000350 mutagenesis Toxicity 0.000 description 1
- 208000027531 mycobacterial infectious disease Diseases 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
- 229960000951 mycophenolic acid Drugs 0.000 description 1
- 210000005012 myelin Anatomy 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- GACQNVJDWUAPFY-UHFFFAOYSA-N n'-[2-[2-(2-aminoethylamino)ethylamino]ethyl]ethane-1,2-diamine;hydrochloride Chemical compound Cl.NCCNCCNCCNCCN GACQNVJDWUAPFY-UHFFFAOYSA-N 0.000 description 1
- UFVHVURXVBHPDA-UHFFFAOYSA-N n-(dichloromethyl)-n-ethylethanamine Chemical compound CCN(CC)C(Cl)Cl UFVHVURXVBHPDA-UHFFFAOYSA-N 0.000 description 1
- NJSMWLQOCQIOPE-OCHFTUDZSA-N n-[(e)-[10-[(e)-(4,5-dihydro-1h-imidazol-2-ylhydrazinylidene)methyl]anthracen-9-yl]methylideneamino]-4,5-dihydro-1h-imidazol-2-amine Chemical compound N1CCN=C1N\N=C\C(C1=CC=CC=C11)=C(C=CC=C2)C2=C1\C=N\NC1=NCCN1 NJSMWLQOCQIOPE-OCHFTUDZSA-N 0.000 description 1
- BLCLNMBMMGCOAS-UHFFFAOYSA-N n-[1-[[1-[[1-[[1-[[1-[[1-[[1-[2-[(carbamoylamino)carbamoyl]pyrrolidin-1-yl]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amin Chemical compound C1CCC(C(=O)NNC(N)=O)N1C(=O)C(CCCN=C(N)N)NC(=O)C(CC(C)C)NC(=O)C(COC(C)(C)C)NC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 BLCLNMBMMGCOAS-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
- XWCCTMBMQUCLSI-UHFFFAOYSA-N n-ethyl-n-propylpropan-1-amine Chemical compound CCCN(CC)CCC XWCCTMBMQUCLSI-UHFFFAOYSA-N 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 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
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- OZGNYLLQHRPOBR-DHZHZOJOSA-N naftifine Chemical compound C=1C=CC2=CC=CC=C2C=1CN(C)C\C=C\C1=CC=CC=C1 OZGNYLLQHRPOBR-DHZHZOJOSA-N 0.000 description 1
- 229960004313 naftifine Drugs 0.000 description 1
- 239000002088 nanocapsule Substances 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-M naproxen(1-) Chemical compound C1=C([C@H](C)C([O-])=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-M 0.000 description 1
- NCXMLFZGDNKEPB-FFPOYIOWSA-N natamycin Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C[C@@H](C)OC(=O)/C=C/[C@H]2O[C@@H]2C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 NCXMLFZGDNKEPB-FFPOYIOWSA-N 0.000 description 1
- 229960003255 natamycin Drugs 0.000 description 1
- 229940086322 navelbine Drugs 0.000 description 1
- 230000017066 negative regulation of growth Effects 0.000 description 1
- 230000031990 negative regulation of inflammatory response Effects 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 230000000626 neurodegenerative effect Effects 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 229960000689 nevirapine Drugs 0.000 description 1
- 229940101771 nexavir Drugs 0.000 description 1
- 229940099635 niacor Drugs 0.000 description 1
- 229960003966 nicotinamide Drugs 0.000 description 1
- 235000005152 nicotinamide Nutrition 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- 229960002644 nifurtimox Drugs 0.000 description 1
- 229960002653 nilutamide Drugs 0.000 description 1
- XWXYUMMDTVBTOU-UHFFFAOYSA-N nilutamide Chemical compound O=C1C(C)(C)NC(=O)N1C1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 XWXYUMMDTVBTOU-UHFFFAOYSA-N 0.000 description 1
- 229960001420 nimustine Drugs 0.000 description 1
- VFEDRRNHLBGPNN-UHFFFAOYSA-N nimustine Chemical compound CC1=NC=C(CNC(=O)N(CCCl)N=O)C(N)=N1 VFEDRRNHLBGPNN-UHFFFAOYSA-N 0.000 description 1
- YMVWGSQGCWCDGW-UHFFFAOYSA-N nitracrine Chemical compound C1=CC([N+]([O-])=O)=C2C(NCCCN(C)C)=C(C=CC=C3)C3=NC2=C1 YMVWGSQGCWCDGW-UHFFFAOYSA-N 0.000 description 1
- 229950008607 nitracrine Drugs 0.000 description 1
- IHRSXGONVFFQQF-SDXDJHTJSA-N nitrazine Chemical compound OS(=O)(=O)C1=CC2=CC(S(O)(=O)=O)=CC=C2C(=O)\C1=N/NC1=CC=C([N+]([O-])=O)C=C1[N+]([O-])=O IHRSXGONVFFQQF-SDXDJHTJSA-N 0.000 description 1
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 1
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 229940042402 non-nucleoside reverse transcriptase inhibitor Drugs 0.000 description 1
- 239000002726 nonnucleoside reverse transcriptase inhibitor Substances 0.000 description 1
- UMRZSTCPUPJPOJ-KNVOCYPGSA-N norbornane Chemical compound C1C[C@H]2CC[C@@H]1C2 UMRZSTCPUPJPOJ-KNVOCYPGSA-N 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 229940023146 nucleic acid vaccine Drugs 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 229960000988 nystatin Drugs 0.000 description 1
- VQOXZBDYSJBXMA-NQTDYLQESA-N nystatin A1 Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/CC/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 VQOXZBDYSJBXMA-NQTDYLQESA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 229930191479 oligomycin Natural products 0.000 description 1
- MNULEGDCPYONBU-AWJDAWNUSA-N oligomycin A Polymers O([C@H]1CC[C@H](/C=C/C=C/C[C@@H](C)[C@H](O)[C@@](C)(O)C(=O)[C@@H](C)[C@H](O)[C@@H](C)C(=O)[C@@H](C)[C@H](O)[C@@H](C)/C=C/C(=O)O[C@@H]([C@@H]2C)[C@@H]1C)CC)[C@@]12CC[C@H](C)[C@H](C[C@@H](C)O)O1 MNULEGDCPYONBU-AWJDAWNUSA-N 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 229940035567 orencia Drugs 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 210000003300 oropharynx Anatomy 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- CXLGNJCMPWUZKM-UHFFFAOYSA-N oxane-4-carbaldehyde Chemical compound O=CC1CCOCC1 CXLGNJCMPWUZKM-UHFFFAOYSA-N 0.000 description 1
- 229960002739 oxaprozin Drugs 0.000 description 1
- OFPXSFXSNFPTHF-UHFFFAOYSA-N oxaprozin Chemical compound O1C(CCC(=O)O)=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 OFPXSFXSNFPTHF-UHFFFAOYSA-N 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 238000006487 oxidative cycloaddition reaction Methods 0.000 description 1
- DXGLGDHPHMLXJC-UHFFFAOYSA-N oxybenzone Chemical compound OC1=CC(OC)=CC=C1C(=O)C1=CC=CC=C1 DXGLGDHPHMLXJC-UHFFFAOYSA-N 0.000 description 1
- 229960001173 oxybenzone Drugs 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000003071 parasitic effect Effects 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000004963 pathophysiological condition Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 230000006320 pegylation Effects 0.000 description 1
- WBXPDJSOTKVWSJ-ZDUSSCGKSA-N pemetrexed Chemical compound C=1NC=2NC(N)=NC(=O)C=2C=1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 WBXPDJSOTKVWSJ-ZDUSSCGKSA-N 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- XDRYMKDFEDOLFX-UHFFFAOYSA-N pentamidine Chemical compound C1=CC(C(=N)N)=CC=C1OCCCCCOC1=CC=C(C(N)=N)C=C1 XDRYMKDFEDOLFX-UHFFFAOYSA-N 0.000 description 1
- 229960004448 pentamidine Drugs 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- XRQDFNLINLXZLB-CKIKVBCHSA-N peramivir Chemical compound CCC(CC)[C@H](NC(C)=O)[C@@H]1[C@H](O)[C@@H](C(O)=O)C[C@H]1NC(N)=N XRQDFNLINLXZLB-CKIKVBCHSA-N 0.000 description 1
- 229960001084 peramivir Drugs 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 229960002895 phenylbutazone Drugs 0.000 description 1
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical class OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- 230000008560 physiological behavior Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 229950010773 pidilizumab Drugs 0.000 description 1
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 1
- 229960000952 pipobroman Drugs 0.000 description 1
- NJBFOOCLYDNZJN-UHFFFAOYSA-N pipobroman Chemical compound BrCCC(=O)N1CCN(C(=O)CCBr)CC1 NJBFOOCLYDNZJN-UHFFFAOYSA-N 0.000 description 1
- NUKCGLDCWQXYOQ-UHFFFAOYSA-N piposulfan Chemical compound CS(=O)(=O)OCCC(=O)N1CCN(C(=O)CCOS(C)(=O)=O)CC1 NUKCGLDCWQXYOQ-UHFFFAOYSA-N 0.000 description 1
- 229950001100 piposulfan Drugs 0.000 description 1
- 229960001221 pirarubicin Drugs 0.000 description 1
- PIDSZXPFGCURGN-UHFFFAOYSA-N pirprofen Chemical compound ClC1=CC(C(C(O)=O)C)=CC=C1N1CC=CC1 PIDSZXPFGCURGN-UHFFFAOYSA-N 0.000 description 1
- 229960000851 pirprofen Drugs 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- 229960000471 pleconaril Drugs 0.000 description 1
- KQOXLKOJHVFTRN-UHFFFAOYSA-N pleconaril Chemical compound O1N=C(C)C=C1CCCOC1=C(C)C=C(C=2N=C(ON=2)C(F)(F)F)C=C1C KQOXLKOJHVFTRN-UHFFFAOYSA-N 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 150000004291 polyenes Chemical class 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 239000008389 polyethoxylated castor oil Substances 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 239000004633 polyglycolic acid Substances 0.000 description 1
- 125000006684 polyhaloalkyl group Polymers 0.000 description 1
- 229940041153 polymyxins Drugs 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229960003101 pranoprofen Drugs 0.000 description 1
- 229960002957 praziquantel Drugs 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 229960004694 prednimustine Drugs 0.000 description 1
- 229940096203 prevalite Drugs 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 239000013615 primer Substances 0.000 description 1
- 239000002987 primer (paints) Substances 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 208000037821 progressive disease Diseases 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- KCXFHTAICRTXLI-UHFFFAOYSA-N propane-1-sulfonic acid Chemical compound CCCS(O)(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-N 0.000 description 1
- 150000005599 propionic acid derivatives Chemical class 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 229950008679 protamine sulfate Drugs 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 238000001742 protein purification Methods 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 239000000649 purine antagonist Substances 0.000 description 1
- 239000002212 purine nucleoside Substances 0.000 description 1
- 239000000296 purinergic P1 receptor antagonist Substances 0.000 description 1
- 230000001696 purinergic effect Effects 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 229950010131 puromycin Drugs 0.000 description 1
- 229960005134 pyrantel Drugs 0.000 description 1
- YSAUAVHXTIETRK-AATRIKPKSA-N pyrantel Chemical compound CN1CCCN=C1\C=C\C1=CC=CS1 YSAUAVHXTIETRK-AATRIKPKSA-N 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- JEXVQSWXXUJEMA-UHFFFAOYSA-N pyrazol-3-one Chemical class O=C1C=CN=N1 JEXVQSWXXUJEMA-UHFFFAOYSA-N 0.000 description 1
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 239000003790 pyrimidine antagonist Substances 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 229910052611 pyroxene Inorganic materials 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 229940073095 questran Drugs 0.000 description 1
- ADYNJDNYIVZXNK-UHFFFAOYSA-N quinazoline;dihydrochloride Chemical compound Cl.Cl.N1=CN=CC2=CC=CC=C21 ADYNJDNYIVZXNK-UHFFFAOYSA-N 0.000 description 1
- 150000003246 quinazolines Chemical class 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 229960001404 quinidine Drugs 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 231100000336 radiotoxic Toxicity 0.000 description 1
- 230000001690 radiotoxic effect Effects 0.000 description 1
- 229960004742 raltegravir Drugs 0.000 description 1
- CZFFBEXEKNGXKS-UHFFFAOYSA-N raltegravir Chemical compound O1C(C)=NN=C1C(=O)NC(C)(C)C1=NC(C(=O)NCC=2C=CC(F)=CC=2)=C(O)C(=O)N1C CZFFBEXEKNGXKS-UHFFFAOYSA-N 0.000 description 1
- 238000002708 random mutagenesis Methods 0.000 description 1
- 229960002185 ranimustine Drugs 0.000 description 1
- 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 1
- BMKDZUISNHGIBY-UHFFFAOYSA-N razoxane Chemical compound C1C(=O)NC(=O)CN1C(C)CN1CC(=O)NC(=O)C1 BMKDZUISNHGIBY-UHFFFAOYSA-N 0.000 description 1
- 229960000460 razoxane Drugs 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000005057 refrigeration Methods 0.000 description 1
- 208000015347 renal cell adenocarcinoma Diseases 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000008261 resistance mechanism Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- 239000002336 ribonucleotide Substances 0.000 description 1
- 125000002652 ribonucleotide group Chemical group 0.000 description 1
- 108091092562 ribozyme Proteins 0.000 description 1
- 229960001225 rifampicin Drugs 0.000 description 1
- BTVYFIMKUHNOBZ-QXMMDKDBSA-N rifamycin s Chemical class O=C1C(C(O)=C2C)=C3C(=O)C=C1NC(=O)\C(C)=C/C=C\C(C)C(O)C(C)C(O)C(C)C(OC(C)=O)C(C)C(OC)\C=C/OC1(C)OC2=C3C1=O BTVYFIMKUHNOBZ-QXMMDKDBSA-N 0.000 description 1
- 229940081192 rifamycins Drugs 0.000 description 1
- 229960000888 rimantadine Drugs 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- LALFOYNTGMUKGG-BGRFNVSISA-L rosuvastatin calcium Chemical compound [Ca+2].CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O.CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O LALFOYNTGMUKGG-BGRFNVSISA-L 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 230000037390 scarring Effects 0.000 description 1
- 238000013391 scatchard analysis Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000002864 sequence alignment Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 230000003007 single stranded DNA break Effects 0.000 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- 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 1
- 229960005456 sisomicin Drugs 0.000 description 1
- URWAJWIAIPFPJE-YFMIWBNJSA-N sisomycin Chemical compound O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H](CC=C(CN)O2)N)[C@@H](N)C[C@H]1N URWAJWIAIPFPJE-YFMIWBNJSA-N 0.000 description 1
- 238000002741 site-directed mutagenesis Methods 0.000 description 1
- 229950001403 sizofiran Drugs 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 230000007958 sleep Effects 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229910001467 sodium calcium phosphate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- KQFAFFYKLIBKDE-UHFFFAOYSA-M sodium;ethanesulfonate Chemical compound [Na+].CCS([O-])(=O)=O KQFAFFYKLIBKDE-UHFFFAOYSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 229950006315 spirogermanium Drugs 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229960000894 sulindac Drugs 0.000 description 1
- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 229960004492 suprofen Drugs 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 210000001258 synovial membrane Anatomy 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
- 230000009885 systemic effect Effects 0.000 description 1
- 230000006794 tachycardia Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- NHKZSTHOYNWEEZ-AFCXAGJDSA-N taribavirin Chemical compound N1=C(C(=N)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NHKZSTHOYNWEEZ-AFCXAGJDSA-N 0.000 description 1
- 229950006081 taribavirin Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229940066453 tecentriq Drugs 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- DOMXUEMWDBAQBQ-WEVVVXLNSA-N terbinafine Chemical compound C1=CC=C2C(CN(C\C=C\C#CC(C)(C)C)C)=CC=CC2=C1 DOMXUEMWDBAQBQ-WEVVVXLNSA-N 0.000 description 1
- 229960002722 terbinafine Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 229960001712 testosterone propionate Drugs 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 229940040944 tetracyclines Drugs 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
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 239000004308 thiabendazole Substances 0.000 description 1
- 235000010296 thiabendazole Nutrition 0.000 description 1
- WJCNZQLZVWNLKY-UHFFFAOYSA-N thiabendazole Chemical compound S1C=NC(C=2NC3=CC=CC=C3N=2)=C1 WJCNZQLZVWNLKY-UHFFFAOYSA-N 0.000 description 1
- 229960004546 thiabendazole Drugs 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000004588 thienopyridyl group Chemical group S1C(=CC2=C1C=CC=N2)* 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- IBBLKSWSCDAPIF-UHFFFAOYSA-N thiopyran Chemical compound S1C=CC=C=C1 IBBLKSWSCDAPIF-UHFFFAOYSA-N 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 229960000187 tissue plasminogen activator Drugs 0.000 description 1
- 229960001017 tolmetin Drugs 0.000 description 1
- UPSPUYADGBWSHF-UHFFFAOYSA-N tolmetin Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC=C(CC(O)=O)N1C UPSPUYADGBWSHF-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 1
- 229960005026 toremifene Drugs 0.000 description 1
- 231100000440 toxicity profile Toxicity 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 102000027257 transmembrane receptors Human genes 0.000 description 1
- 108091008578 transmembrane receptors Proteins 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000009529 traumatic brain injury Effects 0.000 description 1
- IUCJMVBFZDHPDX-UHFFFAOYSA-N tretamine Chemical compound C1CN1C1=NC(N2CC2)=NC(N2CC2)=N1 IUCJMVBFZDHPDX-UHFFFAOYSA-N 0.000 description 1
- 229950001353 tretamine Drugs 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- PXSOHRWMIRDKMP-UHFFFAOYSA-N triaziquone Chemical compound O=C1C(N2CC2)=C(N2CC2)C(=O)C=C1N1CC1 PXSOHRWMIRDKMP-UHFFFAOYSA-N 0.000 description 1
- 229960004560 triaziquone Drugs 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 229940055755 tricor Drugs 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- KVJXBPDAXMEYOA-CXANFOAXSA-N trilostane Chemical compound OC1=C(C#N)C[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@@]32O[C@@H]31 KVJXBPDAXMEYOA-CXANFOAXSA-N 0.000 description 1
- 229960001670 trilostane Drugs 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 229940111527 trizivir Drugs 0.000 description 1
- 229960000875 trofosfamide Drugs 0.000 description 1
- UMKFEPPTGMDVMI-UHFFFAOYSA-N trofosfamide Chemical compound ClCCN(CCCl)P1(=O)OCCCN1CCCl UMKFEPPTGMDVMI-UHFFFAOYSA-N 0.000 description 1
- 229960000832 tromantadine Drugs 0.000 description 1
- UXQDWARBDDDTKG-UHFFFAOYSA-N tromantadine Chemical compound C1C(C2)CC3CC2CC1(NC(=O)COCCN(C)C)C3 UXQDWARBDDDTKG-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 229940008349 truvada Drugs 0.000 description 1
- 229960001005 tuberculin Drugs 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 229940046728 tumor necrosis factor alpha inhibitor Drugs 0.000 description 1
- 239000002452 tumor necrosis factor alpha inhibitor Substances 0.000 description 1
- 230000005751 tumor progression Effects 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 230000005951 type IV hypersensitivity Effects 0.000 description 1
- 208000027930 type IV hypersensitivity disease Diseases 0.000 description 1
- 229950009811 ubenimex Drugs 0.000 description 1
- 230000024275 uncoating of virus Effects 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 229960005356 urokinase Drugs 0.000 description 1
- 208000023747 urothelial carcinoma Diseases 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 229940124856 vaccine component Drugs 0.000 description 1
- 229960002149 valganciclovir Drugs 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- CILBMBUYJCWATM-PYGJLNRPSA-N vinorelbine ditartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC CILBMBUYJCWATM-PYGJLNRPSA-N 0.000 description 1
- 230000017613 viral reproduction Effects 0.000 description 1
- 229960004854 viral vaccine Drugs 0.000 description 1
- PNAMDJVUJCJOIX-XVZWKFLSSA-N vytorin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1.N1([C@@H]([C@H](C1=O)CC[C@@H](O)C=1C=CC(F)=CC=1)C=1C=CC(O)=CC=1)C1=CC=C(F)C=C1 PNAMDJVUJCJOIX-XVZWKFLSSA-N 0.000 description 1
- 229940009349 vytorin Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 229940111503 welchol Drugs 0.000 description 1
- UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 0.000 description 1
- 229960000523 zalcitabine Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229940072168 zocor Drugs 0.000 description 1
- 229960003414 zomepirac Drugs 0.000 description 1
- ZXVNMYWKKDOREA-UHFFFAOYSA-N zomepirac Chemical compound C1=C(CC(O)=O)N(C)C(C(=O)C=2C=CC(Cl)=CC=2)=C1C ZXVNMYWKKDOREA-UHFFFAOYSA-N 0.000 description 1
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 1
- 229960000641 zorubicin Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D405/14—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 three or more hetero rings
-
- 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
- A61K31/28—Compounds containing heavy metals
- A61K31/282—Platinum compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/243—Platinum; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Inorganic Chemistry (AREA)
- Molecular Biology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本文描述了抑制A2A和A2B腺苷受体中的至少一种的化合物,以及包含该化合物的组合物和该化合物的合成方法。还描述了此类化合物和组合物用于治疗多种疾病,病症和病状的用途,包括至少部分由腺苷A2A受体和/或腺苷A2B受体介导的癌症和免疫相关病症。
Description
相关申请的交叉引用
本申请要求享有2018年7月27日提交的美国临时申请号62/711,273的优先权权益,其公开内容全部通过引用并入本文。
联邦资助研发下作出发明的权属声明
不适用
引用“序列表”、表格或以光盘形式提交的计算机程序列表附件
不适用
发明背景
腺苷是嘌呤核苷化合物,包含腺嘌呤和核糖分子(核呋喃糖)的复合物。腺苷天然存在于哺乳动物中,并在多种生化过程中起重要作用,包括能量转移(如三磷酸腺苷和单磷酸腺苷)和信号传导(如环状单磷酸腺苷)。腺苷还用于与血管舒张有关的过程,包括心脏血管舒张,并且充当神经调节剂(例如,据认为与促进睡眠有关)。腺苷除了参与这些生化过程外,还用作治疗性抗心律不齐药,以治疗例如室上性心动过速。如本文进一步讨论的,肿瘤通过抑制免疫功能和促进耐受而逃避宿主反应,并且腺苷已经显示出在介导免疫系统的肿瘤逃避中起重要作用。通过A2ARs和A2BRs的腺苷信号在多种免疫细胞亚群和内皮细胞上表达,已被确定在炎症反应过程中对保护组织具有重要作用。因此,在某些条件下,腺苷可保护肿瘤免受免疫破坏(参见,例如费曼(Fishman),P等人,(2009)汉博专家医药(Handb ExpPharmacol)193:399-441)。
腺苷受体是一类以腺苷为内源性配体的嘌呤能G蛋白偶联受体。人类的四种腺苷受体称为A1,A2A,A2B和A3。已经提出了调节A1以用于例如神经系统疾病,哮喘以及心和肾衰竭的管理和治疗;已经提出了A2A拮抗剂来管理和治疗例如帕金森氏病;已经提出调节A2B用于管理和治疗例如包括哮喘的慢性肺部疾病;已经提出了通过调节A3来管理和治疗例如哮喘和慢性阻塞性肺疾病,青光眼,癌症和中风。
历史上,腺苷受体的调节剂是非选择性的。这在某些适应症中是可以接受的,例如对心脏组织中所有四个腺苷受体起作用的内源性激动剂腺苷经胃肠外给药治疗严重的心动过速。然而,亚型选择性腺苷受体激动剂和拮抗剂的使用提供了实现期望结果的可能性,同时最小化或消除了不利影响。
因此,本领域需要亚型选择性腺苷受体激动剂。本发明满足了这种需求并且还提供了相关的优点。
发明内容
本发明涉及调节腺苷A2A受体(A2AR)和/或腺苷A2B受体(A2BR)的化合物,以及包含该化合物的组合物(例如药物组合物)。下面详细描述这些化合物,包括其合成方法和组合物。
本发明还涉及此类化合物和组合物在治疗和/或预防由腺苷A2A受体(A2AR)和/或腺苷A2B受体(A2BR)全部或部分介导的多种疾病,病症和病状中的用途。这样的疾病,病症和病状在本文其他地方详细描述。除非另有说明,否则当在本文中描述本发明化合物的用途时,应理解此类化合物可以是组合物(例如,药物组合物)的形式。
如下所述,尽管本发明的化合物被认为通过抑制腺苷A2A受体(A2AR)和腺苷A2B受体(A2BR)来影响其活性,但是不需要精确了解化合物用于实施本发明的潜在反应机制。设想这些化合物可以通过直接或间接抑制腺苷酸环化酶来影响其活性。还设想该化合物可以通过抑制A2A受体(A2AR)和/或腺苷A2B受体(A2BR)二者以及腺苷酸环化酶来影响其活性。尽管本发明的化合物在本文中通常指的是腺苷A2A受体(A2AR)和/或腺苷A2B受体(A2BR)抑制剂,但应理解,术语“A2AR/A2BR抑制剂”涵盖通过抑制A2AR、A2BR或腺苷酸环化酶而单独发挥作用的化合物,和/或通过抑制A2AR、A2BR和腺苷酸环化酶起作用的化合物。
发现A2A和A2B细胞表面腺苷受体在各种肿瘤细胞中均被上调。因此,A2A和/或A2B腺苷受体的拮抗剂代表了一类新的有希望的肿瘤治疗剂。
A2A腺苷受体的激活,通过抑制T调节细胞功能和抑制自然杀伤细胞的细胞毒性以及肿瘤特异性CD4+/CD8+活性来抑制对肿瘤的免疫反应。因此,通过特异性拮抗剂抑制该受体亚型可增强癌症治疗中的免疫治疗。通过上调微血管内皮细胞中血管生成因子的表达水平,A2B腺苷受体的激活在肿瘤的发展中起作用。[参见,例如,P.Fishman等人,Handb ExpPharmacol(2009);193:399-441]。此外,已证明腺苷受体2A阻断可通过增强的抗肿瘤T细胞反应提高抗PD-1的疗效(P.Beavis等人,Cancer Immunol Res DOI:10.1158/2326-6066.CIR-14-0211 2015年2月11日公布)。下文将对多种A2AR和A2BR的作用进行更全面的讨论。
腺苷2A受体(A2AR)
A2AR(也称为ADORA2A)是一种G蛋白偶联受体(GPCR),其家族成员具有七个跨膜α螺旋。基于其晶体学结构,A2AR包含一个与其他结构确定的GPCR(例如,β-2肾上腺素能受体)不同的配体结合口袋。
如本文其他地方所述,腺苷参与介导免疫系统的肿瘤逃避。A2AR在介导腺苷诱导的抗炎反应中起着至关重要的非冗余作用。A2AR负调节免疫反应,因此已证明A2AR活化的药理抑制作用是增强免疫疗法的可行手段。
如上所述,A2AR的激活会影响适应性免疫反应,举例来说,A2AR不仅通过急性抑制T细胞功能,而且还通过促进调节性T细胞的发育,来保护宿主免受过度的组织破坏。由于A2AR激活是适应性免疫反应的有效抑制剂,因此,肿瘤来源的腺苷可能与阻断抗肿瘤免疫有关。
除了其他作用外,A2AR还与选择性增强抗炎细胞因子,促进PD-1和CTLA-4的上调,促进LAG-3和Foxp3+调节性T细胞的产生以及介导调节性T细胞的抑制有关。PD-1,CTLA-4和其他免疫检查点会在本文中进一步讨论。由于已将所有这些免疫抑制特性鉴定为肿瘤逃避宿主反应的机制,因此,包含A2AR拮抗剂的癌症免疫治疗方案可能会导致增强的肿瘤免疫治疗。一般参见Naganuma,M.等人,(2006)J Immunol 177:2765-769]
A2AR拮抗剂可能在化学疗法和放射疗法中起重要作用。从机理上讲,已提出在化学疗法或放射疗法期间伴随施用A2AR拮抗剂可导致肿瘤特异性T细胞扩增,同时防止诱导肿瘤特异性调节T细胞。此外,考虑到它们的不同作用机理,将A2AR拮抗剂与肿瘤疫苗联合使用被认为至少可提供累加作用。最后,A2AR拮抗剂可以最有效地与肿瘤疫苗和其他检查点阻断剂联合使用。举例来说,阻断PD-1参与以及抑制A2AR可能减轻肿瘤关闭肿瘤特异性效应T细胞的能力(参见,例如,Fishman,P等,(2009)Handb Exp Pharmacol 193:399-441)。此外,已经发现通过A2AR受体的腺苷信号传导被认为是有前景的负反馈回路,并且临床前研究证实,阻断A2AR激活可以显着增强抗肿瘤免疫力(Sitkovsky,MV等,(2014)Cancer Immun.Res 2:598-605)。
腺苷2B受体(A2BR)
A2bR(也称为ADORA2B)是在许多不同细胞类型中发现的GPCR。与其他腺苷受体亚型(例如A1R,A2AR和A3R)相比,它需要更高浓度的腺苷进行激活(Fredholm BB等人,(2001)Biochem Pharmacol 61:443-448)。例如,在通常观察到缺氧的肿瘤中已经看到了这种状况。与其他腺苷受体亚型相反,A2BR可能在与大量腺苷释放相关的病理生理状况中发挥重要作用。因此,对该腺苷受体亚型的选择性阻断或刺激可能不会干扰通过其他腺苷受体亚型介导的腺苷的许多重要生理功能。但是,导致A2BR介导的抑制的途径尚不完全清楚。
血管生成代表肿瘤生长的关键机制。血管生成过程受到一系列血管生成因子的高度调节,并在与缺氧有关的特定情况下由腺苷触发。A2BR在人微血管内皮细胞中表达,在调节血管生成因子(如血管内皮生长因子(VEGF))的表达中起着重要作用。在某些肿瘤类型中,已观察到缺氧导致多种A2BR的上调,这表明多种A2BR在介导腺苷对血管生成的影响中起关键作用。因此,对多种A2BR的阻断可通过限制肿瘤细胞的氧气供应来限制肿瘤的生长。此外,涉及腺苷酸环化酶激活的实验表明,多种A2BR是某些肿瘤细胞中唯一的腺苷受体亚型,这表明A2BR拮抗剂可能对特定的肿瘤类型具有作用(参见例如Feoktistov,I等人,(2003)Circ Res 92:485-492)。
最近的数据使人们对A2BR调节剂的精确作用的理解更加复杂。如上所述,数据证实多种A2BR在介导腺苷对肿瘤生长和进展的影响中起重要作用。事实上,抑制血管生成和抑制ERK 1/2磷酸化代表了一种基于A2BR作为靶标的潜在抗癌治疗的最有趣的效果。然而,尽管抑制血管生成需要使用A2BR拮抗剂,但通过其他临床相关途径(例如MAP激酶途径)抑制生长信号传导,可以通过使用A2BR激动剂治疗来达到(参见例如Graham,S.等人,(2001)Eur JPharmaol 420:19-26)。附加实验的结果可能表明,如果在疾病及其治疗的不同阶段使用,则激动剂和拮抗剂与其他治疗措施相结合,将为治疗提供有用的选择。
在一个特定方面,本文提供具有式(I)的化合物,或其药学上可接受的盐,水合物或溶剂化物,
其中,
G1为N或CR3a;
G2为N或CR3b;
R3a和R3b各自独立地为H或C1-3烷基;
R1a和R1b各自独立地选自下组:
i)H
ii)C1-8烷基,任选被1-3个R5取代基取代,
iii)-X1-O-C1-8烷基,任选地被1-3个R5取代基取代,
iv)-C(O)-R6,
v)Y,任选地被1-3个R7取代基取代,并且
vi)-X1-Y,任选被1-3个R7取代基取代;或
vii)R1a和R1b与它们所连接的氮一起形成5-6元杂环烷基环,该环任选被1-3个R8取代基取代,其中杂环烷基具有0-2个额外的选自下组的杂原子环顶点:O,N和S;
每个Y是C3-8环烷基或具有1-3个选自O,N和S的杂原子环顶点的4至6元杂环烷基;
R2和R4各自独立地为H或C1-3烷基;
每个X1是C1-6亚烷基;
每个R5独立地选自下组:羟基,C3-8环烷基,苯基,-O-苯基,-C(O)ORa和氧代;
每个R6为C1-8烷基或Y,其各自任选地被1-3个选自下组的取代基取代:羟基,-O-苯基,苯基和-O-C1-8烷基;
每个R7独立地选自下组:C1-8烷基,羟基,-O-C1-8烷基,氧代和C(O)ORa;
每个R8独立地选自下组:C1-8烷基,羟基和氧代;
下标n为0、1、2或3;
每个R9独立选自下组:C1-8烷基,-O-C1-8烷基,-X1-O-C1-8烷基,-O-X1-O-C1-8烷基,-X1-O-X1-O-C1-8烷基,-C(O)ORa,卤素,氰基,-NRbRc,Y,-X1-C3-8环烷基,和-X2-Z,其中X2选自下组:C1-6亚烷基,-C1-6亚烷基-O-,-C1-4亚烷基-O-C1-4亚烷基,-C(O)-和-S(O)2-,Z为具有1-3个杂原子环顶点的4至6元杂环烷基,所述杂原子选自下组:O,N和S,其中每个所述R9取代基任选地被1-3个R11取代;
R10a,R10b,R10c和R10d各自独立地选自下组:H,C1-8烷基,卤素,氰基,-O-C1-8烷基,-X1-O-C1-8烷基,-O-X1-O-C1-8烷基,-S(O)2-C1-6烷基,-C(O)NRdRe和具有1-3个选自O,N和S的杂原子环顶点的4-6元杂芳基,其中每个所述R10a-d取代基任选地被1-3个R12取代,或相邻环顶点上的R10a,R10b,R10c和R10d中的两个任选地结合以形成任选地被1-2个卤素取代的5元杂环;
每个R11独立地选自下组:羟基,氧代,卤素,氰基,-NRdRe,-C(O)ORa,苯基,C3-8环烷基和任选被C(O)ORa取代的C1-4烷基;
每个R12独立地选自下组:卤素,氰基,羟基,-C(O)ORa;和
每个Ra是H或C1-6烷基;
每个Rb和Rc独立地选自下组:H,C1-8烷基,-S(O)2-C1-6烷基,-C(O)ORa和-X1-C(O)ORa;和
每个Rd和Re独立地选自下组:H,C1-8烷基,-S(O)2-C1-6烷基。
在一些实施方案中,本文提供了用于治疗或预防受试者(例如人)的癌症的方法,其包括向受试者施用治疗有效量的至少一种本文所述的A2AR/A2BR抑制剂。在一些实施方案中,本文提供了通过以有效逆转或终止A2AR介导的免疫抑制发展作用的量向受试者施用至少一种本文所述的化合物来治疗或预防受试者的癌症的方法。在一些实施方案中,A2AR介导的免疫抑制是由抗原呈递细胞(APC)介导的。
可以使用本文所述的化合物和组合物治疗的癌症的例子包括但不限于:前列腺癌,结肠直肠癌,胰腺癌,子宫颈癌,胃癌,子宫内膜癌,脑癌,肝癌,膀胱癌,卵巢癌,睾丸癌,头癌,颈癌,皮肤癌(包括黑色素瘤和基底细胞癌),间皮内膜癌,白细胞癌(包括淋巴瘤和白血病)食道癌,乳腺癌,肌肉癌,结缔组织癌,肺癌(包括小细胞肺癌和非小细胞肺癌),肾上腺癌,甲状腺癌,肾脏癌,或骨骼癌;胶质母细胞瘤,间皮瘤,肾细胞癌,胃癌,肉瘤,绒毛膜癌,皮肤基底细胞癌,和睾丸精原细胞瘤。在本发明的一些实施方案中,癌症是黑色素瘤,结肠癌,胰腺癌,乳腺癌,前列腺癌,肺癌,白血病,脑瘤,淋巴瘤,肉瘤,卵巢癌,头颈癌,宫颈癌或卡波西氏肉瘤。下文将进一步讨论候选用本发明化合物和组合物治疗的癌症。
本文还提供了通过施用治疗有效量的A2AR/A2BR抑制剂来治疗接受骨髓移植或外周血干细胞移植的对象的方法,该剂量应足以增加对肿瘤抗原的迟发型超敏反应,延迟移植后恶性肿瘤的复发的时间,增加移植后无复发的生存时间,和/或增加移植后的长期生存率。
在某些实施方案中,本文提供了用于治疗或预防受试者(例如人)的感染性疾病(例如病毒感染)的方法,包括向受试者施用治疗有效量的至少一种A2AR/A2BR抑制剂(例如,本发明的新型抑制剂)。在一些实施方案中,感染性疾病是病毒感染(例如慢性病毒感染),细菌感染,真菌感染或寄生虫感染。在某些实施方案中,病毒感染是人免疫缺陷病毒或巨细胞病毒。
在其他实施方案中,本文提供了用于治疗或预防受试者(例如人)的免疫相关疾病,病症或病状的方法,包括向受试者施用治疗有效量的至少一种这里描述的A2AR/A2BR抑制剂。免疫相关疾病,病症和状况的实例在下文中描述。
可以通过调节A2AR/A2BR活性来全部或部分治疗或预防的其他疾病,病症和病状,是本文提供的A2AR/A2BR抑制剂化合物的候选适应症。
本文还提供了所描述的A2AR/A2BR抑制剂与一种或多种其他试剂组合的用途。所述一种或多种其他试剂可以具有一些腺苷A2A受体和/或腺苷A2B受体调节活性;或者,它们可以通过不同的作用机制起作用。在一些实施方案中,此类试剂包括放射(例如,局部放射疗法或全身放射疗法)和/或其他非药理学性质的治疗方式。当使用联合疗法时,本文所述的化合物和一种或多种其他试剂可以呈单一组合物或多种组合物的形式,并且治疗方式可以同时、顺序或通过一些其他方案来施用。举例来说,本发明涵盖了一种治疗方案,其中放射阶段之后,接着的是化学治疗阶段。联合疗法可具有累加或协同作用。下文描述了联合疗法的其他益处。
在特定的实施方案中,本文提供了其中本文所述的A2AR/A2BR抑制剂与免疫检查点抑制剂组合使用的方法。
导致抗原特异性T细胞应答的扩增的免疫检查点的阻断,已被证明是人类癌症治疗方法中的一种有前途的方法。其中一些在各种类型的肿瘤细胞中选择性上调的,可以是被阻断的候选物的免疫检查点(配体和受体)的例子包括PD1(程序性细胞死亡蛋白1)、PDL1(PD1配体)、BTLA(B和T淋巴细胞衰减剂)、CTLA4(细胞毒性T淋巴细胞相关抗原4)、TIM3(T细胞膜蛋白3)、LAG3(淋巴细胞激活基因3)、TIGIT(具有Ig和ITIM结构域的T细胞免疫受体)和杀伤抑制受体。免疫检查点抑制剂及其联合治疗在本文其他地方详细讨论。
在其他实施方案中,本文提供了用于治疗受试者癌症的方法,包括向受试者施用治疗有效量的至少一种A2AR/A2BR抑制剂和至少一种化学治疗剂,此类试剂包括但不限于烷基化剂(例如氮芥,例如苯丁酸氮芥,环磷酰胺,异环磷酰胺(isofamide),二氯甲基二乙胺,美法仑,和尿嘧啶氮芥;氮丙啶,例如塞替派(thiotepa);甲磺酸酯,例如白消安;核苷类似物(例如,吉西他滨);亚硝基脲,例如卡莫斯汀(carmustine),洛莫西汀(lomustine),和链脲霉素;拓扑异构酶1抑制剂(例如,伊立替康(irinotecan));铂络合物,例如顺铂,奥沙铂和卡铂;生物还原性烷基化剂,例如丝裂霉素,甲基苄肼(procarbazin),达卡巴嗪(dacarbazine)和六甲蜜胺(altretamine);基于蒽环类的疗法(例如,阿霉素,柔红霉素,表柔比星和伊达比星);DNA链断裂剂(例如博来霉素);拓扑异构酶II抑制剂(例如,安吖啶,放线菌素,柔红霉素,伊达比星,米托蒽醌,阿霉素,依托泊苷和替尼泊苷);DNA小沟结合剂(例如普卡霉素(plicamydin));抗代谢物(例如叶酸拮抗剂,如甲氨蝶呤、三甲曲沙和培美曲塞;嘧啶拮抗剂,如氟尿嘧啶,氟脱氧尿苷,CB3717,阿扎胞苷,阿糖胞苷和氟尿苷;嘌呤拮抗剂,如巯基嘌呤,6-硫鸟嘌呤,氟达拉滨和喷司他丁(pentostatin);天冬酰胺酶;和核糖核苷酸还原酶抑制剂,例如羟基脲);微管蛋白相互作用剂(例如长春新碱,雌莫司汀,长春碱,多西紫杉醇,埃坡霉素衍生物和紫杉醇);激素药物(例如雌激素;共轭雌激素;乙炔雌二醇;己烯雌酚;氯三苯胺;艾地雌酚(idenestrol);孕激素如己酸羟孕酮,甲羟孕酮,和孕酮;和雄激素如睾丸酮,丙酸睾丸酮,氟甲睾酮和甲基睾丸酮);肾上腺皮质类固醇(例如强的松,地塞米松,甲基泼尼松龙和泼尼松龙);黄体激素释放剂或促性腺激素释放激素拮抗剂(例如醋酸亮丙瑞林和醋酸戈舍瑞林);和抗激素抗原(例如他莫昔芬,抗雄激素药,如氟他胺;和抗肾上腺药,如米塔坦(mitotane)和氨基谷氨酰胺)。本发明还预期将A2AR/A2BR抑制剂与本领域已知的其他试剂(例如三氧化二砷)和将来开发的其他化学治疗剂组合使用。
在一些实施方案中,本文提供了治疗癌症的方法,其中将治疗有效量的本文所述的A2AR/A2BR抑制剂与至少一种化学治疗剂组合施用,导致癌症存活率大于单独施用其中一种观察到的癌症存活率。在涉及治疗癌症的方法的其他实施方案中,组合施用治疗有效量的本文所述的A2AR/A2BR抑制剂与至少一种化学治疗剂,导致肿瘤大小的减小或肿瘤生长的减慢大于单独使用一种药物观察到的肿瘤大小或肿瘤生长的减慢。
在另外的实施方案中,本发明考虑了用于治疗或预防受试者中的癌症的方法,其包括向受试者施用治疗有效量的至少一种本文所述的A2AR/A2BR抑制剂和至少一种信号转导抑制剂(STI)。
在一个特定的实施方案中,至少一种STI选自下组:bcr/abl激酶抑制剂,表皮生长因子(EGF)受体抑制剂,her-2/neu受体抑制剂和法呢基转移酶抑制剂(FTI)。其他候选STI试剂在本文其他地方阐述。
本发明还考虑了在受试者中增加肿瘤细胞排斥的方法,其包括与至少一种化学治疗剂和/或放射疗法联合施用A2AR/A2BR抑制剂,其中所得的肿瘤细胞排斥大于单独使用A2AR/A2BR抑制剂,化学治疗剂或放射疗法获得的肿瘤细胞排斥。
在另外的实施方案中,本发明提供了用于治疗受试者中的癌症的方法,包括向受试者施用治疗有效量的至少一种A2AR/A2BR抑制剂和至少一种除A2AR/A2BR抑制剂以外的免疫调节剂。在特定的实施方案中,至少一种免疫调节剂选自下组:CD4OL,B7,B7RP1,抗CD40,抗CD38,抗ICOS,4-IBB配体,树突状细胞癌疫苗,IL2,IL12,ELC/CCL19,SLC/CCL21,MCP-1,IL-4,IL-18,TNF,IL-15,MDC,IFN-a/-13,M-CSF,IL-3,GM-CSF,IL-13,抗-IL-10和吲哚胺2,3-二加氧酶1(IDO1)。其他候选免疫调节剂在本文其他地方列出。
本发明涉及包含用于治疗或预防受试者(例如人)的感染性疾病(例如病毒感染)的方法的实施方案,该方法包括向受试者施用治疗有效量的至少一种本文所述的A2AR/A2BR抑制剂,和治疗有效量的抗感染剂。
在本发明的一些实施方案中,其他治疗剂是细胞因子,包括例如粒细胞-巨噬细胞集落刺激因子(GM-CSF)或flt3-配体。本发明还涵盖了用于治疗或预防病毒感染(例如,慢性病毒感染)的方法,所述病毒感染包括但不限于丙型肝炎病毒(HCV),人乳头瘤病毒(HPV),巨细胞病毒(CMV),爱泼斯坦-巴尔病毒(EBV),水痘带状疱疹病毒,柯萨奇病毒和人类免疫缺陷病毒(HIV)。下文将进一步讨论本文所述的化合物用于治疗(单独或作为联合疗法的组分)感染的用途。
在另外的实施方案中,通过共同施用疫苗并联合施用治疗有效量的本发明的A2AR/A2BR抑制剂来实现感染性疾病的治疗。在一些实施方案中,疫苗是抗病毒疫苗,包括例如抗HIV疫苗。在其他实施方案中,疫苗对结核或疟疾有效。仍在其他实施方案中,疫苗是肿瘤疫苗(例如,有效对抗黑素瘤的疫苗);所述肿瘤疫苗可以包含基因修饰的肿瘤细胞或基因修饰的细胞系,包括已被转染以表达粒细胞-巨噬细胞刺激因子(GM-C SF)的基因修饰的肿瘤细胞或基因修饰的细胞系。在特定的实施方案中,疫苗包括一种或多种免疫原性肽和/或树突细胞。
在一些实施方案中,本发明涵盖了将本文所述的化合物与一种或多种抗微生物试剂组合使用的方法。
在通过施用A2AR/A2BR抑制剂和至少一种其他治疗剂来治疗感染的某些实施方案中,在同时施用A2AR/A2BR抑制剂和其他治疗剂后观察到的感染症状比单独给药后观察到相同的感染症状得到改善。在一些实施方案中,观察到的感染症状可以是病毒载量减少,CD4+T细胞计数增加,机会性感染减少,存活时间增加,根除慢性感染或其组合。
附图的简要说明
不适用
具体实施方式
在进一步描述本发明之前,应当理解,本发明不限于在此阐述的特定实施例,并且还应当理解,在此使用的术语仅出于描述特定实施例的目的,并且并非旨在进行限制。
在提供数值范围的情况下,应理解为,除非上下文另有明确规定,否则每个中间值均应达到该下限单位的十分之一,应介于该范围的上限和下限之间,且所述范围中的任何其他所述或中间值包括在本发明内。这些较小范围的上限和下限可以独立地包括在较小范围内,并且也包括在本发明内,以所述范围内的任何明确排除的限制为准。当所述范围包括一个或两个限制时,排除那些所包括的限制中的一个或两个的范围也包括在本发明中。除非另有定义,否则本文使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常所理解的相同含义。
如本文所用,单数形式的“一个”,“一种”和“该”包括复数指示物,除非上下文另外明确指出。还应注意的是,权利要求书可以被撰写为排除任何可选要素。这样,该陈述旨在作为与权利要求要素的叙述结合使用诸如“唯一”,“仅”等排他性术语的先行基础,或使用“否定”限制。
仅在本申请的提交日期之前提供本文讨论的出版物用于公开。此外,提供的出版日期可能与实际的出版日期不同,实际的出版日期可能需要独立确认。总述
例如,本文提供了用于抑制腺苷A2A受体(A2AR)和/或腺苷A2B受体(A2BR)的化合物和组合物,以及包含它们的药物组合物。本文还提供了例如治疗或预防由腺苷A2A受体(A2AR)和/或腺苷A2B受体(A2BR)的抑制介导的疾病,病症或病状或其症状的方法。
定义
除非另有说明,否则以下术语旨在具有以下阐述的含义。在整个说明书的其他地方定义了其他术语。
除非另外说明,术语“烷基”本身或作为另一取代基的一部分的含义是指具有指定碳原子数的直链或支链烃基(如C1-8表示一至八个碳)。烷基可以包括任何数目的碳,例如C1-2,C1-3,C1-4,C1-5,C1-6,C1-7,C1-8,C1-9,C1-10,C2-3,C2-4,C2-5,C2-6,C3-4,C3-5,C3-6,C4-5,C4-6和C5-6。烷基的实例包括甲基,乙基,正丙基,异丙基,正丁基,叔丁基,异丁基,仲丁基,正戊基,正己基,正庚基,正辛基等。
术语“亚烷基”是指具有所示碳原子数并连接至少两个其他基团的直链或支链的饱和脂族基团,即,二价烃基。连接至亚烷基的两个部分可以连接至亚烷基的相同原子或不同原子。例如,直链亚烷基可以是-(CH2)n-的二价基团,其中n为1、2、3、4、5或6。代表性的亚烷基包括但不限于亚甲基,亚乙基,亚丙基,异亚丙基,丁烯基,异丁烯基,仲丁烯基,戊烯基和己烯基。亚烷基在本申请中通常被称为X1或X2基团,可以被取代或未被取代。当包含X1或X2的基团被任选地取代时,应理解的是,任选的取代可以在该部分的亚烷基部分上。
术语“环烷基”是指具有指定数目的环原子的烃环(例如,C3-6环烷基)并且是完全饱和的或在环顶点之间具有不超过一个双键的烃环。“环烷基”还指双环和多环烃环,例如双环[2.2.1]庚烷,双环[2.2.2]辛烷等。在一些实施方案中,本发明的环烷基化合物为单环C3-6环烷基部分。
术语“杂环烷基”是指具有指定数目的环顶点(或成员)并且具有1-5个选自N,O和S的杂原子的环烷基环,其取代了1-5个碳顶点,并且其中氮和硫原子被任选地氧化,并且氮原子被任选地季铵化。环杂烷基可以是单环,双环或多环系统。环杂烷基的非限制性实例包括吡咯烷,咪唑烷,吡唑烷,丁内酰胺,戊内酰胺,咪唑啉酮,乙内酰脲,二氧戊环,邻苯二甲酰亚胺,哌啶,1,4-二恶烷,吗啉,硫代吗啉,硫代吗啉-S-氧化物,硫代吗啉-S,S-氧化物,哌嗪,吡喃,吡啶酮,3-吡咯啉,噻喃,吡喃酮,四氢呋喃,四氢噻吩,奎尼丁等。环杂烷基可通过环碳或杂原子连接至分子的其余部分。
如本文所用,在本文所述的任何化学结构中与单,双或三键相交的波浪线表示单,双或三键与分子其余部分的点连接。另外,延伸至环(例如苯环)中心的键是指表示在任何可用的环顶点上的连接。本领域技术人员将理解,显示为连接到环上的多个取代基将占据提供稳定化合物并在空间上相容的环顶点。对于二价成分,表示应包括任意方向(正向或反向)。例如,基团“–C(O)NH-”-旨在包括以下任一方向的连接:-C(O)NH-或–NHC(O)-,类似地,“-O-CH2CH2”旨在同时包括-O-CH2CH2-和-CH2CH2-O-。
除非另有说明,术语“卤代”或“卤素”本身或作为另一取代基的一部分是指氟,氯,溴或碘原子。另外,诸如“卤代烷基”的术语是指包括单卤代烷基和多卤代烷基。例如,术语“C1-4卤代烷基”是指包括三氟甲基,2,2,2-三氟乙基,4-氯丁基,3-溴丙基等。
除非另有说明,术语“芳基”是指多不饱和的,通常为芳族的烃基,其可以是稠合在一起或共价连接的单环或多环(至多三个环)。芳基的非限制性实例包括苯基,萘基和联苯基。
术语“杂芳基”是指包含选自N,O和S的1-5个杂原子的芳基(或环),其中氮和硫原子任选被氧化,并且氮原子任选被季铵化。杂芳基可通过杂原子连接至分子的其余部分。杂芳基基团的非限制性实例包括吡啶基,哒嗪基,吡嗪基,嘧啶基,三嗪基,喹啉基,喹喔啉基,喹唑啉基,噌啉基,酞嗪基,苯并三嗪基,嘌呤基,苯并咪唑基,苯并吡唑基,苯并三唑基、苯并异恶唑基、异苯并呋喃基、异吲哚基、吲哚嗪基、苯并三嗪基、噻吩并吡啶基、噻吩并嘧啶基、吡唑并嘧啶基、咪唑并吡啶、苯并噻唑基、苯并呋喃基、苯并噻吩基、吲哚基、喹啉基、异喹啉基、异噻唑基、吡唑基、吲唑基、蝶啶基、咪唑基、三唑基、四唑基、恶唑基、异恶唑基,噻二唑基、吡咯基、噻唑基、呋喃基、噻吩基等。杂芳基环的取代基可以选自下述可接受的取代基。
在一些实施方案中,以上术语(例如,“烷基”,“芳基”和“杂芳基”)将被任选地取代。下面提供了每种类型基团的选定取代基。
烷基(包括通常称为亚烷基,烯基和炔基的那些基团)的任选的取代基可以是选自以下的各种基团:-卤素-,-OR’,-NR’R”,-SR’,-SiR’R”R”’,-OC(O)R’,-C(O)R’,-CO2R’,-CONR’R”,-OC(O)NR’R”,-NR”C(O)R’,-NR’-C(O)NR”R”’,-NR”C(O)2R’,-NH-C(NH2)=NH,-NR’C(NH2)=NH,-NH-C(NH2)=NR’,-S(O)R’,-S(O)2R’,-S(O)2NR’R”,-NR’S(O)2R”,-CN(氰基-),-NO2,芳基,芳氧基,氧代,环烷基和数量范围为零至(2m’+1)的杂环烷基,其中m’是该基团中碳原子的总数。R’,R”和R”’分别独立地是指氢,未取代的C1-8烷基,未取代的芳基,被1-3个卤素取代的芳基,C1-8烷氧基或C1-8硫代烷氧基或未取代的芳基-C1-4烷基。当R’和R”与相同的氮原子连接时,它们可以与氮原子结合形成3、4、5、6或7元环。例如,-NR’R”是指包括1-吡咯烷基和4-吗啉基。
环烷基和杂环烷基的任选的取代基可以是选自以下的各种基团:任选地被以下集团取代的烷基:C(O)OR’,卤素,-OR’,-NR’R”,-SR’,-SiR’R”R”’,-OC(O)R’,-C(O)R’,-CO2R’,-CONR’R”,-OC(O)NR’R”,-NR”C(O)R’,-NR’-C(O)NR”R”’,-NR”C(O)2R’,-NH-C(NH2)=NH,-NR’C(NH2)=NH,-NH-C(NH2)=NR’,-S(O)R’,-S(O)2R’,-S(O)2NR’R”,-NR’S(O)2R”,-CN(-氰基),-NO2,芳基-,芳氧基和氧代。R’,R”和R”’分别独立地是指氢,未取代的C1-8烷基,未取代的芳基,被1-3个卤素取代的芳基,C1-8烷氧基或C1-8硫代烷氧基或未取代的芳基-C1-4烷基。
同样,芳基和杂芳基的可选取代基也有所不同,通常选自:-卤素,-OR’,-OC(O)R’,-NR’R”,-SR’,-R’,-CN,-NO2,-CO2R’,-CONR’R”,-C(O)R’,-OC(O)NR’R”,-NR”C(O)R’,-NR”C(O)2R’,-NR’-C(O)NR”R”’,-NH-C(NH2)=NH,-NR’C(NH2)=NH,-NH-C(NH2)=NR’,-S(O)R’,-S(O)2R’,-S(O)2NR’R”,-NR’S(O)2R”,-N3,全氟(C1-C4)烷氧基和全氟-(C1-C4)烷基,其数量范围为零至芳环系统上的开环总数;其中R’,R”和R”’独立地选自氢,C1-8烷基,C1-8卤代烷基,C3-6环烷基,C2-8烯基和C2-8炔基。其他合适的取代基包括通过1-6个碳原子的亚烷基系链连接到环原子上的每个上述芳基取代基。
芳基或杂芳基环的相邻原子上的两个取代基可任选地被下式的取代基取代:-T-C(O)-(CH2)q-U-,其中T和U独立地为-NH-,-O-,-CH2-或单键,且q为0到2的整数。可选地,芳基或杂芳基环的相邻原子上的两个取代基可以任选地被下式取代基取代:-A-(CRfRg)r-B-,其中A和B独立地为-CH2-,-O-,-NH-,-S-,-S(O)-,-S(O)2-,-S(O)2NR’-或单键,r为1至3中的整数,R f和Rg分别独立地为卤素的H。如此形成的新环的单键之一可以任选地被双键取代。可选择地,芳基或杂芳基环的相邻原子上的两个取代基可以任选地被式-(CH2)s-X-(CH2)t-的取代基取代,其中s和t独立地是从0到3的整数,X是-O-,-NR’-,-S-,-S(O)-,-S(O)2-,或-S(O)2NR’-。-NR’-和-S(O)2NR’-中的取代基R’选自氢或未取代的C1-6烷基。
如本文所用,术语“杂原子”是指包括氧(O),氮(N),硫(S)和硅(Si)。
术语“药学上可接受的盐”是指包括用相对无毒的酸或碱制备的活性化合物的盐,这取决于本文所述化合物上发现的特定取代基。当本发明的化合物含有相对酸性的官能团时,可以通过使这类化合物的中性形式与足够量的纯净或在合适的惰性溶剂中的所需碱接触而获得碱加成盐。衍生自药学上可接受的无机碱的盐的实例包括铝盐,铵盐,钙盐,铜盐,铁盐,亚铁盐,锂盐,镁盐,锰盐,亚锰盐,钾盐,钠盐,锌盐等。衍生自药学上可接受的有机碱的盐包括伯,仲和叔胺的盐,包括取代的胺,环胺,天然存在的胺等,例如精氨酸,甜菜碱,咖啡因,胆碱,N,N'-二苄基乙二胺,二乙胺,2-二乙基氨基乙醇,2-二甲基氨基乙醇,乙醇胺,乙二胺,N-乙基吗啉,N-乙基哌啶,葡糖胺,氨基葡萄糖,组氨酸,肼苯胺,异丙胺,赖氨酸,甲基葡糖胺,吗啉,哌嗪,哌啶,聚胺树脂,普鲁卡因(procaine),嘌呤,可可碱,三乙胺,三甲胺,三丙胺,氨丁三醇等。当本发明的化合物包含相对碱性的官能团时,可以通过使这种化合物的中性形式与足够量的纯净或在合适的惰性溶剂中的所需酸接触来获得酸加成盐。药学上可接受的酸加成盐的实例包括衍生自无机酸(例如盐酸,氢溴酸,硝酸,碳酸,一氢碳酸,磷酸,一氢磷酸,二氢磷酸,硫酸,一氢硫酸,氢氟酸或亚磷酸等)的那些,以及衍生自相对无毒的有机酸(例如乙酸,丙酸,异丁酸,丙二酸,苯甲酸,琥珀酸,辛二酸,富马酸,扁桃酸,邻苯二甲酸,苯磺酸,对甲苯磺酸,柠檬酸,酒石酸,甲磺酸等)的盐。还包括氨基酸的盐,例如精氨酸盐等,以及有机酸(例如葡萄糖醛酸或半乳糖醛酸等)的盐(参见,例如,Berge,S.M.等人,“Pharmaceutical Salts”,Journal of Pharmaceutical Science,1977,66,1-19)。本发明的某些特定化合物同时包含碱性和酸性官能团,这使得该化合物可以转化为碱或酸加成盐。
化合物的中性形式可以通过使盐与碱或酸接触并以常规方式分离母体化合物来再生。化合物的母体形式在某些物理性质(例如在极性溶剂中的溶解度)方面与各种盐形式不同,但是除此之外,对于本发明的目的而言盐与化合物的母体形式等效。除盐形式外,本发明提供了前药形式的化合物。本文所述化合物的前药是那些在生理条件下容易发生化学变化以提供本发明化合物的化合物。另外,前药可以在离体环境中通过化学或生化方法转化为本发明的化合物。例如,将前药与合适的酶或化学试剂一起置于透皮贴剂储库中时,其可以缓慢地转化为本发明的化合物。前药在本文其他地方有更详细的描述。
除盐形式外,本发明提供了前药形式的化合物。本文所述化合物的前药是那些在生理条件下容易发生化学变化以提供本发明化合物的化合物。另外,前药可以在离体环境中通过化学或生化方法转化为本发明的化合物。例如,将前药与合适的酶或化学试剂一起置于透皮贴剂储库中时,其可以缓慢地转化为本发明的化合物。
本发明的某些化合物可以以非溶剂化物形式以及包括水合形式的溶剂化物形式存在。通常,溶剂化形式等同于非溶剂化形式,并且旨在包括在本发明的范围内。本发明的某些化合物可以多种结晶或无定形形式存在。通常,所有物理形式对于本发明涵盖的用途是等同的,并且意在落入本发明的范围内。
在特定条件下,本发明的某些化合物可以多晶型物的形式存在。多态性是指固体材料以一种以上的晶体结构形式或相存在的能力,其中晶格中的分子具有不同的排列或构象。如果由于堆积而存在这种类型的差异,则称为“堆积型多晶型”,如果由于构象的差异而存在,则称为“构象型多晶型”。同一化合物的不同多晶型物通常表现出不同的物理性质,包括堆积性质,光谱性质,热力学性质,溶解度和熔点;动力学特性,例如溶解速度和稳定性;以及机械性能,例如硬度和抗拉强度。根据其在不同温度和压力范围内的稳定性,多晶型物可分为两种类型之一。在单向性体系中,只有一种多晶型物(即单向立体物)是稳定的,并且在低于熔点的所有温度和压力下均表现出较低的自由能含量和溶解度。在对映体系中,一种多晶型物在一定温度和压力下是稳定的,而其他多晶型物在各种温度和压力下是稳定的。
本发明的某些化合物具有不对称碳原子(光学中心)或双键;外消旋体,非对映异构体,几何异构体,区域异构体和单独的异构体(例如,单独的对映异构体)均旨在涵盖在本发明的范围内。当显示立体化学描述时,是指其中一种异构体存在且基本不含另一种异构体的化合物。“基本上不含”另一种异构体表示两种异构体的比率至少为80/20,更优选为90/10,或95/5或更高。在一些实施方案中,异构体之一将以至少99%的量存在。
本发明的化合物还可在构成此类化合物的一个或多个原子上包含非天然比例的原子同位素。同位素的非自然比例可以定义为从自然界中发现的量到由所讨论原子的100%组成的量。例如,化合物可以掺入放射性同位素,例如氚(3H),碘125(125I)或碳14(14C),或非放射性同位素,例如氘(2H)或碳13(13C)。这样的同位素变体可以为本申请中其他地方描述的那些提供额外的效用。例如,本发明化合物的同位素变体可以发现另外的用途,包括但不限于作为诊断和/或成像试剂,或作为细胞毒性/放射毒性治疗剂。另外,本发明化合物的同位素变体可以具有改变的药代动力学和药效学特征,这可以有助于在治疗过程中提高安全性,耐受性或功效。本发明化合物的所有同位素变体,无论是否具有放射性,都旨在涵盖在本发明的范围内。
术语“患者”或“受试者”可互换使用,是指人类或非人类动物(例如,哺乳动物)。
术语“施用”、“给予”等,例如,应用于受试者,细胞,组织,器官或生物流体,是指例如A2AR/A2BR抑制剂,包含其的药物组合物,或诊断试剂和受试者,细胞,组织,器官或生物流体接触。在细胞的情况下,施用包括(例如,体外或离体)试剂与细胞的接触,以及试剂与流体的接触,其中流体与细胞接触。
术语“治疗”、“疗愈”、“治疗方法”等是指在已经被诊断,观察等的疾病,病症或病状或症状后开始的一系列行动(例如施用A2AR/A2BR抑制剂或包含其的药物组合物)过程,以暂时性地或永久性地消除,减少,抑制,减轻或改善至少一种造成受试者疾病,病症或病状的根本原因,或至少一种与困扰受试者的疾病,病症,病状相关的症状。因此,治疗包括抑制(例如,阻止疾病,病症或病状或与其相关的临床症状的发展或进一步发展)一种活性疾病。
如本文所用,术语“需要治疗”是指医师或其他护理者做出的受试者需要或将从治疗中受益的判断。该判断是基于医师或护理人员专业知识范围内的多种因素做出的。
术语“预防(prevent/preventing/prevention)”等是指一系列以一定方式(例如在疾病,病症,病状或其症状发作之前)开始的行动(例如施用A2AR/A2BR抑制剂或包含该化合物的药物组合物),通常是在受试者倾向于患有特定疾病,病症或病状的情况下,以暂时或永久地预防,抑制,阻止或减少受试者罹患疾病,病症,状况等的风险(例如由缺乏临床症状确定)或其延迟发作。在某些情况下,该术语还指减慢疾病,病症或病状的进展或抑制其发展成有害或不希望的状态。
如本文所用,术语“需要预防”是指医师或其他护理者做出的受试者需要或将从中受益的判断。该判断是基于医师或护理人员的专业知识范围内的多种因素做出的。
短语“治疗有效量”是指以单独或作为药物组合物的一部分的形式,或者以单独剂量或部分剂量的形式,当给予受试者时,以能够检测的、对疾病、病症或病状的任何症状、方面或特征具有积极作用的量,向受试者给药。治疗有效量可以通过测量相关的生理效应来确定,并且可以结合给药方案和对受试者状况的诊断分析等进行调整。举例来说,在给药后的特定时间测量A2AR/A2BR抑制剂(或其代谢物)的血清水平可指示是否已使用治疗有效量。
短语“以足以改变的量”是指在施用特定疗法之前和之后所测量的指标水平(例如,基线水平)之间存在可检测的差异。指标包括任何客观参数(例如,血清浓度)或主观参数(例如,受试者的舒适感)。
术语“小分子”是指分子量小于约10kDa,小于约2kDa或小于约1kDa的化合物。小分子包括但不限于无机分子,有机分子,包含无机成分的有机分子,包含放射性原子的分子和合成分子。在治疗上,与大分子相比,小分子对细胞的渗透性更高,更不容易降解,更不可能引起免疫反应。
术语“配体”是指例如可以充当受体激动剂或拮抗剂的肽,多肽,与膜相关或与膜结合的分子或其复合物。配体包括天然和合成的配体,例如细胞因子,细胞因子变体,类似物,突变蛋白和衍生自抗体以及小分子的结合组合物。该术语还涵盖既不是激动剂也不是拮抗剂,但是可以结合受体而不显著影响其生物学特性(例如信号传导或粘附)的试剂。此外,该术语包括膜结合的配体,该膜结合的配体已经通过例如化学或重组方法改变为膜结合的配体的可溶形式。配体或受体可以完全在细胞内,也就是说,它可以驻留在细胞质,细胞核或某些其他细胞内区室中。配体和受体的复合物称为“配体-受体复合物”。
术语“抑制剂”和“拮抗剂”,或“活化剂”和“激动剂”分别是指抑制或活化分子,例如,用于活化例如配体,受体,辅因子,基因,细胞,组织,或器官。抑制剂是减少,阻断,阻止,延迟激活,失活,脱敏或下调例如基因,蛋白质,配体,受体或细胞的分子。激活剂是增加,激活,促进,增强激活,敏化或上调例如基因,蛋白质,配体,受体或细胞的分子。抑制剂也可以定义为减少,阻断或灭活组成性活性的分子。“激动剂”是与靶标相互作用以引起或促进靶标活化增加的分子。“拮抗剂”是与激动剂的作用相反的分子。拮抗剂防止,降低,抑制或中和激动剂的活性,并且即使没有确定的激动剂,拮抗剂也可以预防,抑制或降低靶标例如靶受体的组成活性。
术语“调节(modulate/modulation)”等是指分子(例如活化剂或抑制剂)直接或间接增加或降低A2AR/A2BR的功能或活性的能力。调节剂可以单独起作用,或者可以使用辅因子,例如蛋白质,金属离子或小分子。调节剂的实例包括小分子化合物和其他生物有机分子。许多小分子化合物的文库(例如组合文库)可商购获得,并且可以用作鉴定调节剂的起点。技术人员能够开发一种或多种测定法(例如,基于生物化学或基于细胞的测定法),其中可以筛选此类化合物文库,以鉴定具有所需性质的一种或多种化合物;此后,熟练的化学药剂师能够通过例如合成和评估其类似物和衍生物来优化这种一种或多种化合物。合成和/或分子模型研究也可以用于鉴定活化剂。
分子的“活性”可以描述成或指的是分子与配体或受体的结合;催化活性;刺激基因表达或细胞信号转导,分化或成熟的能力;抗原活性;调节其他分子的活性的能力;等等。术语“增殖活性”包括促进例如正常细胞分裂以及癌症,肿瘤,发育异常,细胞转化,转移和血管生成所必需的或与之特异性相关的活性。
如本文所用,“可比较的”,“可比的活性”,“与……可比的活性”,“可比的效果”,“与……可比的效果”等是可以被定量和/或定性观察的相对术语。所述术语的含义通常取决于使用它们的上下文。举例来说,从定性的角度来看,两种均激活受体的试剂可被视为具有可比的效果,但从定量的角度来看,如果一种试剂仅能达到在本领域接受的测定(例如,剂量反应测定)或本领域接受的动物模型中确定的另一种试剂活性的20%的效果,则可将这两种试剂视为不具有可比的效果。当将一个结果与另一个结果(例如,一个结果与参考标准)进行比较时,“可比”经常(尽管不总是)表示一个结果与参考标准的偏离小于35%,小于30%,小于25%,小于20%,小于15%,小于10%,小于7%,小于5%,小于4%,小于3%,小于2%,或少于1%。在特定的实施方案中,如果一个结果与参考标准的偏差小于15%,小于10%或小于5%,则该结果与参考标准相当。作为示例而非限制,活性或效果可以指功效,稳定性,溶解性或免疫原性。
“基本上纯的”表示组分占组合物总含量的大于约50%,并且典型地占总多肽含量的大于约60%。更典型地,“基本上纯的”是指其中总组合物的至少75%,至少85%,至少90%或更多是目标组分的组合物。在某些情况下,多肽将占组合物总含量的大于约90%,或大于约95%。
术语“特异性结合”或“选择性结合”,当指配体/受体,抗体/抗原或其他结合对时,表示一种结合反应,该反应决定了蛋白质在蛋白质和其他生物制品的异质种群中的存在。因此,在指定的条件下,指定的配体与特定的受体结合,并且与样品中存在的其他蛋白质的结合量不明显。预期方法的抗体或衍生自抗体的抗原结合位点的结合组合物以与任何其他抗体或由其衍生的结合组合物的亲和力比至少两倍大,至少十倍大,至少20倍大,或至少100倍大的亲和力结合其抗原或其变体或突变蛋白。。在一个特定的实施方案中,该抗体具有的亲和力大于约109升/摩尔,如通过例如Scatchard分析(Munsen等,1980年,Analyt.Biochem.,107:220-239)确定的。
例如,细胞,组织,器官或有机体的术语“反应”涵盖生物化学或生理行为的变化,例如浓度,密度,粘附力或在生物室内的迁移,基因表达的速率或分化状态,其中变化与激活,刺激或治疗或内部机制(如基因编程)相关。在某些情况下,术语“激活”,“刺激”等指的是受内部机制以及外部或环境因素调节的细胞激活;而术语“抑制”,“下调”等是相反的作用。
本文可互换使用的术语“多肽”,“肽”和“蛋白质”是指任何长度的氨基酸的聚合形式,其可以包括遗传编码和非遗传编码的氨基酸、化学或生物化学修饰或衍生的氨基酸和具有修饰的多肽骨架的多肽。该术语包括融合蛋白,包括但不限于具有异源氨基酸序列的融合蛋白,具有异源和同源前导序列、具有或不具有N末端甲硫氨酸残基的融合蛋白;免疫标记蛋白等等。
如本文所用,术语“变体”和“同源物”可互换使用,以分别指与参考氨基酸或核酸序列相似的氨基酸或DNA序列。该术语包括天然存在的变体和非天然存在的变体。天然存在的变体包括同源物(一个物种到另一个物种的氨基酸或核苷酸序列分别不同的多肽和核酸)和等位基因变体(一个物种中的一个个体到另一个个体的氨基酸或核苷酸序列分别不同的多肽和核酸)。因此,变体和同源物涵盖天然存在的DNA序列和由其编码的蛋白质及其同种型,以及蛋白质或基因的剪接变体。该术语还涵盖与天然存在的DNA序列具有一个或多个碱基变化但由于遗传密码的简并性而仍翻译成对应于天然存在的蛋白质的氨基酸序列的核酸序列。非天然存在的变体和同源物分别包括氨基酸或核苷酸序列改变的多肽和核酸,其中序列的改变是人为引入的(例如突变蛋白);例如,变化是在实验室中通过人为干预(“人之手”)产生的。因此,非天然存在的变体和同源物也可以指通过一个或多个保守取代和/或标签和/或缀合物而与天然存在的序列不同的那些。
如本文所用,术语“突变蛋白”广泛地指突变的重组蛋白。这些蛋白质通常带有一个或多个氨基酸取代,通常来自已进行定点诱变或随机诱变的克隆基因或完全合成的基因。
术语“DNA”,“核酸”,“核酸分子”,“多核苷酸”等在本文可互换使用,是指任何长度的核苷酸的聚合形式,即脱氧核糖核苷酸或核糖核苷酸或其类似物。多核苷酸的非限制性实例包括线性和环状核酸,信使RNA(mRNA),互补DNA(cDNA),重组多核苷酸,载体,探针,引物等。
腺苷A2A受体和腺苷A2B受体及其抑制
如上所述,尽管对于本发明的实施并不需要对本发明化合物影响其活性的基本作用机理的精确理解,但是据信该化合物(或其子集)抑制腺苷A2A受体(A2AR)和/或腺苷A2B受体(A2BR)。或者,化合物(或其子集)可抑制腺苷酸环化酶功能。
化合物(或其子集)还可以对A2A受体(A2AR),腺苷A2B受体(A2BR)以及腺苷酸环化酶具有抑制剂活性。尽管本发明的化合物在本文中通常被称为腺苷A2A受体(A2AR)和/或腺苷A2B受体(A2BR)抑制剂,但应理解,术语“A2AR/A2BR抑制剂”包括通过抑制A2AR,A2BR或腺苷酸环化酶单独起作用的化合物,和/或通过抑制A2AR,A2BR和腺苷酸环化酶起作用的化合物。
具有理想特性的腺苷A2A受体和腺苷A2B受体抑制剂的鉴定
本发明部分地涉及鉴定具有至少一种与治疗相关的特性或特征的腺苷A2A受体和/或腺苷A2B受体的抑制剂。候选抑制剂可通过使用例如本领域公认的测定法或模型来鉴定,其实例在本文中描述。
鉴定后,可以通过使用提供关于抑制剂特性的数据(例如,药代动力学参数,确定溶解度或稳定性的手段)的技术来进一步评估候选抑制剂。候选抑制剂与参考标准(可能是目前抑制剂的“同类最佳”)的比较表明了此类候选药物的潜在活力。
本发明的化合物
在一个特定方面,本文提供具有式(I)的化合物,或其药学上可接受的盐,水合物或溶剂化物,
其中,
G1为N或CR3a;
G2为N或CR3b;
R3a和R3b各自独立地为H或C1-3烷基;
R1a和R1b各自独立地选自下组:
i)H;
ii)C1-8烷基,任选被1-3个R5取代基取代;
iii)-X1-O-C1-8烷基,任选地被1-3个R5取代基取代;
iv)-C(O)-R6,
v)Y,任选地被1-3个R7取代基取代,并且
vi)-X1-Y,任选地被1-3个R7取代基取代;或者
vii)R1a和R1b与它们所连接的氮一起形成5-6元杂环烷基环,该环任选被1-3个R8取代基取代,其中杂环烷基具有0-2个额外的选自O,N和S的杂原子环顶点;
每个Y是C3-8环烷基或具有1-3个选自O,N和S的杂原子环顶点的4至6元杂环烷基;
R2和R4各自独立地为H或C1-3烷基;
每个X1是C1-6亚烷基;
每个R5独立地选自下组:羟基,C3-8环烷基,苯基,-O-苯基,-C(O)ORa和氧代;
每个R6为C1-8烷基或Y,其各自任选地被1-3个选自下组的取代基取代:羟基,-O-苯基,苯基和-O-C1-8烷基;
每个R7独立地选自下组:C1-8烷基,羟基,-O-C1-8烷基,氧代和C(O)ORa;
每个R8独立地选自下组:C1-8烷基,羟基和氧代;
下标n为0、1、2或3;
每个R9独立选自下组:C1-8烷基,-O-C1-8烷基,-X1-O-C1-8烷基,-O-X1-O-C1-8烷基,-X1-O-X1-O-C1-8烷基,-C(O)ORa,卤素,氰基,-NRbRc,Y,-X1-C3-8环烷基,和-X2-Z,其中X2选自下组:C1-6亚烷基,-C1-6亚烷基-O-,-C1-4亚烷基-O-C1-4亚烷基,-C(O)-和–S(O)2-,Z为具有1-3个杂原子环顶点的4至6元杂环烷基,该杂原子选自下组:O,N和S,其中每个所述R9取代基任选地被1-3个R11取代;
R10a,R10b,R10c和R10d各自独立地选自下组:C1-8烷基,卤素,氰基,-O-C1-8烷基,-X1-O-C1-8烷基,-O-X1-O-C1-8烷基,-S(O)2-C1-6烷基,-C(O)NRdRe和具有1-3个选自O,N和S的杂原子环顶点的4-6元杂芳基,其中每个所述R10a-d取代基任选地被1-3个R12取代,或相邻环顶点上的R10a,R10b,R10c和R10d中的两个任选地结合以形成任选地被1-2个卤素取代的5元杂环;
每个R11独立地选自下组:羟基,氧代,卤素,氰基,-NRdRe,-C(O)ORa,苯基,C3-8环烷基和任选被C(O)ORa取代的C1-4烷基;
每个R12独立地选自下组:卤素,氰基,羟基,-C(O)ORa;和
每个Ra是H或C1-6烷基;
每个Rb和Rc独立地选自下组:H,C1-8烷基,-S(O)2-C1-6烷基,-C(O)ORa和-X1-C(O)ORa;和
每个Rd和Re独立地选自下组:H,C1-8烷基,-S(O)2-C1-6烷基。
在一些选定的实施方案中,式(I)的化合物由式(Ia)表示
在一些选定的实施方案中,式(I)的化合物由式(Ib)表示
在一些选定的实施方案中,提供了式(I),(Ia)和(Ib)的化合物,其中至少一种R10为甲氧基。
在一些选定的实施方案中,式(I)的化合物由式(Ic)表示
在一些选定的实施方案中,式(I)的化合物由式(Id)表示
在一些选定的实施方案中,提供式(I),(Ia),(Ib),(Ic)和(Id)的化合物,其中每个R9独立地选自下组:C1-8烷基,-O-C1-8烷基,-X1-O-C1-8烷基,-O-X1-O-C1-8烷基,-X1-O-X1-O-C1-8烷基,其中每个所述R9取代基均可选地被1-3个R11取代。
在一些选择的实施方案中,提供式(I),(Ia),(Ib),(Ic)和(Id)的化合物,其中每个R9独立地选自下组:-C(O)ORa,-NRbRc,Y,-X1-C3-8环烷基,和-X2-Z,其中X2选自下组:C1-6亚烷基,-C1-6亚烷基-O-,-C(O)-,和–S(O)2-,Z是具有1-3个选自O,N和S的杂原子环顶点的4至6元杂环烷基,其中每个所述R9取代基均可选地被1-3R11取代。
在一些选定的实施方案中,式(I)的化合物由式(Ie)表示
在一些选择的实施方案中,式(I)的化合物由式(If)表示
在一些选定的实施方案中,式(I)的化合物由式(Ig)表示
在一些选定的实施方案中,式(I)的化合物由式(Ih)表示
在一些选择的实施方案中,式(I)的化合物由式(Ii)表示
在一些选定的实施方案中,本文提供的化合物选自下组:
在一些选择的实施方案中,提供表1的任何一种化合物。
合成方法
通常,本文提供的化合物可以通过以下实施例中所述的常规方法制备。
前药和其他药物递送方式和/或延长半衰期
在本发明的一些方面,本文所述的化合物以前药形式给药。
为了实现治疗活性的扩展,可以对药物分子进行改造以利用载体进行递送。此类载体可以以非共价方式使用,将药物部分通过物理化学方法配制成溶剂-载体混合物,或者通过将载体试剂永久共价连接到药物部分的一个官能团上(一般参见WO 20150202317)。
几种非共价方法受到青睐。举例但非限制性地,在某些实施方案中,采用包含将非共价药物包封到聚合物载体中的储库制剂。在这样的制剂中,药物分子与载体材料结合并被处理,使得药物分子变得分布在本体载体内。实例包括微粒聚合物-药物聚集体(例如,微球(Phosphorex公司)),其以可注射悬浮液形式给药;配制为凝胶的聚合物-药物分子聚集体(例如Lupron(AbbVie公司)),以单次大剂量注射的形式给药;以及脂质体制剂(例如,(Pacira医药)),其中载体可以是能够溶解药物的聚合物或非聚合物实体。在这些制剂中,当载体膨胀或物理退化时,可能会发生药物分子的释放。在另一些情况下,化学降解使药物扩散到生物环境中。这样的化学降解过程可以是自水解的或酶催化的。除其他限制外,非共价药物封装要求防止药物的不受控制的释放,并且药物释放机制对生物降解的依赖性可能导致患者之间的差异。
在特定的实施方案中,包括小分子和大分子的药物分子通过永久性共价键与载体缀合。某些在水性流体中表现出低溶解度的小分子治疗剂可通过与亲水性聚合物结合而增溶,其实例在本文其他地方有所描述。关于大分子蛋白质,半衰期延长可以通过例如用棕榈酰基部分的永久性共价修饰,以及通过本身具有延长的半衰期的另一种蛋白质(例如)的永久性共价修饰来实现。通常,当载体与药物共价缀合时,药物分子显示出降低的生物学活性。
在某些情况下,可以通过采用前药方法将药物与聚合物载体化学结合来成功解决与包含非共价聚合物混合物的药物分子或永久性共价连接相关的限制。在这种情况下,无活性或比药物部分本身活性低的治疗剂可预测地转化为活性分子实体。如果需要缓慢或控制释放药物,则与释放的药物相比,前药的生物活性降低是有利的。在这种情况下,药物的释放会随着时间而发生,从而减少了重复和频繁给药的必要性。当药物部分本身在胃肠道中没有被吸收或没有达到最佳吸收时,前药方法也可能是有利的。在这些情况下,前药促进药物部分的吸收,然后在以后的某个时间被裂解(例如,通过首过代谢)。生物活性药物分子通常通过在载体部分与药物分子的羟基,氨基或羧基之间形成的临时键与聚合物载体部分连接。
上述方法与若干限制相关联。前药的活化可以通过载体或药物分子之间的临时键的酶促或非酶促裂解,或两者的顺序结合来发生(例如,酶促步骤,然后是非酶促修饰)。在无酶的体外环境(例如,缓冲水溶液)中,诸如酯或酰胺的临时键可以进行水解,但是相应的水解速率可以使得其在治疗有用范围之外。相反,在体内环境中,通常存在酯酶或酰胺酶,并且该酯酶和酰胺酶可引起水解动力学的显著催化加速,从两倍到几个数量级(参见,例如,Greenwald等人,(1999)J Med Chem 42(18):3857-67)。
如本文所述,前药可以分类为i)生物前体和ii)载体连接的前药。生物前体不包含载体基团,并且通过功能基团的代谢产生而被激活。相反,在载体连接的前药中,活性物质通过在生物活性实体的官能团上的临时连接而与载体部分缀合。优选的官能团是羟基或氨基。附着化学和水解条件均取决于所用官能团的类型。载体可以是生物学惰性的(例如,PEG)或可以具有靶向特性(例如,抗体)。载体连接的前药的载体部分的切割产生感兴趣的生物活性实体,并且该生物活性实体的脱保护的官能团的性质通常有助于其生物活性。
专利和科学文献描述了许多大分子前药,其中的临时连接是不稳定的酯键。在这些情况下,生物活性实体的官能团是羟基或羧酸(参见,例如,Cheng等人。(2003)Bioconjugate Chem 14:1007-17)。另外,对于生物大分子和某些小分子药物而言,将载体连接至生物活性实体的一个或多个氨基(例如,蛋白质的N-末端或赖氨酸的氨基)通常是有利的。在前药的制备过程中,由于氨基与羟基或酚基相比具有更大的亲核性,因此可以对其进行化学选择性处理。这对于包含多种不同反应官能团的蛋白质和肽尤为重要,在这些蛋白质和多肽中,非选择性缀合反应导致不需要的产物混合物需要大量表征或纯化,因此降低了反应产率和活性部分的治疗效率。
通常,酰胺键比酯键对水解更稳定,并且酰胺键的裂解速率对于在与载体连接的前药中的治疗用途而言可能太慢。结果,添加结构化学成分以实现对前药酰胺键的可裂解性的控制可能是有利的。既不由载体实体也不由药物提供的这些额外的裂解控制化学成分通常称为“接头”。前药连接基可以对临时键的水解速率产生重大影响,并且连接基化学性质的变化通常导致特定的性质。用于靶向释放的通过特定酶对含胺的生物活性部分的前药活化要求接头的结构显示出被相应的内源酶识别为底物的结构基序。在这些情况下,临时键的裂解是通过酶催化的一步法进行的。例如,cytarabin的酶促释放受蛋白酶纤溶酶的影响,该纤溶酶的浓度在各种肿瘤块中相对较高。
患者之间的差异是主要的酶促切割的主要缺点。受试者之间的酶水平可能显著不同,从而通过酶促裂解导致前药活化的生物学变化。酶水平也可以根据给药部位而变化(例如,对于皮下注射,身体的某些区域比其他区域产生更可预测的治疗效果)。此外,很难建立酶依赖性载体连接的前药在体内-体外的药代动力学特性的相关性。
使用与药物部分中的氨基临时连接的其他载体前药是基于级联机制的。级联裂解可通过由掩蔽基团和活化基团的结构组合组成的接头化合物实现。掩蔽基团通过第一临时键如酯或氨基甲酸酯连接到活化基团上。活化基团通过第二个临时键(例如氨基甲酸酯)连接到药物分子的氨基上。第二种临时键的水解稳定性或敏感性取决于掩蔽基团的存在与否。在存在掩蔽基团的情况下,第二个临时键是高度稳定的,并且不太可能以治疗上有用的动力学释放药物分子,而在没有掩蔽基团的情况下,该键变得非常不稳定,从而导致药物部分的快速裂解和释放。
第一临时连接的裂解是级联机制中的限速步骤。第一步可以诱导活化基团的分子重排(例如,Greenwald等人,(1999)J Med Chem 42:3657-67中描述的1,6-排除),并且重排使得第二个临时连接更加不稳定,从而诱导其裂解。理想地,在给定的治疗方案中,第一临时键的裂解速率与药物分子的所需释放速率相同。另外,期望的是,在通过第一临时键的断裂已经诱导了其不稳定性之后,第二临时键的断裂基本上是瞬时的。
另一个实施方案包括基于三甲基锁内酯化的聚合的含氨基的前药(参见,例如,Greenwald等人,(2000)J Med Chem 43(3):457-87)。在该前药系统中,取代的邻羟基苯二甲基丙酸通过酯,碳酸酯或氨基甲酸酯基团作为第一临时键与PEG相连,并通过酰胺键作为第二临时键与药物分子的氨基相连。药物释放的决定速率的步骤是第一键的酶促裂解,然后通过内酯化快速酰胺裂解,从而释放出芳香族内酯副产物。Greenwald等人描述的前药系统的主要缺点是裂解临时键后释放出高反应性和潜在毒性的芳香族小分子副产物,如醌甲基化物或芳香族内酯。潜在的毒性实体与药物以1:1的化学计量比释放,并且可以呈现较高的体内浓度。
在包含基于1,6-消除的芳族活化基团的级联前药的某些实施方案中,掩蔽基团在结构上与载体分开。这可以通过在聚合物载体和活化基团之间采用稳定键来实现,其中该稳定键不参与级联裂解机理。如果载体不充当掩蔽基团并且活化基团通过稳定键与载体偶联,则避免释放潜在有毒的副产物(例如活化基团)。活化基团和聚合物的稳定连接还抑制了药理学不确定的药物连接中间体的释放。
前段中所述方法的第一个实例包括基于扁桃酸活化基团的聚合物前药系统(参见例如Shabat等人,(2004)Chem Eur J 10:2626-34)。在这种方法中,掩蔽基团通过氨基甲酸酯键与活化基团相连。活化基团通过酰胺键永久地共轭到聚丙烯酰胺聚合物上。在通过催化抗体将掩蔽基团酶促活化后,掩蔽基团被环化裂解并释放出药物。药物释放后,活化基团仍与聚丙烯酰胺聚合物连接。相似的前药系统是基于扁桃酸活化基团和酶可裂解的酯连接的掩蔽基团(参见例如Lee等人,(2004)Angew Chem 116:1707-10)。
当使用上述连接基时,1,6-消除步骤仍然产生高反应性的芳族中间体。即使芳族部分永久性地附着在聚合物载体上,也可能导致具有潜在的有毒副产物或免疫原性作用的副反应。因此,有利的是使用不依赖于酶并且在裂解过程中不产生反应性芳族中间体的脂族前药接头产生用于形成含胺活性剂的聚合物前药的接头技术。一个这样的例子使用PEG5000-马来酸酐在组织型纤溶酶原激活剂和尿激酶中对氨基的可逆修饰(参见例如(1987)Garman等人,FEBS Lett 223(2):361-65)。在pH 7.4缓冲液中孵育时,通过裂解马来酰胺酸键,可从PEG-uPA共轭物再生功能酶,遵循一级动力学,半衰期约为6小时。马来酰胺酸键的缺点是在较低的pH值下结合物缺乏稳定性。
进一步的方法包括基于N,N-双-(2-羟乙基)甘氨酸酰胺(N,N-二羟乙基甘氨酸)接头的PEG级联前药系统(参见例如(2004)J Med Chem 47:726-34)。在该系统中,两个PEG载体分子通过临时键连接至与药物分子的氨基偶联的N,N-二羟乙基甘氨酸分子。前药活化的第一步涉及将两个PEG载体分子与N,N-二羟乙基甘氨酸活化基团的羟基连接的第一临时键的酶促裂解。PEG与N,N-二羟乙基甘氨酸之间的不同连接导致不同的前药活化动力学。前药激活的第二步涉及第二个临时连接键的裂解,该第二连接将N,N-二羟乙基甘氨酸激活基团连接到药物分子的氨基上。该系统的一个缺点是第二个临时的N,N-二羟乙基甘氨酸酰胺连接键的水解速度慢,导致与原始的母体药物分子相比,N,N-二羟乙基甘氨酸修饰的前药中间体的释放具有不同药代动力学,免疫原性,毒性和药效学性质。
在特定的实施方案中,由于二肽是酶或生物转运系统的底物,因此被用于靶向或靶向转运的前药开发。二肽前药形成的非酶途径,即进行分子内环化以形成相应的二酮哌嗪(DKP)并释放活性药物的能力,尚未得到很好的定义。
在一些实施方案中,二肽经由酯键连接至药物部分,如对药物扑热息痛的二肽酯所描述的(Gomes等人,(2005)有机生物和医药化学期刊(Bio&Med Chem Lett))。在这种情况下,环化反应包括酯碳原子上的肽的N末端胺的亲核攻击,形成四面体中间体,紧接着,质子从胺转移到离去基团氧阴离子,同时形成肽键产生环DKP产物和游离药物。该方法适用于体外含羟基的药物,但已发现其可与体内酯键的酶水解竞争,因为相应的二肽酯以比在缓冲液中快得多的速率释放扑热息痛(Gomes等人,(分子12(2007)2484-2506)。基于二肽的前药对肽酶的敏感性可以通过在二肽基序中掺入至少一种非天然氨基酸来解决。然而,能够裂解酯键的内源酶不限于肽酶,并且这种前药裂解的酶依赖性仍然引起不可预测的体内性能。
在一些实施方案中,酶依赖性被有意地改造成DKP前药,例如其中二肽酯前药在二肽的氨基末端被甲酰化,并且酶促甲酰基化被用来引发二酮哌嗪形成和随后裂解酯-二肽键,紧接着,释放药物分子(参见,例如,USP 7,163,923)。作为进一步的实例,八肽通过酯键连接至长春碱的4-羟基基团,并且在N-末端六肽的特定酶促去除之后,通过DKP形成经历酯键裂解(参见Brady等人,(2002)J Med Chem 45:4706-15)。
DKP形成反应的范围也已扩展到酰胺前药。举例来说,USP 5,952,294描述了使用二酮哌嗪形成阿糖胞苷二肽酰胺前药的前药活化。在这种情况下,在二肽的羰基和阿糖胞苷的芳族氨基之间形成临时键。然而,由于不存在载体或其他延长半衰期的部分或官能团,因此对于此类缀合物不可能实现缓释效果。
还已经描述了包含生物活性肽如GLP-1的二肽前药,所述生物活性肽能够通过二肽延伸的二肽哌嗪形成而释放肽(参见,例如,WO 2009/099763)。生物活性肽部分可在其氨基酸侧链残基之一上包括另外的PEG链,以实现延长的生物活性肽循环。但是,这种方法具有几个明显的缺点。首先,PEG链必须与肽连接而不损害其生物活性,这对于许多基于肽的生物活性剂而言可能很难实现。其次,由于聚乙二醇化肽本身具有生物活性,因此二肽基团对肽的生物活性有影响,并可能对其受体结合特性产生负面影响。
可与本发明的化合物一起使用的具体示例性技术包括由普罗林科斯(ProLynx)(加利福尼亚州,旧金山)和阿森德斯医药(Ascendis Pharma)(加利福尼亚州,帕洛阿尔托)开发的技术。普罗林科斯(ProLynx)技术平台利用了一套新颖的接头,这些接头经过预先编程,可以以不同的速率裂解,从而可以从循环的半固体大分子偶联物中控制,预测和持续释放小分子和肽。该技术可将治疗剂的所需稳态血清水平维持数周至数月。
阿森德斯(Ascendis)技术平台结合了前药和持续释放技术的优势,以增强小分子和肽的特性。在流通时,专有的前药以生理pH和温度条件控制的预定速率释放未修饰的活性母体治疗剂。由于治疗剂以其未修饰的形式释放,因此保留了其原始的作用机理。
修饰以增强抑制剂特性
改善本文公开的治疗方式的多种物理性质和/或它们的给药方式常常是有益的,有时是必要的。物理性质的改善包括,例如,增加水溶性,生物利用度,血清半衰期和/或治疗半衰期的方法;和/或调节生物活性的方法。
本领域已知的修饰包括聚乙二醇化,Fc-融合和白蛋白融合。尽管通常与大分子试剂(例如多肽)有关,但是最近已经用特定的小分子评估了这种修饰。举个例子,Chiang,M等人,(美国化学会志,2014,136(9):3370-73)描述了与免疫球蛋白Fc结构域缀合的腺苷2a受体的小分子激动剂。与未结合的小分子相比,小分子-Fc结合物保留了有效的Fc受体和腺苷2a受体相互作用,并显示出优越的性能。还已经描述了PEG分子与小分子治疗剂的共价附接(Li,W等人,聚合物科学进程(Progress in Polymer Science),2013 38:421-44)。
其他已知的修饰包括氘化以改善药代动力学,药理学和毒性概况。由于氘的原子量较大,所以碳-氘键的裂解比碳-氢键的裂解需要更多的能量。因为这些更牢固的键更难以断裂,所以与非氘代形式相比,药物代谢的速度较慢,这使得给药频率降低,并可能进一步降低毒性。(Charles Schmidt,自然生物科技(Nature Biotechnology),2017,35(6):493-494;Harbeson,S.和Tung,R.,Medchem News,2014(2):8-22).
