TWI689490B - 用於治療纖維化之經取代之芳族化合物及相關方法 - Google Patents
用於治療纖維化之經取代之芳族化合物及相關方法 Download PDFInfo
- Publication number
- TWI689490B TWI689490B TW103108723A TW103108723A TWI689490B TW I689490 B TWI689490 B TW I689490B TW 103108723 A TW103108723 A TW 103108723A TW 103108723 A TW103108723 A TW 103108723A TW I689490 B TWI689490 B TW I689490B
- Authority
- TW
- Taiwan
- Prior art keywords
- fibrosis
- compound
- alkenyl
- linear
- alkyl
- Prior art date
Links
- 206010016654 Fibrosis Diseases 0.000 title claims abstract description 68
- 230000004761 fibrosis Effects 0.000 title claims abstract description 57
- 238000000034 method Methods 0.000 title abstract description 42
- 238000011282 treatment Methods 0.000 title abstract description 41
- 150000001491 aromatic compounds Chemical class 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 146
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 76
- 201000010099 disease Diseases 0.000 claims abstract description 69
- 230000003176 fibrotic effect Effects 0.000 claims abstract description 67
- 208000005069 pulmonary fibrosis Diseases 0.000 claims abstract description 45
- 150000003839 salts Chemical class 0.000 claims abstract description 40
- 208000019425 cirrhosis of liver Diseases 0.000 claims abstract description 38
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 31
- 206010050207 Skin fibrosis Diseases 0.000 claims abstract description 29
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 22
- 201000002793 renal fibrosis Diseases 0.000 claims abstract description 21
- 230000009787 cardiac fibrosis Effects 0.000 claims abstract description 17
- 201000009594 Systemic Scleroderma Diseases 0.000 claims abstract description 14
- 206010042953 Systemic sclerosis Diseases 0.000 claims abstract description 14
- 208000002780 macular degeneration Diseases 0.000 claims abstract description 12
- 210000000496 pancreas Anatomy 0.000 claims abstract description 4
- 239000003814 drug Substances 0.000 claims description 32
- 102000008186 Collagen Human genes 0.000 claims description 29
- 108010035532 Collagen Proteins 0.000 claims description 29
- 229920001436 collagen Polymers 0.000 claims description 29
- 241000282414 Homo sapiens Species 0.000 claims description 22
- 229940079593 drug Drugs 0.000 claims description 21
- 210000004072 lung Anatomy 0.000 claims description 20
- 208000027418 Wounds and injury Diseases 0.000 claims description 18
- 208000036971 interstitial lung disease 2 Diseases 0.000 claims description 18
- 210000003734 kidney Anatomy 0.000 claims description 18
- 210000000056 organ Anatomy 0.000 claims description 18
- 210000003491 skin Anatomy 0.000 claims description 18
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 claims description 17
- 230000029663 wound healing Effects 0.000 claims description 16
- 208000020832 chronic kidney disease Diseases 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 14
- 239000003963 antioxidant agent Substances 0.000 claims description 11
- 210000002216 heart Anatomy 0.000 claims description 11
- 208000014674 injury Diseases 0.000 claims description 11
- 208000017169 kidney disease Diseases 0.000 claims description 11
- 159000000000 sodium salts Chemical class 0.000 claims description 11
- 206010052428 Wound Diseases 0.000 claims description 10
- 206010012601 diabetes mellitus Diseases 0.000 claims description 10
- 210000004185 liver Anatomy 0.000 claims description 10
- 230000036573 scar formation Effects 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 239000000428 dust Substances 0.000 claims description 8
- 201000000523 end stage renal failure Diseases 0.000 claims description 8
- 241000124008 Mammalia Species 0.000 claims description 7
- 206010039710 Scleroderma Diseases 0.000 claims description 7
- 230000008021 deposition Effects 0.000 claims description 7
- 208000028208 end stage renal disease Diseases 0.000 claims description 7
- 239000003112 inhibitor Substances 0.000 claims description 7
- 208000019423 liver disease Diseases 0.000 claims description 7
- 102000004169 proteins and genes Human genes 0.000 claims description 7
- 108090000623 proteins and genes Proteins 0.000 claims description 7
- 201000003883 Cystic fibrosis Diseases 0.000 claims description 6
- 206010035653 pneumoconiosis Diseases 0.000 claims description 6
- 230000028327 secretion Effects 0.000 claims description 6
- 206010035664 Pneumonia Diseases 0.000 claims description 5
- 108020003175 receptors Proteins 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- 208000008589 Obesity Diseases 0.000 claims description 4
- 229940127361 Receptor Tyrosine Kinase Inhibitors Drugs 0.000 claims description 4
- 208000025865 Ulcer Diseases 0.000 claims description 4
- 239000000443 aerosol Substances 0.000 claims description 4
- 230000000172 allergic effect Effects 0.000 claims description 4
- 208000006682 alpha 1-Antitrypsin Deficiency Diseases 0.000 claims description 4
- 229940124599 anti-inflammatory drug Drugs 0.000 claims description 4
- 208000010668 atopic eczema Diseases 0.000 claims description 4
- 230000037319 collagen production Effects 0.000 claims description 4
- 238000000502 dialysis Methods 0.000 claims description 4
- 239000003018 immunosuppressive agent Substances 0.000 claims description 4
- 229940124589 immunosuppressive drug Drugs 0.000 claims description 4
- 102000006495 integrins Human genes 0.000 claims description 4
- 108010044426 integrins Proteins 0.000 claims description 4
- 235000020824 obesity Nutrition 0.000 claims description 4
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 4
- 102000005962 receptors Human genes 0.000 claims description 4
- 231100000397 ulcer Toxicity 0.000 claims description 4
- 208000009304 Acute Kidney Injury Diseases 0.000 claims description 3
- 208000033116 Asbestos intoxication Diseases 0.000 claims description 3
- 206010003827 Autoimmune hepatitis Diseases 0.000 claims description 3
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 claims description 3
- 208000033222 Biliary cirrhosis primary Diseases 0.000 claims description 3
- 206010018364 Glomerulonephritis Diseases 0.000 claims description 3
- 208000002720 Malnutrition Diseases 0.000 claims description 3
- 208000012654 Primary biliary cholangitis Diseases 0.000 claims description 3
- 208000001647 Renal Insufficiency Diseases 0.000 claims description 3
- 208000033626 Renal failure acute Diseases 0.000 claims description 3
- 201000010001 Silicosis Diseases 0.000 claims description 3
- 201000011040 acute kidney failure Diseases 0.000 claims description 3
- 230000003042 antagnostic effect Effects 0.000 claims description 3
- 206010003441 asbestosis Diseases 0.000 claims description 3
- 208000029078 coronary artery disease Diseases 0.000 claims description 3
- 230000003111 delayed effect Effects 0.000 claims description 3
- 239000002532 enzyme inhibitor Substances 0.000 claims description 3
- 231100000573 exposure to toxins Toxicity 0.000 claims description 3
- 206010061989 glomerulosclerosis Diseases 0.000 claims description 3
- 201000006370 kidney failure Diseases 0.000 claims description 3
- 235000000824 malnutrition Nutrition 0.000 claims description 3
- 230000001071 malnutrition Effects 0.000 claims description 3
- 208000015380 nutritional deficiency disease Diseases 0.000 claims description 3
- 239000000779 smoke Substances 0.000 claims description 3
- 238000011200 topical administration Methods 0.000 claims description 3
- 230000008733 trauma Effects 0.000 claims description 3
- 208000022309 Alcoholic Liver disease Diseases 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 208000008960 Diabetic foot Diseases 0.000 claims description 2
- 206010020772 Hypertension Diseases 0.000 claims description 2
- 208000029523 Interstitial Lung disease Diseases 0.000 claims description 2
- 208000032984 Intraoperative Complications Diseases 0.000 claims description 2
- 208000002260 Keloid Diseases 0.000 claims description 2
- 208000005230 Leg Ulcer Diseases 0.000 claims description 2
- 208000004210 Pressure Ulcer Diseases 0.000 claims description 2
- 201000004681 Psoriasis Diseases 0.000 claims description 2
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- 208000010123 anthracosis Diseases 0.000 claims description 2
- 229940127003 anti-diabetic drug Drugs 0.000 claims description 2
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 2
- 239000003472 antidiabetic agent Substances 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 150000001879 copper Chemical class 0.000 claims description 2
- 208000006454 hepatitis Diseases 0.000 claims description 2
- 231100000283 hepatitis Toxicity 0.000 claims description 2
- 208000002672 hepatitis B Diseases 0.000 claims description 2
- 208000010710 hepatitis C virus infection Diseases 0.000 claims description 2
- 208000029570 hepatitis D virus infection Diseases 0.000 claims description 2
- 230000001969 hypertrophic effect Effects 0.000 claims description 2
- 239000012678 infectious agent Substances 0.000 claims description 2
- 210000001117 keloid Anatomy 0.000 claims description 2
- 159000000003 magnesium salts Chemical class 0.000 claims description 2
- 230000005855 radiation Effects 0.000 claims description 2
- 201000000306 sarcoidosis Diseases 0.000 claims description 2
- 201000004409 schistosomiasis Diseases 0.000 claims description 2
- 239000002341 toxic gas Substances 0.000 claims description 2
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims 1
- 206010011985 Decubitus ulcer Diseases 0.000 claims 1
- 206010023330 Keloid scar Diseases 0.000 claims 1
- 206010040943 Skin Ulcer Diseases 0.000 claims 1
- 150000003863 ammonium salts Chemical class 0.000 claims 1
- 159000000007 calcium salts Chemical class 0.000 claims 1
- UQHKFADEQIVWID-UHFFFAOYSA-N cytokinin Natural products C1=NC=2C(NCC=C(CO)C)=NC=NC=2N1C1CC(O)C(CO)O1 UQHKFADEQIVWID-UHFFFAOYSA-N 0.000 claims 1
- 239000004062 cytokinin Substances 0.000 claims 1
- 230000035876 healing Effects 0.000 claims 1
- 150000002505 iron Chemical class 0.000 claims 1
- 229910003002 lithium salt Inorganic materials 0.000 claims 1
- 159000000002 lithium salts Chemical class 0.000 claims 1
- 150000002696 manganese Chemical class 0.000 claims 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims 1
- 150000003751 zinc Chemical class 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 41
- 230000002265 prevention Effects 0.000 abstract description 8
- 125000003342 alkenyl group Chemical group 0.000 abstract description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract description 6
- 125000000217 alkyl group Chemical group 0.000 abstract description 4
- 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 abstract description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- 210000001519 tissue Anatomy 0.000 description 36
- 239000000243 solution Substances 0.000 description 34
- 238000005481 NMR spectroscopy Methods 0.000 description 31
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 30
- 210000004027 cell Anatomy 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- 210000002950 fibroblast Anatomy 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- 230000000694 effects Effects 0.000 description 17
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
- 239000012071 phase Substances 0.000 description 16
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
- 239000003795 chemical substances by application Substances 0.000 description 14
- 230000006378 damage Effects 0.000 description 14
- 230000008569 process Effects 0.000 description 14
- 239000008194 pharmaceutical composition Substances 0.000 description 13
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 13
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 12
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 12
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 12
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 12
- 241000699670 Mus sp. Species 0.000 description 12
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 12
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 12
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 12
- 235000019253 formic acid Nutrition 0.000 description 12
- 231100000241 scar Toxicity 0.000 description 12
- 239000011734 sodium Substances 0.000 description 12
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 12
- 241001465754 Metazoa Species 0.000 description 11
- 230000007882 cirrhosis Effects 0.000 description 11
- 230000007705 epithelial mesenchymal transition Effects 0.000 description 11
- 210000002744 extracellular matrix Anatomy 0.000 description 11
- 210000000651 myofibroblast Anatomy 0.000 description 11
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 11
- 230000000750 progressive effect Effects 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- 241000282412 Homo Species 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 235000006708 antioxidants Nutrition 0.000 description 10
- 230000001684 chronic effect Effects 0.000 description 10
- 230000037390 scarring Effects 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000011161 development Methods 0.000 description 9
- 210000002919 epithelial cell Anatomy 0.000 description 9
- 239000003981 vehicle Substances 0.000 description 9
- 206010061218 Inflammation Diseases 0.000 description 8
- 229940125904 compound 1 Drugs 0.000 description 8
- 238000009472 formulation Methods 0.000 description 8
- 230000006870 function Effects 0.000 description 8
- 230000004054 inflammatory process Effects 0.000 description 8
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 description 8
- 239000002245 particle Substances 0.000 description 8
- 229920001223 polyethylene glycol Polymers 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 239000011780 sodium chloride Substances 0.000 description 8
- 208000024891 symptom Diseases 0.000 description 8
- 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 7
- 102100031168 CCN family member 2 Human genes 0.000 description 7
- 101000777550 Homo sapiens CCN family member 2 Proteins 0.000 description 7
- 239000002202 Polyethylene glycol Substances 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 238000009825 accumulation Methods 0.000 description 7
- -1 but not limited to Substances 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 230000035755 proliferation Effects 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- 239000000377 silicon dioxide Substances 0.000 description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- 235000011152 sodium sulphate Nutrition 0.000 description 7
- 239000007790 solid phase Chemical group 0.000 description 7
- 238000002054 transplantation Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 208000032544 Cicatrix Diseases 0.000 description 6
- 208000019693 Lung disease Diseases 0.000 description 6
- 229940126214 compound 3 Drugs 0.000 description 6
- 208000035475 disorder Diseases 0.000 description 6
- 235000011187 glycerol Nutrition 0.000 description 6
- 230000037387 scars Effects 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- BMIBJCFFZPYJHF-UHFFFAOYSA-N 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound COC1=NC=C(C)C=C1B1OC(C)(C)C(C)(C)O1 BMIBJCFFZPYJHF-UHFFFAOYSA-N 0.000 description 5
- 108010006654 Bleomycin Proteins 0.000 description 5
- 108010074328 Interferon-gamma Proteins 0.000 description 5
- 230000003510 anti-fibrotic effect Effects 0.000 description 5
- 229960001561 bleomycin Drugs 0.000 description 5
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 210000002808 connective tissue Anatomy 0.000 description 5
- 238000002650 immunosuppressive therapy Methods 0.000 description 5
- 239000004615 ingredient Substances 0.000 description 5
- 230000003902 lesion Effects 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 229940124597 therapeutic agent Drugs 0.000 description 5
- 230000001988 toxicity Effects 0.000 description 5
- 231100000419 toxicity Toxicity 0.000 description 5
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 4
- 102000004127 Cytokines Human genes 0.000 description 4
- 108090000695 Cytokines Proteins 0.000 description 4
- 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 4
- 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 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- 102000004388 Interleukin-4 Human genes 0.000 description 4
- 108090000978 Interleukin-4 Proteins 0.000 description 4
- 102000015696 Interleukins Human genes 0.000 description 4
- 108010063738 Interleukins Proteins 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- 206010067472 Organising pneumonia Diseases 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 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 4
- 229930006000 Sucrose Natural products 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- GWFKSQSXNUNYAC-AATRIKPKSA-N [(e)-hex-1-enyl]boronic acid Chemical compound CCCC\C=C\B(O)O GWFKSQSXNUNYAC-AATRIKPKSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 229910052791 calcium Inorganic materials 0.000 description 4
- 239000011575 calcium Substances 0.000 description 4
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 4
- 201000009805 cryptogenic organizing pneumonia Diseases 0.000 description 4
- 230000006866 deterioration Effects 0.000 description 4
- 239000003974 emollient agent Substances 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 239000012530 fluid Substances 0.000 description 4
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 229940028885 interleukin-4 Drugs 0.000 description 4
- 230000002427 irreversible effect Effects 0.000 description 4
- 239000003550 marker Substances 0.000 description 4
- 230000005012 migration Effects 0.000 description 4
- 238000013508 migration Methods 0.000 description 4
- 230000001575 pathological effect Effects 0.000 description 4
- 239000000825 pharmaceutical preparation Substances 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 208000017520 skin disease Diseases 0.000 description 4
- 235000015424 sodium Nutrition 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000000600 sorbitol Substances 0.000 description 4
- 239000005720 sucrose Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 230000009466 transformation Effects 0.000 description 4
- 210000004926 tubular epithelial cell Anatomy 0.000 description 4
- 102000007469 Actins Human genes 0.000 description 3
- 108010085238 Actins Proteins 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 238000011740 C57BL/6 mouse Methods 0.000 description 3
- 208000017667 Chronic Disease Diseases 0.000 description 3
- 208000000668 Chronic Pancreatitis Diseases 0.000 description 3
- 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 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 102000008070 Interferon-gamma Human genes 0.000 description 3
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- 206010033649 Pancreatitis chronic Diseases 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- 238000011529 RT qPCR Methods 0.000 description 3
- QNVSXXGDAPORNA-UHFFFAOYSA-N Resveratrol Natural products OC1=CC=CC(C=CC=2C=C(O)C(O)=CC=2)=C1 QNVSXXGDAPORNA-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- LUKBXSAWLPMMSZ-OWOJBTEDSA-N Trans-resveratrol Chemical compound C1=CC(O)=CC=C1\C=C\C1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-OWOJBTEDSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229930003427 Vitamin E Natural products 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- 230000003187 abdominal effect Effects 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 230000001363 autoimmune Effects 0.000 description 3
- 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 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- 208000037976 chronic inflammation Diseases 0.000 description 3
- 230000006020 chronic inflammation Effects 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
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 239000003086 colorant Substances 0.000 description 3
- 208000018631 connective tissue disease Diseases 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 239000000945 filler Substances 0.000 description 3
- 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 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 230000024924 glomerular filtration Effects 0.000 description 3
- 239000003102 growth factor Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000003906 humectant Substances 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 229960003130 interferon gamma Drugs 0.000 description 3
- 229940047122 interleukins Drugs 0.000 description 3
- 230000003907 kidney function Effects 0.000 description 3
- 229910052744 lithium Inorganic materials 0.000 description 3
- 239000007937 lozenge Substances 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 108020004999 messenger RNA Proteins 0.000 description 3
- 229960000485 methotrexate Drugs 0.000 description 3
- 244000005700 microbiome Species 0.000 description 3
- 210000003205 muscle Anatomy 0.000 description 3
- RTGDFNSFWBGLEC-SYZQJQIISA-N mycophenolate mofetil Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(/C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-SYZQJQIISA-N 0.000 description 3
- 229960004866 mycophenolate mofetil Drugs 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- ISWRGOKTTBVCFA-UHFFFAOYSA-N pirfenidone Chemical compound C1=C(C)C=CC(=O)N1C1=CC=CC=C1 ISWRGOKTTBVCFA-UHFFFAOYSA-N 0.000 description 3
- 229960003073 pirfenidone Drugs 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 3
- 229960004618 prednisone Drugs 0.000 description 3
- 230000002206 pro-fibrotic effect Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 235000021283 resveratrol Nutrition 0.000 description 3
- 229940016667 resveratrol Drugs 0.000 description 3
- 150000003431 steroids Chemical class 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 230000008719 thickening Effects 0.000 description 3
- 230000000451 tissue damage Effects 0.000 description 3
- 231100000827 tissue damage Toxicity 0.000 description 3
- 230000002792 vascular Effects 0.000 description 3
- 239000011709 vitamin E Substances 0.000 description 3
- 235000019165 vitamin E Nutrition 0.000 description 3
- 229940046009 vitamin E Drugs 0.000 description 3
- 229910052725 zinc Inorganic materials 0.000 description 3
- 239000011701 zinc Substances 0.000 description 3
- 235000016804 zinc Nutrition 0.000 description 3
- BUJAGSGYPOAWEI-SECBINFHSA-N (2r)-2-amino-n-(2,6-dimethylphenyl)propanamide Chemical compound C[C@@H](N)C(=O)NC1=C(C)C=CC=C1C BUJAGSGYPOAWEI-SECBINFHSA-N 0.000 description 2
- LJRDOKAZOAKLDU-UDXJMMFXSA-N (2s,3s,4r,5r,6r)-5-amino-2-(aminomethyl)-6-[(2r,3s,4r,5s)-5-[(1r,2r,3s,5r,6s)-3,5-diamino-2-[(2s,3r,4r,5s,6r)-3-amino-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-hydroxycyclohexyl]oxy-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl]oxyoxane-3,4-diol;sulfuric ac Chemical compound OS(O)(=O)=O.N[C@@H]1[C@@H](O)[C@H](O)[C@H](CN)O[C@@H]1O[C@H]1[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](N)C[C@@H](N)[C@@H]2O)O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)N)O[C@@H]1CO LJRDOKAZOAKLDU-UDXJMMFXSA-N 0.000 description 2
- VIGJPLLOGSYVQF-UHFFFAOYSA-N 1,3-dibromo-5-(bromomethyl)-2-fluorobenzene Chemical compound FC1=C(Br)C=C(CBr)C=C1Br VIGJPLLOGSYVQF-UHFFFAOYSA-N 0.000 description 2
- RSINTYZGAWHRBE-UHFFFAOYSA-N 1,3-thiazole-4,5-dione Chemical compound O=C1SC=NC1=O RSINTYZGAWHRBE-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 2
- NYYKLRQNNOBRQG-UHFFFAOYSA-N 2-(2-hydroxy-3,5-dipentylphenyl)acetic acid Chemical compound CCCCCC1=CC(CCCCC)=C(O)C(CC(O)=O)=C1 NYYKLRQNNOBRQG-UHFFFAOYSA-N 0.000 description 2
- PMAHTUAKLYOXGN-UHFFFAOYSA-N 2-(3,5-dibromo-2-hydroxyphenyl)acetic acid Chemical compound OC(=O)CC1=CC(Br)=CC(Br)=C1O PMAHTUAKLYOXGN-UHFFFAOYSA-N 0.000 description 2
- PZUUZXMFJVRIKM-UHFFFAOYSA-N 2-(3,5-dibromo-2-hydroxyphenyl)acetonitrile Chemical compound OC1=C(Br)C=C(Br)C=C1CC#N PZUUZXMFJVRIKM-UHFFFAOYSA-N 0.000 description 2
- WZHLZXHHXUHDDU-UHFFFAOYSA-N 2-(3,5-dibromo-4-hydroxyphenyl)acetic acid Chemical compound OC(=O)CC1=CC(Br)=C(O)C(Br)=C1 WZHLZXHHXUHDDU-UHFFFAOYSA-N 0.000 description 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- CFKMVGJGLGKFKI-UHFFFAOYSA-N 4-chloro-m-cresol Chemical compound CC1=CC(O)=CC=C1Cl CFKMVGJGLGKFKI-UHFFFAOYSA-N 0.000 description 2
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 244000215068 Acacia senegal Species 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 241001116389 Aloe Species 0.000 description 2
- 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 2
- 208000023275 Autoimmune disease Diseases 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 201000004569 Blindness Diseases 0.000 description 2
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 2
- 102100021943 C-C motif chemokine 2 Human genes 0.000 description 2
- 101710155857 C-C motif chemokine 2 Proteins 0.000 description 2
- 208000004434 Calcinosis Diseases 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 2
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 2
- 108010036949 Cyclosporine Proteins 0.000 description 2
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- 206010061818 Disease progression Diseases 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 206010064571 Gene mutation Diseases 0.000 description 2
- 108010024636 Glutathione Proteins 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- 208000031071 Hamman-Rich Syndrome Diseases 0.000 description 2
- 206010019280 Heart failures Diseases 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 208000031226 Hyperlipidaemia Diseases 0.000 description 2
- 206010021143 Hypoxia Diseases 0.000 description 2
- 102100037850 Interferon gamma Human genes 0.000 description 2
- 102000003816 Interleukin-13 Human genes 0.000 description 2
- 108090000176 Interleukin-13 Proteins 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 206010023421 Kidney fibrosis Diseases 0.000 description 2
- 229940123977 Lysophosphatidic acid receptor antagonist Drugs 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 108700011259 MicroRNAs Proteins 0.000 description 2
- 208000003250 Mixed connective tissue disease Diseases 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 108091000080 Phosphotransferase Proteins 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- 102000001253 Protein Kinase Human genes 0.000 description 2
- 239000008156 Ringer's lactate solution Substances 0.000 description 2
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 2
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 239000000205 acacia gum Substances 0.000 description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 201000004073 acute interstitial pneumonia Diseases 0.000 description 2
- 239000003463 adsorbent Substances 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 235000011399 aloe vera Nutrition 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- IYIKLHRQXLHMJQ-UHFFFAOYSA-N amiodarone Chemical compound CCCCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(I)=C(OCCN(CC)CC)C(I)=C1 IYIKLHRQXLHMJQ-UHFFFAOYSA-N 0.000 description 2
- 229960005260 amiodarone Drugs 0.000 description 2
- 230000033115 angiogenesis Effects 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 229940027983 antiseptic and disinfectant quaternary ammonium compound Drugs 0.000 description 2
- 239000010425 asbestos Substances 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- ISAOCJYIOMOJEB-UHFFFAOYSA-N benzoin Chemical compound C=1C=CC=CC=1C(O)C(=O)C1=CC=CC=C1 ISAOCJYIOMOJEB-UHFFFAOYSA-N 0.000 description 2
- 229960002903 benzyl benzoate Drugs 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 210000001185 bone marrow Anatomy 0.000 description 2
- 229960002092 busulfan Drugs 0.000 description 2
- 230000002308 calcification Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 210000001054 cardiac fibroblast Anatomy 0.000 description 2
- IBGLGMOPHJQDJB-IHRRRGAJSA-N chembl1950289 Chemical compound C1C[C@@H](O)CC[C@@H]1NC1=NC=C(N=C(NC=2C(=CC(F)=CC=2F)F)N2[C@@H]3COCC3)C2=N1 IBGLGMOPHJQDJB-IHRRRGAJSA-N 0.000 description 2
- 229960004926 chlorobutanol Drugs 0.000 description 2
- 208000022831 chronic renal failure syndrome Diseases 0.000 description 2
- 229960001265 ciclosporin Drugs 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 239000003246 corticosteroid Substances 0.000 description 2
- 229960001334 corticosteroids Drugs 0.000 description 2
- 229960004397 cyclophosphamide Drugs 0.000 description 2
- 229930182912 cyclosporin Natural products 0.000 description 2
- UFULAYFCSOUIOV-UHFFFAOYSA-N cysteamine Chemical compound NCCS UFULAYFCSOUIOV-UHFFFAOYSA-N 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 239000008355 dextrose injection Substances 0.000 description 2
- 208000033679 diabetic kidney disease Diseases 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- 230000005750 disease progression Effects 0.000 description 2
- 239000002612 dispersion medium Substances 0.000 description 2
- 229940000406 drug candidate Drugs 0.000 description 2
- 230000004064 dysfunction Effects 0.000 description 2
- 230000002500 effect on skin Effects 0.000 description 2
- 239000012636 effector Substances 0.000 description 2
- 210000002889 endothelial cell Anatomy 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 210000002615 epidermis Anatomy 0.000 description 2
- 210000000981 epithelium Anatomy 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- 230000009795 fibrotic process Effects 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 210000004907 gland Anatomy 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 229960003180 glutathione Drugs 0.000 description 2
- 208000019622 heart disease Diseases 0.000 description 2
- 210000003709 heart valve Anatomy 0.000 description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 210000004969 inflammatory cell Anatomy 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- 230000001788 irregular Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 239000011777 magnesium 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
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 229960003151 mercaptamine Drugs 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- KFRPYXLEHUASEB-UHFFFAOYSA-N methyl 2-(2-hydroxy-3,5-dipentylphenyl)acetate Chemical compound CCCCCC1=CC(CCCCC)=C(O)C(CC(=O)OC)=C1 KFRPYXLEHUASEB-UHFFFAOYSA-N 0.000 description 2
- XDOIIYQCWBRFOY-UHFFFAOYSA-N methyl 2-(3,5-dibromo-2-hydroxyphenyl)acetate Chemical compound COC(=O)CC1=CC(Br)=CC(Br)=C1O XDOIIYQCWBRFOY-UHFFFAOYSA-N 0.000 description 2
- UQDUPQYQJKYHQI-UHFFFAOYSA-N methyl laurate Chemical compound CCCCCCCCCCCC(=O)OC UQDUPQYQJKYHQI-UHFFFAOYSA-N 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 239000002679 microRNA Substances 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- 238000013059 nephrectomy Methods 0.000 description 2
- NXFQHRVNIOXGAQ-YCRREMRBSA-N nitrofurantoin Chemical compound O1C([N+](=O)[O-])=CC=C1\C=N\N1C(=O)NC(=O)C1 NXFQHRVNIOXGAQ-YCRREMRBSA-N 0.000 description 2
- 229960000564 nitrofurantoin Drugs 0.000 description 2
- 230000000414 obstructive effect Effects 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- 230000007310 pathophysiology Effects 0.000 description 2
- 229960001639 penicillamine Drugs 0.000 description 2
- 102000020233 phosphotransferase Human genes 0.000 description 2
- 230000035479 physiological effects, processes and functions Effects 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- 239000003223 protective agent Substances 0.000 description 2
- 108060006633 protein kinase Proteins 0.000 description 2
- 230000002685 pulmonary effect Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 210000001525 retina Anatomy 0.000 description 2
- 229910052895 riebeckite Inorganic materials 0.000 description 2
- 229910052711 selenium Inorganic materials 0.000 description 2
- 239000011669 selenium Substances 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 230000037380 skin damage Effects 0.000 description 2
- 210000001626 skin fibroblast Anatomy 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000008354 sodium chloride injection Substances 0.000 description 2
- OHGWIXASWPCFMS-UHFFFAOYSA-M sodium;2-(3,5-dipentylphenyl)acetate Chemical compound [Na+].CCCCCC1=CC(CCCCC)=CC(CC([O-])=O)=C1 OHGWIXASWPCFMS-UHFFFAOYSA-M 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
- 210000000130 stem cell Anatomy 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- HLZKNKRTKFSKGZ-UHFFFAOYSA-N tetradecan-1-ol Chemical compound CCCCCCCCCCCCCCO HLZKNKRTKFSKGZ-UHFFFAOYSA-N 0.000 description 2
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 2
- 229940033663 thimerosal Drugs 0.000 description 2
- 229960002872 tocainide Drugs 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 210000000591 tricuspid valve Anatomy 0.000 description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 230000004393 visual impairment Effects 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- BMQDAIUNAGXSKR-UHFFFAOYSA-N (3-hydroxy-2,3-dimethylbutan-2-yl)oxyboronic acid Chemical compound CC(C)(O)C(C)(C)OB(O)O BMQDAIUNAGXSKR-UHFFFAOYSA-N 0.000 description 1
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- JCIIKRHCWVHVFF-UHFFFAOYSA-N 1,2,4-thiadiazol-5-amine;hydrochloride Chemical compound Cl.NC1=NC=NS1 JCIIKRHCWVHVFF-UHFFFAOYSA-N 0.000 description 1
- SRXPLJYKMAEZKI-UHFFFAOYSA-N 1,3-dibromo-2-fluoro-5-methylbenzene Chemical compound CC1=CC(Br)=C(F)C(Br)=C1 SRXPLJYKMAEZKI-UHFFFAOYSA-N 0.000 description 1
- 125000006039 1-hexenyl group Chemical group 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
- NZJXADCEESMBPW-UHFFFAOYSA-N 1-methylsulfinyldecane Chemical compound CCCCCCCCCCS(C)=O NZJXADCEESMBPW-UHFFFAOYSA-N 0.000 description 1
- 125000006023 1-pentenyl group Chemical group 0.000 description 1
- 238000004293 19F NMR spectroscopy Methods 0.000 description 1
- 239000000263 2,3-dihydroxypropyl (Z)-octadec-9-enoate Substances 0.000 description 1
- JFCAJAFMTMKVJK-UHFFFAOYSA-N 2,3-dimethylbutane-2,3-diol pentoxyboronic acid Chemical compound CC(C)(O)C(C)(C)O.CCCCCOB(O)O JFCAJAFMTMKVJK-UHFFFAOYSA-N 0.000 description 1
- SPUZPJKEJXIRSF-UHFFFAOYSA-N 2,4-dibromo-6-(bromomethyl)phenol Chemical compound OC1=C(Br)C=C(Br)C=C1CBr SPUZPJKEJXIRSF-UHFFFAOYSA-N 0.000 description 1
- MXEUSWZBXYCKCM-UHFFFAOYSA-N 2-(3,5-dihexyl-2-hydroxyphenyl)acetic acid Chemical compound CCCCCCC1=CC(CCCCCC)=C(O)C(CC(O)=O)=C1 MXEUSWZBXYCKCM-UHFFFAOYSA-N 0.000 description 1
- XSWUWPVGSZQANY-UHFFFAOYSA-N 2-(3,5-dihexyl-4-hydroxyphenyl)acetic acid Chemical compound CCCCCCC1=CC(CC(O)=O)=CC(CCCCCC)=C1O XSWUWPVGSZQANY-UHFFFAOYSA-N 0.000 description 1
- ZKRZLLWCJPYOCK-UHFFFAOYSA-N 2-(3,5-dihexylphenyl)acetic acid Chemical compound CCCCCCC1=CC(CCCCCC)=CC(CC(O)=O)=C1 ZKRZLLWCJPYOCK-UHFFFAOYSA-N 0.000 description 1
- HFEDEAWUDQDOSS-UHFFFAOYSA-N 2-(3,5-dipentylphenyl)acetic acid Chemical compound CCCCCC1=CC(CCCCC)=CC(CC(O)=O)=C1 HFEDEAWUDQDOSS-UHFFFAOYSA-N 0.000 description 1
- OLKONWWYPKOGQO-UHFFFAOYSA-N 2-(4-fluoro-3,5-dihexylphenyl)acetic acid Chemical compound CCCCCCC1=CC(CC(O)=O)=CC(CCCCCC)=C1F OLKONWWYPKOGQO-UHFFFAOYSA-N 0.000 description 1
- YLZCRHXGJUPONH-UHFFFAOYSA-N 2-(4-fluoro-3,5-dipentylphenyl)acetic acid Chemical compound CCCCCC1=CC(CC(O)=O)=CC(CCCCC)=C1F YLZCRHXGJUPONH-UHFFFAOYSA-N 0.000 description 1
- FOIZRLGQKPGLNB-UHFFFAOYSA-N 2-(4-hydroxy-3,5-dipentylphenyl)acetic acid Chemical compound CCCCCC1=CC(CC(O)=O)=CC(CCCCC)=C1O FOIZRLGQKPGLNB-UHFFFAOYSA-N 0.000 description 1
- 125000006040 2-hexenyl group Chemical group 0.000 description 1
- ZVTDEEBSWIQAFJ-KHPPLWFESA-N 2-hydroxypropyl (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(C)O ZVTDEEBSWIQAFJ-KHPPLWFESA-N 0.000 description 1
- 125000006024 2-pentenyl group Chemical group 0.000 description 1
- ILYSAKHOYBPSPC-UHFFFAOYSA-N 2-phenylbenzoic acid Chemical class OC(=O)C1=CC=CC=C1C1=CC=CC=C1 ILYSAKHOYBPSPC-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- RZRNAYUHWVFMIP-GDCKJWNLSA-N 3-oleoyl-sn-glycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-GDCKJWNLSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- 206010033646 Acute and chronic pancreatitis Diseases 0.000 description 1
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 1
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 1
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 1
- 101150029409 CFTR gene Proteins 0.000 description 1
- 201000002829 CREST Syndrome Diseases 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 1
- 229940123150 Chelating agent Drugs 0.000 description 1
- GHXZTYHSJHQHIJ-UHFFFAOYSA-N Chlorhexidine Chemical compound C=1C=C(Cl)C=CC=1NC(N)=NC(N)=NCCCCCCN=C(N)N=C(N)NC1=CC=C(Cl)C=C1 GHXZTYHSJHQHIJ-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 206010008609 Cholangitis sclerosing Diseases 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 208000012661 Dyskinesia Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 102000016942 Elastin Human genes 0.000 description 1
- 108010014258 Elastin Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010014954 Eosinophilic fasciitis Diseases 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 206010064503 Excessive skin Diseases 0.000 description 1
- 208000004930 Fatty Liver Diseases 0.000 description 1
- 208000022461 Glomerular disease Diseases 0.000 description 1
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 description 1
- 206010019668 Hepatic fibrosis Diseases 0.000 description 1
- 206010019708 Hepatic steatosis Diseases 0.000 description 1
- 206010019799 Hepatitis viral Diseases 0.000 description 1
- GVGLGOZIDCSQPN-PVHGPHFFSA-N Heroin Chemical compound O([C@H]1[C@H](C=C[C@H]23)OC(C)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4OC(C)=O GVGLGOZIDCSQPN-PVHGPHFFSA-N 0.000 description 1
- 239000004705 High-molecular-weight polyethylene Substances 0.000 description 1
- 101001043352 Homo sapiens Lysyl oxidase homolog 2 Proteins 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 208000037147 Hypercalcaemia Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- 206010022004 Influenza like illness Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 102000006992 Interferon-alpha Human genes 0.000 description 1
- 108010047761 Interferon-alpha Proteins 0.000 description 1
- 102000013462 Interleukin-12 Human genes 0.000 description 1
- 108010065805 Interleukin-12 Proteins 0.000 description 1
- UETNIIAIRMUTSM-UHFFFAOYSA-N Jacareubin Natural products CC1(C)OC2=CC3Oc4c(O)c(O)ccc4C(=O)C3C(=C2C=C1)O UETNIIAIRMUTSM-UHFFFAOYSA-N 0.000 description 1
- 208000012659 Joint disease Diseases 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- 208000004852 Lung Injury Diseases 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000238367 Mya arenaria Species 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- AXFZADXWLMXITO-UHFFFAOYSA-N N-acetylcysteamine Chemical class CC(=O)NCCS AXFZADXWLMXITO-UHFFFAOYSA-N 0.000 description 1
- 206010073310 Occupational exposures Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 208000031481 Pathologic Constriction Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 239000004264 Petrolatum Substances 0.000 description 1
- 108010040201 Polymyxins Proteins 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 208000006994 Precancerous Conditions Diseases 0.000 description 1
- 208000032056 Radiation Fibrosis Syndrome Diseases 0.000 description 1
- 206010067953 Radiation fibrosis Diseases 0.000 description 1
- 208000003782 Raynaud disease Diseases 0.000 description 1
- 208000012322 Raynaud phenomenon Diseases 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 206010061481 Renal injury Diseases 0.000 description 1
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 1
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 1
- 206010039163 Right ventricular failure Diseases 0.000 description 1
- MEFKEPWMEQBLKI-AIRLBKTGSA-N S-adenosyl-L-methioninate Chemical compound O[C@@H]1[C@H](O)[C@@H](C[S+](CC[C@H](N)C([O-])=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 MEFKEPWMEQBLKI-AIRLBKTGSA-N 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 208000016780 Scleredema Diseases 0.000 description 1
- 206010055953 Scleroedema Diseases 0.000 description 1
- 208000034189 Sclerosis Diseases 0.000 description 1
- 101710151387 Serine protease 1 Proteins 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 208000021386 Sjogren Syndrome Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- SSZBUIDZHHWXNJ-UHFFFAOYSA-N Stearinsaeure-hexadecylester Natural products CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC SSZBUIDZHHWXNJ-UHFFFAOYSA-N 0.000 description 1
- 244000028419 Styrax benzoin Species 0.000 description 1
- 235000000126 Styrax benzoin Nutrition 0.000 description 1
- 206010049418 Sudden Cardiac Death Diseases 0.000 description 1
- 235000008411 Sumatra benzointree Nutrition 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- 206010069363 Traumatic lung injury Diseases 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 101710162629 Trypsin inhibitor Proteins 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- FMRLDPWIRHBCCC-UHFFFAOYSA-L Zinc carbonate Chemical compound [Zn+2].[O-]C([O-])=O FMRLDPWIRHBCCC-UHFFFAOYSA-L 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 229960004308 acetylcysteine Drugs 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- HDYRYUINDGQKMC-UHFFFAOYSA-M acetyloxyaluminum;dihydrate Chemical compound O.O.CC(=O)O[Al] HDYRYUINDGQKMC-UHFFFAOYSA-M 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000009692 acute damage Effects 0.000 description 1
- 229960001570 ademetionine Drugs 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 description 1
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 206010001584 alcohol abuse Diseases 0.000 description 1
- 208000025746 alcohol use disease Diseases 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229940037003 alum Drugs 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 229940009827 aluminum acetate Drugs 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 description 1
- 210000000436 anus Anatomy 0.000 description 1
- 230000009118 appropriate response Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 150000007860 aryl ester derivatives Chemical class 0.000 description 1
- 230000005784 autoimmunity Effects 0.000 description 1
- 229960002170 azathioprine Drugs 0.000 description 1
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 210000002469 basement membrane Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000000440 bentonite Substances 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
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- 229960001950 benzethonium chloride Drugs 0.000 description 1
- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- 229960002130 benzoin Drugs 0.000 description 1
- 229960004217 benzyl alcohol Drugs 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 108700004675 bleomycetin Proteins 0.000 description 1
- QYOAUOAXCQAEMW-UTXKDXHTSA-N bleomycin A5 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCCNCCCCN)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C QYOAUOAXCQAEMW-UTXKDXHTSA-N 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000000476 body water Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- 229940043253 butylated hydroxyanisole Drugs 0.000 description 1
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 1
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- BPKIGYQJPYCAOW-FFJTTWKXSA-I calcium;potassium;disodium;(2s)-2-hydroxypropanoate;dichloride;dihydroxide;hydrate Chemical compound O.[OH-].[OH-].[Na+].[Na+].[Cl-].[Cl-].[K+].[Ca+2].C[C@H](O)C([O-])=O BPKIGYQJPYCAOW-FFJTTWKXSA-I 0.000 description 1
- BMLSTPRTEKLIPM-UHFFFAOYSA-I calcium;potassium;disodium;hydrogen carbonate;dichloride;dihydroxide;hydrate Chemical compound O.[OH-].[OH-].[Na+].[Na+].[Cl-].[Cl-].[K+].[Ca+2].OC([O-])=O BMLSTPRTEKLIPM-UHFFFAOYSA-I 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 229960002798 cetrimide Drugs 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 229960001927 cetylpyridinium chloride Drugs 0.000 description 1
- YMKDRGPMQRFJGP-UHFFFAOYSA-M cetylpyridinium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+]1=CC=CC=C1 YMKDRGPMQRFJGP-UHFFFAOYSA-M 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- 229960003260 chlorhexidine Drugs 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229960002242 chlorocresol Drugs 0.000 description 1
- 108010081033 chymotrypsinogen C Proteins 0.000 description 1
- 235000019504 cigarettes Nutrition 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- ZPUCINDJVBIVPJ-LJISPDSOSA-N ***e Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 description 1
- 230000011382 collagen catabolic process Effects 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 230000002508 compound effect Effects 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002537 cosmetic 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
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 208000031513 cyst Diseases 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- LTNZEXKYNRNOGT-UHFFFAOYSA-N dequalinium chloride Chemical compound [Cl-].[Cl-].C1=CC=C2[N+](CCCCCCCCCC[N+]3=C4C=CC=CC4=C(N)C=C3C)=C(C)C=C(N)C2=C1 LTNZEXKYNRNOGT-UHFFFAOYSA-N 0.000 description 1
- 229960001378 dequalinium chloride Drugs 0.000 description 1
- 210000004207 dermis Anatomy 0.000 description 1
- 229960002069 diamorphine Drugs 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 229940008099 dimethicone Drugs 0.000 description 1
- 239000004205 dimethyl polysiloxane Substances 0.000 description 1
- 235000013870 dimethyl polysiloxane Nutrition 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- 229920002549 elastin Polymers 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 230000007368 endocrine function Effects 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 229960004667 ethyl cellulose Drugs 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 208000010706 fatty liver disease Diseases 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 210000000232 gallbladder Anatomy 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000002518 glial effect Effects 0.000 description 1
- 231100000852 glomerular disease Toxicity 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 230000004153 glucose metabolism Effects 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 235000019382 gum benzoic Nutrition 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 210000003780 hair follicle Anatomy 0.000 description 1
- 230000009931 harmful effect Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000005802 health problem Effects 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 208000014951 hematologic disease Diseases 0.000 description 1
- 230000010224 hepatic metabolism Effects 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- 235000009200 high fat diet Nutrition 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 230000000148 hypercalcaemia Effects 0.000 description 1
- 208000030915 hypercalcemia disease Diseases 0.000 description 1
- 208000018875 hypoxemia Diseases 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 229940060367 inert ingredients Drugs 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000037456 inflammatory mechanism Effects 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 229940117681 interleukin-12 Drugs 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000005865 ionizing radiation Effects 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 238000010829 isocratic elution Methods 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 229940074928 isopropyl myristate Drugs 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 208000010729 leg swelling Diseases 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 230000005976 liver dysfunction Effects 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 235000014659 low sodium diet Nutrition 0.000 description 1
- 230000004199 lung function Effects 0.000 description 1
- 231100000515 lung injury Toxicity 0.000 description 1
- 201000003866 lung sarcoma Diseases 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000004630 mental health Effects 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- PURZNDMCBOHOBG-UHFFFAOYSA-N methyl 2-(3,5-dibromo-2-phenylmethoxyphenyl)acetate Chemical compound COC(=O)CC1=CC(Br)=CC(Br)=C1OCC1=CC=CC=C1 PURZNDMCBOHOBG-UHFFFAOYSA-N 0.000 description 1
- LMLSBPHXMGSGCR-UHFFFAOYSA-N methyl 2-(3,5-dihydroxyphenyl)acetate Chemical compound COC(=O)CC1=CC(O)=CC(O)=C1 LMLSBPHXMGSGCR-UHFFFAOYSA-N 0.000 description 1
- BDIHIABNTIWSSP-UHFFFAOYSA-N methyl 2-(3,5-dipentylphenyl)acetate Chemical compound CCCCCC1=CC(CCCCC)=CC(CC(=O)OC)=C1 BDIHIABNTIWSSP-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 108091062762 miR-21 stem-loop Proteins 0.000 description 1
- 108091041631 miR-21-1 stem-loop Proteins 0.000 description 1
- 108091044442 miR-21-2 stem-loop Proteins 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
- 235000020802 micronutrient deficiency Nutrition 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- RZRNAYUHWVFMIP-UHFFFAOYSA-N monoelaidin Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-UHFFFAOYSA-N 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 230000004660 morphological change Effects 0.000 description 1
- 239000002324 mouth wash Substances 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 229940043348 myristyl alcohol Drugs 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- XZXHXSATPCNXJR-ZIADKAODSA-N nintedanib Chemical compound O=C1NC2=CC(C(=O)OC)=CC=C2\C1=C(C=1C=CC=CC=1)\NC(C=C1)=CC=C1N(C)C(=O)CN1CCN(C)CC1 XZXHXSATPCNXJR-ZIADKAODSA-N 0.000 description 1
- 229960004378 nintedanib Drugs 0.000 description 1
- 239000002687 nonaqueous vehicle Substances 0.000 description 1
- 230000037311 normal skin Effects 0.000 description 1
- 210000001331 nose Anatomy 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 231100000675 occupational exposure Toxicity 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 150000004010 onium ions Chemical class 0.000 description 1
- 210000004789 organ system Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000003791 organic solvent mixture Substances 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 210000003254 palate Anatomy 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000003950 pathogenic mechanism Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 210000003800 pharynx Anatomy 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 229940096826 phenylmercuric acetate Drugs 0.000 description 1
- PDTFCHSETJBPTR-UHFFFAOYSA-N phenylmercuric nitrate Chemical compound [O-][N+](=O)O[Hg]C1=CC=CC=C1 PDTFCHSETJBPTR-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940100467 polyvinyl acetate phthalate Drugs 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 201000000742 primary sclerosing cholangitis Diseases 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000007425 progressive decline Effects 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000003909 protein kinase inhibitor Substances 0.000 description 1
- 210000003102 pulmonary valve Anatomy 0.000 description 1
- 230000010349 pulsation Effects 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 235000020095 red wine Nutrition 0.000 description 1
- 238000005057 refrigeration Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 201000004193 respiratory failure Diseases 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 230000008458 response to injury Effects 0.000 description 1
- LUKBXSAWLPMMSZ-UHFFFAOYSA-N resveratrol Chemical compound C1=CC(O)=CC=C1C=CC1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-UHFFFAOYSA-N 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 210000004761 scalp Anatomy 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
- 210000003786 sclera Anatomy 0.000 description 1
- 208000007754 scleredema adultorum Diseases 0.000 description 1
- 208000010157 sclerosing cholangitis Diseases 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 208000015891 sexual disease Diseases 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 238000004513 sizing Methods 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- RHVBEXZEZHFKLE-UHFFFAOYSA-M sodium 2-(2-hydroxy-3,5-dipentylphenyl)acetate Chemical compound [Na+].CCCCCC1=CC(CCCCC)=C(O)C(CC([O-])=O)=C1 RHVBEXZEZHFKLE-UHFFFAOYSA-M 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 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
- 229940001607 sodium bisulfite Drugs 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 231100000240 steatosis hepatitis Toxicity 0.000 description 1
- 230000036262 stenosis Effects 0.000 description 1
- 208000037804 stenosis Diseases 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- NCEXYHBECQHGNR-QZQOTICOSA-N sulfasalazine Chemical compound C1=C(O)C(C(=O)O)=CC(\N=N\C=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-QZQOTICOSA-N 0.000 description 1
- 229960001940 sulfasalazine Drugs 0.000 description 1
- NCEXYHBECQHGNR-UHFFFAOYSA-N sulfasalazine Natural products C1=C(O)C(C(=O)O)=CC(N=NC=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-UHFFFAOYSA-N 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 210000000106 sweat gland Anatomy 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012385 systemic delivery Methods 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229950002902 tanzisertib Drugs 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 230000007838 tissue remodeling Effects 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 210000002105 tongue Anatomy 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 208000037999 tubulointerstitial fibrosis Diseases 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000009777 vacuum freeze-drying Methods 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 230000006492 vascular dysfunction Effects 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- 206010047302 ventricular tachycardia Diseases 0.000 description 1
- 201000001862 viral hepatitis Diseases 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000008136 water-miscible vehicle Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000011667 zinc carbonate Substances 0.000 description 1
- 235000004416 zinc carbonate Nutrition 0.000 description 1
- 229910000010 zinc carbonate Inorganic materials 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- 235000014692 zinc oxide Nutrition 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
- C07C59/52—Unsaturated compounds containing hydroxy or O-metal groups a hydroxy or O-metal group being bound to a carbon atom of a six-membered aromatic ring
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—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
- A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
-
- 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
-
- 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
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/10—Anthelmintics
- A61P33/12—Schistosomicides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- 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
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
- C07C53/132—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen containing rings
- C07C53/134—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen containing rings monocyclic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/30—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/52—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen
- C07C57/58—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen containing six-membered aromatic rings
-
- 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
Abstract
或其醫藥學上可接受之鹽,其中A為C5烷基、C6烷基、C5烯基、C6烯基、C(O)-(CH2)n-CH3或CH(OH)-(CH2)n-CH3,其中n為3或4;R1為H、F或OH;R2為C5烷基、C6烷基、C5烯基、C6烯基、C(O)-(CH2)n-CH3或CH(OH)-(CH2)n-CH3,其中n為3或4;R3為H、F、OH或CH2Ph;R4為H、F或OH;Q為1)(CH2)mC(O)OH,其中m為1或2,2)CH(CH3)C(O)OH,
3)C(CH3)2C(O)OH,4)CH(F)-C(O)OH,5)CF2-C(O)OH,或6)C(O)-C(O)OH;和包含其之組成物以及使用其用於預防或治療個體之各種纖維變性疾病及病狀,包括肺纖維化、肝纖維化、皮膚纖維化、腎纖維化、胰纖維化、全身性硬化、心臟纖維化或黃斑變性的方法。
Description
本發明係關於經取代之芳族化合物、其製備、包含其之組成物以及使用其用於預防或治療個體之各種纖維變性疾病及病狀,包括肺纖維化、肝纖維化、皮膚纖維化、腎纖維化、胰纖維化、全身性硬化、心臟纖維化或黃斑變性的方法。
纖維化為特徵在於細胞外基質(ECM)過度積聚從而導致所涉及組織變硬及/或瘢痕形成的慢性及進行性過程。其經由複雜細胞、細胞外基質、細胞介素及生長因子相互作用而發展。涉及到不同的細胞類型,諸如常駐間質細胞(纖維母細胞及肌纖維母細胞)及源自上皮及內皮細胞之ECM產生細胞(經由稱為上皮-間質轉化及內皮-間質轉化之過程)、局部或骨髓源幹細胞(纖維細胞)。肌纖維母細胞長久以來已被視為正常傷口癒合中所涉及之主要細胞類型,且作為纖維生成之關鍵效應細胞。其可高度合成膠原及其他ECM組分,且特徵為α-平滑肌肌動蛋白(α-SMA)之重新表現(評述於Scotton C.J.及Chambers R.C.,2007中)。纖維化動物模型中之纖維變性病變中肌纖維母細胞的存在與活性纖維化之發展有關,且其持續存在及對於人類疾病中纖維變性位點之定位與疾病進展有關(Kuhn C.及McDonald J.A.,1991;及Zhang等人,1994)。肌纖維母細胞亦展現增強之遷移表现型(Suganuma等人,1995)且能夠釋放眾多促纖維變性介體。
纖維變性疾病,包括肺纖維化、全身性硬化、肝硬化、心血
管疾病、進行性腎臟疾病及黃斑變性,為發病率及死亡率之首要原因且可影響所有組織及器官系統。纖維變性組織重塑亦可影響癌症轉移且於移植接受者中加速慢性移植排斥反應。具有多種/單一器官表現之原發性(特發性)及繼發性纖維變性病症之實例列於表1中。然而,儘管其對人類健康影響巨大,但目前尚未批准有直接針對纖維化機制之治療。
肺纖維化(lung fibrosis/pulmonary fibrosis)為一種涉及肺組織瘢痕形成之嚴重醫學病狀。當肺泡及肺間質組織發炎且在組織上形成瘢痕以試圖自我修復時,出現此病狀。肺纖維化涉及正常肺實質與纖維變性組織(纖維瘢痕)之逐漸交換。正常之肺經瘢痕組織置換造成氧擴散能力不可逆地下降。目前,尚未有可逆轉肺組織之此瘢痕形成的治療措施或手段。
可以造成肺纖維化之許多病狀包括慢性發炎過程(肉狀瘤病、韋格納氏肉芽腫病(Wegener's granulomatosis))、感染、環境劑(石棉、二氧化矽、暴露於某些氣體)、曝露於電離輻射(諸如治療胸部腫瘤之輻射療法)、慢性病狀(狼瘡),以及某些藥物治療(例如胺碘酮(amiodarone)、
博萊黴素(bleomycin)、平陽黴素(pingyangmycin)、白消安(busulfan)、甲胺喋呤(methotrexate)及呋喃妥因(nitrofurantoin))。
在稱為過敏性肺炎之病狀中,針對吸入有機粉塵或職業化學物質之免疫反應提高後可形成肺之纖維化。此病狀最通常起因於吸入受細菌、真菌或動物產品污染之粉塵。
在一些個體中,在無可鑒別原因之情況下形成慢性肺部炎症及纖維化。大部分此等個體具有稱為特發性肺纖維化(IPF)之病狀。IPF為一種病因不明之慢性進行性肺纖維化。潑尼松(prednisone)為IPF之常用治療,但其可用目標在於減少作為肺纖維化前奏之炎症的其他免疫抑制療法來治療。儘管潑尼松對改善肺功能具有適度可量測的作用,但對於其長期功效之證據缺乏以及關於其安全性之擔憂限制了其使用。實際上大部分免疫抑制藥物很少有治療作用並且肺移植可能為必要的。遺憾的是,末期肺病患者中之移植成功率有限且患者之中位存活時間為診斷後四至六年。因而,需要新穎但有效之IPF治療。
關於特異性處理肺中纖維化之抑制或減緩之候選藥物(諸如干擾素-γ(IFN-γ)及黴酚酸嗎啉乙酯(mycophenolate mofetil))的一些臨床試驗正在進行中。其他實施例包括:吡非尼酮,其作用機制並不明確,但似乎減少CTGF且已在臨床階段中顯示一些成果;經取代之聯苯羧酸,其充當溶血磷脂酸受體拮抗劑且在標準肺纖維化小鼠模型(博萊黴素誘發之肺纖維化)中顯示顯著的抗纖維變性活性。因而,據報導此化合物正處於IPF治療之臨床試驗中。用口服活性候選藥物抑制蛋白激酶或用口服活性抗氧化劑進行治療提供兩種對於肺纖維化之治療方法:多重受體酪胺酸激酶抑制劑(諸如尼達尼布(nintedanib))及JNK(激酶)抑制劑(諸如坦茲替布(tanzisertib))。此外,IPF候選藥物包括抗氧化劑N-乙醯基半胱胺酸。然而迄今為止,由於毒性及/或功效問題,蛋白激酶抑制劑及抗氧化劑之發展對於治療IPF一直是值得商榷的。在正常及病變細胞群體中普通存在蛋白激酶及相關受體,因此特定言之在迅速增殖之細胞群體中抑制作用會導致產生毒性。
另外,關於靶向用於治療IPF之不同促纖維變性蛋白(細胞
介素(CTGF、TGF-β、MCP-1、IL-4及IL-13)、整合素(αvβ6)及酶(離胺醯氧化酶樣2)之單株抗體的臨床試驗正在進行中。然而,用於治療IPF之單株抗體(其應用於其他重組蛋白)的發展及使用產生許多相關問題,包括毒性(包括蛋白免疫原性)、製造難度(批次一致性、擴大規模、費用)及投予難度(需要冷藏,而非口服活性)。
此外,雖然研究試驗正在進行,但無證據表明任何藥物治療可顯著有助於此病狀。肺移植為嚴重情況下唯一可用之治療選擇。遺憾的是,末期肺病患者中之移植成功率有限。因而,需要新穎但有效之IPF治療。因此,需要新穎但方便投予(口服活性)之有效的合成(容易製造)化合物。
肝纖維化(liver fibrosis/hepatic fibrosis)為細胞外基質蛋白(包括膠原)之過度積聚以及後續瘢痕形成過程,其發生於大多數慢性肝病中。隨著時間推移,晚期肝纖維化導致肝硬化。肝硬化為慢性肝病之最終階段並且一般長期預後不良且不可逆。在晚期階段,唯一選擇為肝移植。肝硬化所伴隨之肝癌風險顯著增加且肝硬化可視為癌前病狀(肝細胞癌)。實際上,肝硬化及肝癌皆屬於全世界範圍內前十大死亡原因。因而,需要新穎但有效的對肝纖維化及後續肝硬化之治療。遺憾的是,可用治療選擇很少且最通常治療由處理肝硬化之病因及/或症狀組成。尚無治療可治癒肝纖維化後續之瘢痕形成及肝硬化。肝移植為晚期纖維化患者唯一可用之治療。因此,需要侵入性較小之替代性方法來治癒肝纖維化、治療肝纖維化、減緩肝纖維化之進展或預防肝纖維化。
腹部流體(腹水)積聚為與肝硬化相關之常見問題。治療選擇包括低鈉飲食、利尿劑以及藉由***針於腹腔中(腹腔穿刺)來移除流體。肝硬化由酒精濫用、病毒性肝炎(B、C及D)、與肥胖症相關之非酒精性脂肪肝病(NAFLD)、糖尿病、蛋白質營養不良、冠狀動脈疾病、皮質類固醇、自體免疫肝炎、遺傳性疾病(囊腫性纖維化、α-1-抗胰蛋白酶缺乏症等)、原發性膽汁性肝硬化、藥物反應及暴露於毒素引起。
關於特異性處理肝纖維化之抑制或減緩之候選藥物的有限數目之臨床試驗正在進行中。然而,此等試驗針對特定肝病,諸如NASH(非酒精性脂肪肝炎)。NASH係指脂肪肝(NAFLD)與炎症之組合且發生於飲酒很少或不飲酒之個體中。半胱胺為有效的肝抗氧化劑麩胱甘肽之前驅體且鹹信麩胱甘肽之活體內產生增加提供NASH相關肝病之改善。因而,半胱胺正在NASH兒童患者中進行臨床試驗評估。其他抗氧化劑諸如維生素E及硒正在進行評估,但其用於治療NASH之效用未知。此外處於NASH治療評估中的是甚至在不具有糖尿病之患者中使用抗糖尿病藥物。此方法處理了大多數NASH患者具有胰島素抗性之事實。再次,需要新穎但方便投予(口服活性)之用於治療肝纖維化、後續瘢痕形成及肝硬化的有效化合物。
皮膚纖維化(skin fibrosis/dermal fibrosis)為皮膚之過度瘢痕形成,且為病理性傷口癒合反應之結果。存在廣泛多種纖維變性皮膚疾病:硬皮病、腎源性纖維化皮膚病、混合性結締組織疾病、硬化性黏液水腫、硬腫病及嗜酸性筋膜炎。暴露於化學物質或物理因素(機械創傷、燒傷創面)亦為纖維變性皮膚疾病之潛在原因。皮膚纖維化可由免疫、自體免疫及炎症機制驅動。膠原產生與由纖維母細胞降解的平衡在皮膚中之纖維變性過程之病理生理學中起關鍵作用。某些細胞介素促進傷口癒合及纖維化,諸如轉化生長因子-β(TGF-β)及介白素-4(IL-4),而其他細胞介素抗纖維變性,諸如干擾素-γ(IFN-γ)及腫瘤壞死因子-α(TNF-α)。正常皮膚之纖維母細胞處於靜止狀態。其合成受控量之結締組織蛋白且具有低增殖活性。在皮膚損傷後,此等細胞變得活化,亦即其增殖、表現α-平滑肌肌動蛋白(α-SMA)且合成大量結締組織蛋白。該等活化細胞通常稱為肌纖維母細胞。
在皮膚纖維化期間,自美容觀點來看,作為傷口癒合過程之一部分且伴隨著纖維化之瘢痕形成為特別不合需要的,尤其當瘢痕形成於面部及/或身體之其他暴露部分上時。硬皮病(scleroderma)係指皮膚纖維
化;sclera表示硬且derma表示皮膚。然而,皮膚纖維化可能具有重要的健康問題,尤其當其為全身性硬皮病之一部分時。全身性硬皮病係指具有自體免疫病因之結締組織疾病。局限皮膚型硬皮病受限於面部上及足部上之皮膚,而彌漫皮膚型硬皮病覆蓋更多皮膚且可發展至內臟器官。
用於治療皮膚纖維化之最流行的方法為使用免疫抑制療法。基本原理在於,自體免疫病因造成疾病之炎症態樣以及後續組織損傷及纖維化。所研究之藥物包括甲胺喋呤、黴酚酸嗎啉乙酯、環磷醯胺及環孢靈(cyclosporine)。儘管已觀測到免疫抑制療法之一些改進,但關於藥物安全性之擔憂以及確定之臨床資料及可證實之功效的缺乏仍然存在。
需要開發用於治療皮膚纖維化、纖維變性皮膚疾病及皮膚之病理性瘢痕形成的有效醫藥製劑。
腎為一種結構複雜的器官,其已進化為執行許多重要功能:***代謝廢物、調節身體水分及鹽分、維持適當的酸平衡,以及分泌多種激素及內分泌物。腎臟疾病與其結構一樣複雜,但可藉由按照作用將其分成四個基本形態組成部分來促進其研究:腎小球、腎小管、間質及血管。遺憾的是,一些病症會影響一個以上之結構且腎臟結構之解剖學相互依賴性意味著對一個結構之損傷幾乎總是繼發性影響其他結構。因此,無論起源如何,存在所有形式之腎病最後皆破壞腎臟之所有四個組成部分且最終導致慢性腎衰竭之傾向。例如,在諸如糖尿病之自體免疫疾病中,腎臟為遭受組織損傷或病變之首要目標。腎切除或腎移除為有時對腎癌(例如腎細胞癌)患者實施之程序且可能對剩餘腎臟之腎功能產生不利影響。化學療法及免疫抑制療法亦為有害影響腎臟之來源。所有此等腎損傷在大多數情況下皆導致腎纖維化。術語「腎纖維化」意謂細胞過度增殖、組織硬化及瘢痕形成。腎纖維化亦可由腎衰竭後之透析及導管置放引起,例如,腹膜及血管通路纖維化。腎纖維化亦可由諸如腎小球疾病(例如腎小球硬化、腎小球腎炎)、慢性腎功能不全、急性腎損傷、末期腎病及腎衰竭之腎病引起。無論病因如何,所有的慢性腎病患者皆顯示腎功能隨時間進行性下降。纖維化(所謂的瘢痕形成)為此病理生理學之關鍵原因。纖維化涉及細胞
外基質(主要由膠原組成)過度積聚且當正常組織經瘢痕組織置換時通常導致功能損失。該過程在很大程度上不可逆,不可避免地導致末期腎衰竭,其為需要終身透析或腎移植之病狀。近來之重大進展已導致對腎纖維化(或腎小管間質纖維化)更好的理解,但仍存在許多問題。對於為何一些傷口癒合而其他傷口形成瘢痕知之甚少,以及有多少假定的抗纖維變性劑起作用亦知之甚少。
需要開發用於治療腎纖維化之有效醫藥製劑。
心臟纖維化(心臟疾病之標誌)被認為促進心臟性猝死、心室性心動過速、左心室(LV)功能障礙及心臟衰竭。心臟纖維化之特徵在於心肌細胞死亡後發生之原纖化膠原的不相稱積聚、炎症、工作負荷增強、肥厚,以及受多種激素、細胞介素及生長因子的刺激。
心臟纖維化亦可指心臟瓣膜由於心臟纖維母細胞之不當增殖而引起的異常增厚,但更通常指心肌中纖維母細胞之增殖。纖維細胞通常分泌膠原,且用於對心臟提供結構支撐。當過度活化時,此過程造成瓣膜增厚及纖維化,其中白色組織主要聚集於三尖瓣上,但亦存在於肺動脈瓣上。增厚及柔性損失最終可導致瓣膜功能不全及右側心臟衰竭。
用於心臟瓣膜纖維化或其他部位纖維化之最明顯治療由停用刺激性藥物或產生血清素組成。在一些患者中有必要為嚴重狹窄(阻塞血流)進行手術三尖瓣置換。此外,已發現紅葡萄酒中存在之化合物白藜蘆醇(resveratrol)可減緩心臟纖維化之發展。[Olson等人,(2005)「Inhibition of cardiac fibroblast proliferation and myofibroblast differentiation by resveratrol」.American journal of physiology.Heart and circulatory physiology 288(3):H1131-8;Aubin等人,(2008)「Female rats fed a high-fat diet were associated with vascular dysfunction and cardiac fibrosis in the absence of overt obesity and hyperlipidemia:Therapeutic potential of resveratrol」.The Journal of Pharmacology and Experimental Therapeutics 325(3):961-8。]正在於動物模型中測試抵抗心臟纖維化之更先進方法如微RNA抑制(例如miR-21)。
市面上不存在用於預防或治療心臟纖維化之藥物且需要開
發有效之醫藥製劑。
慢性胰腺炎(CP)為進行性胰腺發炎疾病,其特徵為不可逆之形態變化及腺體之逐漸纖維變性置換。外分泌及內分泌功能損失由實質性纖維化引起。CP之主要症狀為腹痛及消化不良。胰腺大概有可能增大或萎縮,存在或不存在囊腫或鈣化或腫瘤。導管可能擴張、不規則或狹窄。基本病理特徵包括腺泡組織之不規則及片狀損失、慢性炎症、導管變化及纖維化。此等總體變化為與以下相關之複雜致病機制之最終表現:基因突變(包括但不限於囊腫性纖維化、陽離子胰蛋白酶原基因、特發性急性及慢性胰腺炎中之CFTR基因突變、胰腺分泌型胰蛋白酶抑制劑基因、胰凝乳蛋白酶原C基因及鈣敏感受體基因、α-1抗胰蛋白酶缺乏症)、代謝性(酒精、吸煙、高鈣血症、高脂質血症、慢性腎衰竭)、環境因素(營養因素如微量營養素缺乏(鋅、銅及硒);以及輻射後暴露)、阻塞性(腫瘤)、缺血性(血管疾病),以及自體免疫,或原發性硬化性膽管炎、休格連氏症候群(Sjögren's syndrome)、原發性膽汁性病症及1型糖尿病。由於診斷及治療上之挑戰,需要跨學科管理策略。
造成災難性視力喪失之大多數疾病(例如黃斑變性)由於通常回應於組織缺血或炎症之異常血管生成及傷口癒合而產生此後果。由血管滲漏、出血及伴隨之纖維化而造成的眼睛中高度有序組織結構之破壞可導致視軸機械破壞及/或生物機能不良。CNS以多種方式高度專一化,包括存在之發炎細胞及傷口癒合細胞之類型。由於視網膜為CNS之一部分,所以其對於損傷之反應利用與大腦其餘部分中所觀測非常類似之機制;不僅對於傷口癒合反應,且亦對於在此高度組織化組織之神經元及血管成分之發育過程中有效之遷移信號的利用而言,此皆為事實(Friedlander M.;Fibrosis and diseases of the eye,J.Clin.Invest.2007)。如下文所述,眼睛前部對於傷口癒合之反應相比於眼睛後部中之此等事件更密切類似於非CNS組織之反應。因此,I係指在前部中之此等傷口癒合事件如纖維化,而視網膜中之類似事件被稱為神經膠樣變性。儘管此種區別在某種程度上為人為
的,但其可用於區分實現傷口癒合及瘢痕形成事件之纖維母細胞及神經膠質細胞。對於炎症、傷口癒合及血管生成之理解增加已導致開發出可有效調節此等生物過程且在某些情形下保全視力之藥物。遺憾的是,此等藥理學干預往往過小,過遲,且經常發生視力喪失之進展。
需要用安全且有效之藥物來預防或治療各纖維變性疾病。
圖1展示db/db糖尿病小鼠相比於C57BL/6小鼠(對照小鼠)之腎小球濾過率(GFR)功能,以及在db/db糖尿病小鼠中在用劑量為10
mg/kg及50mg/kg之化合物1經口處理後之腎小球濾過率(GFR)功能。
更特定言之,本發明關於如下文之式所定義之新穎的經取代之芳族化合物。與已知芳族化合物相比,本發明化合物在位置R2具有較長之鏈;且本發明化合物之此特殊性已表明對活性具有有利且令人驚訝之影響。因此,本發明關於一種由下式定義之化合物:
或其醫藥學上可接受之鹽,其中A為C5烷基、C6烷基、C5烯基、C6烯基、C(O)-(CH2)n-CH3或CH(OH)-(CH2)n-CH3,其中n為3或4;或較佳為C5烷基、C5烯基、C(O)-(CH2)n-CH3或CH(OH)-(CH2)n-CH3,其中n為3;或較佳為C6烷基、C6烯基、C(O)-(CH2)n-CH3或CH(OH)-(CH2)n-CH3,其中n為4;R1為H、F或OH;或較佳為H或OH;R2為C5烷基、C6烷基、C5烯基、C6烯基、C(O)-(CH2)n-CH3或CH(OH)-(CH2)n-CH3,其中n為3或4;或較佳為C5烷基、C5烯基、C(O)-(CH2)n-CH3或CH(OH)-(CH2)n-CH3,其中n為3;或較佳為C6烷基、C6烯基、C(O)-(CH2)n-CH3或CH(OH)-(CH2)n-CH3,其中n為4;R3為H、F、OH或CH2Ph;或較佳為H、F或OH;或較佳為H或OH;R4為H、F或OH;或較佳為H或OH;Q為1)(CH2)mC(O)OH,其中m為1或2,
2)CH(CH3)C(O)OH,3)C(CH3)2C(O)OH,4)CH(F)-C(O)OH,5)CF2-C(O)OH,或6)C(O)-C(O)OH。
在一較佳實施方案中,化合物之醫藥學上可接受之鹽為鈉鹽、鉀鹽、鋰鹽、銨鹽、鈣鹽、鎂鹽、錳鹽、鋅鹽、鐵鹽或銅鹽。較佳的化合物之醫藥學上可接受之鹽為鈉鹽。
本發明亦關於一種用於減少細胞中之膠原產生之方法,其包括使該等細胞與治療有效量之本發明化合物接觸。該膠原較佳為膠原1。該膠原產生較佳為膠原mRNA表現及膠原蛋白產生。根據一較佳實施方案,細胞處於培養中,為器官之一部分或為完全為活動物之一部分之器官的一部分,其中該動物包括但不限於小鼠、大鼠或人類。在細胞為完全為活動物之一部分之器官的一部分的情況下,使細胞與治療有效量之本發明化合物接觸的步驟等效于向動物投予化合物。在細胞為完全為活動物之一部分之器官的一部分且活動物為人類的情況下,化合物之治療有效量對應於較佳約0.01%至約10%(w/w)、或約0.1%至10%(w/w)、或約1.0%至約10%(w/w)、約0.1%至約5%(w/w)、或約1.0%至約5%(w/w)之局部投予
量,或對應於較佳約1mg/kg至約50mg/kg、或約1mg/kg至25mg/kg、或約1mg/kg至約10mg/kg、約5mg/kg至約25mg/kg、或約10mg/kg至約20mg/kg之經口投予量。在培養細胞之情況下,化合物之治療有效量對應於0.01mM至0.5mM,且較佳為約0.2mM。
本發明進一步關於一種用於在有需要之個體中預防纖維變性疾病及/或減緩纖維變性疾病之進展及/或治療纖維變性疾病的方法,其包括投予治療有效量之本發明化合物。在本發明之一較佳實施方案中,該纖維變性疾病為肺纖維化、肝纖維化、皮膚纖維化、腎纖維化、胰纖維化、全身性硬化、心臟纖維化或黃斑變性。
該化合物較佳經口投予。該個體較佳為人類。當化合物經口投予且個體為人類時,治療有效量較佳為約1mg/kg至約50mg/kg、或約1mg/kg至約25mg/kg、或約5mg/kg至約25mg/kg、或約1mg/kg至約20mg/kg、或約1mg/kg至約10mg/kg、或約10mg/kg至約20mg/kg。
根據本發明之一較佳實施方案,纖維變性疾病為肺纖維化。肺纖維化較佳為特發性肺纖維化、肉狀瘤病、囊腫性纖維化、家族性肺纖維化、矽肺病、石綿沈著病、煤礦工人塵肺病、碳塵肺病、過敏性肺炎、由吸入無機粉塵引起之肺纖維化、由感染物引起之肺纖維化、由吸入有毒氣體、氣溶膠、化學粉塵、煙霧或蒸氣引起之肺纖維化、藥物誘發之間質性肺病或肺性高血壓。
在一實施方案中,纖維變性疾病為肝纖維化。根據本發明之一較佳實施方案,肝纖維化由慢性肝病、B型肝炎病毒感染、C型肝炎病毒感染、D型肝炎病毒感染、血吸蟲病、酒精性肝病或非酒精性脂肪肝炎、肥胖症、糖尿病、蛋白質營養不良、冠狀動脈疾病、自體免疫肝炎、囊腫性纖維化、α-1-抗胰蛋白酶缺乏症、原發性膽汁性肝硬化、藥物反應及暴露於毒素引起。
在一實施方案中,纖維變性疾病為皮膚纖維化。根據本發明之一較佳實施方案,皮膚纖維化為瘢痕形成、增生性瘢痕形成、瘢痕瘤、皮膚纖維變性病症、傷口癒合、傷口延遲癒合、牛皮癬或硬皮病。該瘢痕形成可能源自燒傷、創傷、手術損傷、輻射或潰瘍。該潰瘍可為糖尿病性
足潰瘍、靜脈性腿潰瘍或壓力性潰瘍。
當纖維變性疾病為皮膚纖維化時,該化合物較佳經局部或經口投予。當該化合物經局部投予且該個體為人類時,本發明化合物之治療有效量較佳為約0.01%至約10%(w/w)、或約0.1%至10%(w/w)、或約1.0%至約10%(w/w)、或約0.1%至約5%(w/w)、或約1.0%至約5%(w/w)。當經口投予時,本發明化合物之治療有效量較佳為約1mg/kg至約50mg/kg、或約1mg/kg至25mg/kg、或約1mg/kg至約10mg/kg、約5mg/kg至約25mg/kg、或約10mg/kg至約20mg/kg,且個體為人類。
在一實施方案中,纖維變性疾病為腎纖維化。根據本發明之一較佳實施方案,腎纖維化由腎衰竭後之透析、導管置放、腎病、腎小球硬化、腎小球腎炎、慢性腎功能不全、急性腎損傷、末期腎病或腎衰竭引起。
根據一較佳實施方案,本發明亦關於一種用於拮抗哺乳動物之器官(諸如肺、肝臟、皮膚或心臟)中之膠原分泌或膠原沈積的方法,其包括向有需要之該哺乳動物投予治療有效量之本發明化合物,其中該器官為腎臟、肺、肝臟、皮膚或心臟。有需要之哺乳動物為在諸如腎臟、肺、肝臟、皮膚或心臟之器官中經受過多膠原分泌或膠原沈積的哺乳動物。通常,器官中之過多膠原分泌或膠原沈積由損傷或傷害引起。該等損傷及傷害具器官特異性且于本文詳細描述於先前技術部分及整個說明書中。上文詳細描述之治療有效量亦適用於拮抗器官中之膠原分泌或膠原沈積之本方法。本文所述之投予途徑亦適用於本方法。該化合物較佳經足夠時段投予以完全或部分拮抗器官中之膠原沈積水准。本文所用之術語「拮抗」欲意謂「降低」或「減少」。足夠時段可為在一周內、或1周至1個月、或1至2個月、或2個月以上。對於慢性病狀,本發明化合物宜終生投予。
在一實施方案中,纖維變性疾病為心臟纖維化。在此實施方案中,治療有效量較佳為約1mg/kg至約50mg/kg,且較佳為或約1mg/kg至25mg/kg、或約1mg/kg至約10mg/kg、約5mg/kg至約25mg/kg、約5mg/kg至約20mg/kg、或約10mg/kg至約20mg/kg。該化合物較佳經口投予。該個體較佳為人類。
在另一較佳實施方案中,本發明化合物可與治療有效量之第二化合物組合投予,其中該第二化合物較佳為已知可有效預防或治療或潛在預防或治療纖維變性疾病的治療劑。根據本發明之一實施方案,該化合物可與治療有效量的第二化合物組合投予,該第二化合物為免疫抑制藥物、消炎藥物、細胞介素、單株抗體、多重受體酪胺酸激酶抑制劑、抗氧化劑、酶抑制劑、整合素抑制劑、高血壓抑制劑、脂質受體調節劑或噻唑啉二酮。
除先前劑量實施方案之外,對於所有上述纖維變性疾病,當本發明化合物經口投予人類時,化合物之治療有效量較佳對應於約0.01%至約10%(w/w)、或約0.1%至10%(w/w)、或約1.0%至約10%(w/w)、約0.1%至約5%(w/w)、或約1.0%至約5%(w/w)。在所有上述纖維變性疾病中,當本發明化合物經口投予人類時,化合物之治療有效量較佳對應於約1mg/kg至約50mg/kg、或約1mg/kg至25mg/kg、或約1mg/kg至約10mg/kg、約5mg/kg至約25mg/kg、或約10mg/kg至約20mg/kg。
或其醫藥學上可接受之鹽,其中A為C5烷基、C6烷基、C5烯基、C6烯基、C(O)-(CH2)n-CH3或CH(OH)-(CH2)n-CH3,其中n為3或4;或較佳為C5烷基、C5烯基、C(O)-(CH2)n-CH3或CH(OH)-(CH2)n-CH3,其中n為3;或較佳為C6烷基、C6烯基、C(O)-(CH2)n-CH3或CH(OH)-(CH2)n-CH3,其中n為4;R1為H、F或OH;或較佳為H或OH;
R2為C5烷基、C6烷基、C5烯基、C6烯基、C(O)-(CH2)n-CH3或CH(OH)-(CH2)n-CH3,其中n為3或4;或較佳為C5烷基、C5烯基、C(O)-(CH2)n-CH3或CH(OH)-(CH2)n-CH3,其中n為3;或較佳為C6烷基、C6烯基、C(O)-(CH2)n-CH3或CH(OH)-(CH2)n-CH3,其中n為4;R3為H、F、OH或CH2Ph;或較佳為H、F或OH;或較佳為H或OH;R4為H、F或OH;或較佳為H或OH;Q為1)(CH2)mC(O)OH,其中m為1或2,2)CH(CH3)C(O)OH,3)C(CH3)2C(O)OH,4)CH(F)-C(O)OH,5)CF2-C(O)OH,或6)C(O)-C(O)OH;以及關於向罹患該纖維變性疾病之個體投予治療有效量之該化合物的說明書。在本發明之一較佳實施方案中,該纖維變性疾病為肺纖維化、肝纖維化、皮膚纖維化、腎纖維化、胰纖維化、全身性硬化、心臟纖維化或黃斑變性。該套組亦可包含關於投予任何上文揭示之治療有效量之經口投予化合物的說明書。
對於所有纖維變性疾病,該套組較佳進一步包含關於向人類個體每天經口投予約1mg/kg至約50mg/kg化合物的說明書。
當纖維變性疾病為皮膚纖維化時,該套組較佳進一步包含表明向人類個體每天經局部投予約0.01%至約10%(w/w)之化合物的說明書;或表明向人類個體每天經口投予約1mg/kg至約50mg/kg化合物的說明書。
如本文所用,術語「烷基」意欲包括具有五個或六個碳原子
之支鏈及直鏈飽和脂族烴基。上文定義之烷基的實例包括但不限於正戊基、正己基、異戊基、異己基、第三戊基及第三己基。類似地,如本文所用,術語「烯基」意欲包括具有五個或六個碳原子且其中至少兩個碳原子由雙鍵彼此鍵結且具有E或Z區域化學及其組合的不飽和直鏈或支鏈烴基。上文定義之烯基的實例包括但不限於1-戊烯基、2-戊烯基、1-己烯基及2-己烯基。
本發明化合物或其醫藥學上可接受之鹽可含有一或多個不對稱中心、手性軸及手性平面,且因此可產生對映異構體、非對映異構體及其他立體異構形式,隨後可根據絕對立體化學諸如(R)-或(S)-進行定義。因此本發明意欲包括所有此等可能的異構體,以及其外消旋及光學純形式。光學活性(+)及(-)、(R)-及(S)-或(D)-及(L);異構體可使用手性合成子或手性試劑製備或使用習知技術諸如逆相HPLC離析。外消旋混合物可經製備且隨後分離為個別光學異構體或此等光學異構體可藉由手性合成來製備。對映異構體可藉由熟習此項技術者已知之方法離析,例如,藉由形成非對映異構鹽,其隨後可藉由結晶、氣相-液相或液相層析分離,或使一種對映異構體與對映異構體特異性試劑選擇性反應。
如本文所用,術語「醫藥學上可接受之鹽」欲意謂保持自由酸之生物效能及特性且在生物學上或在其他方面非不合需要之彼等鹽。此等鹽衍生自無機鹼或有機鹼與有機酸之加成。由無機鹼製備之鹽包括但不限於鈉鹽、鉀鹽、鋰鹽、銨鹽、鈣鹽、鎂鹽、錳鹽、鋅鹽、鐵鹽、銅鹽及其類似物。由有機鹼製備之鹽包括但不限於以下各物之鹽:一級、二級及三級胺、經取代之胺(包括天然存在之經取代之胺)、環胺及鹼性胺基酸(離胺酸、精胺酸及組胺酸)。醫藥學上可接受之鹽的實例亦描述於例如Berge等人,「Pharmaceutical Salts」,J.Pharm.Sci.66,1-19(1977)中。本發明化合物之較佳鹽為鈉鹽、鉀鹽、鋰鹽、銨鹽、鈣鹽及鎂鹽;且更佳為鈉鹽。醫藥學上可接受之鹽可藉由習知化學方法由含有酸部分之母體化合物合成。一般而言,此等鹽係藉由使此等化合物之自由酸形式與化學計算量之適當鹼于水中或於有機溶劑中或於水性/有機溶劑混合物中反應來製備。鹽可在化合物之最終分離或純化期間就地製備或藉由分別使自由酸形式之經純化
本發明化合物與所需相應鹼反應且分離產物鹽來製備。
如上文所指示及下文所例示,本發明化合物具有有益之醫藥特性並且可具有用於預防及/或治療個體之各種纖維變性疾病及相關病狀的醫藥應用。本發明人所預期之藥學及醫藥應用包括但不限於處理肺纖維化、肝纖維化、皮膚纖維化、腎纖維化、胰纖維化、全身性硬化、心臟纖維化或黃斑變性之彼等應用。
術語「個體」包括可能發生纖維變性疾病或易於患上此病狀之活有機體。術語「個體」包括動物,諸如哺乳動物或鳥類。個體較佳為哺乳動物。個體更佳為人類。個體甚至更佳為需要治療之人類患者。
如本文所用,「預防」欲指至少降低獲得疾病或病症之風險(或易感性)的可能性(亦即,在可能患上或易患上疾病但尚未經歷或顯示該疾病之症狀的患者中造成該疾病之至少一種臨床症狀未出現)。用於鑒別此等患者之生物及生理參數提供于本文中且亦為醫師所熟知。
術語個體之「治療」包括向個體施用或投予本發明化合物(或向來自個體之細胞或組織施用或投予本發明化合物),目的在於延遲、減緩、穩定化、治療、治癒、緩解、減輕、改變、醫治、減少惡化、改善、改進或影響疾病或病狀、疾病或病狀之症狀、或疾病或病狀之風險(或易感性)。術語「治療」係指損傷、病變或病狀之治療或改善成功的任何指示,包括任何客觀或主觀參數,諸如消除;緩解;惡化速率減小;疾病嚴重程度減小;穩定化、減輕症狀或使個體更耐受損傷、病變或病狀;減緩惡化或衰退之速率;使惡化終點之衰弱程度較小;或改善個體之身體或精神健康狀況。
本發明係關於用於預防及/或治療纖維變性疾病之方法、化合物、組成物及套組。
術語「纖維變性疾病」意謂特徵為細胞外基質(主要由膠原組成)過度積聚且當正常組織經瘢痕組織置換時導致功能損失的任何纖維化或疾病。纖維變性疾病包括但不限於肺纖維化、肝纖維化、皮膚纖維化、腎纖維化、胰纖維化、全身性硬化、心臟纖維化及黃斑變性。
術語「肺纖維化」意謂肺中形成或產生過多纖維結締組織(纖
維化),從而導致產生瘢痕化(纖維變性)組織。更確切地說,肺纖維化為造成肺泡及肺間質組織腫脹及瘢痕形成之慢性疾病。瘢痕組織置換健康組織且造成炎症。此慢性炎症又為纖維化之前奏。此種對肺組織之損傷造成肺變硬,隨後使呼吸愈來愈困難。
肺纖維化為可由許多不同原因引起之複雜疾病,該等原因包括因吸入小粒子(石棉、磨細石料、金屬粉塵、香煙煙霧中存在之粒子、二氧化矽粉塵等)誘發之肺部微觀損傷。或者,肺纖維化可作為其他疾病(自體免疫疾病、病毒性或細菌性感染等)之副作用而出現。某些藥物,諸如細胞毒性劑(例如博萊黴素、白消安及甲胺喋呤)、抗生素(例如呋喃妥因、柳氮磺胺吡啶)、抗心律失常藥(例如胺碘達隆(amiodarone)、妥卡胺(tocainide))、消炎藥物(例如金、青黴胺)、違禁藥物(例如快克***、***),亦可造成肺纖維化。然而,當在無已知原因下出現肺纖維化時,將其稱為「特發性」或特發性肺纖維化(IPF)。
肺纖維變性病症被認為是起始於肺實質之急性損傷,其導致慢性間質性炎症,隨後纖維母細胞活化及增殖,且最終發展為肺纖維化及組織破壞之常見終點。當前研究表明,炎症在IPF中不甚重要,IPF似乎主要為回應一些未知觸發之纖維母細胞活化及增殖病症。廣義而言,纖維變性肺部疾病之表現可以歸納如下:其可為慢性、隱伏性及緩慢進行性的;其可為亞急性的,具有消散性、緩解性、復發性或進行性過程;以及其可為急性的,具有爆發性、進行性、緩解性或消散性過程。具有慢性、隱伏性及緩慢進行性過程之病症為臨床上類似於IPF且通常有共同病理學者(亦即UIP)。許多結締組織疾病(例如類風濕性關節炎;CREST症候群(皮膚鈣沈著症、雷諾氏症候群(Raynaud's syndrome)、食管運動障礙、指硬皮病及毛細管擴張症);症候群/進行性全身性硬皮病;全身性紅斑狼瘡;混合性結締組織疾病;塵肺病(例如石綿沈著病、矽肺病);慢性過敏性肺炎;及藥物相關之肺纖維化(例如由於博萊黴素))一般屬於此類別。與職業暴露相關之臨床上明顯之肺部疾病(例如塵肺病)的發展一般在暴露後很多年才出現。輻射性纖維化通常在輻射曝露後數月至數年才出現。在使用肺毒性藥物與產生纖維變性疾病之間可能出現數月或數年之滯後時間。該作用
可為劑量依賴性(例如博萊黴素),但在其他情況下,關係不甚明顯。結締組織疾病之肺部表現可能在關節疾病發作之前、同時或很多年後才出現。肺部肉狀瘤病儘管有時急性或亞急性發作,但在一些情況下可能隨時間隱伏存在。具有可變過程之亞急性表現以隱源性機化肺炎(COP)為代表。COP通常在流感樣疾病發作後數周或數月才出現。該過程為可變的且可自發緩解或進展。該病症被認為對類固醇療法極具反應性,但當類固醇類撤除或逐漸減少時其可再次出現。在一些情況下,COP可進展為末期纖維變性肺部疾病。具有急性發作之病症以急性間質性肺炎(AIP)為代表,其為重度肺損傷之特發形式。組織病理學為具有彌漫性肺泡損傷之成人呼吸窘迫症候群之組織病理學。患者不具有早先肺病史或存在潛在間質性疾病之加速期的一部分。大多數患者迅速進展為呼吸衰竭。一些患者可用類固醇類或其他免疫抑制療法進行改善。
術語「肝纖維化」意謂肝臟中形成或產生過多纖維結締組織(纖維化),從而導致產生瘢痕化(纖維變性)組織。瘢痕化組織藉由纖維化過程置換健康組織且導致後續肝硬化及肝細胞癌。
術語「皮膚纖維化」意謂上皮細胞或纖維結締組織之過度增殖(纖維化),從而導致產生瘢痕化(纖維變性)組織。瘢痕化組織藉由纖維化過程置換健康組織且可為全身性硬皮病之前奏。皮膚纖維化意欲涵蓋任何皮膚組織及上皮細胞之纖維化,包括但不限於血管及靜脈、器官或腺體之內腔諸如下頜下、膽囊、甲狀腺毛囊、汗腺管、卵巢、腎臟之導管;齒齦、舌、齶、鼻、喉、食道、胃、腸、直腸、肛門及***之上皮細胞;真皮、瘢痕、皮膚及頭皮。本發明化合物可有效促進傷口癒合且具有一或多種下列活性:- 改善膠原組織化及/或減少該傷口中之傷口多孔性;- 減少該傷口中由纖維母細胞及上皮細胞產生之膠原過度產生;- 減少該傷口中之上皮間質轉化;- 減少該傷口中之纖維母細胞遷移及活化;
- 減少及/或抑制該傷口中之皮膚增厚;- 減少及/或抑制炎性細胞向該傷口之募集。
一般而言,預防性及治療性用途包括向有需要之個體、較佳人類患者投予如本文所述之化合物。根據本發明之化合物可與治療有效量之第二化合物組合投予,該第二化合物可包括於相同的醫藥組成物中或第二醫藥組成物中。該第二化合物宜為免疫抑制藥物,包括但不限於環孢靈、硫唑嘌呤、環磷醯胺或黴酚酸嗎啉乙酯;消炎藥物,包括但不限於皮質類固醇(例如潑尼松);細胞介素,包括但不限於干擾素-α、干擾素-γ、介白素12;單株抗體,包括但不限於CTGF、TGF-β、MCP-1、IL-4及IL-13;多重受體酪胺酸激酶抑制劑,包括但不限於尼達尼布及JNK(激酶)抑制劑坦茲替布(CC-930);抗氧化劑,諸如但不限於N-乙醯基半胱胺酸、吡非尼酮(pirfenidone)、維生素E、S-腺苷甲硫胺酸或青黴胺;酶抑制劑,包括但不限於離胺醯氧化酶樣2(LOXL2酶);整合素抑制劑,例如但不限於αvβ6;脂質受體調節劑,包括但不限於溶血磷脂酸受體拮抗劑;吡非尼酮或噻唑啉二酮。
本發明之一相關態樣關於包含一或多種本文所述之本發明化合物的醫藥組成物及套組。如上文所指示,本發明化合物可用於預防及/或治療纖維變性疾病。
本發明之一相關態樣關於與纖維變性疾病有關之化合物的預防性及治療性用途。
肺纖維化可導致若干嚴重併發症。因為纖維變性之肺部的氧攝入能力受損,所以可能產生低血氧含量(低血氧症)。氧缺乏可能影響整個身體。肺纖維化之另一併發症為肺性高血壓(肺動脈高血壓)。肺部瘢痕組織可使得血液更難以流過。壓力增加使得心臟負荷更大且導致心臟衰弱並擴張,使其泵送效率降低並產生心臟衰竭。當人們產生腹部流體積聚、腿部腫脹或頸靜脈脈動顯著時,疑似此病症。
肝纖維化可導致嚴重的肝臟機能不良且可導致肝臟完全失去功能。
在因手術或事故造成之皮膚損傷後,皮膚纖維化可導致雜亂印記、永久傷痕及瘢痕,造成嚴重的美觀問題及皮膚變硬。
如本文所用,術語「治療有效量」意謂當投予個體用於治療或預防特定病症、疾病或病狀時,足以實現該病症、疾病或病狀之此種治療或預防的化合物量。劑量及治療有效量可例如根據多種因素而改變,該等因素包括所用特定藥劑之活性、個體之年齡、體重、一般健康狀況、性別及飲食、投藥時間、投藥途徑、***速率、及任何藥物組合(若適用)、專業人員希望化合物對個體之作用及化合物之特性(例如,生物可用性、穩定性、效能、毒性等),以及個體所罹患之特定病症。另外,經靜脈內投予之治療有效量可取決於個體之血液參數,例如脂質概況、胰島素含量、血糖或肝臟代謝。治療有效量亦將根據疾病狀態之嚴重程度、器官功能或潛在之疾病或併發症而改變。可使用任何可用之檢定(包括本文所述之檢定)來確定此等適當劑量。當一或多種本發明化合物欲投予人類時,醫師可例如首先規定相對低之劑量,隨後增大劑量直至獲得適當的反應。在人類中,根據本發明之化合物在人類中之經口投予劑量為1mg/kg至50mg/kg、較佳5mg/kg至20mg/kg、更佳5mg/kg至15mg/kg、此外更佳約1mg/kg至10mg/kg。本發明化合物在人類中之局部投予劑量為0.01%至10%(w/w)、較佳0.1%至5%(w/w)且更佳1%至5%。小鼠代謝比人類代謝更快地消除任何化合物,因此對於化合物於小鼠中之測試,劑量可倍增10倍至20倍。
如本文所用,術語「醫藥組成物」係指存在至少一種根據本發明之化合物及醫藥學上可接受之媒劑。
「醫藥學上可接受之媒劑」係指與化合物一起投予之稀釋劑、佐劑、賦形劑或載劑。術語「醫藥學上可接受」係指適用於與人類及低等動物之組織接觸而無不當毒性、不相容性、不穩定性、刺激性、過敏反應及其類似特性且與合理的效益/風險比相稱的藥物、藥劑、惰性成分等。其較佳係指已由或可由聯邦或州政府之管理機構批准或列於美國藥典或其他公認藥典中用於動物且更特定言之用於人類的化合物或組成物。醫藥學上可接受之媒劑可為溶劑或分散介質,其包含例如水、乙醇、多元醇(例
如甘油、丙二醇及液體聚乙二醇)、其合適混合物以及植物油。醫藥學上可接受之媒劑的其他實例包括但不限於:注射用水USP;水性媒劑,諸如但不限於氯化鈉注射液、林格氏注射液、右旋糖注射液、右旋糖/氯化鈉注射液及乳酸化林格氏注射液;水可混溶性媒劑,諸如但不限於乙醇、聚乙二醇及聚丙二醇;及非水性媒劑,諸如但不限於玉米油、棉籽油、花生油、芝麻油、油酸乙酯、肉豆蔻酸異丙酯及苯甲酸苄酯。可藉由添加抗細菌劑及抗真菌劑(例如對羥基苯甲酸酯、氯丁醇、苯酚、抗壞血酸、硫柳汞及其類似物)來達成微生物作用之預防。在許多情況下,組成物中包括等滲劑,例如糖、氯化鈉或多元醇諸如甘露糖醇及山梨糖醇。可藉由在組成物中包括延遲吸收劑(例如單硬脂酸鋁或明膠)來產生可注射組成物之延長吸收。
在一些實施方案中,本發明組成物包含有效量之具有上文式之化合物。尤其較佳為2-[3,5-二戊基苯基]乙酸鈉鹽。
在一些實施方案中,本發明關於用於預防及/或治療肺纖維化、肝纖維化、皮膚纖維化、腎纖維化、胰纖維化、全身性硬化、心臟纖維化或黃斑變性的醫藥組成物。
本發明化合物可在投予之前使用可用技術及程序調配成醫藥組成物。例如,可以適於藉由局部、經口、靜脈內(iv)、肌肉內(im)、儲槽式肌肉內(depo-im)、皮下(sc)、儲槽式皮下(depo-sc)、舌下、鼻內、鞘內局部或直腸途徑投予的方式調配醫藥組成物。
較佳地,本發明化合物可經口投予或局部投予。調配物宜以單位劑型呈現且可藉由製藥技術中熟知之任何方法製備。製備此等調配物或組成物之方法包括使本發明化合物與醫藥學上可接受之媒劑(例如,惰性稀釋劑或可同化之食用載劑)及視情況一或多種輔助成分締合的步驟。一般而言,藉由使本發明化合物與液體載劑或細粉狀固體載劑或兩者均勻且緊密地締合以及隨後必要時成形產品來製備調配物。此等治療上有用之組成物中之治療劑的量使得可獲得合適劑量。
適於經口投予之本發明調配物可呈以下形式:膠囊(例如硬殼或軟殼明膠膠囊)、扁囊劑、丸劑、錠劑、***錠、散劑、顆粒劑、錠片、
糖衣丸(例如有包衣(例如腸溶包衣)或無包衣),或於水性或非水性液體中之溶液或懸浮液,或水包油或油包水乳液,或酏劑或糖漿,或片劑或漱口劑以及其類似形式,其各含有預定量之本發明化合物作為活性成分。本發明化合物亦可以大丸劑、舐劑或糊劑形式投予,或直接併入個體之飲食中。此外,在某些實施方案中,此等錠片可經調配以(a)提供暫態或快速藥物釋放(亦即其上面無塗層);(b)經包覆例如以隨時間提供持續藥物釋放;或(c)包覆腸溶包衣以提供更好胃腸耐受性。可藉由習知方法達成包衣包覆,典型地為pH或時間依賴性包衣,以使得本發明化合物於所需位置附近釋放,或在多個時間釋放以延長所需作用。此等劑型典型地包括但不限於鄰苯二甲酸乙酸纖維素、聚乙酸乙烯酯鄰苯二甲酸酯、鄰苯二甲酸羥丙基甲基纖維素、乙基纖維素、蠟及蟲膠中之一或多者。
在用於經口投予之固體劑型中,本發明化合物可與一或多種醫藥學上可接受之載劑混合,諸如檸檬酸鈉或磷酸二鈣,或下列中之任一者:填充劑或增量劑,諸如澱粉、乳糖、蔗糖、葡萄糖、甘露糖醇或矽酸;黏合劑,例如羧甲基纖維素、海藻酸鹽、明膠、聚乙烯吡咯啶酮、蔗糖或***膠;保濕劑,諸如甘油;崩解劑,諸如瓊脂、碳酸鈣、馬鈴薯或木薯澱粉、海藻酸、某些矽酸鹽及碳酸鈉;溶解阻滯劑,諸如石蠟;吸收促進劑,諸如四級銨化合物;濕潤劑,例如鯨蠟醇及單硬脂酸甘油酯;吸收劑,諸如高嶺土及膨潤土;潤滑劑,諸如滑石、硬脂酸鈣、硬脂酸鎂、固體聚乙二醇、月桂基硫酸鈉及其混合物;以及著色劑。在膠囊、錠劑及丸劑之情況下,醫藥組成物亦可包含緩衝劑。相似類型之固體組成物亦可用作使用諸如乳糖或奶糖以及高分子量聚乙二醇及其類似物之賦形劑之軟填充明膠膠囊及硬填充明膠膠囊中的填充劑。
經口組成物典型地包括液體溶液、乳液、懸浮液及其類似物。適於製備此等組成物之醫藥學上可接受之媒劑為本領域中所熟知。用於糖漿、酏劑、乳液及懸浮液之典型載劑組分包括乙醇、甘油、丙二醇、聚乙二醇、液體蔗糖、山梨糖醇及水。對於懸浮液而言,典型的懸浮劑包括甲基纖維素、羧甲基纖維素鈉、黃蓍膠及海藻酸鈉;典型的濕潤劑包括卵磷脂及聚山梨醇酯80;且典型的防腐劑包括對羥基苯甲酸甲酯及苯甲酸
鈉。經口液體組成物亦可含有一或多種組分,諸如上文揭示之甜味劑、調味劑及著色劑。
適於注射用途之醫藥製劑可包括無菌水溶液(具水溶性時)或分散液及用於臨時製備無菌可注射溶液或分散液之無菌粉末。在所有情況下,組成物必須無菌且必須為流體以便存在易注射性。其在製造及儲存條件下必須穩定且必須抵抗諸如細菌及真菌之微生物的污染作用。可藉由將所需量之治療劑與所需要之上文所列成分中之一者或組合併入適當溶劑中,接著過濾滅菌來製備無菌可注射溶液。一般而言,藉由將治療劑併入含有基本分散介質及來自上文所列成分之所需其他成分的無菌媒劑中來製備分散液。在用於製備無菌可注射溶液之無菌粉末之情況下,製備方法為真空乾燥及冷凍乾燥,其得到活性成分(亦即治療劑)加來自其先前無菌過濾溶液之任何額外所需成分的粉末。
亦提供適於以氣霧劑形式藉由吸入投予之醫藥調配物。此等調配物包含具有任何本文式之所需化合物或此(等)化合物之複數個固體粒子的溶液或懸浮液。例如,預期本發明化合物之金屬鹽具有可用於製備用於藉由吸入投予之活性醫藥成分(API)之精細粒子而非此等化合物之自由酸形式的物理化學特性。所需調配物可置於小腔中且噴霧。可藉由壓縮空氣或藉由超音能量來實現噴霧以形成複數個包含藥劑或鹽之液滴或固體粒子。該等液滴或固體粒子應具有約0.5至約5微米範圍內之粒徑。可藉由以本領域中已知之任何適當方式、諸如藉由微米尺寸化加工具有任何本文所述式之固體劑或其鹽來獲得固體粒子。固體粒子或液滴之尺寸應為例如約1至約2微米。在此方面,商業噴霧器可用于達成此目的。適於以氣霧劑形式投予之醫藥調配物可為液體形式,該調配物應于包含水之載劑中包含具有任何本文所述式之水溶性劑或其鹽。可存在介面活性劑,當進行噴霧時,該介面活性劑充分降低調配物之表面張力以導致形成在所需尺寸範圍內之液滴。
本發明組成物亦可經局部投予個體,例如,藉由將組成物直接放置於個體之表皮或上皮組織上或使組成物在個體之表皮或上皮組織上擴散,或經由「貼片」經皮投予。此等組成物包括例如洗劑、乳膏、溶液、
凝膠、乳液及固體。此等局部組成物可包含有效量、通常約0.01%至約10%(w/w)、或約0.1%至約5%(w/w)、或約1%至約5%(w/w)的本發明化合物。適於局部投予之載劑典型地以連續膜形式原位保留於皮膚上,且抵抗因排汗或浸于水中而移除。一般而言,載劑為有機性質且能夠於其中分散或溶解治療劑。該載劑可包括醫藥學上可接受之潤膚劑、乳化劑、增稠劑、溶劑及其類似物。載劑可包括胎脂。局部調配物包括一或多種賦形劑,諸如但不限於保護劑、吸附劑、緩和劑、潤膚劑、防腐劑、抗氧化劑、保濕劑、緩衝劑、增溶劑、皮膚滲透劑及介面活性劑。合適的保護劑及吸附劑包括但不限於粉塵劑、硬脂酸鋅、火棉膠、二甲聚矽氧烷、聚矽氧、碳酸鋅、蘆薈凝膠及其他蘆薈產品、維生素E油、尿囊素(allatoin)、甘油、礦脂及氧化鋅。合適的緩和劑包括但不限於安息香、羥丙基纖維素、羥丙基甲基纖維素及聚乙烯醇。合適的潤膚劑包括但不限於動物及植物脂肪及油、肉豆蔻醇、明礬及乙酸鋁。合適的防腐劑包括但不限於四級銨化合物,諸如氯化苯甲烴銨、苄索氯銨、西曲溴銨(cetrimide)、地喹氯銨(dequalinium chloride)及氯化十六烷基吡錠;汞劑,諸如硝酸苯汞、乙酸苯汞及硫柳汞;醇劑,例如氯丁醇、苯乙醇及苄醇;抗細菌酯,例如對羥基苯甲酸酯;及其他抗微生物劑,諸如氯己定(chlorhexidine)、氯甲酚、苯甲酸及多黏菌素。合適的抗氧化劑包括但不限於抗壞血酸及其酯、亞硫酸氫鈉、丁基化羥基甲苯、丁基化羥基苯甲醚、生育酚,及螯合劑如EDTA及檸檬酸。合適的保濕劑包括但不限於甘油、山梨糖醇、聚乙二醇、尿素及丙二醇。適於本發明使用之緩衝劑包括但不限於乙酸鹽緩衝劑、檸檬酸鹽緩衝劑、磷酸鹽緩衝劑、乳酸緩衝劑及硼酸鹽緩衝劑。合適的增溶劑包括但不限於四級銨氯化物、環糊精、苯甲酸苄酯、卵磷脂及聚山梨醇酯。合適的皮膚滲透劑包括但不限於乙醇、異丙醇、辛基苯基聚乙二醇、油酸、聚乙二醇400、丙二醇、N-癸基甲基亞碸、脂肪酸酯(例如,肉豆蔻酸異丙酯、月桂酸甲酯、單油酸甘油酯及丙二醇單油酸酯);及N-甲基吡咯啶酮。
可用于獲得藥劑於個體中之全身性傳遞的其他組成物可包括舌下、經頰及經鼻劑型。此等組成物典型地包含一或多種可溶性填充劑物質,諸如蔗糖、山梨糖醇及甘露糖醇;及黏合劑,諸如***膠、微晶
纖維素、羧甲基纖維素及羥丙基甲基纖維素。亦可包括上文揭示之助流劑、潤滑劑、甜味劑、著色劑、抗氧化劑及調味劑。
根據本發明之化合物亦可非經腸、經腹膜內、經脊柱內或經腦內投予。對於此等組成物,本發明化合物可於甘油、液體聚乙二醇及其混合物中以及於油中製備。在普通儲存及使用條件下,此製劑可含有防腐劑以防止微生物之生長。
對於預防纖維變性疾病/減緩纖維變性疾病之進展/治療纖維變性疾病之方法,本發明之方法亦可包括共同投予至少一種根據本發明之化合物或其醫藥學上可接受之鹽以及投予另一治療有效劑用於預防纖維變性疾病及/或減緩纖維變性疾病之進展及/或治療纖維變性疾病。因此,本發明亦關於一種用於預防、減少或消除上述疾病或病狀中之任一者之症狀或併發症的方法。該方法包括向有需要之個體投予包含至少一種本發明化合物之第一醫藥化合物及包含一或多種其他活性成分之第二醫藥組成物,其中所有活性成分以足以抑制、降低或消除欲治療之疾病或病狀之一或多種症狀或併發症的量投予。在一個態樣中,第一醫藥組成物與第二醫藥組成物之投予短暫間隔至少約兩分鐘。第一藥劑較佳為式I化合物。第二藥劑可選自上文給出化合物之清單。
本發明不欲局限于本文所示之實施方案,但符合與本文公開之原理及新穎特徵一致的最廣泛範疇。
除非上下文另外明確指示,否則單數形式「一」及「該」包括相應的複數個提及物。
除非另外指示,否則本說明書及申請專利範圍中所用之所有表示成分量、反應條件、濃度、性質等之數目應理解為在所有情形下皆由術語「約」修飾。最起碼,每個數值參數應當至少按照所報導之有效數字的數目且藉由應用普通捨入技術理解。因此,除非相反指示,否則本說明書及隨附申請專利範圍中所述之數值參數為近似值,其可能根據欲獲得之特性而改變。儘管闡述實施方案之寬泛範疇之數值範圍及參數為近似值,但特定實施例中闡述之數值盡可能精確地報導。然而,任何數值皆固有地含有由實驗、測試量測、統計分析及此類之變化而產生的某些誤差。
熟習此項技術者應僅使用常規實驗可認識到或能夠確定本文所述之具體程序、實施方案、申請專利範圍及實施例的眾多等效物。此等等效物視為在本發明之範疇內且由其隨附申請專利範圍所涵蓋。本發明由下列實施例進一步說明,該等實施例不應理解為進一步限制本發明。
下文闡述之實施例提供由式I涵蓋之某些代表性化合物之例示性製備方法。一些實施例提供某些代表性本發明化合物之例示性用途。亦提供用於檢定本發明化合物之功效的例示性方法。
下文闡述之實施例提供由通式I涵蓋之某些代表性化合物之例示性製備方法。一些實施例提供某些代表性本發明化合物之例示性用途。亦提供用於檢定本發明化合物之試管內及活體內功效的例示性方法。
儀器:
所有HPLC層析圖及質譜記錄於HP 1100 LC-MS Agilent儀器上,其中使用分析型C18管柱(250×4.6mm,5微米),以3分鐘內含0.01% TFA之50-99% CH3CN-H2O之梯度作為洗提劑,接著3分鐘內等度洗提且流速為2mL/min。
步驟1:
在0℃下在氮氣下用三乙胺(1.68ml,12.1mmol)處理2-[3,5-
二羥基苯基]乙酸甲酯(1.00g,5.49mmol)及N-苯基-雙(三氟甲基磺醯基)醯亞胺(4.31g,12.1mmol)於二氯甲烷(20ml)中之懸浮液。形成澄清溶液。反應物隨後在0℃下在氮氣下攪拌2小時,且在室溫下攪拌21小時。用乙酸乙酯(100ml)稀釋反應物,且溶液用0.5M氫氧化鈉水溶液(2×100ml)及飽和氯化鈉水溶液(75ml)洗滌;隨後經硫酸鈉脫水;過濾且於真空中蒸發,得到粗產物。利用以乙酸乙酯/己烷0:1至1:9洗提之BiotageTM 40iM管柱(二氧化矽)純化,得到呈灰白色油狀之2-[3,5-雙(三氟甲基磺醯氧基)苯基]乙酸甲酯(2.23g,91%)。1H NMR(400MHz,CDCl3):δ 7.32(d,J=2.2Hz,2H),7.18(dd,J=2.2,2.2Hz,1H),3.72(s,5H);19F NMR(377MHz,CDCl3):δ -73.20(s,3F);13C NMR(101MHz,CDCl3):δ 170.05,149.48,139.01,122.95,118.87(q,JCF=320.5Hz),114.42,52.62,40.29。
步驟2:
用碳酸鈉(1.59g,15.0mmol)于水(8ml)中之溶液處理雙(三氟甲磺酸)芳基酯(2.23g,4.99mmol)及(E)-1-戊烯-1-基硼酸頻哪醇酯(2.45g,12.5mmol)於1,2-二甲氧基乙烷(25ml)中之溶液。用氮氣使溶液去氧,且隨後用肆(三苯基膦)鈀(0.58g,0.50mmol)處理。混合物于密封管中在90℃下加熱17小時。將反應物冷卻至室溫且分配於乙酸乙酯(200ml)與1M鹽酸水溶液(150ml)之間。有機相以5%碳酸氫鈉水溶液(150ml)及飽和氯化鈉水溶液(150ml)洗滌;隨後經硫酸鈉脫水;過濾且於真空中蒸發,得到粗產物。利用以乙酸乙酯/己烷0:1至3:97洗提之BiotageTM 40iL管柱(二氧化矽)純化,得到與過量(E)-1-戊烯-1-基硼酸酸頻哪醇酯呈不可分離之10:4混合物形式的2-[3,5-二[(E)-1-戊-1-烯基]苯基]乙酸甲酯(1.12g,61%)。1H NMR(400MHz,CDCl3):δ 7.21(s,1H),7.10(d,J=1.3Hz,2H),6.34(d,J=15.8Hz,1H),6.22(dd,J=15.8,6.7Hz,1H),3.65(s,3H),3.55(s,2H),2.18(tdd,J=6.8,6.8,1.0Hz,2H),1.49(qt,J=7.4,7.2Hz,2H),0.96(t,J=7.4Hz,3H);13C NMR(101MHz,CDCl3):δ 172.04,138.59,134.47,131.34,129.97,125.57,122.75,52.07,41.32,35.39,22.77,13.97。
步驟3:
用鈀/碳(10% w/w Pd;0.12g)處理不飽和化合物(1.12g,78.5% w/w,3.07mmol)於乙酸乙酯(1ml)及甲醇(1ml)中之溶液。用氫氣使混合物脫氣,且在室溫下在1atm氫氣下攪拌22小時。將反應物過濾且於真空中蒸發,得到與戊基硼酸頻哪醇酯呈不可分離之10:4混合物形式的2-[3,5-二戊基苯基]乙酸甲酯(0.86g,76%)。1H NMR(400MHz,CDCl3):δ 6.93(s,3H),3.70(s,3H),3.59(s,2H),2.58(t,J=7.9Hz,2H),1.58-1.66(m,2H),1.32-1.38(m,4H),0.91(t,J=6.8Hz,3H)。
步驟4:
用氫氧化鋰(0.28g,11.7mmol)于水(6ml)中之溶液處理甲酯(0.86g,79% w/w,2.34mmol)於乙腈(24ml)中之溶液,且在室溫下攪拌反應物22小時。用1M鹽酸水溶液(55ml)中止反應,隨後用乙酸乙酯(100ml)萃取。有機萃取物用飽和氯化鈉水溶液(50ml)洗滌;隨後經硫酸鈉脫水;過濾且於真空中蒸發,得到粗產物。利用以乙酸乙酯/己烷0:1至1:4洗提之SiliaSep二氧化矽管柱純化,得到呈無色油狀之2-[3,5-二戊基]苯基]乙酸(0.55g,84%)。1H NMR(400MHz,CDCl3):δ 6.99(s,3H),3.65(s,2H),2.63(t,J=7.8Hz,2H),1.64-71(m,2H),1.36-1.44(m,4H),0.97(t,J=6.9Hz,3H);13C NMR(101MHz,CDCl3):δ 178.96,143.55,133.21,127.93,127.06,41.47,36.13,31.94,31.47,22.86,14.34。
步驟5:
用碳酸氫鈉(0.15g,1.75mmol)于水(3ml)中之溶液處理酸(0.48g,1.75mmol)於乙醇(12ml)中之溶液,且反應物在室溫下攪拌3天。在真空中蒸發乙醇,且殘餘水性糖漿狀物用水(50ml)稀釋,
過濾(PES,0.2μm),且凍幹,得到呈白色固體狀之2-[3,5-二戊基苯基]乙酸鈉(0.52g,定量)。熔點225-230℃;1H NMR(400MHz,CD3OD+D2O):δ 6.92(s,2H),6.76(s,1H),3.41(s,2H),2.50(t,J=7.5Hz,2H),1.52-1.59(m,2H),1.23-1.33(m,4H),0.85(t,J=6.9Hz,3H);13C NMR(101MHz,CD3OD+D2O):δ 179.99,142.66,137.63,126.66,126.16,45.11,35.61,31.36,31.19,22.41,13.47;LRMS(ESI):m/z 277.5(w,[M-Na++2H+]),231.1(100%,來自羧基損失之鎓離子);HPLC:3.0分鐘。
化合物2:2-(3,5-二己基苯基)乙酸之鈉鹽
如關於化合物1所述自(E)-己-1-烯基硼酸頻哪醇酯製備上述化合物。白色固體;1H NMR(400MHz,CD3OD):δ 6.96(s,2H),6.79(s,1H),3.43(s,2H),2.54(d,J=7.7Hz,4H),1.55-1.63(m,4H),1.28-1.36(m,12H),0.89(t,J=6.8Hz,6H);13C NMR(101MHz,CD3OD):δ 179.68,142.38,137.82,126.55,126.07,45.30,35.87,31.83,31.67,29.02,22.61,13.42;LRMS(ESI):m/z 322.0(100%,M-Na++H++NH4 +)及259.0(35%,M-CO2Na);UPLC(系統A):8.9分鐘。UPLC系統A:移動相A=10mM碳酸氫銨水溶液;移動相B=乙腈;固相=HSS T3管柱;梯度=含5-100% B之A,經10分鐘。
化合物3:2-(2-羥基-3,5-二戊基苯基)乙酸之鈉鹽
步驟1
用氫化鈉(2.5g,50.0mmol)之溶液處理2,4-二溴-6-(溴甲基)苯酚(3.5g,10.0mmol)於乙腈(17ml)中之溶液並且反應物在100℃下回流加熱1小時。將反應混合物冷卻至室溫且傾倒入水(100ml)中。用1M鹽酸水溶液將pH自10調節至8,且用乙酸乙酯(3×250ml)萃取混合物。經合併之萃取物用1M鹽酸水溶液(250ml)及飽和氯化鈉水溶液(250ml)洗滌;經硫酸鈉脫水;過濾且在真空中蒸發,得到粗產物。用丙酮萃取;過濾;且在真空中蒸發,得到2-(3,5-二溴-2-羥基苯基)乙腈(2.6g,90%)。1H NMR(400MHz,d 6-丙酮):δ 8.75(br s,1H),7.69(d,J=2.3Hz,1H),7.54(d,J=2.3Hz,1H),3.92(s,2H);13C NMR(101MHz,d 6-丙酮):δ 151.31,134.51,131.92,122.80,117.43,111.89,111.53,18.70。
步驟2
用硫酸(2.5ml)、乙酸(2.5ml)及水(2.5ml)之混合物處理2-(3,5-二溴-2-羥基苯基)乙腈(2.6g,9.0mmol),且反應物在125℃下回流加熱2小時。將反應混合物冷卻至室溫且傾倒入冰(50ml)與水(50ml)之混合物中,隨後攪拌直至冰融化。用乙酸乙酯(250ml)萃取混合物;且隨後萃取物用水(100ml)及飽和氯化鈉水溶液(100ml)洗滌;經硫酸鈉脫水;過濾且在真空中蒸發,得到粗製2-(3,5-二溴-2-羥基苯基)乙酸(3.1g)。此物質不經進一步純化或表徵即直接用於下一步驟中。
步驟3
用硫酸(0.43ml,8.1mmol)處理粗製2-(3,5-二溴-2-羥基苯基)乙酸(3.1g,9.0mmol)於甲醇(17ml)中之溶液且在環境溫度下攪拌反應物16小時。在真空中蒸發甲醇,且將殘餘物溶解於乙酸乙酯(270ml)中。溶液用水(2×200ml)及飽和氯化鈉水溶液(130ml)洗滌;經硫酸鈉脫水;過濾且在真空中蒸發,得到粗產物。利用以含0-20%乙酸乙酯之己烷洗提的BiotageTM SP1系統(120g二氧化矽濾筒)純化,得到2-(3,5-二溴-2-羥基苯基)乙酸甲酯(1.4g,49%)。1H NMR(400MHz,CDCl3):δ 7.52(d,J=2.2Hz,1H),7.23(d,J=2.2Hz,1H),6.42(br s,1H),3.72(s,3H),3.65(s,2H);13C NMR(101MHz,CDCl3):δ 172.06,150.60,133.74,133.50,123.94,112.62,111.77,52.78,36.61。
步驟4
用碳酸鉀(0.26g,1.86mmol)、碘化鉀(0.05g,0.32mmol)及苄基溴(0.20ml,1.7mmol)處理2-(3,5-二溴-2-羥基苯基)乙酸甲酯(0.5g,1.54mmol)於丙酮(5ml)中之溶液,且在室溫下攪拌反應物1小時。
在真空中蒸發丙酮,且殘餘物分配於乙酸乙酯(50ml)與1M鹽酸水溶液(50ml)之間。有機相用飽和氯化鈉水溶液(50ml)洗滌;經硫酸鈉脫水;過濾且在真空中蒸發,得到粗產物。利用以含0-10%乙酸乙酯之己烷洗提之BiotageTM SP1系統(40g二氧化矽濾筒)純化,得到2-(2-(苄氧基)-3,5-二溴苯基)乙酸甲酯(0.6g,95%)。1H NMR(400MHz,CDCl3):δ 7.67(d,J=2.4Hz,1H),7.48-7.51(m,2H),7.37(d,J=2.4Hz,1H),7.34-7.43(m,3H),4.99(s,2H),3.66(s,3H),3.60(s,2H);13C NMR(101MHz,CDCl3):δ 171.26,153.79,136.56,135.38,133.57,132.04,128.82,128.64,128.52,118.69,117.56,75.53,52.50,35.86。
步驟5
如化合物I步驟2所述使2-(2-(苄氧基)-3,5-二溴苯基)乙酸甲酯(0.3g,0.73mmol)與(E)-戊-1-烯基硼酸頻哪醇酯(0.4g,1.79mmol)偶合,得到2-(2-(苄氧基)-3,5-二((E)-戊-1-烯基)苯基)乙酸甲酯(0.21mg,72%)。1H NMR(400MHz,CDCl3):δ 7.50(d,J=7.2Hz,2H),7.44(dd,J=7.2,7.2Hz,2H),7.43(d,J=2.1Hz,1H),7.38(dd,J=7.2,7.2Hz,1H),7.18(d,J=2.1Hz,1H),6.72(d,J=15.8Hz,1H),6.39(d,J=15.8Hz,1H),6.32(dt,J=15.8,7.0Hz,1H),6.22(dt,J=15.8,6.8Hz,1H),4.87(s,2H),3.69(s,3H),3.67(s,2H),2.20-2.29(m,4H),1.50-1.60(m,4H),1.01(t,J=7.3Hz,3H),1.00(t,J=7.4Hz,3H);13C NMR(101MHz,CDCl3):δ 172.49,153.59,137.58,134.35,132.91,131.91,130.84,129.53,128.78,128.32,128.30,128.24,127.26,125.21,123.89,75.89,52.21,35.94,35.74,35.42,22.87,22.77,14.07,14.06。
步驟6
如化合物I步驟3所述使2-(2-(苄氧基)-3,5-二((E)-戊-1-烯基)
苯基)乙酸甲酯(0.2g,0.53mmol)氫化,得到2-(2-羥基-3,5-二戊基苯基)乙酸甲酯(0.12g,73%)。1H NMR(400MHz,CDCl3):δ 7.37(s,1H),6.92(d,J=2.1Hz,2H),6.77(d,J=2.1Hz,1H),3.76(s,3H),3.67(s,2H),2.65(t,J=7.8Hz,2H),2.51(t,J=7.8Hz,2H),1.58-1.66(m,4H),1.31-1.41(m,8H),0.93(t,J=7.0Hz,3H),0.92(t,J=6.9Hz,3H);13C NMR(101MHz,CDCl3):δ 175.01,151.27,135.14,131.48,129.92,128.52,120.30,52.95,38.35,35.34,32.15,31.86,31.74,30.61,30.03,22.87,22.83,14.34,14.31。
步驟7
如化合物I步驟4所述使2-(2-羥基-3,5-二戊基苯基)乙酸甲酯(0.2g,0.53mmol)水解,得到與丙酮化物質混合之粗產物。利用以含0-100%乙酸乙酯之己烷洗提之BiotageTM SP1系統(120g二氧化矽濾筒)純化一小份,得到2-(2-羥基-3,5-二戊基苯基)乙酸(13.5mg)。1H NMR(400MHz,CDCl3):δ 10.5(br s,1H),6.89(d,J=2.2Hz,1H),6.78(d,J=2.2Hz,1H),6.32(br s,1H),3.66(s,2H),2.58(t,J=7.9Hz,2H),2.48(t,J=7.8Hz,2H),1.52-1.63(m,4H),1.26-1.37(m,8H),0.90(t,J=7.0Hz,3H),0.88(t,J=6.8Hz,3H)。
步驟8
如化合物I步驟5所述使2-(2-羥基-3,5-二戊基苯基)乙酸(13.5mg,0.046mmol)轉化為鈉鹽,得到2-(2-羥基-3,5-二戊基苯基)乙酸鈉(11mg,77%)。1H NMR(400MHz,CD3OD):δ 6.72(d,J=2.0Hz,1H),6.69(d,J=2.0Hz,1H),3.46(s,2H),2.56(t,J=7.6Hz,2H),2.44(t,J=7.6Hz,2H),1.50-1.61(m,4H),1.25-1.37(m,8H),0.90(t,J=6.8Hz,3H),0.88(t,J=7.0Hz,3H);13C NMR(101MHz,CD3OD):δ 180.33,151.94,133.47,130.37,128.21,127.81,123.99,42.90,34.97,31.81,31.60,31.40,30.25,29.88,22.51,
22.45,13.29,13.24;LRMS(ESI負模式):m/z 291.2(100%,M-Na+);UPLC(系統B):7.7分鐘。UPLC系統B:移動相A=0.1%甲酸水溶液;移動相B=含0.1%甲酸之乙腈;固相=HSS T3管柱;梯度=含5-100% B之A,經10分鐘。
化合物4:2-(3,5-二己基-2-羥基苯基)乙酸之鈉鹽
如關於化合物3所述使用(E)-己-1-烯基硼酸頻哪醇酯製備上述化合物。1H NMR(400MHz,CD3OD):δ 6.72(d,J=2.0Hz,1H),6.69(d,J=2.0Hz,1H),3.46(s,2H),2.56(t,J=7.6Hz,2H),2.44(t,J=7.5Hz,2H),1.50-1.60(m,4H),1.27-1.37(m,12H),0.89(t,J=6.6Hz,3H),0.88(t,J=6.80Hz,3H);LRMS(ESI負模式):m/z 319(100%,M-Na+);UPLC(系統B):8.7分鐘。ULC系統B:移動相A=0.1%甲酸水溶液;移動相B=含0.1%甲酸之乙腈;固相=HSS T3管柱;梯度=含5-100% B之A,經10分鐘。
化合物5:2-(4-羥基-3,5-二戊基苯基)乙酸之鈉鹽
如關於化合物3所述自2-(3,5-二溴-4-羥基苯基)乙酸製備上述化合物。1H NMR(400MHz,CD3OD):δ 6.87(s,2H),3.33(s,2H),2.55(t,J=7.7Hz,4H),1.53-1.61(m,4H),1.31-1.37(m,8H),0.90(t,J=7.0Hz,6H);LRMS(ESI負模式):m/z 291.1(100%,M-Na+);UPLC(系統B):6.8分鐘。UPLC系統B:移動相A=0.1%甲酸水溶液;移動相B=含0.1%甲酸之乙腈;固相=HSS T3管柱;梯度=含5-100% B之A,經10分鐘。
化合物6:2-(3,5-二己基-4-羥基苯基)乙酸之鈉鹽
如關於化合物3所述自2-(3,5-二溴-4-羥基苯基)乙酸及(E)-己-1-烯基硼酸頻哪醇酯製備上述化合物。1H NMR(400MHz,CD3OD):δ
6.72(d,J=2.0Hz,1H),6.69(d,J=2.0Hz,1H),3.46(s,2H),2.56(t,J=7.6Hz,2H),2.44(t,J=7.5Hz,2H),1.50-1.60(m,4H),1.27-1.37(m,12H),0.89(t,J=6.6Hz,3H),0.88(t,J=6.8Hz,3H);LRMS(ESI負模式):m/z 319.1(100%,M-Na+);UPLC(系統B):7.6分鐘。UPLC系統B:移動相A=0.1%甲酸水溶液;移動相B=含0.1%甲酸之乙腈;固相=HSS T3管柱;梯度=含5-100% B之A,經10分鐘。
化合物7:2-(4-氟-3,5-二己基苯基)乙酸之鈉鹽
如關於化合物3所述以3,5-二溴-4-氟苄基溴及(E)-己-1-烯基硼酸頻哪醇酯為起始物質來製備上述化合物。藉由在80℃下于乙腈中用N-溴代丁二醯亞胺及偶氮雙異丁腈使3,5-二溴-4-氟甲苯溴化來製備3,5-二溴-4-氟苄基溴。1H NMR(400MHz,CD3OD):δ 6.98(d,J HF=7.0Hz,2H),3.38(s,2H),2.57(t,J=7.7Hz,4H),1.54-1.61(m,4H),1.28-1.37(m,12H),0.89(t,J=6.7Hz,6H);19F NMR(377MHz,CD3OD):δ -132.17(d,J HF=6.6Hz,1F);13C NMR(101MHz,CD3OD):δ 179.44,158.11(d,J CF=239.8Hz),133.26(d,J CF=3.8Hz),128.73(d,J CF=5.4Hz),128.56(d,J CF=16.9Hz),44.52,31.69,30.35(d,J CF=1.5Hz),28.98,28.97(d,J CF=3.1Hz),22.51,13.29;LRMS(ESI負模式):m/z 321.0(100%,M-Na+);UPLC(系統B):9.2分鐘。UPLC系統B:移動相A=0.1%甲酸水溶液;移動相B=含0.1%甲酸之乙腈;固相=HSS T3管柱;梯度=含5-100% B之A,經10分鐘。
化合物8:2-(4-氟-3,5-二戊基苯基)乙酸之鈉鹽
如關於化合物3所述以3,5-二溴-4-氟苄基溴為起始物質來製備上述化合物。1H NMR(400MHz,CD3OD):δ 6.98(d,J HF=6.8Hz,2H),3.37(s,2H),2.57(t,J=7.6Hz,4H),1.54-1.62(m,4H),1.28-1.37(m,8H),0.90
(t,J=7.0Hz,6H);19F NMR(377MHz,CD3OD):δ -132.34(d,J HF=6.6Hz,1F);13C NMR(101MHz,CD3OD):δ 179.41,158.10(d,J CF=239.8Hz),133.26(d,J CF=3.8Hz),128.72(d,J CF=4.6Hz),128.56(d,J CF=16.9Hz),44.51,31.54,30.07,28.92(d,J CF=3.1Hz),22.38,13.22;LRMS(ESI負模式):m/z 293.0(100%,M-Na+);UPLC(系統B):8.4分鐘。UPLC系統B:移動相A=0.1%甲酸水溶液;移動相B=含0.1%甲酸之乙腈;固相=HSS T3管柱;梯度=含5-100% B之A,經10分鐘。
纖維化為特徵在於細胞外基質(ECM)過度積聚從而導致所涉及組織變硬及/或瘢痕形成的慢性及進行性過程。其經由複雜細胞、細胞外基質、細胞介素及生長因子相互作用而發展。涉及到不同的細胞類型,諸如常駐間質細胞(纖維母細胞及肌纖維母細胞)及源自上皮及內皮細胞之ECM產生細胞(經由稱為上皮-間質轉化及內皮-間質轉化之過程)、局部或骨髓源幹細胞(纖維細胞)。肌纖維母細胞長久以來已被視為正常傷口癒合中所涉及之主要細胞類型,且作為纖維生成之關鍵效應細胞。其可高度合成膠原及其他ECM組分,且特徵為α-平滑肌肌動蛋白(α-SMA)之重新表現(評述於Scotton C.J.及Chambers R.C.,2007中)。纖維化動物模型中之纖維變性病變中肌纖維母細胞的存在與活性纖維化之發展有關,且其持續存在及對於人類疾病中纖維變性位點之定位與疾病進展有關(Kuhn C.及McDonald J.A.,1991;及Zhang等人,1994)。肌纖維母細胞亦展現增強之遷移表现型(Suganuma等人,1995)且能夠釋放眾多促纖維變性介體。
在纖維母細胞中,已進行分析來測定較佳之本發明化合物對正常大鼠腎纖維母細胞(NRK-49F)上TGF-β誘導之α-SMA(纖維化標誌物)mRNA表現的影響。NRK-49F以濃度為10ng/ml之TGF-β處理且變得活化(肌纖維母細胞)並表現α-SMA。藉由定量即時PCR測定促纖維變性標誌物α-SMA之表現。如表2中所示,本發明化合物在TGF-β誘導之NRK-49F細胞中抑制α-SMA的表現。
在組織損傷期間導致器官纖維化(膠原、彈性蛋白、細胞黏合素(tenacin)及其他基質分子之沈積)之EMT作用變得日益清晰。關於與進行性腎臟疾病、肺、皮膚、心臟以及肝臟相關之EMT存在大量此種證據。舉例而言,在腎臟中,新興證據表明,腎小管上皮細胞可在病理條件下經歷上皮-間質轉化(EMT)而變為產生基質之纖維母細胞(Strutz F.,Müller G.A.,2000;及Yang J.,Liu Y.,2001)。此表现型轉化不僅說明成熟的分化腎上皮細胞之顯著塑性,且亦在根本上牽涉於廣泛多種慢性腎病之發病機制中(Iwano M.等人,2002;Yang J.等人,2002;Zeisberg M.等人,2001;及Yang J.,Liu Y.,2002)。近來之研究提供令人信服之證據表明,纖維變性之腎臟中很大比例之間質纖維母細胞經由EMT源自腎小管上皮細胞(Iwano M.等人,2002)。同樣,腎小管EMT之選擇性阻斷由於在tPA-/-小鼠中保持了腎小管基底膜完整性而保護腎臟免於在阻塞性損傷後產生纖維變性病變(Yang J.等人,2002)。此等觀測結果強調腎小管EMT在慢性腎纖維化(其最終導致末期腎衰竭)之發作及進展中的關鍵重要性。在不同的試管內及活體內模型中,已表明若干因子為EMT之潛在起始劑(Yang J,Liu Y.,2001;Kalluri R.,Neilson E.G.,2003;Okada H.等人,1997;Fan J.M.等人,2001;Strutz F.等人,2002;Ha H.,Lee H.B.,2003;Lan H.Y.,2003;Lee J.M.等人,2006;及Zavadil J.,Böttinger E.P.,2005)。除CTGF之外,此等介體各自需要誘導TGF-β以完成EMT過程(Yang J.,Liu Y.,2001;Liu Y.,2004;及Lan H.Y.,2003)。
在上皮細胞中,進行分析以測定本發明化合物對人類近端腎
小管上皮細胞(HK-2)上TGF-β誘導之膠原1(纖維化標誌物)的影響。HK-2細胞為來自人類腎臟之永生化近端腎小管上皮細胞,用濃度為10ng/mL之TGF-β處理,藉由定量即時PCR測定促纖維變性標誌物膠原1之表現。如表3中所示,化合物1及2抑制TGF-β誘導之HK-2細胞中膠原之表現。
亦使用正常人類皮膚纖維母細胞(NHDF)研究本發明化合物1對皮膚纖維化之作用。
進行試管內分析以測定化合物I對正常人類皮膚纖維母細胞(NHDF)上TGF-β誘導之CTGF及α-SMA(纖維化標誌物)的影響。藉由定量即時PCR測定促纖維變性標誌物(CTGF)及纖維變性標誌物
(α-SMA)之表現。如表4中所示,化合物1對α-SMA及CTGF之mRNA之表現的抑制率分別為99%及85%。
小鼠或大鼠中之典型的腎纖維化實驗模型包括db/db腎病小鼠(糖尿病性腎病模型)且反映在人類中觀測到之腎病。在db/db小鼠模型中評估化合物1對糖尿病性腎病之作用。簡言之,在第0天進行右腎完全切除術,自第1天起用媒劑或化合物1(10mg/kg及50mg/kg,每天一次經口)處理db/db小鼠(6周齡)且在第119天量測腎小球濾過率(GFR)作為腎功能之直接量度。圖1展示db/db糖尿病小鼠相比於C57BL/6小鼠(對照小鼠)之GFR降低,明確顯示與糖尿病相關之腎病。用10mg/kg及50mg/kg經口處理使腎臟GFR功能增加至正常(C57BL/6)小鼠水準,如圖1中所示。此結果明確指示,用化合物1處理減少糖尿病db/db小鼠之腎臟的腎病及纖維化。
本文提及或引用之所有專利、專利申請案、臨時申請案及公開案皆以全文引用之方式併入,包括所有圖式及表格,引用程度使得其與本說明書之明確教示不一致。
應理解,本文所述之實施例及實施方案僅為說明性目的且根據其之各種修改或變化應為熟習此項技術者所想到且包括於本申請案之精神及範圍內。
Claims (26)
- 如申請專利範圍第1項之鹽,其中該化合物之醫藥學上可接受之鹽為鈉鹽、鉀鹽、鋰鹽、銨鹽、鈣鹽、鎂鹽、錳鹽、鋅鹽、鐵鹽或銅鹽。
- 如申請專利範圍第2項之鹽,其中該化合物之醫藥學上可接受之鹽為鈉鹽。
- 如申請專利範圍第4項之化合物,其中該化合物為化合物1至8之一者。
- 一種治療有效量之由下式表示之化合物或其醫藥學上可接受之鹽於製造藥物上的用途,該藥物是用於減少細胞中之膠原產生:
- 如申請專利範圍第6項之用途,其中係使用該化合物之醫藥學上可接受之鹽。
- 一種治療有效量之由下式表示之化合物或其醫藥學上可接受之鹽於製造藥物上的用途,該藥物是用於在有需要之個體中預防纖維化及/或減緩纖維化之進展及/或治療纖維化:
- 如申請專利範圍第8項之用途,其中係使用該化合物之醫藥學上可接受之鹽。
- 如申請專利範圍第8項之用途,其中該纖維變性疾病為肺纖維化、肝纖 維化、皮膚纖維化、腎纖維化、胰纖維化、全身性硬化、心臟纖維化或黃斑變性。
- 如申請專利範圍第8項之用途,其中該治療有效量為1至50mg/kg之間,該化合物係經口投予,且該個體為人類。
- 如申請專利範圍第11項之用途,其中該治療有效量為1至20mg/kg之間。
- 如申請專利範圍第10項之用途,其中該肺纖維化為特發性肺纖維化、肉狀瘤病、囊腫性纖維化、家族性肺纖維化、矽肺病、石綿沈著病、煤礦工人塵肺病、碳塵肺病、過敏性肺炎、由吸入無機粉塵引起之肺纖維化、由感染物引起之肺纖維化、由吸入有毒氣體、氣溶膠、化學粉塵、煙霧或蒸氣引起之肺纖維化、藥物誘發之間質性肺病、肺性高血壓或慢性阻塞性肺病。
- 如申請專利範圍第10項之用途,其中該肝纖維化由慢性肝病、B型肝炎病毒感染、C型肝炎病毒感染、D型肝炎病毒感染、血吸蟲病、酒精性肝病或非酒精性脂肪肝炎、肥胖症、糖尿病、蛋白質營養不良、冠狀動脈疾病、自體免疫肝炎、囊腫性纖維化、α-1-抗胰蛋白酶缺乏症、原發性膽汁性肝硬化、藥物反應及暴露於毒素引起。
- 如申請專利範圍第10項之用途,其中該皮膚纖維化為瘢痕形成、增生性瘢痕形成、瘢痕瘤、皮膚纖維變性病症、傷口癒合、傷口延遲癒合、牛皮癬或硬皮病。
- 如申請專利範圍第15項之用途,其中該瘢痕形成源自燒傷、創傷、手 術損傷、輻射或潰瘍。
- 如申請專利範圍第16項之用途,其中該潰瘍為糖尿病性足潰瘍、靜脈性腿潰瘍或壓力性潰瘍。
- 如申請專利範圍第10項之用途,其中該腎纖維化由腎衰竭後之透析、導管置放、腎病、腎小球硬化、腎小球腎炎、慢性腎功能不全、急性腎損傷、慢性腎病、末期腎病或腎衰竭引起。
- 一種治療有效量之由下式表示之化合物或其醫藥學上可接受之鹽於製造藥物上的用途,該藥物是用於在有需要之哺乳動物之器官中拮抗膠原分泌或膠原沈積,其中該器官為肺、肝臟、腎臟、胰臟、皮膚或心臟:
- 如申請專利範圍第19項之用途,其中係使用該化合物之醫藥學上可接受之鹽。
- 如申請專利範圍第6項至第20項中任一項之用途,其中該化合物與治療有效量之第二化合物組合投予,該第二化合物為免疫抑制藥物、消炎藥物、細胞介素、單株抗體、多重受體酪胺酸激酶抑制劑、抗氧化劑、酶抑制劑、整合素抑制劑、高血壓抑制劑、脂質受體調節劑或抗糖尿病藥物。
- 一種用於在有需要之個體中預防纖維變性疾病及/或減緩纖維變性疾病之進展及/或治療纖維變性疾病的套組,其包含由下式表示之化合物:
- 如申請專利範圍第22項之套組,其中該纖維變性疾病為肺纖維化、肝纖維化、皮膚纖維化、腎纖維化、胰纖維化、全身性硬化、心臟纖維化或黃斑變性。
- 如申請專利範圍第22項之套組,其進一步包含關於向人類個體每天經口投予約1至約50mg/kg之間之該化合物的說明書。
- 如申請專利範圍第23項之套組,其進一步包含關於向人類個體每天經局部投予約0.01%至約10%(w/w)之該化合物的說明書,且其中該纖維變性疾病為皮膚纖維化。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201361798269P | 2013-03-15 | 2013-03-15 | |
US61/798,269 | 2013-03-15 |
Publications (2)
Publication Number | Publication Date |
---|---|
TW201441186A TW201441186A (zh) | 2014-11-01 |
TWI689490B true TWI689490B (zh) | 2020-04-01 |
Family
ID=51535669
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW103108723A TWI689490B (zh) | 2013-03-15 | 2014-03-12 | 用於治療纖維化之經取代之芳族化合物及相關方法 |
Country Status (26)
Country | Link |
---|---|
US (3) | US10023518B2 (zh) |
EP (1) | EP2970089B1 (zh) |
JP (1) | JP6448562B2 (zh) |
KR (1) | KR102196721B1 (zh) |
CN (2) | CN105189438A (zh) |
AR (1) | AR095429A1 (zh) |
AU (1) | AU2014231648B2 (zh) |
BR (1) | BR112015022008A2 (zh) |
CA (1) | CA2905621C (zh) |
CL (1) | CL2015002535A1 (zh) |
DK (1) | DK2970089T3 (zh) |
EA (1) | EA030651B1 (zh) |
ES (1) | ES2741439T3 (zh) |
HK (1) | HK1220440A1 (zh) |
IL (1) | IL241178B (zh) |
MX (1) | MX2015011878A (zh) |
MY (1) | MY180305A (zh) |
NZ (1) | NZ712797A (zh) |
PH (1) | PH12015502011A1 (zh) |
PL (1) | PL2970089T3 (zh) |
PT (1) | PT2970089T (zh) |
SG (1) | SG11201507408XA (zh) |
TW (1) | TWI689490B (zh) |
UY (1) | UY35402A (zh) |
WO (1) | WO2014138906A1 (zh) |
ZA (1) | ZA201507061B (zh) |
Families Citing this family (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP6437452B2 (ja) | 2013-01-14 | 2018-12-12 | インサイト・ホールディングス・コーポレイションIncyte Holdings Corporation | Pimキナーゼ阻害剤として有用な二環式芳香族カルボキサミド化合物 |
ME03780B (me) | 2013-01-15 | 2021-04-20 | Incyte Holdings Corp | Jedinjenja tiazolkarboksamida i piridinkarboksamida korisna kao inhibitori pim kinaze |
TWI742541B (zh) * | 2013-03-15 | 2021-10-11 | 英商邊緣生物科技有限公司 | 用於治療肺纖維化、肝纖維化、皮膚纖維化及心臟纖維化之經取代之芳族化合物 |
WO2015027124A1 (en) | 2013-08-23 | 2015-02-26 | Incyte Corporation | Furo- and thieno-pyridine carboxamide compounds useful as pim kinase inhibitors |
US9580418B2 (en) | 2014-07-14 | 2017-02-28 | Incyte Corporation | Bicyclic aromatic carboxamide compounds useful as Pim kinase inhibitors |
US9822124B2 (en) | 2014-07-14 | 2017-11-21 | Incyte Corporation | Bicyclic heteroaromatic carboxamide compounds useful as Pim kinase inhibitors |
CN106999456B (zh) * | 2014-10-10 | 2020-07-10 | 里米诺生物科学有限公司 | 用于预防和治疗骨质疏松症的被取代的芳族化合物和药物组合物 |
EP3203998B1 (en) * | 2014-10-10 | 2021-03-10 | Liminal Biosciences Limited | Substituted aromatic compounds and pharmaceutical compositions for the prevention and treatment of diabetes |
WO2016074068A1 (en) | 2014-11-12 | 2016-05-19 | Prometic Biosciences Inc. | Substituted aromatic compounds and pharmaceutical compositions for tissue self-repair and regeneration |
NZ736165A (en) * | 2015-03-18 | 2022-07-01 | Vectus Biosystems Ltd | Compositions for the treatment of kidney and/or liver disease |
US9540347B2 (en) | 2015-05-29 | 2017-01-10 | Incyte Corporation | Pyridineamine compounds useful as Pim kinase inhibitors |
AR105967A1 (es) | 2015-09-09 | 2017-11-29 | Incyte Corp | Sales de un inhibidor de pim quinasa |
TW201718546A (zh) | 2015-10-02 | 2017-06-01 | 英塞特公司 | 適用作pim激酶抑制劑之雜環化合物 |
US20190144547A1 (en) * | 2015-11-23 | 2019-05-16 | Merck Patent Gmbh | Anti-alpha-v integrin antibody for the treatment of fibrosis and/or fibrotic disorders |
WO2017198114A1 (zh) * | 2016-05-19 | 2017-11-23 | 长弘生物科技股份有限公司 | 用于延缓肺纤维化的发病及/或治疗肺纤维化的药剂 |
TW202123963A (zh) | 2016-12-15 | 2021-07-01 | 大陸商深圳瑞健生命科學研究院有限公司 | 一種治療冠狀動脈粥樣硬化及其併發症的方法 |
US10596161B2 (en) | 2017-12-08 | 2020-03-24 | Incyte Corporation | Low dose combination therapy for treatment of myeloproliferative neoplasms |
KR102126389B1 (ko) * | 2018-09-14 | 2020-06-25 | 셀라이온바이오메드 주식회사 | 벤즈히드릴티오 아세트아미드 화합물을 유효성분으로 포함하는 간 질환의 예방 또는 치료용 조성물 |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020183519A1 (en) * | 2001-03-13 | 2002-12-05 | Herbert Nar | Antithrombotic carboxylic acid amides |
WO2007140189A2 (en) * | 2006-05-26 | 2007-12-06 | Auspex Pharmaceuticals, Inc. | Preparation and utility of substituted carboxylic acid compounds |
MX340993B (es) * | 2007-02-08 | 2016-08-02 | Emisphere Tech Inc * | Agentes de suministro de acido fenilalquilcarboxilico. |
DK2427416T3 (en) * | 2009-05-04 | 2016-06-13 | Prometic Pharma Smt Ltd | Substituted aromatic compounds, and pharmaceutical uses thereof |
US8637574B2 (en) * | 2009-05-04 | 2014-01-28 | Prometic Biosciences, Inc. | Salts of 3-pentylphenylacetic acid and pharmaceutical uses thereof |
AT509045B1 (de) * | 2010-01-29 | 2011-06-15 | Planta Naturstoffe Vertriebsges M B H | Verbindungen zur behandlung von asthma bronchiale |
-
2014
- 2014-03-12 TW TW103108723A patent/TWI689490B/zh not_active IP Right Cessation
- 2014-03-13 UY UY0001035402A patent/UY35402A/es not_active Application Discontinuation
- 2014-03-13 AR ARP140100973A patent/AR095429A1/es unknown
- 2014-03-14 US US14/776,328 patent/US10023518B2/en active Active
- 2014-03-14 BR BR112015022008-8A patent/BR112015022008A2/pt active Search and Examination
- 2014-03-14 WO PCT/CA2014/000236 patent/WO2014138906A1/en active Application Filing
- 2014-03-14 JP JP2015561849A patent/JP6448562B2/ja active Active
- 2014-03-14 MX MX2015011878A patent/MX2015011878A/es unknown
- 2014-03-14 PL PL14764458T patent/PL2970089T3/pl unknown
- 2014-03-14 EA EA201591775A patent/EA030651B1/ru not_active IP Right Cessation
- 2014-03-14 PT PT14764458T patent/PT2970089T/pt unknown
- 2014-03-14 DK DK14764458.7T patent/DK2970089T3/da active
- 2014-03-14 CA CA2905621A patent/CA2905621C/en active Active
- 2014-03-14 MY MYPI2015002293A patent/MY180305A/en unknown
- 2014-03-14 NZ NZ712797A patent/NZ712797A/en not_active IP Right Cessation
- 2014-03-14 EP EP14764458.7A patent/EP2970089B1/en active Active
- 2014-03-14 KR KR1020157029293A patent/KR102196721B1/ko active IP Right Grant
- 2014-03-14 ES ES14764458T patent/ES2741439T3/es active Active
- 2014-03-14 CN CN201480013578.9A patent/CN105189438A/zh active Pending
- 2014-03-14 CN CN201910355464.7A patent/CN110105200B/zh not_active Expired - Fee Related
- 2014-03-14 AU AU2014231648A patent/AU2014231648B2/en not_active Ceased
- 2014-03-14 SG SG11201507408XA patent/SG11201507408XA/en unknown
-
2015
- 2015-09-03 IL IL241178A patent/IL241178B/en active IP Right Grant
- 2015-09-09 PH PH12015502011A patent/PH12015502011A1/en unknown
- 2015-09-09 CL CL2015002535A patent/CL2015002535A1/es unknown
- 2015-09-22 ZA ZA2015/07061A patent/ZA201507061B/en unknown
-
2016
- 2016-07-15 HK HK16108391.0A patent/HK1220440A1/zh unknown
-
2018
- 2018-04-04 US US15/945,408 patent/US10550066B2/en not_active Expired - Fee Related
-
2020
- 2020-02-03 US US16/780,316 patent/US11524930B2/en active Active
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI689490B (zh) | 用於治療纖維化之經取代之芳族化合物及相關方法 | |
TWI689489B (zh) | 用於治療肺纖維化、肝纖維化、皮膚纖維化及心臟纖維化之經取代之芳族化合物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MM4A | Annulment or lapse of patent due to non-payment of fees |