JP7185681B2 - 免疫調節化合物 - Google Patents
免疫調節化合物 Download PDFInfo
- Publication number
- JP7185681B2 JP7185681B2 JP2020503970A JP2020503970A JP7185681B2 JP 7185681 B2 JP7185681 B2 JP 7185681B2 JP 2020503970 A JP2020503970 A JP 2020503970A JP 2020503970 A JP2020503970 A JP 2020503970A JP 7185681 B2 JP7185681 B2 JP 7185681B2
- Authority
- JP
- Japan
- Prior art keywords
- alkyl
- cancer
- group
- pharmaceutically acceptable
- agents
- 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
- 150000001875 compounds Chemical class 0.000 title claims description 171
- 230000002519 immonomodulatory effect Effects 0.000 title description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 112
- 150000003839 salts Chemical class 0.000 claims description 81
- -1 guanidinyl Chemical group 0.000 claims description 66
- 239000000203 mixture Substances 0.000 claims description 57
- 229910052757 nitrogen Inorganic materials 0.000 claims description 42
- 125000001424 substituent group Chemical group 0.000 claims description 37
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 36
- 229910052799 carbon Inorganic materials 0.000 claims description 32
- 125000006648 (C1-C8) haloalkyl group Chemical group 0.000 claims description 30
- 125000003118 aryl group Chemical group 0.000 claims description 30
- 229910052739 hydrogen Inorganic materials 0.000 claims description 30
- 239000003814 drug Substances 0.000 claims description 29
- 238000000034 method Methods 0.000 claims description 29
- 101710089372 Programmed cell death protein 1 Proteins 0.000 claims description 28
- 229910052736 halogen Inorganic materials 0.000 claims description 28
- 239000003795 chemical substances by application Substances 0.000 claims description 26
- 150000002367 halogens Chemical class 0.000 claims description 26
- 125000005842 heteroatom Chemical group 0.000 claims description 25
- 125000000623 heterocyclic group Chemical group 0.000 claims description 25
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 24
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 20
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 20
- 206010028980 Neoplasm Diseases 0.000 claims description 19
- 239000001257 hydrogen Substances 0.000 claims description 19
- 229910052717 sulfur Inorganic materials 0.000 claims description 17
- 239000002246 antineoplastic agent Substances 0.000 claims description 16
- 229910052760 oxygen Inorganic materials 0.000 claims description 16
- 125000003342 alkenyl group Chemical group 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 14
- 201000010099 disease Diseases 0.000 claims description 14
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- 150000001413 amino acids Chemical class 0.000 claims description 13
- 125000001072 heteroaryl group Chemical group 0.000 claims description 12
- 229940124597 therapeutic agent Drugs 0.000 claims description 12
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 11
- 125000004429 atom Chemical group 0.000 claims description 11
- 201000011510 cancer Diseases 0.000 claims description 11
- 229940127089 cytotoxic agent Drugs 0.000 claims description 11
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 11
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 11
- 125000002947 alkylene group Chemical group 0.000 claims description 10
- 208000035475 disorder Diseases 0.000 claims description 10
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 239000002955 immunomodulating agent Substances 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 125000000304 alkynyl group Chemical group 0.000 claims description 7
- 239000004037 angiogenesis inhibitor Substances 0.000 claims description 7
- 230000028993 immune response Effects 0.000 claims description 7
- 230000001404 mediated effect Effects 0.000 claims description 7
- 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims description 6
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 6
- 230000003510 anti-fibrotic effect Effects 0.000 claims description 5
- 230000001028 anti-proliverative effect Effects 0.000 claims description 5
- 239000004599 antimicrobial Substances 0.000 claims description 5
- 229940034982 antineoplastic agent Drugs 0.000 claims description 5
- 239000003443 antiviral agent Substances 0.000 claims description 5
- 239000002254 cytotoxic agent Substances 0.000 claims description 5
- 231100000599 cytotoxic agent Toxicity 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 230000014509 gene expression Effects 0.000 claims description 5
- 208000015181 infectious disease Diseases 0.000 claims description 5
- 230000003439 radiotherapeutic effect Effects 0.000 claims description 5
- 238000001959 radiotherapy Methods 0.000 claims description 5
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 4
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims description 4
- 201000009030 Carcinoma Diseases 0.000 claims description 4
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 claims description 4
- 206010009944 Colon cancer Diseases 0.000 claims description 4
- 206010025323 Lymphomas Diseases 0.000 claims description 4
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims description 4
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 4
- 206010060862 Prostate cancer Diseases 0.000 claims description 4
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 4
- 208000006265 Renal cell carcinoma Diseases 0.000 claims description 4
- 206010041067 Small cell lung cancer Diseases 0.000 claims description 4
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 4
- 210000003169 central nervous system Anatomy 0.000 claims description 4
- 206010017758 gastric cancer Diseases 0.000 claims description 4
- 230000002401 inhibitory effect Effects 0.000 claims description 4
- 201000001441 melanoma Diseases 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 4
- 208000003154 papilloma Diseases 0.000 claims description 4
- 125000003386 piperidinyl group Chemical group 0.000 claims description 4
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 4
- 201000011549 stomach cancer Diseases 0.000 claims description 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 3
- 208000035473 Communicable disease Diseases 0.000 claims description 3
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims description 3
- 206010027476 Metastases Diseases 0.000 claims description 3
- 241001631646 Papillomaviridae Species 0.000 claims description 3
- 206010039491 Sarcoma Diseases 0.000 claims description 3
- 208000009956 adenocarcinoma Diseases 0.000 claims description 3
- 125000005213 alkyl heteroaryl group Chemical group 0.000 claims description 3
- 239000013059 antihormonal agent Substances 0.000 claims description 3
- 125000002393 azetidinyl group Chemical group 0.000 claims description 3
- 230000010261 cell growth Effects 0.000 claims description 3
- 230000004663 cell proliferation Effects 0.000 claims description 3
- 230000001684 chronic effect Effects 0.000 claims description 3
- 230000002708 enhancing effect Effects 0.000 claims description 3
- 206010022000 influenza Diseases 0.000 claims description 3
- 208000032839 leukemia Diseases 0.000 claims description 3
- 230000009401 metastasis Effects 0.000 claims description 3
- 125000002757 morpholinyl group Chemical group 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
- SBYHFKPVCBCYGV-UHFFFAOYSA-N quinuclidine Chemical compound C1CC2CCN1CC2 SBYHFKPVCBCYGV-UHFFFAOYSA-N 0.000 claims description 3
- 230000019491 signal transduction Effects 0.000 claims description 3
- 208000000587 small cell lung carcinoma Diseases 0.000 claims description 3
- 238000006467 substitution reaction Methods 0.000 claims description 3
- 241001529453 unidentified herpesvirus Species 0.000 claims description 3
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 2
- 125000001054 5 membered carbocyclic group Chemical group 0.000 claims description 2
- 125000004008 6 membered carbocyclic group Chemical group 0.000 claims description 2
- DGGKXQQCVPAUEA-UHFFFAOYSA-N 8-azabicyclo[3.2.1]octane Chemical compound C1CCC2CCC1N2 DGGKXQQCVPAUEA-UHFFFAOYSA-N 0.000 claims description 2
- 206010000830 Acute leukaemia Diseases 0.000 claims description 2
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 claims description 2
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 claims description 2
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 2
- 208000003200 Adenoma Diseases 0.000 claims description 2
- 206010001233 Adenoma benign Diseases 0.000 claims description 2
- 201000003076 Angiosarcoma Diseases 0.000 claims description 2
- 208000003950 B-cell lymphoma Diseases 0.000 claims description 2
- 208000035143 Bacterial infection Diseases 0.000 claims description 2
- 206010004146 Basal cell carcinoma Diseases 0.000 claims description 2
- 206010004593 Bile duct cancer Diseases 0.000 claims description 2
- 206010005003 Bladder cancer Diseases 0.000 claims description 2
- 206010005949 Bone cancer Diseases 0.000 claims description 2
- 208000018084 Bone neoplasm Diseases 0.000 claims description 2
- 206010006143 Brain stem glioma Diseases 0.000 claims description 2
- 206010006187 Breast cancer Diseases 0.000 claims description 2
- 208000026310 Breast neoplasm Diseases 0.000 claims description 2
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims description 2
- 206010007953 Central nervous system lymphoma Diseases 0.000 claims description 2
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 2
- 201000005262 Chondroma Diseases 0.000 claims description 2
- 208000005243 Chondrosarcoma Diseases 0.000 claims description 2
- 208000006332 Choriocarcinoma Diseases 0.000 claims description 2
- 206010048832 Colon adenoma Diseases 0.000 claims description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 2
- 201000005171 Cystadenoma Diseases 0.000 claims description 2
- 208000001976 Endocrine Gland Neoplasms Diseases 0.000 claims description 2
- 206010014733 Endometrial cancer Diseases 0.000 claims description 2
- 206010014759 Endometrial neoplasm Diseases 0.000 claims description 2
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 2
- 201000008808 Fibrosarcoma Diseases 0.000 claims description 2
- 206010017533 Fungal infection Diseases 0.000 claims description 2
- 201000003741 Gastrointestinal carcinoma Diseases 0.000 claims description 2
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 claims description 2
- 208000002250 Hematologic Neoplasms Diseases 0.000 claims description 2
- 208000005176 Hepatitis C Diseases 0.000 claims description 2
- 208000005331 Hepatitis D Diseases 0.000 claims description 2
- 208000017604 Hodgkin disease Diseases 0.000 claims description 2
- 208000010747 Hodgkins lymphoma Diseases 0.000 claims description 2
- 208000007766 Kaposi sarcoma Diseases 0.000 claims description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 2
- 208000018142 Leiomyosarcoma Diseases 0.000 claims description 2
- 206010024612 Lipoma Diseases 0.000 claims description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- 206010025219 Lymphangioma Diseases 0.000 claims description 2
- 206010052178 Lymphocytic lymphoma Diseases 0.000 claims description 2
- 208000032271 Malignant tumor of penis Diseases 0.000 claims description 2
- 208000002030 Merkel cell carcinoma Diseases 0.000 claims description 2
- 206010027406 Mesothelioma Diseases 0.000 claims description 2
- 208000034578 Multiple myelomas Diseases 0.000 claims description 2
- 208000031888 Mycoses Diseases 0.000 claims description 2
- 201000003793 Myelodysplastic syndrome Diseases 0.000 claims description 2
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 2
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 claims description 2
- 206010061306 Nasopharyngeal cancer Diseases 0.000 claims description 2
- 206010029266 Neuroendocrine carcinoma of the skin Diseases 0.000 claims description 2
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 2
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 2
- 206010033128 Ovarian cancer Diseases 0.000 claims description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 2
- 208000000821 Parathyroid Neoplasms Diseases 0.000 claims description 2
- 206010061336 Pelvic neoplasm Diseases 0.000 claims description 2
- 208000002471 Penile Neoplasms Diseases 0.000 claims description 2
- 206010034299 Penile cancer Diseases 0.000 claims description 2
- 208000007913 Pituitary Neoplasms Diseases 0.000 claims description 2
- 201000005746 Pituitary adenoma Diseases 0.000 claims description 2
- 206010061538 Pituitary tumour benign Diseases 0.000 claims description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 2
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 claims description 2
- 208000034541 Rare lymphatic malformation Diseases 0.000 claims description 2
- 208000015634 Rectal Neoplasms Diseases 0.000 claims description 2
- 206010038389 Renal cancer Diseases 0.000 claims description 2
- 208000005678 Rhabdomyoma Diseases 0.000 claims description 2
- 206010040047 Sepsis Diseases 0.000 claims description 2
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 2
- 208000021712 Soft tissue sarcoma Diseases 0.000 claims description 2
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 claims description 2
- 206010042971 T-cell lymphoma Diseases 0.000 claims description 2
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 claims description 2
- 208000024313 Testicular Neoplasms Diseases 0.000 claims description 2
- 206010057644 Testis cancer Diseases 0.000 claims description 2
- 208000037432 Thymic tumor Diseases 0.000 claims description 2
- 208000000728 Thymus Neoplasms Diseases 0.000 claims description 2
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 2
- 208000023915 Ureteral Neoplasms Diseases 0.000 claims description 2
- 206010046392 Ureteric cancer Diseases 0.000 claims description 2
- 206010046431 Urethral cancer Diseases 0.000 claims description 2
- 206010046458 Urethral neoplasms Diseases 0.000 claims description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 2
- 208000002495 Uterine Neoplasms Diseases 0.000 claims description 2
- 201000005969 Uveal melanoma Diseases 0.000 claims description 2
- 208000036142 Viral infection Diseases 0.000 claims description 2
- 206010047741 Vulval cancer Diseases 0.000 claims description 2
- 208000004354 Vulvar Neoplasms Diseases 0.000 claims description 2
- 208000008383 Wilms tumor Diseases 0.000 claims description 2
- 201000005188 adrenal gland cancer Diseases 0.000 claims description 2
- 208000024447 adrenal gland neoplasm Diseases 0.000 claims description 2
- 208000022362 bacterial infectious disease Diseases 0.000 claims description 2
- 208000026900 bile duct neoplasm Diseases 0.000 claims description 2
- 208000003362 bronchogenic carcinoma Diseases 0.000 claims description 2
- 201000010881 cervical cancer Diseases 0.000 claims description 2
- 208000024207 chronic leukemia Diseases 0.000 claims description 2
- 208000029742 colonic neoplasm Diseases 0.000 claims description 2
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 claims description 2
- 208000017763 cutaneous neuroendocrine carcinoma Diseases 0.000 claims description 2
- 208000002445 cystadenocarcinoma Diseases 0.000 claims description 2
- 201000004101 esophageal cancer Diseases 0.000 claims description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
- 208000021045 exocrine pancreatic carcinoma Diseases 0.000 claims description 2
- 206010016629 fibroma Diseases 0.000 claims description 2
- 208000005017 glioblastoma Diseases 0.000 claims description 2
- 201000010536 head and neck cancer Diseases 0.000 claims description 2
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 2
- 201000000459 head and neck squamous cell carcinoma Diseases 0.000 claims description 2
- 201000011066 hemangioma Diseases 0.000 claims description 2
- 208000006454 hepatitis Diseases 0.000 claims description 2
- 231100000283 hepatitis Toxicity 0.000 claims description 2
- 208000002672 hepatitis B Diseases 0.000 claims description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- 208000026278 immune system disease Diseases 0.000 claims description 2
- 208000027866 inflammatory disease Diseases 0.000 claims description 2
- 201000002313 intestinal cancer Diseases 0.000 claims description 2
- 201000010982 kidney cancer Diseases 0.000 claims description 2
- 201000010260 leiomyoma Diseases 0.000 claims description 2
- 206010024627 liposarcoma Diseases 0.000 claims description 2
- 210000004185 liver Anatomy 0.000 claims description 2
- 201000005202 lung cancer Diseases 0.000 claims description 2
- 208000020816 lung neoplasm Diseases 0.000 claims description 2
- 201000008443 lung non-squamous non-small cell carcinoma Diseases 0.000 claims description 2
- 208000012804 lymphangiosarcoma Diseases 0.000 claims description 2
- 208000029559 malignant endocrine neoplasm Diseases 0.000 claims description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 2
- 206010027191 meningioma Diseases 0.000 claims description 2
- 201000011216 nasopharynx carcinoma Diseases 0.000 claims description 2
- 208000025402 neoplasm of esophagus Diseases 0.000 claims description 2
- 201000008026 nephroblastoma Diseases 0.000 claims description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 2
- 208000008798 osteoma Diseases 0.000 claims description 2
- 201000008968 osteosarcoma Diseases 0.000 claims description 2
- 201000002528 pancreatic cancer Diseases 0.000 claims description 2
- 201000008129 pancreatic ductal adenocarcinoma Diseases 0.000 claims description 2
- 201000010198 papillary carcinoma Diseases 0.000 claims description 2
- 208000021310 pituitary gland adenoma Diseases 0.000 claims description 2
- 208000004333 pleomorphic adenoma Diseases 0.000 claims description 2
- 208000016800 primary central nervous system lymphoma Diseases 0.000 claims description 2
- 206010038038 rectal cancer Diseases 0.000 claims description 2
- 201000001275 rectum cancer Diseases 0.000 claims description 2
- 201000009410 rhabdomyosarcoma Diseases 0.000 claims description 2
- 210000003491 skin Anatomy 0.000 claims description 2
- 201000000849 skin cancer Diseases 0.000 claims description 2
- 206010041823 squamous cell carcinoma Diseases 0.000 claims description 2
- 201000003120 testicular cancer Diseases 0.000 claims description 2
- 201000009377 thymus cancer Diseases 0.000 claims description 2
- 201000002510 thyroid cancer Diseases 0.000 claims description 2
- 206010044412 transitional cell carcinoma Diseases 0.000 claims description 2
- 208000022271 tubular adenoma Diseases 0.000 claims description 2
- 230000005747 tumor angiogenesis Effects 0.000 claims description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 2
- 201000011294 ureter cancer Diseases 0.000 claims description 2
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 2
- 206010046766 uterine cancer Diseases 0.000 claims description 2
- 206010046885 vaginal cancer Diseases 0.000 claims description 2
- 208000013139 vaginal neoplasm Diseases 0.000 claims description 2
- 230000009385 viral infection Effects 0.000 claims description 2
- 201000005102 vulva cancer Diseases 0.000 claims description 2
- 102100023990 60S ribosomal protein L17 Human genes 0.000 claims 2
- QPEJAHMNOVMSOZ-UHFFFAOYSA-N 2-azaspiro[3.3]heptane Chemical compound C1CCC21CNC2 QPEJAHMNOVMSOZ-UHFFFAOYSA-N 0.000 claims 1
- 208000033116 Asbestos intoxication Diseases 0.000 claims 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims 1
- 206010006417 Bronchial carcinoma Diseases 0.000 claims 1
- 201000009051 Embryonal Carcinoma Diseases 0.000 claims 1
- 208000001258 Hemangiosarcoma Diseases 0.000 claims 1
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 claims 1
- 229910018828 PO3H2 Inorganic materials 0.000 claims 1
- 206010003441 asbestosis Diseases 0.000 claims 1
- 210000005252 bulbus oculi Anatomy 0.000 claims 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims 1
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 claims 1
- 208000010932 epithelial neoplasm Diseases 0.000 claims 1
- 201000001343 fallopian tube carcinoma Diseases 0.000 claims 1
- 230000003325 follicular Effects 0.000 claims 1
- 208000026045 malignant tumor of parathyroid gland Diseases 0.000 claims 1
- 230000000926 neurological effect Effects 0.000 claims 1
- 125000004193 piperazinyl group Chemical group 0.000 claims 1
- 230000004936 stimulating effect Effects 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 63
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 62
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 61
- 239000011541 reaction mixture Substances 0.000 description 44
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 32
- 235000019439 ethyl acetate Nutrition 0.000 description 31
- 239000000243 solution Substances 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
- 102100040678 Programmed cell death protein 1 Human genes 0.000 description 26
- 229910004298 SiO 2 Inorganic materials 0.000 description 22
- 238000003818 flash chromatography Methods 0.000 description 22
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
- 108010074708 B7-H1 Antigen Proteins 0.000 description 18
- 102000008096 B7-H1 Antigen Human genes 0.000 description 18
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 17
- 239000013058 crude material Substances 0.000 description 17
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 16
- 235000019341 magnesium sulphate Nutrition 0.000 description 16
- 229940079593 drug Drugs 0.000 description 15
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 14
- 229940002612 prodrug Drugs 0.000 description 14
- 239000000651 prodrug Substances 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- 239000002253 acid Substances 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 239000000725 suspension Substances 0.000 description 12
- 238000005481 NMR spectroscopy Methods 0.000 description 11
- 239000012043 crude product Substances 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 239000004480 active ingredient Substances 0.000 description 10
- 150000002148 esters Chemical class 0.000 description 10
- 239000003112 inhibitor Substances 0.000 description 10
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 description 10
- 229920006395 saturated elastomer Polymers 0.000 description 10
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 9
- 229940024606 amino acid Drugs 0.000 description 9
- 235000001014 amino acid Nutrition 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 150000002431 hydrogen Chemical class 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- GZPHSAQLYPIAIN-UHFFFAOYSA-N 3-pyridinecarbonitrile Chemical compound N#CC1=CC=CN=C1 GZPHSAQLYPIAIN-UHFFFAOYSA-N 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 8
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 238000002953 preparative HPLC Methods 0.000 description 8
- 229960001153 serine Drugs 0.000 description 8
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 8
- 230000001225 therapeutic effect Effects 0.000 description 8
- SAUFKLQHUAGUNO-HNNXBMFYSA-N 4-[[(1S)-4-bromo-2,3-dihydro-1H-inden-1-yl]oxy]-5-chloro-2-hydroxybenzaldehyde Chemical compound BrC1=C2CC[C@@H](C2=CC=C1)OC1=CC(=C(C=O)C=C1Cl)O SAUFKLQHUAGUNO-HNNXBMFYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 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 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 238000009472 formulation Methods 0.000 description 7
- 230000003993 interaction Effects 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 7
- 208000024891 symptom Diseases 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- 238000011282 treatment Methods 0.000 description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 7
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 6
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 6
- 229920001213 Polysorbate 20 Polymers 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000005557 antagonist Substances 0.000 description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 229910052796 boron Inorganic materials 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 230000008878 coupling Effects 0.000 description 6
- 238000010168 coupling process Methods 0.000 description 6
- 238000005859 coupling reaction Methods 0.000 description 6
- 239000000796 flavoring agent Substances 0.000 description 6
- 125000004404 heteroalkyl group Chemical group 0.000 description 6
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 230000036961 partial effect Effects 0.000 description 6
- 230000037361 pathway Effects 0.000 description 6
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 6
- 229920001223 polyethylene glycol Polymers 0.000 description 6
- 229920000642 polymer Polymers 0.000 description 6
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 6
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 210000002966 serum Anatomy 0.000 description 6
- 235000009518 sodium iodide Nutrition 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- TYFQFVWCELRYAO-UHFFFAOYSA-N suberic acid Chemical compound OC(=O)CCCCCCC(O)=O TYFQFVWCELRYAO-UHFFFAOYSA-N 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 239000003765 sweetening agent Substances 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- 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 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 239000004473 Threonine Substances 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 125000002619 bicyclic group Chemical group 0.000 description 5
- 239000007859 condensation product Substances 0.000 description 5
- 235000014113 dietary fatty acids Nutrition 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000000194 fatty acid Substances 0.000 description 5
- 229930195729 fatty acid Natural products 0.000 description 5
- 150000004665 fatty acids Chemical class 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 235000003599 food sweetener Nutrition 0.000 description 5
- 239000004615 ingredient Substances 0.000 description 5
- 230000000155 isotopic effect Effects 0.000 description 5
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 5
- 235000011056 potassium acetate Nutrition 0.000 description 5
- 230000004850 protein–protein interaction Effects 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 235000015424 sodium Nutrition 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 229960002898 threonine Drugs 0.000 description 5
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 4
- ZPHMIBHXIIWOLP-UHFFFAOYSA-N 1-bromo-3-(3-chloropropoxy)-2-methylbenzene Chemical compound BrC1=C(C(=CC=C1)OCCCCl)C ZPHMIBHXIIWOLP-UHFFFAOYSA-N 0.000 description 4
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- AKNITNDYEBNBSM-UHFFFAOYSA-N ClCCCOC=1C(=C(C=CC=1)B1OC(C(O1)(C)C)(C)C)C Chemical compound ClCCCOC=1C(=C(C=CC=1)B1OC(C(O1)(C)C)(C)C)C AKNITNDYEBNBSM-UHFFFAOYSA-N 0.000 description 4
- 238000002965 ELISA Methods 0.000 description 4
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical class C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 4
- 101000914484 Homo sapiens T-lymphocyte activation antigen CD80 Proteins 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 239000007832 Na2SO4 Substances 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- 102100027222 T-lymphocyte activation antigen CD80 Human genes 0.000 description 4
- 235000010443 alginic acid Nutrition 0.000 description 4
- 229920000615 alginic acid Polymers 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 239000007900 aqueous suspension Substances 0.000 description 4
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 4
- 125000002837 carbocyclic group Chemical group 0.000 description 4
- 239000003638 chemical reducing agent Substances 0.000 description 4
- 239000003086 colorant Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 239000002270 dispersing agent Substances 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 235000013355 food flavoring agent Nutrition 0.000 description 4
- 150000002430 hydrocarbons Chemical group 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- LAQPNDIUHRHNCV-UHFFFAOYSA-N isophthalonitrile Chemical compound N#CC1=CC=CC(C#N)=C1 LAQPNDIUHRHNCV-UHFFFAOYSA-N 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 230000002285 radioactive effect Effects 0.000 description 4
- 238000006268 reductive amination reaction Methods 0.000 description 4
- 125000004434 sulfur atom Chemical group 0.000 description 4
- 239000000375 suspending agent Substances 0.000 description 4
- YAPQBXQYLJRXSA-UHFFFAOYSA-N theobromine Chemical compound CN1C(=O)NC(=O)C2=C1N=CN2C YAPQBXQYLJRXSA-UHFFFAOYSA-N 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 229910052723 transition metal Inorganic materials 0.000 description 4
- 150000003624 transition metals Chemical class 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- 239000000080 wetting agent Substances 0.000 description 4
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 3
- ZIMLRKWQDLVPEK-UHFFFAOYSA-N 1-[4-(4-chloro-3-methoxyphenyl)piperazin-1-yl]-2-[3-(1H-imidazol-2-yl)pyrazolo[3,4-b]pyridin-1-yl]ethanone Chemical compound C1=C(Cl)C(OC)=CC(N2CCN(CC2)C(=O)CN2C3=NC=CC=C3C(C=3NC=CN=3)=N2)=C1 ZIMLRKWQDLVPEK-UHFFFAOYSA-N 0.000 description 3
- DCMBLUHPVYNRBQ-UHFFFAOYSA-N 1-bromo-3-(3-bromopropoxy)-2-chlorobenzene Chemical compound BrC1=C(C(=CC=C1)OCCCBr)Cl DCMBLUHPVYNRBQ-UHFFFAOYSA-N 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- LUUMLYXKTPBTQR-UHFFFAOYSA-N 4-chloro-n-[5-methyl-2-(7h-pyrrolo[2,3-d]pyrimidine-4-carbonyl)pyridin-3-yl]-3-(trifluoromethyl)benzenesulfonamide Chemical compound C=1C(C)=CN=C(C(=O)C=2C=3C=CNC=3N=CN=2)C=1NS(=O)(=O)C1=CC=C(Cl)C(C(F)(F)F)=C1 LUUMLYXKTPBTQR-UHFFFAOYSA-N 0.000 description 3
- JRWROCIMSDXGOZ-UHFFFAOYSA-N 4-tert-butyl-n-[4-chloro-2-(1-oxidopyridin-1-ium-4-carbonyl)phenyl]benzenesulfonamide Chemical compound C1=CC(C(C)(C)C)=CC=C1S(=O)(=O)NC1=CC=C(Cl)C=C1C(=O)C1=CC=[N+]([O-])C=C1 JRWROCIMSDXGOZ-UHFFFAOYSA-N 0.000 description 3
- 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 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 3
- 239000004475 Arginine Substances 0.000 description 3
- 239000005711 Benzoic acid Substances 0.000 description 3
- MHIQHLAGUHABIV-UHFFFAOYSA-N BrC=1C(=C(OCCCN2CC(C2)O)C=CC=1)Cl Chemical compound BrC=1C(=C(OCCCN2CC(C2)O)C=CC=1)Cl MHIQHLAGUHABIV-UHFFFAOYSA-N 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 229920000084 Gum arabic Polymers 0.000 description 3
- 102100034458 Hepatitis A virus cellular receptor 2 Human genes 0.000 description 3
- 101710083479 Hepatitis A virus cellular receptor 2 homolog Proteins 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 101000666896 Homo sapiens V-type immunoglobulin domain-containing suppressor of T-cell activation Proteins 0.000 description 3
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 3
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 3
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical class NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 3
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 3
- 239000004472 Lysine Chemical class 0.000 description 3
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Chemical class NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
- 101100407308 Mus musculus Pdcd1lg2 gene Proteins 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- 108700030875 Programmed Cell Death 1 Ligand 2 Proteins 0.000 description 3
- 102100024213 Programmed cell death 1 ligand 2 Human genes 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 3
- 229940126547 T-cell immunoglobulin mucin-3 Drugs 0.000 description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 3
- 102100038282 V-type immunoglobulin domain-containing suppressor of T-cell activation Human genes 0.000 description 3
- 241000700605 Viruses Species 0.000 description 3
- NXQGGXCHGDYOHB-UHFFFAOYSA-L [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) Substances [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 3
- 235000010489 acacia gum Nutrition 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- IAJILQKETJEXLJ-RSJOWCBRSA-N aldehydo-D-galacturonic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-RSJOWCBRSA-N 0.000 description 3
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 3
- 229940072056 alginate Drugs 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 3
- 229960003121 arginine Drugs 0.000 description 3
- PUKBOVABABRILL-YZNIXAGQSA-N avacopan Chemical compound C1=C(C(F)(F)F)C(C)=CC=C1NC(=O)[C@@H]1[C@H](C=2C=CC(NC3CCCC3)=CC=2)N(C(=O)C=2C(=CC=CC=2C)F)CCC1 PUKBOVABABRILL-YZNIXAGQSA-N 0.000 description 3
- 229950001740 avacopan Drugs 0.000 description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 3
- 229940092714 benzenesulfonic acid Drugs 0.000 description 3
- 235000010233 benzoic acid Nutrition 0.000 description 3
- 230000002051 biphasic effect Effects 0.000 description 3
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- JCWIWBWXCVGEAN-UHFFFAOYSA-L cyclopentyl(diphenyl)phosphane;dichloropalladium;iron Chemical compound [Fe].Cl[Pd]Cl.[CH]1[CH][CH][CH][C]1P(C=1C=CC=CC=1)C1=CC=CC=C1.[CH]1[CH][CH][CH][C]1P(C=1C=CC=CC=1)C1=CC=CC=C1 JCWIWBWXCVGEAN-UHFFFAOYSA-L 0.000 description 3
- 238000007872 degassing Methods 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 238000000132 electrospray ionisation Methods 0.000 description 3
- IJJVMEJXYNJXOJ-UHFFFAOYSA-N fluquinconazole Chemical compound C=1C=C(Cl)C=C(Cl)C=1N1C(=O)C2=CC(F)=CC=C2N=C1N1C=NC=N1 IJJVMEJXYNJXOJ-UHFFFAOYSA-N 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 239000001530 fumaric acid Substances 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 229940097043 glucuronic acid Drugs 0.000 description 3
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 229940121354 immunomodulator Drugs 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 229940057995 liquid paraffin Drugs 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 229910052749 magnesium Inorganic materials 0.000 description 3
- 229960002510 mandelic acid Drugs 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 229940098779 methanesulfonic acid Drugs 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 239000004006 olive oil Substances 0.000 description 3
- 235000008390 olive oil Nutrition 0.000 description 3
- 125000003367 polycyclic group Chemical group 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 150000003141 primary amines Chemical class 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 229910052710 silicon Inorganic materials 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 239000011975 tartaric acid Substances 0.000 description 3
- 235000002906 tartaric acid Nutrition 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
- 238000000844 transformation Methods 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- QPMSJEFZULFYTB-PGMHMLKASA-N (3r)-pyrrolidin-3-ol;hydrochloride Chemical compound Cl.O[C@@H]1CCNC1 QPMSJEFZULFYTB-PGMHMLKASA-N 0.000 description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 2
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-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
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 2
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 2
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 2
- 229940013085 2-diethylaminoethanol Drugs 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- ILFQCLAIWIDRPN-INIZCTEOSA-N 4-[[(1S)-4-bromo-2,3-dihydro-1H-inden-1-yl]oxy]-5-chloro-2-ethoxybenzaldehyde Chemical compound CCOC1=CC(O[C@H]2CCC3=C2C=CC=C3Br)=C(Cl)C=C1C=O ILFQCLAIWIDRPN-INIZCTEOSA-N 0.000 description 2
- RNXQQZNOSYBFTN-UHFFFAOYSA-N 4-bromo-2,3-dihydro-1h-inden-1-ol Chemical class C1=CC=C(Br)C2=C1C(O)CC2 RNXQQZNOSYBFTN-UHFFFAOYSA-N 0.000 description 2
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 2
- 244000215068 Acacia senegal Species 0.000 description 2
- 235000006491 Acacia senegal Nutrition 0.000 description 2
- 101150051188 Adora2a gene Proteins 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 2
- KWIUHFFTVRNATP-UHFFFAOYSA-N Betaine Natural products C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 description 2
- 108091033409 CRISPR Proteins 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 2
- 108010019670 Chimeric Antigen Receptors Proteins 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- JNDFHCSLERQLSX-HKBQPEDESA-N ClC1=CC(=C(OCC=2C=NC=C(C#N)C=2)C=C1O[C@H]1CCC2=C(C=CC=C12)C1=C(C(=CC=C1)OCCCCl)C)C=O Chemical compound ClC1=CC(=C(OCC=2C=NC=C(C#N)C=2)C=C1O[C@H]1CCC2=C(C=CC=C12)C1=C(C(=CC=C1)OCCCCl)C)C=O JNDFHCSLERQLSX-HKBQPEDESA-N 0.000 description 2
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 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
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical group [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- 241000283086 Equidae Species 0.000 description 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 208000031886 HIV Infections Diseases 0.000 description 2
- 208000037357 HIV infectious disease Diseases 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 2
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 2
- KWIUHFFTVRNATP-UHFFFAOYSA-O N,N,N-trimethylglycinium Chemical compound C[N+](C)(C)CC(O)=O KWIUHFFTVRNATP-UHFFFAOYSA-O 0.000 description 2
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 2
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 2
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical class CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 2
- 235000019483 Peanut oil Nutrition 0.000 description 2
- 241001494479 Pecora Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229920000954 Polyglycolide Polymers 0.000 description 2
- 241000288906 Primates Species 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 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 2
- 241000282887 Suidae Species 0.000 description 2
- 230000006044 T cell activation Effects 0.000 description 2
- 210000001744 T-lymphocyte Anatomy 0.000 description 2
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 2
- 229920001615 Tragacanth Polymers 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- PNDPGZBMCMUPRI-XXSWNUTMSA-N [125I][125I] Chemical compound [125I][125I] PNDPGZBMCMUPRI-XXSWNUTMSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 150000001350 alkyl halides Chemical class 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 2
- 230000003388 anti-hormonal effect Effects 0.000 description 2
- 239000000611 antibody drug conjugate Substances 0.000 description 2
- 229940049595 antibody-drug conjugate Drugs 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000003886 aromatase inhibitor Substances 0.000 description 2
- 229940046844 aromatase inhibitors Drugs 0.000 description 2
- 150000001502 aryl halides Chemical class 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- GMWFCJXSQQHBPI-UHFFFAOYSA-N azetidin-3-ol Chemical compound OC1CNC1 GMWFCJXSQQHBPI-UHFFFAOYSA-N 0.000 description 2
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 2
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 2
- 229960003237 betaine Drugs 0.000 description 2
- 229960001948 caffeine Drugs 0.000 description 2
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 235000010216 calcium carbonate Nutrition 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 2
- 229960001231 choline Drugs 0.000 description 2
- 229960004106 citric acid Drugs 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 229910052805 deuterium Inorganic materials 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 239000000890 drug combination Substances 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 229960002442 glucosamine Drugs 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 125000001188 haloalkyl group Chemical group 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 125000004474 heteroalkylene group Chemical group 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 2
- XGIHQYAWBCFNPY-AZOCGYLKSA-N hydrabamine Chemical class C([C@@H]12)CC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC[C@@]1(C)CNCCNC[C@@]1(C)[C@@H]2CCC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC1 XGIHQYAWBCFNPY-AZOCGYLKSA-N 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 229940044173 iodine-125 Drugs 0.000 description 2
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical class CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229910001509 metal bromide Inorganic materials 0.000 description 2
- 229910001511 metal iodide Inorganic materials 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- GVGCUCJTUSOZKP-UHFFFAOYSA-N nitrogen trifluoride Chemical class FN(F)F GVGCUCJTUSOZKP-UHFFFAOYSA-N 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 239000000312 peanut oil Substances 0.000 description 2
- 150000002989 phenols Chemical class 0.000 description 2
- 230000004962 physiological condition Effects 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229920000747 poly(lactic acid) Polymers 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 2
- 229960004919 procaine Drugs 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- 230000006340 racemization Effects 0.000 description 2
- 125000006413 ring segment Chemical group 0.000 description 2
- 150000003335 secondary amines Chemical class 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 2
- 235000011069 sorbitan monooleate Nutrition 0.000 description 2
- 239000001593 sorbitan monooleate Substances 0.000 description 2
- 229940035049 sorbitan monooleate Drugs 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 125000003003 spiro group Chemical group 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 229960001367 tartaric acid Drugs 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 2
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 2
- 125000003831 tetrazolyl group Chemical group 0.000 description 2
- 229960004559 theobromine Drugs 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 125000005309 thioalkoxy group Chemical group 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 238000011269 treatment regimen 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
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 2
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 229910052722 tritium Inorganic materials 0.000 description 2
- 229960000281 trometamol Drugs 0.000 description 2
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 2
- 229960005486 vaccine Drugs 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 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 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- CYEXXDYQJPRMIQ-UHFFFAOYSA-N (5-cyanopyridin-3-yl)boronic acid Chemical compound OB(O)C1=CN=CC(C#N)=C1 CYEXXDYQJPRMIQ-UHFFFAOYSA-N 0.000 description 1
- KFJLLOJCPFYWRV-WCCKRBBISA-N (5s)-5-aminopiperidin-2-one;hydrochloride Chemical compound Cl.N[C@H]1CCC(=O)NC1 KFJLLOJCPFYWRV-WCCKRBBISA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- VEFLKXRACNJHOV-UHFFFAOYSA-N 1,3-dibromopropane Chemical compound BrCCCBr VEFLKXRACNJHOV-UHFFFAOYSA-N 0.000 description 1
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- 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
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 1
- ZPSJGADGUYYRKE-UHFFFAOYSA-N 2H-pyran-2-one Chemical compound O=C1C=CC=CO1 ZPSJGADGUYYRKE-UHFFFAOYSA-N 0.000 description 1
- UAIUNKRWKOVEES-UHFFFAOYSA-N 3,3',5,5'-tetramethylbenzidine Chemical compound CC1=C(N)C(C)=CC(C=2C=C(C)C(N)=C(C)C=2)=C1 UAIUNKRWKOVEES-UHFFFAOYSA-N 0.000 description 1
- WPDXAMRGYMDTOV-UHFFFAOYSA-N 3-bromo-2-methylphenol Chemical compound CC1=C(O)C=CC=C1Br WPDXAMRGYMDTOV-UHFFFAOYSA-N 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- DBXBTMSZEOQQDU-UHFFFAOYSA-N 3-hydroxyisobutyric acid Chemical compound OCC(C)C(O)=O DBXBTMSZEOQQDU-UHFFFAOYSA-N 0.000 description 1
- JVQIKJMSUIMUDI-UHFFFAOYSA-N 3-pyrroline Chemical compound C1NCC=C1 JVQIKJMSUIMUDI-UHFFFAOYSA-N 0.000 description 1
- UCFSYHMCKWNKAH-UHFFFAOYSA-N 4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound CC1(C)OBOC1(C)C UCFSYHMCKWNKAH-UHFFFAOYSA-N 0.000 description 1
- GAMYYCRTACQSBR-UHFFFAOYSA-N 4-azabenzimidazole Chemical compound C1=CC=C2NC=NC2=N1 GAMYYCRTACQSBR-UHFFFAOYSA-N 0.000 description 1
- IXENWFQXVCOHAZ-UHFFFAOYSA-N 4-fluoropiperidine;hydrochloride Chemical compound Cl.FC1CCNCC1 IXENWFQXVCOHAZ-UHFFFAOYSA-N 0.000 description 1
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- QEBGPJKCHSERLZ-UHFFFAOYSA-N 5-(chloromethyl)benzene-1,3-dicarbonitrile Chemical compound ClCC1=CC(C#N)=CC(C#N)=C1 QEBGPJKCHSERLZ-UHFFFAOYSA-N 0.000 description 1
- LGCQUQNHKPLVMR-HKBQPEDESA-N 5-[4-chloro-5-[[(1S)-4-[2-chloro-3-[3-(3-hydroxyazetidin-1-yl)propoxy]phenyl]-2,3-dihydro-1H-inden-1-yl]oxy]-2-formylphenyl]pyridine-3-carbonitrile Chemical compound ClC1=CC(=C(C=C1O[C@H]1CCC2=C(C=CC=C12)C1=C(C(=CC=C1)OCCCN1CC(C1)O)Cl)C=1C=NC=C(C#N)C=1)C=O LGCQUQNHKPLVMR-HKBQPEDESA-N 0.000 description 1
- OZLGASHQESISLU-VWLOTQADSA-N 5-[[4-chloro-2-formyl-5-[[(1S)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl]oxy]phenoxy]methyl]pyridine-3-carbonitrile Chemical compound ClC1=CC(=C(OCC=2C=NC=C(C#N)C=2)C=C1O[C@H]1CCC2=C(C=CC=C12)B1OC(C(O1)(C)C)(C)C)C=O OZLGASHQESISLU-VWLOTQADSA-N 0.000 description 1
- AVRWMPRNRKHSRJ-ZMEFLVBSSA-N 5-[[4-chloro-5-[[(1S)-4-[3-[3-(4-fluoropiperidin-1-yl)propoxy]-2-methylphenyl]-2,3-dihydro-1H-inden-1-yl]oxy]-2-[[[(3S)-6-oxopiperidin-3-yl]amino]methyl]phenoxy]methyl]benzene-1,3-dicarbonitrile Chemical compound ClC1=CC(=C(OCC=2C=C(C=C(C#N)C=2)C#N)C=C1O[C@H]1CCC2=C(C=CC=C12)C1=C(C(=CC=C1)OCCCN1CCC(CC1)F)C)CN[C@@H]1CNC(CC1)=O AVRWMPRNRKHSRJ-ZMEFLVBSSA-N 0.000 description 1
- BDSZUQOQSLPLTI-NRFANRHFSA-N 5-[[5-[[(1S)-4-bromo-2,3-dihydro-1H-inden-1-yl]oxy]-4-chloro-2-formylphenoxy]methyl]pyridine-3-carbonitrile Chemical compound BrC1=C2CC[C@@H](C2=CC=C1)OC=1C(=CC(=C(OCC=2C=C(C=NC=2)C#N)C=1)C=O)Cl BDSZUQOQSLPLTI-NRFANRHFSA-N 0.000 description 1
- FJBSGFGJEPZSJN-IBGZPJMESA-N 5-chloro-2-hydroxy-4-[[(1S)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzaldehyde Chemical compound ClC=1C(=CC(=C(C=O)C=1)O)O[C@H]1CCC2=C(C=CC=C12)B1OC(C(O1)(C)C)(C)C FJBSGFGJEPZSJN-IBGZPJMESA-N 0.000 description 1
- AOHGVDVHAZPUBZ-UHFFFAOYSA-N 5-chloro-4-[[4-[3-(3-chloropropoxy)-2-methylphenyl]-2,3-dihydro-1H-inden-1-yl]oxy]-2-hydroxybenzaldehyde Chemical compound Cc1c(OCCCCl)cccc1-c1cccc2C(CCc12)Oc1cc(O)c(C=O)cc1Cl AOHGVDVHAZPUBZ-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 241001465677 Ancylostomatoidea Species 0.000 description 1
- 235000003911 Arachis Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 208000006400 Arbovirus Encephalitis Diseases 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 102100029822 B- and T-lymphocyte attenuator Human genes 0.000 description 1
- 241000223848 Babesia microti Species 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 241000193738 Bacillus anthracis Species 0.000 description 1
- 241000228405 Blastomyces dermatitidis Species 0.000 description 1
- DHKWRZDKGPKJFD-IERDGZPVSA-N BrC1=C2CC[C@@H](C2=CC=C1)OC1=CC(=C(C=O)C=C1Cl)OCCCN1C[C@@H](CC1)O Chemical compound BrC1=C2CC[C@@H](C2=CC=C1)OC1=CC(=C(C=O)C=C1Cl)OCCCN1C[C@@H](CC1)O DHKWRZDKGPKJFD-IERDGZPVSA-N 0.000 description 1
- VUYYMYUQTVRDMG-QFIPXVFZSA-N BrCCCOC=1C(=C(C=CC=1)C1=C2CC[C@@H](C2=CC=C1)OC1=CC(=C(C=O)C=C1Cl)O)Cl Chemical compound BrCCCOC=1C(=C(C=CC=1)C1=C2CC[C@@H](C2=CC=C1)OC1=CC(=C(C=O)C=C1Cl)O)Cl VUYYMYUQTVRDMG-QFIPXVFZSA-N 0.000 description 1
- QJMBGXHNMMXACW-NDEPHWFRSA-N BrCCCOC=1C(=C(C=CC=1)C1=C2CC[C@@H](C2=CC=C1)OC=1C(=CC(=C(C=1)C=1C=NC=C(C#N)C=1)C=O)Cl)Cl Chemical compound BrCCCOC=1C(=C(C=CC=1)C1=C2CC[C@@H](C2=CC=C1)OC=1C(=CC(=C(C=1)C=1C=NC=C(C#N)C=1)C=O)Cl)Cl QJMBGXHNMMXACW-NDEPHWFRSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 102100032957 C5a anaphylatoxin chemotactic receptor 1 Human genes 0.000 description 1
- 101710098483 C5a anaphylatoxin chemotactic receptor 1 Proteins 0.000 description 1
- 102100036008 CD48 antigen Human genes 0.000 description 1
- 238000010354 CRISPR gene editing Methods 0.000 description 1
- 108010021064 CTLA-4 Antigen Proteins 0.000 description 1
- 102000008203 CTLA-4 Antigen Human genes 0.000 description 1
- 229940045513 CTLA4 antagonist Drugs 0.000 description 1
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 1
- 102000000905 Cadherin Human genes 0.000 description 1
- 108050007957 Cadherin Proteins 0.000 description 1
- 206010058019 Cancer Pain Diseases 0.000 description 1
- OKTJSMMVPCPJKN-OUBTZVSYSA-N Carbon-13 Chemical compound [13C] OKTJSMMVPCPJKN-OUBTZVSYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 241000606161 Chlamydia Species 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- SUMKPJIVYGYIME-HDDYVPAUSA-N ClC1=C(O[C@H]2CCC3=C(C=CC=C23)C=2C(=C(OCCCN3CCC(CC3)O)C=CC=2)C)C=C(C(=C1)CN[C@H]1[C@H](CCCC1)O)OCCCN1C[C@@H](CC1)O Chemical compound ClC1=C(O[C@H]2CCC3=C(C=CC=C23)C=2C(=C(OCCCN3CCC(CC3)O)C=CC=2)C)C=C(C(=C1)CN[C@H]1[C@H](CCCC1)O)OCCCN1C[C@@H](CC1)O SUMKPJIVYGYIME-HDDYVPAUSA-N 0.000 description 1
- FVWYCSNWYAEQMS-XIFFEERXSA-N ClC1=CC(=C(OCC=2C=C(C=C(C#N)C=2)C#N)C=C1O[C@H]1CCC2=C(C=CC=C12)C1=C(C(=CC=C1)OCCCCl)C)C=O Chemical compound ClC1=CC(=C(OCC=2C=C(C=C(C#N)C=2)C#N)C=C1O[C@H]1CCC2=C(C=CC=C12)C1=C(C(=CC=C1)OCCCCl)C)C=O FVWYCSNWYAEQMS-XIFFEERXSA-N 0.000 description 1
- SRTKWIAUTGWRCY-LHEWISCISA-N ClC1=CC(=C(OCC=2C=C(C=C(C#N)C=2)C#N)C=C1O[C@H]1CCC2=C(C=CC=C12)C1=C(C(=CC=C1)OCCCN1CCC(CC1)F)C)C=O Chemical compound ClC1=CC(=C(OCC=2C=C(C=C(C#N)C=2)C#N)C=C1O[C@H]1CCC2=C(C=CC=C12)C1=C(C(=CC=C1)OCCCN1CCC(CC1)F)C)C=O SRTKWIAUTGWRCY-LHEWISCISA-N 0.000 description 1
- AFZLAAMESHCXLZ-LHEWISCISA-N ClC1=CC(=C(OCC=2C=C(C=C(C#N)C=2)C#N)C=C1O[C@H]1CCC2=C(C=CC=C12)C1=C(C(=CC=C1)OCCCN1CCC(CC1)O)C)C=O Chemical compound ClC1=CC(=C(OCC=2C=C(C=C(C#N)C=2)C#N)C=C1O[C@H]1CCC2=C(C=CC=C12)C1=C(C(=CC=C1)OCCCN1CCC(CC1)O)C)C=O AFZLAAMESHCXLZ-LHEWISCISA-N 0.000 description 1
- TYLWOIREQHRZJH-SANMLTNESA-N ClC=1C(=CC(=C(C=O)C=1)OCC)O[C@H]1CCC2=C(C=CC=C12)C1=C(C(=CC=C1)OCCCCl)C Chemical compound ClC=1C(=CC(=C(C=O)C=1)OCC)O[C@H]1CCC2=C(C=CC=C12)C1=C(C(=CC=C1)OCCCCl)C TYLWOIREQHRZJH-SANMLTNESA-N 0.000 description 1
- ARZZAEUZIORVJY-DJUQAAIZSA-N ClC=1C(=CC(=C(C=O)C=1)OCC)O[C@H]1CCC2=C(C=CC=C12)C1=C(C(=CC=C1)OCCCN1C[C@@H](CC1)O)C Chemical compound ClC=1C(=CC(=C(C=O)C=1)OCC)O[C@H]1CCC2=C(C=CC=C12)C1=C(C(=CC=C1)OCCCN1C[C@@H](CC1)O)C ARZZAEUZIORVJY-DJUQAAIZSA-N 0.000 description 1
- ASVPKNRVZOJUAN-XJFCNFDWSA-N ClC=1C(=CC(=C(C=O)C=1)OCCCN1C[C@@H](CC1)O)O[C@H]1CCC2=C(C=CC=C12)C1=C(C(=CC=C1)OCCCCl)C Chemical compound ClC=1C(=CC(=C(C=O)C=1)OCCCN1C[C@@H](CC1)O)O[C@H]1CCC2=C(C=CC=C12)C1=C(C(=CC=C1)OCCCCl)C ASVPKNRVZOJUAN-XJFCNFDWSA-N 0.000 description 1
- RMJTYONEKZMBSE-ZADIWHOSSA-N ClC=1C(=CC(=C(C=O)C=1)OCCCN1C[C@@H](CC1)O)O[C@H]1CCC2=C(C=CC=C12)C1=C(C(=CC=C1)OCCCN1CCC(CC1)O)C Chemical compound ClC=1C(=CC(=C(C=O)C=1)OCCCN1C[C@@H](CC1)O)O[C@H]1CCC2=C(C=CC=C12)C1=C(C(=CC=C1)OCCCN1CCC(CC1)O)C RMJTYONEKZMBSE-ZADIWHOSSA-N 0.000 description 1
- DERHUCRFODBIKQ-BAOFOTJISA-N ClC=1C(=CC(=C(CN[C@](C(=O)O)(CO)C)C=1)C=1C=NC=C(C=1)C#N)O[C@H]1CCC2=C(C=CC=C12)C1=C(C(=CC=C1)OCCCN1CC(C1)O)Cl Chemical compound ClC=1C(=CC(=C(CN[C@](C(=O)O)(CO)C)C=1)C=1C=NC=C(C=1)C#N)O[C@H]1CCC2=C(C=CC=C12)C1=C(C(=CC=C1)OCCCN1CC(C1)O)Cl DERHUCRFODBIKQ-BAOFOTJISA-N 0.000 description 1
- BVMKIPFXRSKXJJ-SRCNPLIFSA-N ClC=1C(=CC(=C(CN[C@](C(=O)O)(CO)C)C=1)OCC1=CC(=CC(=C1)C#N)C#N)O[C@H]1CCC2=C(C=CC=C12)C1=C(C(=CC=C1)OCCCN1CCC(CC1)O)C Chemical compound ClC=1C(=CC(=C(CN[C@](C(=O)O)(CO)C)C=1)OCC1=CC(=CC(=C1)C#N)C#N)O[C@H]1CCC2=C(C=CC=C12)C1=C(C(=CC=C1)OCCCN1CCC(CC1)O)C BVMKIPFXRSKXJJ-SRCNPLIFSA-N 0.000 description 1
- UXADYMMYESJBSC-AJCPBJRWSA-N ClC=1C(=CC(=C(CN[C@](C(=O)O)(CO)C)C=1)OCC=1C=NC=C(C=1)C#N)O[C@H]1CCC2=C(C=CC=C12)C1=C(C(=CC=C1)OCCCN1CC(C1)O)Cl Chemical compound ClC=1C(=CC(=C(CN[C@](C(=O)O)(CO)C)C=1)OCC=1C=NC=C(C=1)C#N)O[C@H]1CCC2=C(C=CC=C12)C1=C(C(=CC=C1)OCCCN1CC(C1)O)Cl UXADYMMYESJBSC-AJCPBJRWSA-N 0.000 description 1
- 241000223205 Coccidioides immitis Species 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
- 241000711573 Coronaviridae Species 0.000 description 1
- 241000709687 Coxsackievirus Species 0.000 description 1
- 241000223935 Cryptosporidium Species 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 241000725619 Dengue virus Species 0.000 description 1
- 241001466953 Echovirus Species 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241000709661 Enterovirus Species 0.000 description 1
- 241000991587 Enterovirus C Species 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 1
- 241000710831 Flavivirus Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 102100031351 Galectin-9 Human genes 0.000 description 1
- 101710121810 Galectin-9 Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 241000224466 Giardia Species 0.000 description 1
- 241000224467 Giardia intestinalis Species 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 1
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 description 1
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 102000004457 Granulocyte-Macrophage Colony-Stimulating Factor Human genes 0.000 description 1
- 241000228404 Histoplasma capsulatum Species 0.000 description 1
- 101000864344 Homo sapiens B- and T-lymphocyte attenuator Proteins 0.000 description 1
- 101000716130 Homo sapiens CD48 antigen Proteins 0.000 description 1
- 101001117317 Homo sapiens Programmed cell death 1 ligand 1 Proteins 0.000 description 1
- 101000611936 Homo sapiens Programmed cell death protein 1 Proteins 0.000 description 1
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 1
- 101000669447 Homo sapiens Toll-like receptor 4 Proteins 0.000 description 1
- 241000598436 Human T-cell lymphotropic virus Species 0.000 description 1
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 1
- MFESCIUQSIBMSM-UHFFFAOYSA-N I-BCP Chemical compound ClCCCBr MFESCIUQSIBMSM-UHFFFAOYSA-N 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 1
- 102000037982 Immune checkpoint proteins Human genes 0.000 description 1
- 108091008036 Immune checkpoint proteins Proteins 0.000 description 1
- 102000006992 Interferon-alpha Human genes 0.000 description 1
- 108010047761 Interferon-alpha Proteins 0.000 description 1
- 102000003996 Interferon-beta Human genes 0.000 description 1
- 108090000467 Interferon-beta Proteins 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 102000000589 Interleukin-1 Human genes 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 102000000588 Interleukin-2 Human genes 0.000 description 1
- 108010002386 Interleukin-3 Proteins 0.000 description 1
- 102000000646 Interleukin-3 Human genes 0.000 description 1
- 241000701460 JC polyomavirus Species 0.000 description 1
- 241000588748 Klebsiella Species 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 1
- 102000017578 LAG3 Human genes 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 101150030213 Lag3 gene Proteins 0.000 description 1
- 241000589248 Legionella Species 0.000 description 1
- 208000007764 Legionnaires' Disease Diseases 0.000 description 1
- 241000222722 Leishmania <genus> Species 0.000 description 1
- 241000222727 Leishmania donovani Species 0.000 description 1
- 241000589902 Leptospira Species 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 208000016604 Lyme disease Diseases 0.000 description 1
- 108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 102000007651 Macrophage Colony-Stimulating Factor Human genes 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241000712079 Measles morbillivirus Species 0.000 description 1
- 108010061593 Member 14 Tumor Necrosis Factor Receptors Proteins 0.000 description 1
- 241000700560 Molluscum contagiosum virus Species 0.000 description 1
- 241000711386 Mumps virus Species 0.000 description 1
- 206010061309 Neoplasm progression Diseases 0.000 description 1
- 208000005890 Neuroma Diseases 0.000 description 1
- 101710163270 Nuclease Proteins 0.000 description 1
- 229910003849 O-Si Inorganic materials 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
- 229910003872 O—Si Inorganic materials 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 241000526686 Paracoccidioides brasiliensis Species 0.000 description 1
- 208000037581 Persistent Infection Diseases 0.000 description 1
- 229940049937 Pgp inhibitor Drugs 0.000 description 1
- 241000223810 Plasmodium vivax Species 0.000 description 1
- 241000233872 Pneumocystis carinii Species 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- 229920001030 Polyethylene Glycol 4000 Polymers 0.000 description 1
- 108010039918 Polylysine Proteins 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- 239000004721 Polyphenylene oxide Substances 0.000 description 1
- 208000006994 Precancerous Conditions Diseases 0.000 description 1
- 206010036711 Primary mediastinal large B-cell lymphomas Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 241000588769 Proteus <enterobacteria> Species 0.000 description 1
- 241000125945 Protoparvovirus Species 0.000 description 1
- 241000589516 Pseudomonas Species 0.000 description 1
- 241000711798 Rabies lyssavirus Species 0.000 description 1
- 241000725643 Respiratory syncytial virus Species 0.000 description 1
- 241000606701 Rickettsia Species 0.000 description 1
- 241000702670 Rotavirus Species 0.000 description 1
- 241000710799 Rubella virus Species 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 241000607720 Serratia Species 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 241000295644 Staphylococcaceae Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 1
- 238000010459 TALEN Methods 0.000 description 1
- 206010043376 Tetanus Diseases 0.000 description 1
- 102100039360 Toll-like receptor 4 Human genes 0.000 description 1
- 241000223997 Toxoplasma gondii Species 0.000 description 1
- 108010043645 Transcription Activator-Like Effector Nucleases Proteins 0.000 description 1
- 241000223104 Trypanosoma Species 0.000 description 1
- 241000223109 Trypanosoma cruzi Species 0.000 description 1
- 102100028785 Tumor necrosis factor receptor superfamily member 14 Human genes 0.000 description 1
- 241000700618 Vaccinia virus Species 0.000 description 1
- 241000607626 Vibrio cholerae Species 0.000 description 1
- 239000012391 XPhos Pd G2 Substances 0.000 description 1
- 241000607479 Yersinia pestis Species 0.000 description 1
- 108010017070 Zinc Finger Nucleases Proteins 0.000 description 1
- BGABKEVTHIJBIW-GMSGAONNSA-N [(1r,4s)-7,7-dimethyl-3-oxo-4-bicyclo[2.2.1]heptanyl]methanesulfonyl chloride Chemical compound C1C[C@@]2(CS(Cl)(=O)=O)C(=O)C[C@@H]1C2(C)C BGABKEVTHIJBIW-GMSGAONNSA-N 0.000 description 1
- WERKSKAQRVDLDW-ANOHMWSOSA-N [(2s,3r,4r,5r)-2,3,4,5,6-pentahydroxyhexyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO WERKSKAQRVDLDW-ANOHMWSOSA-N 0.000 description 1
- VWOJCEPSMYGGQT-LVARUYSCSA-N [5-[[(1S)-4-bromo-2,3-dihydro-1H-inden-1-yl]oxy]-4-chloro-2-formylphenyl] [(1R,4R)-7,7-dimethyl-2-oxo-1-bicyclo[2.2.1]heptanyl]methanesulfonate Chemical compound CC1([C@]2(C(C[C@H]1CC2)=O)CS(=O)(=O)OC1=C(C=C(C(=C1)O[C@H]1CCC2=C(C=CC=C12)Br)Cl)C=O)C VWOJCEPSMYGGQT-LVARUYSCSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 235000004279 alanine Nutrition 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
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 125000004450 alkenylene group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 125000005237 alkyleneamino group Chemical group 0.000 description 1
- 125000005238 alkylenediamino group Chemical group 0.000 description 1
- 125000005530 alkylenedioxy group Chemical group 0.000 description 1
- 125000005529 alkyleneoxy group Chemical group 0.000 description 1
- 125000004419 alkynylene group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 229920000469 amphiphilic block copolymer Polymers 0.000 description 1
- 239000002269 analeptic agent Substances 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000002111 antiemetic agent Substances 0.000 description 1
- 229940125683 antiemetic agent Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000003080 antimitotic agent Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 229960003852 atezolizumab Drugs 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229950002916 avelumab Drugs 0.000 description 1
- 229940065181 bacillus anthracis Drugs 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- GPRLTFBKWDERLU-UHFFFAOYSA-N bicyclo[2.2.2]octane Chemical compound C1CC2CCC1CC2 GPRLTFBKWDERLU-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000002306 biochemical method Methods 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 239000004305 biphenyl Chemical group 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000012830 cancer therapeutic Substances 0.000 description 1
- 125000004452 carbocyclyl group Chemical group 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 150000007942 carboxylates Chemical group 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 150000005829 chemical entities Chemical class 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 235000015218 chewing gum Nutrition 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- RSLSVURFMXHEEU-UHFFFAOYSA-M chloropalladium(1+);dicyclohexyl-[3-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane;2-phenylaniline Chemical compound [Pd+]Cl.NC1=CC=CC=C1C1=CC=CC=[C-]1.CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC(P(C2CCCCC2)C2CCCCC2)=C1 RSLSVURFMXHEEU-UHFFFAOYSA-M 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 238000004590 computer program Methods 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 description 1
- 208000024558 digestive system cancer Diseases 0.000 description 1
- 239000012897 dilution medium Substances 0.000 description 1
- 206010013023 diphtheria Diseases 0.000 description 1
- 238000000375 direct analysis in real time Methods 0.000 description 1
- 208000037765 diseases and disorders Diseases 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000012063 dual-affinity re-targeting Methods 0.000 description 1
- 229950009791 durvalumab Drugs 0.000 description 1
- 239000007911 effervescent powder Substances 0.000 description 1
- 239000007938 effervescent tablet Substances 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical group C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 201000003444 follicular lymphoma Diseases 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229940083124 ganglion-blocking antiadrenergic secondary and tertiary amines Drugs 0.000 description 1
- 201000010231 gastrointestinal system cancer Diseases 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 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
- 229940085435 giardia lamblia Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 239000002748 glycoprotein P inhibitor Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 208000005252 hepatitis A Diseases 0.000 description 1
- FBPFZTCFMRRESA-UHFFFAOYSA-N hexane-1,2,3,4,5,6-hexol Chemical compound OCC(O)C(O)C(O)C(O)CO FBPFZTCFMRRESA-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229940125697 hormonal agent Drugs 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 102000048776 human CD274 Human genes 0.000 description 1
- 102000048362 human PDCD1 Human genes 0.000 description 1
- WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 description 1
- 229940091173 hydantoin Drugs 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- RCCPEORTSYDPMB-UHFFFAOYSA-N hydroxy benzenecarboximidothioate Chemical compound OSC(=N)C1=CC=CC=C1 RCCPEORTSYDPMB-UHFFFAOYSA-N 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 239000012216 imaging agent Substances 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 1
- 229960002411 imatinib Drugs 0.000 description 1
- YLMAHDNUQAMNNX-UHFFFAOYSA-N imatinib methanesulfonate Chemical compound CS(O)(=O)=O.C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 YLMAHDNUQAMNNX-UHFFFAOYSA-N 0.000 description 1
- YAMHXTCMCPHKLN-UHFFFAOYSA-N imidazolidin-2-one Chemical compound O=C1NCCN1 YAMHXTCMCPHKLN-UHFFFAOYSA-N 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000001024 immunotherapeutic effect Effects 0.000 description 1
- 125000003114 inden-1-yl group Chemical group [H]C1=C([H])C([H])(*)C2=C([H])C([H])=C([H])C([H])=C12 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 239000008101 lactose Substances 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
- 229960003881 letrozole Drugs 0.000 description 1
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 1
- 201000002364 leukopenia Diseases 0.000 description 1
- 231100001022 leukopenia Toxicity 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000005259 measurement 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
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000006682 monohaloalkyl group Chemical group 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 239000002324 mouth wash Substances 0.000 description 1
- LBWFXVZLPYTWQI-IPOVEDGCSA-N n-[2-(diethylamino)ethyl]-5-[(z)-(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C LBWFXVZLPYTWQI-IPOVEDGCSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 208000004235 neutropenia Diseases 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- OSTGTTZJOCZWJG-UHFFFAOYSA-N nitrosourea Chemical compound NC(=O)N=NO OSTGTTZJOCZWJG-UHFFFAOYSA-N 0.000 description 1
- 229960003301 nivolumab Drugs 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- UMRZSTCPUPJPOJ-KNVOCYPGSA-N norbornane Chemical compound C1C[C@H]2CC[C@@H]1C2 UMRZSTCPUPJPOJ-KNVOCYPGSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 244000309459 oncolytic virus Species 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 229940127084 other anti-cancer agent Drugs 0.000 description 1
- 210000003101 oviduct Anatomy 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- QJPQVXSHYBGQGM-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 QJPQVXSHYBGQGM-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 201000003913 parathyroid carcinoma Diseases 0.000 description 1
- 208000017954 parathyroid gland carcinoma Diseases 0.000 description 1
- 239000004031 partial agonist Substances 0.000 description 1
- 229960002621 pembrolizumab Drugs 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 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
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920000768 polyamine Chemical class 0.000 description 1
- 229920001610 polycaprolactone Polymers 0.000 description 1
- 229920002721 polycyanoacrylate Polymers 0.000 description 1
- 229920000570 polyether Polymers 0.000 description 1
- 239000008389 polyethoxylated castor oil Substances 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 239000004633 polyglycolic acid Substances 0.000 description 1
- 125000006684 polyhaloalkyl group Polymers 0.000 description 1
- 229940115272 polyinosinic:polycytidylic acid Drugs 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 229920000656 polylysine Polymers 0.000 description 1
- 108091033319 polynucleotide Proteins 0.000 description 1
- 102000040430 polynucleotide Human genes 0.000 description 1
- 239000002157 polynucleotide Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 229920006324 polyoxymethylene Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000000700 radioactive tracer Substances 0.000 description 1
- 231100000336 radiotoxic Toxicity 0.000 description 1
- 230000001690 radiotoxic effect Effects 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 231100000205 reproductive and developmental toxicity Toxicity 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 238000002603 single-photon emission computed tomography Methods 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910001467 sodium calcium phosphate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 229940083466 soybean lecithin Drugs 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 1
- 229960001796 sunitinib Drugs 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 229940034785 sutent Drugs 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- 125000005247 tetrazinyl group Chemical group N1=NN=NC(=C1)* 0.000 description 1
- OUOJIFQQBPKAMU-UHFFFAOYSA-N tetrazol-5-one Chemical compound O=C1N=NN=N1 OUOJIFQQBPKAMU-UHFFFAOYSA-N 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- IBBLKSWSCDAPIF-UHFFFAOYSA-N thiopyran Chemical compound S1C=CC=C=C1 IBBLKSWSCDAPIF-UHFFFAOYSA-N 0.000 description 1
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- 235000019798 tripotassium phosphate Nutrition 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 230000005751 tumor progression Effects 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229940118696 vibrio cholerae Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/12—Oxygen or sulfur atoms
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- 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
- A61P31/12—Antivirals
-
- 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
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/12—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/267—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/38—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D211/74—Oxygen atoms
- C07D211/76—Oxygen atoms attached in position 2 or 6
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
- C07D213/85—Nitriles in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
- C07D451/06—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed 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
- C07D487/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Immunology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Virology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pyrrole Compounds (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
本出願は、2017年7月28日に出願された米国特許仮出願第62/538,123号の優先権を主張するものであり、この仮出願の内容は、その全体が引用により本明細書中に組み込まれている。
該当なし
該当なし
プログラムされた細胞死タンパク質-1(PD-1)は、その2つのリガンドであるPD-L1又はPD-L2との相互作用時に、負のシグナルを送達する、CD28スーパーファミリーの一員である。PD-1とそのリガンドは、広範に発現され、且つT細胞活性化及び耐性において広い範囲の免疫調節の役割を発揮する。PD-1とそのリガンドは、感染性免疫及び腫瘍性免疫の減弱化、並びに慢性感染症及び腫瘍の進行の促進に関与している。
一態様において、式(I)の化合物、又はその医薬として許容し得る塩が、本明細書に提供される:
該当なし。
略語及び定義
本明細書において使用される用語「ある(“a”、“an”)又はその(“the”)」は、一つのメンバーによる態様を含むのみではなく、2以上のメンバーによる態様も含む。例えば、単数形(“a”、“an”及び“the”)は、文脈が明確にそうでないことを指示しない限りは、複数の言及を含む。従って、例えば「ある細胞(“a cell”)の言及は、複数のそのような細胞を含み、「その物質(“the agent”)」の言及は、当業者に公知の1又は複数の物質の言及を含むなどである。
一態様において、本開示は、式(I)を有する化合物、又はその医薬として許容し得る塩、又はそのプロドラッグもしくは生物学的等価物を提供する:
R1a、R1b、R1c及びR1dの各々は、独立して、H、ハロゲン、CF3、CN、C1-4アルキル及び-O-C1-4アルキルからなる群から選択され、ここでC1-4アルキル及び-O-C1-4アルキルは任意に、ハロゲン、ヒドロキシル、メトキシ又はエトキシにより更に置換され;
Lは:
Zは、アゼチジニル、ピロリジニル、ピペリジニル、モルホリニル、ピリジル、ピリミジニル、グアニジニル、キヌクリジン、及び8-アザビシクロ[3.2.1]オクタンからなる群から選択され、その各々は任意に、ハロゲン、ヒドロキシ、C1-3アルキル、-NH2、-NHC1-3アルキル、-N(C1-3アルキル)2、-O-C1-3アルキル、C1-3ヒドロキシアルキル、C1-3ハロアルキル、及び-CO2Hから独立して選択された1~3個の基により置換されるか;
あるいは
Zは、-CO2Ra及び-NRaRbからなる群から選択され;ここでRaは、H、C1-8アルキル、C1-8ハロアルキル及びC1-8ヒドロキシアルキルからなる群から選択され;並びに、Rbは、-C1-8アルキル、C1-8ハロアルキル、C1-8アルキル-COOH、C1-8アルキル-OH、C1-8アルキル-CONH2、C1-8アルキル-SO2NH2、C1-8アルキル-PO3H2、C1-8アルキル-C(O)NHOH、-C(O)-C1-8アルキル-OH、-C(O)-C1-8アルキル-COOH、C3-10シクロアルキル、-C3-10シクロアルキル-COOH、-C3-10シクロアルキル-OH、C4-8ヘテロシクリル、-C4-8ヘテロシクリル-COOH、-C4-8ヘテロシクリル-OH、-C1-8アルキル-C4-8ヘテロシクリル、-C1-8アルキル-C3-10シクロアルキル、C5-10ヘテロアリール及び-C1-8アルキル-C5-10ヘテロアリールから選択され;
R2a、R2b及びR2cの各々は独立して、H、ハロゲン、-CN、-Rd、-CO2Re、-CONReRf、-OC(O)NReRf、-NRfC(O)Re、-NRfC(O)2Rd、-NRe-C(O)NReRf、-NReRf、-ORe、-X2-ORe、-X2-NReRf、-X2-CO2Re、-SF5、及び-S(O)2NReRfからなる群から選択され、ここで各X2は、C1-4アルキレンであり;Re及びRfの各々は独立して、水素、C1-8アルキル、及びC1-8ハロアルキルから選択されるか、あるいは同じ窒素原子に結合された場合、その窒素原子と一緒に、環員としてN、O及びSから選択された0~2個の追加のヘテロ原子を有し、並びに任意にオキソにより置換された、5又は6-員環を形成することができ;各Rdは独立して、C1-8アルキル、C2-8アルケニル、及びC1-8ハロアルキルからなる群から選択され;
R3は、-NRgRh及びC4-12ヘテロシクリルからなる群から選択され、ここでC4-12ヘテロシクリルは任意に、1~6個のR3aにより置換され;
各R3aは独立して、ハロゲン、-CN、-Ri、-CONRjRk、-CONHC1-6アルキル-OH、-C(O)Rj、-OC(O)NRjRk、-NRjC(O)Rk、-NRjC(O)2Rk、-CONHOH、-PO3H2、-NRj-X3-C(O)2Rk、-NRjC(O)NRjRk、-NRjRk、-ORj、-S(O)2NRjRk、-O-X3-ORj、-O-X3-NRjRk、-O-X3-CO2Rj、-O-X3-CONRjRk、-X3-ORj、-X3-NRjRk、-X3-CO2Rj、-X3-CONRjRk、及びSF5からなる群から選択され;ここで、X3は、C1-6アルキレンであり、並びに任意に、OH、SO2NH2、CONH2、C(O)NHOH、PO3H2、COO-C1-8アルキル又はCO2Hにより更に置換され、ここでRj及びRkの各々は独立して、水素;OH、SO2NH2、CONH2、C(O)NHOH、PO3H2、COO-C1-8アルキルもしくはCO2Hから選択された1~2個の置換基により任意に置換されたC1-8アルキル;及びOH、SO2NH2、CONH2、C(O)NHOH、PO3H2、COO-C1-8アルキルもしくはCO2Hから選択された1~2個の置換基により任意に置換されたC1-8ハロアルキルから選択されるか、あるいは、同じ窒素原子に結合された場合、Rj及びRkは、その窒素原子と一緒に、環員としてN、O及びSから選択された0~2個の追加のヘテロ原子を有し、並びに任意にオキソにより置換された、5又は6-員環を形成することができ;各Riは独立して、その各々は任意に、OH、SO2NH2、CONH2、C(O)NHOH、PO3H2、COO-C1-8アルキル又はCO2Hにより置換されてよい、-OH、C1-8アルキル、C2-8アルケニル、及びC1-8ハロアルキルからなる群から選択され;
Rgは、H、C1-8ハロアルキル及びC1-8アルキルからなる群から選択され;
Rhは、-C1-8アルキル、C1-8ハロアルキル、C1-8ヒドロキシアルキル、C1-8アルキル-CO2Rj、C1-8アルキル-CONRjRk、及びC1-8アルキル-CONHSO2Rj、C1-8アルキル-SO2NRjRk、C1-8アルキル-PO3H2、C1-8アルキル-C(O)NHOH、C1-8アルキル-NRh1Rh2、-C(O)Rj、C3-10シクロアルキル、-C3-10シクロアルキル-COORj、-C3-10シクロアルキル-ORj、C4-8ヘテロシクリル、-C4-8ヘテロシクリル-COORj、-C4-8ヘテロシクリル-ORj、-C1-8アルキル-C4-8ヘテロシクリル、-C(=O)OC1-8アルキル-C4-8 ヘテロシクリル、-C1-8アルキル-C3-10シクロアルキル、C5-10ヘテロアリール、-C1-8アルキル-C5-10ヘテロアリール、-C1-8アルキル-C6-10アリール、-C1-8アルキル-(C=O)-C6-10アリール、-CO2-C1-8アルキル-O2C-C1-8アルキル、-C1-8アルキル-NH(C=O)-C2-8アルケニル、-C1-8アルキル-NH(C=O)-C1-8アルキル、-C1-8アルキル-NH(C=O)-C2-8アルキニル、-C1-8アルキル-(C=O)-NH-C1-8アルキル-COORj、及び任意にCO2Hにより置換された-C1-8アルキル-(C=O)-NH-C1-8アルキル-ORjから選択されるか;あるいは
Rhは、それが結合したNと一緒に、1~3個の天然のアミノ酸及び0~2個の非天然のアミノ酸を含む、モノ-、ジ-又はトリ-ペプチドであり、ここで
非-天然のアミノ酸は、C2-4ヒドロキシアルキル、C1-3アルキル-グアニジニル、及びC1-4アルキル-ヘテロアリールからなる群から選択されるアルファ炭素置換基を有し、
各天然又は非-天然のアミノ酸のアルファ炭素は任意に、メチル基により更に置換され、並びに
モノ-、ジ-、又はトリ-ペプチドの末端部分は、C(O)OH、C(O)O-C1-6アルキル、及びPO3H2からなる群から選択され、ここで
Rh1及びRh2は各々独立して、H、C1-6アルキル、及びC1-4ヒドロキシアルキルからなる群から選択され;
RhのC1-8アルキル部位は任意に、OH、COOH、SO2NH2、CONH2、C(O)NHOH、COO-C1-8アルキル、PO3H2、及び1~2個のC1-3アルキル置換基により任意に置換されたC5-6ヘテロアリールから独立して選択された1~3個の置換基により更に置換され、
RhのC5-10ヘテロアリール及びC6-10アリール部位は任意に、OH、B(OH)2、COOH、SO2NH2、CONH2、C(O)NHOH、PO3H2、COO-C1-8アルキル、C1-4アルキル、C1-4アルキル-OH、C1-4アルキル-SO2NH2、C1-4アルキルCONH2、C1-4アルキル-C(O)NHOH、C1-4アルキル-PO3H2、C1-4アルキル-COOH、及びフェニルから独立して選択された1~3個の置換基により置換され、並びにRhのC4-8ヘテロシクリル及びC3-10シクロアルキル部位は任意に、1~4個のRw置換基により置換され;
各Rw置換基は、C1-4アルキル、C1-4アルキル-OH、C1-4アルキル-COOH、C1-4アルキル-SO2NH2、C1-4アルキルCONH2、C1-4アルキル-C(O)NHOH、C1-4アルキル-PO3H、OH、COO-C1-8アルキル、COOH、SO2NH2、CONH2、C(O)NHOH、PO3H2及びオキソから独立して選択され;
R4は、O-C1-8アルキル、O-C1-8ハロアルキル、C6-10アリール、C5-10ヘテロアリール、-O-C1-4アルキル-C4-7ヘテロシクロアルキル、-O-C1-4アルキル-C6-10アリール及び-O-C1-4アルキル-C5-10ヘテロアリールからなる群から選択され、その各々は任意に、1~5個のR4aにより置換され;
各R4aは、ハロゲン、-CN、-Rm、-CO2Rn、-CONRnRp、-C(O)Rn、-OC(O)NRnRp、-NRnC(O)Rp、-NRnC(O)2Rm、-NRn-C(O)NRnRp、-NRnRp、-ORn、-O-X4-ORn、-O-X4-NRnRp、-O-X4-CO2Rn、-O-X4-CONRnRp、-X4-ORn、-X4-NRnRp、-X4-CO2Rn、-X4-CONRnRp、-SF5、-S(O)2RnRp、-S(O)2NRnRp、C3-7シクロアルキル及びC4-7ヘテロシクロアルキルからなる群から独立して選択され、ここでシクロアルキル環及びヘテロシクロアルキル環は任意に、1~5個のRtにより置換され、ここで各Rtは、C1-8アルキル、C1-8ハロアルキル、-CO2Rn、-CONRnRp、-C(O)Rn、-OC(O)NRnRp、-NRnC(O)Rp、-NRnC(O)2Rm、-NRn-C(O)NRnRp、-NRnRp、-ORn、-O-X4-ORn 、-O-X4-NRnRp、-O-X4-CO2Rn、-O-X4-CONRnRp、-X4-ORn、-X4-NRnRp、-X4-CO2Rn、-X4-CONRnRp、-SF5、及び-S(O)2NRnRpからなる群から独立して選択され;
ここで各X4は、C1-6アルキレンであり;Rn及びRpの各々は、水素、C1-8アルキル、及びC1-8ハロアルキルから独立して選択されるか、あるいは同じ窒素原子に結合された場合、その窒素原子と一緒に、環員としてN、O及びSから選択された0~2個の追加のヘテロ原子を有し、並びに任意にオキソにより置換された、5又は6-員環を形成することができ;各Rmは、C1-8アルキル、C2-8アルケニル、及びC1-8ハロアルキルからなる群から独立して選択され;並びに、任意に、2個のR4a置換基が隣接原子上にある場合は、これらは一緒に、任意にオキソにより置換された、縮合した5又は6-員の炭素環又は複素環を形成し;
nは、0、1、2又は3であり;
各R5は、ハロゲン、-CN、-Rq、-CO2Rr、-CONRrRs、-C(O)Rr、-OC(O)NRrRs、-NRrC(O)Rs、-NRrC(O)2Rq、-NRr-C(O)NRrRs、-NRrRs、-ORr、-O-X5-ORr 、-O-X5-NRrRs、-O-X5-CO2Rr、-O-X5-CONRrRs、-X5-ORr、-X5-NRrRs、-X5-CO2Rr、-X5-CONRrRs、-SF5、-S(O)2NRrRsからなる群から独立して選択され、ここで各X5は、C1-4アルキレンであり;Rr及びRsの各々は、水素、C1-8アルキル、及びC1-8ハロアルキルから独立して選択されるか、あるいは同じ窒素原子に結合された場合、その窒素原子と一緒に、環員としてN、O及びSから選択された0~2個の追加のヘテロ原子を有し、並びに任意にオキソにより置換された、5又は6-員環を形成することができ;各Rqは、C1-8アルキル、及びC1-8ハロアルキルからなる群から独立して選択され;
R6aは、H、C1-4アルキル及びC1-4ハロアルキルからなる群から選択され;
mは、0、1、2、3又は4であり;
各R6bは、F、C1-4アルキル、O-Ru、C1-4ハロアルキル、NRuRvからなる群から独立して選択され、ここでRu及びRvの各々は、水素、C1-8アルキル、及びC1-8ハロアルキルから独立して選択されるか、あるいは同じ窒素原子に結合された場合、その窒素原子と一緒に、環員としてN、O及びSから選択された0~2個の追加のヘテロ原子を有し、並びに任意にオキソにより置換された、5又は6-員環を形成することができる)。
非天然のアミノ酸は、C2-4ヒドロキシアルキル、C1-3アルキル-グアニジニル、及びC1-4アルキル-ヘテロアリールからなる群から選択されるアルファ炭素置換基を有し、
各天然又は非天然のアミノ酸のアルファ炭素は任意に、メチル基により更に置換され、並びに
モノ-、ジ-、又はトリ-ペプチドの末端部分は、C(O)OH、C(O)O-C1-6アルキル、及びPO3H2からなる群から選択される。
選択された実施態様において、R4は、以下からなる群から選択される:
本明細書に提供される化合物に加え、それらの化合物の組成物は、典型的には医薬担体又は希釈剤を含むであろう。
本開示の化合物は、免疫調節物質として使用され得る。本開示の化合物は、インビトロ及びインビボの両方において、様々な状況で、PD-1及び/又はPD-L1のアゴニスト、アンタゴニスト、部分アゴニスト、インバースアゴニスト、インヒビターとして使用され得る。一部の実施態様において、本開示の化合物は、PD-1/PD-L1タンパク質-タンパク質相互作用のインヒビターとして使用され得る。一部の実施態様において、本開示の化合物は、PD-L1のインヒビターとして使用され得る。一部の実施態様において、本開示の化合物は、CD80/PD-L1タンパク質-タンパク質相互作用のインヒビターとして使用され得る。一部の実施態様において、本開示の化合物は、インビトロ及びインビボにおいて、PD-1とPD-L1及び/又はPD-1とCD80及び/又はPD-1とPD-L2の間の相互作用を阻害するために使用され得る。一部の実施態様において、本開示の化合物は、VISTA及び/又はTIM-3を阻害するために使用され得る。一部の実施態様において、本開示の化合物は、PD-1/PD-L1タンパク質-タンパク質相互作用のインヒビター、並びにVISTA及び/又はTIM-3のインヒビターであり得る。一部の実施態様において、本開示の化合物は、PD-1/PD-L1タンパク質-タンパク質相互作用のインヒビターであることに加え、CTLA-4及び/又はBTLA及び/又はLAG-3及び/又はKLRG-1及び/又は2B4及び/又はCD160及び/又はHVEM及び/又はCD48及び/又はE-カドヘリン及び/又はMHC-II及び/又はガレクチン-9及び/又はCD86及び/又はPD-L2及び/又はVISTA及び/又はTIM-3及び/又はCD80のインヒビターであり得る。
本開示の化合物及び他の薬物を含有する併用薬は、両方の成分が単独の製剤中に含まれる組合せ調製品として投与されるか、又は個別の製剤として投与されてよい。個別の製剤による投与は、同時投与及びある時間間隔を伴う投与を含む。ある時間間隔を伴う投与の場合、本開示の化合物を最初に、引き続き別の薬物を投与するか、又は別の薬物を最初に、引き続き本開示の化合物を投与することができる。それぞれの薬物の投与方法は、同じでも異なってもよい。
用量レベル1日あたり体重1kgあたり約0.1mg~約140mgの桁が、PD-1/PD-L1相互作用に関与した状態の治療又は予防に有用である(約0.5mg~約7g/ヒト患者/日)。単独剤形を製造するために担体物質と組合せてよい活性成分の量は、治療される宿主及び特定の投与様式に応じて変動するであろう。単位剤形は、一般に、活性成分を約1mg~約500mg含むであろう。経口、経皮、静脈内又は皮下に投与される化合物に関して、血清濃度5ng(ナノグラム)/mL~10μg(マイクログラム)/mL血清を達成するために投与される化合物の十分量が好ましく、より好ましくは血清濃度20ng~1μg/ml血清を達成するのに十分な化合物が投与されるべきであり、最も好ましくは血清濃度50ng/ml~200ng/ml血清を達成するのに十分な化合物が投与されるべきである。滑膜への直接注入(関節炎の治療のため)に関して、局所濃度およそ1マイクロモルを達成するのに十分な化合物が、投与されるべきである。
本実施態様はまた、対象化合物又はその医薬として許容し得る塩の調製に有用な、プロセス及び中間体にも関する。
下記実施例は、式(I)、(Ia)、又は(Ib)の化合物を含む本開示の化合物を製造する様々な方法を例示している。下記実施例は、請求された開示を例証するために提示され、限定するものではない。
+、20000nM≧IC50≧500nM;
++、500nM>IC50≧5nM;
+++、5nM>IC50。
表1の保持時間を決定するために使用した逆相HPLC条件:
カラム:ZORBAX(SB-C18、2.1×50mm、5μm)
移動相A:95%H2O、5%MeCN(0.1%ギ酸を含む)
移動相B:5%H2O、95%MeCN(0.1%ギ酸を含む)
流量:1.0mL/分
勾配:3.5分間で20%から100%のBまで(Rtに関して*なし)、又は5.5分間で20%から100%のBまで(Rtに関して*あり)。
96ウェルプレートを、PBS中の1μg/mLヒトPD-L1(R&D社から入手)により、4℃で、一晩コーティングした。その後ウェルを、0.05%TWEEN-20を含むPBS中の2%BSA(W/V)により、37℃で1時間ブロックした。プレートを、PBS/0.05%TWEEN-20により、3回洗浄し、当該化合物を希釈媒体中で連続希釈し(1:5)、且つ、ELISAプレートに加えた。ヒトPD-1及びビオチン0.3μg/mL(ACRO Biosystems社)を添加し、37℃で1時間インキュベーションし、PBS/0.05%TWEEN-20により3回洗浄した。二次ブロックを、PBS中の2%BSA(W/V)/0.05%TWEEN-20により、37℃で10分間実行し、且つPBS/0.05%TWEEN-20により3回洗浄した。ストレプトアビジン-HRPを、37℃で1時間添加し、その後PBS/0.05%TWEEN-20により3回洗浄した。TMB基質を添加し、37℃で20分間反応させた。停止溶液(2N水性H2SO4)を添加した。吸光度を、マイクロプレート分光計を用い、450nmで測定した。結果を、表1に示している。
Claims (38)
- 式(I)の化合物、又はその医薬として許容し得る塩:
R1a、R1b、R1c及びR1dの各々は、独立して、H、ハロゲン、CF3、CN、C1-4アルキル及び-O-C1-4アルキルからなる群から選択され、ここでC1-4アルキル及び-O-C1-4アルキルは任意に、ハロゲン、ヒドロキシル、メトキシ又はエトキシにより更に置換され;
Lは:
Zは、アゼチジニル、ピロリジニル、ピペリジニル、ピペラジニル、モルホリニル、ピリジル、ピリミジニル、イミダゾリル、グアニジニル、キヌクリジン、2-アザスピロ[3.3]ヘプタン及び8-アザビシクロ[3.2.1]オクタンからなる群から選択され、その各々は任意に、ハロゲン、CN、ヒドロキシ、オキソ、C1-4アルキル、-NH2、-NHC1-3アルキル、-N(C1-3アルキル)2、-O-C1-3アルキル、C1-3ヒドロキシアルキル、C1-3ハロアルキル、-OC(O)(C1-4アルキル)、-CO2(C1-4アルキル)及び-CO2Hから独立して選択された1~4個の基により置換されるか;
あるいは
Zは、-CO2Ra及び-NRaRbからなる群から選択され;ここでRaは、H、C1-8アルキル、C1-8ハロアルキル及びC1-8ヒドロキシアルキルからなる群から選択され;並びに、Rbは、H、-C1-8アルキル、C1-8ハロアルキル、C1-8アルキル-COOH、C1-8アルキル-OH、C1-8アルキル-CONH2、C1-8アルキル-SO2NH2、C1-8アルキル-PO3H2、C1-8アルキル-C(O)NHOH、-C(O)-C1-8アルキル-OH、-C(O)-C1-8アルキル-COOH、C3-10シクロアルキル、-C3-10シクロアルキル-COOH、-C3-10シクロアルキル-OH、C4-8ヘテロシクリル、-C4-8ヘテロシクリル-COOH、-C4-8ヘテロシクリル-OH、-C1-8アルキル-C4-8ヘテロシクリル、-C1-8アルキル-C3-10シクロアルキル、C5-10ヘテロアリール及び-C1-8アルキル-C5-10ヘテロアリールから選択され;
R2a、R2b及びR2cの各々は独立して、H、ハロゲン、-CN、-Rd、-CO2Re、-CONReRf、-OC(O)NReRf、-NRfC(O)Re、-NRfC(O)2Rd、-NRe-C(O)NReRf、-NReRf、-ORe、-X2-ORe、-X2-NReRf、-X2-CO2Re、-SF5、及び-S(O)2NReRfからなる群から選択され、ここで各X2は、C1-4アルキレンであり;Re及びRfの各々は独立して、水素、C1-8アルキル、及びC1-8ハロアルキルから選択されるか、あるいは同じ窒素原子に結合された場合、その窒素原子と一緒に、環員としてN、O又はSから選択された0~2個の追加のヘテロ原子を有し、並びに任意にオキソにより置換された、5又は6-員環を形成することができ;各Rdは独立して、C1-8アルキル、C2-8アルケニル、及びC1-8ハロアルキルからなる群から選択され;
R3は、-NRgRh及びC4-12ヘテロシクリルからなる群から選択され、ここでC4-12ヘテロシクリルは任意に、1~6個のR3aにより置換され;
各R3aは独立して、ハロゲン、-CN、オキソ、-Ri、-CO2Rj、-CONRjRk、-CONHC1-6アルキル-OH、-C(O)Rj、-OC(O)NRjRk、-NRjC(O)Rk、-NRjC(O)2Rk、-CONHOH、-PO3H2、-NRj-X3-C(O)2Rk、-NRjC(O)NRjRk、-NRjRk、-ORj、-S(O)2NRjRk、-O-X3-ORj、-O-X3-NRjRk、-O-X3-CO2Rj、-O-X3-CONRjRk、-X3-ORj、-X3-NRjRk、-X3-CO2Rj、-X3-CONRjRk、-X3-CONHSO2Rj及びSF5からなる群から選択され;ここで、X3は、C1-6アルキレンであり、並びに任意に、OH、SO2NH2、CONH2、C(O)NHOH、PO3H2、COO-C1-8アルキル又はCO2Hにより更に置換され、ここでRj及びRkの各々は独立して、水素、OH、SO2NH2、CONH2、C(O)NHOH、PO3H2、COO-C1-8アルキルもしくはCO2Hから選択された1~2個の置換基により任意に置換されたC1-8アルキル、及びOH、SO2NH2、CONH2、C(O)NHOH、PO3H2、COO-C1-8アルキルもしくはCO2Hから選択された1~2個の置換基により任意に置換されたC1-8ハロアルキルから選択されるか、あるいは、同じ窒素原子に結合された場合、Rj及びRkは、その窒素原子と一緒に、環員としてN、O又はSから選択された0~2個の追加のヘテロ原子を有し、並びに任意にオキソにより置換された、5又は6-員環を形成することができ;各Riは独立して、その各々は任意に、OH、SO2NH2、CONH2、C(O)NHOH、PO3H2、COO-C1-8アルキル又はCO2Hにより置換されてよい、-OH、C1-8アルキル、C2-8アルケニル、及びC1-8ハロアルキルからなる群から選択され;
Rgは、H、C1-8ハロアルキル及びC1-8アルキルからなる群から選択され;
Rhは、-C1-8アルキル、C1-8ハロアルキル、C1-8ヒドロキシアルキル、C1-8アルキル-CO2Rj、C1-8アルキル-CONRjRk、及びC1-8アルキル-CONHSO2Rj、C1-8アルキル-SO2NRjRk、C1-8アルキル-SO3Rj、C1-8アルキル-B(OH)2、C1-8アルキル-PO3H2、C1-8アルキル-C(O)NHOH、C1-8アルキル-NRh1Rh2、-C(O)Rj、C3-10シクロアルキル、-C3-10シクロアルキル-COORj、-C3-10シクロアルキル-ORj、C4-8ヘテロシクリル、-C4-8ヘテロシクリル-COORj、-C4-8ヘテロシクリル-ORj、-C1-8アルキル-C4-8ヘテロシクリル、-C(=O)OC1-8アルキル-C4-8ヘテロシクリル、-C1-8アルキル-C3-10シクロアルキル、C5-10ヘテロアリール、-C1-8アルキル-C5-10ヘテロアリール、-C1-8アルキル-C6-10アリール、-C1-8アルキル-(C=O)-C6-10アリール、-CO2-C1-8アルキル-O2C-C1-8アルキル、-C1-8アルキル-NH(C=O)-C2-8アルケニル、-C1-8アルキル-NH(C=O)-C1-8アルキル、-C1-8アルキル-NH(C=O)-C2-8アルキニル、-C1-8アルキル-(C=O)-NH-C1-8アルキル-COORj、及び任意にCO2Hにより置換された-C1-8アルキル-(C=O)-NH-C1-8アルキル-ORjから選択されるか;あるいは
Rhは、それが結合したNと一緒に、1~3個の天然のアミノ酸及び0~2個の非天然のアミノ酸を含む、モノ-、ジ-又はトリ-ペプチドであり、ここで
非-天然のアミノ酸は、C2-4ヒドロキシアルキル、C1-3アルキル-グアニジニル、及びC1-4アルキル-ヘテロアリールからなる群から選択されるアルファ炭素置換基を有し、
各天然又は非-天然のアミノ酸のアルファ炭素は任意に、メチル基により更に置換され、並びに
モノ-、ジ-、又はトリ-ペプチドの末端部分は、C(O)OH、C(O)O-C1-6アルキル、及びPO3H2からなる群から選択され、ここで
Rh1及びRh2は各々独立して、H、C1-6アルキル、及びC1-4ヒドロキシアルキルからなる群から選択され;
RhのC1-8アルキル部位は任意に、OH、COOH、SO2NH2、CONH2、C(O)NHOH、COO-C1-8アルキル、PO3H2、及び1~2個のC1-3アルキル置換基により任意に置換されたC5-6ヘテロアリールから独立して選択された1~3個の置換基により更に置換され、
RhのC5-10ヘテロアリール及びC6-10アリール部位は任意に、OH、B(OH)2、COOH、SO2NH2、CONH2、C(O)NHOH、PO3H2、COO-C1-8アルキル、C1-4アルキル、C1-4アルキル-OH、C1-4アルキル-SO2NH2、C1-4アルキルCONH2、C1-4アルキル-C(O)NHOH、C1-4アルキル-PO3H2、C1-4アルキル-COOH、及びフェニルから独立して選択された1~3個の置換基により置換され、並びにRhのC4-8ヘテロシクリル及びC3-10シクロアルキル部位は任意に、1~4個のRw置換基により置換され;
各Rw置換基は、C1-4アルキル、C1-4アルキル-OH、C1-4アルキル-COOH、C1-4アルキル-SO2NH2、C1-4アルキルCONH2、C1-4アルキル-C(O)NHOH、C1-4アルキル-PO3H、OH、COO-C1-8アルキル、COOH、SO2NH2、CONH2、C(O)NHOH、PO3H2及びオキソから独立して選択され;
R4は、O-C1-8アルキル、O-C1-8ハロアルキル、C6-10アリール、C5-10ヘテロアリール、-O-C1-4アルキル-C4-7ヘテロシクロアルキル、-O-C1-4アルキル-C6-10アリール及び-O-C1-4アルキル-C5-10ヘテロアリールからなる群から選択され、その各々は任意に、1~5個のR4aにより置換され;
各R4aは、ハロゲン、-CN、-Rm、-CO2Rn、-CONRnRp、-C(O)Rn、-OC(O)NRnRp、-NRnC(O)Rp、-NRnC(O)2Rm、-NRn-C(O)NRnRp、-NRnRp、-ORn、-O-X4-ORn、-O-X4-NRnRp、-O-X4-CO2Rn、-O-X4-CONRnRp、-X4-ORn、-X4-NRnRp、-X4-CO2Rn、-X4-CONRnRp、-SF5、-S(O)2RnRp、-S(O)2NRnRp、C3-7シクロアルキル及びC4-7ヘテロシクロアルキルからなる群から独立して選択され、ここでシクロアルキル環及びヘテロシクロアルキル環は任意に、1~5個のRtにより置換され、ここで各Rtは、C1-8アルキル、C1-8ハロアルキル、-CO2Rn、-CONRnRp、-C(O)Rn、-OC(O)NRnRp、-NRnC(O)Rp、-NRnC(O)2Rm、-NRn-C(O)NRnRp、-NRnRp、-ORn、-O-X4-ORn、-O-X4-NRnRp、-O-X4-CO2Rn、-O-X4-CONRnRp、-X4-ORn、-X4-NRnRp、-X4-CO2Rn、-X4-CONRnRp、-SF5、及び-S(O)2NRnRpからなる群から独立して選択され;
ここで各X4は、C1-6アルキレンであり;Rn及びRpの各々は、水素、C1-8アルキル、及びC1-8ハロアルキルから独立して選択されるか、あるいは同じ窒素原子に結合された場合、その窒素原子と一緒に、環員としてN、O又はSから選択された0~2個の追加のヘテロ原子を有し、並びに任意にオキソにより置換された、5又は6-員環を形成することができ;各Rmは、C1-8アルキル、C2-8アルケニル、及びC1-8ハロアルキルからなる群から独立して選択され;並びに、任意に、2個のR4a置換基が隣接原子上にある場合は、これらは一緒に、任意にオキソにより置換された、縮合した5又は6-員の炭素環又は複素環を形成し;
nは、0、1、2又は3であり;
各R5は、ハロゲン、-CN、-Rq、-CO2Rr、-CONRrRs、-C(O)Rr、-OC(O)NRrRs、-NRrC(O)Rs、-NRrC(O)2Rq、-NRr-C(O)NRrRs、-NRrRs、-ORr、-O-X5-ORr、-O-X5-NRrRs、-O-X5-CO2Rr、-O-X5-CONRrRs、-X5-ORr、-X5-NRrRs、-X5-CO2Rr、-X5-CONRrRs、-SF5、-S(O)2NRrRsからなる群から独立して選択され、ここで各X5は、C1-4アルキレンであり;Rr及びRsの各々は、水素、C1-8アルキル、及びC1-8ハロアルキルから独立して選択されるか、あるいは同じ窒素原子に結合された場合、その窒素原子と一緒に、環員としてN、O又はSから選択された0~2個の追加のヘテロ原子を有し、並びに任意にオキソにより置換された、5又は6-員環を形成することができ;各Rqは、C1-8アルキル、及びC1-8ハロアルキルからなる群から独立して選択され;
R6aは、H、C1-4アルキル及びC1-4ハロアルキルからなる群から選択され;
mは、0、1、2、3又は4であり;
各R6bは、F、C1-4アルキル、O-Ru、C1-4ハロアルキル、NRuRvからなる群から独立して選択され、ここでRu及びRvの各々は、水素、C1-8アルキル、及びC1-8ハロアルキルから独立して選択されるか、あるいは同じ窒素原子に結合された場合、その窒素原子と一緒に、環員としてN、O又はSから選択された0~2個の追加のヘテロ原子を有し、並びに任意にオキソにより置換された、5又は6-員環を形成することができる)。 - 前記R2a、R2b及びR2cの各々が、水素、ハロゲン、CN、C1-4アルキル、及びC1-4ハロアルキルからなる群から独立して選択される、請求項1~3のいずれか一項記載の化合物、又はその医薬として許容し得る塩。
- 前記R3が、-NRgRhである、請求項1~3のいずれか一項記載の化合物、又はその医薬として許容し得る塩。
- 前記R3が、C4-12ヘテロシクリルであり、ここでC4-12ヘテロシクリルが任意に、1~6個のR3aにより置換されている、請求項1~3のいずれか一項記載の化合物、又はその医薬として許容し得る塩。
- 前記C4-12ヘテロシクリルが、C7-11スピロヘテロシクリルであり、そして任意に、1~6個のR3aにより置換されている、請求項7記載の化合物。
- 前記nが、0である、請求項1~11のいずれか一項記載の化合物、又はその医薬として許容し得る塩。
- 前記R6a及びR6bが、水素、ハロゲン、C1-4アルキル及びC1-4ハロアルキルからなる群から各々独立して選択される、請求項1~12のいずれか一項記載の化合物、又はその医薬として許容し得る塩。
- 前記R2b及びR2cが両方共、Hであり、並びにR2aが、ハロゲン、C1-4アルキル、C2-4アルケニル、C1-3ハロアルキル、-CN、-OMe及びOEtからなる群から選択される、請求項1~3のいずれか一項記載の化合物、又はその医薬として許容し得る塩。
- 前記R2b及びR2cが、両方共Hであり、並びにR2aがハロゲンである、請求項1~3のいずれか一項記載の化合物、又はその医薬として許容し得る塩。
- 前記R2b及びR2cが、両方共Hであり、並びにR2aがClである、請求項1~3のいずれか一項記載の化合物、又はその医薬として許容し得る塩。
- 前記R6aがHである、請求項1~3のいずれか一項記載の化合物、又はその医薬として許容し得る塩。
- 前記mが0である、請求項1~3のいずれか一項記載の化合物、又はその医薬として許容し得る塩。
- 前記mが1であり、並びにR6bが、F、C1-4アルキル、O-Ru、C1-4ハロアルキル及びNRuRvからなる群から選択され、ここでRu及びRvの各々は、水素、C1-8アルキル、及びC1-8ハロアルキルから独立して選択される、請求項1~3のいずれか一項記載の化合物、又はその医薬として許容し得る塩。
- 前記mが1であり、並びにR6bがFである、請求項1~3のいずれか一項記載の化合物、又はその医薬として許容し得る塩。
- 請求項1~27のいずれか一項記載の化合物、又はその医薬として許容し得る塩、並びに医薬として許容し得る賦形剤を含有する医薬組成物。
- 更に1又は複数の追加の治療薬を含有する、請求項28記載の医薬組成物。
- 前記1又は複数の追加の治療薬が、抗微生物薬、抗ウイルス薬、細胞毒性物質、遺伝子発現モジュレーター、化学療法薬、抗癌剤、血管新生阻害剤、免疫療法薬、抗ホルモン剤、抗線維化物質、放射線治療、放射性治療薬、抗悪性腫瘍薬、及び抗増殖性物質からなる群から選択される、請求項29記載の医薬組成物。
- 対象におけるPD-1シグナル伝達経路により媒介された免疫応答を調節する方法における使用のための、請求項1~27のいずれか一項記載の化合物若しくはその医薬として許容し得る塩を含有する組成物、又は請求項28~30のいずれか一項記載の組成物であって、前記方法が前記組成物の治療的有効量を、対象へ投与することを含む、組成物。
- 免疫応答を増強、刺激、調節及び/又は増大することを必要とする対象において免疫応答を増強、刺激、調節及び/又は増大する方法における使用のための、請求項1~27のいずれか一項記載の化合物若しくはその医薬として許容し得る塩を含有する組成物、又は請求項28~30のいずれか一項記載の組成物であって、前記方法が前記組成物の治療的有効量を、対象へ投与することを含む、組成物。
- 癌細胞の成長、増殖、又は転移を阻害することを必要とする対象において癌細胞の成長、増殖、又は転移を阻害する方法における使用のための、請求項1~27のいずれか一項記載の化合物若しくはその医薬として許容し得る塩を含有する組成物、又は請求項28~30のいずれか一項記載の組成物であって、前記方法が前記組成物の治療的有効量を、対象へ投与することを含む、組成物。
- PD-1シグナル伝達経路により媒介される疾患又は障害に罹患した又は易罹患性である対象を治療する方法における使用のための、請求項1~27のいずれか一項記載の化合物若しくはその医薬として許容し得る塩を含有する組成物、又は請求項28~30のいずれか一項記載の組成物であって、前記方法が前記組成物の治療的有効量を、対象へ投与することを含む、組成物。
- 前記対象が、感染症、細菌感染症、ウイルス感染症、真菌感染症、固形癌、悪性血液疾患、免疫障害、炎症疾患、及び癌からなる群から選択される疾患又は障害に罹患している、請求項31~34のいずれか一項記載の組成物。
- 前記疾患又は障害が、メラノーマ、膠芽細胞腫、食道腫瘍、鼻咽頭癌、ブドウ膜メラノーマ、リンパ腫、リンパ球性リンパ腫、原発性CNSリンパ腫、T細胞リンパ腫、びまん性大細胞型B細胞リンパ腫、縦隔原発大細胞型B細胞リンパ腫、前立腺癌、去勢療法-抵抗性前立腺癌、慢性骨髄性白血病、カポジ肉腫、線維肉腫、脂肪肉腫、軟骨肉腫、骨原性肉腫、血管肉腫、リンパ管肉腫、滑液腫、髄膜腫、平滑筋肉腫、横紋筋肉腫、軟組織の肉腫、肉腫、敗血症、胆管腫瘍、基底細胞癌、胸腺腫瘍、甲状腺癌、副甲状腺癌、子宮癌、副腎癌、肝臓感染症、メルケル細胞癌、神経腫瘍、濾胞中心リンパ腫、結腸癌、ホジキン病、非ホジキンリンパ腫、白血病、急性骨髄性白血病、慢性骨髄性白血病、急性リンパ芽球性白血病、慢性リンパ球性白血病を含む慢性又は急性白血病、多発性骨髄腫、卵巣腫瘍、骨髄異形成症候群、皮膚又は眼球内の悪性黒色腫、腎細胞癌、小細胞肺癌、肺癌、中皮腫、乳癌、扁平上皮非小細胞肺癌(SCLC)、非扁平上皮NSCLC、結腸直腸癌、卵巣癌、胃癌、肝細胞癌、膵臓の癌腫、膵臓癌、膵管腺癌、頭頸部の扁平上皮癌、頭頸部癌、消化管癌、胃癌、HIV、A型肝炎、B型肝炎、C型肝炎、D型肝炎、ヘルペスウイルス、パピローマウイルス、インフルエンザ、骨癌、皮膚癌、直腸癌、肛門領域の癌、精巣癌、ファローピウス管の癌腫、子宮内膜癌、子宮頸癌、膣癌、陰門癌、食道癌、小腸癌、内分泌系癌、尿道癌、陰茎癌、膀胱癌、腎臓癌、尿管癌、腎盂癌、中枢神経系(CNS)の腫瘍、腫瘍血管新生、脊髄軸の腫瘍、脳幹神経膠腫、下垂体腺腫、類表皮癌、石綿症、癌腫、腺癌、乳頭状癌、嚢胞腺癌、気管支癌、腎細胞癌腫、移行上皮癌、絨毛癌、精上皮腫、胎生期癌、ウィルムス腫瘍、多形腺腫、肝細胞乳頭腫、腎尿細管腺腫、嚢胞腺腫、乳頭腫、腺腫、平滑筋腫、横紋筋腫、血管腫、リンパ管腫、骨腫、軟骨腫、脂肪腫及び線維腫からなる群から選択される、請求項34記載の組成物。
- 前記方法が更に1又は複数の追加の治療薬の治療的有効量を対象へ投与することを含む、請求項31~36のいずれか一項記載の組成物。
- 前記1又は複数の追加の治療薬が、抗微生物薬、抗ウイルス薬、細胞毒性物質、遺伝子発現モジュレーター、化学療法薬、抗癌剤、血管新生阻害剤、免疫療法薬、抗ホルモン剤、抗線維化物質、放射線治療、放射性治療薬、抗悪性腫瘍薬、及び抗増殖性物質からなる群から選択される、請求項37記載の組成物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201762538123P | 2017-07-28 | 2017-07-28 | |
US62/538,123 | 2017-07-28 | ||
PCT/US2018/044088 WO2019023575A1 (en) | 2017-07-28 | 2018-07-27 | IMMUNOMODULATORY COMPOUNDS |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2020528905A JP2020528905A (ja) | 2020-10-01 |
JP2020528905A5 JP2020528905A5 (ja) | 2021-08-26 |
JP7185681B2 true JP7185681B2 (ja) | 2022-12-07 |
Family
ID=65041004
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2020503970A Active JP7185681B2 (ja) | 2017-07-28 | 2018-07-27 | 免疫調節化合物 |
Country Status (10)
Country | Link |
---|---|
US (2) | US10919852B2 (ja) |
EP (1) | EP3658522B1 (ja) |
JP (1) | JP7185681B2 (ja) |
KR (1) | KR102647257B1 (ja) |
CN (1) | CN111225896B (ja) |
AU (1) | AU2018306619B2 (ja) |
CA (1) | CA3070794A1 (ja) |
IL (1) | IL272258B (ja) |
MA (1) | MA49701A (ja) |
WO (1) | WO2019023575A1 (ja) |
Families Citing this family (37)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW201718581A (zh) | 2015-10-19 | 2017-06-01 | 英塞特公司 | 作為免疫調節劑之雜環化合物 |
ES2928856T3 (es) | 2015-11-19 | 2022-11-23 | Incyte Corp | Compuestos heterocíclicos como inmunomoduladores |
AU2016379372A1 (en) | 2015-12-22 | 2018-08-02 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
AR108396A1 (es) | 2016-05-06 | 2018-08-15 | Incyte Corp | Compuestos heterocíclicos como inmunomoduladores |
EP3464279B1 (en) | 2016-05-26 | 2021-11-24 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
CA3028685A1 (en) | 2016-06-20 | 2017-12-28 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
JP7185532B2 (ja) | 2016-06-27 | 2022-12-07 | ケモセントリックス,インコーポレイティド | 免疫調節化合物 |
ES2930092T3 (es) | 2016-07-14 | 2022-12-07 | Incyte Corp | Compuestos heterocíclicos como inmunomoduladores |
MA46045A (fr) | 2016-08-29 | 2021-04-28 | Incyte Corp | Composés hétérocycliques utilisés comme immunomodulateurs |
MA47120A (fr) | 2016-12-22 | 2021-04-28 | Incyte Corp | Dérivés pyridine utilisés en tant qu'immunomodulateurs |
UA126394C2 (uk) | 2016-12-22 | 2022-09-28 | Інсайт Корпорейшн | Похідні бензоксазолу як імуномодулятори |
ES2874756T3 (es) | 2016-12-22 | 2021-11-05 | Incyte Corp | Derivados de triazolo[1,5-A]piridina como inmunomoduladores |
PT3558990T (pt) | 2016-12-22 | 2022-11-21 | Incyte Corp | Derivados de tetrahidroimidazo[4,5-c]piridina como indutores da internalização de pd-l1 |
WO2019023575A1 (en) | 2017-07-28 | 2019-01-31 | Chemocentryx, Inc. | IMMUNOMODULATORY COMPOUNDS |
JP7198269B2 (ja) | 2017-08-08 | 2022-12-28 | ケモセントリックス,インコーポレイティド | 大員環免疫調節剤 |
IL300572A (en) | 2018-02-13 | 2023-04-01 | Gilead Sciences Inc | PD–1/PD–L1 inhibitors |
EP3755311A4 (en) * | 2018-02-22 | 2021-11-10 | ChemoCentryx, Inc. | USEFUL INDANE-AMINES AS AN AGONISTS OF PD-L1 |
US11578054B2 (en) | 2018-03-01 | 2023-02-14 | Bristol-Myers Squibb Company | Compounds useful as immunomodulators |
IL313101A (en) | 2018-03-30 | 2024-07-01 | Incyte Corp | Heterocyclic compounds as immunomodulators |
US10899735B2 (en) | 2018-04-19 | 2021-01-26 | Gilead Sciences, Inc. | PD-1/PD-L1 inhibitors |
SG11202011165TA (en) | 2018-05-11 | 2020-12-30 | Incyte Corp | Tetrahydro-imidazo[4,5-c]pyridine derivatives as pd-l1 immunomodulators |
PE20210642A1 (es) | 2018-07-13 | 2021-03-23 | Gilead Sciences Inc | Inhibidores de pd-1/pd-l1 |
MA53506A (fr) * | 2018-08-29 | 2021-07-07 | Chemocentryx Inc | Méthodes de traitement du cancer avec des inhibiteurs de pd-l1 à petites molécules |
AU2019366355B2 (en) | 2018-10-24 | 2022-10-13 | Gilead Sciences, Inc. | PD-1/PD-L1 inhibitors |
BR112021025888A2 (pt) | 2019-07-10 | 2022-04-26 | Chemocentryx Inc | Indanos como inibidores de pd-l1 |
CA3150434A1 (en) | 2019-08-09 | 2021-02-18 | Incyte Corporation | Salts of a pd-1/pd-l1 inhibitor |
CN112457305A (zh) * | 2019-09-09 | 2021-03-09 | 上海长森药业有限公司 | 含三环结构的芳香杂环化合物,及其制备方法和应用 |
US11401279B2 (en) | 2019-09-30 | 2022-08-02 | Incyte Corporation | Pyrido[3,2-d]pyrimidine compounds as immunomodulators |
JP2022551972A (ja) | 2019-10-16 | 2022-12-14 | ケモセントリックス,インコーポレイティド | Pd-l1疾患の治療のためのヘテロアリール-ビフェニルアミン |
BR112022009031A2 (pt) | 2019-11-11 | 2022-10-11 | Incyte Corp | Sais e formas cristalinas de um inibidor de pd-1/pd-l1 |
JP2023525116A (ja) | 2020-05-11 | 2023-06-14 | シャンハイ ロングウッド バイオファルマシューティカルズ カンパニー リミテッド | 免疫調節剤としてのビアリール環結合芳香族複素環誘導体の調製およびその適用 |
AU2021297216A1 (en) * | 2020-06-23 | 2023-02-02 | Chemocentryx, Inc. | Methods of treating cancer using heteroaryl-biphenyl amide derivatives |
CN111544599B (zh) * | 2020-07-10 | 2020-12-01 | 有术肌肤管理(深圳)有限公司 | 一种用于治疗痤疮的化合物及其用于制备药物或化妆品的用途 |
IL302590A (en) | 2020-11-06 | 2023-07-01 | Incyte Corp | Process for preparing PD-1/PD-L1 inhibitor and salts and crystalline forms thereof |
US11780836B2 (en) | 2020-11-06 | 2023-10-10 | Incyte Corporation | Process of preparing a PD-1/PD-L1 inhibitor |
US11760756B2 (en) | 2020-11-06 | 2023-09-19 | Incyte Corporation | Crystalline form of a PD-1/PD-L1 inhibitor |
WO2022235754A1 (en) * | 2021-05-05 | 2022-11-10 | Bristol-Myers Squibb Company | Lactone and lactam containing compounds useful as immunomodulators |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017066227A1 (en) | 2015-10-15 | 2017-04-20 | Bristol-Myers Squibb Company | Compounds useful as immunomodulators |
Family Cites Families (86)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL120266A (en) | 1996-02-28 | 2005-05-17 | Pfizer | Use of estrogen antagonists and estrogen agonists in the preparation of medicaments for inhibiting pathological conditions |
AR036237A1 (es) | 2001-07-27 | 2004-08-25 | Bayer Corp | Derivados del acido indan acetico, intermediarios, y metodo para su preparacion, composicion farmaceutica y el uso de dichos derivados para la manufactura de un medicamento |
WO2007033002A1 (en) * | 2005-09-14 | 2007-03-22 | Amgen Inc. | Conformationally constrained 3- (4-hydroxy-phenyl) - substituted-propanoic acids useful for treating metabolic disorders |
PL2402319T3 (pl) | 2006-03-31 | 2018-02-28 | Novartis Ag | Inhibitory DGAT |
WO2008008059A1 (en) | 2006-07-12 | 2008-01-17 | Locus Pharmaceuticals, Inc. | Anti-cancer agents ans uses thereof |
WO2008089307A2 (en) | 2007-01-18 | 2008-07-24 | Lexicon Pharmaceuticals, Inc. | Delta 5 desaturase inhibitors for the treatment of pain, inflammation and cancer |
EP2207781B1 (en) * | 2007-09-24 | 2012-11-28 | Genentech, Inc. | Thiazolopyrimidine p13k inhibitor compounds and methods of use |
US8338441B2 (en) | 2009-05-15 | 2012-12-25 | Gilead Sciences, Inc. | Inhibitors of human immunodeficiency virus replication |
RU2524341C2 (ru) * | 2010-03-19 | 2014-07-27 | Пфайзер Инк. | Производные 2,3-дигидро-1н-инден-1-ил-2,7-диазаспиро[3.5]нонана и их применение в качестве антагонистов или обратных агонистов грелинового рецептора |
US9308236B2 (en) | 2013-03-15 | 2016-04-12 | Bristol-Myers Squibb Company | Macrocyclic inhibitors of the PD-1/PD-L1 and CD80(B7-1)/PD-L1 protein/protein interactions |
JP6417419B2 (ja) * | 2013-09-04 | 2018-11-07 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | 免疫調節剤として有用な化合物 |
EP3363790B1 (en) | 2013-09-06 | 2020-02-19 | Aurigene Discovery Technologies Limited | 1,2,4-oxadiazole derivatives as immunomodulators |
KR20160081898A (ko) | 2013-09-06 | 2016-07-08 | 오리진 디스커버리 테크놀로지스 리미티드 | 면역조절제로서 1,3,4-옥사디아졸 및 1,3,4-티아디아졸 유도체 |
US9850225B2 (en) * | 2014-04-14 | 2017-12-26 | Bristol-Myers Squibb Company | Compounds useful as immunomodulators |
CA2979163A1 (en) | 2015-03-10 | 2016-09-15 | Aurigene Discovery Technologies Limited | 3-substituted 1,3,4-oxadiazole and thiadiazole compounds as immunomodulators |
AU2016230759A1 (en) | 2015-03-10 | 2017-09-07 | Aurigene Discovery Technologies Limited | 3-substituted-1,2,4-oxadiazole and thiadiazole compounds as immunomodulators |
TW201718581A (zh) | 2015-10-19 | 2017-06-01 | 英塞特公司 | 作為免疫調節劑之雜環化合物 |
ES2928856T3 (es) | 2015-11-19 | 2022-11-23 | Incyte Corp | Compuestos heterocíclicos como inmunomoduladores |
ES2916874T3 (es) | 2015-12-17 | 2022-07-06 | Incyte Corp | Derivados de N-fenil-piridina-2-carboxamida y su uso como moduladores de la interacción proteína/proteína PD-1/PD-L1 |
AU2016379372A1 (en) | 2015-12-22 | 2018-08-02 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
EP3190103A1 (en) * | 2016-01-08 | 2017-07-12 | Rijksuniversiteit Groningen | Inhibitors of the pd-1/pd-l1 protein/protein interaction |
BR112018070361A2 (pt) | 2016-04-07 | 2019-01-29 | Chemocentryx Inc | redução da carga tumoral através da administração de antagonistas do ccr1 em combinação com inibidores de pd-1 ou inibidores de pd-l1 |
US10545298B2 (en) | 2016-12-21 | 2020-01-28 | Corning Research & Development Corporation | Traceable fiber optic cable assembly with illumination structure and tracing optical fibers for carrying light received from a light launch device |
AR108396A1 (es) | 2016-05-06 | 2018-08-15 | Incyte Corp | Compuestos heterocíclicos como inmunomoduladores |
KR102364344B1 (ko) | 2016-05-23 | 2022-02-18 | 인스티튜드 오브 머테리아 메디카, 차이니스 아케데미 오브 메디컬 싸이언시스 | 니코티닐 알콜 에테르 유도체, 그의 제조 방법, 및 그의 약학적 조성물 및 용도 |
EP3464279B1 (en) | 2016-05-26 | 2021-11-24 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
CA3028685A1 (en) | 2016-06-20 | 2017-12-28 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
JP7185532B2 (ja) | 2016-06-27 | 2022-12-07 | ケモセントリックス,インコーポレイティド | 免疫調節化合物 |
US11078192B2 (en) | 2016-07-05 | 2021-08-03 | Guangzhou Maxinovel Pharmaceuticals Co., Ltd. | Aromatic acetylene or aromatic ethylene compound, intermediate, preparation method, pharmaceutical composition and use thereof |
KR102491992B1 (ko) | 2016-07-08 | 2023-01-25 | 브리스톨-마이어스 스큅 컴퍼니 | 면역조정제로서 유용한 1,3-디히드록시-페닐 유도체 |
ES2930092T3 (es) | 2016-07-14 | 2022-12-07 | Incyte Corp | Compuestos heterocíclicos como inmunomoduladores |
MA46045A (fr) | 2016-08-29 | 2021-04-28 | Incyte Corp | Composés hétérocycliques utilisés comme immunomodulateurs |
US10144706B2 (en) | 2016-09-01 | 2018-12-04 | Bristol-Myers Squibb Company | Compounds useful as immunomodulators |
US20180065917A1 (en) | 2016-09-02 | 2018-03-08 | Polaris Pharmaceuticals, Inc. | Immune checkpoint inhibitors, compositions and methods thereof |
WO2018051255A1 (en) | 2016-09-14 | 2018-03-22 | Aurigene Discovery Technologies Limited | Cyclic substituted-1,3,4-oxadiazole and thiadiazole compounds as immunomodulators |
WO2018051254A1 (en) | 2016-09-14 | 2018-03-22 | Aurigene Discovery Technologies Limited | Cyclic substituted-1,2,4-oxadiazole compounds as immunomodulators |
EP3558970B1 (en) | 2016-12-20 | 2021-09-01 | Bristol-Myers Squibb Company | Compounds useful as immunomodulators |
US20180177784A1 (en) | 2016-12-22 | 2018-06-28 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
ES2874756T3 (es) | 2016-12-22 | 2021-11-05 | Incyte Corp | Derivados de triazolo[1,5-A]piridina como inmunomoduladores |
MA47120A (fr) | 2016-12-22 | 2021-04-28 | Incyte Corp | Dérivés pyridine utilisés en tant qu'immunomodulateurs |
PT3558990T (pt) | 2016-12-22 | 2022-11-21 | Incyte Corp | Derivados de tetrahidroimidazo[4,5-c]piridina como indutores da internalização de pd-l1 |
UA126394C2 (uk) | 2016-12-22 | 2022-09-28 | Інсайт Корпорейшн | Похідні бензоксазолу як імуномодулятори |
WO2018119286A1 (en) | 2016-12-22 | 2018-06-28 | Incyte Corporation | Bicyclic heteroaromatic compounds as immunomodulators |
EP3564237A4 (en) | 2016-12-29 | 2020-06-10 | Shenzhen Chipscreen Biosciences Co., Ltd. | UREA COMPOUND AND PRODUCTION METHOD AND USE THEREOF |
CN108395443B (zh) | 2017-02-04 | 2021-05-04 | 广州丹康医药生物有限公司 | 抑制程序性死亡受体配体1的环状化合物及其用途 |
ES2961550T3 (es) | 2017-03-27 | 2024-03-12 | Bristol Myers Squibb Co | Derivados de isoquinolina sustituidos como inmunomoduladores |
JOP20180040A1 (ar) | 2017-04-20 | 2019-01-30 | Gilead Sciences Inc | مثبطات pd-1/pd-l1 |
WO2018196768A1 (zh) | 2017-04-26 | 2018-11-01 | 南京圣和药业股份有限公司 | 作为pd-l1抑制剂的杂环类化合物 |
CN108863963B (zh) | 2017-05-08 | 2022-05-27 | 南京圣和药物研发有限公司 | 作为pd-l1抑制剂的杂环类化合物 |
WO2019023575A1 (en) | 2017-07-28 | 2019-01-31 | Chemocentryx, Inc. | IMMUNOMODULATORY COMPOUNDS |
JP7198269B2 (ja) | 2017-08-08 | 2022-12-28 | ケモセントリックス,インコーポレイティド | 大員環免疫調節剤 |
US11787766B2 (en) | 2017-08-18 | 2023-10-17 | Shanghai Ennovabio Pharmaceuticals Co., Ltd. | Compound having PD-L1 inhibitory activity, preparation method therefor and use thereof |
EP3692053A1 (en) | 2017-10-03 | 2020-08-12 | Bristol-Myers Squibb Company | Immunomodulators |
CN109665968B (zh) | 2017-10-16 | 2022-02-22 | 四川科伦博泰生物医药股份有限公司 | 并环化合物及其制备方法和用途 |
CN109678796B (zh) | 2017-10-19 | 2023-01-10 | 上海长森药业有限公司 | Pd-1/pd-l1小分子抑制剂及其制备方法和用途 |
CN109721527B (zh) | 2017-10-27 | 2024-03-12 | 广州丹康医药生物有限公司 | 一种新型抗pd-l1化合物、其应用及含其的组合物 |
SG11202004143XA (en) | 2017-11-06 | 2020-06-29 | Jubilant Prodel LLC | Pyrimidine derivatives as inhibitors of pd1/pd-l1 activation |
CN109956898B (zh) | 2017-12-22 | 2021-03-26 | 上海海雁医药科技有限公司 | 免疫调节剂及其制法与医药上的用途 |
JP7293560B2 (ja) | 2017-12-29 | 2023-06-20 | グアンジョウ マキシノベル ファーマシューティカルズ カンパニー リミテッド | 芳香族ビニルまたは芳香族エチル系誘導体、その製造方法、中間体、薬物組成物および使用 |
CN111868061A (zh) | 2018-01-23 | 2020-10-30 | 百时美施贵宝公司 | 用作免疫调节剂的2,8-二酰基-2,8-二氮杂螺[5.5]十一烷化合物 |
CN111448189A (zh) | 2018-02-05 | 2020-07-24 | 上海和誉生物医药科技有限公司 | 一种联芳基衍生物、其制备方法和在药学上的应用 |
IL300572A (en) | 2018-02-13 | 2023-04-01 | Gilead Sciences Inc | PD–1/PD–L1 inhibitors |
EP3755311A4 (en) | 2018-02-22 | 2021-11-10 | ChemoCentryx, Inc. | USEFUL INDANE-AMINES AS AN AGONISTS OF PD-L1 |
US11578054B2 (en) | 2018-03-01 | 2023-02-14 | Bristol-Myers Squibb Company | Compounds useful as immunomodulators |
CN112105610B (zh) | 2018-03-13 | 2024-01-26 | 朱比连特普罗德尔有限责任公司 | 作为pd1/pd-l1相互作用/活化的抑制剂的双环化合物 |
WO2019174533A1 (zh) | 2018-03-13 | 2019-09-19 | 广东东阳光药业有限公司 | Pd-1/pd-l1类小分子抑制剂及其在药物中的应用 |
IL313101A (en) | 2018-03-30 | 2024-07-01 | Incyte Corp | Heterocyclic compounds as immunomodulators |
JP2021520342A (ja) | 2018-04-03 | 2021-08-19 | ベータ ファーマシューティカルズ カンパニー リミテッド | 免疫調節物質、組成物及びそれらの方法 |
US10899735B2 (en) | 2018-04-19 | 2021-01-26 | Gilead Sciences, Inc. | PD-1/PD-L1 inhibitors |
SG11202011165TA (en) | 2018-05-11 | 2020-12-30 | Incyte Corp | Tetrahydro-imidazo[4,5-c]pyridine derivatives as pd-l1 immunomodulators |
WO2020011209A1 (zh) | 2018-07-11 | 2020-01-16 | 上海和誉生物医药科技有限公司 | 免疫抑制剂及其制备方法和在药学上的应用 |
US20220119411A1 (en) | 2018-07-12 | 2022-04-21 | Betta Pharmaceuticals Co., Ltd | Immunomodulators, compositions and methods thereof |
PE20210642A1 (es) | 2018-07-13 | 2021-03-23 | Gilead Sciences Inc | Inhibidores de pd-1/pd-l1 |
US20210269440A1 (en) | 2018-07-19 | 2021-09-02 | Betta Pharmaceuticals Co., Ltd | Immunomodulators, compositions and methods thereof |
US20210300909A1 (en) | 2018-07-19 | 2021-09-30 | Betta Pharmaceuticals Co., Ltd | Immunomodulators, compositions and methods thereof |
US20210347785A1 (en) | 2018-08-01 | 2021-11-11 | Shanghai Ennovabio Pharmaceuticals Co., Ltd. | Preparation and application of aromatic compound having immunoregulatory function |
MA53506A (fr) | 2018-08-29 | 2021-07-07 | Chemocentryx Inc | Méthodes de traitement du cancer avec des inhibiteurs de pd-l1 à petites molécules |
CN109336857A (zh) | 2018-11-13 | 2019-02-15 | 南方医科大学 | 一种含取代联苯的黄酮及其应用 |
CN109438263A (zh) | 2018-11-28 | 2019-03-08 | 南方医科大学 | 一种含取代联苯的萘及其应用 |
CN109503546A (zh) | 2019-01-10 | 2019-03-22 | 南方医科大学 | 一种间苯二酚二苯甲醚及其应用 |
CN109776377B (zh) | 2019-02-01 | 2021-08-24 | 沈阳药科大学 | 吲哚啉类化合物及其制备方法和应用 |
CN109776445B (zh) | 2019-03-28 | 2022-12-06 | 中国药科大学 | 苯并噁二唑类化合物及其制备方法和医药用途 |
BR112021022659A2 (pt) | 2019-05-15 | 2022-03-29 | Chemocentryx Inc | Compostos triarílicos para o tratamento de doenças pd-l1 |
CN110200959A (zh) | 2019-05-30 | 2019-09-06 | 天津科技大学 | 一种黄酮类化合物的应用 |
CN110128415B (zh) | 2019-05-31 | 2022-03-25 | 沈阳药科大学 | 用作免疫调节剂的吲哚啉类化合物及其制备方法 |
BR112021025888A2 (pt) | 2019-07-10 | 2022-04-26 | Chemocentryx Inc | Indanos como inibidores de pd-l1 |
-
2018
- 2018-07-27 WO PCT/US2018/044088 patent/WO2019023575A1/en active Application Filing
- 2018-07-27 JP JP2020503970A patent/JP7185681B2/ja active Active
- 2018-07-27 CN CN201880050031.4A patent/CN111225896B/zh active Active
- 2018-07-27 EP EP18837877.2A patent/EP3658522B1/en active Active
- 2018-07-27 US US16/047,545 patent/US10919852B2/en active Active
- 2018-07-27 CA CA3070794A patent/CA3070794A1/en active Pending
- 2018-07-27 AU AU2018306619A patent/AU2018306619B2/en active Active
- 2018-07-27 MA MA049701A patent/MA49701A/fr unknown
- 2018-07-27 KR KR1020207005493A patent/KR102647257B1/ko active IP Right Grant
- 2018-07-27 IL IL272258A patent/IL272258B/en unknown
-
2020
- 2020-11-30 US US17/106,309 patent/US11708326B2/en active Active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017066227A1 (en) | 2015-10-15 | 2017-04-20 | Bristol-Myers Squibb Company | Compounds useful as immunomodulators |
Non-Patent Citations (1)
Title |
---|
Expert Opinion on Therapeutic Patents,2016年,26(9),973-977 |
Also Published As
Publication number | Publication date |
---|---|
US20190135745A1 (en) | 2019-05-09 |
JP2020528905A (ja) | 2020-10-01 |
CN111225896A (zh) | 2020-06-02 |
EP3658522A1 (en) | 2020-06-03 |
MA49701A (fr) | 2020-06-03 |
AU2018306619B2 (en) | 2022-06-02 |
EP3658522A4 (en) | 2020-11-25 |
IL272258B (en) | 2022-08-01 |
WO2019023575A1 (en) | 2019-01-31 |
AU2018306619A1 (en) | 2020-02-06 |
CN111225896B (zh) | 2024-03-26 |
IL272258A (en) | 2020-03-31 |
KR20200057700A (ko) | 2020-05-26 |
US20210147356A1 (en) | 2021-05-20 |
CA3070794A1 (en) | 2019-01-31 |
KR102647257B1 (ko) | 2024-03-13 |
US11708326B2 (en) | 2023-07-25 |
US10919852B2 (en) | 2021-02-16 |
EP3658522B1 (en) | 2021-12-22 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7185681B2 (ja) | 免疫調節化合物 | |
US11793771B2 (en) | Immunomodulator compounds | |
US11691985B2 (en) | Macrocyclic immunomodulators | |
US11266643B2 (en) | Triaryl compounds for treatment of PD-L1 diseases | |
US11759458B2 (en) | Indane-amines as PD-L1 antagonists | |
US11713307B2 (en) | Heteroaryl-biphenyl amides for the treatment of PD-L1 diseases | |
JP2022551972A (ja) | Pd-l1疾患の治療のためのヘテロアリール-ビフェニルアミン | |
JP2022539830A (ja) | Pd-l1阻害剤としてのインダン |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20210713 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20210713 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20220628 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20220630 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20220928 |
|
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: 20221101 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20221125 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 7185681 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |