JP6243062B2 - Syk阻害剤 - Google Patents
Syk阻害剤 Download PDFInfo
- Publication number
- JP6243062B2 JP6243062B2 JP2016560876A JP2016560876A JP6243062B2 JP 6243062 B2 JP6243062 B2 JP 6243062B2 JP 2016560876 A JP2016560876 A JP 2016560876A JP 2016560876 A JP2016560876 A JP 2016560876A JP 6243062 B2 JP6243062 B2 JP 6243062B2
- Authority
- JP
- Japan
- Prior art keywords
- pharmaceutically acceptable
- crystal
- compound
- acceptable salt
- cancer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 239000003112 inhibitor Substances 0.000 title description 20
- 150000001875 compounds Chemical class 0.000 claims description 451
- 150000003839 salts Chemical class 0.000 claims description 311
- 239000013078 crystal Substances 0.000 claims description 266
- -1 stereoisomer Substances 0.000 claims description 159
- 239000000203 mixture Substances 0.000 claims description 155
- 206010028980 Neoplasm Diseases 0.000 claims description 128
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 126
- 201000010099 disease Diseases 0.000 claims description 102
- 201000011510 cancer Diseases 0.000 claims description 94
- 238000011282 treatment Methods 0.000 claims description 92
- 239000008194 pharmaceutical composition Substances 0.000 claims description 54
- 210000004027 cell Anatomy 0.000 claims description 51
- 206010025323 Lymphomas Diseases 0.000 claims description 40
- 210000003719 b-lymphocyte Anatomy 0.000 claims description 39
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 31
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 30
- 239000003814 drug Substances 0.000 claims description 29
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims description 25
- 208000010668 atopic eczema Diseases 0.000 claims description 25
- 208000023275 Autoimmune disease Diseases 0.000 claims description 24
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims description 22
- 208000003950 B-cell lymphoma Diseases 0.000 claims description 21
- 208000006673 asthma Diseases 0.000 claims description 21
- 230000000172 allergic effect Effects 0.000 claims description 20
- 208000035475 disorder Diseases 0.000 claims description 19
- 208000027866 inflammatory disease Diseases 0.000 claims description 18
- 208000032839 leukemia Diseases 0.000 claims description 18
- ZRYZTVGYFNTCJF-UHFFFAOYSA-N 6-(6-amino-5-methylpyrazin-2-yl)-n-[4-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]imidazo[1,2-a]pyrazin-8-amine Chemical compound N1=C(N)C(C)=NC=C1C(N=C1NC=2C=CC(=CC=2)N2CCN(CC2)C2COC2)=CN2C1=NC=C2 ZRYZTVGYFNTCJF-UHFFFAOYSA-N 0.000 claims description 16
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 16
- 208000002250 Hematologic Neoplasms Diseases 0.000 claims description 15
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 claims description 15
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims description 15
- 238000004519 manufacturing process Methods 0.000 claims description 15
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 15
- 239000007787 solid Substances 0.000 claims description 14
- 206010040047 Sepsis Diseases 0.000 claims description 13
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 claims description 13
- 210000004369 blood Anatomy 0.000 claims description 13
- 239000008280 blood Substances 0.000 claims description 13
- 201000001441 melanoma Diseases 0.000 claims description 13
- 201000006417 multiple sclerosis Diseases 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 206010009944 Colon cancer Diseases 0.000 claims description 12
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 claims description 12
- 206010040070 Septic Shock Diseases 0.000 claims description 12
- XCIGZBVOUQVIPI-UHFFFAOYSA-N lanraplenib Chemical compound NC1=CN=CC(=N1)C=1N=C(C=2N(C1)C=CN2)NC2=CC=C(C=C2)N2CCN(CC2)C2COC2 XCIGZBVOUQVIPI-UHFFFAOYSA-N 0.000 claims description 12
- 238000002560 therapeutic procedure Methods 0.000 claims description 12
- WFQLDXGNAYZMLS-UHFFFAOYSA-N 6-(6-aminopyrazin-2-yl)-5-methyl-N-[4-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]imidazo[1,2-a]pyrazin-8-amine Chemical compound NC1=CN=CC(=N1)C=1N=C(C=2N(C1C)C=CN2)NC2=CC=C(C=C2)N2CCN(CC2)C2COC2 WFQLDXGNAYZMLS-UHFFFAOYSA-N 0.000 claims description 11
- 201000009030 Carcinoma Diseases 0.000 claims description 11
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 11
- 206010021245 Idiopathic thrombocytopenic purpura Diseases 0.000 claims description 11
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 11
- 208000031981 Thrombocytopenic Idiopathic Purpura Diseases 0.000 claims description 11
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 claims description 11
- 230000001154 acute effect Effects 0.000 claims description 11
- 201000003710 autoimmune thrombocytopenic purpura Diseases 0.000 claims description 11
- 230000001684 chronic effect Effects 0.000 claims description 11
- 208000014674 injury Diseases 0.000 claims description 11
- 210000000265 leukocyte Anatomy 0.000 claims description 11
- 206010039491 Sarcoma Diseases 0.000 claims description 10
- 206010042971 T-cell lymphoma Diseases 0.000 claims description 10
- 206010028417 myasthenia gravis Diseases 0.000 claims description 10
- 206010028537 myelofibrosis Diseases 0.000 claims description 10
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 9
- 208000011231 Crohn disease Diseases 0.000 claims description 9
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 9
- 201000004681 Psoriasis Diseases 0.000 claims description 9
- 208000021386 Sjogren Syndrome Diseases 0.000 claims description 9
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 9
- 201000003444 follicular lymphoma Diseases 0.000 claims description 9
- 208000002551 irritable bowel syndrome Diseases 0.000 claims description 9
- 201000007924 marginal zone B-cell lymphoma Diseases 0.000 claims description 9
- 208000021937 marginal zone lymphoma Diseases 0.000 claims description 9
- 201000005962 mycosis fungoides Diseases 0.000 claims description 9
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 8
- 206010035664 Pneumonia Diseases 0.000 claims description 8
- 208000002552 acute disseminated encephalomyelitis Diseases 0.000 claims description 8
- 210000004556 brain Anatomy 0.000 claims description 8
- 206010012601 diabetes mellitus Diseases 0.000 claims description 8
- 208000011580 syndromic disease Diseases 0.000 claims description 8
- 230000008733 trauma Effects 0.000 claims description 8
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 claims description 7
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 claims description 7
- 208000025324 B-cell acute lymphoblastic leukemia Diseases 0.000 claims description 7
- 206010006187 Breast cancer Diseases 0.000 claims description 7
- 208000026310 Breast neoplasm Diseases 0.000 claims description 7
- 102000004127 Cytokines Human genes 0.000 claims description 7
- 108090000695 Cytokines Proteins 0.000 claims description 7
- 201000004624 Dermatitis Diseases 0.000 claims description 7
- 206010015866 Extravasation Diseases 0.000 claims description 7
- 208000035186 Hemolytic Autoimmune Anemia Diseases 0.000 claims description 7
- 208000034578 Multiple myelomas Diseases 0.000 claims description 7
- 201000003793 Myelodysplastic syndrome Diseases 0.000 claims description 7
- 208000014767 Myeloproliferative disease Diseases 0.000 claims description 7
- 206010060862 Prostate cancer Diseases 0.000 claims description 7
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 7
- 208000029052 T-cell acute lymphoblastic leukemia Diseases 0.000 claims description 7
- 201000000448 autoimmune hemolytic anemia Diseases 0.000 claims description 7
- 230000036251 extravasation Effects 0.000 claims description 7
- 201000006845 reticulosarcoma Diseases 0.000 claims description 7
- 208000029922 reticulum cell sarcoma Diseases 0.000 claims description 7
- LFSWUEFCKBOGCG-UHFFFAOYSA-N 2-[5-[[6-(6-amino-5-methylpyrazin-2-yl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-[4-(oxetan-3-yl)piperazin-1-yl]phenoxy]ethanol Chemical compound NC1=C(N=CC(=N1)C=1N=C(C=2N(C1)C=CN2)NC=2C=CC(=C(OCCO)C2)N2CCN(CC2)C2COC2)C LFSWUEFCKBOGCG-UHFFFAOYSA-N 0.000 claims description 6
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 6
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 6
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims description 6
- 206010005003 Bladder cancer Diseases 0.000 claims description 6
- 208000011691 Burkitt lymphomas Diseases 0.000 claims description 6
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 claims description 6
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 6
- 206010014733 Endometrial cancer Diseases 0.000 claims description 6
- 206010014759 Endometrial neoplasm Diseases 0.000 claims description 6
- 206010020751 Hypersensitivity Diseases 0.000 claims description 6
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 6
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 6
- 206010027476 Metastases Diseases 0.000 claims description 6
- 206010033128 Ovarian cancer Diseases 0.000 claims description 6
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 6
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 6
- 206010038389 Renal cancer Diseases 0.000 claims description 6
- 208000007660 Residual Neoplasm Diseases 0.000 claims description 6
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims description 6
- 206010041067 Small cell lung cancer Diseases 0.000 claims description 6
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 6
- 208000024780 Urticaria Diseases 0.000 claims description 6
- 201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 6
- 208000026935 allergic disease Diseases 0.000 claims description 6
- 201000007455 central nervous system cancer Diseases 0.000 claims description 6
- 208000029742 colonic neoplasm Diseases 0.000 claims description 6
- 201000010982 kidney cancer Diseases 0.000 claims description 6
- 201000005202 lung cancer Diseases 0.000 claims description 6
- 208000020816 lung neoplasm Diseases 0.000 claims description 6
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 6
- 230000009401 metastasis Effects 0.000 claims description 6
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 6
- 210000000056 organ Anatomy 0.000 claims description 6
- 201000008482 osteoarthritis Diseases 0.000 claims description 6
- 201000002528 pancreatic cancer Diseases 0.000 claims description 6
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 6
- 208000000587 small cell lung carcinoma Diseases 0.000 claims description 6
- 231100000419 toxicity Toxicity 0.000 claims description 6
- 230000001988 toxicity Effects 0.000 claims description 6
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 6
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 6
- RWEICHZKRDIUMB-UHFFFAOYSA-N 2-[5-[[6-(6-aminopyrazin-2-yl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-[4-(oxetan-3-yl)piperazin-1-yl]phenoxy]ethanol Chemical compound NC1=CN=CC(=N1)C=1N=C(C=2N(C1)C=CN2)NC=2C=CC(=C(OCCO)C2)N2CCN(CC2)C2COC2 RWEICHZKRDIUMB-UHFFFAOYSA-N 0.000 claims description 5
- ZJIGGUNEWCTZJO-UHFFFAOYSA-N 2-[[4-[4-[[6-(6-aminopyrazin-2-yl)imidazo[1,2-a]pyrazin-8-yl]amino]phenyl]piperazin-1-yl]methyl]propane-1,3-diol Chemical compound NC1=CN=CC(=N1)C=1N=C(C=2N(C1)C=CN2)NC2=CC=C(C=C2)N2CCN(CC2)CC(CO)CO ZJIGGUNEWCTZJO-UHFFFAOYSA-N 0.000 claims description 5
- 208000006468 Adrenal Cortex Neoplasms Diseases 0.000 claims description 5
- 208000035285 Allergic Seasonal Rhinitis Diseases 0.000 claims description 5
- 206010003445 Ascites Diseases 0.000 claims description 5
- 206010003571 Astrocytoma Diseases 0.000 claims description 5
- 208000032568 B-cell prolymphocytic leukaemia Diseases 0.000 claims description 5
- 206010005949 Bone cancer Diseases 0.000 claims description 5
- 208000018084 Bone neoplasm Diseases 0.000 claims description 5
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 5
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 5
- 239000000055 Corticotropin-Releasing Hormone Substances 0.000 claims description 5
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 5
- 208000004262 Food Hypersensitivity Diseases 0.000 claims description 5
- 208000022072 Gallbladder Neoplasms Diseases 0.000 claims description 5
- 208000007766 Kaposi sarcoma Diseases 0.000 claims description 5
- 201000003791 MALT lymphoma Diseases 0.000 claims description 5
- 206010026673 Malignant Pleural Effusion Diseases 0.000 claims description 5
- 206010027406 Mesothelioma Diseases 0.000 claims description 5
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims description 5
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 5
- 208000037538 Myelomonocytic Juvenile Leukemia Diseases 0.000 claims description 5
- 201000007224 Myeloproliferative neoplasm Diseases 0.000 claims description 5
- 206010029260 Neuroblastoma Diseases 0.000 claims description 5
- 206010029461 Nodal marginal zone B-cell lymphomas Diseases 0.000 claims description 5
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 5
- 208000007452 Plasmacytoma Diseases 0.000 claims description 5
- 208000035416 Prolymphocytic B-Cell Leukemia Diseases 0.000 claims description 5
- 206010039085 Rhinitis allergic Diseases 0.000 claims description 5
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 5
- 208000031673 T-Cell Cutaneous Lymphoma Diseases 0.000 claims description 5
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 5
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 5
- 206010047115 Vasculitis Diseases 0.000 claims description 5
- 208000030002 adult glioblastoma Diseases 0.000 claims description 5
- 201000010105 allergic rhinitis Diseases 0.000 claims description 5
- 150000001412 amines Chemical class 0.000 claims description 5
- 201000010881 cervical cancer Diseases 0.000 claims description 5
- IDLFZVILOHSSID-OVLDLUHVSA-N corticotropin Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](N)CO)C1=CC=C(O)C=C1 IDLFZVILOHSSID-OVLDLUHVSA-N 0.000 claims description 5
- 229960000258 corticotropin Drugs 0.000 claims description 5
- 201000007241 cutaneous T cell lymphoma Diseases 0.000 claims description 5
- 238000005520 cutting process Methods 0.000 claims description 5
- 201000004101 esophageal cancer Diseases 0.000 claims description 5
- 210000000416 exudates and transudate Anatomy 0.000 claims description 5
- 235000020932 food allergy Nutrition 0.000 claims description 5
- 201000010175 gallbladder cancer Diseases 0.000 claims description 5
- 206010017758 gastric cancer Diseases 0.000 claims description 5
- 208000005017 glioblastoma Diseases 0.000 claims description 5
- 201000009277 hairy cell leukemia Diseases 0.000 claims description 5
- 201000010536 head and neck cancer Diseases 0.000 claims description 5
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 5
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 5
- 231100000844 hepatocellular carcinoma Toxicity 0.000 claims description 5
- 230000009610 hypersensitivity Effects 0.000 claims description 5
- 208000015181 infectious disease Diseases 0.000 claims description 5
- 208000030603 inherited susceptibility to asthma Diseases 0.000 claims description 5
- 201000005992 juvenile myelomonocytic leukemia Diseases 0.000 claims description 5
- 201000011649 lymphoblastic lymphoma Diseases 0.000 claims description 5
- 210000004698 lymphocyte Anatomy 0.000 claims description 5
- 210000003563 lymphoid tissue Anatomy 0.000 claims description 5
- 210000004877 mucosa Anatomy 0.000 claims description 5
- 201000006039 nodal marginal zone lymphoma Diseases 0.000 claims description 5
- 208000025638 primary cutaneous T-cell non-Hodgkin lymphoma Diseases 0.000 claims description 5
- 206010062113 splenic marginal zone lymphoma Diseases 0.000 claims description 5
- 206010041823 squamous cell carcinoma Diseases 0.000 claims description 5
- 201000011549 stomach cancer Diseases 0.000 claims description 5
- 201000002510 thyroid cancer Diseases 0.000 claims description 5
- 210000001685 thyroid gland Anatomy 0.000 claims description 5
- 206010001889 Alveolitis Diseases 0.000 claims description 4
- 208000024827 Alzheimer disease Diseases 0.000 claims description 4
- 206010003011 Appendicitis Diseases 0.000 claims description 4
- 201000001320 Atherosclerosis Diseases 0.000 claims description 4
- 201000001178 Bacterial Pneumonia Diseases 0.000 claims description 4
- 208000009137 Behcet syndrome Diseases 0.000 claims description 4
- 206010006458 Bronchitis chronic Diseases 0.000 claims description 4
- 206010006895 Cachexia Diseases 0.000 claims description 4
- 206010010744 Conjunctivitis allergic Diseases 0.000 claims description 4
- 201000003883 Cystic fibrosis Diseases 0.000 claims description 4
- 206010012438 Dermatitis atopic Diseases 0.000 claims description 4
- 206010012442 Dermatitis contact Diseases 0.000 claims description 4
- 206010014561 Emphysema Diseases 0.000 claims description 4
- 208000004232 Enteritis Diseases 0.000 claims description 4
- 206010016946 Food allergy Diseases 0.000 claims description 4
- 208000007882 Gastritis Diseases 0.000 claims description 4
- 206010018364 Glomerulonephritis Diseases 0.000 claims description 4
- 208000024869 Goodpasture syndrome Diseases 0.000 claims description 4
- 201000005569 Gout Diseases 0.000 claims description 4
- 206010018634 Gouty Arthritis Diseases 0.000 claims description 4
- 208000009329 Graft vs Host Disease Diseases 0.000 claims description 4
- 208000030836 Hashimoto thyroiditis Diseases 0.000 claims description 4
- 208000032843 Hemorrhage Diseases 0.000 claims description 4
- 206010019728 Hepatitis alcoholic Diseases 0.000 claims description 4
- 206010023330 Keloid scar Diseases 0.000 claims description 4
- 206010069698 Langerhans' cell histiocytosis Diseases 0.000 claims description 4
- 201000009906 Meningitis Diseases 0.000 claims description 4
- 208000037039 Monarthritis Diseases 0.000 claims description 4
- 208000003445 Mouth Neoplasms Diseases 0.000 claims description 4
- 208000000112 Myalgia Diseases 0.000 claims description 4
- 208000009525 Myocarditis Diseases 0.000 claims description 4
- 201000002481 Myositis Diseases 0.000 claims description 4
- 206010051606 Necrotising colitis Diseases 0.000 claims description 4
- 206010031252 Osteomyelitis Diseases 0.000 claims description 4
- 206010033645 Pancreatitis Diseases 0.000 claims description 4
- 208000029082 Pelvic Inflammatory Disease Diseases 0.000 claims description 4
- 201000001263 Psoriatic Arthritis Diseases 0.000 claims description 4
- 208000036824 Psoriatic arthropathy Diseases 0.000 claims description 4
- 206010037394 Pulmonary haemorrhage Diseases 0.000 claims description 4
- 206010037660 Pyrexia Diseases 0.000 claims description 4
- 208000003782 Raynaud disease Diseases 0.000 claims description 4
- 208000012322 Raynaud phenomenon Diseases 0.000 claims description 4
- 206010063837 Reperfusion injury Diseases 0.000 claims description 4
- 201000000582 Retinoblastoma Diseases 0.000 claims description 4
- 201000010001 Silicosis Diseases 0.000 claims description 4
- 201000002661 Spondylitis Diseases 0.000 claims description 4
- 206010042496 Sunburn Diseases 0.000 claims description 4
- 206010044248 Toxic shock syndrome Diseases 0.000 claims description 4
- 231100000650 Toxic shock syndrome Toxicity 0.000 claims description 4
- 206010052779 Transplant rejections Diseases 0.000 claims description 4
- 206010053613 Type IV hypersensitivity reaction Diseases 0.000 claims description 4
- 208000006593 Urologic Neoplasms Diseases 0.000 claims description 4
- 206010046851 Uveitis Diseases 0.000 claims description 4
- 208000008383 Wilms tumor Diseases 0.000 claims description 4
- 208000002353 alcoholic hepatitis Diseases 0.000 claims description 4
- 208000002205 allergic conjunctivitis Diseases 0.000 claims description 4
- 206010002224 anaplastic astrocytoma Diseases 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 208000024998 atopic conjunctivitis Diseases 0.000 claims description 4
- 201000008937 atopic dermatitis Diseases 0.000 claims description 4
- 208000034158 bleeding Diseases 0.000 claims description 4
