WO1998007321A1 - Method for inhibiting the expression of fas - Google Patents
Method for inhibiting the expression of fas Download PDFInfo
- Publication number
- WO1998007321A1 WO1998007321A1 PCT/US1997/014792 US9714792W WO9807321A1 WO 1998007321 A1 WO1998007321 A1 WO 1998007321A1 US 9714792 W US9714792 W US 9714792W WO 9807321 A1 WO9807321 A1 WO 9807321A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- carbon atoms
- hydrogen
- lower alkyl
- adrenoceptor
- oxygen
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 33
- 230000002401 inhibitory effect Effects 0.000 title claims abstract description 23
- 150000001875 compounds Chemical class 0.000 claims abstract description 70
- 102000015005 beta-adrenergic receptor activity proteins Human genes 0.000 claims abstract description 35
- 108040006818 beta-adrenergic receptor activity proteins Proteins 0.000 claims abstract description 35
- 230000009977 dual effect Effects 0.000 claims abstract description 34
- 241000124008 Mammalia Species 0.000 claims abstract 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 198
- 229910052739 hydrogen Inorganic materials 0.000 claims description 110
- 239000001257 hydrogen Substances 0.000 claims description 110
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 110
- 125000000217 alkyl group Chemical group 0.000 claims description 88
- 229910052760 oxygen Inorganic materials 0.000 claims description 45
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 44
- 239000001301 oxygen Substances 0.000 claims description 44
- 229960004195 carvedilol Drugs 0.000 claims description 34
- 239000000674 adrenergic antagonist Substances 0.000 claims description 26
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 23
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 22
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 22
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 22
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 22
- 125000003545 alkoxy group Chemical group 0.000 claims description 22
- 125000004414 alkyl thio group Chemical group 0.000 claims description 22
- 125000003435 aroyl group Chemical group 0.000 claims description 22
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 22
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 22
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 22
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 22
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 22
- 229910052794 bromium Inorganic materials 0.000 claims description 22
- 125000001589 carboacyl group Chemical group 0.000 claims description 22
- 239000000460 chlorine Substances 0.000 claims description 22
- 229910052801 chlorine Inorganic materials 0.000 claims description 22
- 239000011737 fluorine Substances 0.000 claims description 22
- 229910052731 fluorine Inorganic materials 0.000 claims description 22
- 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 claims description 22
- 125000001624 naphthyl group Chemical group 0.000 claims description 22
- 125000004344 phenylpropyl group Chemical group 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 22
- 229910052717 sulfur Inorganic materials 0.000 claims description 22
- 239000011593 sulfur Substances 0.000 claims description 22
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 claims description 22
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 21
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 21
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 21
- -1 methylenedioxy Chemical group 0.000 claims description 18
- 230000006907 apoptotic process Effects 0.000 claims description 16
- 239000005557 antagonist Substances 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 8
- 230000001404 mediated effect Effects 0.000 claims description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 230000005764 inhibitory process Effects 0.000 claims description 6
- 208000028867 ischemia Diseases 0.000 claims description 6
- 208000023275 Autoimmune disease Diseases 0.000 claims description 5
- 230000000903 blocking effect Effects 0.000 claims description 5
- 201000010099 disease Diseases 0.000 claims description 5
- 210000002064 heart cell Anatomy 0.000 claims description 5
- 230000007838 tissue remodeling Effects 0.000 claims description 5
- 206010027476 Metastases Diseases 0.000 claims description 4
- 230000009401 metastasis Effects 0.000 claims description 4
- 230000004614 tumor growth Effects 0.000 claims description 4
- NPAKNKYSJIDKMW-UHFFFAOYSA-N carvedilol Chemical compound COC1=CC=CC=C1OCCNCC(O)COC1=CC=CC2=NC3=CC=C[CH]C3=C12 NPAKNKYSJIDKMW-UHFFFAOYSA-N 0.000 claims 10
- 238000004519 manufacturing process Methods 0.000 claims 5
- 239000002876 beta blocker Substances 0.000 abstract description 2
- 239000000951 adrenergic alpha-1 receptor antagonist Substances 0.000 abstract 1
- OGHNVEJMJSYVRP-UHFFFAOYSA-N carvedilol Chemical compound COC1=CC=CC=C1OCCNCC(O)COC1=CC=CC2=C1C1=CC=CC=C1N2 OGHNVEJMJSYVRP-UHFFFAOYSA-N 0.000 description 26