治疗和预防用途
本发明考虑了本文所述的A2AR/A2BR抑制剂在治疗或预防多种疾病,病症和/或状况和/或其症状中的用途。尽管在下文中详细描述了特定的用途,但是应该理解,本发明不限于此。此外,尽管下文阐述了特定疾病,病症和病状的一般类别,但是某些疾病,病症和病状可以是一个以上类别的成员,而其他疾病,病症或病状可能不是任何公开类别的成员。
在一些实施方案中,本文所述的疾病,病症和/或病状至少部分地由腺苷A2A受体(A2AR)介导。在一些实施方案中,本文所述的疾病,病症和/或病状至少部分地由腺苷A2B受体(A2BR)介导。在一些实施方案中,本文所述的疾病,病症和/或病状至少部分地由A2AR和A2BR两者介导。
在一些实施方案中,以有效逆转或终止A2AR介导的免疫抑制进程的量施用本文所述的A2AR/A2BR抑制剂。
与肿瘤有关的疾病。如本文其他地方所指出的,除了腺苷参与适于肿瘤发作和进展的免疫耐受的微环境的产生外,腺苷还通过参与肿瘤细胞上表达的受体的参与,还通过癌细胞增殖,凋亡和转移的作用,直接调节肿瘤块的生长和扩散。腺苷还可以通过激活A2A和A2B受体来促进细胞增殖。
通过增强CD8+T细胞的抗肿瘤作用以及抑制肿瘤新血管形成,生长和转移潜力,A2A受体的药理学阻断导致癌症的发展和扩散减少。同样,A2B受体的药理阻断作用会导致肿瘤生长延迟和转移性扩散减少。参见例如Antonioli L.等人,Expert Op on Ther Targets,18(9):973-77(2014)。
根据本发明,A2AR/A2BR抑制剂可用于治疗或预防增生性疾病或病症,包括癌症,例如子宫癌,子宫颈癌,乳腺癌,前列腺癌,睾丸癌,胃肠道(例如食道,口咽癌,胃,小肠或大肠,结肠或直肠)癌,肾脏癌,肾细胞癌,膀胱癌,骨骼癌,骨髓癌,皮肤癌,头部癌或颈部癌,肝脏癌,胆囊癌,心脏癌,肺癌,胰腺癌,唾液腺癌,肾上腺癌,甲状腺癌,大脑癌(例如神经胶质瘤),神经节癌,中枢神经系统(CNS)癌和周围神经系统(PNS)癌,以及造血系统和免疫系统的癌症(例如脾脏或胸腺)。本发明还提供了治疗或预防其他癌症相关疾病,病症或病状的方法,包括例如免疫原性肿瘤,非免疫原性肿瘤,休眠性肿瘤,病毒诱导的癌症(例如上皮细胞癌,内皮细胞癌,鳞状细胞癌和乳头瘤病毒),腺癌,淋巴瘤,癌,黑素瘤,白血病,骨髓瘤,肉瘤,畸胎瘤,化学性癌症,转移和血管生成。本发明涵盖了通过例如调节调节性T细胞和/或CD8+T细胞的活性来降低对肿瘤细胞或癌细胞抗原的耐受性(参见,例如,Ramirez-Montagut等,(2003)Oncogene 22:3180-87;和Sawaya等,(2003)New Engl.J.Med.349:1501-09)。在特定的实施方案中,肿瘤或癌症是结肠癌,卵巢癌,乳腺癌,黑素瘤,肺癌,成胶质细胞瘤或白血病。术语与癌症有关的疾病,病症和病状的使用意在广泛地指代与癌症直接或间接相关的病状,包括例如血管生成和癌前病状,例如发育不良。
在某些实施方案中,癌症是转移性的或有转移性的风险,或可以在弥漫性组织中发生,包括血液或骨髓的癌症(例如白血病)。在一些其他实施方案中,本发明的化合物可用于克服T细胞耐受性。
在一些实施方案中,本发明提供了用A2AR/A2BR抑制剂和至少一种其他治疗或诊断剂治疗增生性疾病,癌症,肿瘤或癌前疾病的方法,其实例在本文其他地方列出。
与免疫和炎症有关的疾病。如本文所用,诸如“免疫疾病”,“免疫病症”,“免疫病状”,“炎性疾病”,“炎性病症”,“炎性病状”等术语旨在广泛地涵盖任何免疫相关疾病(例如自身免疫性疾病)或具有炎症成分的疾病,可以用本文所述的A2AR/A2BR抑制剂治疗,从而获得一定的治疗效果。这样的状况经常与其他疾病,病症和病状密不可分。举例来说,“免疫疾病”可以指增殖性疾病,例如癌症,肿瘤和血管生成;包括感染(急性和慢性),抵抗免疫系统根除的肿瘤和癌症。
本发明的A2AR/A2BR抑制剂可用于增加或增强免疫反应;改善免疫,包括提高疫苗效力;并增加炎症。可以使用本文公开的化合物治疗与免疫缺陷疾病,免疫抑制医学治疗,急性和/或慢性感染以及衰老相关的免疫缺陷。A2AR/A2BR抑制剂还可以用于刺激患有医源性免疫抑制的患者的免疫系统,包括那些接受了骨髓移植,化学疗法或放射疗法的患者。
在本公开的特定实施方案中,A2AR/A2BR抑制剂用于通过提供佐剂活性来增加或增强对抗原的免疫应答。在一个具体的实施方案中,将至少一种抗原或疫苗与至少一种本发明的A2AR/A2BR抑制剂组合给予受试者,以延长对抗原或疫苗的免疫应答。还提供了治疗组合物,其包括至少一种抗原剂或疫苗组分,包括但不限于病毒,细菌和真菌或其部分,蛋白质,肽,肿瘤特异性抗原和核酸疫苗与至少一种本发明的A2AR/A2BR抑制剂的组合。
可以用本发明的化合物和组合物治疗或预防的与免疫和炎性相关的疾病,病症和病状的非限制性列表包括关节炎(例如类风湿性关节炎),肾衰竭,狼疮,哮喘,牛皮癣,结肠炎,胰腺炎,过敏,纤维化,手术并发症(例如,炎症细胞因子阻止愈合的地方),贫血和纤维肌痛。可能与慢性炎症相关的其他疾病和病症包括阿尔茨海默氏病,充血性心力衰竭,中风,主动脉瓣狭窄,动脉硬化,骨质疏松,帕金森氏病,感染,炎性肠病(例如克罗恩病和溃疡性结肠炎),过敏性接触性皮炎其他湿疹,全身性硬化症,移植和多发性硬化症。
在其他与免疫相关的疾病中,可以预期对A2AR/A2BR功能的抑制也可能在免疫耐受和预防子宫内胎儿排斥中发挥作用。
在一些实施方案中,本文所述的A2AR/A2BR抑制剂可以与免疫抑制剂组合以减少免疫效应细胞的数量。
下文将更详细地描述A2AR/A2BR抑制剂特别有效的上述某些疾病,病症和病状(例如由于当前疗法的局限性)。
类风湿关节炎(RA)通常以关节的膜层(滑膜)中的慢性炎症为特征,它影响着大约1%的美国人口(-210万人)。对包括TNF-a和IL-1在内的细胞因子在炎性过程中的作用的进一步了解使得能够开发和引入一类新型的疾病修饰抗风湿药物(DMARD)。药物(其中一些与RA的治疗方式重叠)包括ENBREL(依那西普(etanercept)),REMICADE(英夫利昔单抗(infliximab)),HUMIRA(阿达木单抗(adalimumab))和KINERET(阿那白滞素(anakinra))。尽管其中一些药物可缓解症状,抑制结构损伤的进展,并改善身体机能特别是在特定的患者人群中,仍然需要具有改善的功效,互补的作用机制以及较少/较少的严重不良反应的替代药物。
银屑病是一种常见的免疫介导的慢性皮肤病,在美国影响了超过450万人,其中150万人被认为患有中度至重度疾病。此外,超过10%的银屑病患者会发展出银屑病关节炎,从而损害关节周围的骨骼和结缔组织。对银屑病的基本生理学的更好的理解导致引入例如靶向该疾病的炎性本质的T淋巴细胞和细胞因子的活性的试剂。此类药物包括TNF-α抑制剂(也用于治疗类风湿关节炎(RA)),包括ENBREL(依那西普(etanercept)),REMICADE(英夫利昔单抗(infliximab))和HUMIRA(阿达木单抗(adalimumab)),以及T细胞抑制剂,例如AMEVIVE(阿法赛特(alefacept))和RAPTIVA(依法珠单抗(efalizumab))。尽管这些药物中的几种在某些患者人群中在一定程度上有效,但尚未显示出能有效治疗所有患者。
与微生物有关的疾病。本发明涵盖了本文所述的A2AR/A2BR抑制剂在治疗和/或预防任何A2AR/A2BR抑制剂治疗有效的病毒,细菌,真菌,寄生虫或其他感染性疾病,病症或病状中的用途。
涵盖的病毒性疾病,病症和病状的示例包括但不限于乙型肝炎病毒(HBV),丙型肝炎病毒(HCV),人乳头瘤病毒(HPV),HIV,艾滋病(包括其表现,例如恶病质,痴呆和腹泻),单纯疱疹病毒(HSV),EB病毒(EBV),水痘带状疱疹病毒,柯萨奇病毒和巨细胞病毒(CMV)。
此类疾病和病症的其他实例包括葡萄球菌和链球菌感染(例如分别为金黄色葡萄球菌和血红球菌),利什曼原虫,弓形虫,滴虫,贾第鞭毛虫,白色念珠菌,炭疽杆菌和铜绿假单胞菌。在一些实施方案中,疾病或病症包括分枝杆菌感染(例如麻风分枝杆菌或结核分枝杆菌)或由单核细胞增生性李斯特菌或弓形体引起的感染。本发明的化合物可用于治疗败血症,减少或抑制细菌生长以及减少或抑制炎性细胞因子。
进一步的实施方案涵盖了寄生虫感染的治疗,包括但不限于:利什曼原虫,热带利什曼原虫,大利什曼原虫,埃塞俄比亚利什曼原虫,墨西哥利什曼原虫,恶性疟原虫,间日疟原虫,卵形疟原虫或疟原虫。通常,预防性地施用抗寄生虫疗法(例如,在受试者前往寄生虫感染频率高的区域之前)。
中枢神经系统相关和神经系统疾病。对于患有神经系统疾病,神经精神疾病,神经退行性疾病或其他与中枢神经系统有关的疾病,病症和病状,包括与认知功能和运动功能受损有关的疾病的患者,抑制A2AR/A2BR可能也是一种重要的治疗策略。例子包括帕金森氏病,锥体外系综合症(EPS),肌张力障碍,静坐无力,迟发性运动障碍,不安腿综合症(RLS),癫痫病,周期性肢体运动(PLMS),注意力缺陷障碍,抑郁症,焦虑症,痴呆症,阿尔茨海默氏病,亨廷顿氏病,多发性硬化症,脑缺血,出血性中风,蛛网膜下腔出血和创伤性脑损伤。
患有多发性硬化症(MS)(一种严重使人衰弱的自身免疫性疾病,包括大脑和脊髓的多个发炎和髓磷脂疤痕形成区域)的受试者可能会因本文所述的A2AR/A2BR抑制剂而特别受益,因为目前的治疗方法只能缓解症状或延缓失能进展。
同样,A2AR/A2BR抑制剂对于患有神经退行性疾病(例如阿尔茨海默氏病(AD),该疾病是一种严重损害患者的思维,记忆和语言能力的脑部疾病;和帕金森氏病(PD),这是一种中枢神经系统进行性疾病,其特征在于,例如异常活动,僵硬和震颤)的受试者尤其有利。这些疾病是进行性的和使人衰弱的,并且没有可用的治疗剂。
其他疾病。本发明的实施方案涵盖了给受试者施用本文所述的A2AR/A2BR抑制剂以治疗或预防可受益于至少一些水平的A2AR/A2BR抑制的任何其他病症。这样的疾病,病症和病状包括例如心血管(例如心脏局部缺血),胃肠道(例如克罗恩氏病),代谢(例如糖尿病),肝(例如肝纤维化,NASH和NAFLD),肺(例如,COPD和哮喘),眼科疾病(例如糖尿病性视网膜病)和肾脏的疾病(例如肾功能衰竭)。
药物组合物
本发明的A2AR/A2BR抑制剂可以是适合于受试者施用的组合物形式。通常,此类组合物是“药物组合物”,其包含一种或多种A2AR/A2BR抑制剂和一种或多种药学上可接受的或生理学上可接受的稀释剂,载体或赋形剂。在某些实施方案中,A2AR/A2BR抑制剂以治疗上可接受的量存在。该药物组合物可用于本发明的方法中;因此,例如,可以将药物组合物离体或体内给予受试者,以实践本文所述的治疗和预防方法和用途。
可以将本发明的药物组合物配制成与预期的给药方法或给药途径相容。本文阐述了示例性的给药途径。此外,药物组合物可以与本文所述的其他治疗活性剂或化合物组合使用,以治疗或预防本发明所涵盖的疾病,病症和病状。
包含活性成分(例如,A2AR/A2BR功能的抑制剂)的药物组合物可以是适合口服使用的形式,例如片剂,胶囊剂,含片,锭剂,水性或油性悬浮液,可分散的粉剂或颗粒剂,乳剂,硬或软胶囊或糖浆,溶液,微珠或酏剂。可以根据用于制造药物组合物的本领域已知的任何方法制备用于口服的药物组合物,并且这种组合物可以包含一种或多种试剂,例如甜味剂,调味剂,着色剂和防腐剂,从而提供药学上优雅和可口的制剂。片剂,胶囊剂等包含活性成分与适于制备片剂的无毒药学上可接受的赋形剂混合物。这些赋形剂可以是,例如,稀释剂,例如碳酸钙,碳酸钠,乳糖,磷酸钙或磷酸钠;制粒和崩解剂,例如玉米淀粉或海藻酸;粘合剂,例如淀粉,明胶或阿拉伯胶,以及润滑剂,例如硬脂酸镁,硬脂酸或滑石。
适用于口服的片剂,胶囊剂等可以通过已知技术进行未包衣或包衣,以延迟在胃肠道中的崩解和吸收,从而提供持续的作用。例如,可以使用延时材料,例如单硬脂酸甘油酯或二硬脂酸甘油酯。它们也可以通过本领域已知的技术进行包衣以形成用于控制释放的渗透性治疗片剂。其他试剂包括可生物降解或可生物相容的颗粒或聚合物,例如聚酯,聚胺酸,水凝胶,聚乙烯吡咯烷酮,聚酸酐,聚乙醇酸,乙烯-乙酸乙烯酯,甲基纤维素,羧甲基纤维素,硫酸鱼精蛋白或丙交酯/乙交酯共聚物,聚丙交酯/乙交酯共聚物,或乙烯乙酸乙烯酯共聚物,以控制所施用组合物的递送。例如,可以分别通过使用羟甲基纤维素或明胶-微胶囊或聚(甲基甲基丙烯酸甲酯)微胶囊,将包囊剂包埋在通过凝聚技术或通过界面聚合制备的微胶囊中,或包封在胶体药物递送系统中。胶体分散系统包括大分子复合物,纳米胶囊,微球,微珠和基于脂质的系统,包括水包油乳液,胶束,混合胶束和脂质体。制备上述制剂的方法对本领域技术人员而言是显而易见的。
口服制剂还可以以硬明胶胶囊剂的形式存在,其中活性成分与惰性固体稀释剂例如碳酸钙,磷酸钙,高岭土或微晶纤维素混合;或者以软明胶胶囊剂的形式存在,其中活性成分与水或油介质(例如花生油,液体石蜡或橄榄油)混合。
水性悬浮液包含与适合于其制造的赋形剂混合的活性物质。这样的赋形剂可以是悬浮剂,例如羧甲基纤维素钠,甲基纤维素,羟丙基甲基纤维素,藻酸钠,聚乙烯吡咯烷酮,黄蓍胶和阿拉伯胶;分散剂或润湿剂,例如天然存在的磷脂(例如卵磷脂),或环氧烷与脂肪酸的缩合产物(例如聚氧乙烯硬脂酸酯),或环氧乙烷与长链脂族醇的缩合产物(例如,例如七十六烷乙烯氧基鲸蜡醇),或环氧乙烷与衍生自脂肪酸和己糖醇的部分酯的缩合产物(例如,聚氧乙烯山梨醇单油酸酯),或环氧乙烷与衍生自脂肪酸和己糖醇酐的部分酯的缩合产物(例如,聚乙烯山梨醇酐单油酸酯)。水性悬浮液还可包含一种或多种防腐剂。
油性悬浮液可通过将活性成分悬浮在植物油(例如花生油,橄榄油,芝麻油或椰子油)或矿物油(例如液体石蜡)中来配制。油性悬浮液可包含增稠剂,例如蜂蜡,硬石蜡或鲸蜡醇。可以添加诸如上述的甜味剂和调味剂以提供可口的口服制剂。
适用于通过加水制备水性悬浮液的可分散粉末和颗粒,可提供与分散剂或湿润剂,助悬剂和一种或多种防腐剂混合的活性成分。合适的分散剂或湿润剂和助悬剂在本文中举例说明。
本发明的药物组合物也可以是水包油乳剂的形式。油相可以是植物油,例如橄榄油或花生油,或矿物油,例如液体石蜡,或这些的混合物。合适的乳化剂可以是天然存在的树胶,例如阿拉伯树胶或黄蓍胶;天然存在的磷脂,例如大豆,卵磷脂和脂肪酸衍生的酯或偏酯;己糖醇酐,例如脱水山梨糖醇单油酸酯;以及偏酯与环氧乙烷的缩合产物,例如聚氧乙烯脱水山梨醇单油酸酯。
药物组合物通常包含治疗有效量的本发明考虑的A2AR/A2BR抑制剂和一种或多种药学和生理学上可接受的制剂剂。合适的药学上可接受或生理学上可接受的稀释剂,载体或赋形剂包括但不限于抗氧化剂(例如抗坏血酸和硫酸氢钠),防腐剂(例如苯甲醇,对羟基苯甲酸甲酯,乙基或正丙基,对羟基苯甲酸酯),乳化剂,助悬剂,分散剂,溶剂,填充剂,蓬松剂,去污剂,缓冲剂,赋形剂,稀释剂和/或助剂。例如,合适的媒介物可以是生理盐溶液或柠檬酸盐缓冲盐,可能补充了用于肠胃外给药的药物组合物中常见的其他物质。中性缓冲盐水或与血清白蛋白混合的盐水是其他示例性载体。本领域技术人员将容易认识到可用于本文涵盖的药物组合物和剂型的多种缓冲剂。典型的缓冲剂包括但不限于药学上可接受的弱酸,弱碱或其混合物。例如,缓冲剂组分可以是水溶性材料,例如磷酸,酒石酸,乳酸,琥珀酸,柠檬酸,乙酸,抗坏血酸,天冬氨酸,谷氨酸及其盐。可接受的缓冲剂包括,例如Tris缓冲液,N-(2-羟乙基)哌嗪-N'-(2-乙磺酸)(HEPES),2-(N-吗啉)乙磺酸(MES),2-(N-吗啉)乙磺酸钠盐(MES),3-(N-吗啉)丙磺酸(MOPS)和N-三[羟甲基]甲基-3-氨基丙磺酸(TAPS)。
在配制药物组合物之后,可以将其以溶液,悬浮液,凝胶,乳剂,固体或脱水或冻干的粉末形式存储在无菌小瓶中。这样的制剂可以以即用形式,在使用前需要重构的冻干形式,在使用前需要稀释的液体形式或其他可接受的形式存储。在一些实施方案中,药物组合物被提供在一次性容器(例如,一次性瓶,安瓿瓶,注射器或自动注射器(类似于,例如)中),而在其他实施例中,提供多次使用的容器(例如,多用途小瓶)。
制剂还可以包括载体以保护组合物免于快速降解或从体内清除,例如控释制剂,包括脂质体,水凝胶,前药和微囊递送系统。例如,可以使用延时材料,例如单硬脂酸甘油酯或硬脂酸甘油酯,或与蜡结合使用。可以使用任何药物输送设备来输送A2AR/A2BR抑制剂,包括植入物(例如,可植入泵)和导管系统,慢速注射泵和装置,这些都是本领域技术人员众所周知的。
通常通过皮下或肌肉内施用的储库注射剂还可用于在限定的时间内释放本文公开的A2AR/A2BR抑制剂。储库注射剂通常是基于固体或油的,并且通常包含本文所述的制剂成分中的至少一种。本领域普通技术人员熟悉储库注射剂的可能配方和用途。
药物组合物可以是无菌可注射的水性或油性悬浮液的形式。该悬浮液可以根据已知技术使用本文提及的那些合适的分散剂或湿润剂和悬浮剂来配制。无菌注射制剂也可以是在无毒的肠胃外可接受的稀释剂或溶剂中的无菌注射溶液或悬浮液,例如在1,3-丁二醇中的溶液。可以使用的可接受的稀释剂,溶剂和分散介质包括水,林格氏溶液,等渗氯化钠溶液,Cremophor ELTM(BASF,Parsippany,NJ)或磷酸盐缓冲盐水(PBS),乙醇,多元醇(例如甘油,丙二醇以及液体聚乙二醇)及其合适的混合物。另外,无菌的不挥发油通常用作溶剂或悬浮介质。为此,可以使用任何温和的不挥发性油,包括合成的甘油单酯或甘油二酯。此外,脂肪酸如油酸可用于制备注射剂。通过包括延迟吸收的试剂(例如单硬脂酸铝或明胶),可以实现特定注射制剂的延长吸收。
本发明考虑了用于直肠给药的栓剂形式的A2AR/A2BR抑制剂的给药。栓剂可以通过将药物与合适的无刺激性的赋形剂混合来制备,该赋形剂在常温下为固体,而在直肠温度下为液体,因此将在直肠中融化以释放出药物。这样的材料包括但不限于可可脂和聚乙二醇。
本发明考虑的A2AR/A2BR抑制剂可以是目前已知或将来开发的任何其他合适的药物组合物的形式(例如,用于鼻或吸入的喷雾剂)。
给药途径
本发明涵盖以任何适当方式施用A2AR/A2BR抑制剂及其组合物。合适的给药途径包括口服,肠胃外(例如,肌内,静脉内,皮下(例如,注射或植入),腹膜内,脑池内,关节内,腹膜内,脑内(脑实质内)和脑室内),鼻,阴道,舌下,眼内,直肠,局部(如透皮),颊和吸入。通常通过皮下或肌肉内给药的贮库注射也可用于在限定的时间内释放本文公开的A2AR/A2BR抑制剂。
本发明的特定实施方案考虑口服施用。
联合疗法
本发明预期单独使用A2AR/A2BR抑制剂或与一种或多种活性治疗剂组合使用。额外的活性治疗剂可以是小的化学分子;大分子,例如蛋白质,抗体,肽体,肽,DNA,RNA或此类大分子的片段;或细胞或基因疗法。在这种联合疗法中,各种活性剂经常具有不同的互补作用机理。通过允许减少一种或多种药剂的剂量,从而减少或消除与一种或多种药剂相关的不利影响,这种组合疗法可能是特别有利的。此外,这种组合疗法可以对潜在的疾病,病症或病状具有协同的治疗或预防作用。
如本文所用,“组合”是指包括可以单独施用的疗法,例如,单独配制用于单独施用的疗法(例如,如可以在试剂盒中提供的),以及可以在单一制剂中一起施用的疗法(即“共同配方”)。
在某些实施方案中,A2AR/A2BR抑制剂是施用或顺序施用的,例如其中一种药物在一种或多种其他药物之前施用。在其他实施方案中,A2AR/A2BR抑制剂是同时施用的,例如其中两种或多种药剂同时或大约同时施用;两种或多种药剂可以两种或多种分开的制剂存在或组合成单一制剂(即,共同制剂)。不管是顺序地还是同时地施用两种或更多种药剂,它们被认为是出于本发明的目的组合施用。
本发明的A2AR/A2BR抑制剂可以在特定情况下以任何合适的方式与至少一种其他(活性)试剂组合使用。在一个实施方案中,在一段时间内维持用至少一种活性剂和至少一种本发明的A2AR/A2BR抑制剂的治疗。在另一个实施方案中,减少或中断用至少一种活性剂的治疗(例如,当受试者稳定时),而本发明A2AR/A2BR抑制剂的治疗维持在恒定的给药方案下。在另一个实施方案中,减少或终止用至少一种活性剂的治疗(例如,当受试者稳定时),同时减少本发明的A2AR/A2BR抑制剂的治疗(例如,较低的剂量,较少的给药频率或较短的治疗方案)。在另一个实施方案中,减少或终止用至少一种活性剂的治疗(例如,当受试者稳定时),并且增加用本发明的A2AR/A2BR抑制剂的治疗(例如,更高剂量,更频繁给药或更长治疗方案)。在又一个实施方案中,维持用至少一种活性剂的治疗并且减少或终止用本发明的A2AR/A2BR抑制剂的治疗(例如,较低剂量,较低频率的给药或较短的治疗方案)。在又一个实施方案中,减少或中断了用至少一种活性剂的治疗和用本发明的A2AR/A2BR抑制剂的治疗(例如,较低的剂量,较低的给药频率或较短的治疗方案)。
与肿瘤有关的疾病。本发明提供了用A2AR/A2BR抑制剂和至少一种另外的治疗或诊断剂治疗和/或预防增生性疾病,癌症,肿瘤或癌前疾病,病症或病状的方法。在一些实施方案中,另外的治疗剂或诊断剂是放射剂,免疫调节剂或化学治疗剂或诊断剂。可用于本发明的合适的免疫调节剂包括CD4OL,B7和B7RP1;和针对刺激性受体(例如抗CD40,抗CD38,抗ICOS和4-IBB配体)的活化单克隆抗体(mAb);树突状细胞抗原负荷(体外或体内);抗癌疫苗,例如树突状细胞癌疫苗;细胞因子/趋化因子,例如ILL IL2,IL12,IL18,ELC/CCL19,SLC/CCL21,MCP-1,IL-4,IL-18,TNF,IL-15,MDC,IFNa/b,M-CSF,IL-3,GM-CSF,IL-13和抗IL-10;细菌脂多糖(LPS);吲哚胺2,3-双加氧酶1(IDO1)抑制剂和免疫刺激性寡核苷酸。
在某些实施方案中,本发明提供了用于抑制肿瘤生长的方法,其包括与信号转导抑制剂(STI)组合施用本文所述的A2AR/A2BR抑制剂以实现累加或协同抑制肿瘤生长。如本文所用,术语“信号转导抑制剂”是指选择性抑制信号传导途径中一个或多个步骤的试剂。本发明的信号转导抑制剂(STI)包括:(i)bcr/abl激酶抑制剂(例如GLEEVEC);(ii)表皮生长因子(EGF)受体抑制剂,包括激酶抑制剂和抗体;(iii)her-2/neu受体抑制剂(例如HERCEPTIN);(iv)Akt家族激酶或Akt途径的抑制剂(例如雷帕霉素(rapamycin));(v)细胞周期激酶抑制剂(例如夫拉平度flavopiridol);和(vi)磷脂酰肌醇激酶抑制剂。免疫调节中涉及的试剂也可以与本文所述的A2AR/A2BR抑制剂组合用于抑制癌症患者中的肿瘤生长。
化疗剂的实例包括但不限于烷基化剂,例如噻替帕和环磷酰胺;烷基磺酸盐,例如白消安,英丙舒凡和哌泊舒凡;氮丙啶类,例如苯并多巴,卡波醌,美多巴和乌多巴;乙亚胺和甲基三聚氰胺,包括六甲蜜胺(altretamine),三亚乙基三聚氰胺,三亚乙基磷酰胺,三亚乙基硫代磷酰胺和三甲基三聚氰胺;氮芥,例如苯丁酸氮芥,萘氮芥,氯磷酰胺,雌莫司汀,异环磷酰胺,甲氯乙胺,盐酸甲氧氮芥,美法仑,新霉素,苯芥胆甾醇,泼尼氮芥,曲磷酰胺,尿嘧啶芥;亚硝基脲,例如卡莫司汀,氯唑霉素,铁莫司汀,洛莫斯汀,尼莫斯汀,拉尼莫司汀;抗生素,如阿克拉霉素,放线菌素,安曲霉素,重氮丝氨酸,博来霉素,放线菌素C,卡奇霉素,卡拉比星,洋红霉素,嗜癌霉素,色霉素,放线菌素D,柔红霉素,地托比星,6-重氮-5-氧代-L-正亮氨酸,阿霉素,表阿霉素,依索比星,伊达比星,麻西罗霉素,丝裂霉素,麦可酚酸,诺加霉素,寡霉素,培洛霉素,波菲霉素,嘌呤霉素,奎拉霉素,罗多比星,链黑霉素,链脲霉素,结核菌素,乌苯美司,净司他丁,佐柔比星;抗代谢物,例如甲氨蝶呤和5-氟尿嘧啶(5-FU);叶酸类似物,如树新蝶呤,甲氨蝶呤,蝶呤,三甲蝶呤;嘌呤类似物,例如氟达拉滨,6-巯基嘌呤,噻虫啉,硫鸟嘌呤;嘧啶类似物,如安西他滨,阿扎胞苷,6-氮杂尿苷,卡莫呋,阿糖胞苷,双脱氧尿苷,多西氟啶,恩诺西汀,氟尿苷,5-FU;雄激素,例如卡普睾酮,丙酸屈他雄酮,环硫雄醇,美雄烷,睾丸内酯;抗肾上腺素,例如胺鲁米特,米托坦,曲洛斯坦(trilostane);叶酸补充剂,例如弗洛林酸(frolinic acid);乙酰葡醛酯;醛磷酰胺糖苷;胺基乙酰丙酸;安吖啶(amsacrine);贝斯布西(bestrabucil);比山群(bisantrene);艾达曲克(edatraxate);得弗伐胺(defofamine);地美可辛(demecolcine);地吖醌(diaziquone);艾福米辛(elformithine);依利醋铵(elliptinium acetate);依托格鲁(etoglucid);硝酸镓;羟基脲;香菇多糖(lentinan);录尼达明(lonidamine);丙米腙(mitoguazone);米托蒽醌(mitoxantrone);莫哌达醇(mopidamol);尼曲吖啶(nitracrine);喷司他丁(pentostatin);笨来美特(phenamet);吡柔比星(pirarunicin);鬼臼酸(podophyllinic acid);2-乙基肼;丙卡巴肼;雷佐生(razoxane);西佐喃(sizofiran);螺旋锗(spirogermanium);细交链孢菌酮酸(tenuazonic acid);三亚胺醌(triaziquone);2,2',2”-三氯三乙胺;乌拉坦(urethan);长春地辛(vindesine);达卡巴嗪;甘露醇氮芥(mannomustine);二溴甘露醇(mitobronitol);哌泊溴烷(pipobroman);加西托星(gacytosine);阿拉伯糖苷(Ara-C);环磷酰胺;噻替派;类紫杉醇(taxoids),例如太平洋紫杉醇和多烯紫杉醇(docetaxel);氯芥苯丁酸;吉西他滨;6-硫鸟嘌呤;巯基嘌呤;甲氨蝶呤;铂和铂配位配合物,例如顺铂,卡铂和奥沙利铂;长春碱;依托泊苷(VP-16);异环磷酰胺(ifosfamide);丝裂霉素C;米托蒽醌;长春新碱;长春瑞滨(vinorelbine);温诺平(navelbine);诺安托(novantrone);替尼泊苷;柔红微素(daunommmycin);胺基碟呤(aminopterin);希罗达(xeloda);伊班膦酸(ibandronate);CPT11;拓扑异构酶抑制剂;二氟甲基鸟氨酸(DMFO);视黄酸;埃斯波微素(esperamicins);卡培他滨(capecitabine);蒽环类药物以及任何上述的药学上可接受的盐,酸或衍生物。
化学治疗剂还包括用于调节或抑制荷尔蒙对肿瘤的作用的抗激素剂,例如抗雌激素,包括他莫昔芬(tamoxifen),雷洛昔芬(raloxifene),抑制芳香酶的4(5)-咪唑,4-羟基他莫昔芬,曲沃昔芬,雷洛西芬,奥那斯酮,和托瑞米芬;和抗雄激素,例如氟他胺,尼鲁米特,比卡鲁胺,亮丙瑞林和戈舍瑞林;以及任何上述的药学上可接受的盐,酸或衍生物。在某些实施方案中,组合疗法包括化学疗法方案,该化学疗法方案包括一种或多种化学治疗剂。在某些实施方案中,联合疗法包括激素或相关激素制剂的施用。
可以与A2AR/A2BR抑制剂组合施用的其他治疗方式包括放射疗法,抗肿瘤抗原的单克隆抗体,单克隆抗体和毒素的复合物,T细胞佐剂,骨髓移植或抗原呈递细胞(例如树突状细胞疗法),包括用于刺激此类抗原呈递细胞的TLR激动剂。。
在某些实施方案中,本发明考虑将本文所述的化合物与过继细胞疗法结合使用,过继细胞疗法是一种新的和有希望的形式的个性化免疫疗法,其中将具有抗肿瘤活性的免疫细胞施用于癌症患者。正在使用肿瘤浸润淋巴细胞(TIL)和工程改造以表达例如嵌合抗原受体(CAR)或T细胞受体(TCR)的T细胞来研究过继性细胞疗法。过继细胞疗法通常涉及从个体收集T细胞,对其进行基因修饰以靶向特定抗原或增强其抗肿瘤作用,将其扩增至足够数量,然后将基因修饰的T细胞输注到癌症患者中。可以从患者中收集T细胞,然后将其再注入输注的细胞中(例如,自体的),或者可以从供体患者中收集(例如,同种异体的)。
在某些实施方案中,本发明考虑将本文所述的化合物与基于RNA干扰的疗法组合使用以沉默基因表达。RNAi从将较长的双链RNA切割成小的干扰RNA(siRNA)开始。一条siRNA链被掺入称为RNA诱导的沉默复合物(RISC)的核糖核蛋白复合物中,然后用于鉴定与掺入的siRNA链至少部分互补的mRNA分子。RISC可以结合或切割mRNA,两者均抑制翻译。
免疫检查点抑制剂。本发明包括将本文所述的A2AR/A2BR功能的抑制剂与免疫检查点抑制剂组合使用。
所有癌症的特征是都具有大量的遗传和表观的改变,这些改变提供了多种抗原,免疫系统可以使用这些抗原来区分肿瘤细胞与正常细胞。对于T细胞,通过T细胞受体(TCR)的抗原识别而启动的应答的最终振幅(例如,细胞因子产生或增殖的水平)和应答的质量(例如,产生的免疫应答的类型,例如细胞因子产生的模式)通过在共刺激信号和抑制信号之间(免疫检查点)的平衡来调节。在正常的生理条件下,免疫检查点对于预防自身免疫(即维持自我耐受)以及在免疫系统对病原体感染作出反应时保护组织免受损伤至关重要。免疫检查点蛋白的表达可能被肿瘤调节为重要的免疫抵抗机制。
T细胞已成为治疗内源性抗肿瘤免疫力的主要工作重点,因为:i)它们能够选择性识别所有细胞区室中源自蛋白质的肽的能力;ii)它们直接识别和杀死表达抗原的细胞的能力(通过CD8+效应T细胞;也称为细胞毒性T淋巴细胞(CTL));和iii)它们通过整合适应性和先天性效应子机制的CD4+辅助性T细胞协调各种免疫反应的能力。
在临床环境中,对免疫检查点的封锁(导致抗原特异性T细胞反应的扩增)已被证明是人类癌症治疗方法中的一种有前途的方法。
T细胞介导的免疫包括多个连续步骤,每个步骤均由平衡刺激和抑制信号来调节,以优化反应。尽管免疫应答中几乎所有抑制信号最终都会调节细胞内信号传导途径,但许多抑制信号是通过膜受体启动的,其配体是膜结合的或可溶的(细胞因子)。尽管相对于正常组织,调节T细胞活化的共刺激和抑制受体和配体在癌症中通常不会过表达,调节组织中T细胞效应子功能的抑制性配体和受体通常在肿瘤细胞或与肿瘤微环境有关的未转化细胞上过表达。可以使用激动剂抗体(用于共刺激途径)或拮抗剂抗体(用于抑制途径)调节可溶性和膜结合受体-配体免疫检查点的功能。因此,与目前被批准用于癌症治疗的大多数抗体相反,阻断免疫检查点的抗体不是直接靶向肿瘤细胞,而是靶向淋巴细胞受体或其配体以增强内源性抗肿瘤活性。[参见Pardoll,(2012年4月)Nature Rev.Cancer 12:252-64]。
免疫检查点(配体和受体)的例子,其中一些在各种类型的肿瘤细胞中选择性上调,这些是可以被阻断的候选物,包括PD1(程序性细胞死亡蛋白1);PDL1(PD1配体);BTLA(B和T淋巴细胞衰减剂);CTLA4(细胞毒性T淋巴细胞相关抗原4);TIM3(T细胞膜蛋白3);LAG3(淋巴细胞激活基因3);TIGIT(具有Ig和ITIM结构域的T细胞免疫受体);和杀手抑制受体,根据其结构特点可分为两类:i)杀伤细胞免疫球蛋白样受体(KIR),和ii)C型凝集素受体(II型跨膜受体家族成员)。文献中还描述了其他不太明确的免疫检查点,包括受体(例如2B4(也称为CD244)受体)和配体(例如某些B7家族抑制性配体,例如B7-H3(也称为CD276)和B7-H4(也称为B7-S1,B7x和VCTN1))。[参见Pardoll,(2012年4月)Nature Rev.Cancer 12:252-64]。
本发明涵盖了将本文所述的A2AR/A2BR功能的抑制剂与上述免疫检查点受体和配体的抑制剂以及尚待描述的免疫检查点受体和配体组合使用。免疫检查点的某些调节剂目前已获批准,许多其他调节剂正在开发中。为了说明这一点,当2011年被批准用于黑色素瘤的治疗时,完全人源化的CTLA4单克隆抗体伊匹单抗(ipilimumab)(YERVOY;Bristol-MyersSquibb)成为美国第一个获得监管部门批准的免疫检查点抑制剂。包含CTLA4和抗体的融合蛋白(CTLA4-Ig;abatcept(ORENCIA;百时美施贵宝))已用于治疗类风湿性关节炎,并且其他融合蛋白已被证明对爱泼斯坦巴尔病毒敏感的肾移植患者有效。下一类获得监管机构批准的免疫检查点抑制剂是针对PD-1及其配体PD-L1和PD-L2的。批准的抗PD1抗体包括用于各种癌症的纳武单抗(nivolumab)(欧狄沃;百时美施贵宝(OPDIVO;Bristol-MyersSquibb))和派姆单抗(pembrolizumab)(可瑞达(KEYTRUDA);默克),包括鳞状细胞癌,经典霍奇金淋巴瘤和尿路上皮癌。批准的抗PDL1抗体包括针对某些癌症(包括尿路上皮癌)的阿维单抗(avelumab)(巴卫尼西欧(BAVENCIO),雪兰诺&辉瑞(EMD Serono&Pfizer)),阿特珠单抗(atezolizumab)(特森奇(TECENTRIQ);罗氏(Roche)/基因泰克(Genentech))和德瓦鲁单抗(durvalumab)(英非凡(IMFINZI);阿斯利康(AstraZeneca))。尽管尚无批准的靶向TIGIT或其配体CD155和CD112的疗法,但正在开发的疗法包括BMS-986207(百时美施贵宝(Bristol-Myers Squibb)),MTIG7192A/RG6058(罗氏(Roche)/基因泰克(Genentech))和OMP-31M32(OncoMed)。
在本发明的一方面,要求保护的A2AR/A2BR抑制剂与免疫肿瘤剂组合,所述免疫肿瘤剂是(i)刺激性(包括共刺激性)受体的激动剂或(ii)T细胞上抑制性信号(包括共抑制性信号)的拮抗剂,这两者都会导致抗原特异性T细胞反应的放大。某些刺激性和抑制性分子是免疫球蛋白超家族(IgSF)的成员。与共刺激或共抑制受体结合的重要的膜结合配体家族是B7家族,包括B7-1,B7-2,B7-H1(PD-L1),B7-DC(PD-L2),B7-H2(ICOS-L),B7-H3,B7-H4,B7-H5(VISTA),B7-H6和B7-H7(HHLA2)。与共刺激或共抑制受体结合的另一类膜结合配体是与同种TNF受体家族成员结合的TNF分子家族,包括CD40和CD4OL,OX-40,OX-40L,CD70,CD27L,CD30,CD3OL,4-1BBL,CD137(4-1BB),TRAIL/Apo2-L,TRAILR1/DR4,TRAILR2/DR5,TRAILR3,TRAILR4,OPG,RANK,RANKL,TWEAKR/Fn14,TWEAK,BAFFR,EDAR,XEDAR,TACI,APRIL,BCMA,LT13R,LIGHT,DcR3,HVEM,VEGI/TL1A,TRAMP/DR3,EDAR,EDA1,XEDAR,EDA2,TNFR1,淋巴毒素a/TNF13,TNFR2,TNFa,LT13R,淋巴毒素a 1132,FAS FASL,RELT,DR6,TROY,NGFR。
在另一方面,免疫肿瘤剂是抑制T细胞活化的细胞因子(例如,IL-6,IL-10,TGF-B,VEGF和其他免疫抑制细胞因子)或刺激T细胞活化的细胞因子以用于刺激免疫反应。
一方面,可以通过所公开的A2AR/A2BR抑制剂和以下一种或多种的组合来刺激T细胞应答:(i)抑制T细胞活化的蛋白质的拮抗剂(例如免疫检查点抑制剂),例如CTLA-4,PD-1,PD-L1,PD-L2,LAG-3,TIM-3,半乳凝素9,CEACAM-1,BTLA,CD69,半乳凝素1,TIGIT,CD113,GPR56,VISTA,2B4,CD48,GARP,PD1H,LAIR1,TIM-1和TIM-4,和/或(ii)刺激T细胞活化的蛋白质的激动剂,例如B7-1,B7-2,CD28、4-1BB(CD137),4-1BBL,ICOS,ICOS-L,OX40,OX4OL,GITR,GITRL,CD70,CD27,CD40,DR3和CD2。可以与本发明的A2AR/A2BR抑制剂组合用于治疗癌症的其他药剂包括NK细胞上抑制性受体的拮抗剂或NK细胞上激活性受体的激动剂。例如,本文的化合物可以与KIR的拮抗剂,例如利瑞路单抗组合。
组合疗法的其他试剂包括抑制或消耗巨噬细胞或单核细胞的试剂,包括但不限于CSF-1R拮抗剂,例如CSF-1R拮抗剂抗体,包括RG7155(W011/70024,W011/107553,W011/131407,WO13/87699,W013/119716,W013/132044)或FPA-008(W011/140249;W013169264;W014/036357)。
在另一方面,所公开的A2AR/A2BR抑制剂可以与一种或多种连接阳性共刺激受体的激动剂,通过抑制性受体减弱信号传导的阻断剂,拮抗剂以及一种或多种全身性增加抗肿瘤T细胞频率的试剂一起使用,克服肿瘤微环境内不同免疫抑制途径(例如,阻断抑制性受体参与(例如,PD-L1/PD-1相互作用)),消耗或抑制Treg(例如,使用抗CD25单克隆抗体(例如,达利珠单抗(daclizumab)或通过体内抗CD25珠粒耗尽)或逆向/预防T细胞无能或力竭)和触发肿瘤部位先天性免疫激活和/或炎症的药物。
一方面,免疫肿瘤剂是CTLA-4拮抗剂,例如拮抗性CTLA-4抗体。合适的CTLA-4抗体包括例如YERVOY伊匹单抗(ipilimumab)或曲美单抗(tremelimumab)。
在另一方面,所述免疫肿瘤剂是PD-1拮抗剂,例如拮抗性PD-1抗体。合适的PD-1抗体包括,例如,OPDIVO(纳武单抗(nivolumab)),KEYTRUDA(派姆单抗(pembrolizumab))或MEDI-0680(AMP-514;WO2012/145493)。尽管对PD-1结合的特异性提出质疑,但该免疫肿瘤治疗剂也可包括皮立珠单抗(pidilizumab)(CT-011)。靶向PD-1受体的另一种方法是重组蛋白,该蛋白由与IgG1的Fc部分融合的PD-L2的胞外域(B7-DC)组成,称为AMP-224。
在另一方面,该免疫肿瘤剂是PD-L1拮抗剂,例如拮抗性PD-L1抗体。合适的PD-L1抗体包括例如TECENTRIC(阿托珠单抗(atezolizumab);
MPDL3280A;W02010/077634),德瓦鲁单抗(durvalumab)(MEDI4736),BMS-936559(W02007/005874)和MSB0010718C(W02013/79174)。
在另一方面,所述免疫肿瘤剂是LAG-3拮抗剂,例如拮抗性LAG-3抗体。合适的LAG3抗体包括,例如,BMS-986016(W010/19570,W014/08218),或IMP-731或IMP-321(W008/132601,W009/44273)。
在另一方面,该免疫肿瘤剂是CD137(4-1BB)激动剂,例如激动性CD137抗体。合适的CD137抗体包括例如优瑞路单抗(urelumab)和PF-05082566(WO12/32433)。
在另一方面,所述免疫肿瘤剂是GITR激动剂,例如激动性GITR抗体。合适的GITR抗体包括例如BMS-986153,BMS-986156,TRX-518(W006/105021,W009/009116)和MK-4166(W011/028683)。
在另一方面,所述免疫肿瘤剂是OX40激动剂,例如激动性OX40抗体。合适的OX40抗体包括例如MEDI-6383或MEDI-6469。
在另一方面,该免疫肿瘤剂是OX4OL拮抗剂,例如拮抗OX40抗体。合适的OX4OL拮抗剂包括例如RG-7888(W006/029879)。
在另一方面,所述免疫肿瘤剂是CD40激动剂,例如激动性CD40抗体。在又一个实施方案中,免疫肿瘤剂是CD40拮抗剂,例如拮抗性CD40抗体。合适的CD40抗体包括,例如,鲁卡木单抗(lucatumumab)或达西珠单抗(dacetuzumab)。
在另一方面,该免疫肿瘤剂是CD27激动剂,例如激动性CD27抗体。合适的CD27抗体包括例如瓦里木单抗(varlilumab)。
在另一方面,免疫肿瘤剂是MGA271(对B7H3)(W011/109400)。
本发明包括以上任何一种的药学上可接受的盐,酸或衍生物。
代谢和心血管疾病。本发明提供了用A2AR/A2BR抑制剂和至少一种另外的治疗剂或诊断剂治疗和/或预防某些与心血管和/或代谢有关的疾病,病症和病状以及与之相关的病症的方法。
可用于治疗高胆固醇血症(以及动脉粥样硬化)的联合疗法的治疗剂的实例包括抑制胆固醇的酶促合成的他汀类药物(例如CRESTOR,LESCOL,LIPITOR,MEVACOR,PRAVACOL和ZOCOR);胆汁酸树脂(例如COLESTID,LO-CHOLEST,PREVALITE,QUESTRAN和WELCHOL),它们螯合胆固醇并阻止其吸收;依泽替米贝(ZETIA),可阻止胆固醇的吸收;降低甘油三酸酯并适度增加HDL的纤维酸(例如TRICOR);烟酸(例如NIACOR),可适度降低LDL胆固醇和甘油三酸酯;和/或上述物质的组合(例如VYTORIN(“依折麦布(ezetimibe)与辛伐他汀(simvastatin))。可能与本文所述的A2AR/A2BR抑制剂组合使用的备选胆固醇治疗方法包括各种补品和草药(例如大蒜,甘蔗原素(policosanol)和香胶(guggul))。
本发明包括以上任何一种的药学上可接受的盐,酸或衍生物。
与免疫和炎症有关的疾病。本发明提供了用于治疗和/或预防免疫相关疾病,病症和病状的方法;以及具有炎症成分的疾病,病症和病状;与A2AR/A2BR抑制剂和至少一种其他治疗剂或诊断剂一起使用。
可用于联合疗法的治疗剂示例包括但不限于以下各项:非甾体抗炎药(NSAID),例如阿司匹林,布洛芬和其他丙酸衍生物(阿米洛芬,贝诺沙芬,丁酸,卡洛芬,芬布芬,非诺洛芬,氟洛芬,氟比洛芬,吲哚洛芬,酮洛芬,米洛芬,萘普生,奥沙普嗪,吡洛芬,普罗洛芬,舒普洛芬,噻洛芬酸和噻洛芬),醋酸衍生物(吲哚美辛,阿西美辛,阿氯芬酸,克林达那,双氯芬酸,芬氯芬酸,芬克洛酸,芬替酸,弗洛芬克,异丁芬酸,伊索克酸,噁平酸,舒林酸,硫平酸,托美丁,齐多美辛(zidometacin)和佐美酸(zomepirac)),芬那酸(fenamic acid)衍生物(氟芬那酸(flufenamic acid),甲氯芬那酸(meclofenamic acid),甲芬那酸(mefenamicacid),烟酸(niflunic acid)和托芬那酸(tolfenamic acid)),联苯甲酸衍生物(二氟尼柳(diflunisal)及氟苯柳(flufenisal)),奥昔康星(oxicams)(伊索昔康(isoxicam),吡罗昔康(piroxicam),苏多西康(sudoxicam)和替诺西康(tenoxican)),水杨酸酯(乙酰水杨酸,柳氮磺吡啶)和二氢吡唑酮(阿帕宗(apazone),苯并哌啶酮(bezpiperylon),非普拉宗(feprazone),莫非布宗(mofebutazone),羟布宗(oxyphenbutazone),苯基丁氮酮)。齐多美汀和唑吡哌),芬那酸衍生物(氟芬那酸,甲氯芬那酸,甲芬那酸,烟酸和甲苯芬那酸),联苯甲酸衍生物(二氟甲萘啶),奥昔康星(oxicams)(异昔康,吡罗昔康,苏多西康(sudoxicam)和腾诺西康(Tenoxican)),水杨酸酯(乙酰水杨酸,柳氮磺吡啶)和吡唑啉酮(阿帕宗(apazone),苯并哌啶酮,非普拉宗(feprazone),莫非丁酮(mofebutazone),氧苯丁酮(oxyphenbutazone),二苯丁唑酮)。其他组合包括环氧合酶2(COX-2)抑制剂。
用于组合的其他活性剂包括类固醇,例如泼尼松龙(prednisolone),泼尼松(prednisone),甲基泼尼松龙(methylprednisolone),倍他米松(betamethasone),地塞米松(dexamethasone)或氢化可的松(hydrocortisone)。这种组合可能是特别有利的,因为可以通过逐渐减少所需的类固醇剂量来减少或甚至消除类固醇的一种或多种副作用。
可以组合使用以治疗例如类风湿性关节炎的活性剂的其他实例包括细胞因子抑制性抗炎药(CSAID);其他人细胞因子或生长因子的抗体或拮抗剂,例如TNF,LT,IL-10,IL-2,IL-6,IL-7,IL-8,IL-15,IL-16,IL-18,EMAP-II,GM-CSF,FGF或PDGF。
活性剂的特定组合可能会干扰自身免疫和随后的炎症级联反应的不同点,并且包括TNF拮抗剂,例如嵌合,人源化或人TNF抗体,REMICADE,抗TNF抗体片段(例如CDP870)和可溶性p55或p75 TNF受体,其衍生物,p75TNFRIgG(ENBREL.)或p55TNFR1gG(LENERCEPT),可溶性IL-13受体(sIL-13),以及TNFa转化酶(TACE)抑制剂;类似地,IL-1抑制剂(例如白介素-1转化酶抑制剂)可能是有效的。其他组合包括白介素11,抗P7s和p-选择蛋白糖蛋白配体(PSGL)。与本文所述的A2AR/A2BR抑制剂组合有用的药物的其他实例包括干扰素-131a(AVONEX);干扰素-13lb(BETASERON);卡波西酮(copaxone);高压氧;静脉注射免疫球蛋白;克拉比滨(clabribine)以及针对其他人类细胞因子或生长因子的抗体或拮抗剂(例如,针对CD40配体和CD80的抗体)。
微生物疾病。本发明提供了用A2AR/A2BR抑制剂和至少一种另外的治疗或诊断剂(例如,一种或多种其他的抗病毒药物和/或一种或多种与病毒治疗无关的药物)治疗和/或预防病毒,细菌,真菌和寄生虫病,病症和病状以及与其相关的病症的方法。
此类联合疗法包括针对各种病毒生命周期阶段并具有不同作用机制的抗病毒药,包括但不限于以下药物:病毒脱壳抑制剂(例如金刚烷胺和金刚乙胺);逆转录酶抑制剂(例如,阿昔洛韦(acyclovir),齐多夫定(zidovudine)和拉米夫定(lamivudine));靶向整合的试剂;阻止转录因子与病毒DNA结合的试剂;影响翻译的试剂(例如反义分子)(例如佛米韦森(fomivirsen));调节翻译/核酶功能的试剂;蛋白酶抑制剂;病毒装配调节剂(例如利福平(rifampicin));抗逆转录病毒药,例如核苷类似物逆转录酶抑制剂(例如叠氮胸苷(AZT),ddl,ddC,3TC,d4T);非核苷类逆转录酶抑制剂(例如依非韦伦(efavirenz),奈韦拉平(nevirapine));核苷酸类似物逆转录酶抑制剂;以及防止病毒颗粒释放的药物(例如扎那米韦(zanamivir)和奥司他韦(oseltamivir))。治疗和/或预防某些病毒感染(例如,HIV)经常需要一组(“混合物”)抗病毒剂。
涵盖的与A2AR/A2BR抑制剂组合使用的其他抗病毒药包括但不限于以下药物:阿巴卡韦(abacavir),阿丹弗(adefovir),金刚胺(amantadine),安普那韦(amprenavir),安普利近(ampligen),阿比朵儿(arbidol),阿扎那韦(atazanavir),阿托伐他汀钙(atripla),波普瑞韦尔特(boceprevirertet),西多福韦(cidofovir),可比韦(combivir),地瑞那韦(darunavir),地拉韦啶(delavirdine),地达诺新(didanosine),多可沙诺(docosanol),依度尿苷(edoxudine),安卓西他宾(emtricitabine),恩夫韦地(enfuvirtide),因提弗(entecavir),泛昔洛韦(famciclovir),夫沙那韦(fosamprenavir),膦甲酸酯(foscarnet),膦乙酸酯(fosfonet),http://en.wikipedia.org/wiki/Fusion_inhibitor更昔洛韦(ganciclovir),伊巴他滨(ibacitabine),异丙基苷(imunovir),碘苷(idoxuridine),咪喹莫特(imiquimod),印地那韦(indinavir),肌苷(inosine),各种干扰四(例如,聚乙二醇化干扰素a-2a),洛匹那韦(lopinavir),洛韦胺(loviride),马拉维诺(maraviroc),吗啉咪胍(moroxydine),美替沙腙(methisazone),奈非那韦(nelfinavir),多吉美(nexavir),喷昔洛韦(penciclovir),帕拉米韦(peramivir),普可那利(pleconaril),鬼臼毒素(podophyllotoxin),雷特格韦(raltegravir),利巴韦林(ribavirin),利托那韦(ritonavir),嘧啶,沙奎那韦(saquinavir),司他夫定(stavudine),特拉匹韦(telaprevir),田诺弗(tenofovir),替拉那韦(tipranavir),曲氟尿苷(trifluridine),曲利志韦(trizivir),曲金刚胺(tromantadine),特鲁瓦达(truvada),伐昔洛韦(valaciclovir),桔更昔洛韦(valganciclovir),维克维若(vicriviroc),阿糖腺苷(vidarabine),伟拉咪定(viramidine),和扎西他滨(zalcitabine)。
本发明涵盖了将本文所述的A2AR/A2BR功能抑制剂与抗寄生虫剂联合使用的用途。这样的试剂包括但不限于噻苯达唑,噻嘧啶,甲苯达唑,吡喹酮,烟酰胺,硫双二氯酚,奥沙尼喹,美曲磷脂,伊维菌素,阿苯达唑,依氟鸟氨酸,melarsoprol,喷他脒,苄硝唑,硝呋替莫和硝基咪唑。技术人员知道可以发现用于治疗寄生虫病的其他试剂。
本发明的实施方案涵盖了将本文所述的A2AR/A2BR抑制剂与可用于治疗或预防细菌疾病的药剂联用的用途。抗菌剂可以以多种方式进行分类,包括基于作用机理,基于化学结构以及基于活性谱。抗菌剂的实例包括靶向细菌细胞壁(例如头孢菌素和青霉素)或细胞膜(例如多粘菌素)或干扰基础细菌酶(例如磺酰胺,利福霉素和喹啉)的那些。靶向蛋白质合成的大多数抗菌剂(例如四环素和大环内酯类)具有抑菌作用,而诸如氨基糖苷类的药剂则具有杀菌作用。抗菌剂分类的另一种方法是基于它们的靶标特异性。“窄谱”试剂靶向特定类型的细菌(例如,革兰氏阳性细菌,如链球菌),而“广谱”试剂对更广泛的细菌具有活性。本领域技术人员知道适用于特定细菌感染的抗菌剂类型。
本发明的实施方案涵盖了将本文所述的A2AR/A2BR抑制剂与可用于治疗或预防真菌疾病的药剂联用的用途。抗真菌剂包括多烯(例如两性霉素,制霉菌素和匹马星(pimaricin));唑类(例如氟康唑,伊曲康唑和酮康唑);烯丙胺(例如萘替芬和特比萘芬)和吗啉(例如阿莫罗芬);和抗代谢物(例如5-氟胞嘧啶)。
本发明包括上述试剂(和试剂类别的成员)的药学上可接受的盐,酸或衍生物。
给药
本发明的A2AR/A2BR抑制剂可以以例如取决于给药目的(例如所需的分辨度)的量施用于受试者。服用该制剂的受试者的年龄,体重,性别,健康和身体状况;施用途径;以及疾病,病症,病状或症状的性质。给药方案还可以考虑与所施用的药剂有关的任何不良作用的存在,性质和程度。有效剂量和剂量方案可以容易地从例如安全性和剂量递增试验,体内研究(例如动物模型)和技术人员已知的其他方法中确定。
通常,剂量参数指示剂量小于对受试者可能具有不可逆毒性的剂量(最大耐受剂量(MTD))且不小于对受试者产生可测量的作用所需的剂量。此类量由例如与ADME相关的药代动力学和药效学参数确定,并考虑了给药途径和其他因素。
有效剂量(ED)是在服用该药物的部分受试者中产生治疗反应或所需效果的药剂的剂量或量。药物的“中位有效剂量”或ED50是指在接受该药物的50%的人群中产生治疗反应或所需效果的剂量或剂量。尽管ED50通常用于衡量对药物作用的合理预期,但考虑到所有相关因素,并不一定是临床医生认为合适的剂量。因此,在某些情况下,有效量大于计算出的ED50,在其他情况下,有效量小于计算出的ED50,在其他情况下,有效量与计算出的ED50相同。
另外,本发明的A2AR/A2BR抑制剂的有效剂量可以是当以一种或多种剂量施用于受试者时相对于健康受试者产生所需结果的量。例如,对于经历特定疾病的受试者,有效剂量可以是将该疾病的诊断参数,量度,标记等改善至少约5%,至少约10%,至少约20%,至少约25%,至少约30%,至少约40%,至少约50%,至少约60%,至少约70%,至少约80%,至少约90%或大于90%,其中100%定义为正常受试者表现出的诊断参数,量度,标记等。
在某些实施方案中,本发明考虑的A2AR/A2BR抑制剂可以受体体重的约0.01mg/kg至约50mg/kg或约1mg/kg至约25mg/kg的剂量水平施用(例如口服),每天一次或多次,以达到理想的治疗效果。
对于口服剂,可以以片剂,胶囊剂等形式提供组合物,其中包含1.0至1000毫克的活性成分,特别是1.0、3.0、5.0、10.0、15.0、20.0、25.0、50.0,75.0、100.0、150.0、200.0、250.0、300.0、400.0、500.0、600.0、750.0、800.0、900.0和1000.0毫克活性成分。
在某些实施方案中,所需的A2AR/A2BR抑制剂的剂量包含在“单位剂型”中。短语“单位剂型”是指物理上离散的单位,每个单位包含预定量的足以产生所需效果的单独或与一种或多种其他试剂组合使用的A2AR/A2BR抑制剂。将理解的是,单位剂型的参数将取决于特定的试剂和要实现的效果。
试剂盒
本发明还考虑了包含本文描述的化合物及其药物组合物的试剂盒。试剂盒通常为容纳各种组件的物理结构的形式,如下所述,并且例如可以用于实施上述方法。
试剂盒可以包含一种或多种本文公开的化合物(例如在无菌容器中提供),其可以是适于给予受试者的药物组合物的形式。本文所述的化合物可以以易于使用的形式(例如片剂或胶囊)或在给药前需要例如重构或稀释的形式(例如粉末)提供。当本文所述的化合物处于需要由使用者重构或稀释的形式时,试剂盒还可包括与本文所述化合物包装在一起或与之分开包装的稀释剂(例如无菌水),缓冲液,药学上可接受的赋形剂等。当考虑组合疗法时,试剂盒可分别包含几种试剂,或者它们可能已经在试剂盒中组合。试剂盒的每个组件都可以封装在一个单独的容器中,并且所有各种容器都可以在一个单独包装中。本发明的试剂盒可以出于适当地保持容纳在其中的部件所必需的条件而设计(例如,冷藏或冷冻)。
试剂盒可能包含标签或包装插页,其中包括其组分的标识信息及其使用说明(例如,剂量参数,有效成分的临床药理,包括作用机理,药代动力学和药效学,不良反应,禁忌症,等)。标签或插页可以包含制造商信息,例如批号和有效期。标签或包装插页可以例如被集成到容纳部件的物理结构中,被单独地包含在物理结构内,或者被粘贴到试剂盒的部件(例如安瓿,管或小瓶)上。
标签或插页可以另外包括或结合到计算机可读介质中,例如磁盘(例如硬盘,卡,存储磁盘),光盘例如CD-或DVD-ROM/RAM,DVD,MP3,磁带,或电存储介质(例如RAM和ROM)或它们的混合体(例如磁/光存储介质,FLASH介质或存储卡)。在一些实施方案中,试剂盒中不存在实际的说明书,但是提供了例如经由互联网从远程端获得说明书的途径。
实验
提出以下实施例以向本领域普通技术人员提供关于如何制作和使用本发明的完整公开和描述,并且无意限制发明人认为的发明的范围,它们也不旨在表示已执行以下实验或它们是可以执行的所有实验。应当理解,不必以当前时态书写示例性描述,而是可以执行描述以生成其中描述的性质的数据等。已经尽力确保所用数字(例如,数量,温度等)的准确性,但是应考虑一些实验误差和偏差。
除非另有说明,否则份数是重量份,分子量是重均分子量,温度是摄氏度(℃),压力是大气压或接近大气压。使用标准缩写,包括以下缩写:wt=野生型;bp=碱基对;kb=千碱基;nt=核苷酸;aa=氨基酸;s或sec=秒;min=分钟;h或hr=小时;ng=纳克;μg=微克;mg=毫克;g=克;kg=公斤;dl或dL=分升;μl或μL=微升;ml或mL=毫升;1或L=升;μM=微摩尔;mM=毫摩尔;M=摩尔;kDa=千道尔顿;i.m.=肌肉内的;i.p.=腹膜内(ly);SC或SQ=皮下(ly);QD=每日;BID=每天两次;QW=每周;QM=每月;HPLC=高效液相色谱;BW=体重;U=单位;ns=无统计学意义;PBS=磷酸盐缓冲盐水;IHC=免疫组化;DMEM=Dulbeco对Eagle媒介的修改;EDTA=乙二胺四乙酸。
材料和方法
在指出的地方使用了以下一般材料和方法,或者可以在以下示例中使用:
分子生物学中的标准方法在科学文献中有描述(参见例如Sambrook and Russell(2001)Molecular Cloning,第三版,Cold Spring Harbor Laboratory Press,ColdSpring Harbor,纽约;和Ausubel等人。(2001)Current Protocols in MolecularBiology,Vols。1-4,John Wiley and Sons,纽约公司,纽约,其描述了细菌细胞中的克隆和DNA诱变(第1卷),哺乳动物细胞和酵母中的克隆(第2卷),糖缀合物和蛋白质表达(第3卷)和生物信息学(第4卷)。
科学文献描述了用于蛋白质纯化的方法,包括免疫沉淀,色谱,电泳,离心和结晶,以及化学分析,化学修饰,翻译后修饰,融合蛋白的产生和蛋白质的糖基化(参见例如Coligan等。(2000)Current Protocols in Protein Science,1-2版,约翰·威利父子公司,纽约)。
提供了用于确定例如抗原性片段,前导序列,蛋白质折叠,功能域,糖基化位点和序列比对的软件包和数据库(参见,例如,GCG威斯康星州包装(Accelrys公司,圣地亚哥,CA);和DeCypherTM(时光物流,内华达州水晶湾)。
文献中充斥着可以用作评估本文所述化合物的基础的测定法和其他实验技术。
例子
制备权利要求的化合物的一般方法
本领域技术人员将认识到,存在多种可用于制备权利要求中表示的分子的方法。通常,用于合成权利要求中表示的化合物的有用方法包括四个部分,可以按任何顺序进行:
a和b片段的连接(或通过b环环化形成a-b-c部分),b和c片段的连接(或通过b环环化形成的a-b-c部分),以及在所有片段中存在的修饰的官能团。将本发明的化合物逆合成断开成片段a-c,该片段可用于构建下面所示的化合物:
制备要求保护的化合物的几种方法是示例性的(等式1-5).等式1展示了一种合成适当官能化的片段c的方法。在等式1的情况下,通过与脲缩合,然后用磷酰氯处理,将容易获得的2-氨基苯甲酸转化为喹唑啉。
或者,在本领域中已知多种用于形成喹唑啉和喹啉环的方法(参见例如朱尔等人,杂环化学,查普曼厅,纽约,或在http://www.organic-chemistry.org/synthesis/heterocycles/benzo-fused/quinazolines.shtm上喹唑啉的合成)。
等式二展示了一种通过铃木反应在片段b和c之间形成键的方法。在等式2的情况下,Z可以选自诸如Cl,Br,I,OTf等的合适的组,并且-B(OR)2是硼酸或酯,并且该偶联是由过渡金属催化剂,优选地,钯与合适的配体介导的。
可以通过使用有机或无机碱来辅助偶联,并且本领域已知多种条件有助于铃木偶联。偶合伴侣的功能化也可以颠倒,如等式3所示。本领域技术人员将认识到,还有其他可能的组合也将产生所需的产品。b和c片段之间的键的形成可以在a和b片段之间的连接形成之前或之后进行,并且可以在连接b和c片段之前或之后进一步修饰基团。。
备选地,b片段可以通过叠氮化物-炔烃汇森(Huisgen)1,3-偶极环加成反应在a和c片段之间环加成而形成(等式四)。在等式4的情况下,可以在叠氮化物和炔烃之间的环加成反应中将适当官能化的a和c片段结合在一起。可以通过使用铜催化剂或其他催化剂来促进反应。
在片段b是三唑的情况下,该环也可以通过钯介导的叠氮化钠加到链烯基卤化物上来合成(巴鲁家(Barluenga)等人,安德鲁,化学公司,编,2006,45、6893-6896),Amberlyst-15催化将叠氮化物加成至硝基烯烃(张等人,合成,2016,48,131-135),I2/TBPB介导N-甲苯磺酰基腙(N-tosylhydrozones)与苯胺的氧化环加成反应(蔡等,有机化学通讯,2014,16,5108-5111)和其他许多方法(请参见www.organic-chemistry.org/synthesis/heterocycles/1,2,3-triazoles.shtm中的“1,2,3-三唑的合成”)。本领域技术人员将理解,存在多种可用于实现这种转化的方法。
式5说明了一种通过烷基化在片段a和b之间形成键的方法。在等式5的情况下,Z是合适的亲电子体,例如Cl,Br,I,OTf等,并且该偶联是通过有机或无机碱介导的。为了最有效地制备本发明的任何特定化合物,本领域技术人员将认识到,在制备任何给定化合物时,片段连接的时间和顺序以及任何片段中存在的官能度的修饰可能会有所不同。
以上描述的各种方法已用于制备本发明的化合物,其中一些在实施例中举例说明。
例1:3-{[4-(2-氨基-8-甲氧基-4-喹唑啉基)-1H-1,2,3-三唑-1-基]甲基}-1-异丙基-1H-吡啶-2-酮
步骤1:将二氯化喹唑啉(100g,437mmol)悬浮在880mL无水THF中。向其中加入TIPS-乙炔(98mL,437mmol)和Et3N(183mL,1.3mol)。将得到的悬浮液脱气15分钟。脱气后,将混合物冷却至0℃,然后添加CuI(2.5g,13mmol)和Pd(PPh3)2Cl2(4.6g,6.6mmol)。然后在氮气下将反应搅拌8小时,缓慢升高至室温(注意:未移去冰浴,而是使其融化并升温至室温)。滤出固体,并用100mL THF洗涤。合并的滤液用1:1NH4Cl/NH4OH(3x200mL)洗涤,经Na2SO4干燥,浓缩,无需进一步纯化即可用于下一步。
第2步:将来自步骤1的粗产物溶于100mL THF和PMB-NH2(144mL,1.1mol)的混合物中,并在80℃加热2.5h。冷却至室温后,加入600mL EtOAc和150mL H2O。分离有机层,随后用5%柠檬酸水溶液(2×400mL)和200mL盐水洗涤。如此获得的有机层经Na2SO4干燥,浓缩,无需进一步纯化即可用于下一步。
步骤3:将来自步骤2的粗物质悬浮在335mL的TFA中,并加热至回流12h。首先蒸出约250mL的TFA,然后与CH2Cl2(2x300mL)共蒸馏。冷却至室温后,加入1L CH2Cl2和1L饱和NaHCO3并搅拌1小时。分离有机层,与50g活性炭搅拌1h,并通过硅藻土垫过滤。将溶剂减少至300mL,并逐滴加入2.7L庚烷。得到细的沉淀物,将其过滤以获得128g的产物。来自母液的第二批收成又得到12g产物。这样获得的总产物140g含有一些未知的杂质(可能是PMB-聚合物)。(注意:沉淀是使用10%CH2Cl2/庚烷进行的。例如,将1g粗品溶于2mL CH2Cl2,然后通过添加庚烷将其调节至10%。
步骤4:将来自步骤3的粗产物(140g,394.4mmol)溶解在790mL THF中。向其中加入20mL H2O,冷却至0℃。在0℃下加入1.0M Bu4NOH水溶液(19.7mL,19.7mmol)。移去冰浴,并在室温下搅拌30分钟。向反应中加入20mL饱和NH4Cl和8.0L H2O,并再搅拌45分钟。过滤由此形成的沉淀物,用500mL H2O洗涤并干燥。将粗物质与50%CH2Cl2/己烷(790mL)一起研磨,得到50.4g的纯产物(4步中为58%),纯度为99%。
第5步:将2-羟基烟碱醛(1.89g,15.4mmol,1当量)溶于MeCN(45mL),K2CO3(4.3g,30.8mmol,2当量),并且添加2-碘丙烷(2.3mL,23.1mmol,1.5当量)。将所得混合物加热至75℃,直到通过LC-MS测定原料被消耗为止。将反应混合物冷却至室温,通过过滤并浓缩。粗残余物无需进一步纯化即可使用。
步骤6:在冰水浴中冷却醛(1.05g,6.4mmol,1当量)在THF(30mL)中的溶液,并加入LAH(2M的THF溶液,3.2mL,6.4mmol,1当量)。15分钟后,通过加入0.24mL H2O,然后加入0.24mL 10%NaOH淬灭反应。将反应混合物搅拌5分钟,并加入0.72mL H2O。加入Na2SO4,并将反应混合物过滤并浓缩。粗残余物无需进一步纯化即可使用。
步骤7:向醇(1.03g,6.2mmol,1当量)在甲苯(8mL)中的溶液中添加DPPA(1.6mL,7.4mmol,1.2当量)和DBU(1.1mL,7.4mmol,1.2当量)。将反应混合物搅拌过夜,并通过SiO2上的快速色谱法直接纯化,得到叠氮化物,为橙色油。
第8步:步骤7的叠氮化物(96mg,0.5mmol,2当量),步骤4的喹唑啉炔(50mg,0.25mmol),五水合硫酸铜(II)(3.3mg,0.0125mmol)和抗坏血酸钠(10mg,0.050mmol)的混合物将在2:1t-BuOH/H2O(1.2mL)中,于60℃搅拌1小时。将混合物浓缩到硅胶上,并通过硅胶色谱法纯化(CH2Cl2中的0至5%MeOH),得到标题化合物,为棕褐色固体(65mg,66%收率)。1H NMR(400MHz,DMSO-d6)δ8.71(d,J=2.0Hz,1H),8.65–8.58(m,1H),7.87–7.79(m,1H),7.47(d,J=6.7Hz,1H),7.23–7.11(m,2H),6.88(s,2H),6.42–6.29(m,1H),5.53(s,2H),5.16–5.01(m,1H),3.88(d,J=1.9Hz,3H),1.29(dd,J=6.8,1.9Hz,6H)。C20H21N7O2的ESI MS[M+H]+,计算值392.2,发现值392.2。
例2:3-{[4-(2-氨基-8-甲氧基-4-喹唑啉基)-1H-1,2,3-三唑-1-基]甲基}-1-甲基-1H-吡啶-2-酮
由相应的叠氮化物和炔烃衍生物以类似于例1的方式合成标题化合物,得到41mg黄色固体。1H NMR(400MHz,DMSO-d6)δ8.70(d,J=1.2Hz,1H),8.63(ddd,J=6.0,3.8,1.1Hz,1H),7.79(dt,J=6.8,1.5Hz,1H),7.57(dd,J=7.0,2.0Hz,1H),7.20–7.11(m,2H),6.88(s,2H),6.29(td,J=6.8,1.1Hz,1H),5.52(s,2H),3.88(d,J=1.0Hz,3H),3.47(d,J=1.1Hz,3H)。C18H17N7O2的ESI MS[M+H]+计算值364.2,发现值364.1。
例3:3-{[4-(2-氨基-8-甲氧基-4-喹唑啉基)-1H-1,2,3-三唑-1-基]甲基}-1-乙基-1H-吡啶-2-酮
由相应的叠氮化物和炔烃衍生物以类似于例1的方式合成标题化合物,得到65mg黄色固体。1H NMR(400MHz,CDCl3)δ8.81(dd,J=8.6,1.2Hz,1H),8.67(d,J=2.8Hz,1H),7.44(dd,J=6.8,2.0Hz,1H),7.33(dd,J=6.8,2.2Hz,1H),7.26(ddd,J=5.3,2.4,1.0Hz,1H),7.10(dd,J=7.8,1.2Hz,1H),6.21(t,J=6.8Hz,1H),5.56(s,2H),5.25(s,2H),4.12–3.97(m,5H),1.47–1.32(m,3H)。C19H19N7O2的ESI MS[M+H]+,计算值378.2,发现值378.2。
例4:3-{[4-(2-氨基-8-甲氧基-4-喹唑啉基)-1H-1,2,3-三唑-1-基]甲基}-1-(环丙基甲基)-1H-吡啶-2-酮
由相应的叠氮化物和炔烃衍生物以类似于例1的方式合成标题化合物,得到64mg黄色固体。1H NMR(400MHz,DMSO-d6)δ8.71(d,J=1.4Hz,1H),8.61(ddd,J=5.4,3.9,1.4Hz,1H),7.89–7.77(m,1H),7.52(d,J=7.0Hz,1H),7.20–7.12(m,2H),6.87(s,2H),6.30(td,J=6.8,1.3Hz,1H),5.53(s,2H),3.88(d,J=1.4Hz,3H),3.77(d,J=7.1Hz,2H),1.22(d,J=14.8Hz,1H),0.46(d,J=7.8Hz,2H),0.37(d,J=4.9Hz,2H)。对于C21H21N7O2的ESI MS[M+H]+,计算值404.2,发现值404.2。
例5:3-{[4-(2-氨基-8-甲氧基-4-喹唑啉基)-1H-1,2,3-三唑-1-基]甲基}-1-(2-羟基-2-甲基丙基)-1H-吡啶-2-酮
以与例1类似的方式,由相应的叠氮化物和炔烃衍生物合成标题化合物,得到33mg黄色固体。1H NMR(400MHz,DMSO-d6)δ8.72–8.66(m,1H),8.59(dd,J=5.4,4.4Hz,1H),7.67(dd,J=6.8,2.4Hz,1H),7.54(d,J=6.7Hz,1H),7.22–7.10(m,2H),6.86(s,2H),6.28(td,J=6.7,2.2Hz,1H),5.52(s,2H),4.81–4.72(m,1H),3.93(d,J=2.4Hz,2H),3.87(s,3H),1.05(d,J=2.4Hz,6H)。对于C21H23N7O3的ESI MS[M+H]+,计算值422.2,发现值422.2。
例6:3-{[4-(2-氨基-8-甲氧基-4-喹唑啉基)-1H-1,2,3-三唑-1-基]甲基}-1-(2-甲氧基-1-甲基乙基)-1H-吡啶-2-酮
由相应的叠氮化物和炔烃衍生物以类似于例1的方式合成标题化合物,得到25mg黄色固体。1H NMR(400MHz,DMSO-d6)δ8.72(d,J=1.9Hz,1H),8.63(dt,J=5.8,2.1Hz,1H),7.78(dd,J=7.0,2.1Hz,1H),7.51–7.41(m,1H),7.24–7.11(m,2H),6.88(s,2H),6.33(t,J=6.9Hz,1H),5.53(s,2H),5.24–5.07(m,1H),3.89(d,J=2.1Hz,3H),3.64(dd,J=10.5,7.9Hz,1H),3.49(dd,J=10.5,4.6Hz,1H),3.20(d,J=1.9Hz,3H),1.32–1.23(m,3H)。对于C21H23N7O3,ESI MS[M+H]+计算值422.2,发现值422.2。
例7:3-{[4-(2-氨基-8-甲氧基-4-喹唑啉基)-1H-1,2,3-三唑-1-基]甲基}-1-(2-羟基-1,2-二甲基丙基)-1H-吡啶-2-酮
由相应的叠氮化物和炔烃衍生物以类似于例1的方式合成标题化合物,得到56mg黄色固体。1H NMR(400MHz,DMSO-d6)δ8.70(d,J=1.2Hz,1H),8.64–8.54(m,1H),7.85–7.73(m,1H),7.48(d,J=6.8Hz,1H),7.22–7.11(m,2H),6.86(s,2H),6.31(t,J=6.9Hz,1H),5.52(s,2H),5.02(s,1H),4.85(s,1H),3.88(d,J=1.1Hz,3H),1.30(d,J=7.1Hz,3H),1.20(s,3H),0.85(s,3H)。对于C22H25N7O3,ESI MS[M+H]+计算值436.2,发现值436.2。
例8:3-{[4-(2-氨基-8-甲氧基-4-喹唑啉基)-1H-1,2,3-三唑-1-基]甲基}-1-环丙基-1H-吡啶-2-酮
步骤1:2-羟基-3-甲基吡啶(2.18g,20.0mmol),乙酸铜(II)(3.63g,20.0mmol),吡啶(4.85mL,60.0mmol),环丙基硼酸频哪醇酯(6.72g,40.0mmol),碳酸铯(3.86g,10.0mmol)和甲苯(40mL)的混合物在空气中于110°C搅拌2天。将混合物冷却,并加入EtOAc(100mL)/水(100mL)。过滤混合物以除去任何固体,用EtOAc/水洗涤滤饼。将得到的两相混合物用EtOAc(3×100mL)萃取。合并的有机相经Na2SO4干燥,浓缩,并通过硅胶色谱法(50至100%EtOAc的己烷溶液)纯化,得到所需产物,为黄色油状物(1.93g;65%)。
步骤2:将步骤1的产物(1.93g,12.9mmol),过氧化苯甲酰(418mg,1.29mmol,75%的水溶液),NBS(2.53g,14.2mmol)和四氯化碳(250mL)的脱气混合物在80℃下搅拌1.5小时。浓缩混合物,并通过硅胶色谱法(50至100%EtOAc的己烷溶液)纯化,得到所需产物,其与琥珀酰亚胺为1∶1混合物。黄色的油(1.87克;64%(琥珀酰亚胺校正))。
步骤3:将来自步骤2的产物(1.14g,5.00mmol(校正琥珀酰亚胺)),叠氮化钠(360mg,6.00mmol)和DMSO(10mL)的混合物在室温搅拌持续2个小时。加入EtOAc(100mL),并将所得混合物用水(4×100mL)洗涤。有机相经Na2SO4干燥,浓缩,并通过硅胶色谱法(50至100%EtOAc的己烷溶液)纯化,得到所需产物,为黄色油状物(500mg;53%)。
步骤4:来自步骤3的产物(86mg,0.45mmol),喹唑啉炔(60mg,0.30mmol),五水合硫酸铜(II)(4mg,0.015mmol),抗坏血酸钠(12mg,0.060mmol)和2∶1t-BuOH/H2O(1.2mL)的混合物在60℃下搅拌1小时。将混合物浓缩到硅胶上,并通过硅胶色谱法(CH2Cl2中的0-5%MeOH)纯化,得到期望的产物,为黄色固体(66mg;56%)。1H NMR(400MHz,DMSO-d6)δ8.72(s,1H),8.66–8.60(m,1H),7.63(d,J=7.0Hz,1H),7.53(d,J=6.9Hz,1H),7.22–7.14(m,2H),6.89(s,2H),6.26(t,J=6.9Hz,1H),5.53(s,2H),3.89(s,3H),3.43–3.36(m,1H),1.04–0.96(m,2H),0.90–0.82(m,2H)。对于C20H20N7O2,ESI MS[M+H]+计算值390.2,发现值390.2。
例9:3-{[4-(2-氨基-8-甲氧基-4-喹唑啉基)-1H-1,2,3-三唑-1-基]甲基}-1-(四氢-2H-吡喃-4–基)-1H-吡啶-2-酮
步骤1:以类似于例1,步骤5的方式合成产物:获得黄色固体(316mg,10%)。
步骤2:在0℃下,向步骤1的产物(316mg,1.52mmol)和THF(7.6mL)的溶液中滴加LAH(762μL,1.52mmol,2M的THF溶液)。将混合物在0℃下搅拌15分钟,并在0℃下逐滴加入1MNaOH(水溶液)(380μL)。加入EtOAc(10mL)和MgSO4。过滤混合物,浓缩,得到所需产物,为黄色油状物(299mg;94%)。
步骤3:在0℃下,向步骤2的产物(299mg,1.43mmol),DPPA(339μL,1.57mmol)和DCE(1.4mL)的溶液中滴加DBU(235μL,1.57mmol)。将混合物在60℃下搅拌3小时。将混合物浓缩到硅胶上,并通过硅胶色谱法(0至100%EtOAc的己烷溶液)纯化,得到期望的产物,为白色固体(24mg;7%)。
步骤4:由相应的叠氮化物和炔烃衍生物以类似于例1的方式合成标题化合物:获得黄色固体(22mg,59%)。1H NMR(400MHz,DMSO-d6)δ8.71(s,1H),8.66–8.59(m,1H),7.86(d,J=7.0Hz,1H),7.51(d,J=7.0Hz,1H),7.21–7.13(m,2H),6.87(s,2H),6.35(t,J=6.9Hz,1H),5.53(s,2H),5.01–4.89(m,1H),4.03–3.92(m,2H),3.88(s,3H),3.46(t,J=11.9Hz,2H),1.96–1.81(m,2H),1.74–1.63(m,2H)。对于C22H24N7O3,ESI MS[M+H]+计算值434.2,发现值434.2。
例10:3-{[4-(2-氨基-8-甲氧基-4-喹唑啉基)-1H-1,2,3-三唑-1-基]甲基}-1-(2-甲氧基乙基)-1H-吡啶-2-酮
由相应的叠氮化物和炔烃衍生物类似于例1合成标题化合物。1H NMR(400MHz,DMSO-d6)δ8.69(s,1H),8.60(m,1H),7.67(d,J=6.8Hz,1H),7.51(d,J=6.9Hz,1H),7.21–7.11(m,2H),6.85(s,2H),6.40–6.19(m,1H),5.51(s,2H),4.14–4.03(m,2H),3.87(s,3H),3.56(m,2H),3.21(s,3H)。C20H21N7O3的ESI MS[M+H]+,计算值408.2,发现值408.2。
例11:3-{[4-(2-氨基-8-甲氧基-4-喹唑啉基)-1H-1,2,3-三唑-1-基]甲基}-1-[(四氢-2H-吡喃-4-基)甲基]-1H-吡啶-2-酮
由相应的叠氮化物和炔烃衍生物类似于例1合成标题化合物。1H NMR(400MHz,DMSO-d6)δ8.71(s,1H),8.59(s,1H),7.71(d,J=6.8Hz,1H),7.49(d,J=6.9Hz,1H),7.17–7.13(m,2H),6.97–6.73(m,2H),6.34–6.16(m,1H),5.59–5.41(m,2H),3.87(s,3H),3.84–3.70(m,4H),3.24–3.13(m,2H),1.98(s,1H),1.43–1.32(m,2H),1.31–1.12(m,2H)。对于C23H25N7O3,ESI MS[M+H]+计算值448.2,发现值448.2。
例12:3-{[4-(2-氨基-8-乙氧基-4-喹唑啉基)-1H-1,2,3-三唑-1-基]甲基}-1-异丙基-1H-吡啶-2-酮
由相应的叠氮化物和炔烃衍生物类似于例1制备标题化合物。1H NMR(400MHz,DMSO-d6)δ8.71(s,1H),8.65–8.58(m,1H),7.83(d,J=7.1Hz,1H),7.48(d,J=7.2Hz,1H),7.19–7.12(m,2H),6.88(s,2H),6.35(t,J=6.9Hz,1H),5.53(s,2H),5.09(hept,J=6.6Hz,1H),4.20–4.08(m,2H),1.42(t,J=7.0Hz,3H),1.29(d,J=6.9Hz,6H)。C21H24N7O2的ESI MS[M+H]+,计算值406.2,发现值406.2。
例13:3-{[4-(2-氨基-8-甲基-4-喹唑啉基)-1H-1,2,3-三唑-1-基]甲基}-1-异丙基-1H-吡啶-2-酮
由相应的叠氮化物和炔烃衍生物以类似于例1的方式合成标题化合物,得到80mg黄色固体。1H NMR(400MHz,DMSO-d6)δ8.91(d,J=8.5Hz,1H),8.72(d,J=0.8Hz,1H),7.83(dt,J=6.9,1.7Hz,1H),7.62–7.52(m,1H),7.48(dt,J=6.9,1.7Hz,1H),7.15(ddd,J=8.3,6.8,1.2Hz,1H),6.80(s,2H),6.35(td,J=6.8,1.3Hz,1H),5.53(s,2H),5.16–5.03(m,1H),2.49(s,3H),1.39–1.18(m,6H)。C20H21N7O的ESI MS[M+H]+,计算值376.2,发现值376.2。
例14:3-{[4-(2-氨基-8-氟-4-喹唑啉基)-1H-1,2,3-三唑-1-基]甲基}-1-异丙基-1H-吡啶-2-酮
由相应的叠氮化物和炔烃衍生物类似于例1合成标题化合物。1H NMR(400MHz,DMSO-d6)δ8.91(d,J=8.5Hz,1H),8.74(s,1H),7.81(d,J=7.0Hz,1H),7.54(m,1H),7.48(d,J=6.9Hz,1H),7.20(m,1H),7.12(s,2H),6.38–6.23(m,1H),5.52(s,2H),5.07(h,J=5.7Hz,1H),1.28(s,3H),1.26(s,3H)。C19H18FN7O的ESI MS[M+H]+,计算值380.2,发现值380.1。
例15:3-{[4-(2-氨基-8-氯-4-喹唑啉基)-1H-1,2,3-三唑-1-基]甲基}-1-异丙基-1H-吡啶-2-酮
由相应的叠氮化物和炔烃衍生物类似于例1合成标题化合物。1H NMR(400MHz,DMSO-d6)δ9.09(d,J=8.5Hz,1H),8.75(d,J=1.5Hz,1H),7.88(d,J=7.5Hz,1H),7.81(d,J=7.0Hz,1H),7.48(d,J=6.9Hz,1H),7.30–7.14(m,3H),6.40–6.27(m,1H),5.52(s,2H),5.22–4.96(m,1H),1.28(s,3H),1.26(s,3H)。C19H18ClN7O的ESI MS[M+H]+,计算值396.1,发现值396.1。
例16:3-{[4-(2-氨基-7-甲氧基-4-喹唑啉基)-1H-1,2,3-三唑-1-基]甲基}-1-异丙基-1H-吡啶-2-酮
由相应的叠氮化物和炔烃衍生物以类似于例1的方式合成标题化合物,得到54mg黄色固体。1H NMR(400MHz,DMSO-d6)δ8.99(dd,J=9.3,1.6Hz,1H),8.69(d,J=1.6Hz,1H),7.92–7.71(m,1H),7.47(d,J=6.8Hz,1H),6.90(dt,J=9.2,2.1Hz,1H),6.83(q,J=3.1,2.2Hz,1H),6.71(s,2H),6.35(td,J=6.9,1.7Hz,1H),5.52(s,2H),5.23–4.95(m,1H),3.88(t,J=2.6Hz,3H),1.29(dd,J=6.8,1.6Hz,6H)。C20H21N7O2的ESI MS[M+H]+,计算值392.2,发现值392.2。
例17:3-{[4-(2-氨基-7-氟-8-甲氧基-4-喹唑啉基)-1H-1,2,3-三唑-1-基]甲基}-1-异丙基-1H-吡啶-2-酮
由相应的叠氮化物和炔烃衍生物以类似于例1的方式合成标题化合物,得到100mg橙色固体。1H NMR(400MHz,DMSO-d6)δ8.96–8.87(m,1H),8.74(d,J=1.3Hz,1H),7.83(dd,J=7.0,2.0Hz,1H),7.51–7.48(m,1H),7.26–7.14(m,1H),7.09(s,2H),6.42–6.29(m,1H),5.53(s,2H),5.09(p,J=6.8Hz,1H),3.99(d,J=1.4Hz,3H),1.29(dd,J=6.8,1.3Hz,6H)。C20H20FN7O2的ESI MS[M+H]+,计算值410.2,发现值410.1。
例18:3-{[4-(2-氨基-6-氟-8-甲氧基-4-喹唑啉基)-1H-1,2,3-三唑-1-基]甲基}-1-异丙基-1H-吡啶-2-酮
由相应的叠氮化物和炔烃衍生物以类似于例1的方式合成标题化合物。1H NMR(400MHz,DMSO-d6)8.74(s,1H),8.43(d,J=8Hz,1H),7.83(d,J=8Hz,1H),7.49(d,J=4Hz,1H),7.16(d,J=8Hz,1H),6.89(s,2H),6.35(s,1H),5.53(s,1H),5.08(s,1H),3.92(s,3H),1.28(d,J=8Hz,6H)。C20H21FN7O2的ESI MS[M+H]+,计算值410.2,发现值410.3。
例19:1-[(R)-1-(四氢-2H-吡喃-4-基)乙基]-3-{[4-(2-氨基-8-甲氧基-4-喹唑啉基)-1H-1,2,3-三唑-1-基]甲基}-1H-吡啶-2-酮
步骤1:在圆底烧瓶中装入向该烧瓶中加入四氢吡喃-4-甲醛(6.0g,52.3mmol),(R)-(-)-叔丁基亚磺酰胺(7.65g,63.2mmol)和75mL二氯乙烷,并在N2下搅拌10分钟然后,添加吡啶鎓对-甲苯磺酸盐(661.3mg,2.63mmol)。将反应混合物在室温搅拌16小时。将形成的固体过滤并将滤液浓缩。通过硅胶色谱法纯化粗物质以获得所需的N-亚磺酰基亚胺(7.5g,65%)。
第2步:在0℃下向步骤1中获得的N-亚磺酰基亚胺(7.5g,34.4mmol)的二氯甲烷溶液中滴加3.0M MeMgBr在Et2O中的溶液(22.9mL,68.8mmol)。加完后,将反应在N2下搅拌16小时,缓慢升温至室温。使用饱和NH4Cl(25mL)淬灭反应,并用CH2Cl2(2×30mL)萃取水层。合并的有机层用Na2SO4干燥,浓缩,得到所需的α-甲基-四氢吡喃衍生物,其无需进一步纯化即可用于下一步。注意:在格利雅(Grignard)加成后,未确定α-甲基-立体中心的绝对立体化学。
步骤3:将由步骤2获得的粗磺酰胺溶解在50mL MeOH中,并逐滴加入40mL HCl溶液(4.0M的二恶烷溶液)。将反应在室温搅拌1小时。蒸发溶剂,并将固体悬浮在200mL MTBE中,并在室温下搅拌10分钟。过滤由此形成的白色固体,并用50mL MTBE快速洗涤,以获得所需的盐酸盐形式的产物(5.0g,2步为89%)。注意:HCl盐极易吸湿,因此将其在N2下储存在密封的小瓶中。
步骤4:在圆底烧瓶中,将2-吡喃-3-羧酸甲酯(3.1g,20.0mmol)溶解在40mL CH2Cl2中。向该溶液中加入由步骤3获得的胺的HCl盐(3.3g,20.0mmol)和i-Pr2NEt(3.7mL,22.0mmol)。将上述反应混合物搅拌8小时后,加入EDCI·HCl(4.6g,24.0mmol)和DMAP(1.2g,10mmol),并在N2下再次搅拌16h。减压除去溶剂,并将粗物质通过硅胶色谱法纯化,以获得所需的吡啶酮(1.9g,35%)。
步骤5:将由步骤4获得的吡啶酮(1.5g,5.6mmol)溶于11.0mL无水THF中。冷却至-78℃后,滴加1.0M DIBAL-H的THF溶液(12.3mL,12.3mmol)。添加后,移去冰浴并缓慢升至室温。在室温下放置1小时后,将反应冷却至0℃,并逐滴添加3.0mL干燥的MeOH,然后添加NaBH4(253.8mg,6.7mmol)。30分钟后,添加20mL的10%柠檬酸溶液使反应淬灭,并在室温下搅拌30分钟。用EtOAc(2×30mL)萃取水层。合并的有机层用Na2SO4干燥,浓缩并通过硅胶色谱法纯化,得到所需的醇(626g,47%)。
步骤6:从步骤5获得的醇以与例1的步骤7类似的方式合成吡啶酮-叠氮化物衍生物。
步骤7:由相应的叠氮化物和炔烃衍生物类似于例1合成标题化合物。1H NMR(400MHz,DMSO-d6)δ8.69(d,J=2.1Hz,1H),8.59(t,J=5.5Hz,1H),7.73(d,J=6.9Hz,1H),7.41(d,J=6.6Hz,1H),7.15(dd,J=3.7,1.9Hz,2H),6.85(s,2H),6.32(t,J=6.8Hz,1H),5.60–5.42(m,2H),4.74(s,1H),3.87(m,4H),3.72(m,1H),3.22(m,1H),3.09(m,1H),1.89(m,1H),1.66(m,1H),1.28(d,J=7.0Hz,3H),1.12(m,3H)。C24H27N7O3的ESI MS[M+H]+,计算值462.2,发现值462.2。
例20:1-[(S)-1-(四氢-2H-吡喃-4-基)乙基]-3-{[4-(2-氨基-8-甲氧基-4-喹唑啉基)-1H-1,2,3-三唑-1-基]甲基}-1H-吡啶-2-酮
从(S)-(-)-叔丁基亚磺酰胺开始,类似于例19合成标题化合物:1H NMR(400MHz,DMSO-d6)δ8.69(d,J=2.1Hz,1H),8.59(t,J=5.5Hz,1H),7.73(d,J=6.9Hz,1H),7.41(d,J=6.6Hz,1H),7.15(dd,J=3.7,1.9Hz,2H),6.85(s,2H),6.32(t,J=6.8Hz,1H),5.60–5.42(m,2H),4.74(s,1H),3.87(m,4H),3.72(m,1H),3.22(m,1H),3.09(m,1H),1.89(m,1H),1.66(m,1H),1.28(d,J=7.0Hz,3H),1.12(m,3H)。C24H27N7O3的ESI MS[M+H]+,计算值462.2,发现值462.2。
例21:3-{[4-(2-氨基-8-甲氧基-4-喹唑啉基)-1H-1,2,3-三唑-1-基]甲基}-1-(顺式-4-羟基环己基)-1H-吡啶-2-酮
步骤1:在装有磁力搅拌棒的250mL圆底烧瓶中,依次加入氨基醇(3.0g,19.78mmol)和CH2Cl2(37.3mL)。将TBSCl(4.48g,29.67mmol),然后咪唑(2.43g,35.80mmol)加入上述溶液中。将该溶液在氮气气氛下于室温搅拌12小时。向上述混合物中加入去离子水(50mL),然后加入盐水(50mL)。分离各层,并用CH2Cl2/MeOH(9∶1)(150mL)萃取水层。合并的有机层经Na2SO4干燥,过滤并减压浓缩。所得粗物质通过硅胶快速色谱法(CH2Cl2/MeOH梯度为100%至70%)纯化。获得期望的产物,为白色固体(2.5g)。
步骤2:在圆底烧瓶中,将2.23g(10mmol)的胺和i Pr2NEt(1.74mL,10mmol)溶于20mL CH2Cl2。向该溶液中加入1.54g(10mmol)的吡喃酮衍生物,在室温下搅拌15min,加入EDCI·HCl(2.3g,12mmol)和DMAP(245mg,2.0mmol),并将该反应混合物在N2下在室温搅拌额外的20小时。反应完成后,除去溶剂,并将粗物质通过硅胶快速色谱(乙酸乙酯/己烷,梯度0%至60%)纯化。获得所需产物,为浅棕色固体(1.03g)。
步骤3:在-78℃下,向羧酸甲酯(1.037g,2.82mmol)在THF(28mL)中的溶液中滴加DIBAL-H(6.2mL,6.2mmol),历时5分钟。然后将溶液在相同温度下搅拌15分钟。将反应混合物在1小时内加热到23℃,并在相同温度下再搅拌1小时。用10%柠檬酸水溶液(30mL)淬灭反应混合物。分离各层,并用iPrOH/CHCl3(1∶2)(100mL)萃取水层。合并的有机层经Na2SO4干燥,并在减压下除去。粗物质通过硅胶快速色谱(己烷/乙酸乙酯梯度0%至100%)纯化。得到所需的醇,为浅黄色固体(0.4g)。
步骤4:按照例19的程序获得所需的叠氮化物,为液体(0.2g)。
步骤5:按照例1,从相应的叠氮化物和炔烃衍生物获得所需的三唑固体(0.14g)。
步骤6:在0℃下,向三唑(0.14g,0.25mmol)在CH2Cl2(0.64mL)中的溶液中滴加4(M)HCl的二恶烷(0.25mL,1.1mmol)溶液。在15分钟内将溶液加热到23℃,并在相同温度下搅拌4小时。蒸发溶剂,并将所得固体用乙酸乙酯洗涤,得到期望的产物,为黄色固体(82mg)。1HNMR(400MHz,DMSO-d6)8.98(s,1H),8.92(s,1H),7.79(d,J=8.0Hz,1H),7.64(d,J=8.0Hz,1H),7.60(d,J=8.0Hz,1H),7.54(t,J=8Hz,1H),6.36(t,J=8Hz,1H),5.58(s,2H),4.67(t,J=12Hz,1H),4.07(s,3H),3.87(s,3H),1.99-1.90(m,2H),1.78(d,J=8Hz,2H),1.58-1.46(m,4H)。C23H26N7O3的ESI MS[M+H]+,计算值448.2,发现值448.3。
例22:3-{[4-(2-氨基-8-甲氧基-4-喹唑啉基)-1H-1,2,3-三唑-1-基]甲基}-1-(反式-4-羟基环己基)-1H-吡啶-2-酮
由相应的叠氮化物和炔烃衍生物类似于例21制备标题化合物。1H NMR(400MHz,DMSO-d6)8.70(s,1H),8.62(s,1H),7.79(d,J=8Hz,1H),7.49(d,J=8Hz,1H),7.16(s,2H),6.87(s,2H),6.34-6.29(m,1H),5.51(s,2H),4.69-4.63(m,2H),3.89(s,3H),3.47(bs,1H),1.94-1.87(m,2H),1.73-1.65(m,.4H),1.35-1.25(m,2H)。对于C23H26N7O3,ESI MS[M+H]+计算值448.2,发现值448.4。
例23:1-[(R)-2-甲氧基-1-甲基乙基]-3-{[4-(2-氨基-8-甲氧基-4-喹唑啉基)-1H-1,2,3-三唑-1-基]甲基}-1H-吡啶-2-酮
由相应的叠氮化物和炔烃衍生物类似于例21制备标题化合物。1H NMR(400MHz,DMSO-d6)δ8.71(s,1H),8.65–8.59(m,1H),7.78(d,J=7.3Hz,1H),7.47(d,J=7.1Hz,1H),7.20–7.13(m,2H),6.88(s,2H),6.33(t,J=6.9Hz,1H),5.53(s,2H),5.22–5.10(m,1H),3.88(s,3H),3.64(dd,J=10.4,7.9Hz,1H),3.49(dd,J=10.5,4.7Hz,1H),3.20(s,3H),1.27(d,J=7.1Hz,3H)。对于C21H24N7O3,ESI MS[M+H]+计算值422.2,发现值422.2。
例24:3-{[4-(2-氨基-8-甲氧基-4-喹唑啉基)-1H-1,2,3-三唑-1-基]甲基}-1-环戊基-1H-吡啶-2-酮
由相应的叠氮化物和炔烃衍生物类似于例21制备标题化合物。1H NMR(400MHz,DMSO-d6)δ8.97(d,J=8.8Hz,1H),8.93(s,1H),7.81(d,J=6.9Hz,1H),7.70–7.47(m,3H),6.42–6.30(m,1H),5.59(s,2H),5.20–5.04(m,1H),4.06(s,3H),2.09–1.91(m,2H),1.91–1.73(m,2H),1.73–1.53(m,4H)。C22H24N7O2的ESI MS[M+H]+,计算值418.2,发现值418.2。
例25:1-[(S)-2-羟基-1,2-二甲基丙基]-3-{[4-(2-氨基-6-氟-8-甲氧基-4-喹唑啉基)-1H-1,2,3-三唑-1-基]甲基}-1H-吡啶-2-酮
由相应的叠氮化物和炔烃衍生物类似于例12制备标题化合物。1H NMR(400MHz,DMSO-d6)δ8.88(s,1H),8.64(d,J=9.8Hz,1H),7.82(d,J=6.9Hz,1H),7.57(d,J=6.6Hz,2H),7.54–7.46(m,1H),6.38–6.27(m,1H),5.58(s,2H),5.04–4.99(m,1H),4.03(s,3H),1.30(d,J=7.0Hz,3H),1.20(s,3H),0.84(s,3H)。对于C22H25FN7O3,ESI MS[M+H]+计算值454.2,发现值454.2。
例26:1-[(S)-2-羟基-1,2-二甲基丙基]-3-{[4-(2-氨基-8-甲氧基-4-喹唑啉基)-1H-1,2,3-三唑-1-基]甲基}-1H-吡啶-2-酮
由相应的叠氮化物和炔烃衍生物以类似于例21的方式合成标题化合物,得到25mg棕褐色固体。1H NMR(400MHz,DMSO-d6)δ8.70(d,J=1.2Hz,1H),8.64–8.54(m,1H),7.85–7.73(m,1H),7.48(d,J=6.8Hz,1H),7.22–7.11(m,2H),6.86(s,2H),6.31(t,J=6.9Hz,1H),5.52(s,2H),5.02(s,1H),4.85(s,1H),3.88(d,J=1.1Hz,3H),1.30(d,J=7.1Hz,3H),1.20(s,3H),0.85(s,3H)。对于C22H25N7O3,ESI MS[M+H]+计算值436.2,发现值436.2。
例27:1-[(R)-2-羟基-1,2-二甲基丙基]-3-{[4-(2-氨基-8-甲氧基-4-喹唑啉基)-1H-1,2,3-三唑-1-基]甲基}-1H-吡啶-2-酮
由相应的叠氮化物和炔烃衍生物以类似于例21的方式合成标题化合物,得到20mg棕褐色固体。1H NMR(400MHz,DMSO-d6)δ8.70(d,J=1.2Hz,1H),8.64–8.54(m,1H),7.85–7.73(m,1H),7.48(d,J=6.8Hz,1H),7.22–7.11(m,2H),6.86(s,2H),6.31(t,J=6.9Hz,1H),5.52(s,2H),5.02(s,1H),4.85(s,1H),3.88(d,J=1.1Hz,3H),1.30(d,J=7.1Hz,3H),1.20(s,3H),0.85(s,3H)。对于C22H25N7O3,ESI MS[M+H]+计算值436.2,发现值436.2。
例28:1-[(S)-1-环丙基乙基]-3-{[4-(2-氨基-8-甲氧基-4-喹唑啉基)-1H-1,2,3-三唑-1-基]甲基}-1H-吡啶-2-酮
由相应的叠氮化物和炔烃衍生物以类似于例21的方式合成标题化合物,得到62mg橙色固体。1H NMR(400MHz,DMSO-d6)δ8.77–8.66(m,1H),8.61(s,1H),7.97(d,J=6.8Hz,1H),7.44(d,J=6.7Hz,1H),7.17(t,J=3.1Hz,2H),6.87(s,2H),6.37(d,J=7.2Hz,1H),5.52(s,2H),4.21(d,J=9.8Hz,1H),3.95–3.80(m,3H),1.35(d,J=6.6Hz,3H),0.63(s,1H),0.41(d,J=6.5Hz,3H),0.15(s,1H)。C22H23N7O2的ESI MS[M+H]+,计算值418.2,发现值418.2。
例29:1-[(R)-四氢呋喃-3-基]-3-{[4-(2-氨基-8-甲氧基-4-喹唑啉基)-1H-1,2,3-三唑-1–基]甲基}-1H-吡啶-2-酮
由相应的叠氮化物和炔烃衍生物类似于例21制备标题化合物。1H NMR(400MHz,DMSO-d6)δ8.71(s,1H),8.65–8.58(m,1H),7.66(d,J=7.0Hz,1H),7.53(d,J=6.8Hz,1H),7.19–7.13(m,2H),6.88(s,2H),6.37(t,J=6.9Hz,1H),5.53(s,2H),5.45–5.38(m,1H),4.09–4.00(m,1H),3.88(s,3H),3.85–3.80(m,2H),3.78–3.69(m,1H),2.48–2.39(m,1H),2.00–1.89(m,1H)。对于C21H22N7O3,ESI MS[M+H]+计算值420.2,发现值420.2。
例30:1-[(S)-2-甲氧基-1-甲基乙基]-3-{[4-(2-氨基-8-甲氧基-4-喹唑啉基)-1H-1,2,3-三唑-1-基]甲基}-1H-吡啶-2-酮
由相应的叠氮化物和炔烃衍生物类似于例21合成标题化合物。1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),8.60(d,J=6.2Hz,1H),7.82–7.71(m,1H),7.49–7.37(m,1H),7.16(d,J=5.1Hz,2H),6.87(s,2H),6.31(t,J=6.9Hz,1H),5.51(s,2H),5.14(m,1H),3.87(s,3H),3.67–3.54(m,1H),3.47(dd,J=10.5,4.6Hz,1H),3.18(s,3H),1.24(d,J=7.0Hz,3H)。对于C21H23N7O3,ESI MS[M+H]+计算值422.2,发现值422.2。
例31:1-[(R)-1-(四氢-2H-吡喃-4-基)乙基]-3-{[4-(2-氨基-6-氟-8-甲氧基-4-喹唑啉基)-1H-1,2,3-三唑-1-基]甲基}-1H-吡啶-2-酮
由相应的叠氮化物和炔烃衍生物类似于例19合成标题化合物。1H NMR(400MHz,DMSO-d6)δ8.72(s,1H),8.41(d,J=8.0Hz,1H),7.73(d,J=6.8Hz,1H),7.42(d,J=5.7Hz,1H),7.15(d,J=8.0Hz,1H),6.86(s,2H),6.32(s,1H),5.61–5.44(m,2H),4.73(m,1H),3.90(s,3H),3.84(m,1H),3.72(d,J=11.3Hz,1H),3.22(t,J=11.7Hz,1H),3.16–3.00(m,1H),1.89(m,1H),1.66(d,J=13.0Hz,1H),1.27(d,J=5.5Hz,3H),1.22(m,1H),1.11–0.94(m,2H)。对于C24H26N7O3,ESI MS[M+H]+计算值480.2,发现值480.2。
例32:1-[(S)-四氢-2H-吡喃-3-基]-3-{[4-(2-氨基-8-甲氧基-4-喹唑啉基)-1H-1,2,3-三唑-1-基]甲基}-1H-吡啶-2-酮
由相应的叠氮化物和炔烃衍生物类似于例21合成标题化合物。1H NMR(400MHz,DMSO-d6)δ8.76–8.67(m,1H),8.60(s,1H),7.88(d,J=6.3Hz,1H),7.49(d,J=6.7Hz,1H),7.15(s,2H),6.86(s,2H),6.41–6.19(m,1H),5.51(s,2H),4.76(m,1H),3.87(s,3H),3.77(m,2H),3.50(t,J=10.1Hz,1H),3.46(t,J=10.1Hz,1H),2.04–1.79(m,2H),1.67(m,2H)。对于C22H23N7O3,ESI MS[M+H]+计算值434.2,发现值434.2。
例33:1-[(R)-四氢-2H-吡喃-3-基]-3-{[4-(2-氨基-8-甲氧基-4-喹唑啉基)-1H-1,2,3-三唑-1-基]甲基}-1H-吡啶-2-酮
由相应的叠氮化物和炔烃衍生物类似于例21合成标题化合物。1H NMR(400MHz,DMSO-d6)δ8.76–8.67(m,1H),8.60(s,1H),7.88(d,J=6.3Hz,1H),7.49(d,J=6.7Hz,1H),7.15(s,2H),6.86(s,2H),6.41–6.19(m,1H),5.51(s,2H),4.76(m,1H),3.87(s,3H),3.77(m,2H),3.50(t,J=10.1Hz,1H),3.46(t,J=10.1Hz,1H),2.04–1.79(m,2H),1.67(m,2H)。对于C22H23N7O3,ESI MS[M+H]+计算值434.2,发现值434.2。
例34:1-[(R)-1-(2-羟基-2-甲基丙酰基)-3-吡咯烷基]-3-{[4-(2-氨基-8-甲氧基-4-喹唑啉基)-1H-1,2,3-三唑-1-基]甲基}-1H-吡啶-2-酮
由相应的叠氮化物和炔烃衍生物类似于例21合成标题化合物。1H NMR(400MHz,DMSO-d6)8.90(s,2H),7.67(s,1H),7.62(d,J=4Hz,1H),7.55(d,J=8Hz,1H),7.48(t,J=8Hz,1H),6.39-6.36(m,1H),5.59(s,2H),5.23(s,2H),4.13-4.11(m,1H),4.03(s,3H),3.99-3.77(m,3H),3.55-3.45(m,2H),2.29-2.07(m,2H),1.29-1.17(m,6H)。C25H29N8O4的ESIMS[M+H]+,计算值505.2,发现值505.3。
例35:1-[(S)-四氢呋喃-3-基]-3-{[4-(2-氨基-8-甲氧基-4-喹唑啉基)-1H-1,2,3-三唑-1–基]甲基}-1H-吡啶-2-酮
步骤1:在配备有磁力搅拌棒的250mL圆底烧瓶中,依次装入不饱和丙二酸二甲酯(17g,84.9mmol),MeOH(40mL)和i Pr2NEt(17.3mL,97.1mmol)。将该溶液加热至60℃,并在氮气氛下于相同温度下搅拌1小时。LCMS分析表明已完成向不饱和丙二酸二甲酯中加胺。然后将反应混合物冷却至23℃。向上述冷却的溶液中,添加RNH2·HCl,然后添加DBU(12mL,97.7mmol)。然后将溶液加热至60℃,并在该温度下搅拌4小时。反应完成后,减压除去溶剂。将MTBE(200mL),然后是H2O(150mL)加入上述粗混合物中。分离各层,并用MTBE(150mL)反萃取水层。用2(M)HCl水溶液将水层酸化至pH=4,然后使用NaHCO3水溶液将其酸化至pH=8。用CH2Cl2/i PrOH(2:1,300mL)萃取碱性水层两次。合并的有机层经Na2SO4干燥,蒸发,得到粗吡啶酮(11.7g,65%),其无需进一步纯化即可用于下一步。
步骤2:以与例19类似的方式,从相应的酯衍生物合成产物,得到黄色油状物(769mg,57%)。
步骤3:以类似于例1的方式合成产物:无色油(118mg,35%)。
步骤4:以类似于例1的方式合成产物:获得黄色固体(54mg,64%)。
1H NMR(400MHz,DMSO-d6)δ8.71(s,1H),8.65–8.59(m,1H),7.66(d,J=7.0Hz,1H),7.53(d,J=6.9Hz,1H),7.20–7.14(m,2H),6.88(s,2H),6.37(t,J=6.9Hz,1H),5.54(s,2H),5.47–5.38(m,1H),4.09–4.00(m,1H),3.89(s,3H),3.86–3.80(m,2H),3.79–3.69(m,1H),2.48–2.39(m,1H),2.00–1.90(m,1H)。对于C21H22N7O3,ESI MS[M+H]+计算值420.2,发现值420.2。
例36:1-[(S)-1-(1-羟基环丙基)乙基]-3-{[4-(2-氨基-8-甲氧基-4-喹唑啉基)-1H-1,2,3-三唑-1-基]甲基}-1H-吡啶-2-酮
由相应的叠氮化物和炔烃衍生物以类似于例35的方式合成标题化合物,得到61mg黄色固体。1H NMR(400MHz,DMSO-d6)δ8.70(d,J=2.9Hz,1H),8.61(s,1H),7.93(s,1H),7.48(s,1H),7.16(d,J=4.6Hz,2H),6.86(s,2H),6.34(s,1H),5.72(s,1H),5.52(s,2H),4.62(s,1H),3.88(d,J=2.7Hz,3H),1.37(s,2H),0.85(s,1H),0.68(s,2H),0.58(s,2H)。对于C22H23N7O3,ESI MS[M+H]+计算值434.2,发现值434.2。
例37:1-[(S)-1-(2-羟基-2-甲基丙酰基)-3-吡咯烷基]-3-{[4-(2-氨基-8-甲氧基-4-喹唑啉基)-1H-1,2,3-三唑-1-基]甲基}-1H-吡啶-2-酮
步骤1-3:类似于例35
步骤4:在23℃下向N-Boc化合物(0.4g,0.77mmol)在CH2Cl2(3.8mL)中的溶液中加入三氟乙酸(TFA,1.92mL,25.1mmol)。将反应混合物在23℃下搅拌12小时。蒸发溶剂,得到TFA盐,其无需进一步纯化即可用于下一步。
在上述TFA盐(0.16g,0.39mmol)的THF:DMF(1:2,0.9mL)溶液中:在23℃下添加Et3N(0.17mL,1.2mmol),并搅拌5分钟。向溶液中加入新鲜制备的粗酰氯(0.82g,6.7mmol),并在23℃下搅拌1.5h。真空除去溶剂,并通过硅胶快速色谱法纯化(CH2Cl2/MeOH梯度为100%至80%),然后进行反相HPLC,得到最终的醇(30mg)。1H NMR(400MHz,DMSO-d6)8.90(s,2H),7.67(s,1H),7.62(d,J=8Hz,1H),7.55(d,J=8Hz,1H),7.48(t,J=8Hz,1H),6.39-6.36(m,1H),5.60(s,2H),5.21(s,2H),4.13-4.11(m,1H),4.03(s,3H),3.98-3.74(m,2H),3.55-3.46(m,2H),2.29-2.08(m,3H),1.30-1.23(m,6H)。C25H29N8O4的ESI MS[M+H]+,计算值505.2,发现值505.4。
例38:3-{[4-(2-氨基-8-氟-4-喹啉基)-1H-1,2,3-三唑-1-基]甲基}-1-异丙基-1H-吡啶-2-酮
步骤1:将m-CPBA(75%,4.61g,20mmol,2当量)添加到氟喹啉(1.82g,10mmol,1当量)在CH2Cl2(20mL)中的溶液中。将混合物搅拌24小时,然后倒入10%KOH水溶液中。用CH2Cl2萃取混合物,将合并的有机层干燥,过滤并浓缩,得到为棕褐色固体的喹啉N-氧化物,其无需进一步纯化即可使用。
步骤2:将喹啉N-氧化物(1.54g,7.8mmol,1当量)和t-BuNH2(4.1mL,39mmol,5当量)溶解在CH2Cl2中,并将混合物在冰水浴中冷却。在10分钟内分三部分添加Ts2O(5.1g,15.6mmol,2当量)。加入TFA(19.5mL),并将混合物加热至70℃,直到通过LCMS观察到完全转化为产物。将混合物冷却至环境温度并浓缩。将粗残余物溶于CH2Cl2,用10%KOH水溶液碱化至pH~10,萃取,干燥并浓缩。将残余物通过快速色谱在SiO2上纯化,得到氨基喹啉,为深色固体。
步骤3:在N2的气氛下,将氨基喹啉(1.50g,7.6mmol,1当量),三甲基甲硅烷基乙炔(5.3mL,38mmol,5当量),Cs2CO3(7.4g,22.8mmol,3当量),Pd(OAc)2(86mg,0.38mmol,5mol%)和XPhos(340mg,0.76mmol,10mol%)溶解在二恶烷中,并将混合物加热至100℃保持1.5小时。将混合物冷却至环境温度,通过过滤并浓缩。将残余物通过SiO2上的快速色谱法纯化,得到甲硅烷基保护的炔,为深色油状物。
步骤4:将受保护的炔烃(123mg,0.48mmol)溶解在~2mL MeOH中,然后添加NH3(在MeOH中7M,0.12mL)。将混合物搅拌2.5小时并浓缩,得到相应的炔,其无需进一步纯化即可使用。
步骤5:由相应的叠氮化物和炔烃衍生物以类似于例1的方式合成标题化合物,得到39mg黄色固体。1H NMR(400MHz,DMSO-d6)δ8.74–8.65(m,1H),8.02(d,J=8.6Hz,1H),7.81(dd,J=6.9,2.1Hz,1H),7.44–7.26(m,2H),7.21–7.11(m,2H),6.81(s,2H),6.34(ddd,J=7.9,6.1,1.2Hz,1H),5.51(s,2H),5.16–5.04(m,1H),1.38–1.22(m,6H)。对于C20H19FN6O,ESIMS[M+H]+计算值379.2,发现值379.2。
例39:3-{[4-(2-氨基-8-甲氧基-4-喹唑啉基)-1H-吡唑-1-基]甲基}-1-异丙基-1H-吡啶-2-酮
步骤1:2,4-二氯-8-甲氧基喹唑啉(61.8g,270mmol),1-(四氢-2H-吡喃-2-基)-1H-吡唑-4-硼酸频哪醇酯(25.0g,90.0mmol),[1,1’-双(二苯基膦基)二茂铁]二氯化钯(II)(6.58g,9.00mmol),三乙胺(75.3mL,540mmol),DME(450mL)和水(11mL)的脱气混合物在80℃下搅拌16小时。将混合物浓缩到硅胶上,并通过硅胶色谱法(CH2Cl2中的0至40%EtOAc)纯化,得到期望的产物,为黄色泡沫状物(6.94g;22%)。
步骤2:将来自步骤1的产物(1.69g,4.90mmol),4-甲氧基苄胺(1.23mL)和THF(2.5mL)的混合物在70℃下搅拌20小时。加入EtOAc(100mL)和10%(w/w)柠檬酸(水溶液)(200mL)。通过过滤收集生成的形成的沉淀,用水和EtOAc洗涤,干燥,得到所需产物,为黄色固体(2.18g,100%)。
步骤3:将来自步骤2的产物(890mg,2.00mmol)和TFA(10mL)的混合物在80℃下搅拌2小时。将混合物加入到水(200mL)的搅拌烧瓶中,并用1M NaOH(水溶液)碱化至pH 10。通过过滤收集固体,用水洗涤,并用MTBE(10mL,60℃)研磨30分钟,得到所需产物,为浅黄色固体(308mg;64%)。
步骤4:将2-羟基-3-甲基吡啶(2.73g,25.0mmol),2-碘丙烷(5.00mL,50.0mmol),碳酸钾(6.90g,50.0mmol)和乙腈(50mL)的混合物在80℃下搅拌3个小时,并在70℃搅拌13个小时。过滤混合物以除去任何固体。将滤液浓缩到硅胶上,并通过硅胶色谱法纯化(0至100%EtOAc的己烷溶液),得到期望的产物,为黄色油状物(977mg;26%)。
步骤5:以类似于例8,步骤2的方式合成产物:获得黄色固体(859mg,58%)。
步骤6:将步骤3的产物(41mg,0.17mmol),步骤5的产物(39mg,0.17mmol),碳酸铯(78mg,0.20mmol)和DMSO(0.7mL)的混合物在80℃下搅拌15小时。将混合物添加到1:1的盐水/水溶液(10mL)中,并通过过滤收集固体。粗物质通过反相HPLC纯化,得到期望的产物,为黄色膜(6.7mg;10%)。1H NMR(400MHz,DMSO-d6)δ8.84(s,1H),8.29(s,1H),7.98(d,J=8.4Hz,1H),7.79(d,J=6.6Hz,1H),7.61(d,J=8.2Hz,1H),7.49(t,J=8.4Hz,1H),7.28(d,J=7.4Hz,1H),6.32(t,J=6.8Hz,1H),5.29(s,2H),5.08(hept,J=6.4Hz,1H),4.06(s,3H),1.29(d,J=6.8Hz,6H)。对于C21H23N6O2,ESI MS[M+H]+计算值391.2,发现值391.2。
例40:3-{[4-(2-氨基-8-甲氧基-4-喹唑啉基)-1H-吡唑-1-基]甲基}-1-乙基-1H-吡啶-2-酮
由相应的溴化物和吡唑衍生物以类似于例39的方式合成标题化合物,得到43mg黄色固体。1H NMR(400MHz,DMSO-d6)δ8.51(s,1H),8.06(s,1H),7.73(s,1H),7.67(d,J=7.4Hz,1H),7.62–7.43(m,1H),7.16–7.08(m,2H),6.76(s,2H),6.26(s,1H),5.24(s,2H),3.94(s,2H),3.87(d,J=2.8Hz,3H),1.22(s,3H)。C20H20N6O2的ESI MS[M+H]+,计算值377.2,发现值377.2。
例41:3-{[4-(2-氨基-8-甲氧基-4-喹唑啉基)-1H-吡唑-1-基]甲基}-1-环丙基-1H-吡啶-2-酮
由相应的溴化物和吡唑衍生物类似于例39制备标题化合物。1H NMR(400MHz,DMSO-d6)δ8.84(s,1H),8.30(s,1H),7.99(d,J=8.5Hz,1H),7.66–7.56(m,2H),7.51(t,J=8.2Hz,1H),7.35(d,J=6.8Hz,1H),6.23(t,J=6.8Hz,1H),5.29(s,2H),4.07(s,3H),3.41–3.32(m,1H),1.05–0.93(m,2H),0.91–0.76(m,2H).。对于C21H21N6O2,ESI MS[M+H]+计算值389.2,发现值389.2。
例42:1-[(R)-1-(四氢-2H-吡喃-4-基)乙基]-3-{[4-(2-氨基-8-甲氧基-4-喹唑啉基)-1H-吡唑-1-基]甲基}-1H-吡啶-2-酮
由相应的溴化物和吡唑衍生物类似于例39合成标题化合物。1H NMR(400MHz,DMSO-d6)δ8.49(s,1H),8.06(d,J=2.5Hz,1H),7.64(d,J=8.8Hz,2H),7.16–6.94(m,3H),6.73(s,2H),6.27(d,J=6.9Hz,1H),5.40–5.04(m,2H),4.75(m,1H),3.92–3.79(m,4H),3.72(d,J=11.5Hz,1H),3.23(t,J=11.7Hz,1H),3.11(t,J=11.7Hz,1H),1.89(m,1H),1.67(d,J=10.0Hz,1H),1.28(d,J=7.1Hz,3H),1.22(m,1H),1.03(m,2H)。C25H28N6O3的ESIMS[M+H]+,计算值461.2,发现值461.2。
例43:3-{[4-(2-氨基-8-甲氧基-4-喹啉基)-1H-1,2,3-三唑-1-基]甲基}-1-异丙基-1H-吡啶-2-酮
由相应的叠氮化物和炔烃衍生物以类似于例38的方式合成标题化合物,得到100mg橙色固体。1H NMR(400MHz,DMSO-d6)δ8.64(s,1H),7.81(dd,J=7.0,2.0Hz,1H),7.72(dd,J=8.3,1.4Hz,1H),7.36(dd,J=6.8,1.8Hz,1H),7.17–6.99(m,3H),6.57(s,2H),6.34(t,J=6.9Hz,1H),5.50(s,2H),5.10(p,J=6.8Hz,1H),3.87(s,3H),1.30(d,J=6.8Hz,6H)。对于C21H22N6O2,ESI MS[M+H]+计算值391.2,发现值391.2。
分析方法:
LC:安捷伦1100系列;质谱仪:安捷伦G6120BA,单四极杆
LC-MS方法:安捷伦Zorbax Eclipse PlusC18,4.6×100mm,3.5μM,35℃,1.5mL/min流速,0%至100%B的2.5分钟梯度,在100%B上洗涤0.5分钟;A=0.1%的甲酸/5%的乙腈/94.9%的水;B=0.1%甲酸/5%水/94.9%乙腈
闪蒸柱:ISCO Rf+
反相HPLC:ISCO-EZ或安捷伦1260;柱:Kinetex 5μm EVO C18 100A;250×21.2毫米(飞诺美公司)
生物实例
使用人2A腺苷受体(A2aR)CHO-TREx cAMP功能测定法测量化合物的腺苷受体活性
在诱导表达人A2AR的CHO-T-REx细胞上进行了cAMP拮抗剂功能测定(PerkinElmer)。将细胞以每孔1,000至2,500个细胞的密度接种到白色的384孔Opti板中,然后在37℃下与各种浓度的化合物(范围从1μM到0μM)孵育1小时。
将NECA(西格玛奥德里奇)从1μM到0μM的1:2系列稀释液添加到细胞刺激混合物中,并在37℃下孵育30分钟。孵育30分钟后,分别将5μLUlight-anti-cAMP(由Perkin Elmer提供的结合物和裂解缓冲液以1:50稀释)和5μL Eu-cAMP示踪剂(由Perkin Elmer提供的结合物和裂解缓冲液以1:50稀释)加入细胞并孵育一个小时。使用装有615nm激发滤光片和665nm发射滤光片的Envision多标记酶标仪(Perkin Elmer)检测FRET信号。
使用GraphPad Prism(7.02版)进行数据分析,以确定测试化合物的KB。
使用人2B腺苷受体CHO-K1 cAMP功能测定法测量化合物的腺苷受体活性
稳定表达人腺苷2B受体(A2BR:编号M000329,GenScript)的CHO-K1细胞购自美国新泽西州08854,皮斯卡塔韦的GenScript公司。
在稳定表达人A2BR的CHO-K1细胞上进行了cAMP拮抗剂功能测定(Perkin Elmer)。将1x 106细胞接种到T75烧瓶中,并在37℃和5%CO2中培养过夜。然后将2,000-4,000个细胞/孔的稳定表达的A2bR CHO-K1细胞接种到白色的384孔Opti平板中,然后化合物1在37℃下以各种浓度(从1μM到0μM)孵育1小时。
将从1μM到0μM的NECA(西格玛奥德里奇)的1:2系列稀释液添加到细胞刺激混合物中,并在37℃下孵育30分钟。孵育30分钟后,分别将5μLUlight-anti-cAMP(由Perkin Elmer提供的结合物和裂解缓冲液以1:50稀释)和5μL Eu-cAMP示踪剂(由Perkin Elmer提供的结合物和裂解缓冲液以1:50稀释),加入细胞并孵育一个小时。使用装有615nm激发滤光片和665nm发射滤光片的Envision多标记酶标仪(Perkin Elmer)检测FRET信号。
使用GraphPad Prism(7.02版)进行数据分析,以确定测试化合物的KB。
表1:具体示例(效力:A2AR和A2BR K B:+表示>1μM,++表示100nM至1μM,+++表示<100nM)
本文描述了本发明的特定实施方案,包括发明人已知的用于实施本发明的最佳模式。在阅读了前述说明之后,所公开的实施例的变型对于本领域技术人员而言将变得显而易见,并且期望那些技术人员可以适当地采用这样的变型。因此,意图以不同于本文具体描述的方式实践本发明,并且本发明包括适用法律允许的所附权利要求中记载的主题的所有修改和等同形式。而且,除非本文另外指出或与上下文明显矛盾,否则本发明涵盖上述元素在其所有可能的变化中的任何组合。
本说明书中引用的所有出版物,专利申请,登录号和其他参考文献均通过引用并入本文,就好像每个单独的出版物或专利申请均被明确地和单独地指出通过引用并入。
Claims (39)
1.式(I)表示的化合物,或其药学上可接受的盐,水合物或溶剂化物,其中,
G1为N或CR3a;
G2为N或CR3b;
R3a和R3b各自独立地为H或C1-3烷基;
R1a和R1b各自独立地选自下组:
i)H,
ii)C1-8烷基,任选地被1-3个R5取代基取代,
iii)-X1-O-C1-8烷基,任选地被1-3个R5取代基取代,
iv)-C(O)-R6,
v)Y,任选地被1-3个R7取代基取代,
vi)-X1-Y,任选地被1-3个R7取代基取代;和
vii)R1a和R1b与它们所连接的氮一起形成5-6元杂环烷基环,该环任选地被1-3个R8取代基取代,其中所述杂环烷基具有0-2个额外的选自O,N和S的杂原子环顶点;
每个Y是C3-8环烷基或具有1-3个选自O,N和S的杂原子环顶点的4至6元杂环烷基;
R2和R4各自独立地为H或C1-3烷基;
每个X1是C1-6亚烷基;
每个R5独立地选自下组:羟基,C3-8环烷基,苯基,-O-苯基,-C(O)ORa和氧代;
每个R6为C1-8烷基或Y,其各自任选地被1-3个选自羟基,-O-苯基,苯基和-O-C1-8烷基的取代基取代;
每个R7独立地选自下组:C1-8烷基,羟基,-O-C1-8烷基,氧代和C(O)ORa;
每个R8独立地选自下组:C1-8烷基,羟基和氧代;下标n为0、1、2或3;
每个R9独立地选自下组:C1-8烷基,-O-C1-8烷基,-X1-O-C1-8烷基,-O-X1-O-C1-8烷基,-X1-O-X1-O-C1-8烷基,-C(O)ORa,卤素,氰基,-NRbRc,Y,-X1-C3-8环烷基,和-X2-Z,其中X2选自下组:C1-6亚烷基,-C1-6亚烷基-O-,-C1-4亚烷基-O-C1-4亚烷基,-C(O)-和-S(O)2-,Z为具有1-3个选自O,N和S的杂原子环顶点的4至6元杂环烷基,其中每个所述R9取代基任选地被1-3个R11取代;
R10a,R10b,R10c和R10d各自独立地选自下组:H,C1-8烷基,卤素,氰基,-O-C1-8烷基,-X1-O-C1-8烷基,-O-X1-O-C1-8烷基,-S(O)2-C1-6烷基,-C(O)NRdRe和具有1-3个选自O,N和S的杂原子环顶点的4-6元杂芳基,其中每个所述R10a-d取代基任选地被1-3个R12取代,或相邻环顶点上的R10a,R10b,R10c和R10d中的两个任选地结合以形成任选地被1-2个卤素取代的5元杂环;
每个R11独立地选自下组:羟基,氧代,卤素,氰基,-NRdRe,-C(O)ORa,苯基,C3-8环烷基和任选被C(O)ORa取代的C1-4烷基;
每个R12独立地选自下组:卤素,氰基,羟基,-C(O)ORa;和
每个Ra是H或C1-6烷基;
每个Rb和Rc独立地选自下组:H,C1-8烷基,-S(O)2-C1-6烷基,-C(O)ORa和-X1-C(O)ORa;和
每个Rd和Re独立地选自下组:H,C1-8烷基,-S(O)2-C1-6烷基。
4.如权利要求1-3任一项所述的化合物,其中R10a,R10b和R10c中的至少一个是甲氧基。
7.如权利要求1-6任一项所述的化合物,或其药学上可接受的盐,水合物或溶剂化物,其中每个R9独立地选自下组:C1-8烷基,-O-C1-8烷基,-X1-O-C1-8烷基,-O-X1-O-C1-8烷基,-X1-O-X1-O-C1-8烷基,其中每个所述R9取代基可选地被1-3个R11取代。
8.如权利要求1-6中任一项所述的化合物,或其药学上可接受的盐,水合物或溶剂化物,其中每个R9独立地选自下组:-C(O)ORa,-NRbRc,Y,-X1-C3-8环烷基和-X2-Z,其中X2选自下组:C1-6亚烷基,-C1-6亚烷基-O-,-C(O)-和-S(O)2-,Z是具有1-3个选自O,N和S的杂原子环顶点的4至6元杂环烷基,并且其中每个所述R9取代基任选地被1-3个R11取代。
15.如权利要求1所述的化合物,选自表1的化合物。
16.一种药物组合物,包含权利要求1至15中任一项所述的化合物和一种药学上可接受的赋形剂。
17.一种治疗至少部分由腺苷A2A受体(A2AR)和/或腺苷A2B受体(A2BR)介导的疾病,病症或病状的方法,其特征在于,所述方法包括给有此需要的对象施用治疗上可接受量的权利要求1-15中任一项所述的化合物。
18.如权利要求17所述的方法,其特征在于,所述疾病,病症或病状至少部分地由A2AR介导。
19.如权利要求17所述的方法,其特征在于,所述疾病,病症或病状至少部分地由A2BR介导。
20.如权利要求17所述的方法,其特征在于,所述疾病,病症或病状至少部分地由A2AR和A2BR介导。
21.如权利要求18所述的方法,其特征在于,所述化合物以有效逆转或终止A2AR介导的免疫抑制进展的量给药。
22.如权利要求17-21所述的方法,其特征在于,所述疾病,病症或病状是癌症。
23.如权利要求22所述的方法,其特征在于,所述癌症是前列腺癌,结肠癌,直肠癌,胰腺癌,子宫颈癌,胃癌,子宫内膜癌,脑癌,肝癌,膀胱癌,卵巢癌,睾丸癌,头癌,颈癌,皮肤癌(包括黑色素瘤和基底癌),间皮内膜癌,白细胞癌(包括淋巴瘤和白血病),食道癌,乳房癌,肌肉癌,结缔组织癌,肺癌(包括小细胞肺癌和非小细胞癌),肾上腺癌,甲状腺癌,肾脏癌或骨骼癌;或是胶质母细胞瘤,间皮瘤,肾细胞癌,胃癌,肉瘤(包括卡波西肉瘤),绒毛膜癌,皮肤基底细胞癌或睾丸精原细胞瘤。
24.如权利要求22所述的方法,其特征在于,所述癌症选自下组:黑素瘤,结肠直肠癌,胰腺癌,乳腺癌,前列腺癌,肺癌,白血病,脑肿瘤,淋巴瘤,卵巢癌,卡波西氏肉瘤,头颈部的鳞状细胞癌,膀胱癌,子宫内膜癌,默克尔细胞癌或胃食管癌。
25.如权利要求17-21任一项所述的方法,其特征在于,所述疾病,病症或病状是免疫相关的疾病,病症或病状。
26.如权利要求25所述的方法,其特征在于,所述免疫相关疾病,病症或病状选自下组:类风湿性关节炎,肾衰竭,狼疮,哮喘,牛皮癣,结肠炎,胰腺炎,过敏,纤维化,贫血纤维肌痛,阿尔茨海默氏病,充血性心力衰竭,中风,主动脉瓣狭窄,动脉硬化,骨质疏松,帕金森氏病,感染,克罗恩病,溃疡性结肠炎,过敏性接触性皮炎和其他湿疹,全身性硬化症和多发性硬化症。
27.一种组合物,其特征在于,包含权利要求1-15任一项所述的化合物和至少一种其他治疗剂。
28.如权利要求27所述的组合物,其特征在于,至少一种其他治疗剂是化学治疗剂,免疫和/或炎症调节剂,抗高胆固醇血症剂,抗感染剂或放射线。
29.如权利要求27所述的组合物,其特征在于,所述至少一种其他治疗剂是免疫检查点抑制剂。
30.如权利要求29所述的组合物,其特征在于,所述免疫检查点抑制剂阻断PD1,PDL1,BTLA,LAG3,TIM-3,TIGIT,B7家族成员或CTLA4中至少一种的活性。
31.一种在受试者中治疗癌症的方法,其特征在于,所述方法包括向所述受试者施用有效量的权利要求1-15中任一项所述的化合物以及至少一种其他治疗剂。
32.如权利要求31所述的方法,其特征在于,所述至少一种其他治疗剂是化学治疗剂,免疫和/或炎症调节剂,抗高胆固醇血症剂,抗感染剂或放射线。
33.如权利要求32所述的方法,其特征在于,所述至少一种其他治疗剂是免疫检查点抑制剂。
34.如权利要求33所述的方法,其特征在于,所述免疫检查点抑制剂阻断PD1,PDL1,BTLA,LAG3,TIM-3,TIGIT,B7家族成员或CTLA4中的至少一种的活性。
35.如权利要求31至34中任一项所述的方法,其特征在于,进一步包括化学治疗剂。
36.如权利要求35所述的方法,其特征在于,所述化学治疗剂选自下组:顺铂,卡铂,奥沙利铂,阿霉素和培美曲塞。
37.如权利要求31至36中任一项所述的方法,其特征在于,所述化合物和所述至少一种其他治疗剂组合施用。
38.如权利要求31至36中任一项所述的方法,其特征在于,所述化合物和所述至少一种其他治疗剂同时但分开施用。
39.如权利要求31至36中任一项所述的方法,其特征在于,所述化合物和所述至少一种其他治疗剂是顺序施用的。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201862711273P | 2018-07-27 | 2018-07-27 | |
US62/711,273 | 2018-07-27 | ||
PCT/US2019/043608 WO2020023846A1 (en) | 2018-07-27 | 2019-07-26 | Pyridone a2r antagonists |
Publications (1)
Publication Number | Publication Date |
---|---|
CN112996509A true CN112996509A (zh) | 2021-06-18 |
Family
ID=69182367
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201980064256.XA Pending CN112996509A (zh) | 2018-07-27 | 2019-07-26 | 吡啶酮a2r拮抗剂 |
Country Status (9)
Country | Link |
---|---|
US (1) | US12064433B2 (zh) |
EP (1) | EP3829581B1 (zh) |
JP (1) | JP7394831B2 (zh) |
KR (1) | KR20210038642A (zh) |
CN (1) | CN112996509A (zh) |
AU (1) | AU2019312296A1 (zh) |
CA (1) | CA3107079A1 (zh) |
PL (1) | PL3829581T3 (zh) |
WO (1) | WO2020023846A1 (zh) |
Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL295569A (en) | 2020-03-19 | 2022-10-01 | Arcus Biosciences Inc | Tetralin and tetrahydroquinoline compounds as inhibitors of hif-2alpha |
US11649261B2 (en) | 2020-06-17 | 2023-05-16 | Arcus Biosciences, Inc. | Crystalline forms of a CD73 inhibitor and uses thereof |
TW202227407A (zh) | 2020-09-03 | 2022-07-16 | 美商免疫感應治療公司 | 喹啉cGAS拮抗劑化合物 |
EP4341262A1 (en) | 2021-05-21 | 2024-03-27 | Arcus Biosciences, Inc. | Axl inhibitor compounds |
WO2022246177A1 (en) | 2021-05-21 | 2022-11-24 | Arcus Biosciences, Inc. | Axl compounds |
EP4423069A1 (en) | 2021-10-29 | 2024-09-04 | Arcus Biosciences, Inc. | Inhibitors of hif-2alpha and methods of use thereof |
US20240002346A1 (en) | 2022-03-02 | 2024-01-04 | Immunesensor Therapeutics, Inc. | QUINOLINE cGAS ANTAGONIST COMPOUNDS |
WO2023215719A1 (en) | 2022-05-02 | 2023-11-09 | Arcus Biosciences, Inc. | Anti-tigit antibodies and uses of the same |
US20240124490A1 (en) | 2022-07-15 | 2024-04-18 | Arcus Biosciences, Inc. | Inhibitors of hpk1 and methods of use thereof |
WO2024020034A1 (en) | 2022-07-20 | 2024-01-25 | Arcus Biosciences, Inc. | Cbl-b inhibitors and methods of use thereof |
WO2024081385A1 (en) | 2022-10-14 | 2024-04-18 | Arcus Biosciences, Inc. | Hpk1 inhibitors and methods of use thereof |
US20240180947A1 (en) | 2022-10-20 | 2024-06-06 | Arcus Biosciences, Inc. | Lyophilized formulations of cd73 compounds |
WO2024097736A1 (en) | 2022-11-02 | 2024-05-10 | Arcus Biosciences, Inc. | Processes for preparing azolopyrimidine compounds |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104520288A (zh) * | 2012-02-29 | 2015-04-15 | 坎莫森特里克斯公司 | 作为ccr9拮抗剂的吡唑-1-基苯磺酰胺 |
WO2016126570A1 (en) * | 2015-02-06 | 2016-08-11 | Merck Sharp & Dohme Corp. | Aminoquinazoline compounds as a2a antagonist |
WO2018035072A1 (en) * | 2016-08-15 | 2018-02-22 | Purdue Research Foundation | 4-substituted aminoisoquinoline derivatives |
WO2018136700A1 (en) * | 2017-01-20 | 2018-07-26 | Arcus Biosciences, Inc. | Azolopyrimidine for the treatment of cancer-related disorders |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004092177A1 (en) | 2003-04-09 | 2004-10-28 | Biogen Idec Ma Inc. | Triazolopyrazines and methods of making and using the same |
TWI309240B (en) | 2004-09-17 | 2009-05-01 | Hoffmann La Roche | Anti-ox40l antibodies |
US7618962B2 (en) | 2005-02-25 | 2009-11-17 | Pgx Health, Llc | Pyrazolyl substituted xanthines |
US7812135B2 (en) | 2005-03-25 | 2010-10-12 | Tolerrx, Inc. | GITR-binding antibodies |
EP1996201A2 (en) * | 2006-03-17 | 2008-12-03 | Cv Therapeutics, Inc. | Method of preventing and treating hepatic disease using a2b adenosine receptor antagonists |
US8242150B2 (en) | 2007-06-13 | 2012-08-14 | Merck Sharp & Dohme Corp. | Triazole derivatives for treating alzheimer'S disease and related conditions |
EP3124046B1 (en) | 2007-07-12 | 2019-12-25 | GITR, Inc. | Combination therapies employing gitr binding molecules |
RU2595409C2 (ru) | 2009-09-03 | 2016-08-27 | Мерк Шарп И Доум Корп., | Анти-gitr-антитела |
CN106279416B (zh) | 2010-03-04 | 2019-08-30 | 宏观基因有限公司 | 与b7-h3反应性的抗体、其免疫学活性片段及其用途 |
CN105481983B (zh) | 2010-09-09 | 2021-09-03 | 辉瑞公司 | 4-1bb结合分子 |
CN105492429A (zh) | 2013-07-02 | 2016-04-13 | 米伦纽姆医药公司 | Sumo活化酶的杂芳基抑制剂 |
-
2019
- 2019-07-26 CN CN201980064256.XA patent/CN112996509A/zh active Pending
- 2019-07-26 US US17/263,016 patent/US12064433B2/en active Active
- 2019-07-26 KR KR1020217005878A patent/KR20210038642A/ko not_active Application Discontinuation
- 2019-07-26 JP JP2021504283A patent/JP7394831B2/ja active Active
- 2019-07-26 AU AU2019312296A patent/AU2019312296A1/en active Pending
- 2019-07-26 PL PL19841391.6T patent/PL3829581T3/pl unknown
- 2019-07-26 WO PCT/US2019/043608 patent/WO2020023846A1/en unknown
- 2019-07-26 CA CA3107079A patent/CA3107079A1/en active Pending
- 2019-07-26 EP EP19841391.6A patent/EP3829581B1/en active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104520288A (zh) * | 2012-02-29 | 2015-04-15 | 坎莫森特里克斯公司 | 作为ccr9拮抗剂的吡唑-1-基苯磺酰胺 |
WO2016126570A1 (en) * | 2015-02-06 | 2016-08-11 | Merck Sharp & Dohme Corp. | Aminoquinazoline compounds as a2a antagonist |
WO2018035072A1 (en) * | 2016-08-15 | 2018-02-22 | Purdue Research Foundation | 4-substituted aminoisoquinoline derivatives |
WO2018136700A1 (en) * | 2017-01-20 | 2018-07-26 | Arcus Biosciences, Inc. | Azolopyrimidine for the treatment of cancer-related disorders |
Non-Patent Citations (2)
Title |
---|
ELISA BONANDI 等: "The 1, 2, 3-triazole ring as a bioisostere in medicinal chemistry", DRUG DISCOVERY TODAY, vol. 22, pages 1572, XP085215112, DOI: 10.1016/j.drudis.2017.05.014 * |
IDREES MOHAMMED 等: "1, 2, 3-Triazoles as Amide Bioisosteres: Discovery of a New Class of Potent HIV‑1 Vif Antagonists", JOURNAL OF MEDICINAL CHEMISTRY, vol. 59, pages 7680 * |
Also Published As
Publication number | Publication date |
---|---|
KR20210038642A (ko) | 2021-04-07 |
EP3829581A1 (en) | 2021-06-09 |
WO2020023846A1 (en) | 2020-01-30 |
PL3829581T3 (pl) | 2024-07-01 |
US20210161898A1 (en) | 2021-06-03 |
EP3829581A4 (en) | 2022-04-27 |
EP3829581B1 (en) | 2024-04-03 |
JP7394831B2 (ja) | 2023-12-08 |
AU2019312296A1 (en) | 2021-03-18 |
CA3107079A1 (en) | 2020-01-30 |
US12064433B2 (en) | 2024-08-20 |
EP3829581C0 (en) | 2024-04-03 |
JP2021531314A (ja) | 2021-11-18 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN110612100B (zh) | 治疗与癌症有关疾病的喹唑啉-吡啶衍生物 | |
JP7394831B2 (ja) | ピリドンa2rアンタゴニスト | |
AU2018210272C1 (en) | Azolopyrimidine for the treatment of cancer-related disorders | |
ES2951809T3 (es) | Derivados de quinazolina-pirazol para el tratamiento de trastornos relacionados con el cáncer | |
CN114206332B (zh) | 2,3,5-三取代吡唑并[1,5-a]嘧啶化合物 | |
TWI828800B (zh) | Arg1及/或arg2之抑制劑 | |
KR102656571B1 (ko) | 아르기나아제 억제제 | |
EA038488B1 (ru) | Азолопиримидины для лечения раковых заболеваний |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 40055891 Country of ref document: HK |