JP6948398B2 - キナーゼ阻害剤としてのアミド化合物 - Google Patents
キナーゼ阻害剤としてのアミド化合物 Download PDFInfo
- Publication number
- JP6948398B2 JP6948398B2 JP2019543185A JP2019543185A JP6948398B2 JP 6948398 B2 JP6948398 B2 JP 6948398B2 JP 2019543185 A JP2019543185 A JP 2019543185A JP 2019543185 A JP2019543185 A JP 2019543185A JP 6948398 B2 JP6948398 B2 JP 6948398B2
- Authority
- JP
- Japan
- Prior art keywords
- alkyl
- disease
- nhc
- cancer
- cycloalkyl
- 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
- -1 Amide compounds Chemical class 0.000 title claims description 139
- 229940043355 kinase inhibitor Drugs 0.000 title 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 155
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 80
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 78
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 74
- 125000003118 aryl group Chemical group 0.000 claims description 69
- 125000000623 heterocyclic group Chemical group 0.000 claims description 60
- 125000005843 halogen group Chemical group 0.000 claims description 48
- 208000035475 disorder Diseases 0.000 claims description 41
- 201000010099 disease Diseases 0.000 claims description 37
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 34
- 125000000018 nitroso group Chemical group N(=O)* 0.000 claims description 33
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims description 31
- 206010028980 Neoplasm Diseases 0.000 claims description 30
- 208000032839 leukemia Diseases 0.000 claims description 25
- 230000000694 effects Effects 0.000 claims description 24
- 201000011510 cancer Diseases 0.000 claims description 21
- 101000932478 Homo sapiens Receptor-type tyrosine-protein kinase FLT3 Proteins 0.000 claims description 19
- 102100020718 Receptor-type tyrosine-protein kinase FLT3 Human genes 0.000 claims description 19
- 101000669921 Homo sapiens Rho-associated protein kinase 2 Proteins 0.000 claims description 18
- 102100039314 Rho-associated protein kinase 2 Human genes 0.000 claims description 18
- 102000001253 Protein Kinase Human genes 0.000 claims description 17
- 108060006633 protein kinase Proteins 0.000 claims description 17
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 16
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 15
- 101000669917 Homo sapiens Rho-associated protein kinase 1 Proteins 0.000 claims description 14
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- 102100039313 Rho-associated protein kinase 1 Human genes 0.000 claims description 14
- 208000023275 Autoimmune disease Diseases 0.000 claims description 13
- 230000001613 neoplastic effect Effects 0.000 claims description 13
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 12
- 208000027866 inflammatory disease Diseases 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 208000011580 syndromic disease Diseases 0.000 claims description 12
- 206010061218 Inflammation Diseases 0.000 claims description 11
- 230000015572 biosynthetic process Effects 0.000 claims description 11
- 230000004054 inflammatory process Effects 0.000 claims description 11
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims description 10
- 208000014767 Myeloproliferative disease Diseases 0.000 claims description 10
- 208000029726 Neurodevelopmental disease Diseases 0.000 claims description 10
- 230000004770 neurodegeneration Effects 0.000 claims description 10
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 10
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 claims description 9
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 claims description 9
- 206010020772 Hypertension Diseases 0.000 claims description 9
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 claims description 9
- 230000033228 biological regulation Effects 0.000 claims description 9
- 208000015181 infectious disease Diseases 0.000 claims description 9
- 125000001624 naphthyl group Chemical group 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 206010006187 Breast cancer Diseases 0.000 claims description 8
- 208000026310 Breast neoplasm Diseases 0.000 claims description 8
- 208000035473 Communicable disease Diseases 0.000 claims description 8
- 206010058314 Dysplasia Diseases 0.000 claims description 8
- 206010033128 Ovarian cancer Diseases 0.000 claims description 8
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 8
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 8
- 206010060862 Prostate cancer Diseases 0.000 claims description 8
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 8
- 230000003176 fibrotic effect Effects 0.000 claims description 8
- 208000014951 hematologic disease Diseases 0.000 claims description 8
- 230000002757 inflammatory effect Effects 0.000 claims description 8
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 8
- 201000000050 myeloid neoplasm Diseases 0.000 claims description 8
- 201000002528 pancreatic cancer Diseases 0.000 claims description 8
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 8
- 108091008598 receptor tyrosine kinases Proteins 0.000 claims description 8
- 102000027426 receptor tyrosine kinases Human genes 0.000 claims description 8
- 208000024827 Alzheimer disease Diseases 0.000 claims description 7
- 208000019838 Blood disease Diseases 0.000 claims description 7
- 206010015150 Erythema Diseases 0.000 claims description 7
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 7
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 7
- 208000018737 Parkinson disease Diseases 0.000 claims description 7
- 206010038389 Renal cancer Diseases 0.000 claims description 7
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- 208000018706 hematopoietic system disease Diseases 0.000 claims description 7
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
- 201000010982 kidney cancer Diseases 0.000 claims description 7
- 201000005202 lung cancer Diseases 0.000 claims description 7
- 208000020816 lung neoplasm Diseases 0.000 claims description 7
- 201000006417 multiple sclerosis Diseases 0.000 claims description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
- 208000010412 Glaucoma Diseases 0.000 claims description 6
- 206010025323 Lymphomas Diseases 0.000 claims description 6
- 208000034578 Multiple myelomas Diseases 0.000 claims description 6
- 201000007224 Myeloproliferative neoplasm Diseases 0.000 claims description 6
- 208000027190 Peripheral T-cell lymphomas Diseases 0.000 claims description 6
- 201000004681 Psoriasis Diseases 0.000 claims description 6
- 208000031672 T-Cell Peripheral Lymphoma Diseases 0.000 claims description 6
- 230000001154 acute effect Effects 0.000 claims description 6
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 6
- 231100000321 erythema Toxicity 0.000 claims description 6
- 230000002489 hematologic effect Effects 0.000 claims description 6
- 208000020968 mature T-cell and NK-cell non-Hodgkin lymphoma Diseases 0.000 claims description 6
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 6
- 208000025638 primary cutaneous T-cell non-Hodgkin lymphoma Diseases 0.000 claims description 6
- 208000023105 Huntington disease Diseases 0.000 claims description 5
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 5
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 5
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 5
- 208000031673 T-Cell Cutaneous Lymphoma Diseases 0.000 claims description 5
- 230000033115 angiogenesis Effects 0.000 claims description 5
- 230000001684 chronic effect Effects 0.000 claims description 5
- 201000007241 cutaneous T cell lymphoma Diseases 0.000 claims description 5
- 230000002526 effect on cardiovascular system Effects 0.000 claims description 5
- 206010017758 gastric cancer Diseases 0.000 claims description 5
- 210000002464 muscle smooth vascular Anatomy 0.000 claims description 5
- 201000005962 mycosis fungoides Diseases 0.000 claims description 5
- 201000011549 stomach cancer Diseases 0.000 claims description 5
- 230000009885 systemic effect Effects 0.000 claims description 5
- 201000001320 Atherosclerosis Diseases 0.000 claims description 4
- 206010007572 Cardiac hypertrophy Diseases 0.000 claims description 4
- 208000006029 Cardiomegaly Diseases 0.000 claims description 4
- 208000011231 Crohn disease Diseases 0.000 claims description 4
- 206010012438 Dermatitis atopic Diseases 0.000 claims description 4
- 206010012688 Diabetic retinal oedema Diseases 0.000 claims description 4
- 208000010228 Erectile Dysfunction Diseases 0.000 claims description 4
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 4
- 201000001263 Psoriatic Arthritis Diseases 0.000 claims description 4
- 208000036824 Psoriatic arthropathy Diseases 0.000 claims description 4
- 208000006289 Rett Syndrome Diseases 0.000 claims description 4
- 206010064930 age-related macular degeneration Diseases 0.000 claims description 4
- 206010003246 arthritis Diseases 0.000 claims description 4
- 208000006673 asthma Diseases 0.000 claims description 4
- 201000008937 atopic dermatitis Diseases 0.000 claims description 4
- 208000010668 atopic eczema Diseases 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 201000011190 diabetic macular edema Diseases 0.000 claims description 4
- 230000004064 dysfunction Effects 0.000 claims description 4
- 208000030533 eye disease Diseases 0.000 claims description 4
- 201000001881 impotence Diseases 0.000 claims description 4
- 208000002780 macular degeneration Diseases 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 208000037803 restenosis Diseases 0.000 claims description 4
- 206010073478 Anaplastic large-cell lymphoma Diseases 0.000 claims description 3
- 206010003210 Arteriosclerosis Diseases 0.000 claims description 3
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims description 3
- 201000006474 Brain Ischemia Diseases 0.000 claims description 3
- 206010008120 Cerebral ischaemia Diseases 0.000 claims description 3
- 201000004624 Dermatitis Diseases 0.000 claims description 3
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims description 3
- 208000011775 arteriosclerosis disease Diseases 0.000 claims description 3
- 206010008118 cerebral infarction Diseases 0.000 claims description 3
- 239000007943 implant Substances 0.000 claims description 3
- 208000001286 intracranial vasospasm Diseases 0.000 claims description 3
- 230000000366 juvenile effect Effects 0.000 claims description 3
- 201000005992 juvenile myelomonocytic leukemia Diseases 0.000 claims description 3
- 208000025113 myeloid leukemia Diseases 0.000 claims description 3
- 201000006845 reticulosarcoma Diseases 0.000 claims description 3
- 208000029922 reticulum cell sarcoma Diseases 0.000 claims description 3
- 210000000278 spinal cord Anatomy 0.000 claims description 3
- 208000002320 spinal muscular atrophy Diseases 0.000 claims description 3
- 208000017604 Hodgkin disease Diseases 0.000 claims description 2
- 208000010747 Hodgkins lymphoma Diseases 0.000 claims description 2
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 2
- 206010038910 Retinitis Diseases 0.000 claims description 2
- 208000029052 T-cell acute lymphoblastic leukemia 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
- 230000002491 angiogenic effect Effects 0.000 claims description 2
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 2
- 230000004060 metabolic process Effects 0.000 claims description 2
- 201000008383 nephritis Diseases 0.000 claims description 2
- 230000002028 premature Effects 0.000 claims description 2
- 208000005069 pulmonary fibrosis Diseases 0.000 claims description 2
- 201000002793 renal fibrosis Diseases 0.000 claims description 2
- 230000002792 vascular Effects 0.000 claims description 2
- 206010019668 Hepatic fibrosis Diseases 0.000 claims 1
- 210000003494 hepatocyte Anatomy 0.000 claims 1
- 210000000440 neutrophil Anatomy 0.000 claims 1
- 201000003068 rheumatic fever Diseases 0.000 claims 1
- 208000012201 sexual and gender identity disease Diseases 0.000 claims 1
- 208000015891 sexual disease Diseases 0.000 claims 1
- 238000000034 method Methods 0.000 description 46
- 125000004093 cyano group Chemical group *C#N 0.000 description 39
- 239000000203 mixture Substances 0.000 description 35
- 150000003839 salts Chemical class 0.000 description 24
- 210000004027 cell Anatomy 0.000 description 23
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 21
- 239000011435 rock Substances 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 17
- 125000004432 carbon atom Chemical group C* 0.000 description 16
- 239000003112 inhibitor Substances 0.000 description 16
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 15
- 239000003814 drug Substances 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- 230000005764 inhibitory process Effects 0.000 description 14
- 108091000080 Phosphotransferase Proteins 0.000 description 13
- 125000004429 atom Chemical group 0.000 description 13
- 102000020233 phosphotransferase Human genes 0.000 description 13
- 230000008569 process Effects 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 125000000217 alkyl group Chemical group 0.000 description 12
- 108010041788 rho-Associated Kinases Proteins 0.000 description 12
- 102000000568 rho-Associated Kinases Human genes 0.000 description 12
- 125000001424 substituent group Chemical group 0.000 description 11
- 239000000758 substrate Substances 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- 230000001225 therapeutic effect Effects 0.000 description 11
- 0 Cc1cc(CN(C)*)c(*)cc1 Chemical compound Cc1cc(CN(C)*)c(*)cc1 0.000 description 10
- 230000004663 cell proliferation Effects 0.000 description 10
- 238000004440 column chromatography Methods 0.000 description 10
- 229940079593 drug Drugs 0.000 description 10
- 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 9
- 239000002253 acid Substances 0.000 description 9
- 230000002062 proliferating effect Effects 0.000 description 9
- 102000004190 Enzymes Human genes 0.000 description 8
- 108090000790 Enzymes Proteins 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- 208000030159 metabolic disease Diseases 0.000 description 8
- 230000026731 phosphorylation Effects 0.000 description 8
- 238000006366 phosphorylation reaction Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 108090000765 processed proteins & peptides Proteins 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- 125000004076 pyridyl group Chemical group 0.000 description 7
- 239000000523 sample Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 101100356682 Caenorhabditis elegans rho-1 gene Proteins 0.000 description 6
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 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 6
- 239000007821 HATU Substances 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 6
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 6
- 101150111584 RHOA gene Proteins 0.000 description 6
- 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 6
- 229910052736 halogen Inorganic materials 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000000651 prodrug Substances 0.000 description 6
- 229940002612 prodrug Drugs 0.000 description 6
- 235000018102 proteins Nutrition 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 206010039073 rheumatoid arthritis Diseases 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 125000003003 spiro group Chemical group 0.000 description 6
- 229910052717 sulfur Inorganic materials 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 5
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 208000012902 Nervous system disease Diseases 0.000 description 5
- 102100027609 Rho-related GTP-binding protein RhoD Human genes 0.000 description 5
- 230000002159 abnormal effect Effects 0.000 description 5
- 125000003342 alkenyl group Chemical group 0.000 description 5
- 125000000304 alkynyl group Chemical group 0.000 description 5
- 239000011575 calcium Substances 0.000 description 5
- 229910052791 calcium Inorganic materials 0.000 description 5
- 239000000969 carrier Substances 0.000 description 5
- 125000004122 cyclic group Chemical group 0.000 description 5
- 208000016097 disease of metabolism Diseases 0.000 description 5
- 150000002367 halogens Chemical class 0.000 description 5
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 5
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 5
- 125000001072 heteroaryl group Chemical group 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 201000007270 liver cancer Diseases 0.000 description 5
- 208000014018 liver neoplasm Diseases 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 125000002950 monocyclic group Chemical group 0.000 description 5
- 230000035772 mutation Effects 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 230000037361 pathway Effects 0.000 description 5
- 230000019491 signal transduction Effects 0.000 description 5
- 239000012453 solvate Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 4
- HBEDSQVIWPRPAY-UHFFFAOYSA-N 2,3-dihydrobenzofuran Chemical compound C1=CC=C2OCCC2=C1 HBEDSQVIWPRPAY-UHFFFAOYSA-N 0.000 description 4
- 206010009944 Colon cancer Diseases 0.000 description 4
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 4
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 4
- 101001000061 Homo sapiens Protein phosphatase 1 regulatory subunit 12A Proteins 0.000 description 4
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 4
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 4
- 102100036547 Protein phosphatase 1 regulatory subunit 12A Human genes 0.000 description 4
- 208000036676 acute undifferentiated leukemia Diseases 0.000 description 4
- 208000009956 adenocarcinoma Diseases 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 208000035269 cancer or benign tumor Diseases 0.000 description 4
- 230000003915 cell function Effects 0.000 description 4
- 230000003833 cell viability Effects 0.000 description 4
- 208000015114 central nervous system disease Diseases 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 125000001309 chloro group Chemical group Cl* 0.000 description 4
- 125000000392 cycloalkenyl group Chemical group 0.000 description 4
- 125000004981 cycloalkylmethyl group Chemical group 0.000 description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 4
- 201000004101 esophageal cancer Diseases 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 235000001727 glucose Nutrition 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 4
- 239000011777 magnesium Substances 0.000 description 4
- 230000003211 malignant effect Effects 0.000 description 4
- 206010028537 myelofibrosis Diseases 0.000 description 4
- 210000002569 neuron Anatomy 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 125000003226 pyrazolyl group Chemical group 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 3
- DZLGZIGLHCRIMF-UHFFFAOYSA-N 4-pyridin-4-ylbenzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C1=CC=NC=C1 DZLGZIGLHCRIMF-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 206010005003 Bladder cancer Diseases 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 238000003734 CellTiter-Glo Luminescent Cell Viability Assay Methods 0.000 description 3
- 206010008342 Cervix carcinoma Diseases 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 206010019280 Heart failures Diseases 0.000 description 3
- 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 101100335081 Mus musculus Flt3 gene Proteins 0.000 description 3
- 102000016349 Myosin Light Chains Human genes 0.000 description 3
- 108010067385 Myosin Light Chains Proteins 0.000 description 3
- 108010037801 Myosin-Light-Chain Phosphatase Proteins 0.000 description 3
- 102000011131 Myosin-Light-Chain Phosphatase Human genes 0.000 description 3
- 208000025966 Neurological disease Diseases 0.000 description 3
- 208000033755 Neutrophilic Chronic Leukemia Diseases 0.000 description 3
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 3
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 3
- 102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 208000024313 Testicular Neoplasms Diseases 0.000 description 3
- 206010057644 Testis cancer Diseases 0.000 description 3
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 3
- 208000024770 Thyroid neoplasm Diseases 0.000 description 3
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 3
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 3
- 208000002495 Uterine Neoplasms Diseases 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 206010002449 angioimmunoblastic T-cell lymphoma Diseases 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 3
- 125000002619 bicyclic group Chemical group 0.000 description 3
- 125000001246 bromo group Chemical group Br* 0.000 description 3
- 238000005251 capillar electrophoresis Methods 0.000 description 3
- 201000010881 cervical cancer Diseases 0.000 description 3
- 201000010903 chronic neutrophilic leukemia Diseases 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 208000029742 colonic neoplasm Diseases 0.000 description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 201000010536 head and neck cancer Diseases 0.000 description 3
- 208000014829 head and neck neoplasm Diseases 0.000 description 3
- 150000004677 hydrates Chemical class 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 238000004020 luminiscence type Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 125000002757 morpholinyl group Chemical group 0.000 description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 125000004193 piperazinyl group Chemical group 0.000 description 3
- 125000003367 polycyclic group Chemical group 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 230000016160 smooth muscle contraction Effects 0.000 description 3
- 201000003120 testicular cancer Diseases 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 150000003536 tetrazoles Chemical class 0.000 description 3
- 201000002510 thyroid cancer Diseases 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
- 125000001425 triazolyl group Chemical group 0.000 description 3
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 3
- 201000005112 urinary bladder cancer Diseases 0.000 description 3
- 206010046766 uterine cancer Diseases 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- TUSDEZXZIZRFGC-UHFFFAOYSA-N 1-O-galloyl-3,6-(R)-HHDP-beta-D-glucose Natural products OC1C(O2)COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC1C(O)C2OC(=O)C1=CC(O)=C(O)C(O)=C1 TUSDEZXZIZRFGC-UHFFFAOYSA-N 0.000 description 2
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 2
- IDUSJBBWEKNWAK-UHFFFAOYSA-N 3,4-dihydro-2h-1,2-benzothiazine Chemical compound C1=CC=C2SNCCC2=C1 IDUSJBBWEKNWAK-UHFFFAOYSA-N 0.000 description 2
- JNZYADHPGVZMQK-UHFFFAOYSA-N 3-(aminomethyl)phenol Chemical compound NCC1=CC=CC(O)=C1 JNZYADHPGVZMQK-UHFFFAOYSA-N 0.000 description 2
- ALKYHXVLJMQRLQ-UHFFFAOYSA-N 3-Hydroxy-2-naphthoate Chemical compound C1=CC=C2C=C(O)C(C(=O)O)=CC2=C1 ALKYHXVLJMQRLQ-UHFFFAOYSA-N 0.000 description 2
- 206010003178 Arterial thrombosis Diseases 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 2
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 description 2
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- 201000009030 Carcinoma Diseases 0.000 description 2
- 206010007559 Cardiac failure congestive Diseases 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- 206010014733 Endometrial cancer Diseases 0.000 description 2
- 206010014759 Endometrial neoplasm Diseases 0.000 description 2
- 206010014950 Eosinophilia Diseases 0.000 description 2
- 241000283073 Equus caballus Species 0.000 description 2
- 239000001263 FEMA 3042 Substances 0.000 description 2
- DHCLVCXQIBBOPH-UHFFFAOYSA-N Glycerol 2-phosphate Chemical compound OCC(CO)OP(O)(O)=O DHCLVCXQIBBOPH-UHFFFAOYSA-N 0.000 description 2
- 208000009329 Graft vs Host Disease Diseases 0.000 description 2
- 241000282414 Homo sapiens Species 0.000 description 2
- 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 2
- 206010022489 Insulin Resistance Diseases 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 2
- 108010089704 Lim Kinases Proteins 0.000 description 2
- 102000008020 Lim Kinases Human genes 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 208000001145 Metabolic Syndrome Diseases 0.000 description 2
- 102000006386 Myelin Proteins Human genes 0.000 description 2
- 108010083674 Myelin Proteins Proteins 0.000 description 2
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 2
- 102100035044 Myosin light chain kinase, smooth muscle Human genes 0.000 description 2
- 108010074596 Myosin-Light-Chain Kinase Proteins 0.000 description 2
- 208000001894 Nasopharyngeal Neoplasms Diseases 0.000 description 2
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 2
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 2
- LRBQNJMCXXYXIU-PPKXGCFTSA-N Penta-digallate-beta-D-glucose Natural products OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-PPKXGCFTSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical class OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 102000009516 Protein Serine-Threonine Kinases Human genes 0.000 description 2
- 108010009341 Protein Serine-Threonine Kinases Proteins 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 208000000453 Skin Neoplasms Diseases 0.000 description 2
- 206010041067 Small cell lung cancer Diseases 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- 208000006011 Stroke Diseases 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical class OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- KKEYFWRCBNTPAC-UHFFFAOYSA-N Terephthalic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-N 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000003275 alpha amino acid group Chemical group 0.000 description 2
- 239000012491 analyte Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 description 2
- 230000028600 axonogenesis Effects 0.000 description 2
- 125000002785 azepinyl group Chemical group 0.000 description 2
- 125000002393 azetidinyl group Chemical group 0.000 description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 2
- 125000005605 benzo group Chemical group 0.000 description 2
- 125000004619 benzopyranyl group Chemical group O1C(C=CC2=C1C=CC=C2)* 0.000 description 2
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 2
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000004305 biphenyl Substances 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000011088 calibration curve Methods 0.000 description 2
- 230000005907 cancer growth Effects 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 230000012292 cell migration Effects 0.000 description 2
- 238000003570 cell viability assay Methods 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 201000007455 central nervous system cancer Diseases 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 2
- 239000008121 dextrose Substances 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 125000002576 diazepinyl group Chemical group N1N=C(C=CC=C1)* 0.000 description 2
- IYYZUPMFVPLQIF-UHFFFAOYSA-N dibenzothiophene Chemical compound C1=CC=C2C3=CC=CC=C3SC2=C1 IYYZUPMFVPLQIF-UHFFFAOYSA-N 0.000 description 2
- 125000005436 dihydrobenzothiophenyl group Chemical group S1C(CC2=C1C=CC=C2)* 0.000 description 2
- 230000006806 disease prevention Effects 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- LRBQNJMCXXYXIU-QWKBTXIPSA-N gallotannic acid Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@H]2[C@@H]([C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-QWKBTXIPSA-N 0.000 description 2
- 208000024908 graft versus host disease Diseases 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 208000035231 inattentive type attention deficit hyperactivity disease Diseases 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
- 208000014674 injury Diseases 0.000 description 2
- 230000009545 invasion Effects 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001786 isothiazolyl group Chemical group 0.000 description 2
- 125000000842 isoxazolyl group Chemical group 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 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
- 238000004519 manufacturing process Methods 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 210000005012 myelin Anatomy 0.000 description 2
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 201000002120 neuroendocrine carcinoma Diseases 0.000 description 2
- 230000000926 neurological effect Effects 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 125000001715 oxadiazolyl group Chemical group 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
- 125000003566 oxetanyl group Chemical group 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 235000019161 pantothenic acid Nutrition 0.000 description 2
- 239000011713 pantothenic acid Substances 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- SONNWYBIRXJNDC-VIFPVBQESA-N phenylephrine Chemical compound CNC[C@H](O)C1=CC=CC(O)=C1 SONNWYBIRXJNDC-VIFPVBQESA-N 0.000 description 2
- 229960001802 phenylephrine Drugs 0.000 description 2
- 235000021317 phosphate Nutrition 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 208000003476 primary myelofibrosis Diseases 0.000 description 2
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 0.000 description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 2
- GHBFNMLVSPCDGN-UHFFFAOYSA-N rac-1-monooctanoylglycerol Chemical compound CCCCCCCC(=O)OCC(O)CO GHBFNMLVSPCDGN-UHFFFAOYSA-N 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 201000000849 skin cancer Diseases 0.000 description 2
- 208000000587 small cell lung carcinoma Diseases 0.000 description 2
- 235000015424 sodium Nutrition 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 208000020431 spinal cord injury Diseases 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 230000035882 stress Effects 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 2
- 229940033123 tannic acid Drugs 0.000 description 2
- 235000015523 tannic acid Nutrition 0.000 description 2
- 229920002258 tannic acid Polymers 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- 206010043554 thrombocytopenia Diseases 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 2
- 239000002691 unilamellar liposome Substances 0.000 description 2
- 230000003827 upregulation Effects 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- OAOBMEMWHJWPNA-UHFFFAOYSA-N (4-aminophenyl)phosphonic acid Chemical compound NC1=CC=C(P(O)(O)=O)C=C1 OAOBMEMWHJWPNA-UHFFFAOYSA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- MHCVCKDNQYMGEX-UHFFFAOYSA-N 1,1'-biphenyl;phenoxybenzene Chemical group C1=CC=CC=C1C1=CC=CC=C1.C=1C=CC=CC=1OC1=CC=CC=C1 MHCVCKDNQYMGEX-UHFFFAOYSA-N 0.000 description 1
- SILNNFMWIMZVEQ-UHFFFAOYSA-N 1,3-dihydrobenzimidazol-2-one Chemical compound C1=CC=C2NC(O)=NC2=C1 SILNNFMWIMZVEQ-UHFFFAOYSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- 125000006039 1-hexenyl group Chemical group 0.000 description 1
- SJJCQDRGABAVBB-UHFFFAOYSA-N 1-hydroxy-2-naphthoic acid Chemical compound C1=CC=CC2=C(O)C(C(=O)O)=CC=C21 SJJCQDRGABAVBB-UHFFFAOYSA-N 0.000 description 1
- 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
- WGUXTQDCAZNJIF-UHFFFAOYSA-N 1-methyl-3,5-bis(trifluoromethyl)benzene Chemical compound CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 WGUXTQDCAZNJIF-UHFFFAOYSA-N 0.000 description 1
- UKAHEJGSNVZSEY-UHFFFAOYSA-N 1-nitro-1-nitrosourea Chemical compound NC(=O)N(N=O)[N+]([O-])=O UKAHEJGSNVZSEY-UHFFFAOYSA-N 0.000 description 1
- RZRNAYUHWVFMIP-KTKRTIGZSA-N 1-oleoylglycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-KTKRTIGZSA-N 0.000 description 1
- 125000006023 1-pentenyl group Chemical group 0.000 description 1
- FRPZMMHWLSIFAZ-UHFFFAOYSA-N 10-undecenoic acid Chemical compound OC(=O)CCCCCCCCC=C FRPZMMHWLSIFAZ-UHFFFAOYSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- AWBOSXFRPFZLOP-UHFFFAOYSA-N 2,1,3-benzoxadiazole Chemical compound C1=CC=CC2=NON=C21 AWBOSXFRPFZLOP-UHFFFAOYSA-N 0.000 description 1
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 1
- YGTUPRIZNBMOFV-UHFFFAOYSA-N 2-(4-hydroxybenzoyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1C(=O)C1=CC=C(O)C=C1 YGTUPRIZNBMOFV-UHFFFAOYSA-N 0.000 description 1
- OIQOAYVCKAHSEJ-UHFFFAOYSA-N 2-[2,3-bis(2-hydroxyethoxy)propoxy]ethanol;hexadecanoic acid;octadecanoic acid Chemical compound OCCOCC(OCCO)COCCO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O OIQOAYVCKAHSEJ-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000006040 2-hexenyl group Chemical group 0.000 description 1
- 125000006024 2-pentenyl group Chemical group 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical class NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- UOQHWNPVNXSDDO-UHFFFAOYSA-N 3-bromoimidazo[1,2-a]pyridine-6-carbonitrile Chemical compound C1=CC(C#N)=CN2C(Br)=CN=C21 UOQHWNPVNXSDDO-UHFFFAOYSA-N 0.000 description 1
- ALKYHXVLJMQRLQ-UHFFFAOYSA-M 3-carboxynaphthalen-2-olate Chemical compound C1=CC=C2C=C(C([O-])=O)C(O)=CC2=C1 ALKYHXVLJMQRLQ-UHFFFAOYSA-M 0.000 description 1
- 125000006041 3-hexenyl group Chemical group 0.000 description 1
- 239000004101 4-Hexylresorcinol Substances 0.000 description 1
- WFJIVOKAWHGMBH-UHFFFAOYSA-N 4-hexylbenzene-1,3-diol Chemical compound CCCCCCC1=CC=C(O)C=C1O WFJIVOKAWHGMBH-UHFFFAOYSA-N 0.000 description 1
- 235000019360 4-hexylresorcinol Nutrition 0.000 description 1
- QRAOZQGIUIDZQZ-UHFFFAOYSA-N 4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1,4-benzoxazine Chemical compound C=1C=C2N(C)CCOC2=CC=1B1OC(C)(C)C(C)(C)O1 QRAOZQGIUIDZQZ-UHFFFAOYSA-N 0.000 description 1
- RWSWNQOCJVPCMF-UHFFFAOYSA-N 5-methyl-6,7-dihydro-4h-pyrazolo[1,5-a]pyrazin-2-amine Chemical compound C1N(C)CCN2N=C(N)C=C21 RWSWNQOCJVPCMF-UHFFFAOYSA-N 0.000 description 1
- BZTDTCNHAFUJOG-UHFFFAOYSA-N 6-carboxyfluorescein Chemical group C12=CC=C(O)C=C2OC2=CC(O)=CC=C2C11OC(=O)C2=CC=C(C(=O)O)C=C21 BZTDTCNHAFUJOG-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 102100023818 ADP-ribosylation factor 3 Human genes 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 108700028369 Alleles Proteins 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
- 201000002862 Angle-Closure Glaucoma Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- GUBGYTABKSRVRQ-DCSYEGIMSA-N Beta-Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-DCSYEGIMSA-N 0.000 description 1
- 206010004593 Bile duct cancer Diseases 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 1
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 1
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 1
- BLRNVJQLSQIPOY-UHFFFAOYSA-N CCOC(COc1cccc(CNC(c(cc2)ccc2-c2ccncc2)=O)c1)=O Chemical compound CCOC(COc1cccc(CNC(c(cc2)ccc2-c2ccncc2)=O)c1)=O BLRNVJQLSQIPOY-UHFFFAOYSA-N 0.000 description 1
- ZUPWTRTWFGHUCT-XMMPIXPASA-N CCc(cc(cc1)-c2c[nH]nc2)c1C(N[C@H](CO)c1cc(C(NC2CCCC2)=O)ccc1)=O Chemical compound CCc(cc(cc1)-c2c[nH]nc2)c1C(N[C@H](CO)c1cc(C(NC2CCCC2)=O)ccc1)=O ZUPWTRTWFGHUCT-XMMPIXPASA-N 0.000 description 1
- PNNWFACEWVYMBX-HHHXNRCGSA-N CN(C)CC(C=C(CC1)c2ccncc2)=C1C(N[C@H](CO)c1cccc(C(NC2CCCC2)=O)c1)=O Chemical compound CN(C)CC(C=C(CC1)c2ccncc2)=C1C(N[C@H](CO)c1cccc(C(NC2CCCC2)=O)c1)=O PNNWFACEWVYMBX-HHHXNRCGSA-N 0.000 description 1
- QBHZZXCHLSMUQI-MUUNZHRXSA-N CN(C)Cc1ccc(CNC(c2cccc([C@@H](CO)NC(c(cc3)ncc3-c3ccncc3)=O)c2)=O)cc1 Chemical compound CN(C)Cc1ccc(CNC(c2cccc([C@@H](CO)NC(c(cc3)ncc3-c3ccncc3)=O)c2)=O)cc1 QBHZZXCHLSMUQI-MUUNZHRXSA-N 0.000 description 1
- HUMKEBLQFMWDFA-AREMUKBSSA-N COCc(cc(cc1)-c2ccncc2)c1C(N[C@H](CO)c1cccc(C(NC2CCCC2)=O)c1)=O Chemical compound COCc(cc(cc1)-c2ccncc2)c1C(N[C@H](CO)c1cccc(C(NC2CCCC2)=O)c1)=O HUMKEBLQFMWDFA-AREMUKBSSA-N 0.000 description 1
- BCJSNQZZTLHTAJ-MRXNPFEDSA-N C[C@H](c1cc(C(NC2CC2)=O)ccc1)NC(c(cc1)ccc1-c1ccncc1)=O Chemical compound C[C@H](c1cc(C(NC2CC2)=O)ccc1)NC(c(cc1)ccc1-c1ccncc1)=O BCJSNQZZTLHTAJ-MRXNPFEDSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 206010007558 Cardiac failure chronic Diseases 0.000 description 1
- 108010031425 Casein Kinases Proteins 0.000 description 1
- 102000005403 Casein Kinases Human genes 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- HQFDERLESLDNOK-HSZRJFAPSA-N Cc(cc(cc1)-c2c[nH]nc2)c1C(N[C@H](CO)c1cccc(C(NC2CCCC2)=O)c1)=O Chemical compound Cc(cc(cc1)-c2c[nH]nc2)c1C(N[C@H](CO)c1cccc(C(NC2CCCC2)=O)c1)=O HQFDERLESLDNOK-HSZRJFAPSA-N 0.000 description 1
- NRSGWEVTVGZDFC-UHFFFAOYSA-N Cc1c[nH]c2nccc(Oc(c(F)cc(Nc3nc(N)nc(Cl)c3)c3)c3F)c12 Chemical compound Cc1c[nH]c2nccc(Oc(c(F)cc(Nc3nc(N)nc(Cl)c3)c3)c3F)c12 NRSGWEVTVGZDFC-UHFFFAOYSA-N 0.000 description 1
- 102000005483 Cell Cycle Proteins Human genes 0.000 description 1
- 108010031896 Cell Cycle Proteins Proteins 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 108010004103 Chylomicrons Proteins 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 206010018325 Congenital glaucomas Diseases 0.000 description 1
- 102000008130 Cyclic AMP-Dependent Protein Kinases Human genes 0.000 description 1
- 108010049894 Cyclic AMP-Dependent Protein Kinases Proteins 0.000 description 1
- 102000004654 Cyclic GMP-Dependent Protein Kinases Human genes 0.000 description 1
- 108010003591 Cyclic GMP-Dependent Protein Kinases Proteins 0.000 description 1
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 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 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
- 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 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- SBJKKFFYIZUCET-JLAZNSOCSA-N Dehydro-L-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(=O)C1=O SBJKKFFYIZUCET-JLAZNSOCSA-N 0.000 description 1
- 206010012565 Developmental glaucoma Diseases 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 102000054300 EC 2.7.11.- Human genes 0.000 description 1
- 108700035490 EC 2.7.11.- Proteins 0.000 description 1
- 102000001301 EGF receptor Human genes 0.000 description 1
- 108060006698 EGF receptor Proteins 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 101150072536 Flt3 gene Proteins 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 102000013446 GTP Phosphohydrolases Human genes 0.000 description 1
- 108091006109 GTPases Proteins 0.000 description 1
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010064571 Gene mutation Diseases 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 208000002705 Glucose Intolerance Diseases 0.000 description 1
- 206010018429 Glucose tolerance impaired Diseases 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000684275 Homo sapiens ADP-ribosylation factor 3 Proteins 0.000 description 1
- 101000861452 Homo sapiens Forkhead box protein P3 Proteins 0.000 description 1
- 101001130437 Homo sapiens Ras-related protein Rap-2b Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 206010060378 Hyperinsulinaemia Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010020853 Hypertonic bladder Diseases 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- 206010065390 Inflammatory pain Diseases 0.000 description 1
- 108010001127 Insulin Receptor Proteins 0.000 description 1
- 102000003746 Insulin Receptor Human genes 0.000 description 1
- 102100032535 L-seryl-tRNA(Sec) kinase Human genes 0.000 description 1
- 101710088843 L-seryl-tRNA(Sec) kinase Proteins 0.000 description 1
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-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
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 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
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 241000282560 Macaca mulatta Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 208000029725 Metabolic bone disease Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 102100027869 Moesin Human genes 0.000 description 1
- 229920000715 Mucilage Polymers 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010028289 Muscle atrophy Diseases 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 208000001738 Nervous System Trauma Diseases 0.000 description 1
- 208000036110 Neuroinflammatory disease Diseases 0.000 description 1
- 208000010577 Niemann-Pick disease type C Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical class O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 206010067013 Normal tension glaucoma Diseases 0.000 description 1
- YDDMLJHCWWQGKS-UHFFFAOYSA-N OC(c1cc(CNC(c(cc2)ccc2-c2ccncc2)=O)ccc1)=O Chemical compound OC(c1cc(CNC(c(cc2)ccc2-c2ccncc2)=O)ccc1)=O YDDMLJHCWWQGKS-UHFFFAOYSA-N 0.000 description 1
- UOVGQCJCXFVKNH-HSZRJFAPSA-N OC[C@H](c1cc(C(NC2CCCC2)=O)ccc1)NC(c(cc1)ncc1-c1ccncc1)=O Chemical compound OC[C@H](c1cc(C(NC2CCCC2)=O)ccc1)NC(c(cc1)ncc1-c1ccncc1)=O UOVGQCJCXFVKNH-HSZRJFAPSA-N 0.000 description 1
- BSRRJYYPRGZMMJ-JOCHJYFZSA-N OC[C@H](c1cc(C(NC2CCCC2)=O)ccc1)NC(c(ccc(-c1c[nH]nc1)c1)c1F)=O Chemical compound OC[C@H](c1cc(C(NC2CCCC2)=O)ccc1)NC(c(ccc(-c1c[nH]nc1)c1)c1F)=O BSRRJYYPRGZMMJ-JOCHJYFZSA-N 0.000 description 1
- IGVPCPKYLXYDRG-OAQYLSRUSA-N OC[C@H](c1cccc(C(NC2CCCC2)=O)c1)NC(c1cc(-c2ccncc2)n[nH]1)=O Chemical compound OC[C@H](c1cccc(C(NC2CCCC2)=O)c1)NC(c1cc(-c2ccncc2)n[nH]1)=O IGVPCPKYLXYDRG-OAQYLSRUSA-N 0.000 description 1
- DUOGRDPDXHCRIM-HSZRJFAPSA-N OC[C@H](c1cccc(C(Nc(cn2)ccc2OI)=O)c1)NC(c(cc1)ccc1-c1ccncc1)=O Chemical compound OC[C@H](c1cccc(C(Nc(cn2)ccc2OI)=O)c1)NC(c(cc1)ccc1-c1ccncc1)=O DUOGRDPDXHCRIM-HSZRJFAPSA-N 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- REYJJPSVUYRZGE-UHFFFAOYSA-N Octadecylamine Chemical compound CCCCCCCCCCCCCCCCCCN REYJJPSVUYRZGE-UHFFFAOYSA-N 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 102000043276 Oncogene Human genes 0.000 description 1
- 206010030348 Open-Angle Glaucoma Diseases 0.000 description 1
- 206010049088 Osteopenia Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 208000009722 Overactive Urinary Bladder Diseases 0.000 description 1
- 108091008606 PDGF receptors Proteins 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 241000282577 Pan troglodytes Species 0.000 description 1
- 241001504519 Papio ursinus Species 0.000 description 1
- 208000005764 Peripheral Arterial Disease Diseases 0.000 description 1
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 description 1
- 241000009328 Perro Species 0.000 description 1
- 208000007913 Pituitary Neoplasms Diseases 0.000 description 1
- 102000011653 Platelet-Derived Growth Factor Receptors Human genes 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920000604 Polyethylene Glycol 200 Polymers 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920000331 Polyhydroxybutyrate Polymers 0.000 description 1
- 108010039918 Polylysine Proteins 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 206010037211 Psychomotor hyperactivity Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- 241001522306 Serinus serinus Species 0.000 description 1
- 201000001880 Sexual dysfunction Diseases 0.000 description 1
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 description 1
- 208000021712 Soft tissue sarcoma Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 235000019486 Sunflower oil Nutrition 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 206010042674 Swelling Diseases 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- 208000030886 Traumatic Brain injury Diseases 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 208000007930 Type C Niemann-Pick Disease Diseases 0.000 description 1
- IVOMOUWHDPKRLL-UHFFFAOYSA-N UNPD107823 Natural products O1C2COP(O)(=O)OC2C(O)C1N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-UHFFFAOYSA-N 0.000 description 1
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 1
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- BDKZHNJTLHOSDW-UHFFFAOYSA-N [Na].CC(O)=O Chemical compound [Na].CC(O)=O BDKZHNJTLHOSDW-UHFFFAOYSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 201000001326 acute closed-angle glaucoma Diseases 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 102000004305 alpha Adrenergic Receptors Human genes 0.000 description 1
- 108090000861 alpha Adrenergic Receptors Proteins 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229940009868 aluminum magnesium silicate Drugs 0.000 description 1
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- HAMNKKUPIHEESI-UHFFFAOYSA-N aminoguanidine Chemical compound NNC(N)=N HAMNKKUPIHEESI-UHFFFAOYSA-N 0.000 description 1
- 229950003153 amsonate Drugs 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- 210000003050 axon Anatomy 0.000 description 1
- OISFUZRUIGGTSD-LJTMIZJLSA-N azane;(2r,3r,4r,5s)-6-(methylamino)hexane-1,2,3,4,5-pentol Chemical compound N.CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO OISFUZRUIGGTSD-LJTMIZJLSA-N 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 125000004069 aziridinyl group Chemical group 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 235000012216 bentonite Nutrition 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- 208000026900 bile duct neoplasm Diseases 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 210000003969 blast cell Anatomy 0.000 description 1
- 201000000053 blastoma Diseases 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 230000009702 cancer cell proliferation Effects 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- KHAVLLBUVKBTBG-UHFFFAOYSA-N caproleic acid Natural products OC(=O)CCCCCCCC=C KHAVLLBUVKBTBG-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- LDVVMCZRFWMZSG-UHFFFAOYSA-N captan Chemical compound C1C=CCC2C(=O)N(SC(Cl)(Cl)Cl)C(=O)C21 LDVVMCZRFWMZSG-UHFFFAOYSA-N 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000009087 cell motility Effects 0.000 description 1
- 230000009134 cell regulation Effects 0.000 description 1
- 238000012054 celltiter-glo Methods 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 208000006990 cholangiocarcinoma Diseases 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 201000010902 chronic myelomonocytic leukemia Diseases 0.000 description 1
- 208000022831 chronic renal failure syndrome Diseases 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000006552 constitutive activation Effects 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 239000013256 coordination polymer Substances 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 229940095074 cyclic amp Drugs 0.000 description 1
- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 description 1
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000522 cyclooctenyl group Chemical group C1(=CCCCCCC1)* 0.000 description 1
- 125000000058 cyclopentadienyl group Chemical group C1(=CC=CC1)* 0.000 description 1
- NISGSNTVMOOSJQ-UHFFFAOYSA-N cyclopentanamine Chemical compound NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 230000021953 cytokinesis Effects 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 230000003436 cytoskeletal effect Effects 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- ACYGYJFTZSAZKR-UHFFFAOYSA-J dicalcium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Ca+2].[Ca+2].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O ACYGYJFTZSAZKR-UHFFFAOYSA-J 0.000 description 1
- XXJWXESWEXIICW-UHFFFAOYSA-N diethylene glycol monoethyl ether Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 description 1
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 description 1
- 125000000723 dihydrobenzofuranyl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 125000005879 dioxolanyl group Chemical group 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 125000005303 dithiazolyl group Chemical group S1SNC(=C1)* 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 229940009662 edetate Drugs 0.000 description 1
- 229960001484 edetic acid Drugs 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 201000008184 embryoma Diseases 0.000 description 1
- ZSWFCLXCOIISFI-UHFFFAOYSA-N endo-cyclopentadiene Natural products C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 1
- 230000002357 endometrial effect Effects 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 201000006517 essential tremor Diseases 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000013401 experimental design Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000006126 farnesylation Effects 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 229940013317 fish oils Drugs 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- SVWLIIFHXFGESG-UHFFFAOYSA-N formic acid;methanol Chemical compound OC.OC=O SVWLIIFHXFGESG-UHFFFAOYSA-N 0.000 description 1
- 229940050411 fumarate Drugs 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 210000004392 genitalia Anatomy 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 229960001731 gluceptate Drugs 0.000 description 1
- KWMLJOLKUYYJFJ-VFUOTHLCSA-N glucoheptonic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)C(O)=O KWMLJOLKUYYJFJ-VFUOTHLCSA-N 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 229940049906 glutamate Drugs 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- RZRNAYUHWVFMIP-HXUWFJFHSA-N glycerol monolinoleate Natural products CCCCCCCCC=CCCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-HXUWFJFHSA-N 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 210000000020 growth cone Anatomy 0.000 description 1
- 239000000122 growth hormone Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 229960003258 hexylresorcinol Drugs 0.000 description 1
- 125000005980 hexynyl group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- XGIHQYAWBCFNPY-AZOCGYLKSA-N hydrabamine Chemical compound 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 1
- 239000000017 hydrogel Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 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
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 230000003451 hyperinsulinaemic effect Effects 0.000 description 1
- 201000008980 hyperinsulinism Diseases 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 230000004068 intracellular signaling Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 230000004410 intraocular pressure Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- 229940099584 lactobionate Drugs 0.000 description 1
- JYTUSYBCFIZPBE-AMTLMPIISA-M lactobionate Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-M 0.000 description 1
- 229940099563 lactobionic acid Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 201000010901 lateral sclerosis Diseases 0.000 description 1
- 229940070765 laurate Drugs 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 201000002978 low tension glaucoma Diseases 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940091250 magnesium supplement Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 150000002689 maleic acids Chemical class 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- OWBKDJSKHXGOJY-UHFFFAOYSA-N methyl 3-(aminomethyl)benzoate Chemical compound COC(=O)C1=CC=CC(CN)=C1 OWBKDJSKHXGOJY-UHFFFAOYSA-N 0.000 description 1
- 229940102396 methyl bromide Drugs 0.000 description 1
- LRMHVVPPGGOAJQ-UHFFFAOYSA-N methyl nitrate Chemical compound CO[N+]([O-])=O LRMHVVPPGGOAJQ-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 108010071525 moesin Proteins 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 208000005264 motor neuron disease Diseases 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 230000020763 muscle atrophy Effects 0.000 description 1
- 230000003387 muscular Effects 0.000 description 1
- 201000000585 muscular atrophy Diseases 0.000 description 1
- 210000001167 myeloblast Anatomy 0.000 description 1
- 230000002071 myeloproliferative effect Effects 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- 125000004370 n-butenyl group Chemical group [H]\C([H])=C(/[H])C([H])([H])C([H])([H])* 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 229950006327 napsilate Drugs 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 125000005244 neohexyl group Chemical group [H]C([H])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 230000014511 neuron projection development Effects 0.000 description 1
- 230000009689 neuronal regeneration Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- UMRZSTCPUPJPOJ-KNVOCYPGSA-N norbornane Chemical compound C1C[C@H]2CC[C@@H]1C2 UMRZSTCPUPJPOJ-KNVOCYPGSA-N 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 125000004365 octenyl group Chemical group C(=CCCCCCC)* 0.000 description 1
- 230000009437 off-target effect Effects 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-M oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC([O-])=O ZQPPMHVWECSIRJ-KTKRTIGZSA-M 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 235000020660 omega-3 fatty acid Nutrition 0.000 description 1
- 229940012843 omega-3 fatty acid Drugs 0.000 description 1
- 239000006014 omega-3 oil Substances 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000011164 ossification Effects 0.000 description 1
- 208000020629 overactive bladder Diseases 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000005968 oxazolinyl group Chemical group 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 229940014662 pantothenate Drugs 0.000 description 1
- 229940055726 pantothenic acid Drugs 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
- 239000002245 particle Substances 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 201000002628 peritoneum cancer Diseases 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 150000008105 phosphatidylcholines Chemical class 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 201000002511 pituitary cancer Diseases 0.000 description 1
- 230000010287 polarization Effects 0.000 description 1
- 239000005015 poly(hydroxybutyrate) Substances 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 229920002721 polycyanoacrylate Polymers 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 229920000656 polylysine Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920006324 polyoxymethylene Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000029279 positive regulation of transcription, DNA-dependent Effects 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 201000006366 primary open angle glaucoma Diseases 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 1
- 201000011303 renal artery atheroma Diseases 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- QSKQVZWVLOIIEV-NSHDSACASA-N ripasudil Chemical compound C[C@H]1CNCCCN1S(=O)(=O)C1=CC=CC2=CN=CC(F)=C12 QSKQVZWVLOIIEV-NSHDSACASA-N 0.000 description 1
- 229950007455 ripasudil Drugs 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
- 235000019204 saccharin Nutrition 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 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
- 239000008299 semisolid dosage form Substances 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 231100000872 sexual dysfunction Toxicity 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 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
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- FYGUBWKMMCWIKB-UHFFFAOYSA-N spiro[2.3]hexane Chemical compound C1CC11CCC1 FYGUBWKMMCWIKB-UHFFFAOYSA-N 0.000 description 1
- LBJQKYPPYSCCBH-UHFFFAOYSA-N spiro[3.3]heptane Chemical compound C1CCC21CCC2 LBJQKYPPYSCCBH-UHFFFAOYSA-N 0.000 description 1
- CTDQAGUNKPRERK-UHFFFAOYSA-N spirodecane Chemical compound C1CCCC21CCCCC2 CTDQAGUNKPRERK-UHFFFAOYSA-N 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 210000004500 stellate cell Anatomy 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000002600 sunflower oil Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000005307 thiatriazolyl group Chemical group S1N=NN=C1* 0.000 description 1
- 125000004305 thiazinyl group Chemical group S1NC(=CC=C1)* 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- VJYJJHQEVLEOFL-UHFFFAOYSA-N thieno[3,2-b]thiophene Chemical compound S1C=CC2=C1C=CS2 VJYJJHQEVLEOFL-UHFFFAOYSA-N 0.000 description 1
- 125000004588 thienopyridyl group Chemical group S1C(=CC2=C1C=CC=N2)* 0.000 description 1
- 125000004587 thienothienyl group Chemical group S1C(=CC2=C1C=CS2)* 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 230000009529 traumatic brain injury Effects 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 229950002929 trinitrophenol Drugs 0.000 description 1
- IHIXIJGXTJIKRB-UHFFFAOYSA-N trisodium vanadate Chemical compound [Na+].[Na+].[Na+].[O-][V]([O-])([O-])=O IHIXIJGXTJIKRB-UHFFFAOYSA-N 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 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
- 229960002703 undecylenic acid Drugs 0.000 description 1
- 229940116269 uric acid Drugs 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-UHFFFAOYSA-N 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000007502 viral entry Effects 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 229930195724 β-lactose Natural products 0.000 description 1
- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-Caprolactone Chemical compound O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- 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
- C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/26—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
-
- 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
- C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/56—Amides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- 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
- C07D213/81—Amides; Imides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- 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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Immunology (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pulmonology (AREA)
- Diabetes (AREA)
- Urology & Nephrology (AREA)
- Cardiology (AREA)
- Dermatology (AREA)
- Physical Education & Sports Medicine (AREA)
- Rheumatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Psychology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hospice & Palliative Care (AREA)
- Endocrinology (AREA)
- Psychiatry (AREA)
- Vascular Medicine (AREA)
- Obesity (AREA)
- Ophthalmology & Optometry (AREA)
- Pain & Pain Management (AREA)
- Communicable Diseases (AREA)
- Gynecology & Obstetrics (AREA)
Description
本出願は、2016年10月24日に出願された米国仮特許出願第62/411,908号に対する優先権を主張し、その内容は、参照により本明細書にそのまま援用される。
本発明は、アミド化合物、それらの組成物および同じものを含有する医薬品ならびにそのような化合物、組成物および医薬品の調製および使用のためのプロセスに関する。そのような化合物は、細胞増殖疾患(例えば癌)ならびに神経疾患および炎症性疾患を含む、不適切なチロシンおよび/またはセリン/スレオニンキナーゼ活性と関係する疾患の処置において有用である可能性がある。具体的には、本開示は、Rho−キナーゼ類を阻害する化合物および組成物、Rho−キナーゼ類と関係する疾患を処置する方法、ならびにこれらの化合物を合成する方法に関する。
本発明の別の側面において、式(II)の化合物が、提供され:
別の態様において、本発明は、化合物に関し、ここでR2およびR3は、独立してH、−C3〜C7シクロアルキルまたは−C3〜C7シクロアルキルメチルであり;ここで−C3〜C7シクロアルキルまたは−C3〜C7シクロアルキルメチルは、場合によりH、ハロ、−OH、−CN、−COOR’、−OR’、−SR’、−OC(O)R’、−NHR’、−NR’R”、−CNR’R”、−NHC(O)R’、−NHC(O)NR’R”、−C(O)NR’R”、−NS(O)2R’、−S(O)2NR’R”、−S(O)2R’、グアニジノ、ニトロ、ニトロソ、−C1〜C6アルキル、アリール、−C3〜C7シクロアルキルまたは3〜10員複素環で置換されており;ただし、R2およびR3は、両方ともHであることはない。
特定の側面において、Z1は、ピリジンであり、場合により以下の1以上で置換されており:ハロ、−OH、−CN、−COOR’、−OR’、−SR’、−OC(O)R’、−NHR’、−NR’R”、−NHC(O)R’、−NHC(O)NR’R”、−C(O)NR’R”、−NS(O)2R’、−S(O)2NR’R”、−S(O)2R’、グアニジノ、ニトロ、ニトロソ、−C1〜C6アルキル、アリールまたは−C3〜C7シクロアルキル;Z2は、C5〜C10員複素環であり、場合によりH、ハロ、−OH、−CN、−COOR’、−OR’、−SR’、−OC(O)R’、−NHR’、−NR’R”、−NHC(O)R’、−NHC(O)NR’R”、−C(O)NR’R”、−NS(O)2R’、−S(O)2NR’R”、−S(O)2R’、グアニジノ、ニトロ、ニトロソ、−C1〜C6アルキル、アリール、−C3〜C7シクロアルキルまたは3〜10員複素環で置換されており;R2およびR3は、独立してH、フェニル、ベンジル、−C3〜C7シクロアルキルまたは−C3〜C7シクロアルキルメチルであり;ここで、フェニル、ベンジル、−C3〜C7シクロアルキルまたは−C3〜C7シクロアルキルメチルは、場合によりH、ハロ、−OH、−CN、−COOR’、−OR’、−SR’、−OC(O)R’、−NHR’、−NR’R”、−NHC(O)R’、−NHC(O)NR’R”、−C(O)NR’R”、−NS(O)2R’、−S(O)2NR’R”、−S(O)2R’、グアニジノ、ニトロ、ニトロソ、−Cl〜C6アルキル、アリール、−C3〜C7シクロアルキルまたは3〜10員複素環で置換されており;ただし、R2およびR3は、両方ともHであることはない。一側面において、R1および/またはR2は、Hである。別の側面において、Z2は、ピリジンまたはピラゾールである。
さらに別の態様において、本発明は、以下の化合物からなる群から選択される化合物に関する:
ある側面において、本発明は、本明細書で開示された化合物および薬学的に許容可能な担体を含む医薬組成物に関する。
一側面において、癌は、皮膚性T細胞リンパ腫(CTCL)、末梢性T細胞リンパ腫(PTCL)、血管免疫芽球性T細胞リンパ腫(AITL)、多発性骨髄腫、白血病、リンパ腫または肺癌、卵巣癌、乳癌、前立腺癌、膵臓癌、肝細胞癌または腎臓癌である。
さらに別の側面において、神経発達障害は、レット症候群またはニーマン・ピックC型である。
他の側面において、本発明は、以下の工程を含む血液悪性新生物性障害を患っている対象を処置する方法を提供する:血液悪性新生物性障害に関する療法を必要とする対象を同定し;そしてそのような処置を必要とする対象に有効量の本明細書で開示された化合物またはその塩を投与して血液悪性新生物性障害を処置する。ある態様において、血液悪性新生物性障害は、制御を外れたFLT3受容体チロシンキナーゼ活性により特性付けられ、悪性新生物性障害は、白血病、骨髄腫、骨髄増殖性疾患、骨髄異形成症候群、ホジキン病、骨髄腫、急性リンパ性白血病(ALL)、急性骨髄性白血病(AML)、急性前骨髄球性白血病(APL)、慢性リンパ性白血病、(CLL)、慢性骨髄性白血病(CML)、慢性好中球性白血病(CNL)、急性未分化型白血病(AUL)、未分化大細胞リンパ腫(ALCL)、前リンパ性白血病(PML)、若年性骨髄単球性白血病(JMML)、成人T細胞ALL、AML、3系列脊髄形成異常を伴うもの(AMLITMDS)、混合系列白血病(MLL)、骨髄異形成症候群(MDS)、骨髄増殖性障害(MPD)および多発性骨髄腫(MM)からなる群から選択される。
−C1〜C6アルキル基は、1〜6個の炭素原子で構成されるあらゆる直鎖または分枝状の、飽和または不飽和の、置換された、または未置換の炭化水素を含む。−C1〜C6アルキル基の例は、メチル、エチル、プロピル、イソプロピル、ブチル、sec−ブチル、tert−ブチル、ペンチル、イソペンチル、ネオペンチル、ヘキシル、イソヘキシル、ネオヘキシル、エチレニル、プロピレニル、1−ブテニル、2−ブテニル、1−ペンテニル、2−ペンテニル、1−ヘキセニル、2−ヘキセニル、3−ヘキセニル、アセチレニル、ペンチニル、1−ブチニル、2−ブチニル、1−ペンチニル、2−ペンチニル、1−ヘキシニル、2−ヘキシニルおよび3−ヘキシニル基を含むが、それらに限定されない。置換−C1〜C6アルキル基は、あらゆる適用可能な化学的部分を含むことができる。上記で列挙された−C1〜C6アルキル基のいずれかの上に置換されることができる基の例は、以下の例を含むが、それらに限定されない:ハロ、−C1〜C6アルキル、−O−(C1〜C6アルキル)、C3〜C7シクロアルキル、−OH、−CN、−COOR’、−OC(O)R’、−NHR’、N(R’)2、−NHC(O)R’または−C(O)NHR’基。上記でR’と表記された基は、−H、あらゆる−C1〜C6アルキルであることができ、または2つのR’は、置換が−N(R’)2である場合、場合によりそれらが結合している窒素もしくは酸素原子と共に、3−、4−、5−、6−、7−員環系を形成してもよい。
冠詞“a”および“an”は、本開示において、その冠詞の文法的目的語の1または1より多く(例えば少なくとも1)を指すために用いられている。例として、“要素(an element)”は、1つの要素または1より多くの要素を意味する。
用語“場合により置換された”は、所与の化学的部分(例えばアルキル基)が他の置換基(例えば複素原子)に結合していることができる(が、必ずしもその必要はない)ことを意味するように理解されている。例えば、場合により置換されているアルキル基は、完全に飽和したアルキル鎖(例えば純粋な炭化水素)であることができる。あるいは、同じ場合により置換されたアルキル基は、水素とは異なる置換基を有することができる。例えば、それは、鎖に沿ったあらゆる点において、ハロゲン原子、ヒドロキシル基または本明細書で記載されるあらゆる他の置換基に結合していることができる。従って、用語“場合により置換された”は、所与の化学的部分が他の官能基を含有する可能性を有するが必ずしもいずれかのさらなる官能基を有しないことを意味する。
用語“カルボニル”は、酸素原子に二重結合した炭素原子を含む官能基を指す。それは、本明細書において“オキソ”、C(O)またはC=0と略され得る。
用語“担体”は、本開示において用いられる際、担体、賦形剤および希釈剤を包含し、医薬的薬剤の対象の1つの器官または体の一部から別の器官または体の一部への運搬または輸送に関わる材料、組成物またはビヒクル、例えば液体もしくは固体増量剤、希釈剤、賦形剤、溶媒またはカプセル封入材料を意味する。
用語“投与する(administer)”、“投与すること(administering)”または“投与(administeration)”は、本開示において用いられる際、開示された化合物もしくは開示された化合物の薬学的に許容可能な塩もしくは組成物を対象に直接投与することまたは対象の体内で同等の量の有効化合物を形成することができる化合物もしくは化合物の薬学的に許容可能な塩のプロドラッグ誘導体もしくは類似体もしくは組成物を対象に投与することの両方を指す。
化合物は、以下の合成スキームおよび実施例により部分的に述べられるような当該技術で既知の有機合成の方法により調製されることができる。下記のスキームにおいて、感受性または反応性の基に関する保護基が、必要な場合に一般的な原理または化学に従って用いられることは、十分に理解されている。保護基は、有機合成の標準的な方法に従って操作される(T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis”, 第3版, Wiley, New York 1999)。これらの基は、当業者に容易に明らかである方法を用いて化合物合成の好都合な段階において除去される。選択プロセスならびに反応条件およびそれらの実行の順序は、式Iの化合物の調製と一致しているものとする。
本開示の化合物の別の療法的使用は、炎症性疾患または障害を処置することである。炎症は、最初の損傷または感染に対する宿主の反応として理解されることができる。炎症の症状は、発赤、腫脹、痛み、熱および機能の喪失を含むことができるが、それらに限定されない。炎症は、炎症促進性サイトカイン、例えばIL−Iβの上方制御およびFOXP3転写因子の増大した発現により引き起こされ得る。
特定の側面において、本発明は、Rhoキナーゼシグナル伝達経路の上方制御に関する疾患の処置における使用のための本明細書で開示された化合物を提供する。
開示された化合物の投与は、療法的薬剤に関するあらゆる投与方式により成し遂げられることができる。これらの方式は、全身または局所投与、例えば経口、経鼻、非経口、経皮、皮下、膣内、バッカル、直腸または局所投与方式を含む。
1B(7mg、0.02mmol)および5−メチル−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピラジン−2−アミン(6mg、0.04mmol)のDMF中における溶液に、ジイソプロピルエチルアミン(DIEA、0.007mL、0.04mmol)およびHATU(15mg、0.04mmol)を添加した。反応を室温で2時間撹拌し、水で希釈した。混合物を濃縮し、C−18カラムクロマトグラフィーにより精製すると、ID#1(8mg)が得られた。
2B(5mg、0.014mmol)およびシクロペンチルアミン(3mg、0.035mmol)のDMF中における溶液に、ジイソプロピルエチルアミン(DIEA、5マイクロL、0.028mmol)およびHATU(7mg、0.018mmol)を添加した。反応を室温で2時間撹拌し、水で希釈した。混合物を濃縮し、C−18カラムクロマトグラフィーにより精製すると、ID#10(5mg)が得られた。
3C(10mg、0.028mmol)およびシクロプロピルアミン(5mg、0.084mmol)のDMF中における溶液に、HATU(13mg、0.034mmol)を添加した。反応を室温で2時間撹拌し、水で希釈した。混合物を濃縮し、C−18カラムクロマトグラフィーにより精製すると、ID#3(10mg)が得られた。
以下のアッセイプロトコルは、ペプチド基質(FAM−KKLRRTLSVA−OH、ここでFAMは、カルボキシフルオレセインである)のリン酸化を測定するためのものである。ペプチドは、キャピラリー電気泳動により純度>98%である。ペプチドは、プロテインキナーゼROCK1またはROCK2によりリン酸化される。ROCK1またはROCK2酵素、基質および補因子(ATPおよびMg2+)は、マイクロタイタープレートのウェル中で組み合わせられ、25℃において阻害剤化合物の存在下または非存在下で3時間インキュベートされる。インキュベーションの終了時に、反応は、EDTAを含有する緩衝液の添加により停止される。基質および生成物は、Caliper Life Sciences(マサチューセッツ州ホプキントン)からの微少流体ベースのLABCHIP(登録商標)3000創薬システムを用いて電気泳動的に分離および定量化される。
100mM HEPES、pH7.5
0.1% BSA
0.01% Triton X−100
1mM DTT
10mM MgCl2
10μM オルトバナジン酸ナトリウム
10μM ベータ−グリセロホスフェート
(ROCK1に関して)5μM ATPまたは(ROCK2に関して)7μM ATP
1% DMSO (化合物由来)
1.25μM FAM−KKLRRTLSVA−OH
3nM ROCK1または2.5nM ROCK2酵素
それぞれの試料中に存在する基質および生成物ペプチドは、LABCHIP(登録商標)3000キャピラリー電気泳動装置を用いて電気泳動的に分離される。基質および生成物ペプチドが分離された際、蛍光の2つのピークが、観察される。基質および生成物ピークの相対的蛍光強度における変化は、酵素活性を反映して測定されたパラメーターである。キャピラリー電気泳動図(RDA獲得ファイル)は、HTS Well分析器ソフトウェア(Caliper Life Sciences、マサチューセッツ州ホプキントン)を用いて分析される。それぞれの試料中のキナーゼ活性は、生成物対合計の比率(PSR):P/(S+P)として決定され、ここでPは、生成物ペプチドのピークの高さであり、Sは、基質ペプチドのピークの高さである。それぞれの化合物に関して、酵素活性は、様々な濃度(3倍希釈間隔で間隔をあけられた化合物の12の濃度)で測定される。陰性対照試料(0%−阻害剤の非存在下での阻害)および陽性対照試料(100%−20mM EDTAの存在下での阻害)が、4つの複製において組み立てられ、それぞれの化合物に関するそれぞれの濃度における%阻害値を計算するために用いられる。パーセント阻害(Pinh)は、以下の方程式を用いて決定される:
Pinh=(PSR0%−PSRinh)/(PSR0%−PSR100%)*100
式中、PSRinhは、阻害剤の存在下での生成物合計比であり、PSR0%は、阻害剤の非存在下での平均生成物合計比であり、PSR100%は、100%−阻害対照試料における平均生成物合計比である。阻害剤のIC50値は、阻害曲線(Pinh対阻害剤濃度)をXLfit 4ソフトウェア(IBDS)を用いる4パラメーターシグモイド用量−反応モデルにより当てはめることにより決定される。
異なる時点における変動する濃度の上記で列挙された化合物の存在下での細胞生存度が、細胞毒性および化合物の細胞増殖への作用を評価するために用いられた。K562またはMV411細胞株における本発明の化合物に関するIC50(またはパーセント活性)データが、表2において要約されている。
単一薬剤試験−細胞が、70%コンフルエンスまで増殖させられ、トリプシン処理され、計数され、96ウェル平底プレート中に2.5×103〜5×103細胞/ウェルの終濃度でまかれた(0日目)。細胞は、増殖培地中で24時間インキュベートしておかれた。試験薬剤または標準薬剤による処理は、1日目に開始し、72時間継続した。72時間の時点で、処理を含有する培地が、除去された。生存可能な細胞数が、上記のようなCELLTITER−GLO(登録商標)細胞生存度アッセイにより定量化された。これらの試験からの結果が、それぞれの化合物に関するIC50値(細胞増殖を対照の50パーセント阻害する薬物の濃度)を計算するために用いられた。
%細胞増殖=(ftest/fvehicle)×100
式中、ftestは、試験された試料の発光であり、fvehicleは、薬物を溶解させるビヒクルの発光である。用量反応グラフおよびIC50値は、次の方程式を用いてPrism 6ソフトウェア(GraphPad)を用いて生成された:
Y=(Top−Bottom)/(1+10((logIC50−X)−Hillの傾き))
式中、Xは、濃度の対数であり、Yは、反応である。Yは、Bottomにおいて開始し、シグモイドの形状でTopへと向かう。
一般に、キナーゼは、細胞増殖、シグナル伝達、代謝等を含む多くの重要な細胞活性を制御する。異なるキナーゼは、異なる機能および経路を有する。ROCK1およびROCK2の選択的阻害は、望ましくない副作用、例えば毒性を引き起こし得るオフターゲット活性を回避する。
化合物を、個々に、そして正確に量り取ってジメチルスルホキシド(DMSO)中で2mg/mLの濃度のストック溶液を生成し、−20℃で保管した。そのストック溶液から、ワーキングストック(working stock)が、それをメタノール−水50:50(v/v)中で20μg/mLで希釈することにより、較正曲線の用意のために調製され、4℃で保管された。定量化および品質管理試料(QC)のために用いられる標準が、試料の処理と同じ日に、未処置マウスから得られたブランク血漿を用いて調製された。それぞれの分析物に関して、標準が、ワーキングストックの0.1、0.5、1.0、10、50、100、500および1000ng/mLの濃度における系列希釈により調製され;QCが、0.75、7.5、75および750ng/mLの中間濃度で調製された。血漿試料は、分析の準備ができるまで−80℃で保管され、次いで融解のために氷上に置かれた。20μLの試料、標準またはQCの分割量が、予め定められた配置図に従って96ウェル抽出プレート中に移された。適切な量のメタノール−ギ酸99.9−内部標準(25ng/mLのベラパミル)を含有する0.1が、それぞれのウェルに添加され、試料が、真空下で抽出された。次いで、溶離液が、分離およびMRM検出のための適切なカラムを用いる分析のためにLCMSプレート中に移された。分析物の濃度が、較正曲線に基づいて計算され、ノンコンパートメント分析(NCA)を用いることにより薬物動態パラメーターに関して分析された。パラメーター、例えばCmax、Tmax、半減期、AUC(0〜最後)、AUC(0〜∞)、分布容積(Vss)およびクリアランス(Cl/F)が、報告された。
Claims (8)
- 式(I)の化合物:
Z1は、ピリジンまたはピラゾールであり、該ピリジンまたはピラゾールはハロ、−OH、−CN、−COOR’、−OR’、−SR’、−OC(O)R’、−NHR’、−NR’R”、−NHC(O)R’、−NHC(O)NR’R”、−C(O)NR’R”、−NHS(O)2R’、−S(O)2NR’R”、−S(O)2R’、グアニジノ、ニトロ、ニトロソ、−C1〜C6アルキル、アリール、−C3〜C7シクロアルキルまたは3〜10員複素環で置換されていてもよく、ここで該−C1〜C6アルキル、アリール、−C3〜C7シクロアルキルまたは3〜10員複素環は以下の1以上で置換されていてもよく:ハロ、−OH、−CN、−COOR’、−OR’、−SR’、−OC(O)R’、−NHR’、−NR’R”、−NHC(O)R’、−NHC(O)NR’R”、−C(O)NR’R”、−NHS(O)2R’、−S(O)2NR’R”、−S(O)2R’、グアニジノ、ニトロ、ニトロソ、−C1〜C6アルキル、アリールもしくは−C3〜C7シクロアルキル;
Z2は、フェニル、ナフチルまたはC5〜C10員複素環であり、該フェニル、ナフチルまたはC5〜C10員複素環はH、ハロ、−OH、−CN、−COOR’、−OR’、−OR’OR”、−O(CH2)2NR’R”、−SR’、−OC(O)R’、−NHR’、−NR’R”、−NHC(O)R’、−NHC(O)NR’R”、−C(O)NR’R”、−NHS(O) 2 R’、−S(O)2NR’R”、−S(O)2R’、グアニジノ、ニトロ、ニトロソ、−C1〜C6アルキル、アリール、−C3〜C7シクロアルキルまたは3〜10員複素環で置換されていてもよく、ここで
該−C1〜C6アルキル、アリール、−C3〜C7シクロアルキルまたは3〜10員複素環は以下の1以上で置換されていてもよく:ハロ、−OH、−CN、−COOR’、−OR’、−SR’、−OC(O)R’、−NHR’、−NR’R”、−NHC(O)R’、−NHC(O)NR’R”、−C(O)NR’R”、−NHS(O)2R’、−S(O)2NR’R”、−S(O)2R’、グアニジノ、ニトロ、ニトロソ、−C1〜C6アルキル、アリールもしくは−C3〜C7シクロアルキル;
R1はH、−C1〜C6アルキルまたは−C3〜C7シクロアルキルであり、該−C1〜C6アルキルまたは−C3〜C7シクロアルキルは以下の1以上で置換されていてもよく:ハロ、−OH、−CN、−COOR’、−OR’、−SR’、−OC(O)R’、−NHR’、−NR’R”、−NHC(O)R’、−NHC(O)NR’R”、−C(O)NR’R”、−NHS(O)2R’、−S(O)2NR’R”、または−S(O)2R’;
Rは、−C1〜C6アルキルであり、該−C1〜C6アルキルは以下の1以上で置換されていてもよく:H、ハロ、−OH、−CN、−COOR’、−OR’、−SR’、−OC(O)R’、−NHR’、−NR’R”、−NHC(O)R’、−NHC(O)NR’R”、−C(O)NR’R”、−NHS(O)2R’、−S(O)2NR’R”または−S(O)2R’;
Xは、結合であり;
R 2 は、Hであり;
R 3 は、シクロペンチルまたはシクロヘキシルであり;そして式中、
R’またはR”は、独立して−Hもしくは−C1〜C6アルキルであるか、またはR’およびR”は一緒に、任意選択でNまたはO原子に結合し、4〜8員環構造を形成する。 - Rho関連プロテインキナーゼ調節と関係する疾患を予防または処置するための、請求項1〜5のいずれか一項に記載の化合物および薬学的に許容可能な担体を含む医薬組成物。
- 請求項6に記載の医薬組成物であって、ここで前記化合物が、ROCK1およびROCK2からなる群から選択されるRho関連プロテインキナーゼを阻害する、医薬組成物。
- 請求項6に記載の医薬組成物であって、ここで前記Rho関連プロテインキナーゼ調節と関係する疾患が、以下:癌、神経変性疾患、神経発達障害、炎症性もしくは自己免疫疾患、感染症、代謝性疾患、線維性障害、心血管疾患もしくは血管平滑筋機能不全、血液疾患、血液悪性新生物性障害、および眼の障害からなる群から選択され;ここで
癌が以下:皮膚性T細胞リンパ腫(CTCL)、末梢性T細胞リンパ腫(PTCL)、血管免疫芽球性T細胞リンパ腫(AITL)、多発性骨髄腫、白血病、リンパ腫、肺癌、卵巣癌、乳癌、胃癌、前立腺癌、膵臓癌、肝細胞癌、および腎臓癌からなる群から選択され;
該神経変性疾患が以下:アルツハイマー病、ハンチントン病、パーキンソ
ン病、筋萎縮性側索硬化症、および脊髄性筋萎縮症からなる群から選択され;
該神経発達障害がレット症候群またはニーマン・ピックC型であり;
該炎症性もしくは自己免疫疾患が以下:喘息、心血管炎症、腎臓炎症、動脈硬化、リウマチ様関節炎、脊椎炎性関節炎、乾癬性関節炎、乾癬、アトピー性皮膚炎、湿疹、多発性硬化症、全身性紅斑性狼瘡、炎症性腸疾患、クローン病、移植片対宿主病、移植片拒絶、および線維性疾患からなる群から選択され;
該心血管疾患もしくは血管平滑筋機能不全が以下:高血圧、アテローム性動脈硬化、再狭窄、心肥大、高眼圧症、脳虚血、脳血管攣縮、および勃起不全からなる群から選択され;
該血液悪性新生物性障害が制御を外れたFLT3受容体チロシンキナーゼ活性により特性付けられ、そして以下:白血病、骨髄腫、骨髄増殖性疾患、骨髄異形成症候群、ホジキン病、急性リンパ性白血病(ALL)、急性骨髄性白血病(AML)、急性前骨髄球性白血病(APL)、慢性リンパ性白血病、(CLL)、慢性骨髄性白血病(CML)、慢性好中球性白血病(CNL)、急性未分化型白血病(AUL)、未分化大細胞リンパ腫(ALCL)、前リンパ性白血病(PML)、若年性骨髄単球性白血病(JMML)、成人T細胞ALL、AML、3系列脊髄形成異常を伴うもの(AMLITMDS)、混合系列白血病(MLL)、骨髄異形成症候群(MDS)、骨髄増殖性障害(MPD)、および多発性骨髄腫(MM)からなる群から選択され;
該眼の障害が以下:加齢黄斑変性(AMD)、脈絡膜血管新生(CNV)、糖尿病性黄斑浮腫(DME)、虹彩血管新生、ブドウ膜炎、血管新生緑内障、および未熟児の網膜炎(ROP)からなる群から選択され;そして
該線維性障害が肝線維症、肺線維症、または腎臓線維症である、医薬組成物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201662411908P | 2016-10-24 | 2016-10-24 | |
US62/411,908 | 2016-10-24 | ||
PCT/US2017/058071 WO2018081108A1 (en) | 2016-10-24 | 2017-10-24 | Amide compounds as kinase inhibitors |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2019535812A JP2019535812A (ja) | 2019-12-12 |
JP2019535812A5 JP2019535812A5 (ja) | 2020-12-03 |
JP6948398B2 true JP6948398B2 (ja) | 2021-10-13 |
Family
ID=62023980
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2019543185A Active JP6948398B2 (ja) | 2016-10-24 | 2017-10-24 | キナーゼ阻害剤としてのアミド化合物 |
Country Status (7)
Country | Link |
---|---|
EP (1) | EP3532479B1 (ja) |
JP (1) | JP6948398B2 (ja) |
CN (2) | CN115160295A (ja) |
AU (1) | AU2017351216C1 (ja) |
CA (1) | CA3078347A1 (ja) |
IL (2) | IL266150B2 (ja) |
WO (1) | WO2018081108A1 (ja) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2021522238A (ja) * | 2018-04-24 | 2021-08-30 | トランスレイショナル・ドラッグ・ディベロップメント・エルエルシー | キナーゼ阻害剤としてのアミド化合物、組成物および処置方法 |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2019201296A1 (zh) * | 2018-04-18 | 2019-10-24 | 南京明德新药研发有限公司 | 作为rho激酶抑制剂的吡唑类化合物 |
EP3782987A4 (en) * | 2018-04-18 | 2021-05-19 | Medshine Discovery Inc. | BENZOPYRAZOLE COMPOUND AS A RHO CINEMA INHIBITOR |
WO2020142745A1 (en) * | 2019-01-04 | 2020-07-09 | Translational Drug Development, Llc | Methods of treating graft versus host disease and neoplastic disease with amide compounds |
WO2021262250A1 (en) * | 2020-06-25 | 2021-12-30 | Woolsey Pharmaceuticals, Inc | Methods of treating neurodevelopmental disorders |
WO2023283425A1 (en) | 2021-07-09 | 2023-01-12 | Plexium, Inc. | Aryl compounds and pharmaceutical compositions that modulate ikzf2 |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5262564A (en) | 1992-10-30 | 1993-11-16 | Octamer, Inc. | Sulfinic acid adducts of organo nitroso compounds useful as retroviral inactivating agents anti-retroviral agents and anti-tumor agents |
WO2010024903A1 (en) * | 2008-08-29 | 2010-03-04 | Yangbo Feng | BENZO[d]OXAZOLES AND BENZO[d]THIAZOLES AS KINASE INHIBITORS |
US20110212969A1 (en) * | 2010-02-26 | 2011-09-01 | Millennium Pharmaceuticals, Inc. | Substituted hydroxamic acids and uses thereof |
US9079880B2 (en) * | 2010-07-07 | 2015-07-14 | Boehringer Ingelheim International Gmbh | Rho kinase inhibitors |
US8697911B2 (en) * | 2010-07-07 | 2014-04-15 | Boehringer Ingelheim International Gmbh | Rho kinase inhibitors |
AR094929A1 (es) * | 2013-02-28 | 2015-09-09 | Bristol Myers Squibb Co | Derivados de fenilpirazol como inhibidores potentes de rock1 y rock2 |
-
2017
- 2017-10-24 CN CN202210797866.4A patent/CN115160295A/zh active Pending
- 2017-10-24 WO PCT/US2017/058071 patent/WO2018081108A1/en active Application Filing
- 2017-10-24 AU AU2017351216A patent/AU2017351216C1/en active Active
- 2017-10-24 IL IL266150A patent/IL266150B2/en unknown
- 2017-10-24 JP JP2019543185A patent/JP6948398B2/ja active Active
- 2017-10-24 CN CN201780079730.7A patent/CN110099906B/zh active Active
- 2017-10-24 CA CA3078347A patent/CA3078347A1/en active Pending
- 2017-10-24 EP EP17863621.3A patent/EP3532479B1/en active Active
-
2023
- 2023-07-18 IL IL304547A patent/IL304547A/en unknown
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2021522238A (ja) * | 2018-04-24 | 2021-08-30 | トランスレイショナル・ドラッグ・ディベロップメント・エルエルシー | キナーゼ阻害剤としてのアミド化合物、組成物および処置方法 |
JP7490569B2 (ja) | 2018-04-24 | 2024-05-27 | トランスレイショナル・ドラッグ・ディベロップメント・エルエルシー | キナーゼ阻害剤としてのアミド化合物、組成物および処置方法 |
Also Published As
Publication number | Publication date |
---|---|
WO2018081108A1 (en) | 2018-05-03 |
AU2017351216A1 (en) | 2019-05-16 |
IL266150B2 (en) | 2023-12-01 |
JP2019535812A (ja) | 2019-12-12 |
AU2017351216C1 (en) | 2021-10-14 |
CA3078347A1 (en) | 2018-05-03 |
EP3532479A1 (en) | 2019-09-04 |
CN110099906A (zh) | 2019-08-06 |
IL304547A (en) | 2023-09-01 |
EP3532479B1 (en) | 2023-06-07 |
AU2017351216B2 (en) | 2021-04-15 |
CN115160295A (zh) | 2022-10-11 |
IL266150A (en) | 2019-06-30 |
EP3532479A4 (en) | 2020-04-22 |
CN110099906B (zh) | 2022-07-26 |
IL266150B1 (en) | 2023-08-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6948398B2 (ja) | キナーゼ阻害剤としてのアミド化合物 | |
AU2022200741B2 (en) | Aminothiazole compounds as c-Kit inhibitors | |
AU2018210196B2 (en) | Pyridine compounds as allosteric SHP2 inhibitors | |
AU2017376629B2 (en) | Benzimidazole compounds as c-Kit inhibitors | |
US10738007B2 (en) | Amide compounds as kinase inhibitors, compositions and methods of treatment | |
JP7335893B2 (ja) | ホスファチジルイノシトールリン酸キナーゼ阻害剤としてのクロメノピリジン誘導体 | |
JP7490569B2 (ja) | キナーゼ阻害剤としてのアミド化合物、組成物および処置方法 | |
JP2024503624A (ja) | C-kit阻害剤としてのアミノチアゾール化合物 | |
AU2022206787C1 (en) | Amide compounds as kinase inhibitors, compositions and methods of treatment |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20201023 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20201023 |
|
A871 | Explanation of circumstances concerning accelerated examination |
Free format text: JAPANESE INTERMEDIATE CODE: A871 Effective date: 20201023 |
|
A975 | Report on accelerated examination |
Free format text: JAPANESE INTERMEDIATE CODE: A971005 Effective date: 20201117 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20201204 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20210303 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20210407 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20210810 |
|
C60 | Trial request (containing other claim documents, opposition documents) |
Free format text: JAPANESE INTERMEDIATE CODE: C60 Effective date: 20210810 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20210819 |
|
C21 | Notice of transfer of a case for reconsideration by examiners before appeal proceedings |
Free format text: JAPANESE INTERMEDIATE CODE: C21 Effective date: 20210820 |
|
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: 20210909 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20210917 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6948398 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R157 | Certificate of patent or utility model (correction) |
Free format text: JAPANESE INTERMEDIATE CODE: R157 |