- 210000004027 cell Anatomy 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 0 C*1(C)c2cccc(OCC(*)C*C(*)C*N(*)*)c2-c2c1cccc2 Chemical compound C*1(C)c2cccc(OCC(*)C*C(*)C*N(*)*)c2-c2c1cccc2 0.000 description 5
- 210000004413 cardiac myocyte Anatomy 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 210000005003 heart tissue Anatomy 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 235000002639 sodium chloride Nutrition 0.000 description 4
- 102000004127 Cytokines Human genes 0.000 description 3
- 108090000695 Cytokines Proteins 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 210000004204 blood vessel Anatomy 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 210000002216 heart Anatomy 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 230000010410 reperfusion Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 2
- 241000283707 Capra Species 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- 108060003951 Immunoglobulin Proteins 0.000 description 2
- 240000007472 Leucaena leucocephala Species 0.000 description 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
- 108010052285 Membrane Proteins Proteins 0.000 description 2
- 102000018697 Membrane Proteins Human genes 0.000 description 2
- 230000001594 aberrant effect Effects 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 230000003276 anti-hypertensive effect Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 102000018358 immunoglobulin Human genes 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000000302 ischemic effect Effects 0.000 description 2
- 239000012669 liquid formulation Substances 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
- 238000012423 maintenance Methods 0.000 description 2
- 238000003801 milling Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- 230000004770 neurodegeneration Effects 0.000 description 2
- 208000015122 neurodegenerative disease Diseases 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- HSTOKWSFWGCZMH-UHFFFAOYSA-N 3,3'-diaminobenzidine Chemical compound C1=C(N)C(N)=CC=C1C1=CC=C(N)C(N)=C1 HSTOKWSFWGCZMH-UHFFFAOYSA-N 0.000 description 1
- 108060003345 Adrenergic Receptor Proteins 0.000 description 1
- 102000017910 Adrenergic receptor Human genes 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 102000015212 Fas Ligand Protein Human genes 0.000 description 1
- 108010039471 Fas Ligand Protein Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 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 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 235000010676 Ocimum basilicum Nutrition 0.000 description 1
- 240000007926 Ocimum gratissimum Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 102000003992 Peroxidases Human genes 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 230000010782 T cell mediated cytotoxicity Effects 0.000 description 1
- 208000001871 Tachycardia Diseases 0.000 description 1
- 102100031988 Tumor necrosis factor ligand superfamily member 6 Human genes 0.000 description 1
- 108050002568 Tumor necrosis factor ligand superfamily member 6 Proteins 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 1
- PASHVRUKOFIRIK-UHFFFAOYSA-L calcium sulfate dihydrate Chemical compound O.O.[Ca+2].[O-]S([O-])(=O)=O PASHVRUKOFIRIK-UHFFFAOYSA-L 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 230000005713 exacerbation Effects 0.000 description 1
- 108010052621 fas Receptor Proteins 0.000 description 1
- 102000018823 fas Receptor Human genes 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 238000012735 histological processing Methods 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000008105 immune reaction Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000007257 malfunction Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229940071648 metered dose inhaler Drugs 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 210000000107 myocyte Anatomy 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 230000036513 peripheral conductance Effects 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000011555 rabbit model Methods 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 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
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 206010042772 syncope Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000759 toxicological effect Toxicity 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
Definitions
- the present invention relates to a new method of treatment using compounds which are dual non-selective ⁇ -adrenoceptor and ⁇ -adrenoceptor antagonists, in particular the carbazolyl-(4)-oxypropanola ⁇ une compounds of
- Formula I preferably carvedilol, for inhibiting the expression of Fas, a cell surface protein
- Fas ligand is a cytokine It is one of the few known cytokines that is a death factor This ligand binds to its receptor, Fas, a cell-surface protein, and induces apoptosis (cell death).
- FasL Fas ligand
- Many tissues and cell lines weakly express Fas, but abundant expression has been found in mouse heart, liver, lung, kidney, ovary and thymus (R. Watanabe-Fukunaga, et al., J.
- Fas and FasL are involved in down-regulation of immune reactions as well as in T cell-mediated cytotoxicity. Malfunction of the Fas system causes lymphoprohferative disorders and accelerates autoimmune diseases, whereas its exacerbation may cause tissue destruction (S. Nagata, et al., Science, 267, 1449- 1456 ( 1995)).
- carvedilol a dual non-selective ⁇ - adrenoceptor and c -adrenoceptor antagonist, inhibits the expression of Fas.
- This inhibition may mean that carvedilol and related Formula I compounds are useful for diseases wherein inhibition of Fas-mediated apoptosis is indicated Particularly, thus inhibition may mean that carvedilol and related Formula I compounds are useful for blocking ischemia-induced apoptosis in cardiac cells, for preventing or inhibiting tissue remodeling, in particular in cardiac tissue and blood vessels, for treating autoimmune diseases, and for inhibiting tumor growth and metastasis Summary of the Invention
- the present invention relates to a new method of treatment using compounds which are dual non-selective ⁇ -adrenoceptor and cq -adrenoceptor antagonists, in particular the carbazolyl-(4)-oxypropanolamine compounds of
- Formula I preferably carvedilol, for inhibiting the expression of Fas.
- the invention also relates to a method of treatment using compounds which are dual non-selective ⁇ -adrenoceptor and cq -adrenoceptor antagonists, in particular the carbazolyl-(4)- oxypropanolamine compounds of Formula I, preferably carvedilol, for inhibiting apoptosis.
- this invention relates to a method of treatment using compounds which are dual non-selective ⁇ -adrenoceptor and cq -adrenoceptor antagonists, in particular the carbazolyl-(4)-oxypropanolamine compounds of Formula I, preferably carvedilol, for diseases wherein inhibition of Fas-mediated apoptosis is indicated.
- this invention is directed to the use of Formula I compounds, preferably carvedilol, to specifically induce Fas-mediated apoptosis of undesirable cells, such as cancer or autoreactive immune cells.
- the Formula I compounds, preferably carvedilol are used to prevent cell depletion in AIDS or neurodegenerative diseases.
- This invention also relates to a method of treatment using compounds which are dual non-selective ⁇ -adrenoceptor and cq -adrenoceptor antagonists, in particular the carbazolyl-(4)-oxypropanolamine compounds of Formula I, preferably carvedilol, for preventing or inhibiting tissue remodeling, in particular in cardiac tissue and blood vessels.
- the present method includes the use of compounds which are dual non-selective ⁇ -adrenoceptor and cq -adrenoceptor antagonists, in particular the carbazolyl-(4)-oxypropanolamine compounds of Formula I, preferably carvedilol, to block ischemia-induced apoptosis in cardiac cells.
- Fas using compounds which are dual non-selective ⁇ -adrenoceptor and cq- adrenoceptor antagonists Preferably, this invention provides a new method for inhibiting the expression of Fas using compounds of Formula I:
- R7-R13 are independently -H or-OH; and A is a moiety of Formula II:
- R* is hydrogen, lower alkanoyl of up to 6 carbon atoms or aroyl selected from benzoyl and naphthoyl;
- R2 is hydrogen, lower alkyl of up to 6 carbon atoms or arylalkyl selected from benzyl, phenylethyl and phenylpropyl;
- R3 is hydrogen or lower alkyl of up to 6 carbon atoms
- R4 is hydrogen or lower alkyl of up to 6 carbon atoms, or when X is oxygen, R4 together with R5 can represent -CH2-O-
- X is a single bond, -CH2, oxygen or sulfur;
- Ar is selected from phenyl, naphthyl, indanyl and tetrahydronaphthyl; R5 and R ⁇ are individually selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, lower alkyl of up to 6 carbon atoms, a
- R5 and Rg together represent methylenedioxy; and pharmaceutically acceptable salts thereof.
- the present invention provides a new method for inhibiting the expression of Fas using compounds of Formula III:
- Rj is hydrogen, lower alkanoyl of up to 6 carbon atoms or aroyl selected from benzoyl and naphthoyl;
- R2 is hydrogen, lower alkyl of up to 6 carbon atoms or arylalkyl selected from benzyl, phenylethyl and phenylpropyl;
- R3 is hydrogen or lower alkyl of up to 6 carbon atoms
- R4 is hydrogen or lower alkyl of up to 6 carbon atoms, or when X is oxygen, R4 together with R5 can represent -CH2-O-
- X is a single bond, -CH2, oxygen or sulfur;
- AT is selected from phenyl, naphthyl, indanyl and tetrahydronaphthyl; R5 and R are individually selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, lower alkyl of up to 6 carbon atoms, a -
- CONH2- group lower alkoxy of up to 6 carbon atoms, benzyloxy, lower alkylthio of up to 6 carbon atoms, lower alkysulphinyl of up to 6 carbon atoms and lower alkylsulphonyl of up to 6 carbon atoms; or R5 and Rg together represent methylenedioxy; and pharmaceutically acceptable salts thereof.
- the present invention provides a new method for inhibiting the expression of Fas using a compound of Formula IV, better known as carvedilol or ( 1 -(carbazol-4-yloxy-3-[[2-(o-methoxyphenoxy)ethyl]amino]-2-propanol):
- the compounds of the present invention are novel multiple action drugs useful in the treatment of mild to moderate hypertension.
- Carvedilol is known to be both a competitive non-selective ⁇ -adrenoceptor antagonist and a vasodilator, and is also a calcium channel antagonist at higher concentrations.
- the vasodilatory actions of carvedilol result primarily from o -adrenoceptor blockade, whereas the ⁇ -adrenoceptor blocking activity of the drug prevents reflex tachycardia when used in the treatment of hypertension.
- These multiple actions of carvedilol are responsible for the antihypertensive efficacy of the drug in animals, particularly in humans. See Willette, R.N., Sauermelch, C.F.
- the antihypertensive action of carvedilol is mediated primarily by decreasing total peripheral vascular resistance without causing the concomitant reflex changes in heart rate commonly associated with other antihypertensive agents.
- Carvedilol also markedly reduces infarct size in rat, canine and porcine models of acute myocardial infarction, Ruffolo, R.R., Jr., et al., Drugs of Today, supra, possibly as a consequence of its antioxidant action in attenuating oxygen free radical-initiated lipid peroxidation. Yue, T.-L., et al. supra.
- the compounds of Formula I preferably carvedilol
- the compounds of Formula I can be used to treat diseases wherein inhibition or control of Fas- mediated apoptosis is indicated.
- the compounds of the current invention preferably carvedilol
- the compounds of the current invention can be used for blocking ischemia-induced apoptosis in cardiac cells, for preventing or inhibiting tissue remodeling, in particular m cardiac tissue and blood vessels, for treating autoimmune diseases, and for inhibiting tumor growth and metastasis.
- the Formula I compounds, preferably carvedilol are used to prevent cell depletion in AIDS or neurodegenerative diseases.
- Some of the compounds of Formula I are known to be metabolites of carvedilol.
- Certain preferred compounds of the present invention that is, the compounds of Formula I wherein A is the moiety of Formula II wherein RI is -H, R2 is -H, R3 is -H, R4 is -H, X is O, Ar is phenyl, R5 is ortho -OH, and R6 is -H. and one of R7, R9, or R 10 is -OH, are metabolites of carvedilol.
- compositions of the compounds of Formula I may be administered to patients according to the present invention in any medically acceptable manner, preferably orally.
- the pharmaceutical composition will be in the form of a sterile injectable liquid stored in a suitable container such as an ampoule, or in the form of an aqueous or nonaqueous liquid suspension.
- suitable container such as an ampoule
- the nature and composition of the pharmaceutical carrier, diluent or excipient will, of course, depend on the intended route of administration, for example whether by intravenous or intramuscular injection
- Pharmaceutical compositions of the compounds of Formula I for use according to the present invention may be formulated as solutions or lyophilized powders for parenteral administration.
- Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use.
- the liquid formulation is generally a buffered, isotonic, aqueous solution.
- suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammonium acetate solution.
- Such formulation is especially suitable for parenteral administration, but may also be used for oral administration or contained in a metered dose inhaler or nebulizer for insufflation.
- excipients such as ethanol, polyvinyi-pyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
- these compounds may be encapsulated, tableted or prepared in a emulsion or syrup for oral administration.
- Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition.
- Liquid carriers include syrup, peanut oil, olive oil, glycerin, saline, ethanol, and water.
- Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin.
- the carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
- the amount of solid carrier varies but, preferably, will be between about 20 mg to about 1 g per dosage unit.
- the pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms.
- the preparation When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension Such a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule.
- Dosing in humans for the treatment of disease according to the present invention should not exceed a dosage range of from about 3 125 to about 50 mg of the compounds of Formula I, particularly carvedilol, preferably given twice daily
- the patient should be started on a low dosage regimen of the desired compound of Formula I, particularly carvedilol, and momtered for well-known symptoms of intolerance, e.g , fainting, to such compound.
- the patient should be brought slowly and incrementally up to the maintenance dose.
- the choice of initial dosage most approp ⁇ ate for the particular patient is determined by the practitioner using well-known medical principles, including, but not limited to, body weight.
- the dosage is doubled at the end of the two weeks and the patient is maintained at the new, higher dosage for two more weeks, and observed for signs of intolerance. This course is continued until the patient is brought to a maintenance dose
- compositions of this invention will vary according to the particular composition formulated, the mode of administration, the particular site of administration and the host being treated
- Heart tissue was fixed in NBF for 24-48 hr at 4 ⁇ C and cut longitudinally into 2-3 mm-thick piece. Following standard histological processing and embedding in paraffin, 5 ⁇ m-thick sections were prepared for immunoperoxidase staining using the Vectastain ABC kit (Vector Laboratories) according to the manufacturer's instructions. Briefly, endogenous peroxidase was quenched with 0.3% H2O2 in methanol for 30 minutes. Nonspecific immunoglobulin binding sites were blocked with normal goat serum for 1 hour and then the sections were incubated with the primary antibody (mouse anti-FAS, 2 ⁇ g/ml, Upstate Biotechnology) for 1 hour at room temperature.
- the primary antibody mouse anti-FAS, 2 ⁇ g/ml, Upstate Biotechnology
- the sections were then incubated for 30 minutes with a biotinylated goat anti-mouse IgM secondary antibody ( 1 :200, Vector Laboratories) followed by 30 minutes of incubation with the Vectastain ABC reagent solution. Immunoglobulin complexes were visualized upon incubation with 3,3'- diaminobenzidine (DAB, Vector Laboratories) at 0.5 mg ml in 50 rnM Tris-HCl, pH 7.4 and 3% H2O2. DAB staining was enhanced by treating the sections for 10 seconds with DAB Enhancing Solution (Vector Laboratories). Sections were washed, counterstained with Gill's Hematoxylin, cleared, mounted with Aquamount (Poly sciences), and then examined by light microscopy.
- DAB 3,3'- diaminobenzidine
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Oncology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Immunology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Separation By Low-Temperature Treatments (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Fats And Perfumes (AREA)
Abstract
Description
Claims
Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP97938525A EP0924985A4 (en) | 1996-08-23 | 1997-08-22 | Method for inhibiting the expression of fas |
AU40830/97A AU4083097A (en) | 1996-08-23 | 1997-08-22 | Method for inhibiting the expression of fas |
US09/242,595 US6096777A (en) | 1996-08-23 | 1997-08-22 | Method for inhibiting the expression of Fas |
JP51099998A JP2001504804A (en) | 1996-08-23 | 1997-08-22 | Method for inhibiting FAS expression |
BR9711228-3A BR9711228A (en) | 1996-08-23 | 1997-08-22 | Method for inhibiting the expression of fas |
CA002264178A CA2264178A1 (en) | 1996-08-23 | 1997-08-22 | Method for inhibiting the expression of fas |
NZ334307A NZ334307A (en) | 1996-08-23 | 1997-08-22 | Compounds for treating diseases wherein inhibition of Fas-mediated apoptosis is indicated |
IL12861397A IL128613A (en) | 1996-08-23 | 1997-08-22 | Dual non-selective beta-adrenoreceptor and alpha1-adrenoreceptor antagonist for inhibiting the expression of fas |
CZ99591A CZ59199A3 (en) | 1996-08-23 | 1997-08-22 | INHIBITION METHOD OF FaS EXPRESSION |
NO990792A NO990792L (en) | 1996-08-23 | 1999-02-19 | Method for inhibiting the expression of FAS |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US2448696P | 1996-08-23 | 1996-08-23 | |
US60/024,486 | 1996-08-23 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1998007321A1 true WO1998007321A1 (en) | 1998-02-26 |
Family
ID=21820837
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1997/014792 WO1998007321A1 (en) | 1996-08-23 | 1997-08-22 | Method for inhibiting the expression of fas |
Country Status (17)
Country | Link |
---|---|
US (1) | US6096777A (en) |
EP (1) | EP0924985A4 (en) |
JP (1) | JP2001504804A (en) |
KR (1) | KR20000068322A (en) |
CN (1) | CN1233150A (en) |
AU (1) | AU4083097A (en) |
BR (1) | BR9711228A (en) |
CA (1) | CA2264178A1 (en) |
CZ (1) | CZ59199A3 (en) |
HU (1) | HUP9904243A3 (en) |
IL (1) | IL128613A (en) |
NO (1) | NO990792L (en) |
NZ (1) | NZ334307A (en) |
PL (1) | PL331766A1 (en) |
TR (1) | TR199900370T2 (en) |
WO (1) | WO1998007321A1 (en) |
ZA (1) | ZA977565B (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004024145A1 (en) * | 2002-09-10 | 2004-03-25 | Dabur Research Foundation | Anti-cancer activity of carvedilol and its isomers |
WO2007042912A2 (en) * | 2005-10-13 | 2007-04-19 | Orchid Research Laboratories Limited | Heterocyclic compounds as pstat3/il-6 inhibitors |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8101209B2 (en) | 2001-10-09 | 2012-01-24 | Flamel Technologies | Microparticulate oral galenical form for the delayed and controlled release of pharmaceutical active principles |
AU2003231283A1 (en) * | 2002-04-30 | 2003-11-17 | Sb Pharmco Puerto Rico Inc. | Carvedilol monocitrate monohydrate |
WO2004002472A1 (en) * | 2002-06-27 | 2004-01-08 | Sb Pharmco Puerto Rico Inc. | Carvedilol hydrobromide |
WO2004002419A2 (en) * | 2002-06-27 | 2004-01-08 | Sb Pharmco Puerto Rico Inc. | Carvedilol phosphate salts and/or solvates thereof, correspondinq compositions, and/or methods of treatment |
US6632832B1 (en) | 2002-09-10 | 2003-10-14 | Dabur Research Foundation | Anti-cancer activity of carvedilol and its isomers |
ES2662903T3 (en) * | 2003-11-25 | 2018-04-10 | Smithkline Beecham (Cork) Limited | Carvedilol-free base, salts, anhydrous or solvate forms thereof, corresponding pharmaceutical compositions, controlled release formulations, and treatment or administration procedures |
EP1686986A4 (en) * | 2003-11-25 | 2009-05-27 | Sb Pharmco Inc | Carvedilol salts, corresponding compositions, methods of delivery and/or treatment |
US20050169994A1 (en) * | 2003-11-25 | 2005-08-04 | Burke Matthew D. | Carvedilol free base, salts, anhydrous forms or solvates thereof, corresponding pharmaceutical compositions, controlled release formulations, and treatment or delivery methods |
JP2012051804A (en) * | 2008-12-26 | 2012-03-15 | Kyoto Univ | Eg5 INHIBITOR |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2815926A1 (en) * | 1978-04-13 | 1979-10-18 | Boehringer Mannheim Gmbh | NEW CARBAZOLYL- (4) -OXY-PROPANOLAMINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
US5393772A (en) * | 1993-11-24 | 1995-02-28 | Boehringer Mannheim Pharmaceuticals Corporation | Use of, and method of treatment using, hydroxycarbazole compounds for inhibition of smooth muscle migration and proliferation |
-
1997
- 1997-08-22 AU AU40830/97A patent/AU4083097A/en not_active Abandoned
- 1997-08-22 NZ NZ334307A patent/NZ334307A/en unknown
- 1997-08-22 US US09/242,595 patent/US6096777A/en not_active Expired - Fee Related
- 1997-08-22 CA CA002264178A patent/CA2264178A1/en not_active Abandoned
- 1997-08-22 HU HU9904243A patent/HUP9904243A3/en unknown
- 1997-08-22 PL PL97331766A patent/PL331766A1/en unknown
- 1997-08-22 CN CN97198851A patent/CN1233150A/en active Pending
- 1997-08-22 KR KR1019997001484A patent/KR20000068322A/en not_active Application Discontinuation
- 1997-08-22 EP EP97938525A patent/EP0924985A4/en not_active Withdrawn
- 1997-08-22 JP JP51099998A patent/JP2001504804A/en not_active Ceased
- 1997-08-22 TR TR1999/00370T patent/TR199900370T2/en unknown
- 1997-08-22 CZ CZ99591A patent/CZ59199A3/en unknown
- 1997-08-22 ZA ZA977565A patent/ZA977565B/en unknown
- 1997-08-22 BR BR9711228-3A patent/BR9711228A/en not_active Application Discontinuation
- 1997-08-22 WO PCT/US1997/014792 patent/WO1998007321A1/en not_active Application Discontinuation
- 1997-08-22 IL IL12861397A patent/IL128613A/en not_active IP Right Cessation
-
1999
- 1999-02-19 NO NO990792A patent/NO990792L/en not_active Application Discontinuation
Non-Patent Citations (3)
Title |
---|
DATABASE HCAPLUS ON STN, LF, MASARYKOVY UNIV., (Brno, Czech Rep.), Document No. 124:250307, VACEK et al., "Protective Effect of Carvedilol on Reperfusion Blood Flow and Tissue Injury in the Rat Ischemic Kidney"; & VNITR. LEK., 40(4), 215-218, 1994. * |
DATABASE HCAPLUS ON STN, SMITHKLINE BEECHAM PHARMACEUTICALS, (King of Prussia, PA), Document No. 124:75193, FEUERSTEIN et al., "Carvedilol Update III: Rationale for use in Congestive Heart Failure"; & DRUGS TODAY, VOLUME DATE 1995, 31(Suppl. F), 1-23, 1995. * |
See also references of EP0924985A4 * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004024145A1 (en) * | 2002-09-10 | 2004-03-25 | Dabur Research Foundation | Anti-cancer activity of carvedilol and its isomers |
WO2007042912A2 (en) * | 2005-10-13 | 2007-04-19 | Orchid Research Laboratories Limited | Heterocyclic compounds as pstat3/il-6 inhibitors |
WO2007042912A3 (en) * | 2005-10-13 | 2007-08-30 | Orchid Res Lab Ltd | Heterocyclic compounds as pstat3/il-6 inhibitors |
US7786142B2 (en) | 2005-10-13 | 2010-08-31 | Orchid Research Laboratories, Ltd. | Heterocyclic compounds as pSTAT3/IL-6 inhibitors |
Also Published As
Publication number | Publication date |
---|---|
IL128613A (en) | 2004-07-25 |
NO990792D0 (en) | 1999-02-19 |
CA2264178A1 (en) | 1998-02-26 |
AU4083097A (en) | 1998-03-06 |
PL331766A1 (en) | 1999-08-02 |
JP2001504804A (en) | 2001-04-10 |
BR9711228A (en) | 2000-01-11 |
NZ334307A (en) | 2000-11-24 |
ZA977565B (en) | 1999-02-17 |
EP0924985A4 (en) | 2000-12-06 |
HUP9904243A2 (en) | 2000-05-28 |
CN1233150A (en) | 1999-10-27 |
KR20000068322A (en) | 2000-11-25 |
TR199900370T2 (en) | 1999-05-21 |
HUP9904243A3 (en) | 2001-09-28 |
CZ59199A3 (en) | 1999-08-11 |
IL128613A0 (en) | 2000-01-31 |
NO990792L (en) | 1999-04-15 |
US6096777A (en) | 2000-08-01 |
EP0924985A1 (en) | 1999-06-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0741567B1 (en) | Inhibition of smooth muscle migration and proliferation with hydroxy carbazole compounds | |
CA2299471C (en) | Combination of tyrosine kinase inhibitor and chemical castration to treat prostate cancer | |
US6455537B1 (en) | Methods for treating opiate intolerance | |
US20050261356A1 (en) | Methods and compositions for the treatment of chronic lymphocytic leukemia | |
CA2157488A1 (en) | Use of, and method of treatment using, carbazolyl-(4)-oxypropanolamine compounds for inhibition of smooth muscle cell proliferation | |
US6096777A (en) | Method for inhibiting the expression of Fas | |
JP2002512591A (en) | Inhibition of stress-activated protein kinases | |
JPH08503710A (en) | Antioxidant cardioprotective use of hydroxycarbazole compounds and methods of treatment using same | |
US20080090893A1 (en) | Medicinal Composition for Prevention of Transition to Operative Treatment for Prostatic Hypertrophy | |
AU3512701A (en) | Method for inhibiting the expression of FAS | |
MXPA99001774A (en) | Method for inhibiting the expression of fas | |
AU679462B2 (en) | Use of, and method of treatment using, carbazolyl-(4)-oxypropanolamine compounds for inhibition of smooth muscle cell proliferation | |
JPH03170424A (en) | Treatment of cancer | |
US20020198235A1 (en) | Use of benzothiopenes to treat and prevent prostate cancer | |
WO2023194528A1 (en) | Combination therapy for treating cancer | |
AU765934B2 (en) | Method for inhibiting stress-activated protein kinases | |
JPH1160483A (en) | Tnf production inhibitor |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 97198851.X Country of ref document: CN |
|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AL AM AU BB BG BR CA CN CZ EE GE GH HU IL IS JP KG KP KR LK LR LT LV MD MG MK MN MX NO NZ PL RO SG SI SK TR TT UA US UZ VN YU AM AZ BY KG KZ MD RU TJ TM |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GH KE LS MW SD SZ UG ZW AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
ENP | Entry into the national phase |
Ref document number: 1998 510999 Country of ref document: JP Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 09242595 Country of ref document: US Ref document number: 1019997001484 Country of ref document: KR Ref document number: 334307 Country of ref document: NZ Ref document number: PA/a/1999/001774 Country of ref document: MX Ref document number: PV1999-591 Country of ref document: CZ Ref document number: 1999/00370 Country of ref document: TR |
|
ENP | Entry into the national phase |
Ref document number: 2264178 Country of ref document: CA Ref document number: 2264178 Country of ref document: CA Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1997938525 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 1997938525 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: PV1999-591 Country of ref document: CZ |
|
WWP | Wipo information: published in national office |
Ref document number: 1019997001484 Country of ref document: KR |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 1997938525 Country of ref document: EP |
|
WWR | Wipo information: refused in national office |
Ref document number: 1019997001484 Country of ref document: KR |
|
WWR | Wipo information: refused in national office |
Ref document number: PV1999-591 Country of ref document: CZ |