- 230000000740 bleeding effect Effects 0.000 claims description 4
- 208000029028 brain injury Diseases 0.000 claims description 4
- 206010006451 bronchitis Diseases 0.000 claims description 4
- 208000007451 chronic bronchitis Diseases 0.000 claims description 4
- 208000010247 contact dermatitis Diseases 0.000 claims description 4
- 201000001981 dermatomyositis Diseases 0.000 claims description 4
- 206010014599 encephalitis Diseases 0.000 claims description 4
- 208000003401 eosinophilic granuloma Diseases 0.000 claims description 4
- 201000001155 extrinsic allergic alveolitis Diseases 0.000 claims description 4
- 208000030533 eye disease Diseases 0.000 claims description 4
- 208000007565 gingivitis Diseases 0.000 claims description 4
- 208000024908 graft versus host disease Diseases 0.000 claims description 4
- 210000003714 granulocyte Anatomy 0.000 claims description 4
- 208000006454 hepatitis Diseases 0.000 claims description 4
- 231100000283 hepatitis Toxicity 0.000 claims description 4
- 208000022098 hypersensitivity pneumonitis Diseases 0.000 claims description 4
- 238000001990 intravenous administration Methods 0.000 claims description 4
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 claims description 4
- 208000004995 necrotizing enterocolitis Diseases 0.000 claims description 4
- 201000008383 nephritis Diseases 0.000 claims description 4
- 201000008026 nephroblastoma Diseases 0.000 claims description 4
- 201000002120 neuroendocrine carcinoma Diseases 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 201000006195 perinatal necrotizing enterocolitis Diseases 0.000 claims description 4
- 208000008423 pleurisy Diseases 0.000 claims description 4
- 208000003476 primary myelofibrosis Diseases 0.000 claims description 4
- 201000003651 pulmonary sarcoidosis Diseases 0.000 claims description 4
- 231100000241 scar Toxicity 0.000 claims description 4
- 230000036303 septic shock Effects 0.000 claims description 4
- 201000009890 sinusitis Diseases 0.000 claims description 4
- 208000020431 spinal cord injury Diseases 0.000 claims description 4
- 210000001519 tissue Anatomy 0.000 claims description 4
- 230000009772 tissue formation Effects 0.000 claims description 4
- 230000005951 type IV hypersensitivity Effects 0.000 claims description 4
- 208000027930 type IV hypersensitivity disease Diseases 0.000 claims description 4
- 208000000143 urethritis Diseases 0.000 claims description 4
- 230000002792 vascular Effects 0.000 claims description 4
- 208000026872 Addison Disease Diseases 0.000 claims description 3
- 208000018737 Parkinson disease Diseases 0.000 claims description 3
- YMHAMCHFUTYGTR-MRXNPFEDSA-N [(2R)-4-[4-[[6-(6-aminopyrazin-2-yl)imidazo[1,2-a]pyrazin-8-yl]amino]phenyl]morpholin-2-yl]methanol Chemical compound NC1=CN=CC(=N1)C=1N=C(C=2N(C1)C=CN2)NC2=CC=C(C=C2)N2C[C@@H](OCC2)CO YMHAMCHFUTYGTR-MRXNPFEDSA-N 0.000 claims description 3
- 208000017733 acquired polycythemia vera Diseases 0.000 claims description 3
- 201000009267 bronchiectasis Diseases 0.000 claims description 3
- 201000001352 cholecystitis Diseases 0.000 claims description 3
- 208000025302 chronic primary adrenal insufficiency Diseases 0.000 claims description 3
- 208000011379 keloid formation Diseases 0.000 claims description 3
- 231100000572 poisoning Toxicity 0.000 claims description 3
- 230000000607 poisoning effect Effects 0.000 claims description 3
- 208000037244 polycythemia vera Diseases 0.000 claims description 3
- 230000002685 pulmonary effect Effects 0.000 claims description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 3
- 208000018464 vernal keratoconjunctivitis Diseases 0.000 claims description 3
- 208000032027 Essential Thrombocythemia Diseases 0.000 claims description 2
- 210000003414 extremity Anatomy 0.000 claims description 2
- 230000002518 glial effect Effects 0.000 claims description 2
- 238000007918 intramuscular administration Methods 0.000 claims description 2
- 201000000564 macroglobulinemia Diseases 0.000 claims description 2
- 201000000050 myeloid neoplasm Diseases 0.000 claims description 2
- 210000004165 myocardium Anatomy 0.000 claims description 2
- 230000007170 pathology Effects 0.000 claims description 2
- 208000030761 polycystic kidney disease Diseases 0.000 claims description 2
- 241000894007 species Species 0.000 claims description 2
- 206010051392 Diapedesis Diseases 0.000 claims 1
- 206010014824 Endotoxic shock Diseases 0.000 claims 1
- 206010021138 Hypovolaemic shock Diseases 0.000 claims 1
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 230000036210 malignancy Effects 0.000 claims 1
- 208000037890 multiple organ injury Diseases 0.000 claims 1
- 208000013223 septicemia Diseases 0.000 claims 1
- 206010040560 shock Diseases 0.000 claims 1
- 210000004872 soft tissue Anatomy 0.000 claims 1
- 238000000034 method Methods 0.000 description 134
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 87
- 230000000694 effects Effects 0.000 description 66
- 238000006243 chemical reaction Methods 0.000 description 55
- 238000003556 assay Methods 0.000 description 39
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 35
- 150000002148 esters Chemical class 0.000 description 34
- 239000000243 solution Substances 0.000 description 33
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 33
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 32
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 30
- 238000005481 NMR spectroscopy Methods 0.000 description 29
- 230000005764 inhibitory process Effects 0.000 description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 27
- 238000000634 powder X-ray diffraction Methods 0.000 description 27
- 229960004641 rituximab Drugs 0.000 description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical group OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 24
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 22
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 22
- 210000003651 basophil Anatomy 0.000 description 22
- 239000002904 solvent Substances 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- 239000003795 chemical substances by application Substances 0.000 description 21
- 210000003494 hepatocyte Anatomy 0.000 description 21
- 102100025222 CD63 antigen Human genes 0.000 description 20
- 101000934368 Homo sapiens CD63 antigen Proteins 0.000 description 20
- 102000000551 Syk Kinase Human genes 0.000 description 20
- 108010016672 Syk Kinase Proteins 0.000 description 20
- 210000004185 liver Anatomy 0.000 description 20
- 229960004397 cyclophosphamide Drugs 0.000 description 19
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 18
- 239000012267 brine Substances 0.000 description 17
- 239000008363 phosphate buffer Substances 0.000 description 17
- 238000002512 chemotherapy Methods 0.000 description 16
- 230000001965 increasing effect Effects 0.000 description 16
- 238000002360 preparation method Methods 0.000 description 16
- 230000001363 autoimmune Effects 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- 239000011734 sodium Substances 0.000 description 15
- 239000003981 vehicle Substances 0.000 description 15
- 230000004913 activation Effects 0.000 description 14
- 239000004480 active ingredient Substances 0.000 description 14
- 230000002401 inhibitory effect Effects 0.000 description 14
- 230000002829 reductive effect Effects 0.000 description 14
- 239000002002 slurry Substances 0.000 description 14
- 208000024891 symptom Diseases 0.000 description 14
- 239000002246 antineoplastic agent Substances 0.000 description 13
- 229960000390 fludarabine Drugs 0.000 description 13
- 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 13
- 239000000463 material Substances 0.000 description 13
- 230000001225 therapeutic effect Effects 0.000 description 13
- 238000002411 thermogravimetry Methods 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 238000000113 differential scanning calorimetry Methods 0.000 description 12
- 235000019439 ethyl acetate Nutrition 0.000 description 12
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 description 12
- 230000009467 reduction Effects 0.000 description 12
- 239000007858 starting material Substances 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 239000000126 substance Substances 0.000 description 12
- 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 11
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 11
- 206010066476 Haematological malignancy Diseases 0.000 description 11
- 238000004458 analytical method Methods 0.000 description 11
- 238000011319 anticancer therapy Methods 0.000 description 11
- 229940127089 cytotoxic agent Drugs 0.000 description 11
- 238000009472 formulation Methods 0.000 description 11
- 229960004618 prednisone Drugs 0.000 description 11
- 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 11
- 229940002612 prodrug Drugs 0.000 description 11
- 239000000651 prodrug Substances 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 11
- 229940124597 therapeutic agent Drugs 0.000 description 11
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- 229910052805 deuterium Inorganic materials 0.000 description 10
- 229960005420 etoposide Drugs 0.000 description 10
- 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 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 229920006395 saturated elastomer Polymers 0.000 description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000013543 active substance Substances 0.000 description 9
- 239000000654 additive Substances 0.000 description 9
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 9
- 239000002552 dosage form Substances 0.000 description 9
- 229960004679 doxorubicin Drugs 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 235000019441 ethanol Nutrition 0.000 description 9
- 230000001976 improved effect Effects 0.000 description 9
- 238000000338 in vitro Methods 0.000 description 9
- 238000005259 measurement Methods 0.000 description 9
- 239000000546 pharmaceutical excipient Substances 0.000 description 9
- 108090000765 processed proteins & peptides Proteins 0.000 description 9
- 239000000377 silicon dioxide Substances 0.000 description 9
- 229960004528 vincristine Drugs 0.000 description 9
- 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 9
- 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 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- 108060003951 Immunoglobulin Proteins 0.000 description 8
- 206010061218 Inflammation Diseases 0.000 description 8
- 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 8
- 238000004440 column chromatography Methods 0.000 description 8
- 239000013058 crude material Substances 0.000 description 8
- 102000018358 immunoglobulin Human genes 0.000 description 8
- 230000004054 inflammatory process Effects 0.000 description 8
- 229960000485 methotrexate Drugs 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 239000012453 solvate Substances 0.000 description 8
- 238000013456 study Methods 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 7
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[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 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 229940121363 anti-inflammatory agent Drugs 0.000 description 7
- 239000002260 anti-inflammatory agent Substances 0.000 description 7
- 238000013459 approach Methods 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 7
- IMBXRZKCLVBLBH-OGYJWPHRSA-N cvp protocol Chemical compound ClCCN(CCCl)P1(=O)NCCCO1.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.C([C@H](C[C@]1(C(=O)OC)C=2C(=C3C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C=O)=CC=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 IMBXRZKCLVBLBH-OGYJWPHRSA-N 0.000 description 7
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 description 7
- 239000000284 extract Substances 0.000 description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 238000001959 radiotherapy Methods 0.000 description 7
- 230000035945 sensitivity Effects 0.000 description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- 235000011152 sodium sulphate Nutrition 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- 229960000235 temsirolimus Drugs 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 description 6
- 241000124008 Mammalia Species 0.000 description 6
- 229930012538 Paclitaxel Natural products 0.000 description 6
- 108091000080 Phosphotransferase Proteins 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- ZNTHWWPFKRIXOD-QGZVFWFLSA-N [(2R)-4-[4-[[6-(6-amino-5-methylpyrazin-2-yl)imidazo[1,2-a]pyrazin-8-yl]amino]phenyl]morpholin-2-yl]methanol Chemical compound NC1=C(N=CC(=N1)C=1N=C(C=2N(C1)C=CN2)NC2=CC=C(C=C2)N2C[C@@H](OCC2)CO)C ZNTHWWPFKRIXOD-QGZVFWFLSA-N 0.000 description 6
- 229960000548 alemtuzumab Drugs 0.000 description 6
- 125000004429 atom Chemical group 0.000 description 6
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 6
- 229960004562 carboplatin Drugs 0.000 description 6
- 229960003957 dexamethasone Drugs 0.000 description 6
- 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 6
- 239000000706 filtrate Substances 0.000 description 6
- 239000012458 free base Substances 0.000 description 6
- 229940072221 immunoglobulins Drugs 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 210000004072 lung Anatomy 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 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 6
- 229960001156 mitoxantrone Drugs 0.000 description 6
- 229960001592 paclitaxel Drugs 0.000 description 6
- 102000020233 phosphotransferase Human genes 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 230000004044 response Effects 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 238000009097 single-agent therapy Methods 0.000 description 6
- 238000011476 stem cell transplantation Methods 0.000 description 6
- 239000001384 succinic acid Substances 0.000 description 6
- 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 6
- QFJCIRLUMZQUOT-UHFFFAOYSA-N temsirolimus Natural products C1CC(O)C(OC)CC1CC(C)C1OC(=O)C2CCCCN2C(=O)C(=O)C(O)(O2)C(C)CCC2CC(OC)C(C)=CC=CC=CC(C)CC(C)C(=O)C(OC)C(O)C(C)=CC(C)C(=O)C1 QFJCIRLUMZQUOT-UHFFFAOYSA-N 0.000 description 6
- 238000011277 treatment modality Methods 0.000 description 6
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 5
- AZBPLRVUZCGSFO-UHFFFAOYSA-N 6-(6-aminopyrazin-2-yl)-N-[4-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]imidazo[1,2-a]pyrazin-8-amine methanesulfonic acid Chemical compound S(C)(=O)(=O)O.NC1=CN=CC(=N1)C=1N=C(C=2N(C1)C=CN2)NC2=CC=C(C=C2)N2CCN(CC2)C2COC2 AZBPLRVUZCGSFO-UHFFFAOYSA-N 0.000 description 5
- 101001043352 Homo sapiens Lysyl oxidase homolog 2 Proteins 0.000 description 5
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 5
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- VWQVUPCCIRVNHF-OUBTZVSYSA-N Yttrium-90 Chemical compound [90Y] VWQVUPCCIRVNHF-OUBTZVSYSA-N 0.000 description 5
- 230000010398 acute inflammatory response Effects 0.000 description 5
- 229940100198 alkylating agent Drugs 0.000 description 5
- 239000002168 alkylating agent Substances 0.000 description 5
- 230000008901 benefit Effects 0.000 description 5
- 229960001467 bortezomib Drugs 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 239000000969 carrier Substances 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 230000003247 decreasing effect Effects 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 229960001101 ifosfamide Drugs 0.000 description 5
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 5
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 5
- 239000000314 lubricant Substances 0.000 description 5
- 229960001924 melphalan Drugs 0.000 description 5
- 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 5
- 229940016286 microcrystalline cellulose Drugs 0.000 description 5
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 5
- 239000008108 microcrystalline cellulose Substances 0.000 description 5
- 230000004048 modification Effects 0.000 description 5
- 238000012986 modification Methods 0.000 description 5
- 230000021766 negative regulation of B cell proliferation Effects 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 229920001184 polypeptide Polymers 0.000 description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
- 102000004196 processed proteins & peptides Human genes 0.000 description 5
- 230000001568 sexual effect Effects 0.000 description 5
- 229960003433 thalidomide Drugs 0.000 description 5
- RTQWWZBSTRGEAV-PKHIMPSTSA-N 2-[[(2s)-2-[bis(carboxymethyl)amino]-3-[4-(methylcarbamoylamino)phenyl]propyl]-[2-[bis(carboxymethyl)amino]propyl]amino]acetic acid Chemical compound CNC(=O)NC1=CC=C(C[C@@H](CN(CC(C)N(CC(O)=O)CC(O)=O)CC(O)=O)N(CC(O)=O)CC(O)=O)C=C1 RTQWWZBSTRGEAV-PKHIMPSTSA-N 0.000 description 4
- UQCZZGIPIMJBCL-UHFFFAOYSA-N 6,8-dibromoimidazo[1,2-a]pyrazine Chemical compound BrC1=NC(Br)=CN2C=CN=C21 UQCZZGIPIMJBCL-UHFFFAOYSA-N 0.000 description 4
- QMUCAJMJJGRIRI-UHFFFAOYSA-N 6-bromo-n-[4-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]imidazo[1,2-a]pyrazin-8-amine Chemical compound N=1C(Br)=CN2C=CN=C2C=1NC(C=C1)=CC=C1N(CC1)CCN1C1COC1 QMUCAJMJJGRIRI-UHFFFAOYSA-N 0.000 description 4
- 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 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- GHAGHRHYUCNTJH-UHFFFAOYSA-N CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cncc(Br)n1 Chemical compound CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cncc(Br)n1 GHAGHRHYUCNTJH-UHFFFAOYSA-N 0.000 description 4
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 4
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 4
- 229940126062 Compound A Drugs 0.000 description 4
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 4
- 108010036949 Cyclosporine Proteins 0.000 description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 4
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 4
- 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 4
- 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 4
- 102100021948 Lysyl oxidase homolog 2 Human genes 0.000 description 4
- 229930195725 Mannitol Natural products 0.000 description 4
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 4
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 4
- 208000021712 Soft tissue sarcoma Diseases 0.000 description 4
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 4
- 201000002454 adrenal cortex cancer Diseases 0.000 description 4
- 230000000735 allogeneic effect Effects 0.000 description 4
- 229910052782 aluminium Inorganic materials 0.000 description 4
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 4
- 229960000397 bevacizumab Drugs 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
- 230000000973 chemotherapeutic effect Effects 0.000 description 4
- 229960001265 ciclosporin Drugs 0.000 description 4
- 229960004316 cisplatin Drugs 0.000 description 4
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 4
- 238000002648 combination therapy Methods 0.000 description 4
- 239000010949 copper Substances 0.000 description 4
- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 description 4
- 229930182912 cyclosporin Natural products 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- 230000003111 delayed effect Effects 0.000 description 4
- 229950009760 epratuzumab Drugs 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 4
- 238000011134 hematopoietic stem cell transplantation Methods 0.000 description 4
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 4
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 4
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 4
- 229960001001 ibritumomab tiuxetan Drugs 0.000 description 4
- 238000009169 immunotherapy Methods 0.000 description 4
- 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 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 229940036646 iodine-131-tositumomab Drugs 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 229960001375 lactose Drugs 0.000 description 4
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 description 4
- 208000025854 malignant tumor of adrenal cortex Diseases 0.000 description 4
- 239000000594 mannitol Substances 0.000 description 4
- 235000010355 mannitol Nutrition 0.000 description 4
- 108020004084 membrane receptors Proteins 0.000 description 4
- 102000006240 membrane receptors Human genes 0.000 description 4
- 230000002503 metabolic effect Effects 0.000 description 4
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 4
- 229940023041 peptide vaccine Drugs 0.000 description 4
- 210000005259 peripheral blood Anatomy 0.000 description 4
- 239000011886 peripheral blood Substances 0.000 description 4
- 239000006187 pill Substances 0.000 description 4
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 229960005205 prednisolone Drugs 0.000 description 4
- 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 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 4
- 229940083542 sodium Drugs 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 235000017550 sodium carbonate Nutrition 0.000 description 4
- 210000000130 stem cell Anatomy 0.000 description 4
- 239000004094 surface-active agent Substances 0.000 description 4
- 238000001356 surgical procedure Methods 0.000 description 4
- 229960001967 tacrolimus Drugs 0.000 description 4
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 4
- 238000003419 tautomerization reaction Methods 0.000 description 4
- 229960005267 tositumomab Drugs 0.000 description 4
- 229940099039 velcade Drugs 0.000 description 4
- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-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
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- DMJNLPHLYGWAQI-UHFFFAOYSA-N 1-[4-nitro-2-[2-(oxan-2-yloxy)ethoxy]phenyl]-4-(oxetan-3-yl)piperazine Chemical compound [N+](=O)([O-])C1=CC(=C(C=C1)N1CCN(CC1)C1COC1)OCCOC1OCCCC1 DMJNLPHLYGWAQI-UHFFFAOYSA-N 0.000 description 3
- AWBLTDFTDYGFGJ-UHFFFAOYSA-N 3,5-dibromo-6-methylpyrazin-2-amine Chemical compound CC1=NC(N)=C(Br)N=C1Br AWBLTDFTDYGFGJ-UHFFFAOYSA-N 0.000 description 3
- ILKJAHWLVRCPRC-UHFFFAOYSA-N 3-[2-(oxan-2-yloxy)ethoxy]-4-[4-(oxetan-3-yl)piperazin-1-yl]aniline Chemical compound O1CC(C1)N1CCN(CC1)C1=C(C=C(N)C=C1)OCCOC1OCCCC1 ILKJAHWLVRCPRC-UHFFFAOYSA-N 0.000 description 3
- PUUBNFFMKVXFAQ-UHFFFAOYSA-N 4-[4-(oxetan-3-ylmethyl)piperazin-1-yl]aniline Chemical compound O1CC(C1)CN1CCN(CC1)C1=CC=C(N)C=C1 PUUBNFFMKVXFAQ-UHFFFAOYSA-N 0.000 description 3
- YIESLHWKUAAJIM-UHFFFAOYSA-N 6,8-dibromo-5-methylimidazo[1,2-a]pyrazine Chemical compound BrC=1N=C(C=2N(C1C)C=CN2)Br YIESLHWKUAAJIM-UHFFFAOYSA-N 0.000 description 3
- DVFRSTNNWJHWGW-UHFFFAOYSA-N 6-(6-aminopyrazin-2-yl)-N-[4-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]imidazo[1,2-a]pyrazin-8-amine butanedioic acid Chemical compound C(CCC(=O)O)(=O)O.NC1=CN=CC(=N1)C=1N=C(C=2N(C1)C=CN2)NC2=CC=C(C=C2)N2CCN(CC2)C2COC2 DVFRSTNNWJHWGW-UHFFFAOYSA-N 0.000 description 3
- UAOOJJPSCLNTOP-UHFFFAOYSA-N 6-methylpyrazin-2-amine Chemical compound CC1=CN=CC(N)=N1 UAOOJJPSCLNTOP-UHFFFAOYSA-N 0.000 description 3
- 206010073128 Anaplastic oligodendroglioma Diseases 0.000 description 3
- 206010003658 Atrial Fibrillation Diseases 0.000 description 3
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 description 3
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 108010006654 Bleomycin Proteins 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 208000031229 Cardiomyopathies Diseases 0.000 description 3
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 3
- MWWSFMDVAYGXBV-RUELKSSGSA-N Doxorubicin hydrochloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-RUELKSSGSA-N 0.000 description 3
- 108010008165 Etanercept Proteins 0.000 description 3
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[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 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 description 3
- 208000031226 Hyperlipidaemia Diseases 0.000 description 3
- 206010020772 Hypertension Diseases 0.000 description 3
- 102000006992 Interferon-alpha Human genes 0.000 description 3
- 108010047761 Interferon-alpha Proteins 0.000 description 3
- 208000012659 Joint disease Diseases 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- 229920000881 Modified starch Polymers 0.000 description 3
- 201000010133 Oligodendroglioma Diseases 0.000 description 3
- 208000008469 Peptic Ulcer Diseases 0.000 description 3
- 208000018262 Peripheral vascular disease Diseases 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 3
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 description 3
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 3
- 102000001253 Protein Kinase Human genes 0.000 description 3
- 208000028017 Psychotic disease Diseases 0.000 description 3
- 206010053879 Sepsis syndrome Diseases 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 208000036765 Squamous cell carcinoma of the esophagus Diseases 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 208000006011 Stroke Diseases 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- 206010051379 Systemic Inflammatory Response Syndrome Diseases 0.000 description 3
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 3
- 208000024799 Thyroid disease Diseases 0.000 description 3
- 108060008683 Tumor Necrosis Factor Receptor Proteins 0.000 description 3
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 3
- 208000027418 Wounds and injury Diseases 0.000 description 3
- 230000000996 additive effect Effects 0.000 description 3
- 239000003708 ampul Substances 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- 230000006907 apoptotic process Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 238000010256 biochemical assay Methods 0.000 description 3
- 229960001561 bleomycin Drugs 0.000 description 3
- 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 3
- 210000001185 bone marrow Anatomy 0.000 description 3
- 210000000481 breast Anatomy 0.000 description 3
- 239000001506 calcium phosphate Substances 0.000 description 3
- 235000010980 cellulose Nutrition 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 208000026106 cerebrovascular disease Diseases 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
- 239000000460 chlorine Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 210000001072 colon Anatomy 0.000 description 3
- 208000029078 coronary artery disease Diseases 0.000 description 3
- 230000000875 corresponding effect Effects 0.000 description 3
- 239000003246 corticosteroid Substances 0.000 description 3
- 229960000684 cytarabine Drugs 0.000 description 3
- 239000007884 disintegrant Substances 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 208000007276 esophageal squamous cell carcinoma Diseases 0.000 description 3
- 229960000403 etanercept Drugs 0.000 description 3
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 230000002068 genetic effect Effects 0.000 description 3
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 3
- 229910052737 gold Inorganic materials 0.000 description 3
- 239000010931 gold Substances 0.000 description 3
- 210000003128 head Anatomy 0.000 description 3
- 208000018578 heart valve disease Diseases 0.000 description 3
- 201000005787 hematologic cancer Diseases 0.000 description 3
- 150000004677 hydrates Chemical class 0.000 description 3
- 239000003018 immunosuppressive agent Substances 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 229910052738 indium Inorganic materials 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 238000007689 inspection Methods 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 210000003734 kidney Anatomy 0.000 description 3
- 229960000681 leflunomide Drugs 0.000 description 3
- VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 description 3
- 229950000128 lumiliximab Drugs 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 229960001855 mannitol Drugs 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- RTGDFNSFWBGLEC-SYZQJQIISA-N mycophenolate mofetil Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(/C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-SYZQJQIISA-N 0.000 description 3
- 229960004866 mycophenolate mofetil Drugs 0.000 description 3
- 210000003739 neck Anatomy 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 3
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 125000006299 oxetan-3-yl group Chemical group [H]C1([H])OC([H])([H])C1([H])* 0.000 description 3
- FYCBRGMZDWYEHI-UHFFFAOYSA-N oxetane-3-carbaldehyde Chemical compound O=CC1COC1 FYCBRGMZDWYEHI-UHFFFAOYSA-N 0.000 description 3
- 238000012856 packing Methods 0.000 description 3
- 230000036961 partial effect Effects 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
- 208000011906 peptic ulcer disease Diseases 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 229940069328 povidone Drugs 0.000 description 3
- 210000002307 prostate Anatomy 0.000 description 3
- 108060006633 protein kinase Proteins 0.000 description 3
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 3
- 238000011363 radioimmunotherapy Methods 0.000 description 3
- BTIHMVBBUGXLCJ-OAHLLOKOSA-N seliciclib Chemical compound C=12N=CN(C(C)C)C2=NC(N[C@@H](CO)CC)=NC=1NCC1=CC=CC=C1 BTIHMVBBUGXLCJ-OAHLLOKOSA-N 0.000 description 3
- 230000035939 shock Effects 0.000 description 3
- DEIYFTQMQPDXOT-UHFFFAOYSA-N sildenafil citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 DEIYFTQMQPDXOT-UHFFFAOYSA-N 0.000 description 3
- 210000003491 skin Anatomy 0.000 description 3
- 210000000813 small intestine Anatomy 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 229940032147 starch Drugs 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- 231100001274 therapeutic index Toxicity 0.000 description 3
- 208000021510 thyroid gland disease Diseases 0.000 description 3
- 238000002877 time resolved fluorescence resonance energy transfer Methods 0.000 description 3
- 102000003298 tumor necrosis factor receptor Human genes 0.000 description 3
- 229960000237 vorinostat Drugs 0.000 description 3
- FMCAFXHLMUOIGG-IWFBPKFRSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2r)-2-formamido-3-sulfanylpropanoyl]amino]-3-methylbutanoyl]amino]-3-(4-hydroxy-2,5-dimethylphenyl)propanoyl]amino]-4-methylsulfanylbutanoic acid Chemical compound O=CN[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCSC)C(O)=O)CC1=CC(C)=C(O)C=C1C FMCAFXHLMUOIGG-IWFBPKFRSA-N 0.000 description 2
- CVCLJVVBHYOXDC-IAZSKANUSA-N (2z)-2-[(5z)-5-[(3,5-dimethyl-1h-pyrrol-2-yl)methylidene]-4-methoxypyrrol-2-ylidene]indole Chemical compound COC1=C\C(=C/2N=C3C=CC=CC3=C\2)N\C1=C/C=1NC(C)=CC=1C CVCLJVVBHYOXDC-IAZSKANUSA-N 0.000 description 2
- DEQANNDTNATYII-OULOTJBUSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-benzyl-n-[(2r,3r)-1,3-dihydroxybutan-2-yl]-7-[(1r)-1-hydroxyethyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxa Chemical compound C([C@@H](N)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)N[C@H](CO)[C@H](O)C)C1=CC=CC=C1 DEQANNDTNATYII-OULOTJBUSA-N 0.000 description 2
- HJTAZXHBEBIQQX-UHFFFAOYSA-N 1,5-bis(chloromethyl)naphthalene Chemical compound C1=CC=C2C(CCl)=CC=CC2=C1CCl HJTAZXHBEBIQQX-UHFFFAOYSA-N 0.000 description 2
- PPCFNCCIOUYYHU-UHFFFAOYSA-N 1-(4-nitrophenyl)-4-(oxetan-3-yl)piperazine Chemical compound C1=CC([N+](=O)[O-])=CC=C1N1CCN(C2COC2)CC1 PPCFNCCIOUYYHU-UHFFFAOYSA-N 0.000 description 2
- KCOFLJRUFNXHOV-UHFFFAOYSA-N 1-(4-nitrophenyl)-4-(oxetan-3-ylmethyl)piperazine Chemical compound [N+](=O)([O-])C1=CC=C(C=C1)N1CCN(CC1)CC1COC1 KCOFLJRUFNXHOV-UHFFFAOYSA-N 0.000 description 2
- AOYSLJHKVBSXRU-UHFFFAOYSA-N 1-(oxetan-3-yl)piperazine Chemical compound C1OCC1N1CCNCC1 AOYSLJHKVBSXRU-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 2
- ASKIVFGGGGIGKH-UHFFFAOYSA-N 2,3-dihydroxypropyl 16-methylheptadecanoate Chemical compound CC(C)CCCCCCCCCCCCCCC(=O)OCC(O)CO ASKIVFGGGGIGKH-UHFFFAOYSA-N 0.000 description 2
- TXQPXJKRNHJWAX-UHFFFAOYSA-N 2-(3-aminopropylamino)ethylsulfanylphosphonic acid;trihydrate Chemical compound O.O.O.NCCCNCCSP(O)(O)=O TXQPXJKRNHJWAX-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
- XPCTZQVDEJYUGT-UHFFFAOYSA-N 3-hydroxy-2-methyl-4-pyrone Chemical compound CC=1OC=CC(=O)C=1O XPCTZQVDEJYUGT-UHFFFAOYSA-N 0.000 description 2
- AKJHMTWEGVYYSE-AIRMAKDCSA-N 4-HPR Chemical compound C=1C=C(O)C=CC=1NC(=O)/C=C(\C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C AKJHMTWEGVYYSE-AIRMAKDCSA-N 0.000 description 2
- NSMYDEYAHKTAGB-UHFFFAOYSA-N 4-[4-(oxetan-3-yl)piperazin-1-yl]aniline Chemical compound C1=CC(N)=CC=C1N1CCN(C2COC2)CC1 NSMYDEYAHKTAGB-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- QLFGSURDJTUOHL-UHFFFAOYSA-N 5-chloropyrazine Chemical group ClC1=C=NC=C[N]1 QLFGSURDJTUOHL-UHFFFAOYSA-N 0.000 description 2
- UVUXRWORQOVWGP-UHFFFAOYSA-N 6-bromo-N-[3-[2-(oxan-2-yloxy)ethoxy]-4-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]imidazo[1,2-a]pyrazin-8-amine Chemical compound BrC=1N=C(C=2N(C1)C=CN2)NC2=CC(=C(C=C2)N2CCN(CC2)C2COC2)OCCOC2OCCCC2 UVUXRWORQOVWGP-UHFFFAOYSA-N 0.000 description 2
- SBBOJTNXLHLKRZ-UHFFFAOYSA-N 6-bromo-N-[4-[4-(oxetan-3-ylmethyl)piperazin-1-yl]phenyl]imidazo[1,2-a]pyrazin-8-amine Chemical compound BrC=1N=C(C=2N(C1)C=CN2)NC2=CC=C(C=C2)N2CCN(CC2)CC2COC2 SBBOJTNXLHLKRZ-UHFFFAOYSA-N 0.000 description 2
- 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 2
- FUXVKZWTXQUGMW-FQEVSTJZSA-N 9-Aminocamptothecin Chemical compound C1=CC(N)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 FUXVKZWTXQUGMW-FQEVSTJZSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.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 WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- 206010003645 Atopy Diseases 0.000 description 2
- 108010012919 B-Cell Antigen Receptors Proteins 0.000 description 2
- 102000019260 B-Cell Antigen Receptors Human genes 0.000 description 2
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 2
- 108010020326 Caspofungin Proteins 0.000 description 2
- UDKCHVLMFQVBAA-UHFFFAOYSA-M Choline salicylate Chemical compound C[N+](C)(C)CCO.OC1=CC=CC=C1C([O-])=O UDKCHVLMFQVBAA-UHFFFAOYSA-M 0.000 description 2
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 2
- GUTLYIVDDKVIGB-OUBTZVSYSA-N Cobalt-60 Chemical compound [60Co] GUTLYIVDDKVIGB-OUBTZVSYSA-N 0.000 description 2
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 2
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- 229940123780 DNA topoisomerase I inhibitor Drugs 0.000 description 2
- 229940124087 DNA topoisomerase II inhibitor Drugs 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
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- OFDNQWIFNXBECV-UHFFFAOYSA-N Dolastatin 10 Natural products CC(C)C(N(C)C)C(=O)NC(C(C)C)C(=O)N(C)C(C(C)CC)C(OC)CC(=O)N1CCCC1C(OC)C(C)C(=O)NC(C=1SC=CN=1)CC1=CC=CC=C1 OFDNQWIFNXBECV-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 108010074604 Epoetin Alfa Proteins 0.000 description 2
- 229910052693 Europium Inorganic materials 0.000 description 2
- 108010029961 Filgrastim Proteins 0.000 description 2
- JRZJKWGQFNTSRN-UHFFFAOYSA-N Geldanamycin Natural products C1C(C)CC(OC)C(O)C(C)C=C(C)C(OC(N)=O)C(OC)CCC=C(C)C(=O)NC2=CC(=O)C(OC)=C1C2=O JRZJKWGQFNTSRN-UHFFFAOYSA-N 0.000 description 2
- 102000006395 Globulins Human genes 0.000 description 2
- 108010044091 Globulins Proteins 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 102100039619 Granulocyte colony-stimulating factor Human genes 0.000 description 2
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 2
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 description 2
- 101000799461 Homo sapiens Thrombopoietin Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 2
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 2
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 2
- 102000003815 Interleukin-11 Human genes 0.000 description 2
- 108090000177 Interleukin-11 Proteins 0.000 description 2
- 102000013462 Interleukin-12 Human genes 0.000 description 2
- 108010065805 Interleukin-12 Proteins 0.000 description 2
- 208000032382 Ischaemic stroke Diseases 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
- XOGTZOOQQBDUSI-UHFFFAOYSA-M Mesna Chemical compound [Na+].[O-]S(=O)(=O)CCS XOGTZOOQQBDUSI-UHFFFAOYSA-M 0.000 description 2
- 241001465754 Metazoa 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
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 2
- PSPFQEBFYXJZEV-UHFFFAOYSA-N N'-(1,8-dimethyl-4-imidazo[1,2-a]quinoxalinyl)ethane-1,2-diamine Chemical compound C1=C(C)C=C2N3C(C)=CN=C3C(NCCN)=NC2=C1 PSPFQEBFYXJZEV-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-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
- BLXXJMDCKKHMKV-UHFFFAOYSA-N Nabumetone Chemical compound C1=C(CCC(C)=O)C=CC2=CC(OC)=CC=C21 BLXXJMDCKKHMKV-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 108010016076 Octreotide Proteins 0.000 description 2
- 206010061534 Oesophageal squamous cell carcinoma Diseases 0.000 description 2
- 239000012828 PI3K inhibitor Substances 0.000 description 2
- 102000038030 PI3Ks Human genes 0.000 description 2
- 108091007960 PI3Ks Proteins 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 108010090931 Proto-Oncogene Proteins c-bcl-2 Proteins 0.000 description 2
- 102000013535 Proto-Oncogene Proteins c-bcl-2 Human genes 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYGQUTWHTHXGQB-FFHKNEKCSA-N Retinol Palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C VYGQUTWHTHXGQB-FFHKNEKCSA-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
- 206010039710 Scleroderma Diseases 0.000 description 2
- ABBQHOQBGMUPJH-UHFFFAOYSA-M Sodium salicylate Chemical compound [Na+].OC1=CC=CC=C1C([O-])=O ABBQHOQBGMUPJH-UHFFFAOYSA-M 0.000 description 2
- 108010090804 Streptavidin Proteins 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 2
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 2
- 239000000365 Topoisomerase I Inhibitor Substances 0.000 description 2
- 239000000317 Topoisomerase II Inhibitor Substances 0.000 description 2
- 102000004243 Tubulin Human genes 0.000 description 2
- 108090000704 Tubulin Proteins 0.000 description 2
- 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 2
- NVTORVANRMKRFV-CQSZACIVSA-N [(2R)-4-[4-[(6-bromoimidazo[1,2-a]pyrazin-8-yl)amino]phenyl]morpholin-2-yl]methanol Chemical compound BrC=1N=C(C=2N(C1)C=CN2)NC2=CC=C(C=C2)N2C[C@@H](OCC2)CO NVTORVANRMKRFV-CQSZACIVSA-N 0.000 description 2
- XJNHONCWGODPIZ-PHEQNACWSA-N [(e)-2-[(e)-2-phenylethenyl]sulfonylethenyl]benzene Chemical compound C=1C=CC=CC=1/C=C/S(=O)(=O)\C=C\C1=CC=CC=C1 XJNHONCWGODPIZ-PHEQNACWSA-N 0.000 description 2
- GNJKPILEVHIXDI-UHFFFAOYSA-N [4-[4-(oxetan-3-yl)piperazin-1-yl]phenyl] carbamate Chemical compound C(N)(OC1=CC=C(C=C1)N1CCN(CC1)C1COC1)=O GNJKPILEVHIXDI-UHFFFAOYSA-N 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 238000011374 additional therapy Methods 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 229940009456 adriamycin Drugs 0.000 description 2
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 description 2
- 125000003158 alcohol group Chemical group 0.000 description 2
- 229960005310 aldesleukin Drugs 0.000 description 2
- 108700025316 aldesleukin Proteins 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 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 2
- 229950010817 alvocidib Drugs 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 229960001097 amifostine Drugs 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 206010002449 angioimmunoblastic T-cell lymphoma Diseases 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 229940045799 anthracyclines and related substance Drugs 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 229940124650 anti-cancer therapies Drugs 0.000 description 2
- 230000001494 anti-thymocyte effect Effects 0.000 description 2
- 238000009175 antibody therapy Methods 0.000 description 2
- 238000011394 anticancer treatment Methods 0.000 description 2
- 229940121375 antifungal agent Drugs 0.000 description 2
- 239000003429 antifungal agent Substances 0.000 description 2
- 239000000427 antigen Substances 0.000 description 2
- 102000036639 antigens Human genes 0.000 description 2
- 108091007433 antigens Proteins 0.000 description 2
- 229950003145 apolizumab Drugs 0.000 description 2
- GOLCXWYRSKYTSP-UHFFFAOYSA-N arsenic trioxide Inorganic materials O1[As]2O[As]1O2 GOLCXWYRSKYTSP-UHFFFAOYSA-N 0.000 description 2
- AUJRCFUBUPVWSZ-XTZHGVARSA-M auranofin Chemical compound CCP(CC)(CC)=[Au]S[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O AUJRCFUBUPVWSZ-XTZHGVARSA-M 0.000 description 2
- 229960005207 auranofin Drugs 0.000 description 2
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 229960002707 bendamustine Drugs 0.000 description 2
- YTKUWDBFDASYHO-UHFFFAOYSA-N bendamustine Chemical compound ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(O)=O)=NC2=C1 YTKUWDBFDASYHO-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 239000003124 biologic agent Substances 0.000 description 2
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 238000010322 bone marrow transplantation Methods 0.000 description 2
- MJQUEDHRCUIRLF-TVIXENOKSA-N bryostatin 1 Chemical compound C([C@@H]1CC(/[C@@H]([C@@](C(C)(C)/C=C/2)(O)O1)OC(=O)/C=C/C=C/CCC)=C\C(=O)OC)[C@H]([C@@H](C)O)OC(=O)C[C@H](O)C[C@@H](O1)C[C@H](OC(C)=O)C(C)(C)[C@]1(O)C[C@@H]1C\C(=C\C(=O)OC)C[C@H]\2O1 MJQUEDHRCUIRLF-TVIXENOKSA-N 0.000 description 2
- 229960005539 bryostatin 1 Drugs 0.000 description 2
- 229960002092 busulfan Drugs 0.000 description 2
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 229960005243 carmustine Drugs 0.000 description 2
- 229960000730 caspofungin acetate Drugs 0.000 description 2
- 229960000590 celecoxib Drugs 0.000 description 2
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 229960002688 choline salicylate Drugs 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 229960002436 cladribine Drugs 0.000 description 2
- 230000007012 clinical effect Effects 0.000 description 2
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 2
- 238000009096 combination chemotherapy Methods 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- 229960004544 cortisone Drugs 0.000 description 2
- 229960000913 crospovidone Drugs 0.000 description 2
- 229940109262 curcumin Drugs 0.000 description 2
- 239000004148 curcumin Substances 0.000 description 2
- 235000012754 curcumin Nutrition 0.000 description 2
- 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 2
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 description 2
- 229960002923 denileukin diftitox Drugs 0.000 description 2
- 108010017271 denileukin diftitox Proteins 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 239000008121 dextrose Substances 0.000 description 2
- ZFTFAPZRGNKQPU-UHFFFAOYSA-N dicarbonic acid Chemical compound OC(=O)OC(O)=O ZFTFAPZRGNKQPU-UHFFFAOYSA-N 0.000 description 2
- 229960001259 diclofenac Drugs 0.000 description 2
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 2
- 229960001193 diclofenac sodium Drugs 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- VFLDPWHFBUODDF-UHFFFAOYSA-N diferuloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-UHFFFAOYSA-N 0.000 description 2
- 229960000616 diflunisal Drugs 0.000 description 2
- 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 2
- PFWDHRASWSUTIA-KAFJHEIMSA-L disodium;(2s)-5-amino-5-oxo-2-[(2-phenylacetyl)amino]pentanoate;2-phenylacetate Chemical compound [Na+].[Na+].[O-]C(=O)CC1=CC=CC=C1.NC(=O)CC[C@@H](C([O-])=O)NC(=O)CC1=CC=CC=C1 PFWDHRASWSUTIA-KAFJHEIMSA-L 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 239000002612 dispersion medium Substances 0.000 description 2
- 229960003668 docetaxel Drugs 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- OFDNQWIFNXBECV-VFSYNPLYSA-N dolastatin 10 Chemical compound CC(C)[C@H](N(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C=1SC=CN=1)CC1=CC=CC=C1 OFDNQWIFNXBECV-VFSYNPLYSA-N 0.000 description 2
- 108010045524 dolastatin 10 Proteins 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 229960002918 doxorubicin hydrochloride Drugs 0.000 description 2
- 230000036267 drug metabolism Effects 0.000 description 2
- 239000012055 enteric layer Substances 0.000 description 2
- 239000002532 enzyme inhibitor Substances 0.000 description 2
- 229960003388 epoetin alfa Drugs 0.000 description 2
- 229960005293 etodolac Drugs 0.000 description 2
- XFBVBWWRPKNWHW-UHFFFAOYSA-N etodolac Chemical compound C1COC(CC)(CC(O)=O)C2=N[C]3C(CC)=CC=CC3=C21 XFBVBWWRPKNWHW-UHFFFAOYSA-N 0.000 description 2
- OGPBJKLSAFTDLK-UHFFFAOYSA-N europium atom Chemical compound [Eu] OGPBJKLSAFTDLK-UHFFFAOYSA-N 0.000 description 2
- 229960005167 everolimus Drugs 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 229960005341 fenoprofen calcium Drugs 0.000 description 2
- VHUXSAWXWSTUOD-UHFFFAOYSA-L fenoprofen calcium (anhydrous) Chemical compound [Ca+2].[O-]C(=O)C(C)C1=CC=CC(OC=2C=CC=CC=2)=C1.[O-]C(=O)C(C)C1=CC=CC(OC=2C=CC=CC=2)=C1 VHUXSAWXWSTUOD-UHFFFAOYSA-L 0.000 description 2
- 229950003662 fenretinide Drugs 0.000 description 2
- 210000004700 fetal blood Anatomy 0.000 description 2
- 229960004177 filgrastim Drugs 0.000 description 2
- 238000000684 flow cytometry Methods 0.000 description 2
- 108700014844 flt3 ligand Proteins 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 229960002390 flurbiprofen Drugs 0.000 description 2
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 2
- 239000013022 formulation composition Substances 0.000 description 2
- 229950001109 galiximab Drugs 0.000 description 2
- QTQAWLPCGQOSGP-GBTDJJJQSA-N geldanamycin Chemical compound N1C(=O)\C(C)=C/C=C\[C@@H](OC)[C@H](OC(N)=O)\C(C)=C/[C@@H](C)[C@@H](O)[C@H](OC)C[C@@H](C)CC2=C(OC)C(=O)C=C1C2=O QTQAWLPCGQOSGP-GBTDJJJQSA-N 0.000 description 2
- 150000002344 gold compounds Chemical class 0.000 description 2
- 229940015045 gold sodium thiomalate Drugs 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- 208000014951 hematologic disease Diseases 0.000 description 2
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- XXSMGPRMXLTPCZ-UHFFFAOYSA-N hydroxychloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 XXSMGPRMXLTPCZ-UHFFFAOYSA-N 0.000 description 2
- 229960004171 hydroxychloroquine Drugs 0.000 description 2
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 2
- 229940071826 hydroxyethyl cellulose Drugs 0.000 description 2
- 229960001680 ibuprofen Drugs 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 229960003444 immunosuppressant agent Drugs 0.000 description 2
- 230000002637 immunotoxin Effects 0.000 description 2
- 239000002596 immunotoxin Substances 0.000 description 2
- 229940051026 immunotoxin Drugs 0.000 description 2
- 231100000608 immunotoxin Toxicity 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- APFVFJFRJDLVQX-AHCXROLUSA-N indium-111 Chemical compound [111In] APFVFJFRJDLVQX-AHCXROLUSA-N 0.000 description 2
- 229960000905 indomethacin Drugs 0.000 description 2
- 239000011261 inert gas Substances 0.000 description 2
- 230000004968 inflammatory condition Effects 0.000 description 2
- 229960000598 infliximab Drugs 0.000 description 2
- 229940074383 interleukin-11 Drugs 0.000 description 2
- 229940117681 interleukin-12 Drugs 0.000 description 2
- 229960000779 irinotecan hydrochloride Drugs 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
- 230000000155 isotopic effect Effects 0.000 description 2
- 229960002014 ixabepilone Drugs 0.000 description 2
- FABUFPQFXZVHFB-CFWQTKTJSA-N ixabepilone Chemical compound C/C([C@@H]1C[C@@H]2O[C@]2(C)CCC[C@@H]([C@@H]([C@H](C)C(=O)C(C)(C)[C@H](O)CC(=O)N1)O)C)=C\C1=CSC(C)=N1 FABUFPQFXZVHFB-CFWQTKTJSA-N 0.000 description 2
- 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 2
- 229960000991 ketoprofen Drugs 0.000 description 2
- 229960001021 lactose monohydrate Drugs 0.000 description 2
- 201000003445 large cell neuroendocrine carcinoma Diseases 0.000 description 2
- 229960004942 lenalidomide Drugs 0.000 description 2
- 229950004563 lucatumumab Drugs 0.000 description 2
- 210000003810 lymphokine-activated killer cell Anatomy 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N malonic acid group Chemical group C(CC(=O)O)(=O)O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- 239000003550 marker Substances 0.000 description 2
- 229960004635 mesna Drugs 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- OJLOPKGSLYJEMD-URPKTTJQSA-N methyl 7-[(1r,2r,3r)-3-hydroxy-2-[(1e)-4-hydroxy-4-methyloct-1-en-1-yl]-5-oxocyclopentyl]heptanoate Chemical compound CCCCC(C)(O)C\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)OC OJLOPKGSLYJEMD-URPKTTJQSA-N 0.000 description 2
- KTMKRRPZPWUYKK-UHFFFAOYSA-N methylboronic acid Chemical compound CB(O)O KTMKRRPZPWUYKK-UHFFFAOYSA-N 0.000 description 2
- 229960004584 methylprednisolone Drugs 0.000 description 2
- 229960005249 misoprostol Drugs 0.000 description 2
- ZAHQPTJLOCWVPG-UHFFFAOYSA-N mitoxantrone dihydrochloride Chemical compound Cl.Cl.O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO ZAHQPTJLOCWVPG-UHFFFAOYSA-N 0.000 description 2
- 229960004169 mitoxantrone hydrochloride Drugs 0.000 description 2
- 210000001616 monocyte Anatomy 0.000 description 2
- AARXZCZYLAFQQU-UHFFFAOYSA-N motexafin gadolinium Chemical compound [Gd].CC(O)=O.CC(O)=O.C1=C([N-]2)C(CC)=C(CC)C2=CC(C(=C2C)CCCO)=NC2=CN=C2C=C(OCCOCCOCCOC)C(OCCOCCOCCOC)=CC2=NC=C2C(C)=C(CCCO)C1=N2 AARXZCZYLAFQQU-UHFFFAOYSA-N 0.000 description 2
- 230000002107 myocardial effect Effects 0.000 description 2
- 229960004270 nabumetone Drugs 0.000 description 2
- 229960002009 naproxen Drugs 0.000 description 2
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 2
- CDBRNDSHEYLDJV-FVGYRXGTSA-M naproxen sodium Chemical compound [Na+].C1=C([C@H](C)C([O-])=O)C=CC2=CC(OC)=CC=C21 CDBRNDSHEYLDJV-FVGYRXGTSA-M 0.000 description 2
- 229960003940 naproxen sodium Drugs 0.000 description 2
- 229950004847 navitoclax Drugs 0.000 description 2
- JLYAXFNOILIKPP-KXQOOQHDSA-N navitoclax Chemical compound C([C@@H](NC1=CC=C(C=C1S(=O)(=O)C(F)(F)F)S(=O)(=O)NC(=O)C1=CC=C(C=C1)N1CCN(CC1)CC1=C(CCC(C1)(C)C)C=1C=CC(Cl)=CC=1)CSC=1C=CC=CC=1)CN1CCOCC1 JLYAXFNOILIKPP-KXQOOQHDSA-N 0.000 description 2
- 239000006199 nebulizer Substances 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- IXOXBSCIXZEQEQ-UHTZMRCNSA-N nelarabine Chemical compound C1=NC=2C(OC)=NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O IXOXBSCIXZEQEQ-UHTZMRCNSA-N 0.000 description 2
- 229960000801 nelarabine Drugs 0.000 description 2
- 229960003347 obinutuzumab Drugs 0.000 description 2
- 230000000414 obstructive effect Effects 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- 229960001494 octreotide acetate Drugs 0.000 description 2
- 229960002450 ofatumumab Drugs 0.000 description 2
- 229940012843 omega-3 fatty acid Drugs 0.000 description 2
- 235000020660 omega-3 fatty acid Nutrition 0.000 description 2
- 229960001756 oxaliplatin Drugs 0.000 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 description 2
- 229960002739 oxaprozin Drugs 0.000 description 2
- 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 2
- AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 description 2
- AHJRHEGDXFFMBM-UHFFFAOYSA-N palbociclib Chemical compound N1=C2N(C3CCCC3)C(=O)C(C(=O)C)=C(C)C2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 AHJRHEGDXFFMBM-UHFFFAOYSA-N 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- HQQSBEDKMRHYME-UHFFFAOYSA-N pefloxacin mesylate Chemical compound [H+].CS([O-])(=O)=O.C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCN(C)CC1 HQQSBEDKMRHYME-UHFFFAOYSA-N 0.000 description 2
- 229960001373 pegfilgrastim Drugs 0.000 description 2
- 108010044644 pegfilgrastim Proteins 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- SZFPYBIJACMNJV-UHFFFAOYSA-N perifosine Chemical compound CCCCCCCCCCCCCCCCCCOP([O-])(=O)OC1CC[N+](C)(C)CC1 SZFPYBIJACMNJV-UHFFFAOYSA-N 0.000 description 2
- 229950010632 perifosine Drugs 0.000 description 2
- 230000003285 pharmacodynamic effect Effects 0.000 description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 2
- 229940043441 phosphoinositide 3-kinase inhibitor Drugs 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 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
- 229960002702 piroxicam Drugs 0.000 description 2
- 210000004180 plasmocyte Anatomy 0.000 description 2
- 229960000502 poloxamer Drugs 0.000 description 2
- 229920001983 poloxamer Polymers 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920001296 polysiloxane Polymers 0.000 description 2
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 2
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 2
- 238000002600 positron emission tomography Methods 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- JDOZJEUDSLGTLU-VWUMJDOOSA-N prednisolone phosphate Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)COP(O)(O)=O)[C@@H]4[C@@H]3CCC2=C1 JDOZJEUDSLGTLU-VWUMJDOOSA-N 0.000 description 2
- 229960002943 prednisolone sodium phosphate Drugs 0.000 description 2
- 229940071643 prefilled syringe Drugs 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 2
- 238000010926 purge Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 150000003212 purines Chemical class 0.000 description 2
- XFTQRUTUGRCSGO-UHFFFAOYSA-N pyrazin-2-amine Chemical compound NC1=CN=CC=N1 XFTQRUTUGRCSGO-UHFFFAOYSA-N 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 210000002345 respiratory system Anatomy 0.000 description 2
- 230000004043 responsiveness Effects 0.000 description 2
- 229960000371 rofecoxib Drugs 0.000 description 2
- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 description 2
- 229960001860 salicylate Drugs 0.000 description 2
- 150000003873 salicylate salts Chemical group 0.000 description 2
- 229960004889 salicylic acid Drugs 0.000 description 2
- 229960002530 sargramostim Drugs 0.000 description 2
- 108010038379 sargramostim Proteins 0.000 description 2
- 229960002639 sildenafil citrate Drugs 0.000 description 2
- 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 2
- 229960002855 simvastatin Drugs 0.000 description 2
- 238000002603 single-photon emission computed tomography Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 229960004025 sodium salicylate Drugs 0.000 description 2
- JGMJQSFLQWGYMQ-UHFFFAOYSA-M sodium;2,6-dichloro-n-phenylaniline;acetate Chemical compound [Na+].CC([O-])=O.ClC1=CC=CC(Cl)=C1NC1=CC=CC=C1 JGMJQSFLQWGYMQ-UHFFFAOYSA-M 0.000 description 2
- AGHLUVOCTHWMJV-UHFFFAOYSA-J sodium;gold(3+);2-sulfanylbutanedioate Chemical compound [Na+].[Au+3].[O-]C(=O)CC(S)C([O-])=O.[O-]C(=O)CC(S)C([O-])=O AGHLUVOCTHWMJV-UHFFFAOYSA-J 0.000 description 2
- 239000008247 solid mixture Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 229960002920 sorbitol Drugs 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 229960004793 sucrose Drugs 0.000 description 2
- NCEXYHBECQHGNR-QZQOTICOSA-N sulfasalazine Chemical compound C1=C(O)C(C(=O)O)=CC(\N=N\C=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-QZQOTICOSA-N 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
- 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 2
- 229960000894 sulindac Drugs 0.000 description 2
- 230000002459 sustained effect Effects 0.000 description 2
- 230000009897 systematic effect Effects 0.000 description 2
- 229950007866 tanespimycin Drugs 0.000 description 2
- AYUNIORJHRXIBJ-TXHRRWQRSA-N tanespimycin Chemical compound N1C(=O)\C(C)=C\C=C/[C@H](OC)[C@@H](OC(N)=O)\C(C)=C\[C@H](C)[C@@H](O)[C@@H](OC)C[C@H](C)CC2=C(NCC=C)C(=O)C=C1C2=O AYUNIORJHRXIBJ-TXHRRWQRSA-N 0.000 description 2
- URFBQWNNBFPMSX-UHFFFAOYSA-N tert-butyl N-(6-bromo-3-chloropyrazin-2-yl)-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate Chemical compound C(C)(C)(C)OC(=O)N(C1=NC(=CN=C1Cl)Br)C(=O)OC(C)(C)C URFBQWNNBFPMSX-UHFFFAOYSA-N 0.000 description 2
- SAWZZKGSWBBYQI-YRTCJPGSSA-N tert-butyl [(2R)-4-[4-[(2-methylpropan-2-yl)oxycarbonyl-(6-tributylstannylimidazo[1,2-a]pyrazin-8-yl)amino]phenyl]morpholin-2-yl]methyl carbonate Chemical compound C(C)(C)(C)OC(=O)OC[C@@H]1OCCN(C1)C1=CC=C(C=C1)N(C(OC(C)(C)C)=O)C=1C=2N(C=C(N1)[Sn](CCCC)(CCCC)CCCC)C=CN2 SAWZZKGSWBBYQI-YRTCJPGSSA-N 0.000 description 2
- SHPHYIRRIKKCOD-UHFFFAOYSA-N tert-butyl [4-(4-carbamoyloxyphenyl)morpholin-2-yl]methyl carbonate Chemical compound C(N)(OC1=CC=C(C=C1)N1CC(OCC1)COC(=O)OC(C)(C)C)=O SHPHYIRRIKKCOD-UHFFFAOYSA-N 0.000 description 2
- MPDGREDXDDKJJG-UHFFFAOYSA-N tert-butyl n-[(2-methylpropan-2-yl)oxycarbonyl]-n-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=CN=CC(B2OC(C)(C)C(C)(C)O2)=N1 MPDGREDXDDKJJG-UHFFFAOYSA-N 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 229960001196 thiotepa Drugs 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 229960000303 topotecan Drugs 0.000 description 2
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000001052 transient effect Effects 0.000 description 2
- 238000002054 transplantation Methods 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
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- LNPDTQAFDNKSHK-UHFFFAOYSA-N valdecoxib Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(N)(=O)=O)C=C1 LNPDTQAFDNKSHK-UHFFFAOYSA-N 0.000 description 2
- 229960002004 valdecoxib Drugs 0.000 description 2
- 229950000815 veltuzumab Drugs 0.000 description 2
- 229960003048 vinblastine Drugs 0.000 description 2
- 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 2
- 229960002110 vincristine sulfate Drugs 0.000 description 2
- AQTQHPDCURKLKT-JKDPCDLQSA-N vincristine sulfate Chemical compound OS(O)(=O)=O.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=O)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 AQTQHPDCURKLKT-JKDPCDLQSA-N 0.000 description 2
- OGUJBRYAAJYXQP-IJFZAWIJSA-N vuw370o5qe Chemical compound CC(O)=O.CC(O)=O.C1([C@H](O)[C@@H](O)[C@H]2C(=O)N[C@H](C(=O)N3CC[C@H](O)[C@H]3C(=O)N[C@H](NCCN)[C@H](O)C[C@@H](C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N2)[C@@H](C)O)=O)NC(=O)CCCCCCCC[C@@H](C)C[C@@H](C)CC)[C@H](O)CCN)=CC=C(O)C=C1 OGUJBRYAAJYXQP-IJFZAWIJSA-N 0.000 description 2
- 239000011534 wash buffer Substances 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- HBUBKKRHXORPQB-FJFJXFQQSA-N (2R,3S,4S,5R)-2-(6-amino-2-fluoro-9-purinyl)-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O HBUBKKRHXORPQB-FJFJXFQQSA-N 0.000 description 1
- JEADNKMTUDRUJL-UHFFFAOYSA-N (6-tributylstannylimidazo[1,2-a]pyrazin-8-yl) carbamate Chemical compound C(N)(OC=1C=2N(C=C(N=1)[Sn](CCCC)(CCCC)CCCC)C=CN=2)=O JEADNKMTUDRUJL-UHFFFAOYSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- VWOJSRICSKDKAW-UHFFFAOYSA-N 1-(4-nitrophenyl)piperazine Chemical compound C1=CC([N+](=O)[O-])=CC=C1N1CCNCC1 VWOJSRICSKDKAW-UHFFFAOYSA-N 0.000 description 1
- GYSCBCSGKXNZRH-UHFFFAOYSA-N 1-benzothiophene-2-carboxamide Chemical compound C1=CC=C2SC(C(=O)N)=CC2=C1 GYSCBCSGKXNZRH-UHFFFAOYSA-N 0.000 description 1
- WFQDTOYDVUWQMS-UHFFFAOYSA-N 1-fluoro-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C=C1 WFQDTOYDVUWQMS-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- PNDPGZBMCMUPRI-HVTJNCQCSA-N 10043-66-0 Chemical compound [131I][131I] PNDPGZBMCMUPRI-HVTJNCQCSA-N 0.000 description 1
- MCTAUZJPEHNUPP-UHFFFAOYSA-N 2-[2-(2-fluoro-5-nitrophenoxy)ethoxy]oxane Chemical compound FC1=C(OCCOC2OCCCC2)C=C(C=C1)[N+](=O)[O-] MCTAUZJPEHNUPP-UHFFFAOYSA-N 0.000 description 1
- JTPXVCKCLBROOJ-UHFFFAOYSA-N 2-amino-6-chloropyrazine Chemical compound NC1=CN=CC(Cl)=N1 JTPXVCKCLBROOJ-UHFFFAOYSA-N 0.000 description 1
- LILXDMFJXYAKMK-UHFFFAOYSA-N 2-bromo-1,1-diethoxyethane Chemical compound CCOC(CBr)OCC LILXDMFJXYAKMK-UHFFFAOYSA-N 0.000 description 1
- WFRLFZAMCVAQLN-UHFFFAOYSA-N 2-fluoro-5-nitrophenol Chemical compound OC1=CC([N+]([O-])=O)=CC=C1F WFRLFZAMCVAQLN-UHFFFAOYSA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- GDHWAMVEOAWHIM-UHFFFAOYSA-N 2-hydroxyoctacosyl 12-hydroxyoctadecanoate Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCC(O)COC(=O)CCCCCCCCCCC(O)CCCCCC GDHWAMVEOAWHIM-UHFFFAOYSA-N 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-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
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 1
- AXRCEOKUDYDWLF-UHFFFAOYSA-N 3-(1-methyl-3-indolyl)-4-[1-[1-(2-pyridinylmethyl)-4-piperidinyl]-3-indolyl]pyrrole-2,5-dione Chemical compound C12=CC=CC=C2N(C)C=C1C(C(NC1=O)=O)=C1C(C1=CC=CC=C11)=CN1C(CC1)CCN1CC1=CC=CC=N1 AXRCEOKUDYDWLF-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- DWOZNANUEDYIOF-UHFFFAOYSA-L 4-ditert-butylphosphanyl-n,n-dimethylaniline;dichloropalladium Chemical compound Cl[Pd]Cl.CN(C)C1=CC=C(P(C(C)(C)C)C(C)(C)C)C=C1.CN(C)C1=CC=C(P(C(C)(C)C)C(C)(C)C)C=C1 DWOZNANUEDYIOF-UHFFFAOYSA-L 0.000 description 1
- BSYNRYMUTXBXSQ-FOQJRBATSA-N 59096-14-9 Chemical compound CC(=O)OC1=CC=CC=C1[14C](O)=O BSYNRYMUTXBXSQ-FOQJRBATSA-N 0.000 description 1
- LYMPGCBRUNBZJX-UHFFFAOYSA-N 6-bromo-3-chloropyrazin-2-amine Chemical compound NC1=NC(Br)=CN=C1Cl LYMPGCBRUNBZJX-UHFFFAOYSA-N 0.000 description 1
- XHQQBGXKSBNPLQ-UHFFFAOYSA-N 6-bromo-5-methyl-N-[4-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]imidazo[1,2-a]pyrazin-8-amine Chemical compound BrC=1N=C(C=2N(C1C)C=CN2)NC2=CC=C(C=C2)N2CCN(CC2)C2COC2 XHQQBGXKSBNPLQ-UHFFFAOYSA-N 0.000 description 1
- SBBQFRYIMUUNFT-UHFFFAOYSA-N 6-bromopyrazin-2-amine Chemical compound NC1=CN=CC(Br)=N1 SBBQFRYIMUUNFT-UHFFFAOYSA-N 0.000 description 1
- WDYVUKGVKRZQNM-UHFFFAOYSA-N 6-phosphonohexylphosphonic acid Chemical compound OP(O)(=O)CCCCCCP(O)(O)=O WDYVUKGVKRZQNM-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 230000035502 ADME Effects 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- 206010027654 Allergic conditions Diseases 0.000 description 1
- 206010073478 Anaplastic large-cell lymphoma Diseases 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 108091008875 B cell receptors Proteins 0.000 description 1
- 208000004736 B-Cell Leukemia Diseases 0.000 description 1
- 208000037914 B-cell disorder Diseases 0.000 description 1
- 208000028564 B-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 230000003844 B-cell-activation Effects 0.000 description 1
- 108091007065 BIRCs Proteins 0.000 description 1
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 1
- 208000019838 Blood disease Diseases 0.000 description 1
- LKXBSIRIAJBQRK-UHFFFAOYSA-N C(CCC(=O)O)(=O)O.N=1C=CN2C1C(=NC=C2)N Chemical group C(CCC(=O)O)(=O)O.N=1C=CN2C1C(=NC=C2)N LKXBSIRIAJBQRK-UHFFFAOYSA-N 0.000 description 1
- KZUCHLWCHAUEEP-UHFFFAOYSA-N C(N)(OC1=NC(=CN=C1Cl)C=1N=C(C=2N(C1)C=CN2)N(C2=CC(=C(C=C2)N2CCN(CC2)C2COC2)OCCOC2OCCCC2)C(=O)OC(C)(C)C)=O Chemical compound C(N)(OC1=NC(=CN=C1Cl)C=1N=C(C=2N(C1)C=CN2)N(C2=CC(=C(C=C2)N2CCN(CC2)C2COC2)OCCOC2OCCCC2)C(=O)OC(C)(C)C)=O KZUCHLWCHAUEEP-UHFFFAOYSA-N 0.000 description 1
- 102100024167 C-C chemokine receptor type 3 Human genes 0.000 description 1
- 101710149862 C-C chemokine receptor type 3 Proteins 0.000 description 1
- 229940124292 CD20 monoclonal antibody Drugs 0.000 description 1
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000006332 Choriocarcinoma Diseases 0.000 description 1
- 208000026372 Congenital cystic kidney disease Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 208000026292 Cystic Kidney disease Diseases 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-N Decanoic acid Natural products CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 1
- 229940124186 Dehydrogenase inhibitor Drugs 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
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 229940117937 Dihydrofolate reductase inhibitor Drugs 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 239000012591 Dulbecco’s Phosphate Buffered Saline Substances 0.000 description 1
- 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 1
- 208000001976 Endocrine Gland Neoplasms Diseases 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 229910004373 HOAc Inorganic materials 0.000 description 1
- 206010018910 Haemolysis Diseases 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 102000055031 Inhibitor of Apoptosis Proteins Human genes 0.000 description 1
- 208000002260 Keloid Diseases 0.000 description 1
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 208000032004 Large-Cell Anaplastic Lymphoma Diseases 0.000 description 1
- 239000005639 Lauric acid Substances 0.000 description 1
- MQHWFIOJQSCFNM-UHFFFAOYSA-L Magnesium salicylate Chemical compound [Mg+2].OC1=CC=CC=C1C([O-])=O.OC1=CC=CC=C1C([O-])=O MQHWFIOJQSCFNM-UHFFFAOYSA-L 0.000 description 1
- HYMLWHLQFGRFIY-UHFFFAOYSA-N Maltol Natural products CC1OC=CC(=O)C1=O HYMLWHLQFGRFIY-UHFFFAOYSA-N 0.000 description 1
- 235000009421 Myristica fragrans Nutrition 0.000 description 1
- SUWJWLSCODFDGM-UHFFFAOYSA-N NC1=CN=CC(=N1)C=1N=C(C=2N(C1)C=CN2)NC2=CC=C(C=C2)N2CCN(CC2)CC(C)C Chemical compound NC1=CN=CC(=N1)C=1N=C(C=2N(C1)C=CN2)NC2=CC=C(C=C2)N2CCN(CC2)CC(C)C SUWJWLSCODFDGM-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- AQLLBJAXUCIJSR-UHFFFAOYSA-N OC(=O)C[Na] Chemical compound OC(=O)C[Na] AQLLBJAXUCIJSR-UHFFFAOYSA-N 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
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 101150003085 Pdcl gene Proteins 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 description 1
- 108010001441 Phosphopeptides Proteins 0.000 description 1
- 229920002507 Poloxamer 124 Polymers 0.000 description 1
- 229920002508 Poloxamer 181 Polymers 0.000 description 1
- 229920002509 Poloxamer 182 Polymers 0.000 description 1
- 229920002511 Poloxamer 237 Polymers 0.000 description 1
- 102100038277 Prostaglandin G/H synthase 1 Human genes 0.000 description 1
- 108050003243 Prostaglandin G/H synthase 1 Proteins 0.000 description 1
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 1
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 1
- 229940079156 Proteasome inhibitor Drugs 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- KSJJHQZEQLXJTG-UHFFFAOYSA-N S(C)(=O)(=O)O.O1CC(C1)N1CCN(CC1)C1=CC=C(C=C1)NC=1C=2N(C=CN1)C=CN2 Chemical group S(C)(=O)(=O)O.O1CC(C1)N1CCN(CC1)C1=CC=C(C=C1)NC=1C=2N(C=CN1)C=CN2 KSJJHQZEQLXJTG-UHFFFAOYSA-N 0.000 description 1
- 208000034189 Sclerosis Diseases 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- BNRNXUUZRGQAQC-UHFFFAOYSA-N Sildenafil Natural products CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 208000032109 Transient ischaemic attack Diseases 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- DOQVQDFDRBYLME-LLVKDONJSA-N [(2r)-4-(4-aminophenyl)morpholin-2-yl]methanol Chemical compound C1=CC(N)=CC=C1N1C[C@H](CO)OCC1 DOQVQDFDRBYLME-LLVKDONJSA-N 0.000 description 1
- DOQVQDFDRBYLME-NSHDSACASA-N [(2s)-4-(4-aminophenyl)morpholin-2-yl]methanol Chemical compound C1=CC(N)=CC=C1N1C[C@@H](CO)OCC1 DOQVQDFDRBYLME-NSHDSACASA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000003070 absorption delaying agent Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 229940081735 acetylcellulose Drugs 0.000 description 1
- 150000008043 acidic salts Chemical class 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 208000038016 acute inflammation Diseases 0.000 description 1
- 230000006022 acute inflammation Effects 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 239000013566 allergen Substances 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 229940063655 aluminum stearate Drugs 0.000 description 1
- 150000001413 amino acids Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 230000005784 autoimmunity Effects 0.000 description 1
- 229960002170 azathioprine Drugs 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- 235000012216 bentonite Nutrition 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 238000001815 biotherapy Methods 0.000 description 1
- 201000000053 blastoma Diseases 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- XNVWFBHTEBDKCA-UHFFFAOYSA-N butanedioic acid;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound OC(=O)CCC(O)=O.OC(=O)CC(O)(C(O)=O)CC(O)=O XNVWFBHTEBDKCA-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- HQABUPZFAYXKJW-UHFFFAOYSA-O butylazanium Chemical compound CCCC[NH3+] HQABUPZFAYXKJW-UHFFFAOYSA-O 0.000 description 1
- 229960005069 calcium Drugs 0.000 description 1
- 235000001465 calcium Nutrition 0.000 description 1
- VTYYLEPIZMXCLO-UHFFFAOYSA-L calcium carbonate Substances [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 229960001714 calcium phosphate Drugs 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000000378 calcium silicate Substances 0.000 description 1
- 229910052918 calcium silicate Inorganic materials 0.000 description 1
- 229960003340 calcium silicate Drugs 0.000 description 1
- 235000012241 calcium silicate Nutrition 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 1
- 238000011088 calibration curve Methods 0.000 description 1
- 229940127093 camptothecin Drugs 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 229940022399 cancer vaccine Drugs 0.000 description 1
- 238000009566 cancer vaccine Methods 0.000 description 1
- 239000007963 capsule composition Substances 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 210000004903 cardiac system Anatomy 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- CBPNZQVSJQDFBE-HXVVJGEPSA-N ccl-779 Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[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 CBPNZQVSJQDFBE-HXVVJGEPSA-N 0.000 description 1
- 238000000423 cell based assay Methods 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000011712 cell development Effects 0.000 description 1
- 230000004709 cell invasion Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 229920003086 cellulose ether Polymers 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 150000005829 chemical entities Chemical class 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 238000011342 chemoimmunotherapy Methods 0.000 description 1
- 238000010568 chiral column chromatography Methods 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 125000004773 chlorofluoromethyl group Chemical group [H]C(F)(Cl)* 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229920001531 copovidone Polymers 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 208000031513 cyst Diseases 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 238000004807 desolvation Methods 0.000 description 1
- 230000001066 destructive effect Effects 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 1
- ZBQUMMFUJLOTQC-UHFFFAOYSA-N dichloronickel;3-diphenylphosphaniumylpropyl(diphenyl)phosphanium Chemical compound Cl[Ni]Cl.C=1C=CC=CC=1[PH+](C=1C=CC=CC=1)CCC[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 ZBQUMMFUJLOTQC-UHFFFAOYSA-N 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 210000002249 digestive system Anatomy 0.000 description 1
- 239000003166 dihydrofolate reductase inhibitor Substances 0.000 description 1
- UFIVEPVSAGBUSI-UHFFFAOYSA-N dihydroorotic acid Chemical compound OC(=O)C1CC(=O)NC(=O)N1 UFIVEPVSAGBUSI-UHFFFAOYSA-N 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
- 230000010339 dilation Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical class [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 230000008406 drug-drug interaction Effects 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 229960002224 eculizumab Drugs 0.000 description 1
- 201000008184 embryoma Diseases 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 238000003366 endpoint assay Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000002662 enteric coated tablet Substances 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 229950002189 enzastaurin Drugs 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 229960004945 etoricoxib Drugs 0.000 description 1
- MNJVRJDLRVPLFE-UHFFFAOYSA-N etoricoxib Chemical compound C1=NC(C)=CC=C1C1=NC=C(Cl)C=C1C1=CC=C(S(C)(=O)=O)C=C1 MNJVRJDLRVPLFE-UHFFFAOYSA-N 0.000 description 1
- GWQVMPWSEVRGPY-UHFFFAOYSA-N europium cryptate Chemical compound [Eu+3].N=1C2=CC=CC=1CN(CC=1N=C(C=CC=1)C=1N=C(C3)C=CC=1)CC(N=1)=CC(C(=O)NCCN)=CC=1C(N=1)=CC(C(=O)NCCN)=CC=1CN3CC1=CC=CC2=N1 GWQVMPWSEVRGPY-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 238000002866 fluorescence resonance energy transfer Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 229910021485 fumed silica Inorganic materials 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 229940014259 gelatin Drugs 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229960001031 glucose Drugs 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 229940074052 glyceryl isostearate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 201000002222 hemangioblastoma Diseases 0.000 description 1
- 208000018706 hematopoietic system disease Diseases 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- 208000007475 hemolytic anemia Diseases 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 102000045293 human LOXL2 Human genes 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- MSYBLBLAMDYKKZ-UHFFFAOYSA-N hydron;pyridine-3-carbonyl chloride;chloride Chemical compound Cl.ClC(=O)C1=CC=CN=C1 MSYBLBLAMDYKKZ-UHFFFAOYSA-N 0.000 description 1
- DOUHZFSGSXMPIE-UHFFFAOYSA-N hydroxidooxidosulfur(.) Chemical compound [O]SO DOUHZFSGSXMPIE-UHFFFAOYSA-N 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 208000021822 hypotensive Diseases 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- IFSDAJWBUCMOAH-HNNXBMFYSA-N idelalisib Chemical compound C1([C@@H](NC=2C=3N=CNC=3N=CN=2)CC)=NC2=CC=CC(F)=C2C(=O)N1C1=CC=CC=C1 IFSDAJWBUCMOAH-HNNXBMFYSA-N 0.000 description 1
- RZLXZEJRGRNLQR-UHFFFAOYSA-N imidazo[1,2-a]pyrazin-8-amine Chemical compound NC1=NC=CN2C=CN=C12 RZLXZEJRGRNLQR-UHFFFAOYSA-N 0.000 description 1
- MBVAHHOKMIRXLP-UHFFFAOYSA-N imidazo[1,2-a]pyrazine Chemical compound C1=CN=CC2=NC=CN21 MBVAHHOKMIRXLP-UHFFFAOYSA-N 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 229940125721 immunosuppressive agent Drugs 0.000 description 1
- 239000005414 inactive ingredient Substances 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- APFVFJFRJDLVQX-UHFFFAOYSA-N indium atom Chemical compound [In] APFVFJFRJDLVQX-UHFFFAOYSA-N 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 208000026876 intravascular large B-cell lymphoma Diseases 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 210000001117 keloid Anatomy 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 208000013104 leukocyte disease Diseases 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000011344 liquid material Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 229960000994 lumiracoxib Drugs 0.000 description 1
- KHPKQFYUPIUARC-UHFFFAOYSA-N lumiracoxib Chemical compound OC(=O)CC1=CC(C)=CC=C1NC1=C(F)C=CC=C1Cl KHPKQFYUPIUARC-UHFFFAOYSA-N 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 229940035824 lymphoma vaccine Drugs 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 229940124302 mTOR inhibitor Drugs 0.000 description 1
- 239000001115 mace Substances 0.000 description 1
- 229940072082 magnesium salicylate Drugs 0.000 description 1
- 229940057948 magnesium stearate Drugs 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 208000029559 malignant endocrine neoplasm Diseases 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- 229940035436 maltitol Drugs 0.000 description 1
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 1
- 229940043353 maltol Drugs 0.000 description 1
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 description 1
- 238000009607 mammography Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 210000003519 mature b lymphocyte Anatomy 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 238000000048 melt cooling Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- AGJSNMGHAVDLRQ-HUUJSLGLSA-N methyl (2s)-2-[[(2r)-2-[[(2s)-2-[[(2r)-2-amino-3-sulfanylpropanoyl]amino]-3-methylbutanoyl]amino]-3-(4-hydroxy-2,3-dimethylphenyl)propanoyl]amino]-4-methylsulfanylbutanoate Chemical compound SC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(=O)N[C@@H](CCSC)C(=O)OC)CC1=CC=C(O)C(C)=C1C AGJSNMGHAVDLRQ-HUUJSLGLSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 201000010879 mucinous adenocarcinoma Diseases 0.000 description 1
- 210000002346 musculoskeletal system Anatomy 0.000 description 1
- 230000001400 myeloablative effect Effects 0.000 description 1
- OQGRFQCUGLKSAV-JTQLQIEISA-N n-[(3s)-2,6-dioxopiperidin-3-yl]-2-phenylacetamide Chemical compound N([C@@H]1C(NC(=O)CC1)=O)C(=O)CC1=CC=CC=C1 OQGRFQCUGLKSAV-JTQLQIEISA-N 0.000 description 1
- 230000017095 negative regulation of cell growth Effects 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 229950006584 obatoclax Drugs 0.000 description 1
- 229960005554 obatoclax mesylate Drugs 0.000 description 1
- 229960000435 oblimersen Drugs 0.000 description 1
- MIMNFCVQODTQDP-NDLVEFNKSA-N oblimersen Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP(S)(=O)O[C@@H]2[C@H](O[C@H](C2)N2C3=NC=NC(N)=C3N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=NC=NC(N)=C3N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)CO)[C@@H](O)C1 MIMNFCVQODTQDP-NDLVEFNKSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 230000009437 off-target effect Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- SWYHWLFHDVMLHO-UHFFFAOYSA-N oxetan-3-ylmethanol Chemical compound OCC1COC1 SWYHWLFHDVMLHO-UHFFFAOYSA-N 0.000 description 1
- 238000006213 oxygenation reaction Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 229940046159 pegylated liposomal doxorubicin Drugs 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 238000003359 percent control normalization Methods 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 229950003203 pexelizumab Drugs 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- DCWXELXMIBXGTH-UHFFFAOYSA-N phosphotyrosine Chemical compound OC(=O)C(N)CC1=CC=C(OP(O)(O)=O)C=C1 DCWXELXMIBXGTH-UHFFFAOYSA-N 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 230000010287 polarization Effects 0.000 description 1
- 229940093448 poloxamer 124 Drugs 0.000 description 1
- 229940085692 poloxamer 181 Drugs 0.000 description 1
- 229940093426 poloxamer 182 Drugs 0.000 description 1
- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 229940044519 poloxamer 188 Drugs 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Chemical class 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- BWILYWWHXDGKQA-UHFFFAOYSA-M potassium propanoate Chemical compound [K+].CCC([O-])=O BWILYWWHXDGKQA-UHFFFAOYSA-M 0.000 description 1
- 235000010332 potassium propionate Nutrition 0.000 description 1
- 239000004331 potassium propionate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 210000001948 pro-b lymphocyte Anatomy 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 229960003712 propranolol Drugs 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
- 229960003415 propylparaben Drugs 0.000 description 1
- 239000003207 proteasome inhibitor Substances 0.000 description 1
- 229940121649 protein inhibitor Drugs 0.000 description 1
- 239000012268 protein inhibitor Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000000541 pulsatile effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000000700 radioactive tracer Substances 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
- 239000011535 reaction buffer Substances 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 210000001525 retina Anatomy 0.000 description 1
- 239000011769 retinyl palmitate Substances 0.000 description 1
- 235000019172 retinyl palmitate Nutrition 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229940120975 revlimid Drugs 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical class O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- 239000012056 semi-solid material Substances 0.000 description 1
- 230000001235 sensitizing effect Effects 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 230000036332 sexual response Effects 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000013464 silicone adhesive Substances 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
- 238000010583 slow cooling Methods 0.000 description 1
- 229940001593 sodium carbonate Drugs 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229940080313 sodium starch Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000007962 solid dispersion Substances 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000012289 standard assay Methods 0.000 description 1
- 238000011255 standard chemotherapy Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000011301 standard therapy Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000002660 stem cell treatment Methods 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000012058 sterile packaged powder Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- XYLAAHDFLMXVHL-UHFFFAOYSA-N tert-butyl 2-[(6-bromopyrazin-2-yl)-[(2-methylpropan-2-yl)oxycarbonyl]amino]-2-oxoacetate Chemical compound BrC1=CN=CC(=N1)N(C(C(=O)OC(C)(C)C)=O)C(=O)OC(C)(C)C XYLAAHDFLMXVHL-UHFFFAOYSA-N 0.000 description 1
- BRDHXWZQYORKJL-UHFFFAOYSA-N tert-butyl N-(6-bromoimidazo[1,2-a]pyrazin-8-yl)-N-[4-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]carbamate Chemical compound BrC=1N=C(C=2N(C1)C=CN2)N(C(OC(C)(C)C)=O)C2=CC=C(C=C2)N2CCN(CC2)C2COC2 BRDHXWZQYORKJL-UHFFFAOYSA-N 0.000 description 1
- AXNZWABHNWHDEH-UHFFFAOYSA-N tert-butyl N-[6-[6-[bis[(2-methylpropan-2-yl)oxycarbonyl]amino]-5-chloropyrazin-2-yl]imidazo[1,2-a]pyrazin-8-yl]-N-[3-[2-(oxan-2-yloxy)ethoxy]-4-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]carbamate Chemical compound ClC1=C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)N=C(C=N1)C=1N=C(N(C2=CC=C(C(OCCOC3OCCCC3)=C2)N2CCN(CC2)C2COC2)C(=O)OC(C)(C)C)C=2N(C=1)C=CN=2 AXNZWABHNWHDEH-UHFFFAOYSA-N 0.000 description 1
- ZQFYCDBWTCXHHQ-UHFFFAOYSA-N tert-butyl N-[6-[6-[bis[(2-methylpropan-2-yl)oxycarbonyl]amino]-5-chloropyrazin-2-yl]imidazo[1,2-a]pyrazin-8-yl]-N-[4-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]carbamate Chemical compound C(C)(C)(C)OC(=O)N(C(OC(C)(C)C)=O)C1=NC(=CN=C1Cl)C=1N=C(C=2N(C1)C=CN2)N(C2=CC=C(C=C2)N2CCN(CC2)C2COC2)C(=O)OC(C)(C)C ZQFYCDBWTCXHHQ-UHFFFAOYSA-N 0.000 description 1
- XAXFOWNNOVYRSO-UHFFFAOYSA-N tert-butyl N-[6-[6-[bis[(2-methylpropan-2-yl)oxycarbonyl]amino]-5-methylpyrazin-2-yl]imidazo[1,2-a]pyrazin-8-yl]-N-[3-[2-(oxan-2-yloxy)ethoxy]-4-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]carbamate Chemical compound C1(=C(N=CC(=N1)C=1N=C(C=2N(C=1)C=CN=2)N(C1=CC=C(C(OCCOC2OCCCC2)=C1)N1CCN(CC1)C1COC1)C(=O)OC(C)(C)C)C)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C XAXFOWNNOVYRSO-UHFFFAOYSA-N 0.000 description 1
- HCBDZGCWNOOTQR-UHFFFAOYSA-N tert-butyl N-[6-[6-[bis[(2-methylpropan-2-yl)oxycarbonyl]amino]pyrazin-2-yl]imidazo[1,2-a]pyrazin-8-yl]-N-[4-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]carbamate Chemical compound C(C)(C)(C)OC(=O)N(C1=CN=CC(=N1)C=1N=C(C=2N(C1)C=CN2)N(C(OC(C)(C)C)=O)C2=CC=C(C=C2)N2CCN(CC2)C2COC2)C(=O)OC(C)(C)C HCBDZGCWNOOTQR-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- PLHJCIYEEKOWNM-HHHXNRCGSA-N tipifarnib Chemical compound CN1C=NC=C1[C@](N)(C=1C=C2C(C=3C=C(Cl)C=CC=3)=CC(=O)N(C)C2=CC=1)C1=CC=C(Cl)C=C1 PLHJCIYEEKOWNM-HHHXNRCGSA-N 0.000 description 1
- 229950009158 tipifarnib Drugs 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- 229960002044 tolmetin sodium Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 231100000816 toxic dose Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 201000010875 transient cerebral ischemia Diseases 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- 210000002229 urogenital system Anatomy 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- LSGOVYNHVSXFFJ-UHFFFAOYSA-N vanadate(3-) Chemical compound [O-][V]([O-])([O-])=O LSGOVYNHVSXFFJ-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 229940094720 viagra Drugs 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- CILBMBUYJCWATM-HGBQGYOLSA-N vinorelbine D-tartrate 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-HGBQGYOLSA-N 0.000 description 1
- 229960002166 vinorelbine tartrate Drugs 0.000 description 1
- GBABOYUKABKIAF-IWWDSPBFSA-N vinorelbinetartrate Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC(C23[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-IWWDSPBFSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 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
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 229940095188 zydelig Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—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
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Description
本開示は、化合物、ならびにがんおよび炎症性状態を含めた様々な疾患の処置におけるこれらの使用に関する。本開示はまた、化合物の調製のための方法およびこのような化合物を含む医薬組成物に関する。
ヒト酵素の最も大きなファミリーであるタンパク質キナーゼは、500種を優に超えるタンパク質を包含する。脾臓チロシンキナーゼ(Syk)は、チロシンキナーゼのSykファミリーのメンバーであり、初期のB細胞の発生ならびに成熟したB細胞の活性化、シグナル伝達、および生存の制御因子である。
したがって、本開示は、Syk阻害剤として機能する化合物を提供する。一実施形態では、本開示は、式Iの化合物
R1は、
R2はHまたは2−ヒドロキシエトキシルであり、
R3はHまたはメチルであり、
R4はHまたはメチルである。
本発明の実施形態において、例えば以下の項目が提供される。
(項目1)
式Iの構造を有する化合物
またはその薬学的に許容される塩、薬学的に許容される共結晶、薬学的に許容されるエステル、立体異性体、立体異性体の混合物、もしくは互変異性体であって、式中、
R 1 は、
からなる群から選択され、ここで、*は、R 1 が結合している、式Iの示されたフェニル環の炭素原子を示し、
R 2 はHまたは2−ヒドロキシエトキシルであり、
R 3 はHまたはメチルであり、
R 4 はHまたはメチルである、
化合物またはその薬学的に許容される塩、薬学的に許容される共結晶、薬学的に許容されるエステル、立体異性体、立体異性体の混合物、もしくは互変異性体。
(項目2)
R 1 が、
である、項目1に記載の化合物、またはその薬学的に許容される塩、薬学的に許容される共結晶、薬学的に許容されるエステル、立体異性体、立体異性体の混合物、もしくは互変異性体。
(項目3)
R 1 が、
である、項目1に記載の化合物、またはその薬学的に許容される塩、薬学的に許容される共結晶、薬学的に許容されるエステル、立体異性体、立体異性体の混合物、もしくは互変異性体。
(項目4)
R 1 が、
である、項目1に記載の化合物、またはその薬学的に許容される塩、薬学的に許容される共結晶、薬学的に許容されるエステル、立体異性体、立体異性体の混合物、もしくは互変異性体。
(項目5)
R 1 が、
である、項目1に記載の化合物、またはその薬学的に許容される塩、薬学的に許容される共結晶、薬学的に許容されるエステル、立体異性体、立体異性体の混合物、もしくは互変異性体。
(項目6)
R 2 が2−ヒドロキシエトキシルである、項目1、2、3、4、または5のいずれかに記載の化合物、またはその薬学的に許容される塩、薬学的に許容される共結晶、薬学的に許容されるエステル、立体異性体、立体異性体の混合物、もしくは互変異性体。
(項目7)
R 2 がHである、項目1、2、3、4、または5のいずれかに記載の化合物、またはその薬学的に許容される塩、薬学的に許容される共結晶、薬学的に許容されるエステル、立体異性体、立体異性体の混合物、もしくは互変異性体。
(項目8)
R 3 がメチルである、項目1、2、3、4、5、6、または7のいずれかに記載の化合物、またはその薬学的に許容される塩、薬学的に許容される共結晶、薬学的に許容されるエステル、立体異性体、立体異性体の混合物、もしくは互変異性体。
(項目9)
R 3 がHである、項目1、2、3、4、5、6、または7のいずれかに記載の化合物、またはその薬学的に許容される塩、薬学的に許容される共結晶、薬学的に許容されるエステル、立体異性体、立体異性体の混合物、もしくは互変異性体。
(項目10)
R 4 がメチルである、項目1、2、3、4、5、6、7、8、または9のいずれかに記載の化合物、またはその薬学的に許容される塩、薬学的に許容される共結晶、薬学的に許容されるエステル、立体異性体、立体異性体の混合物、もしくは互変異性体。
(項目11)
R 4 がHである、項目1、2、3、4、5、6、7、8、または9のいずれかに記載の化合物、またはその薬学的に許容される塩、薬学的に許容される共結晶、薬学的に許容されるエステル、立体異性体、立体異性体の混合物、もしくは互変異性体。
(項目12)
R 2 がHであり、R 4 がHである、項目1、2、3、4、5、6、7、8、9、10、または11のいずれかに記載の化合物、またはその薬学的に許容される塩、薬学的に許容される共結晶、薬学的に許容されるエステル、立体異性体、立体異性体の混合物、もしくは互変異性体。
(項目13)
R 2 がHであり、R 4 がメチルである、項目1、2、3、4、5、6、7、8、9、10、または11のいずれかに記載の化合物、またはその薬学的に許容される塩、薬学的に許容される共結晶、薬学的に許容されるエステル、立体異性体、立体異性体の混合物、もしくは互変異性体。
(項目14)
2−(5−((6−(6−アミノ−5−メチルピラジン−2−イル)イミダゾ[1,2−a]ピラジン−8−イル)アミノ)−2−(4−(オキセタン−3−イル)ピペラジン−1−イル)フェノキシ)エタノール;
6−(6−アミノピラジン−2−イル)−N−(4−(4−(オキセタン−3−イル)ピペラジン−1−イル)フェニル)イミダゾ[1,2−a]ピラジン−8−アミン;
2−((4−(4−((6−(6−アミノピラジン−2−イル)イミダゾ[1,2−a]ピラジン−8−イル)アミノ)フェニル)ピペラジン−1−イル)メチル)プロパン−1,3−ジオール;
2−(5−((6−(6−アミノピラジン−2−イル)イミダゾ[1,2−a]ピラジン−8−イル)アミノ)−2−(4−(オキセタン−3−イル)ピペラジン−1−イル)フェノキシ)エタノール;
(R)−(4−(4−((6−(6−アミノピラジン−2−イル)イミダゾ[1,2−a]ピラジン−8−イル)アミノ)フェニル)モルホリン−2−イル)メタノール;
6−(6−アミノピラジン−2−イル)−5−メチル−N−(4−(4−(オキセタン−3−イル)ピペラジン−1−イル)フェニル)イミダゾ[1,2−a]ピラジン−8−アミン;および
6−(6−アミノ−5−メチルピラジン−2−イル)−N−(4−(4−(オキセタン−3−イル)ピペラジン−1−イル)フェニル)イミダゾ[1,2−a]ピラジン−8−アミン
からなる群から選択される、項目1、2、3、4、5、6、7、8、9、10、11、12、または13のいずれかに記載の化合物、またはその薬学的に許容される塩、薬学的に許容される共結晶、薬学的に許容されるエステル、立体異性体、立体異性体の混合物、もしくは互変異性体。
(項目15)
項目1、2、3、4、5、6、7、8、9、10、11、12、13、または14のいずれかに記載の化合物、またはその薬学的に許容される塩、薬学的に許容される共結晶、薬学的に許容されるエステル、立体異性体、立体異性体の混合物、もしくは互変異性体と、少なくとも1種の薬学的に許容されるビヒクルとを含む医薬組成物。
(項目16)
それを必要とする被験体において、炎症性障害、アレルギー性障害、自己免疫性疾患、およびがんからなる群から選択される疾患または状態を処置するための方法であって、治療有効量の項目1、2、3、4、5、6、7、8、9、10、11、12、13、または14のいずれかに記載の化合物、またはその薬学的に許容される塩、薬学的に許容される共結晶、薬学的に許容されるエステル、立体異性体、立体異性体の混合物、もしくは互変異性体、または項目15に記載の医薬組成物を、前記被験体に投与することを含む、方法。
(項目17)
前記疾患または状態が、血液悪性腫瘍および固形腫瘍からなる群から選択されるがんである、項目16に記載の方法。
(項目18)
前記疾患または状態が、リンパ腫、多発性骨髄腫、または白血病からなる群から選択される血液悪性腫瘍である、項目16に記載の方法。
(項目19)
前記疾患または状態が、小リンパ球性リンパ腫、非ホジキンリンパ腫、緩慢性非ホジキンリンパ腫、不応性iNHL、マントル細胞リンパ腫、濾胞性リンパ腫、リンパ形質細胞性リンパ腫、辺縁帯リンパ腫、免疫芽球性大細胞型リンパ腫、リンパ芽球性リンパ腫、脾辺縁帯B細胞リンパ腫(+/−絨毛状リンパ球)、節性辺縁帯リンパ腫(+/−単球様B細胞)、粘膜関連リンパ組織型の節外性辺縁帯B細胞リンパ腫、皮膚T細胞リンパ腫、節外性T細胞リンパ腫、未分化大細胞型リンパ腫、血管免疫芽球性T細胞リンパ腫、菌状息肉腫、B細胞リンパ腫、びまん性大細胞型B細胞リンパ腫、縦隔大細胞型B細胞リンパ腫、血管内大細胞型B細胞リンパ腫、原発性滲出液リンパ腫、小型非切れ込み核細胞性リンパ腫、バーキットリンパ腫、多発性骨髄腫、形質細胞腫、急性リンパ性白血病、T細胞急性リンパ芽球性白血病、B細胞急性リンパ芽球性白血病、B細胞前リンパ球性白血病、急性骨髄性白血病、慢性リンパ球性白血病、若年性骨髄単球性白血病、微小残存病変、有毛細胞白血病、原発性骨髄線維症、続発性骨髄線維症、慢性骨髄性白血病、骨髄異形成症候群、骨髄増殖性疾患、およびワルデンシュトレーム型マクログロブリン血症からなる群から選択される、項目18に記載の方法。
(項目20)
前記疾患または状態が固形腫瘍であり、前記固形腫瘍が、膵臓がん、泌尿器がん、膀胱がん、結腸直腸がん、結腸がん、乳がん、前立腺がん、腎がん、肝細胞がん、甲状腺がん、胆嚢がん、肺がん(例えば、非小細胞肺がん、小細胞肺がん)、卵巣がん、子宮頸がん、胃がん、子宮内膜がん、食道がん、頭頸部がん、黒色腫、神経内分泌がん、CNSがん、脳腫瘍(例えば、神経膠種、未分化乏突起細胞腫、成人多形神経膠芽腫、および成人未分化星状細胞腫)、骨がん、軟部組織肉腫、網膜芽腫、神経芽細胞腫、腹水、悪性胸水、中皮腫、ウィルムス腫瘍、絨毛性腫瘍、血管外皮細胞腫、カポジ肉腫、粘液様癌、円形細胞癌、扁平上皮癌、食道扁平上皮癌、口腔癌、副腎皮質のがん、ならびにACTH産生腫瘍からなる群から選択されるがん由来である、項目17に記載の方法。
(項目21)
前記疾患または状態が、全身性エリテマトーデス、重症筋無力症、グッドパスチャー症候群、糸球体腎炎、出血、肺出血、アテローム性動脈硬化症、関節リウマチ、乾癬性関節炎、単関節炎、骨関節炎、痛風性関節炎、椎骨炎、ベーチェット病、自己免疫性甲状腺炎、レイノー症候群、急性散在性脳脊髄炎、慢性特発性血小板減少性紫斑病、多発性硬化症、シェーグレン症候群、自己免疫性溶血性貧血、組織移植片拒絶、移植器官の超急性拒絶、同種移植片拒絶、移植片対宿主病、白血球血管外漏出を伴う疾患、白血球悪液質および転移に起因する病態、顆粒球輸血関連症候群、サイトカイン誘発毒性、強皮症、血管炎、喘息、乾癬、慢性炎症性腸疾患、潰瘍性大腸炎、クローン病、壊死性腸炎、過敏性腸症候群、皮膚筋炎、アジソン病、パーキンソン病、アルツハイマー病、糖尿病、I型真性糖尿病、敗血症、敗血症性ショック、エンドトキシンショック、グラム陰性敗血症、グラム陽性敗血症、および毒素性ショック症候群、敗血症に続発する多臓器傷害症候群、外傷、血液量減少性ショック、アレルギー性結膜炎、春季カタル、および甲状腺関連の眼疾患、好酸球性肉芽腫、湿疹、慢性気管支炎、急性呼吸促迫症候群、アレルギー性鼻炎、鼻感冒、枯草熱、気管支喘息、珪肺症、肺サルコイドーシス、胸膜炎、肺胞炎、肺気腫、肺炎、細菌性肺炎、気管支拡張症、および肺酸素中毒、心筋、脳、または四肢の再灌流傷害、熱傷、嚢胞性線維症、ケロイド形成または瘢痕組織形成、感染による発熱および筋痛、ならびに軽度の外傷による脳または脊髄損傷、白血球血管外漏出を伴う疾患、急性過敏症、遅延型過敏症、じんま疹、食物アレルギー、皮膚の日焼け、炎症性骨盤疾患、尿道炎、ブドウ膜炎、副鼻腔炎、肺炎、脳炎、髄膜炎、心筋炎、腎炎、骨髄炎、筋炎、肝炎、アルコール性肝炎、胃炎、腸炎、接触性皮膚炎、アトピー性皮膚炎、歯肉炎、虫垂炎、膵炎、胆嚢炎、真性赤血球増加症、本態性血小板血症、および多発性嚢胞腎疾患からなる群から選択される、項目16に記載の方法。
(項目22)
前記疾患または状態が、全身性エリテマトーデス、重症筋無力症、関節リウマチ、急性散在性脳脊髄炎、特発性血小板減少性紫斑病、多発性硬化症、シェーグレン症候群、乾癬、自己免疫性溶血性貧血、喘息、潰瘍性大腸炎、クローン病、過敏性腸疾患、慢性閉塞性肺疾患、全身性エリテマトーデス、重症筋無力症、関節リウマチ、急性散在性脳脊髄炎、特発性血小板減少性紫斑病、多発性硬化症、シェーグレン症候群、乾癬、自己免疫性溶血性貧血、喘息、潰瘍性大腸炎、クローン病、過敏性腸疾患、慢性閉塞性肺疾患からなる群から選択される、項目16に記載の方法。
(項目23)
前記疾患または状態が、喘息、関節リウマチ、多発性硬化症、慢性閉塞性肺疾患、および全身性エリテマトーデスからなる群から選択される、項目16に記載の方法。
(項目24)
前記被験体がヒトである、項目16から23のいずれか一項に記載の方法。
(項目25)
前記化合物、またはその薬学的に許容される塩もしくは共結晶が、静脈内、筋肉内、非経口、経鼻または経口投与される、項目16から24のいずれか一項に記載の方法。
(項目26)
前記化合物、またはその薬学的に許容される塩もしくは共結晶が、QD経口投与される、項目25に記載の方法。
(項目27)
前記化合物、またはその薬学的に許容される塩もしくは共結晶が、BID経口投与される、項目25に記載の方法。
(項目28)
治療における使用のための、項目1、2、3、4、5、6、7、8、9、10、11、12、13、または14のいずれかに記載の化合物、またはその薬学的に許容される塩もしくは共結晶、または項目15に記載の医薬組成物。
(項目29)
項目16、17、18、19、20、21、22、23、24、25、26または27のいずれか一項に記載の方法における使用のための、項目1、2、3、4、5、6、7、8、9、10、11、12、13、または14のいずれかに記載の化合物、またはその薬学的に許容される塩もしくは共結晶、または項目15に記載の医薬組成物。
(項目30)
項目16、17、18、19、20、21、22、23、24、25、26または27のいずれか一項に記載の疾患または状態の処置のための医薬の製造における、項目1、2、3、4、5、6、7、8、9、10、11、12、13、または14のいずれかに記載の化合物、またはその薬学的に許容される塩もしくは共結晶の使用。
(項目31)
前記化合物が6−(6−アミノピラジン−2−イル)−N−(4−(4−(オキセタン−3−イル)ピペラジン−1−イル)フェニル)イミダゾ[1,2−a]ピラジン−8−アミンまたはその薬学的に許容される塩もしくは共結晶である、項目1に記載の化合物、項目15に記載の医薬組成物、項目16、17、18、19、20、21、22、23、24、25、26もしくは27のいずれか一項に記載の方法、項目28もしくは29に記載の使用のための化合物、または項目30に記載の使用。
(項目32)
前記薬学的に許容される塩または共結晶がメシル酸塩または共結晶である、項目1、2、3、4、5、6、7、8、9、10、11、12、13、14、28、または29のいずれかに記載の化合物。
(項目33)
前記薬学的に許容される塩または共結晶が、コハク酸塩または共結晶である、項目1、2、3、4、5、6、7、8、9、10、11、12、13、14、28、または29のいずれかに記載の化合物。
驚くことに、式Iの化合物、またはその薬学的に許容される塩もしくは共結晶は有利な特性を保有しており、そのことによりそれらが本明細書中に記載されているような使用に対して興味深い化合物となることが発見された。化合物は、Syk阻害剤であることに加えて、望ましい溶解度および薬物動態特性を保有する。これらの知見は、同様の基礎構造の化合物の相当するパラメーターの特性を考慮すると特に顕著である。
本開示に使用されているように、以下の単語および句は、これらが使用されている文脈が他を示す場合を除いて、以下に示されているような意味を有することを一般に意図する。
(i)疾患もしくは状態を阻害すること(例えば、疾患もしくは状態から結果として生じる一つもしくは複数の症状を低減させること、および/または疾患もしくは状態の程度を縮小させること);
(ii)疾患もしくは状態に関連する一つもしくは複数の臨床症状の発生を遅らせるもしくは抑止すること(例えば、疾患もしくは状態を安定化させること、疾患もしくは状態の悪化もしくは進行を予防するもしくは遅延させること、ならびに/または疾患もしくは状態の拡散(例えば、転移)を予防するもしくは遅延させること);ならびに/または
(iii)疾患を緩和する、すなわち、臨床症状の退行を引き起こすこと(例えば、病態を回復させること、疾患もしくは状態の部分的もしくは全体的な寛解をもたらすこと、別の薬物適用の効果を増強すること、疾患の進行を遅延させること、生活の質を高めること、および/または生存を長引かせること)。
化合物は、ここおよび他の箇所で全体にわたり、例えば、発明の概要および実施例などにおいて提供される。
R10は、
ここで、*は、R1が結合している、式IIの示されたフェニル環の炭素原子を示し、
R20は、Hまたは2−ヒドロキシエトキシルであり、
R30は、Hまたはメチルであり、
R40は、H、ハロゲン(すなわちF、Cl、Br、またはI)、メチル、またはハロ置換メチル(すなわち、1〜3個の水素原子が、同じであっても異なっていてもよい1〜3個のハロゲン原子で置換されているメチル、例えばフルオロメチル、クロロメチル、ジフルオロメチル、ジクロロメチル、クロロフルオロメチル、トリフルオロメチルなど)である。
本発明は、治療における使用のための、式Iの化合物、またはその薬学的に許容される塩もしくは共結晶を提供する。Syk活性の阻害に応答する疾患を有する被験体、例えば、ヒトなどの哺乳動物を処置する方法であって、そのような疾患を有する、または有すると疑われている被験体に、有効量の式Iの化合物、またはその薬学的に許容される塩もしくは共結晶を投与することを含む方法が提供される。一態様では、ヒトなどの被験体に、式Iの化合物、またはその薬学的に許容される塩もしくは共結晶と、薬学的に許容されるビヒクルとを含む医薬組成物が投与される。本発明は、このような方法における使用のための、式Iの化合物、またはその薬学的に許容される塩もしくは共結晶をさらに提供する。
提供される処置の方法のいずれかは、アレルギー性障害ならびに/または自己免疫性および/もしくは炎症性疾患、ならびに/または急性炎症性反応またはがんであると診断された、またはそれを有すると疑われる被験体を処置するために使用することができる。
式Iの化合物、またはその薬学的に許容される塩もしくは共結晶が、被験体に与えられる唯一の活性剤である処置の方法もまた提供され、式Iの化合物、またはその薬学的に許容される塩もしくは共結晶が、1種または複数種の追加の活性剤と組み合わせて被験体に与えられる処置の方法もまた含まれる。単剤療法と併用療法の両方が、本明細書で詳述された方法における、例えば、本明細書で詳述された疾患または状態のいずれかを処置する方法などでの使用に対して、および本明細書で詳述された任意の被験体での使用に対して意図され、記載されている。
一部の実施形態では、がん、アレルギー性障害ならびに/または自己免疫性および/もしくは炎症性疾患、ならびに/または急性炎症性反応を処置する方法は、有効量の式Iの化合物、またはその薬学的に許容される塩もしくは共結晶を、それを必要とする被験体に投与することを含み、被験体は、同じ疾患または状態に対して、別の剤または手順を用いた治療を受けていない。
一部の実施形態では、がん、アレルギー性障害ならびに/または自己免疫性および/もしくは炎症性疾患、ならびに/または急性炎症性反応を処置する方法は、それを必要とする被験体に、有効量の式Iの化合物、またはその薬学的に許容される塩もしくは共結晶を、がん、アレルギー性障害ならびに/または自己免疫性および/もしくは炎症性疾患、ならびに/または急性炎症性反応を処置するのに有用であり得る第2の活性剤と一緒に投与することを含む。例えば、第2の剤は抗炎症剤であってよい。第2の活性剤での処置は、式Iの化合物、またはその薬学的に許容される塩もしくは共結晶での処置の前であっても、それと同時であっても、その後であってもよい。一部の実施形態では、式Iの化合物、またはその薬学的に許容される塩もしくは共結晶は、単一剤形内で別の活性剤と組み合わされる。一実施形態では、本発明は、治療、例えば、がん、アレルギー性障害ならびに/または自己免疫性および/もしくは炎症性疾患、ならびに/または急性炎症性反応を処置する方法における同時、別々または逐次的使用のための組み合わせた調製物として、式Iの化合物、またはその薬学的に許容される塩もしくは共結晶と、追加の治療剤とを含む製品を提供する。
式Iの化合物、またはその薬学的に許容される塩もしくは共結晶は通常、医薬組成物の形態で投与される。したがって、本開示は、活性成分として、記載されている化合物の1種もしくは複数種、またはその薬学的に許容される塩、薬学的に許容される共結晶もしくは薬学的に許容されるエステル、および1種または複数種の薬学的に許容されるビヒクル、例えば、添加剤、不活性な固体賦形剤および充填剤を含めた担体、無菌水溶液および様々な有機溶媒を含めた賦形剤、浸透増強剤、可溶化剤ならびにアジュバントを含有する医薬組成物を提供する。医薬組成物は、単独でまたは他の治療剤と組み合わせて投与され得る。このような組成物は、製薬技術において周知の様式で調製される(例えば、Remington’s Pharmaceutical Sciences、Mace Publishing Co.、Philadelphia、PA、第17版(1985年);およびModern Pharmaceutics、Marcel Dekker, Inc.、第3版(G.S. BankerおよびC.T. Rhodes編を参照されたい)。
本明細書において提供されている方法では、式Iの化合物、またはその薬学的に許容される塩もしくは共結晶、またはその医薬組成物は、その意図する目的を達成するための治療有効量で投与される。治療有効量の決定は、特に本明細書において提供されている詳述された開示に照らせば、十分に当業者の能力内である。一部の実施形態では(がんを処置する方法)、治療有効量の式Iの化合物、またはその薬学的に許容される塩もしくは共結晶は、(i)がん細胞の数を減少させることができる;(ii)腫瘍サイズを減少させることができる;(iii)末梢器官へのがん細胞浸潤を阻害し、遅滞させ、ある程度遅らせ、そして好ましくは停止させることができる;(iv)腫瘍転移を阻害する(例えば、ある程度遅らせるおよび好ましくは停止させる)ことができる;(v)腫瘍成長を阻害することができる;(vi)腫瘍の出現および/もしくは再発を遅延させることができる;ならびに/または(vii)がんに関連する症状の一つもしくは複数をある程度緩和することができる。様々な実施形態では、この量はがんの症状の一つまたは複数を回復させ、和らげ、少なくし、そして/または遅延させるのに十分である。
式Iの化合物、またはその薬学的に許容される塩もしくは共結晶を含む組成物(例えば、製剤および単位投薬量を含む)を調製し、適当な容器内に配置し、指示される状態の処置のために標識され得る。したがって、式Iの化合物、またはその薬学的に許容される塩もしくは共結晶の単位剤形と、化合物の使用のための指示を含んでいるラベルとを含む容器などの製造物品もまた提供される。一部の実施形態では、製造物品は、式Iの化合物、またはその薬学的に許容される塩もしくは共結晶の単位剤形と、少なくとも1種の薬学的に許容されるビヒクルとを含む容器である。製造物品は、本開示において提供されている医薬組成物を含有する、ビン、バイアル、アンプル、単回使用の使い捨てアプリケーターなどであってよい。容器は、ガラスまたはプラスチックなどの様々な材料から形成することができ、一態様ではまた、容器上に、または容器に付随したラベルを含み、それは、がんまたは炎症性の状態の処置における使用のための指示を示す。活性成分は、化学的および物理的安定性を改善することが可能な任意の材料、例えば、アルミ箔バッグなどの中にパッケージングすることができることを理解すべきである。一部の実施形態では、ラベル上に示された疾患または状態は、例えば、がんの処置を含むことができる。
本開示の化合物は、本明細書で開示されている方法、ならびに本明細書の開示および当技術分野で周知の方法を考慮すれば明らかであるその所定の修正を使用して調製することができる。本明細書での教示に加えて、従来および周知の合成法を使用することができる。典型的な式Iの化合物、またはその薬学的に許容される塩もしくは共結晶の合成は、以下の実施例に記載されているように達成することができる。入手可能であれば、試薬を、例えば、Sigma Aldrichまたは他の化学薬品供給業者から商業的に購入することができる。
本開示による化合物の典型的な実施形態は、以下に記載されている一般反応スキームを使用して合成することができる。本明細書の記載を考慮すると、出発材料を同様の構造を有する他の材料で置き換えることで、それに対応して異なる生成物をもたらすように一般スキームを変更することができることは明らかである。以下の合成の記載は、対応する生成物を得るために出発材料がどのように変わり得るかについての多くの例を提供するためのものです。置換基が定義されている所望の生成物を考慮すると、必要な出発材料は一般に検査により決定することができる。出発材料は通常商業源から得るか、または公開された方法を使用して合成される。本開示の実施形態である化合物を合成するために、合成する化合物の構造の検査により、各置換基の同一性を提供する。本明細書の実施例を考慮すれば、最終生成物の同一性によって、単純な検査プロセスにより必要な出発材料の同一性が一般に明らかとなる。
本開示の化合物は、例えば、以下の一般的方法および手順を使用して、容易に入手できる出発材料から調製することができる。典型的なまたは好ましいプロセス条件(すなわち、反応の温度、時間、反応物質のモル比、溶媒、圧力など)が与えられた場合、特に述べられていない限り、他のプロセス条件もまた使用することができることを認識されたい。最適な反応条件は、使用される特定の反応物質または溶媒と共に変わる得るが、このような条件は、所定の最適化手順により当業者が決定できる。
中間体1.01.tert−ブチル(6−ブロモイミダゾ[1,2−a]ピラジン−8−イル)(4−(4−(オキセタン−3−イル)ピペラジン−1−イル)フェニル)カルバメートIVおよびtert−ブチル4−(4−(オキセタン−3−イル)ピペラジン−1−イル)フェニル(6−(トリブチルスタンニル)イミダゾ[1,2−a]ピラジン−8−イル)カルバメートVの調製
(実施例1)
6−(6−アミノ−5−メチルピラジン−2−イル)−N−(4−(4−(オキセタン−3−イル)ピペラジン(piperazn)−1−イル)フェニル)イミダゾ[1,2−a]ピラジン−8−アミン(1)の調製
代わりに、化合物XIIをこのステップに直接取り込み、同様に脱保護することによって、5−クロロピラジン置換類似体を得ることができた。
6−(6−アミノピラジン−2−イル)−N−(4−(4−(オキセタン−3−イル)ピペラジン−1−イル)フェニル)イミダゾ[1,2−a]ピラジン−8−アミン(2)の調製
代替の合成
LCMS−ESI+ (m/z): [M+H]+: 644.3. 1H NMR (400 MHz, CDCl3) δ: 9.43 (s, 1H), 8.58 (s, 1H), 8.53 (s, 1H), 8.02 (s, 1H), 7.84 (m, 2H), 7.63 (d, 1H), 7.61 (d, 1H), 7.04 (m, 2H), 4.71 (m,4H), 3.59 (m,1H), 3.27 (m, 4H), 2.55 (m, 4H), 1.46 (s, 18H).
LCMS−ESI+ (m/z): [M+H]+: 620.65. 1H NMR (400 MHz d6−DMSO) δ: 12.2 (broad s,1.5H), 9.58 (s, 1H), 8.63 (s, 1H), 8.50 (s, 1H), 8.15 (s, 1H), 7.95 (d, 2H), 7.90 (s, 1H), 7.64 (s, 1H), 7.00 (d, 2H), 6.50 (s, 2H), 4.52 (dd, 4H), 3.45 (m, 1H), 3.19 (m, 4H), 2.40 (m, 10H).
(R)−(4−(4−((6−(6−アミノピラジン−2−イル)イミダゾ[1,2−a]ピラジン−8−イル)アミノ)フェニル)モルホリン−2−イル)メタノール(3)の調製
6−(6−アミノピラジン−2−イル)−5−メチル−N−(4−(4−(オキセタン−3−イル)ピペラジン−1−イル)フェニル)イミダゾ[1,2−a]ピラジン−8−アミン(4)の調製
2−(5−((6−(6−アミノピラジン−2−イル)イミダゾ[1,2−a]ピラジン−8−イル)アミノ)−2−(4−(オキセタン−3−イル)ピペラジン−1−イル)フェノキシ)エタノール(5)の調製
2−((4−(4−((6−(6−アミノピラジン−2−イル)イミダゾ[1,2−a]ピラジン−8−イル)アミノ)フェニル)ピペラジン−1−イル)メチル)プロパン−1,3−ジオール(6)の調製
2−(5−((6−(6−アミノ−5−メチルピラジン−2−イル)イミダゾ[1,2−a]ピラジン−8−イル)アミノ)−2−(4−(オキセタン−3−イル)ピペラジン−1−イル)フェノキシ)エタノール(7)の調製
本明細書の実施例2の化合物のモノメシレート(MSA)およびスクシネート形態のX線粉末回折(XRPD)分析を、銅放射線(Cu Kα、λ=1.5418Å)を使用して、回折計(PANanalytical XPERT−PRO、PANalytical B.V.、Almelo、Netherlands)で行った。ゼロバックグランドプレートを備えたアルミニウムホルダーの中央に粉末状試料を堆積させることによって、分析のために試料を調製した。45kVの電圧および40mAのアンペア数で発生器を作動させた。使用したスリットは、Soller0.02rad.、抗分散1.0°、および発散であった。試料回転速度は2秒であった。2〜40°2θでスキャンを実施した。データ分析をX’Pert Highscoreバージョン2.2c(PANalytical B.V.、Almelo、Netherlands)およびX’Pertデータビューアーバージョン1.2d(PANalytical B.V.、Almelo、Netherlands)で実施した。以下のような機器設定を使用して、モノMSA 形態I&IIに対するXRPDパターンを得た。45KV、40mA、Cu Kα、λ=1.5418Å、スキャン範囲2〜40°、ステップサイズ0.0167°、カウンティング時間:15.875s。以下のような機器設定を使用して、スクシネート形態I&IIに対するXRPDパターンを得た。45KV、40mA、Cu Kα、λ=1.5418Å、スキャン範囲2〜40°、ステップサイズ0.0084°、カウンティング時間:95.250s。
6−(6−アミノピラジン−2−イル)−N−(4−(4−(オキセタン−3−イル)ピペラジン−1−イル)フェニル)イミダゾ[1,2−a]ピラジン−8−アミンモノメシレート形態I
室温で、6−(6−アミノピラジン−2−イル)−N−(4−(4−(オキセタン−3−イル)ピペラジン−1−イル)フェニル)イミダゾ[1,2−a]ピラジン−8−アミン(実施例2)を、11容量のアセトン/H2O(36:64vol.%)に、1モル当量のメタンスルホン酸(MSA)と共に溶解させることによって、メタンスルホン酸(MSA)塩形態Iを調製した。次いで、溶液に19容量のアセトンを1時間にわたり入れ、反応器の内容物を室温で一晩撹拌した。
1H NMR (400 MHz, DMSO−d6) δ 10.57 (s, 1H), 9.60 (s, 1H), 8.62 (s, 1H), 8.47 (s, 1H), 8.17 (d, J = 1.2 Hz, 1H), 8.03 − 7.96 (m, 2H), 7.90 (s, 1H), 7.69 (d, J = 1.2 Hz, 1H), 7.09 (d, J = 9.0 Hz, 2H), 4.78 (p, J = 8.0 Hz, 4H), 4.49 (m, 1H), 4.00 − 2.8 (m, 10H), 2.32 (s, 3H).
6−(6−アミノピラジン−2−イル)−N−(4−(4−(オキセタン−3−イル)ピペラジン−1−イル)フェニル)イミダゾ[1,2−a]ピラジン−8−アミンモノメシレート形態II
6−(6−アミノピラジン−2−イル)−N−(4−(4−(オキセタン−3−イル)ピペラジン−1−イル)フェニル)イミダゾ[1,2−a]ピラジン−8−アミンモノMSA塩形態I(実施例8)を真空オーブン内で、約40℃でN2パージを用いて乾燥させることによって、6−(6−アミノピラジン−2−イル)−N−(4−(4−(オキセタン−3−イル)ピペラジン−1−イル)フェニル)イミダゾ[1,2−a]ピラジン−8−アミンモノMSA塩形態IIを調製した。
1H NMR (400 MHz, DMSO−d6) δ 9.61 (s, 1H), 8.63 (s, 1H), 8.47 (s, 1H), 8.19 (d, J = 1.2 Hz, 1H), 8.02 − 7.95 (m, 2H), 7.91 (s, 1H), 7.72 (d, J = 1.2 Hz, 1H), 7.13 − 7.06 (m, 2H), 4.85 − 4.72 (m, 4H), 4.53 − 4.45 (m, 1H), 4.30 − 2.75 (m, 10H), 2.34 (s, 3H).
6−(6−アミノピラジン−2−イル)−N−(4−(4−(オキセタン−3−イル)ピペラジン−1−イル)フェニル)イミダゾ[1,2−a]ピラジン−8−アミンスクシネート形態I
最初にTHF中に1.6モル当量のコハク酸を溶解させ、次いでこの酸性溶液を6−(6−アミノピラジン−2−イル)−N−(4−(4−(オキセタン−3−イル)ピペラジン−1−イル)フェニル)イミダゾ[1,2−a]ピラジン−8−アミンに充填することによって、6−(6−アミノピラジン−2−イル)−N−(4−(4−(オキセタン−3−イル)ピペラジン−1−イル)フェニル)イミダゾ[1,2−a]ピラジン−8−アミンスクシネート形態Iを調製した。次いで、磁気撹拌棒を用いて、この材料を室温で一晩撹拌した。
1H NMR (400 MHz, DMSO−d6) δ 12.12 (s, 2H), 9.48 (s, 1H), 8.59 (s, 1H), 8.48 (s, 1H), 8.12 (d, J = 1.1 Hz, 1H), 7.97 − 7.86 (m, 3H), 7.62 (d, J = 1.1 Hz, 1H), 7.01 − 6.94 (m, 2H), 6.45 (s, 2H), 4.55 (t, J = 6.5 Hz, 2H), 4.46 (t, J = 6.1 Hz, 2H), 3.49 − 3.38 (m, 1H), 3.13 (t, J = 4.9 Hz, 4H), 2.40 (s, 10H).
6−(6−アミノピラジン−2−イル)−N−(4−(4−(オキセタン−3−イル)ピペラジン−1−イル)フェニル)イミダゾ[1,2−a]ピラジン−8−アミンスクシネート形態II
6−(6−アミノピラジン−2−イル)−N−(4−(4−(オキセタン−3−イル)ピペラジン−1−イル)フェニル)イミダゾ[1,2−a]ピラジン−8−アミン遊離塩基に10.0部の2−プロパノールを充填し、これに続いて急速に撹拌してスラリーを形成した。2−プロパノール(15部)中のコハク酸(0.43部、1.6モル当量)の別の溶液を周囲温度で調製し、スラリーに加えた。次いで、生成したスラリーを周囲温度で約1日撹拌した。2−プロパノール(3部)中のコハク酸(0.09部、0.3モル当量)の別の溶液をスラリーに加え、生成したスラリーを周囲温度で約2日間撹拌した。2−プロパノール(8部)中のコハク酸(0.27部、1.0モル当量)の追加の溶液を周囲温度で調製し、スラリーに加え、生成したスラリーを約2日間撹拌した。次いで、内容物の温度を40℃に調節し、スラリーを約2時間撹拌した。次いで、内容物を周囲温度に戻し、約16時間撹拌した。次いで、生成したスラリーを濾過し、2−プロパノール(7.0部)ですすぎ、60℃で乾燥させた。
1H NMR (400 MHz, DMSO−d6) δ 12.13 (s, 2H), 9.48 (s, 1H), 8.58 (s, 1H), 8.47z (s, 1H), 8.12 (d, J = 1.1 Hz, 1H), 7.97 − 7.86 (m, 3H), 7.62 (d, J = 1.1 Hz, 1H), 7.02 − 6.94 (m, 2H), 6.45 (s, 2H), 4.55 (t, J = 6.5 Hz, 2H), 4.46 (t, J = 6.0 Hz, 2H), 3.44 (p, J = 6.3 Hz, 1H), 3.17 − 3.10 (m, 4H), 2.40 (s, 10H), 1.02 (d, J = 6.1 Hz, 2H).
(実施例12)
高生産性Syk生化学的アッセイ
KinEASE(Cisbio)、時間分解蛍光共鳴エネルギー移動法(TR−FRET)イムノアッセイを使用して、Syk活性を測定した。このアッセイでは、XL665標識したペプチド基質のリン酸化をSyk−触媒する。ユウロピウムコンジュゲートホスホ−チロシンに特異的な抗体は、生成したリン酸化ペプチドに結合する。2ステップエンドポイントアッセイにおいて、ユウロピウムをドナーとして用い、XL665をアクセプターとして用いて、リン酸化ペプチドの形成をTR−FRETで定量した。手短に言えば、DMSOで連続的に希釈された試験化合物を、Echo550アコースティックリキッドディスペンサー(Labcyte(登録商標))を使用して、Corningの白色の低容量非結合384ウェルプレートに送達した。Multi−Flo(Bio−Tek Instruments)を使用してSyk酵素および基質をアッセイプレートに分配した。5μLの標準的反応混合物は、反応物緩衝液(50mM Hepes、pH7.0、0.02%NaN3、0.1%BSA、0.1mMオルトバナジン酸塩、5mM MgCl2、1mM DTT、0.025%NP−40)中の20μM ATP、1μMビオチン化ペプチド、0.015nMのSykを含有した。室温で30分間のインキュベーション後、5μLのStop and Detect Solution(十分なEDTAを含有する50mM Hepes pH7.0検出緩衝液中の1:200ユウロピウムクリプテート標識した抗リン酸化ペプチド抗体溶液および125nMのストレプトアビジン(strepavidin)−XL665トレイサー)を加えた。次いで、このプレートを室温で120分間さらにインキュベートし、340nm/615nm/665nmでの励起/発光/FRET発光をそれぞれ用いて、Envision 2103 Multilabeledリーダー(PerkinElmer)を使用して読み取りを行った。615nmおよび665nm発光波長での蛍光強度を比(665nm/615nm)として表現した。阻害率を以下の通り計算した。
%阻害=100×(比試料−比0%阻害)/(比100%阻害−比0%阻害)
式中、0.1%DMSO(0%阻害)は陰性対照であり、1μM K252a(100%阻害)を陽性対照として使用した。実施例1〜7の化合物の活性が以下の表に提供されており、これらは、化合物が50nM未満のIC50を有するSyk阻害剤であることを実証している。
384−ウェルHTBS全血CD63好塩基球アッセイ
ヒト全血好塩基球細胞アッセイ(25%血液)におけるCD63の発現により測定される好塩基球の活性化の減少に関してSyk活性を評価した。Flow CASTキット(Buhlmann Laboratories AG、Baselstrasse、Switzerland)を使用して、軽微な修正付きで製造業者により提供されたプロトコルに従い、ヒト全血中の好塩基球活性化を測定した。ヘパリン中の新鮮なヒト全血を収集し、同じ日に送った(AllCells、Emeryville、CA)。全血試料をDMSO(最終1%)またはDMSO中の段階希釈した化合物のいずれかと共に37℃で60分間インキュベートした。抗FceRI mAbを使用して好塩基球を活性化し、抗CD63−FITCおよび抗CCR3−PEで、37℃で20分間染色した(1ウェル当たり:50μLの全血を113μLの刺激緩衝液、8.5μLの抗FceRI mAb、8.5μLのAb染色CCR3−PE/CD63−FITCと混合した)。細胞を1000×gで18分間遠心分離し、150μL/ウェルの上清を除去した。赤血球を溶解させ、2回の細胞の溶解:150μL/ウェルの1×溶解緩衝液を用いて細胞ペレットを再度懸濁させ、室温で10分間インキュベートし、1200rpmで5分間遠心分離することで細胞ペレットを収集することにより細胞を固定した。即時のフローサイトメトリー分析または4℃での一晩のインキュベーション、これに続くフローサイトメトリー分析のいずれかのために、細胞を150μL/ウェルの洗浄緩衝液で2回洗浄し、最終的な容量である75μL/ウェルの洗浄緩衝液中に再度懸濁させた。脱顆粒(好塩基球活性化)を、CCR3陽性細胞上のCD63表面発現により検出した。ゲーティングした好塩基球集団内のCD63陽性細胞の百分率を決定し、DMSO(陰性対照)および対照化合物(陽性対照)に対して正規化した。実施例1〜7の化合物の活性が以下の表に提供され、これは、200nM未満のEC50で、化合物が好塩基球の活性化の減少に有効であることを実証している。
動力学的溶解度
pH7.4のリン酸緩衝液中での化合物の動力学的溶解度を評価した。試験する化合物を10mMの濃度でジメチルスルホキシド中に溶解させた。ストック試料、3μlをpH7.4のリン酸緩衝液297μlで希釈した(ダルベッコリン酸緩衝生理食塩水(Sigma−Aldrich D8662)、全モル濃度は0.149MおよびpH7.43である)。次いで、振盪しながら、試料を37℃で24時間インキュベートし、遠心分離し、アリコートにし、公知の標準的濃度である0.1mMと比較して試験した。実施例1〜7の化合物の動力学的溶解度が以下の表に提供されており、これは、化合物がpH7.4で90μM超の動力学的溶解度を有することを実証している。
ヒト肝細胞安定性アッセイ
L/hr/kg単位の予測肝細胞クリアランスとして化合物のヒト血球安定性を評価した。試験する化合物を200μMに希釈した(4μlの10mM DMSOストックを196μlのACN:H2O(50:50)に入れた)。プロプラノロールを陽性対照として使用し、肝細胞が無いだけの緩衝液を0%対照として使用した。これらは、4μlを891μlのKHB緩衝液(In VitroGROカタログ番号Z99074)でさらに希釈することによって、2×投薬溶液を得た。24ウェルプレートの各ウェルに対して、250μlの2×投薬溶液を250μlの肝細胞(1ウェル当たり、1×106生存細胞/ml)を有する各ウェルに加えるか、または対照試料用のKHBを加えて、インキュベーションの間の最終化合物濃度である1μMを達成した。最終的な溶媒濃度は0.01%DMSOおよび0.25%ACNであった。培養物プレートをロッカーに配置し、37℃、5%CO2でインキュベートした。試料を0、1、3、および6時間の時点で収集した。LC−MS法を使用して、検量線に対して親化合物の損失を決定した。実施例1〜7の化合物の活性が以下の表に提供されており、これは、約0.12L/hr/kgまたはそれ未満の肝細胞クリアランスを示している。
公知のSyk阻害剤との比較
実施例8〜11のアッセイを使用して、本明細書中に記載されているような化合物を、当技術分野で公知の化合物と比較した。実施例1〜7の化合物を、以前に記載された化合物と比較しているデータが以下の表に提供されている。これらの結果から、公知の化合物と比較して、改善されたSykおよびCD63活性、改善された動力学的溶解度(少なくとも約9倍高い溶解性)および肝細胞クリアランス(約2分の1以下であるクリアランス)を有する本明細書中に記載されているような化合物は、Syk阻害剤として望ましいことが明白である。よって、改善されたSykおよびCD63阻害活性と、改善された動力学的溶解度およびクリアランスとの組合せにより、改善された薬物動態特性を有する、本明細書中に記載されているような疾患を処置するのに有効と予想される化合物が得られる。
Claims (50)
- 式Iの構造を有する化合物
またはその薬学的に許容される塩、薬学的に許容される共結晶、立体異性体、立体異性体の混合物、もしくは互変異性体であって、式中、
R1は、
であり、ここで、*は、R1が結合している、式Iの示されたフェニル環の炭素原子を示し、
R2はHまたは2−ヒドロキシエトキシルであり、
R3はHまたはメチルであり、
R4はHまたはメチルである、
化合物またはその薬学的に許容される塩、薬学的に許容される共結晶、立体異性体、立体異性体の混合物、もしくは互変異性体。 - R1が、
である、請求項1に記載の化合物、またはその薬学的に許容される塩、薬学的に許容される共結晶、立体異性体、立体異性体の混合物、もしくは互変異性体。 - R1が、
である、請求項1に記載の化合物、またはその薬学的に許容される塩、薬学的に許容される共結晶、立体異性体、立体異性体の混合物、もしくは互変異性体。 - R1が、
である、請求項1に記載の化合物、またはその薬学的に許容される塩、薬学的に許容される共結晶、立体異性体、立体異性体の混合物、もしくは互変異性体。 - R1が、
である、請求項1に記載の化合物、またはその薬学的に許容される塩、薬学的に許容される共結晶、立体異性体、立体異性体の混合物、もしくは互変異性体。 - R2が2−ヒドロキシエトキシルである、請求項1、2、3、4、または5のいずれかに記載の化合物、またはその薬学的に許容される塩、薬学的に許容される共結晶、立体異性体、立体異性体の混合物、もしくは互変異性体。
- R2がHである、請求項1、2、3、4、または5のいずれかに記載の化合物、またはその薬学的に許容される塩、薬学的に許容される共結晶、立体異性体、立体異性体の混合物、もしくは互変異性体。
- R3がメチルである、請求項1、2、3、4、5、6、または7のいずれかに記載の化合物、またはその薬学的に許容される塩、薬学的に許容される共結晶、立体異性体、立体異性体の混合物、もしくは互変異性体。
- R3がHである、請求項1、2、3、4、5、6、または7のいずれかに記載の化合物、またはその薬学的に許容される塩、薬学的に許容される共結晶、立体異性体、立体異性体の混合物、もしくは互変異性体。
- R4がメチルである、請求項1、2、3、4、5、6、7、8、または9のいずれかに記載の化合物、またはその薬学的に許容される塩、薬学的に許容される共結晶、立体異性体、立体異性体の混合物、もしくは互変異性体。
- R4がHである、請求項1、2、3、4、5、6、7、8、または9のいずれかに記載の化合物、またはその薬学的に許容される塩、薬学的に許容される共結晶、立体異性体、立体異性体の混合物、もしくは互変異性体。
- R2がHであり、R4がHである、請求項1、2、3、4、5、6、7、8、9、10、または11のいずれかに記載の化合物、またはその薬学的に許容される塩、薬学的に許容される共結晶、立体異性体、立体異性体の混合物、もしくは互変異性体。
- R2がHであり、R4がメチルである、請求項1、2、3、4、5、6、7、8、9、10、または11のいずれかに記載の化合物、またはその薬学的に許容される塩、薬学的に許容される共結晶、立体異性体、立体異性体の混合物、もしくは互変異性体。
- 2−(5−((6−(6−アミノ−5−メチルピラジン−2−イル)イミダゾ[1,2−a]ピラジン−8−イル)アミノ)−2−(4−(オキセタン−3−イル)ピペラジン−1−イル)フェノキシ)エタノール;
6−(6−アミノピラジン−2−イル)−N−(4−(4−(オキセタン−3−イル)ピペラジン−1−イル)フェニル)イミダゾ[1,2−a]ピラジン−8−アミン;
2−((4−(4−((6−(6−アミノピラジン−2−イル)イミダゾ[1,2−a]ピラジン−8−イル)アミノ)フェニル)ピペラジン−1−イル)メチル)プロパン−1,3−ジオール;
2−(5−((6−(6−アミノピラジン−2−イル)イミダゾ[1,2−a]ピラジン−8−イル)アミノ)−2−(4−(オキセタン−3−イル)ピペラジン−1−イル)フェノキシ)エタノール;
(R)−(4−(4−((6−(6−アミノピラジン−2−イル)イミダゾ[1,2−a]ピラジン−8−イル)アミノ)フェニル)モルホリン−2−イル)メタノール;
6−(6−アミノピラジン−2−イル)−5−メチル−N−(4−(4−(オキセタン−3−イル)ピペラジン−1−イル)フェニル)イミダゾ[1,2−a]ピラジン−8−アミン;および
6−(6−アミノ−5−メチルピラジン−2−イル)−N−(4−(4−(オキセタン−3−イル)ピペラジン−1−イル)フェニル)イミダゾ[1,2−a]ピラジン−8−アミン
から選択される、請求項1、2、3、4、5、6、7、8、9、10、11、12、または13のいずれかに記載の化合物、またはその薬学的に許容される塩、薬学的に許容される共結晶、立体異性体、立体異性体の混合物、もしくは互変異性体。 - 請求項1、2、3、4、5、6、7、8、9、10、11、12、13、または14のいずれかに記載の化合物、またはその薬学的に許容される塩、薬学的に許容される共結晶、立体異性体、立体異性体の混合物、もしくは互変異性体と、少なくとも1種の薬学的に許容されるビヒクルとを含む医薬組成物。
- それを必要とする被験体において、炎症性障害、アレルギー性障害、自己免疫性疾患、およびがんから選択される疾患または状態を処置するための組成物であって、治療有効量の請求項1、2、3、4、5、6、7、8、9、10、11、12、13、または14のいずれかに記載の化合物、またはその薬学的に許容される塩、薬学的に許容される共結晶、立体異性体、立体異性体の混合物、もしくは互変異性体、または請求項15に記載の医薬組成物を含む、組成物。
- 前記疾患または状態が、血液悪性腫瘍および固形腫瘍から選択されるがんである、請求項16に記載の組成物。
- 前記疾患または状態が、リンパ腫、多発性骨髄腫、および白血病から選択される血液悪性腫瘍である、請求項17に記載の組成物。
- 前記疾患または状態が、小リンパ球性リンパ腫、非ホジキンリンパ腫、緩慢性非ホジキンリンパ腫、不応性iNHL、マントル細胞リンパ腫、濾胞性リンパ腫、リンパ形質細胞性リンパ腫、辺縁帯リンパ腫、免疫芽球性大細胞型リンパ腫、リンパ芽球性リンパ腫、脾辺縁帯B細胞リンパ腫(+/−絨毛状リンパ球)、節性辺縁帯リンパ腫(+/−単球様B細胞)、粘膜関連リンパ組織型の節外性辺縁帯B細胞リンパ腫、皮膚T細胞リンパ腫、節外性T細胞リンパ腫、未分化大細胞型リンパ腫、血管免疫芽球性T細胞リンパ腫、菌状息肉腫、B細胞リンパ腫、びまん性大細胞型B細胞リンパ腫、縦隔大細胞型B細胞リンパ腫、血管内大細胞型B細胞リンパ腫、原発性滲出液リンパ腫、小型非切れ込み核細胞性リンパ腫、バーキットリンパ腫、多発性骨髄腫、形質細胞腫、急性リンパ性白血病、T細胞急性リンパ芽球性白血病、B細胞急性リンパ芽球性白血病、B細胞前リンパ球性白血病、急性骨髄性白血病、慢性リンパ球性白血病、若年性骨髄単球性白血病、微小残存病変、有毛細胞白血病、原発性骨髄線維症、続発性骨髄線維症、慢性骨髄性白血病、骨髄異形成症候群、骨髄増殖性疾患、およびワルデンシュトレーム型マクログロブリン血症から選択される、請求項16に記載の組成物。
- 前記疾患または状態が固形腫瘍であり、前記固形腫瘍が、膵臓がん、泌尿器がん、膀胱がん、結腸直腸がん、結腸がん、乳がん、前立腺がん、腎がん、肝細胞がん、甲状腺がん、胆嚢がん、肺がん(例えば、非小細胞肺がん、および小細胞肺がん)、卵巣がん、子宮頸がん、胃がん、子宮内膜がん、食道がん、頭頸部がん、黒色腫、神経内分泌がん、CNSがん、脳腫瘍(例えば、神経膠種、未分化乏突起細胞腫、成人多形神経膠芽腫、および成人未分化星状細胞腫)、骨がん、軟部組織肉腫、網膜芽腫、神経芽細胞腫、腹水、悪性胸水、中皮腫、ウィルムス腫瘍、絨毛性腫瘍、血管外皮細胞腫、カポジ肉腫、粘液様癌、円形細胞癌、扁平上皮癌、食道扁平上皮癌、口腔癌、副腎皮質のがん、ならびにACTH産生腫瘍から選択されるがん由来である、請求項17に記載の組成物。
- それを必要とする被験体において、疾患または状態を処置するための組成物であって、治療有効量の請求項1、2、3、4、5、6、7、8、9、10、11、12、13、または14のいずれかに記載の化合物、またはその薬学的に許容される塩、薬学的に許容される共結晶、立体異性体、立体異性体の混合物、もしくは互変異性体、または請求項15に記載の医薬組成物を含み、
前記疾患または状態が、全身性エリテマトーデス、重症筋無力症、グッドパスチャー症候群、糸球体腎炎、出血、肺出血、アテローム性動脈硬化症、関節リウマチ、乾癬性関節炎、単関節炎、骨関節炎、痛風性関節炎、椎骨炎、ベーチェット病、自己免疫性甲状腺炎、レイノー症候群、急性散在性脳脊髄炎、慢性特発性血小板減少性紫斑病、多発性硬化症、シェーグレン症候群、自己免疫性溶血性貧血、組織移植片拒絶、移植器官の超急性拒絶、同種移植片拒絶、移植片対宿主病、白血球血管外漏出を伴う疾患、白血球悪液質および転移に起因する病態、顆粒球輸血関連症候群、サイトカイン誘発毒性、強皮症、血管炎、喘息、乾癬、慢性炎症性腸疾患、潰瘍性大腸炎、クローン病、壊死性腸炎、過敏性腸症候群、皮膚筋炎、アジソン病、パーキンソン病、アルツハイマー病、糖尿病、I型真性糖尿病、敗血症、敗血症性ショック、エンドトキシンショック、グラム陰性敗血症、グラム陽性敗血症、毒素性ショック症候群、敗血症に続発する多臓器傷害症候群、外傷、血液量減少性ショック、アレルギー性結膜炎、春季カタル、および甲状腺関連の眼疾患、好酸球性肉芽腫、湿疹、慢性気管支炎、急性呼吸促迫症候群、アレルギー性鼻炎、鼻感冒、枯草熱、気管支喘息、珪肺症、肺サルコイドーシス、胸膜炎、肺胞炎、肺気腫、肺炎、細菌性肺炎、気管支拡張症、肺酸素中毒、心筋、脳、または四肢の再灌流傷害、熱傷、嚢胞性線維症、ケロイド形成または瘢痕組織形成、感染による発熱および筋痛、軽度の外傷による脳または脊髄損傷、白血球血管外漏出を伴う疾患、急性過敏症、遅延型過敏症、じんま疹、食物アレルギー、皮膚の日焼け、炎症性骨盤疾患、尿道炎、ブドウ膜炎、副鼻腔炎、肺炎、脳炎、髄膜炎、心筋炎、腎炎、骨髄炎、筋炎、肝炎、アルコール性肝炎、胃炎、腸炎、接触性皮膚炎、アトピー性皮膚炎、歯肉炎、虫垂炎、膵炎、胆嚢炎、真性赤血球増加症、本態性血小板血症、および多発性嚢胞腎疾患から選択される、
組成物。 - 前記疾患または状態が、全身性エリテマトーデス、重症筋無力症、関節リウマチ、急性散在性脳脊髄炎、特発性血小板減少性紫斑病、多発性硬化症、シェーグレン症候群、乾癬、自己免疫性溶血性貧血、喘息、潰瘍性大腸炎、クローン病、過敏性腸疾患、および慢性閉塞性肺疾患から選択される、請求項16に記載の組成物。
- 前記疾患または状態が、喘息、関節リウマチ、多発性硬化症、慢性閉塞性肺疾患、および全身性エリテマトーデスから選択される、請求項16に記載の組成物。
- 前記被験体がヒトである、請求項16から23のいずれか一項に記載の組成物。
- 前記組成物が、静脈内、筋肉内、非経口、経鼻、または経口投与されることを特徴とする、請求項15から24のいずれか一項に記載の組成物。
- 前記組成物が、QD経口投与されることを特徴とする、請求項25に記載の組成物。
- 前記組成物が、BID経口投与されることを特徴とする、請求項25に記載の組成物。
- 治療における使用のための組成物であって、請求項1、2、3、4、5、6、7、8、9、10、11、12、13、または14のいずれかに記載の化合物、またはその薬学的に許容される塩、薬学的に許容される共結晶、立体異性体、立体異性体の混合物、もしくは互変異性体、または請求項15に記載の医薬組成物を含む、組成物。
- 請求項16、17、18、19、20、21、または22のいずれか一項に記載の疾患または状態の処置のための医薬の製造における、請求項1、2、3、4、5、6、7、8、9、10、11、12、13、または14のいずれかに記載の化合物、またはその薬学的に許容される塩もしくは共結晶の使用。
- 前記化合物が6−(6−アミノピラジン−2−イル)−N−(4−(4−(オキセタン−3−イル)ピペラジン−1−イル)フェニル)イミダゾ[1,2−a]ピラジン−8−アミンまたはその薬学的に許容される塩もしくは共結晶である、請求項1に記載の化合物。
- 前記化合物が6−(6−アミノピラジン−2−イル)−N−(4−(4−(オキセタン−3−イル)ピペラジン−1−イル)フェニル)イミダゾ[1,2−a]ピラジン−8−アミンまたはその薬学的に許容される塩もしくは共結晶である、請求項15に記載の医薬組成物、または請求項16、17、18、19、20、21、22、23、24、25、26、27もしくは28のいずれか一項に記載の組成物。
- 前記化合物が6−(6−アミノピラジン−2−イル)−N−(4−(4−(オキセタン−3−イル)ピペラジン−1−イル)フェニル)イミダゾ[1,2−a]ピラジン−8−アミンまたはその薬学的に許容される塩もしくは共結晶である、請求項29に記載の使用。
- 前記薬学的に許容される塩または共結晶がメシル酸塩または共結晶である、請求項1、2、3、4、5、6、7、8、9、10、11、12、13、または14のいずれかに記載の化合物。
- 前記薬学的に許容される塩または共結晶がメシル酸塩または共結晶である、請求項15に記載の医薬組成物、あるいは、請求項16、17、18、19、20、21、22、23、24、25、26、27、または28のいずれか一項に記載の組成物。
- 前記薬学的に許容される塩または共結晶が、コハク酸塩または共結晶である、請求項1、2、3、4、5、6、7、8、9、10、11、12、13、または14のいずれかに記載の化合物。
- 前記薬学的に許容される塩または共結晶が、コハク酸塩または共結晶である、請求項15に記載の医薬組成物、または請求項16、17、18、19、20、21、22、23、24、25、26、27または28のいずれか一項に記載の組成物。
- 以下の式の化合物:
- 以下の式の化合物:
- 以下の式の化合物:
- 以下の式の化合物:
- 以下の式の化合物:
- 以下の式の化合物:
- 以下の式の化合物:
- 治療有効量の以下の式の化合物:
- 治療有効量の以下の式の化合物:
- 治療有効量の以下の式の化合物:
- 治療有効量の以下の式の化合物:
- 治療有効量の以下の式の化合物:
- 治療有効量の以下の式の化合物:
- 治療有効量の以下の式の化合物:
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201361920407P | 2013-12-23 | 2013-12-23 | |
US61/920,407 | 2013-12-23 | ||
PCT/US2014/071842 WO2015100217A1 (en) | 2013-12-23 | 2014-12-22 | Syk inhibitors |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2017172941A Division JP6530792B2 (ja) | 2013-12-23 | 2017-09-08 | Syk阻害剤 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2017501229A JP2017501229A (ja) | 2017-01-12 |
JP6243062B2 true JP6243062B2 (ja) | 2017-12-06 |
Family
ID=52350364
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2016560876A Active JP6243062B2 (ja) | 2013-12-23 | 2014-12-22 | Syk阻害剤 |
JP2017172941A Active JP6530792B2 (ja) | 2013-12-23 | 2017-09-08 | Syk阻害剤 |
JP2019093810A Pending JP2019172680A (ja) | 2013-12-23 | 2019-05-17 | Syk阻害剤 |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2017172941A Active JP6530792B2 (ja) | 2013-12-23 | 2017-09-08 | Syk阻害剤 |
JP2019093810A Pending JP2019172680A (ja) | 2013-12-23 | 2019-05-17 | Syk阻害剤 |
Country Status (42)
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2018513173A (ja) * | 2015-04-21 | 2018-05-24 | ギリアード サイエンシーズ, インコーポレイテッド | Syk阻害剤を用いた慢性移植片対宿主病の処置 |
Families Citing this family (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2745871C (en) | 2008-12-08 | 2018-02-20 | Gilead Connecticut, Inc. | Imidazopyrazine syk inhibitors |
US9562056B2 (en) | 2010-03-11 | 2017-02-07 | Gilead Connecticut, Inc. | Imidazopyridines Syk inhibitors |
US9657023B2 (en) | 2013-07-30 | 2017-05-23 | Gilead Connecticut, Inc. | Polymorph of Syk inhibitors |
WO2015017610A1 (en) | 2013-07-31 | 2015-02-05 | Gilead Sciences, Inc. | Syk inhibitors |
EA201690608A1 (ru) | 2013-12-04 | 2016-12-30 | Джилид Сайэнс, Инк. | Способы лечения раковых заболеваний |
TWI662037B (zh) | 2013-12-23 | 2019-06-11 | 美商基利科學股份有限公司 | 脾酪胺酸激酶抑制劑 |
TW201617074A (zh) | 2014-07-14 | 2016-05-16 | 吉李德科學股份有限公司 | Syk(脾酪胺酸激酶)抑制劑 |
NZ726365A (en) | 2014-07-14 | 2018-06-29 | Gilead Sciences Inc | Combinations for treating cancers |
WO2017106564A1 (en) * | 2015-12-17 | 2017-06-22 | Gilead Sciences, Inc. | Combination of a jak inhibitor and a syk inhibitor for treating cancers and inflammatory disorders |
TW201822764A (zh) * | 2016-09-14 | 2018-07-01 | 美商基利科學股份有限公司 | Syk抑制劑 |
EP3512519A1 (en) | 2016-09-14 | 2019-07-24 | Gilead Sciences, Inc. | Syk inhibitors |
JOP20180040A1 (ar) | 2017-04-20 | 2019-01-30 | Gilead Sciences Inc | مثبطات pd-1/pd-l1 |
KR102399996B1 (ko) | 2017-08-25 | 2022-05-20 | 길리애드 사이언시즈, 인코포레이티드 | Syk 억제제의 다형체 |
JP2020537678A (ja) | 2017-10-19 | 2020-12-24 | バイエル・アニマル・ヘルス・ゲーエムベーハー | 動物における疾患の治療および予防のための縮合ヘテロ芳香族ピロリドンの使用 |
PL3752501T3 (pl) | 2018-02-13 | 2023-08-21 | Gilead Sciences, Inc. | Inhibitory pd-1/pd-l1 |
US10899735B2 (en) | 2018-04-19 | 2021-01-26 | Gilead Sciences, Inc. | PD-1/PD-L1 inhibitors |
EP3793565B1 (en) | 2018-05-14 | 2022-01-05 | Gilead Sciences, Inc. | Mcl-1 inhibitors |
JP7105359B2 (ja) | 2018-07-13 | 2022-07-22 | ギリアード サイエンシーズ, インコーポレイテッド | Pd-1/pd-l1阻害剤 |
CN110833549B (zh) * | 2018-08-15 | 2023-05-02 | 广西梧州制药(集团)股份有限公司 | 吡唑并嘧啶衍生物在治疗慢性盆腔炎的用途 |
AU2019366355B2 (en) | 2018-10-24 | 2022-10-13 | Gilead Sciences, Inc. | PD-1/PD-L1 inhibitors |
WO2020172431A1 (en) * | 2019-02-22 | 2020-08-27 | Gilead Sciences, Inc. | Solid forms of condensed pyrazines as syk inhibitors |
AU2020242287A1 (en) | 2019-03-21 | 2021-09-02 | INSERM (Institut National de la Santé et de la Recherche Médicale) | A Dbait molecule in combination with kinase inhibitor for the treatment of cancer |
WO2021089791A1 (en) | 2019-11-08 | 2021-05-14 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for the treatment of cancers that have acquired resistance to kinase inhibitors |
WO2021148581A1 (en) | 2020-01-22 | 2021-07-29 | Onxeo | Novel dbait molecule and its use |
WO2022026753A1 (en) * | 2020-07-29 | 2022-02-03 | University Of Kentucky Research Foundation | Gold(iii) compounds and cancer cell-selective modulation of mitochondrial respiration and metabolism |
US20230277586A1 (en) * | 2020-07-29 | 2023-09-07 | University Of Kentucky Research Foundation | Accelerating repair of mucosal injury using gold(iii) compounds |
CN112939983A (zh) * | 2021-02-01 | 2021-06-11 | 暨明医药科技(苏州)有限公司 | 一种SYK激酶抑制剂Lanraplenib的合成方法 |
CN113480543B (zh) * | 2021-07-07 | 2022-05-17 | 无锡市第二人民医院 | 2,6,8-多取代咪唑并[1,2-a]吡嗪及其合成方法和应用 |
WO2024037910A1 (en) * | 2022-08-17 | 2024-02-22 | Institut National de la Santé et de la Recherche Médicale | Syk inhibitors for use in the treatment of cancer |
Family Cites Families (93)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3845770A (en) | 1972-06-05 | 1974-11-05 | Alza Corp | Osmatic dispensing device for releasing beneficial agent |
US4326525A (en) | 1980-10-14 | 1982-04-27 | Alza Corporation | Osmotic device that improves delivery properties of agent in situ |
US5364620A (en) | 1983-12-22 | 1994-11-15 | Elan Corporation, Plc | Controlled absorption diltiazem formulation for once daily administration |
US5023252A (en) | 1985-12-04 | 1991-06-11 | Conrex Pharmaceutical Corporation | Transdermal and trans-membrane delivery of drugs |
FR2607813B1 (fr) | 1986-12-05 | 1989-03-31 | Montpellier I Universite | Alkylamino-8 imidazo (1,2-a) pyrazines et derives, leur preparation et leur application en therapeutique |
US4992445A (en) | 1987-06-12 | 1991-02-12 | American Cyanamid Co. | Transdermal delivery of pharmaceuticals |
US5001139A (en) | 1987-06-12 | 1991-03-19 | American Cyanamid Company | Enchancers for the transdermal flux of nivadipine |
US4902514A (en) | 1988-07-21 | 1990-02-20 | Alza Corporation | Dosage form for administering nilvadipine for treating cardiovascular symptoms |
US5137876A (en) | 1990-10-12 | 1992-08-11 | Merck & Co., Inc. | Nucleoside antiviral and anti-inflammatory compounds and compositions and methods for using same |
DE4327027A1 (de) | 1993-02-15 | 1994-08-18 | Bayer Ag | Imidazoazine |
DE4337611A1 (de) | 1993-11-04 | 1995-05-11 | Boehringer Ingelheim Kg | Neue Benzoylguanidine, ihre Herstellung und ihre Verwendung in Arzneimitteln |
DE4337609A1 (de) | 1993-11-04 | 1995-05-11 | Boehringer Ingelheim Kg | Neue Pyrazincarboxamidderivate, ihre Herstellung und ihre Verwendung in Arzneimitteln |
FR2711993B1 (fr) | 1993-11-05 | 1995-12-01 | Rhone Poulenc Rorer Sa | Médicaments contenant des dérivés de 7H-imidazol[1,2-a]pyrazine-8-one, les nouveaux composés et leur préparation. |
US6334997B1 (en) | 1994-03-25 | 2002-01-01 | Isotechnika, Inc. | Method of using deuterated calcium channel blockers |
JP3696884B2 (ja) | 1994-03-25 | 2005-09-21 | アイソテクニカ、インコーポレーテッド | ジュウテリウム化による薬物の効能の増強 |
FR2723373B1 (fr) | 1994-08-02 | 1996-09-13 | Rhone Poulenc Rorer Sa | Forme purifiee de streptogramines, sa preparation et les compositions pharmaceutiques qui la contiennent |
JPH11505524A (ja) | 1995-05-01 | 1999-05-21 | 藤沢薬品工業株式会社 | イミダゾ1,2−aピリジンおよびイミダゾ1,2−aピリデジン誘導体、および骨吸収阻害剤としてのその用途 |
US5593997A (en) | 1995-05-23 | 1997-01-14 | Pfizer Inc. | 4-aminopyrazolo(3-,4-D)pyrimidine and 4-aminopyrazolo-(3,4-D)pyridine tyrosine kinase inhibitors |
SE9704404D0 (sv) | 1997-11-28 | 1997-11-28 | Astra Ab | New compounds |
DE60004635T2 (de) | 1999-01-25 | 2004-06-09 | Biogen, Inc., Cambridge | Baff, dessen inhibitoren und dessen verwendung zur modulierung der b-zell-antwort |
DE19948434A1 (de) | 1999-10-08 | 2001-06-07 | Gruenenthal Gmbh | Substanzbibliothek enthaltend bicyclische Imidazo-5-amine und/oder bicyclische Imidazo-3-amine |
DE60028754T2 (de) | 1999-11-12 | 2007-05-31 | Abbott Laboratories, Abbott Park | Feste dispersion mit ritonavir, fenofibrat oder griseofulvin |
AP2002002552A0 (en) | 1999-12-23 | 2002-06-30 | Pfizer Prod Inc | Pharmaceutical compositions providing enhanced drug concentrations. |
JP2001302667A (ja) | 2000-04-28 | 2001-10-31 | Bayer Ag | イミダゾピリミジン誘導体およびトリアゾロピリミジン誘導体 |
GB0018473D0 (en) | 2000-07-27 | 2000-09-13 | Merck Sharp & Dohme | Therapeutic agents |
DE10050663A1 (de) | 2000-10-13 | 2002-04-18 | Gruenenthal Gmbh | Verwendung von substituierten Imidazo[1,2-a]pyridin-, -pyrimidin- und pyrazin-3-yl-amin-Derivaten zur Herstellung von Medikamenten zur NOS-Inhibierung |
US20040102455A1 (en) | 2001-01-30 | 2004-05-27 | Burns Christopher John | Method of inhibiting kinases |
GB0103926D0 (en) | 2001-02-17 | 2001-04-04 | Astrazeneca Ab | Chemical compounds |
WO2002076985A1 (en) | 2001-03-23 | 2002-10-03 | Smithkline Beecham Corporation | Compounds useful as kinase inhibitors for the treatment of hyperproliferative diseases |
JP2005523288A (ja) | 2002-02-19 | 2005-08-04 | ファルマシア・アンド・アップジョン・カンパニー・エルエルシー | 疾病治療用の縮合した二環式−n−架橋−複素環式芳香族カルボキサミド |
WO2003089434A2 (en) | 2002-04-19 | 2003-10-30 | Cellular Genomics, Inc. | IMIDAZO[1,2-a]PYRAZIN-8-YLAMINES METHOD OF MAKING AND METHOD OF USE THEREOF |
DE60326341D1 (de) | 2002-05-14 | 2009-04-09 | Xenova Ltd | Verfahren zur herstellung von anthranilsäurederivat-hydrat |
KR20040012451A (ko) | 2002-05-14 | 2004-02-11 | 어플라이드 머티어리얼스, 인코포레이티드 | 포토리소그래픽 레티클을 에칭하는 방법 |
US7312341B2 (en) | 2002-09-09 | 2007-12-25 | Cgi Pharmaceuticals, Inc. | 6-aryl-imidazo[1,2-a] pyrazin-8-ylamines, method of making, and method of use thereof |
AR041291A1 (es) | 2002-09-19 | 2005-05-11 | Schering Corp | Imidazopiridinas como inhibidores de quinasa dependientes de ciclina |
PE20050081A1 (es) | 2002-09-23 | 2005-03-01 | Schering Corp | Nuevas imidazopirazinas como inhibidores de cinasas dependientes de ciclinas |
TW200412967A (en) | 2002-09-23 | 2004-08-01 | Schering Corp | Novel imidazopyrazines as cyclin dependent kinase inhibitors |
WO2004072080A1 (en) | 2003-02-10 | 2004-08-26 | Cellular Genomics, Inc. | Certain 8-heteroaryl-6-phenyl-imidazo[1,2-a]pyrazines as modulators of hsp90 complex activity |
US7186832B2 (en) | 2003-02-20 | 2007-03-06 | Sugen Inc. | Use of 8-amino-aryl-substituted imidazopyrazines as kinase inhibitors |
US7157460B2 (en) | 2003-02-20 | 2007-01-02 | Sugen Inc. | Use of 8-amino-aryl-substituted imidazopyrazines as kinase inhibitors |
WO2005014599A1 (en) | 2003-06-04 | 2005-02-17 | Cellular Genomics, Inc. | Imidazo[1,2-a]pyrazin-8-ylamines and method of inhibition of bruton’s tyrosine kinase by such compounds |
US20060183746A1 (en) | 2003-06-04 | 2006-08-17 | Currie Kevin S | Certain imidazo[1,2-a]pyrazin-8-ylamines and method of inhibition of Bruton's tyrosine kinase by such compounds |
WO2005005429A1 (en) | 2003-06-30 | 2005-01-20 | Cellular Genomics, Inc. | Certain heterocyclic substituted imidazo[1,2-a]pyrazin-8-ylamines and methods of inhibition of bruton’s tyrosine kinase by such compounds |
US7259164B2 (en) | 2003-08-11 | 2007-08-21 | Cgi Pharmaceuticals, Inc. | Certain substituted imidazo[1,2-a]pyrazines, as modulators of kinase activity |
US20050288295A1 (en) | 2003-11-11 | 2005-12-29 | Currie Kevin S | Certain imidazo[1,2-a]pyrazin-8-ylamines, method of making, and method of use thereof |
US7973161B2 (en) | 2003-11-13 | 2011-07-05 | Abbott Laboratories | Apoptosis promoters |
WO2005085252A1 (en) | 2004-03-04 | 2005-09-15 | Biofocus Discovery Limited | Imidazo ‘1,2-a’ pyrazine compounds which interact with protein kinases |
AU2005265031A1 (en) | 2004-06-17 | 2006-01-26 | Forest Laboratories, Inc. | Modified release formulation of memantine |
US7713973B2 (en) | 2004-10-15 | 2010-05-11 | Takeda Pharmaceutical Company Limited | Kinase inhibitors |
CN101124227A (zh) | 2004-11-10 | 2008-02-13 | Cgi制药有限公司 | 可用作激酶活性调节剂的咪唑并[1,2-a]吡嗪-8-基胺 |
CA2587192A1 (en) | 2004-11-10 | 2006-05-18 | Cgi Pharmaceuticals, Inc. | Imidazo[1 , 2-a] pyrazin-8-ylamines useful as modulators of kinase activity |
CN101175738B (zh) | 2005-05-12 | 2010-10-27 | 雅培制药有限公司 | 细胞凋亡促进剂 |
AR056785A1 (es) | 2005-11-10 | 2007-10-24 | Schering Corp | COMPUESTOS DE IMIDAZO[1,2-A]PIRAZINAS, uTILES COMO INHIBIDORES, REGULADORES O MODULADORES DE PROTEINQUINASAS |
JP5336375B2 (ja) | 2006-08-30 | 2013-11-06 | セルゾーム リミテッド | キナーゼ阻害剤としてのトリアゾール誘導体 |
PE20080839A1 (es) | 2006-09-11 | 2008-08-23 | Cgi Pharmaceuticals Inc | Determinadas amidas sustituidas, metodo de elaboracion y metodo de uso de las mismas |
CL2008002793A1 (es) | 2007-09-20 | 2009-09-04 | Cgi Pharmaceuticals Inc | Compuestos derivados de amidas sustituidas, inhibidores de la actividad de btk; composicion farmaceutica que los comprende; utiles en el tratamiento del cancer, trastornos oseos, enfermedades autoinmunes, entre otras |
JP5563472B2 (ja) | 2007-11-28 | 2014-07-30 | アイ アール エックス セーラピューティクス, インコーポレイテッド | 免疫学的効果を増大させる方法 |
CN101952283B (zh) | 2007-12-14 | 2013-04-17 | 霍夫曼-拉罗奇有限公司 | 咪唑并[1,2-a]吡啶和咪唑并[1,2-b]哒嗪衍生物 |
AR075257A1 (es) | 2008-02-01 | 2011-03-23 | Hexima Ltd | Sistema de proteccion de plantas contra la infeccion por agentes patogenos |
TW200942537A (en) | 2008-02-01 | 2009-10-16 | Irm Llc | Compounds and compositions as kinase inhibitors |
AU2009215191A1 (en) | 2008-02-13 | 2009-08-20 | Gilead Connecticut, Inc. | 6-aryl-imidaz0[l, 2-a] pyrazine derivatives, method of making, and method of use thereof |
US8588172B2 (en) | 2008-02-15 | 2013-11-19 | Telefonaktiebolaget L M Ericsson (Pub) | Methods and network nodes that simultaneously assign temporary block flows for uplink and downlink communication channels to a mobile station |
US20110002989A1 (en) | 2008-03-07 | 2011-01-06 | Pfizer Inc. | Methods, dosage forms and kits for administering ziprasidone without food |
AU2009244291B2 (en) | 2008-05-06 | 2014-02-13 | Genentech, Inc. | Substituted amides, method of making, and use as Btk inhibitors |
EP2297142B1 (en) | 2008-06-24 | 2015-10-14 | F. Hoffmann-La Roche AG | Novel substituted pyridin-2-ones and pyridazin-3-ones |
RU2507202C2 (ru) | 2008-07-02 | 2014-02-20 | Ф.Хоффманн-Ля Рош Аг | Новые фенилпиразиноны в качестве ингибиторов киназы |
JP5318952B2 (ja) | 2008-07-15 | 2013-10-16 | エフ.ホフマン−ラ ロシュ アーゲー | 新規なフェニル−イミダゾピリジン類及びピリダジン類 |
TWI453207B (zh) | 2008-09-08 | 2014-09-21 | Signal Pharm Llc | 胺基三唑并吡啶,其組合物及使用其之治療方法 |
CA2745871C (en) | 2008-12-08 | 2018-02-20 | Gilead Connecticut, Inc. | Imidazopyrazine syk inhibitors |
US8450321B2 (en) | 2008-12-08 | 2013-05-28 | Gilead Connecticut, Inc. | 6-(1H-indazol-6-yl)-N-[4-(morpholin-4-yl)phenyl]imidazo-[1,2-A]pyrazin-8-amine, or a pharmaceutically acceptable salt thereof, as a SYK inhibitor |
KR20170013414A (ko) | 2008-12-08 | 2017-02-06 | 질레드 코네티컷 인코포레이티드 | 이미다조피라진 syk 억제제 |
US8362013B2 (en) | 2009-04-30 | 2013-01-29 | Abbvie Inc. | Salt of ABT-263 and solid-state forms thereof |
US8546399B2 (en) | 2009-05-26 | 2013-10-01 | Abbvie Inc. | Apoptosis inducing agents for the treatment of cancer and immune and autoimmune diseases |
DK2512455T3 (en) | 2009-12-18 | 2014-03-24 | Frieslandcampina Nederland Holding B V | Co-treated tablet adjuvant composition, its preparation and use |
US9562056B2 (en) | 2010-03-11 | 2017-02-07 | Gilead Connecticut, Inc. | Imidazopyridines Syk inhibitors |
SI2643322T1 (en) | 2010-11-23 | 2018-01-31 | Abbvie Inc. | Salts and crystalline forms of an apoptosis induction agent |
EP2703400A4 (en) | 2011-04-27 | 2014-10-08 | Daiichi Sankyo Co Ltd | PHENYLPYRROLDERIVAT CRYSTAL |
US20130338142A1 (en) | 2012-06-14 | 2013-12-19 | Gilead Connecticut, Inc. | Imidazopyrazine syk inhibitors |
EP2884980A1 (en) | 2012-08-14 | 2015-06-24 | Gilead Calistoga LLC | Combination therapies for treating cancer |
US20140148430A1 (en) | 2012-11-26 | 2014-05-29 | Gilead Connecticut, Inc. | Imidazopyridines syk inhibitors |
MD4684B1 (ro) | 2013-07-30 | 2020-03-31 | Gilead Connecticut INc. | Formulări pe bază de imidazopirazine în calitate de inhibitori SYK |
US9657023B2 (en) | 2013-07-30 | 2017-05-23 | Gilead Connecticut, Inc. | Polymorph of Syk inhibitors |
WO2015017610A1 (en) | 2013-07-31 | 2015-02-05 | Gilead Sciences, Inc. | Syk inhibitors |
EA201690608A1 (ru) | 2013-12-04 | 2016-12-30 | Джилид Сайэнс, Инк. | Способы лечения раковых заболеваний |
TWI662037B (zh) | 2013-12-23 | 2019-06-11 | 美商基利科學股份有限公司 | 脾酪胺酸激酶抑制劑 |
SG11201604482QA (en) | 2013-12-23 | 2016-07-28 | Gilead Sciences Inc | Synthesis of a macrocyclic hcv ns3 inhibiting tripeptide |
US9290505B2 (en) | 2013-12-23 | 2016-03-22 | Gilead Sciences, Inc. | Substituted imidazo[1,2-a]pyrazines as Syk inhibitors |
TW201617074A (zh) | 2014-07-14 | 2016-05-16 | 吉李德科學股份有限公司 | Syk(脾酪胺酸激酶)抑制劑 |
NZ726365A (en) | 2014-07-14 | 2018-06-29 | Gilead Sciences Inc | Combinations for treating cancers |
TW201639573A (zh) | 2015-02-03 | 2016-11-16 | 吉李德科學股份有限公司 | 有關治療癌症之合併治療 |
CA2983611A1 (en) | 2015-04-21 | 2016-10-27 | Gilead Sciences, Inc. | Treatment of chronic graft versus host disease with syk inhibitors |
EP3512519A1 (en) | 2016-09-14 | 2019-07-24 | Gilead Sciences, Inc. | Syk inhibitors |
TW201822764A (zh) | 2016-09-14 | 2018-07-01 | 美商基利科學股份有限公司 | Syk抑制劑 |
-
2014
- 2014-12-19 TW TW103144664A patent/TWI662037B/zh active
- 2014-12-19 UY UY0001035898A patent/UY35898A/es not_active Application Discontinuation
- 2014-12-19 TW TW108110295A patent/TWI735853B/zh active
- 2014-12-22 LT LTEP14827669.4T patent/LT3087075T/lt unknown
- 2014-12-22 MX MX2016008456A patent/MX371024B/es active IP Right Grant
- 2014-12-22 CR CR20160287A patent/CR20160287A/es unknown
- 2014-12-22 PE PE2016000814A patent/PE20160995A1/es active IP Right Grant
- 2014-12-22 EP EP18156034.3A patent/EP3342773B9/en active Active
- 2014-12-22 ES ES14827669.4T patent/ES2664799T3/es active Active
- 2014-12-22 NZ NZ721175A patent/NZ721175A/en unknown
- 2014-12-22 PT PT148276694T patent/PT3087075T/pt unknown
- 2014-12-22 HU HUE18156034A patent/HUE053815T2/hu unknown
- 2014-12-22 EP EP14827669.4A patent/EP3087075B1/en active Active
- 2014-12-22 RS RS20180332A patent/RS57182B1/sr unknown
- 2014-12-22 AP AP2016009274A patent/AP2016009274A0/en unknown
- 2014-12-22 MX MX2020000404A patent/MX2020000404A/es unknown
- 2014-12-22 KR KR1020187034638A patent/KR102146477B1/ko active Application Filing
- 2014-12-22 DK DK18156034.3T patent/DK3342773T3/da active
- 2014-12-22 PL PL18156034T patent/PL3342773T3/pl unknown
- 2014-12-22 AU AU2014370010A patent/AU2014370010B2/en active Active
- 2014-12-22 SG SG10201707432SA patent/SG10201707432SA/en unknown
- 2014-12-22 KR KR1020167019931A patent/KR101925859B1/ko active IP Right Grant
- 2014-12-22 KR KR1020207023431A patent/KR20200098735A/ko not_active Application Discontinuation
- 2014-12-22 AR ARP140104854A patent/AR098912A1/es unknown
- 2014-12-22 JP JP2016560876A patent/JP6243062B2/ja active Active
- 2014-12-22 CA CA2875877A patent/CA2875877C/en active Active
- 2014-12-22 SI SI201431765T patent/SI3342773T1/sl unknown
- 2014-12-22 DK DK14827669.4T patent/DK3087075T3/en active
- 2014-12-22 EA EA201690989A patent/EA031131B1/ru unknown
- 2014-12-22 CN CN201711091018.7A patent/CN107746405B/zh active Active
- 2014-12-22 HU HUE14827669A patent/HUE037662T2/hu unknown
- 2014-12-22 BR BR112016014643-3A patent/BR112016014643B1/pt active IP Right Grant
- 2014-12-22 UA UAA201606436A patent/UA118463C2/uk unknown
- 2014-12-22 PL PL14827669T patent/PL3087075T3/pl unknown
- 2014-12-22 ME MEP-2018-85A patent/ME03001B/me unknown
- 2014-12-22 SG SG11201604491VA patent/SG11201604491VA/en unknown
- 2014-12-22 PT PT181560343T patent/PT3342773T/pt unknown
- 2014-12-22 CN CN201480070710.XA patent/CN105934434B/zh active Active
- 2014-12-22 SG SG10201912586UA patent/SG10201912586UA/en unknown
- 2014-12-22 WO PCT/US2014/071842 patent/WO2015100217A1/en active Application Filing
- 2014-12-22 EA EA201891553A patent/EA201891553A1/ru unknown
- 2014-12-22 SI SI201430630T patent/SI3087075T1/en unknown
- 2014-12-22 MD MDA20160078A patent/MD4666C1/ro active IP Right Grant
- 2014-12-22 ES ES18156034T patent/ES2851335T3/es active Active
-
2015
- 2015-08-07 NO NO15766627A patent/NO3183247T3/no unknown
-
2016
- 2016-02-05 US US15/017,394 patent/US9968601B2/en active Active
- 2016-05-25 IL IL245846A patent/IL245846B/en active IP Right Grant
- 2016-06-15 DO DO2016000140A patent/DOP2016000140A/es unknown
- 2016-06-16 SV SV2016005229A patent/SV2016005229A/es unknown
- 2016-06-16 CL CL2016001537A patent/CL2016001537A1/es unknown
- 2016-06-17 GT GT201600123A patent/GT201600123A/es unknown
- 2016-06-20 PH PH12016501204A patent/PH12016501204A1/en unknown
- 2016-06-23 CU CUP2016000097A patent/CU20160097A7/es unknown
-
2017
- 2017-09-08 JP JP2017172941A patent/JP6530792B2/ja active Active
- 2017-09-14 AU AU2017228612A patent/AU2017228612B2/en active Active
-
2018
- 2018-02-12 ZA ZA2018/00913A patent/ZA201800913B/en unknown
- 2018-03-19 HR HRP20180460TT patent/HRP20180460T1/hr unknown
- 2018-03-30 CY CY20181100354T patent/CY1120104T1/el unknown
- 2018-04-04 US US15/945,685 patent/US10342794B2/en active Active
- 2018-08-27 HK HK18111002.3A patent/HK1251563A1/zh unknown
- 2018-12-14 HK HK18116112.9A patent/HK1256999A1/zh unknown
-
2019
- 2019-05-15 US US16/413,458 patent/US10828299B2/en active Active
- 2019-05-17 JP JP2019093810A patent/JP2019172680A/ja active Pending
- 2019-09-26 AU AU2019236696A patent/AU2019236696B2/en active Active
-
2020
- 2020-10-28 US US17/082,595 patent/US11517570B2/en active Active
-
2021
- 2021-02-11 HR HRP20210233TT patent/HRP20210233T1/hr unknown
-
2022
- 2022-11-18 US US18/057,195 patent/US20230158023A1/en active Pending
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2018513173A (ja) * | 2015-04-21 | 2018-05-24 | ギリアード サイエンシーズ, インコーポレイテッド | Syk阻害剤を用いた慢性移植片対宿主病の処置 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6530792B2 (ja) | Syk阻害剤 | |
JP6292691B2 (ja) | Syk阻害剤 | |
US9290505B2 (en) | Substituted imidazo[1,2-a]pyrazines as Syk inhibitors | |
OA20934A (en) | Syk inhibitors | |
BR122020009305B1 (pt) | Forma cristalina de 6-(6-aminopirazin-2-il)-n-(4-(4-(oxetan-3-il)piperazin-1- il)fenil)imidazo[1,2-a]pirazin-8-amina, composição farmacêutica, e, uso de uma forma cristalina | |
EA040127B1 (ru) | Кристаллические формы соединений и их применение для лечения лейкоза |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20160728 Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20160808 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20160728 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20170608 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20170615 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20170908 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20171012 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20171108 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6243062 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |