WO2023125536A1 - 用于抑制血管内皮生长的化合物及其用途 - Google Patents
用于抑制血管内皮生长的化合物及其用途 Download PDFInfo
- Publication number
- WO2023125536A1 WO2023125536A1 PCT/CN2022/142336 CN2022142336W WO2023125536A1 WO 2023125536 A1 WO2023125536 A1 WO 2023125536A1 CN 2022142336 W CN2022142336 W CN 2022142336W WO 2023125536 A1 WO2023125536 A1 WO 2023125536A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pharmaceutical composition
- disease
- formula
- endothelial growth
- diseases
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 43
- 230000002401 inhibitory effect Effects 0.000 title claims abstract description 12
- 230000012010 growth Effects 0.000 title description 5
- 230000003511 endothelial effect Effects 0.000 title description 3
- 230000002792 vascular Effects 0.000 title description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 42
- 201000010099 disease Diseases 0.000 claims abstract description 40
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 claims abstract description 26
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 claims abstract description 26
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 230000000694 effects Effects 0.000 claims abstract description 13
- 238000011282 treatment Methods 0.000 claims abstract description 8
- 230000002265 prevention Effects 0.000 claims abstract description 5
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 claims description 23
- 239000008194 pharmaceutical composition Substances 0.000 claims description 21
- 239000003814 drug Substances 0.000 claims description 20
- 229940079593 drug Drugs 0.000 claims description 10
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 7
- 206010029113 Neovascularisation Diseases 0.000 claims description 7
- 208000033679 diabetic kidney disease Diseases 0.000 claims description 7
- 201000009925 nephrosclerosis Diseases 0.000 claims description 7
- 230000002062 proliferating effect Effects 0.000 claims description 7
- 230000001225 therapeutic effect Effects 0.000 claims description 7
- 201000001320 Atherosclerosis Diseases 0.000 claims description 6
- 206010028980 Neoplasm Diseases 0.000 claims description 6
- 208000030533 eye disease Diseases 0.000 claims description 6
- 210000003584 mesangial cell Anatomy 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 4
- 206010018364 Glomerulonephritis Diseases 0.000 claims description 4
- 201000004681 Psoriasis Diseases 0.000 claims description 4
- 208000034841 Thrombotic Microangiopathies Diseases 0.000 claims description 4
- 206010052779 Transplant rejections Diseases 0.000 claims description 4
- 206010064930 age-related macular degeneration Diseases 0.000 claims description 4
- 206010012601 diabetes mellitus Diseases 0.000 claims description 4
- 230000003176 fibrotic effect Effects 0.000 claims description 4
- 208000002780 macular degeneration Diseases 0.000 claims description 4
- 230000003211 malignant effect Effects 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
- 208000011580 syndromic disease Diseases 0.000 claims description 4
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 claims description 3
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 claims description 3
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 3
- 206010051113 Arterial restenosis Diseases 0.000 claims description 3
- 208000023275 Autoimmune disease Diseases 0.000 claims description 3
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims description 3
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims description 3
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 claims description 3
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 206010055665 Corneal neovascularisation Diseases 0.000 claims description 3
- 206010012688 Diabetic retinal oedema Diseases 0.000 claims description 3
- 201000009273 Endometriosis Diseases 0.000 claims description 3
- 208000032759 Hemolytic-Uremic Syndrome Diseases 0.000 claims description 3
- 206010020772 Hypertension Diseases 0.000 claims description 3
- 208000007766 Kaposi sarcoma Diseases 0.000 claims description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims description 3
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 3
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 claims description 3
- 206010060862 Prostate cancer Diseases 0.000 claims description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 3
- 206010041067 Small cell lung cancer Diseases 0.000 claims description 3
- 208000038016 acute inflammation Diseases 0.000 claims description 3
- 230000006022 acute inflammation Effects 0.000 claims description 3
- 230000002491 angiogenic effect Effects 0.000 claims description 3
- 201000005667 central retinal vein occlusion Diseases 0.000 claims description 3
- 208000023819 chronic asthma Diseases 0.000 claims description 3
- 208000029742 colonic neoplasm Diseases 0.000 claims description 3
- 201000000159 corneal neovascularization Diseases 0.000 claims description 3
- 201000011190 diabetic macular edema Diseases 0.000 claims description 3
- 230000001631 hypertensive effect Effects 0.000 claims description 3
- 208000032839 leukemia Diseases 0.000 claims description 3
- 201000005202 lung cancer Diseases 0.000 claims description 3
- 208000020816 lung neoplasm Diseases 0.000 claims description 3
- 230000004770 neurodegeneration Effects 0.000 claims description 3
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 3
- 230000003449 preventive effect Effects 0.000 claims description 3
- 208000004644 retinal vein occlusion Diseases 0.000 claims description 3
- 208000000587 small cell lung carcinoma Diseases 0.000 claims description 3
- 210000004204 blood vessel Anatomy 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 239000003112 inhibitor Substances 0.000 claims description 2
- 108010041308 Endothelial Growth Factors Proteins 0.000 claims 1
- 208000037765 diseases and disorders Diseases 0.000 claims 1
- 210000003566 hemangioblast Anatomy 0.000 claims 1
- 239000002525 vasculotropin inhibitor Substances 0.000 claims 1
- 239000000203 mixture Substances 0.000 description 24
- 239000000243 solution Substances 0.000 description 13
- 210000004027 cell Anatomy 0.000 description 10
- 239000000546 pharmaceutical excipient Substances 0.000 description 10
- 239000004480 active ingredient Substances 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 230000033115 angiogenesis Effects 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 210000003711 chorioallantoic membrane Anatomy 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 238000007911 parenteral administration Methods 0.000 description 4
- 239000006187 pill Substances 0.000 description 4
- 241000287828 Gallus gallus Species 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 208000017169 kidney disease Diseases 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 206010016654 Fibrosis Diseases 0.000 description 2
- 208000017442 Retinal disease Diseases 0.000 description 2
- 206010038923 Retinopathy Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 230000007882 cirrhosis Effects 0.000 description 2
- 208000019425 cirrhosis of liver Diseases 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 239000012055 enteric layer Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 201000002222 hemangioblastoma Diseases 0.000 description 2
- 201000011066 hemangioma Diseases 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 238000001802 infusion Methods 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
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 description 2
- 239000008247 solid mixture Substances 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 210000003556 vascular endothelial cell Anatomy 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- BZISNWGGPWSXTK-UHFFFAOYSA-N 3-hydroxypropyl benzoate Chemical compound OCCCOC(=O)C1=CC=CC=C1 BZISNWGGPWSXTK-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- 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
- 208000003120 Angiofibroma Diseases 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 206010063209 Chronic allograft nephropathy Diseases 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
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108090000386 Fibroblast Growth Factor 1 Proteins 0.000 description 1
- 102100031706 Fibroblast growth factor 1 Human genes 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 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
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 208000003788 Neoplasm Micrometastasis Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 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
- 229920002472 Starch Polymers 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 229940081735 acetylcellulose Drugs 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 238000004115 adherent culture Methods 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 229960001714 calcium phosphate Drugs 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000000378 calcium silicate Substances 0.000 description 1
- 229910052918 calcium silicate Inorganic materials 0.000 description 1
- 229960003340 calcium silicate Drugs 0.000 description 1
- 235000012241 calcium silicate Nutrition 0.000 description 1
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 239000012059 conventional drug carrier Substances 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 239000008157 edible vegetable oil Substances 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 210000002257 embryonic structure Anatomy 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 210000004696 endometrium Anatomy 0.000 description 1
- 230000010595 endothelial cell migration Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 238000013213 extrapolation Methods 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 239000012054 flavored emulsion Substances 0.000 description 1
- 235000020375 flavoured syrup Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229940014259 gelatin Drugs 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000001434 glomerular Effects 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000010874 in vitro model Methods 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000000185 intracerebroventricular administration Methods 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 210000002510 keratinocyte Anatomy 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000011344 liquid material Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 230000006510 metastatic growth Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000012982 microporous membrane Substances 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 201000003142 neovascular glaucoma Diseases 0.000 description 1
- 201000008383 nephritis Diseases 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000012053 oil suspension Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- -1 sachet Substances 0.000 description 1
- 239000012056 semi-solid material Substances 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 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
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000012058 sterile packaged powder Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 230000008728 vascular permeability Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
-
- 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
- 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
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
- 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
-
- 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
- A61P9/12—Antihypertensives
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the disclosure relates to compounds for inhibiting vascular endothelial growth and uses thereof, belonging to the field of medicine.
- VEGF Vascular Endothelial Growth Factor
- diseases are known to be associated with continued angiogenesis, for example, diseases such as tumor growth or metastatic growth; psoriasis; arthritis such as rheumatoid arthritis, hemangiomas, endometriosis, angiofibromas; eye diseases such as diabetes retinopathy, neovascular glaucoma; renal disease such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndrome, transplant rejection and glomerulopathy; fibrotic disease such as cirrhosis, mesangial cell Proliferative diseases and arteriosclerosis.
- diseases such as tumor growth or metastatic growth
- psoriasis arthritis
- arthritis such as rheumatoid arthritis, hemangiomas, endometriosis, angiofibromas
- eye diseases such as diabetes retinopathy, neovascular glaucoma
- renal disease such as glomerulonephritis, diabetic
- the drug is used to inhibit the activity of vascular endothelial growth factor (VEGF).
- VEGF vascular endothelial growth factor
- the drug may be selected from a pharmaceutical composition.
- the compound represented by the formula (I) may be an E-type or Z-type isomer, preferably an E-type isomer represented by the following formula (I-1), that is, 5-[( E)-2-Styryl]-2-isopropyl-1,3-benzenediol:
- the present disclosure also provides the use of the compound represented by formula (I) or formula (I-1) or a pharmaceutically acceptable salt thereof for inhibiting the activity of vascular endothelial growth factor.
- the present disclosure also provides a method for inhibiting the activity of vascular endothelial growth factor, comprising administering the compound represented by formula (I) or formula (I-1) or a pharmaceutically acceptable salt thereof to a patient in need.
- the present disclosure also provides a compound represented by formula (I) or formula (I-1) or a pharmaceutically acceptable salt thereof, which is used for inhibiting the activity of vascular endothelial growth factor.
- the present disclosure also provides a pharmaceutical composition, which comprises a compound represented by formula (I) or formula (I-1) or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the drug
- the composition is used for inhibiting the activity of vascular endothelial growth factor.
- the drug or pharmaceutical composition may be selected from inhibitors of vascular endothelial growth factor.
- the medicament or pharmaceutical composition is used to treat the following diseases or conditions: diseases caused by ocular neovascularization, such as angiogenic eye disease, psoriasis, hemangioblastoma, mesangial cell Proliferative diseases, atherosclerosis, arterial restenosis, autoimmune diseases, acute inflammation, fibrotic diseases, diabetes mellitus, endometriosis, chronic asthma, arterial or post-graft atherosclerosis, neurodegenerative diseases, leukemia, Examples include acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, and solid tumors;
- diseases caused by ocular neovascularization such as angiogenic eye disease, psoriasis, hemangioblastoma, mesangial cell Proliferative diseases, atherosclerosis, arterial restenosis, autoimmune diseases, acute inflammation, fibrotic diseases, diabetes mellitus, endometriosis, chronic asthma, arterial or post-graft athe
- the disease caused by said ocular neovascularization is preferably an angiogenic eye disease selected from the group consisting of age-related macular degeneration, diabetic retinopathy, diabetic macular edema, central retinal vein occlusion and corneal neovascularization;
- the mesangial cell proliferative disease is preferably selected from diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndrome or transplant rejection, glomerulonephritis, hemolytic uremic syndrome, diabetic nephropathy and hypertensive nephrosclerosis ;
- the solid tumor is selected from breast cancer, colon cancer, lung cancer (eg small cell lung cancer), prostate cancer and Kaposi's sarcoma.
- the medicament or pharmaceutical composition is used to treat the following diseases or conditions: diseases caused by ocular neovascularization, such as angiogenesis eye disease;
- the angiogenesis eye disease is selected from age-related macular degeneration, Diabetic retinopathy, diabetic macular edema, central retinal vein occlusion, and corneal neovascularization e.g. retinopathy such as diabetic retinopathy or age-related macular degeneration; psoriasis, hemangioblastoma such as hemangioma, glomerular membranous cell proliferative disease such as chronic or acute kidney disease, e.g.
- diabetic nephropathy malignant nephrosclerosis, thrombotic microangiopathy syndrome or transplant rejection, or e.g. inflammatory kidney disease such as glomerulonephritis, e.g. mesangial proliferative glomeruli Nephritis, hemolytic uremic syndrome, diabetic nephropathy, hypertensive nephrosclerosis, atherosclerosis, arterial restenosis, autoimmune disease, acute inflammation, fibrotic disease (eg, cirrhosis), diabetes mellitus, endometrium Ectopic, chronic asthma, arterial or post-graft atherosclerosis, neurodegenerative diseases and, for example, neoplastic diseases such as leukemias, such as acute lymphoblastic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia and other "liquid tumors", and solid Tumors (eg carcinomas), eg breast cancer, colon cancer, lung cancer (eg small cell lung cancer), prostate cancer or Kaposi's
- the drug or pharmaceutical composition may be selected from therapeutic or preventive agents for the above-mentioned diseases or conditions.
- the disclosed compounds may be administered in the form of pharmaceutical compositions.
- These compositions can be prepared in manners well known in the art of pharmacy and can be administered by a variety of routes depending upon whether local or systemic treatment is desired and the area to be treated.
- Topical e.g., transdermal, dermal, ocular, and mucous membranes, including intranasal, vaginal, and rectal delivery
- pulmonary e.g., by inhalation or insufflation of powder or aerosol, including by nebulizer; intratracheal, intranasal
- Oral or parenteral administration e.g., transdermal, dermal, ocular, and mucous membranes, including intranasal, vaginal, and rectal delivery
- pulmonary e.g., by inhalation or insufflation of powder or aerosol, including by nebulizer; intratracheal, intranasal
- Oral or parenteral administration e.g., transdermal
- Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, eg, intrathecal or intracerebroventricular, administration.
- Administration can be parenteral in the form of a bolus, or it can be administered, for example, by means of a continuous infusion pump.
- Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, powders and powders. Conventional pharmaceutical carriers, water, powder or oily bases, thickening agents and the like may be necessary or desired.
- the active ingredient will generally be admixed with an excipient, diluted by means of an excipient, or enclosed within a carrier such as a capsule, sachet, paper or other container.
- a carrier such as a capsule, sachet, paper or other container.
- the excipient acts as a diluent, it can be a solid, semi-solid or liquid material which acts as a vehicle, carrier or medium for the active ingredient.
- the composition may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or dissolved in liquid vehicles); ointments, soft and hard gelatine capsules, suppositories, sterile injectable solutions and sterile packaged powders containing, for example, up to 10% by weight of the active compound.
- excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, poly Vinylpyrrolidone, cellulose, water, syrup and methylcellulose.
- the formulations may also contain: lubricating agents such as talc, sodium stearate, magnesium stearate, sodium oleate, sodium benzoate, sodium acetate, sodium chloride, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as Methyl benzoate and hydroxypropyl benzoate; sweeteners and flavorings.
- the compositions of the present disclosure can be formulated so as to provide immediate, sustained or delayed release of the active ingredient after administration to the patient by employing methods known in the art.
- compositions may be formulated in unit dosage form, each dose containing from about 5 to 1000 mg, more usually from about 100 to 500 mg, of the active ingredient.
- unit dosage form means physically discrete units suitable as unitary dosages for human patients and other mammals, each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect, in admixture with a suitable pharmaceutical excipient. substance.
- the effective dose of the active compound can vary widely and is usually administered in a pharmaceutically effective amount. However, it is understood that the amount of compound actually administered will generally be determined by the physician based on relevant circumstances, which include the condition being treated, the route of administration chosen, the actual compound being administered; the age, weight and response of the individual patient; the severity of the patient's symptoms; severity etc.
- the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of the disclosed compounds.
- these preformulation compositions are referred to as homogeneous, it is meant that the active ingredient is generally uniformly distributed throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
- the solid preformulation is then subdivided into unit dosage forms of the type described above containing, for example, from about 0.1 to 1000 mg of the active ingredient of the disclosure.
- Tablets or pills of the present disclosure may be coated or compounded to provide dosage forms which provide the advantage of prolonged action.
- a tablet or pill contains an inner dose and an outer dose component, the latter being a coated form of the former.
- the two components can be separated by an enteric layer, which is used to prevent disintegration in the stomach, allowing the inner component to pass through the duodenum intact or to delay release.
- enteric layers or coatings such materials including various polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
- liquid forms for oral or parenteral administration include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions; and edible oils such as cottonseed oil, sesame oil, coconut oil, oil or peanut oil flavored emulsions; and elixirs and similar pharmaceutical vehicles.
- compositions for inhalation or insufflation include solutions, suspensions, and powders dissolved in pharmaceutically acceptable water or organic solvents or mixtures thereof.
- Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above.
- the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
- Compositions can be nebulized by use of inert gases. The nebulized solution can be inhaled directly from the nebulizing device, or the nebulizing device can be connected to a face mask or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be administered orally or nasally from devices that deliver the formulation in an appropriate manner.
- the amount of the compound or composition administered to a patient is not fixed, depending on the drug administered, the purpose of administration such as prophylaxis or treatment; the state of the patient, the mode of administration, and the like.
- an amount of the composition sufficient to cure or at least partially suppress the symptoms of the disease and its complications may be administered to a patient already suffering from the disease. Effective doses will depend on the disease state being treated and on the judgment of the attending clinician which will depend on factors such as the severity of the disease, the age, weight and general condition of the patient.
- compositions administered to the patient may be in the form of the pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques or by filter sterilization. Aqueous solutions can be used as received as packaged, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.
- the pH of the compound preparation is usually 3-11, more preferably 5-9, most preferably 7-8. It will be appreciated that the use of certain of the foregoing excipients, carriers or stabilizers will result in the formation of pharmaceutical salts.
- Therapeutic dosages of compounds of the present disclosure may depend, for example, on the particular use for the treatment, the mode of administration of the compound, the health and state of the patient, and the judgment of the prescribing physician.
- the ratio or concentration of the disclosed compounds in the pharmaceutical compositions may vary and depend on a variety of factors including dosage, chemical properties (eg, hydrophobicity), and route of administration.
- a compound of the present disclosure may be provided, for example, as an aqueous physiologically buffered solution containing about 0.1-10% (w/v) of the compound.
- Some typical dosages range from about 1 ⁇ g/kg to about 1 g/kg body weight per day. In certain embodiments, the dosage range is from about 0.01 mg/kg to about 100 mg/kg body weight/day.
- the dosage will likely depend on such variables as the type and extent of the disease or condition, the general health of the particular patient, the relative biological potency of the compound selected, the formulation of the excipient and its route of administration. Effective doses may be obtained by extrapolation from dose-response curves derived from in vitro or animal model test systems.
- the compound represented by formula (I) or formula (I-1) or a pharmaceutically acceptable salt thereof and its medicine or pharmaceutical composition can inhibit the activity of vascular endothelial growth factor on the Diseases and conditions are prophylactic or therapeutic.
- the pharmaceutically acceptable salt may be selected from addition salts of compounds of formula (I) or formula (I-1) with bases.
- the disease or disorder may be a disease or disorder associated with VEGF.
- the inventors unexpectedly found that the compound represented by formula (I) or formula (I-1) or a pharmaceutically acceptable salt thereof has VEGF inhibitory effect and can be used for the prevention and treatment of diseases or diseases related to VEGF activity. This discovery provides an improved technical solution for the prevention and treatment of such diseases.
- Embodiment 1 The impact of the compound containing formula (I-1) on the content of vascular endothelial growth factor
- the HaCaT cell model was cultured in vitro.
- the HaCaT cell strain was inoculated at 1 ⁇ 10 7 /mL in DMEM medium containing 10% fetal bovine serum and PR-MI1640 medium, and placed in a 37°C, 5% CO incubator for adherent culture. Change the medium every other day, observe the cell morphology under an inverted microscope, and digest the cells with 0.25% trypsin to collect and passage when the cells are overgrown. Cells in the logarithmic growth phase after changing the medium for 24 hours were used in the experiment.
- *% is the percentage relative to the control group, where T represents the test group and C represents the control group.
- Embodiment 2 The effect of the compound containing formula (I-1) on the neovascularization of chicken embryo chorioallantoic membrane (CAM)
Landscapes
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Immunology (AREA)
- Cardiology (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Pulmonology (AREA)
- Heart & Thoracic Surgery (AREA)
- Urology & Nephrology (AREA)
- Oncology (AREA)
- Dermatology (AREA)
- Reproductive Health (AREA)
- Vascular Medicine (AREA)
- Epidemiology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Gastroenterology & Hepatology (AREA)
- Ophthalmology & Optometry (AREA)
- Obesity (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Emergency Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本公开提供了一种式(I)所示的化合物或其药学上可接受的盐,该化合物具有VEGF抑制作用,可用于与VEGF活性相关的疾病或病症的预防和治疗。该发现为此类疾病的预防和治疗提供了改善的技术方案:
Description
本发明要求享有于2021年12月28日向中国国家知识产权局提交的,专利申请号为202111683652.6,名称为“用于抑制血管内皮生长的化合物及其用途”的在先申请的优先权。该在先申请的全文通过引用的方式结合于本申请中。
本公开涉及用于抑制血管内皮生长的化合物及其用途,属于医药领域。
血管内皮生长因子(Vascular Endothelial Growth Factor,VEGF)是一种高度特异性的促血管内皮细胞生长因子,其具有促进血管通透性增加、细胞外基质变性、血管内皮细胞迁移、增殖、血管形成和发生等作用。已知许多疾病与持续血管发生相关,例如,疾病如肿瘤生长或转移生长;银屑病;关节炎如类风湿性关节炎、血管瘤、子宫内膜异位症、血管纤维瘤;眼病如糖尿病性视网膜病变、新生血管性青光眼;肾病如肾小球肾炎、糖尿病肾病、恶性肾硬化、血栓性微血管病综合征、移植排斥和肾小球病;纤维化病如肝硬化、肾小球膜细胞增生性疾病和动脉硬化。
因此,开发具有VEGF抑制活性的新药物,对于改善或丰富与VEGF相关的疾病或病症的预防和治疗具有重要意义。
发明内容
为改善上述技术问题,本公开提供如下式(I)所示化合物或其药学上可接受的盐在制备药物中的用途:
其中,所述药物用于抑制血管内皮生长因子(VEGF)的活性。
根据本公开的实施方案,所述药物可以选自药物组合物。
根据本公开的实施方案,所述式(I)所示的化合物可以为E型或Z型异构体,优选下式(I-1)所示的E型异构体,即5-[(E)-2-苯乙烯基]-2-异丙基-1,3-苯二酚:
本公开还提供式(I)或式(I-1)所示化合物或其药学上可接受的盐的用途,其用于抑制血管内皮生长因子的活性。
本公开还提供一种抑制血管内皮生长因子的活性的方法,包括将式(I)或式(I-1)所示化合物或其药学上可接受的盐施用于有需要的患者。
本公开还提供式(I)或式(I-1)所示化合物或其药学上可接受的盐,其用于抑制血管内皮生长因子的活性。
本公开还提供一种药物组合物,所述药物组合物包含式(I)或式(I-1)所示化合物或其药学上可接受的盐以及药学上可接受的辅料,其中所述药物组合物用于抑制血管内皮生长因子的活性。
根据本公开的实施方案,所述药物或药物组合物可以选自血管内皮生长因子抑制剂。
根据本公开的实施方案,所述药物或药物组合物用于治疗下列疾病或病症:眼部新血管化导致的疾病,如血管生成眼病、银屑病、成血管细胞瘤、肾小球膜 细胞增殖疾病、动脉粥样化、动脉再狭窄、自身免疫疾病、急性炎症、纤维化疾病、糖尿病、子宫内膜异位、慢性哮喘、动脉或移植后动脉粥样硬化、神经变性疾病以、白血病,例如急性淋巴细胞白血病、急性髓性白血病、慢性髓性白血病和实体肿瘤;
所述眼部新血管化导致的疾病优选为血管生成眼病,所述血管生成眼病选自与年龄相关的黄斑变性、糖尿病性视网膜病、糖尿病性黄斑水肿、视网膜中央静脉闭塞和角膜新血管生成;
所述肾小球膜细胞增殖疾病优选自糖尿病性肾病、恶性肾硬化、血栓性微血管病综合征或移植排斥、肾小球肾炎、溶血性尿毒症综合征、糖尿病性肾病和高血压性肾硬化;
所述实体肿瘤选自乳腺癌、结肠癌、肺癌(例如小细胞肺癌)、前列腺癌和卡波西氏肉瘤。
根据本公开的实施方案,所述药物或药物组合物用于治疗下列疾病或病症:眼部新血管化导致的疾病,如血管生成眼病;所述血管生成眼病选自与年龄相关的黄斑变性、糖尿病性视网膜病、糖尿病性黄斑水肿、视网膜中央静脉闭塞和角膜新血管生成,例如视网膜病如糖尿病性视网膜病或年龄相关性黄斑变性;银屑病、成血管细胞瘤如血管瘤、肾小球膜细胞增殖疾病如慢性或急性肾病,例如糖尿病性肾病、恶性肾硬化、血栓性微血管病综合征或移植排斥,或例如炎性肾病如肾小球肾炎,例如肾小球膜增殖性肾小球肾炎、溶血性尿毒症综合征、糖尿病性肾病、高血压性肾硬化、动脉粥样化、动脉再狭窄、自身免疫疾病、急性炎症、纤维化疾病(例如肝硬变)、糖尿病、子宫内膜异位、慢性哮喘、动脉或移植后动脉粥样硬化、神经变性疾病以及例如肿瘤性疾病如白血病,例如急性淋巴细胞白血病、急性髓性白血病、慢性髓性白血病和其它“液体肿瘤”,以及实体肿瘤(如癌),例如乳腺癌、结肠癌、肺癌(例如小细胞肺癌)、前列腺癌或卡波西氏肉瘤,例如上述肿瘤生长或转移性扩散和微小转移灶的生长。
根据本公开的实施方案,所述药物或药物组合物可以选自上述疾病或病症的治疗剂或预防剂。
作为药物时,可按药物组合物的形式给予本公开化合物。可按药剂领域中熟知的方式制备这些组合物,可通过多种途径给予它们,这取决于是否需要局部或全身治疗和所治疗的区域。可局部(例如,透皮、皮肤、眼和粘膜包括鼻内、阴道和直肠递药)、肺(例如,通过吸入或吹入粉末或气雾剂,包括通过喷雾器;气管内、鼻内)、口服或肠胃外给药。肠胃外给药包括静脉内、动脉内、皮下、腹膜内或肌内注射或输注;或颅内例如鞘内或脑室内给药。可按单次大剂量形式肠胃外给药,或可通过例如连续灌注泵给药。局部给予的药用组合物和制剂可包括透皮贴剂、软膏、洗剂、霜剂、凝胶剂、滴剂、栓剂、喷雾剂、液体剂、粉末制剂和散剂。常规药物载体、水、粉末或油性基质、增稠剂等可能是必须的或需要的。
在制备本公开的组合物时,通常将活性成分与赋形剂混合,通过赋形剂稀释或装入例如胶囊、小药囊、纸或其它容器形式的这种载体内。当赋形剂用作稀释剂时,它可以是固体、半固体或液体物质,用作溶媒、载体或活性成分的介质。因此,组合物可以是以下形式:片剂、丸剂、散剂、锭剂、小药囊、扁囊剂、酏剂、混悬剂、乳剂、溶液剂、糖浆剂、气雾剂(固体或溶于液体溶媒);含例如高达10%重量活性化合物的软膏剂、软和硬明胶胶囊、栓剂、无菌注射溶液和无菌包装粉末。
适宜的赋形剂的某些实例包括乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、淀粉、阿拉伯胶、磷酸钙、藻酸盐、黄蓍胶、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆和甲基纤维素。制剂还可含有:润滑剂例如滑石粉、硬脂酸钠、硬脂酸镁、油酸钠、苯甲酸钠、乙酸钠、氯化钠和矿物油;湿润剂;乳化剂和悬浮剂;防腐剂例如苯甲酸甲酯和苯甲酸羟基丙酯;甜味剂和矫味剂。可通过使用本领域中已知的方法配制本公开组合物,以便在给予患者后提供速释、 缓释或延迟释放活性成分的作用。
可按单位剂型配制组合物,每一剂量含约5~1000mg,更通常约100~500mg活性成分。术语“单位剂型”是指物理上分离的适宜作为用于人患者和其它哺乳动物的单一剂量单位,各单位含有与适宜的药物赋形剂混合的经计算可产生所需疗效的预定量的活性物质。
活性化合物的有效剂量的范围可很大,通常按药用有效量给药。但是,可以理解实际给予的化合物的量通常由医师根据相关情况决定,它们包括所治疗的病症、所选择的给药途径、所给予的实际化合物;患者个体的年龄、重量和反应;患者症状的严重程度等。
对于制备固体组合物例如片剂,将主要的活性成分与药物赋形剂混合,形成含本公开化合物的均匀混合物的固体预制剂组合物。当称这些预制剂组合物为均匀时,是指活性成分通常均匀地分布在整个组合物中,致使该组合物可容易地划分为同等有效的单位剂型例如片剂、丸剂和胶囊剂。然后将该固体预制剂划分为上述类型的含例如约0.1~1000mg本公开活性成分的单位剂型。
可将本公开片剂或丸剂包衣或复合,得到提供长效作用优点的剂型。例如,片剂或丸剂含内剂量和外剂量组分,后者是前者的被膜形式。可通过肠溶层将两种组分隔离,肠溶层用于在胃中阻止崩解,以使内组分完整通过十二指肠或延迟释放。多种物质可用于此类肠溶层或包衣剂,此类物质包括多种高分子酸和高分子酸与此类物质如虫胶、鲸蜡醇和醋酸纤维素的混合物。
其中可掺入本公开化合物和组合物,用于口服或注射给药的液体形式包括水溶液、适当矫味的糖浆剂、水或油混悬液;和用食用油例如棉子油、芝麻油、椰子油或花生油矫味的乳剂;以及酏剂和类似的药用溶媒。
用于吸入或吹入的组合物包括溶于药学上可接受的水或有机溶剂或其混合物的溶液剂和混悬液、散剂。液体或固体组合物可含有如上所述适宜的药学上可接受的赋形剂。在某些实施方案中,通过口服或鼻呼吸途径给予组合物,实现局 部或全身作用。可通过使用呈惰性的气体,使组合物成雾化。可直接由雾化装置吸入雾化溶液,或雾化装置可与面罩帷或间歇正压呼吸机连接。可通过口服或由按适当方式递送制剂的装置通过鼻给予溶液、混悬液或粉末组合物。
给予患者的化合物或组合物的量不固定,取决于给予的药物、给药的目的例如预防或治疗;患者的状态、给药的方式等。在治疗应用时,可给予已患疾病的患者足够治愈或至少部分抑制疾病及其并发症症状的量的组合物。有效剂量应取决于所治疗的疾病状态和主治临床医师的判断,该判断取决于例如疾病的严重程度、患者的年龄、体重和一般状况等因素。
给予患者的组合物可以是上述药用组合物形式。可通过常规灭菌技术或可过滤灭菌,将这些组合物灭菌。可将水溶液包装原样使用,或冻干,给药前,将冻干制剂与无菌水性载体混合。化合物制剂的pH通常为3~11,更优选5~9,最优选7~8。可以理解,使用某些前述赋形剂、载体或稳定剂会导致形成药物盐。
本公开化合物的治疗剂量可根据例如以下而定:治疗的具体用途、给予化合物的方式、患者的健康和状态,以及签处方医师的判断。本公开化合物在药用组合物中的比例或浓度可不固定,取决于多种因素,它们包括剂量、化学特性(例如疏水性)和给药途径。例如可通过含约0.1~10%(w/v)该化合物的生理缓冲水溶液提供本公开化合物,用于肠胃外给药。某些典型剂量范围为约1μg/kg~约1g/kg体重/日。在某些实施方案中,剂量范围为约0.01mg/kg~约100mg/kg体重/日。剂量很可能取决于此类变量,如疾病或病症的种类和发展程度、具体患者的一般健康状态、所选择的化合物的相对生物学效力、赋形剂制剂及其给药途径。可通过由体外或动物模型试验系统导出的剂量-反应曲线外推,得到有效剂量。
根据本公开的实施方案,所述式(I)或式(I-1)所示化合物或其药学上可接受的盐及其药物或药物组合物通过抑制血管内皮生长因子的活性而对所述疾病和病症产生预防或治疗作用。
根据本公开的实施方案,所述药学上可接受的盐可以选自式(I)或式(I-1) 化合物与碱的加成盐。
根据本公开的实施方案,所述疾病或病症可以是与VEGF相关的疾病或病症。
发明人意外发现式(I)或式(I-1)所示的化合物或其药学上可接受的盐具有VEGF抑制作用,可用于与VEGF活性相关的疾病或病症的预防和治疗。该发现为此类疾病的预防和治疗提供了改善的技术方案。
下文将结合具体实施例对本公开的技术方案做更进一步的详细说明。应当理解,下列实施例仅为示例性地说明和解释本公开,而不应被解释为对本公开保护范围的限制。凡基于本公开上述内容所实现的技术均涵盖在本公开旨在保护的范围内。
除非另有说明,以下实施例中使用的原料和试剂均为市售商品,或者可以通过已知方法制备。
以下实施例中所述受试化合物为下式(I-1)所示的化合物:
实施例1:含式(I-1)化合物对血管内皮生长因子含量的影响
体外培养HaCaT细胞模型。将HaCaT细胞株以1×10
7/mL接种于含有10%胎牛血清的DMEM培养液及PR-MI1640培养液中,置37℃、5%CO细胞恒温培养箱内贴壁培养。隔日换液1次,倒置显微镜下观察细胞形态,细胞长满则用0.25%胰蛋白酶消化细胞收集并传代。实验选用换液24h后对数生长期的细胞。
血管内皮生长因子含量测定:
HaCaT细胞96孔板培养24h后,显微镜下观察细胞已贴壁生长良好,达40%~50%融合,吸去培养液加药。分别加入已制备的各组药物缓冲液,A(I-1 0μg/mL),B(I-1 0.01μg/mL),C(I-1 0.1μg/mL),D(I-11μg/mL),E(I-110μg/mL)。每组分设8孔,5%CO
2培养箱中37℃恒温培养48h后吸出培养液,2000r/min离心10min以去除细胞碎片,取上清液,于酶标仪450nm处ELISA检测VEGF含量,按试剂盒说明书操作,测试结果见下表1。
表1血管内皮生长因子含量测定
*%为相对于对照组的百分比,其中T代表受试组,C代表对照组。
结果表明,经rhTGF-α处理24小时后,角质形成细胞的上清液中的VEGF浓度呈现出被式(I-1)化合物剂量依赖性的抑制。
实施例2:含式(I-1)化合物对鸡胚绒毛尿囊膜(CAM)新生血管生成的影响
取20个鸡胚随机分为2组:PBS溶液对照组、实验组(含式(I-1)化合物溶液),于CAM上植入混合纤维素酯微孔滤膜药物载体,实验组加入1.5μg/ml的式(I-1)化合物,对照组加入PBS溶液,孵化3天,进行标本采集,观察各组CAM新生血管生长的情况,测试结果见下表2。
表2标准鸡胚血管生成模型的试验结果
组别 | 新生血管数量 | 抑制率% |
PBS溶液对照组 | 58.07 | 0 |
式(I-1)化合物) | 13.02 | 77.57 |
结果表明,式(I-1)化合物能够显著抑制血管生成。
以上对本公开技术方案的实施方式进行了示例性的说明。应当理解,本公开的保护范围不拘囿于上述实施方式。凡在本公开的精神和原则之内,本领域技术人员所做的任何修改、等同替换、改进等,均应包含在本申请权利要求书的保护范围之内。
Claims (10)
- 根据权利要求1所述的用途,其特征在于,所述药物为血管内皮生长因子抑制剂。
- 根据权利要求1至3中任一项所述的用途,其特征在于,所述药学上可接受的盐选自式(I)化合物与碱的加成盐。
- 一种药物组合物的用途,所述药物组合物包含权利要求1中式(I)所示化合物或其药学上可接受的盐以及药学上可接受的辅料,其中所述药物组合物用于抑制血管内皮生长因子的活性。
- 根据权利要求5所述的药物组合物,其特征在于,所述药物组合物为血管内皮生长因子抑制剂。
- 根据权利要求1至6中任一项所述的用途,其特征在于,所述药物或药物组合物用于治疗与VEGF相关的疾病或病症。
- 根据权利要求7所述的用途,其特征在于,所述药物或药物组合物用于预防和/或治疗选自下列疾病或病症:眼部新血管化导致的疾病、银屑病、成血管细胞瘤、肾小球膜细胞增殖疾病、动脉粥样化、动脉再狭窄、自身免疫疾病、急性炎症、纤维化疾病、糖尿病、子宫内膜异位、慢性哮喘、动脉或移植后动脉粥样硬化、神经变性疾病以、白血病,例如急性淋巴细胞白血病、急性髓性白血病、慢性髓性白血病和实体肿瘤;所述眼部新血管化导致的疾病优选为血管生成眼病,所述血管生成眼病选自与年龄相关的黄斑变性、糖尿病性视网膜病、糖尿病性黄斑水肿、视网膜中央静脉闭塞和角膜新血管生成;所述肾小球膜细胞增殖疾病优选自糖尿病性肾病、恶性肾硬化、血栓性微血管病综合征或移植排斥、肾小球肾炎、溶血性尿毒症综合征、糖尿病性肾病和高血压性肾硬化;所述实体肿瘤选自乳腺癌、结肠癌、肺癌(例如小细胞肺癌)、前列腺癌和卡波西氏肉瘤。
- 根据权利要求8所述的用途,其特征在于,所述药物或药物组合物选自所述疾病或病症的治疗剂或预防剂。
- 根据权利要求8所述的用途,其特征在于,所述药物或药物组合物通过抑制血管内皮生长因子的活性而对所述疾病和病症产生预防或治疗作用。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111683652.6A CN116350609A (zh) | 2021-12-28 | 2021-12-28 | 用于抑制血管内皮生长的化合物及其用途 |
CN202111683652.6 | 2021-12-28 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2023125536A1 true WO2023125536A1 (zh) | 2023-07-06 |
Family
ID=86926072
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2022/142336 WO2023125536A1 (zh) | 2021-12-28 | 2022-12-27 | 用于抑制血管内皮生长的化合物及其用途 |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN116350609A (zh) |
WO (1) | WO2023125536A1 (zh) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1407978A (zh) * | 1999-12-06 | 2003-04-02 | 陈庚辉 | 用羟基芪、新型芪衍生物及其类似物抗发炎、治疗牛皮癣和抑制蛋白质致活酶 |
WO2004031117A1 (en) * | 2000-10-06 | 2004-04-15 | Welichem Biotech Inc. | Novel bioactive diphenyl ethene compounds and their therapeutic applications |
WO2020255135A1 (en) * | 2019-06-17 | 2020-12-24 | Sol-Gel Technologies Ltd. | Treatment of ocular inflammatory diseases with topical ophthalmic tapinarof compositions |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080255245A1 (en) * | 1999-12-06 | 2008-10-16 | Welichem Biotech Inc. | Anti-Inflammatory and Psoriasis Treatment and Protein Kinase Inhibition by Hydroxystilbenes and Novel Stilbene Derivatives and Analogues |
-
2021
- 2021-12-28 CN CN202111683652.6A patent/CN116350609A/zh active Pending
-
2022
- 2022-12-27 WO PCT/CN2022/142336 patent/WO2023125536A1/zh unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1407978A (zh) * | 1999-12-06 | 2003-04-02 | 陈庚辉 | 用羟基芪、新型芪衍生物及其类似物抗发炎、治疗牛皮癣和抑制蛋白质致活酶 |
WO2004031117A1 (en) * | 2000-10-06 | 2004-04-15 | Welichem Biotech Inc. | Novel bioactive diphenyl ethene compounds and their therapeutic applications |
WO2020255135A1 (en) * | 2019-06-17 | 2020-12-24 | Sol-Gel Technologies Ltd. | Treatment of ocular inflammatory diseases with topical ophthalmic tapinarof compositions |
Non-Patent Citations (3)
Title |
---|
CHEN MING, ZHONG JIE-MIN, LIU GUAN-PING, LI BO-LIN, CHEN XIN : "Progress of development and research on targets and therapeutic drugs for psoriasis ", CHINESE JOURNAL OF HOSPITAL PHARMACY, vol. 35, no. 9, 1 January 2015 (2015-01-01), pages 846 - 850, XP093076481 * |
PSORIASIS RESEARCH GROUP OF CHINESE SOCIETY DERMATOLOGY: "Consensus on the Treatment of Psoriasis with Benvitimod Cream", THE CHINESE JOURNAL OF DERMATOVENEREOLOGY, vol. 35, no. 06, 30 June 2021 (2021-06-30), XP009547530 * |
SUSAN H. SMITH, JAYAWICKREME CHANNA, RICKARD DAVID J., NICODEME EDWIGE, BUI THI, SIMMONS CATHY, COQUERY CHRISTINE M., NEIL JESSICA: "Tapinarof Is a Natural AhR Agonist that Resolves Skin Inflammation in Mice and Humans", JOURNAL OF INVESTIGATIVE DERMATOLOGY, ELSEVIER, NL, vol. 137, no. 10, 31 October 2017 (2017-10-31), NL , pages 2110 - 2119, XP055727670, ISSN: 0022-202X, DOI: 10.1016/j.jid.2017.05.004 * |
Also Published As
Publication number | Publication date |
---|---|
CN116350609A (zh) | 2023-06-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11564925B2 (en) | Treatment of respiratory diseases | |
JP5020227B2 (ja) | 癌療法性粘膜炎の治療および予防のためのベンズアミジン誘導体 | |
CA2549801A1 (en) | Use of treprostinil to improve kidney functions | |
US10660865B2 (en) | Cannabidiol for the prevention and treatment of graft-versus-host disease | |
JPH09506622A (ja) | α−2−アドレノセプター作動剤として有用な6−(2−イミダゾリニルアミノ)キノキサリン化合物 | |
US20230107479A1 (en) | Methods and compositions for preventing and treating fibrosis resulting from a coronavirus infection | |
CN112656788B (zh) | 用于治疗眼部疾病的中药有效成分及其组合物 | |
US11266646B2 (en) | Use of chymase inhibitors for the treatment of endometriosis, post operative fibrosis and diseases which are characterized by fibrosis formation | |
CA3133189A1 (en) | Methods of treating influenza in subjects with influenza and a complication risk factor | |
US20130324520A1 (en) | Rxrg modulators for the treatment of cancer | |
WO2023125536A1 (zh) | 用于抑制血管内皮生长的化合物及其用途 | |
WO2014063660A1 (en) | Naringenin and asiatic acid combination treatment of fibrosis | |
JPH03109324A (ja) | 血管新生阻害剤 | |
WO2017127810A1 (en) | Methods for repairing lung tissue | |
CN115066244A (zh) | 用于治疗局部缺血-再灌注损伤和/或肺损伤的化合物、组合物和方法 | |
JPS63104960A (ja) | α−[(フェニルメトキシ)メチル]ピリジンアルカノール誘導体 | |
JP2015134732A (ja) | 血管透過性亢進抑制剤 | |
US7252835B2 (en) | Agent for preventing and/or treating sinusitis | |
CN110403924A (zh) | 一种治疗皮肤黑色素瘤的药物组合物及其制备方法 | |
WO2023046182A1 (zh) | 一种吡啶并[1,2-a]嘧啶酮类化合物的应用 | |
CN114569601B (zh) | 新藤黄酸在制备预防和/或治疗肾脏病的药物中的应用 | |
US7842702B2 (en) | Treatment for irritable bowel syndrome | |
CN116492319B (zh) | 岩藻糖醇在制备治疗主动脉夹层的药物中的应用 | |
JP7219476B2 (ja) | 腱滑膜病変を主体とした疾患の治療薬 | |
US20220168297A1 (en) | Methods and compositions for treating chronic obstructive pulmonary disease, asthma, pneumonia, bronchitis, cystic fibrosis, pulmonary edema, interstitial lung disease, sarcoidosis, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, and pulmonary arterial hypertension |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 22914789 Country of ref document: EP Kind code of ref document: A1 |