WO1997044027A1 - Compositions de traitement journalier monodose de maladies a mediation cyclooxygenase-2 - Google Patents
Compositions de traitement journalier monodose de maladies a mediation cyclooxygenase-2 Download PDFInfo
- Publication number
- WO1997044027A1 WO1997044027A1 PCT/US1997/007985 US9707985W WO9744027A1 WO 1997044027 A1 WO1997044027 A1 WO 1997044027A1 US 9707985 W US9707985 W US 9707985W WO 9744027 A1 WO9744027 A1 WO 9744027A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- treatment
- methylsulfonyl
- dimethyl
- fluorophenyl
- furanone
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 43
- 108010037462 Cyclooxygenase 2 Proteins 0.000 title claims abstract description 18
- 201000010099 disease Diseases 0.000 title claims abstract description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 16
- 230000001404 mediated effect Effects 0.000 title claims abstract description 15
- 102000010907 Cyclooxygenase 2 Human genes 0.000 title claims abstract 5
- 238000000034 method Methods 0.000 claims abstract description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 15
- 238000004519 manufacturing process Methods 0.000 claims abstract description 14
- 239000003814 drug Substances 0.000 claims abstract description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 24
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 14
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 14
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 14
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 14
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 claims description 14
- 235000019359 magnesium stearate Nutrition 0.000 claims description 12
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 claims description 12
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 10
- 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 claims description 10
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 10
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 10
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.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 WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 claims description 8
- 229960001021 lactose monohydrate Drugs 0.000 claims description 8
- 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 claims description 7
- 229960001375 lactose Drugs 0.000 claims description 7
- 239000008101 lactose Substances 0.000 claims description 7
- 201000008482 osteoarthritis Diseases 0.000 claims description 7
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 6
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 5
- 208000002193 Pain Diseases 0.000 claims description 5
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 5
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 5
- 206010019233 Headaches Diseases 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 3
- 230000008961 swelling Effects 0.000 claims description 3
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- 229920001213 Polysorbate 20 Polymers 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 239000006186 oral dosage form Substances 0.000 claims 9
- 208000027866 inflammatory disease Diseases 0.000 claims 8
- 208000000094 Chronic Pain Diseases 0.000 claims 2
- 206010042674 Swelling Diseases 0.000 claims 2
- 239000004615 ingredient Substances 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- 239000003826 tablet Substances 0.000 description 15
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 229940111134 coxibs Drugs 0.000 description 12
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 235000019439 ethyl acetate Nutrition 0.000 description 8
- 239000013543 active substance Substances 0.000 description 7
- 208000024827 Alzheimer disease Diseases 0.000 description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 230000002496 gastric effect Effects 0.000 description 5
- -1 3,4-di-substituted furanones Chemical class 0.000 description 4
- 239000007891 compressed tablet Substances 0.000 description 4
- 230000003389 potentiating effect Effects 0.000 description 4
- 239000007916 tablet composition Substances 0.000 description 4
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- YEAUYVGUXSZCFI-UHFFFAOYSA-N 2-(3-fluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC(F)=C1 YEAUYVGUXSZCFI-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 108010037464 Cyclooxygenase 1 Proteins 0.000 description 2
- 206010012289 Dementia Diseases 0.000 description 2
- 208000005171 Dysmenorrhea Diseases 0.000 description 2
- 206010013935 Dysmenorrhoea Diseases 0.000 description 2
- 208000032843 Hemorrhage Diseases 0.000 description 2
- 102100038277 Prostaglandin G/H synthase 1 Human genes 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- 230000000740 bleeding effect Effects 0.000 description 2
- 239000012876 carrier material Substances 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 231100000869 headache Toxicity 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- LZFDOCGPXDEJNG-UHFFFAOYSA-N methyl 2-methyl-2-trimethylsilyloxypropanoate Chemical compound COC(=O)C(C)(C)O[Si](C)(C)C LZFDOCGPXDEJNG-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229940127293 prostanoid Drugs 0.000 description 2
- 150000003814 prostanoids Chemical class 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- YEUYZNNBXLMFCW-UHFFFAOYSA-N 1-bromo-4-methylsulfanylbenzene Chemical compound CSC1=CC=C(Br)C=C1 YEUYZNNBXLMFCW-UHFFFAOYSA-N 0.000 description 1
- UXGJQQXURDIXEB-UHFFFAOYSA-N 2-hydroxy-2-methyl-1-(4-methylsulfonylphenyl)propan-1-one Chemical compound CC(C)(O)C(=O)C1=CC=C(S(C)(=O)=O)C=C1 UXGJQQXURDIXEB-UHFFFAOYSA-N 0.000 description 1
- ITRAFVXDRJVJPX-UHFFFAOYSA-N 2-methyl-1-(4-methylsulfanylphenyl)-2-trimethylsilyloxypropan-1-one Chemical compound CSC1=CC=C(C(=O)C(C)(C)O[Si](C)(C)C)C=C1 ITRAFVXDRJVJPX-UHFFFAOYSA-N 0.000 description 1
- BSMGLVDZZMBWQB-UHFFFAOYSA-N 2-methyl-1-phenylpropan-1-one Chemical compound CC(C)C(=O)C1=CC=CC=C1 BSMGLVDZZMBWQB-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 208000009657 Aspirin-Induced Asthma Diseases 0.000 description 1
- 208000008035 Back Pain Diseases 0.000 description 1
- 206010006811 Bursitis Diseases 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 206010053567 Coagulopathies Diseases 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 208000033131 Congenital factor II deficiency Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 208000007882 Gastritis Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 208000031220 Hemophilia Diseases 0.000 description 1
- 208000009292 Hemophilia A Diseases 0.000 description 1
- 208000007646 Hypoprothrombinemias Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 208000008930 Low Back Pain Diseases 0.000 description 1
- XYVQFUJDGOBPQI-UHFFFAOYSA-N Methyl-2-hydoxyisobutyric acid Chemical compound COC(=O)C(C)(C)O XYVQFUJDGOBPQI-UHFFFAOYSA-N 0.000 description 1
- 201000002481 Myositis Diseases 0.000 description 1
- 206010028836 Neck pain Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- 208000006399 Premature Obstetric Labor Diseases 0.000 description 1
- 206010036600 Premature labour Diseases 0.000 description 1
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 1
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 206010062237 Renal impairment Diseases 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 208000010040 Sprains and Strains Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 208000034158 bleeding Diseases 0.000 description 1
- 208000015294 blood coagulation disease Diseases 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000009852 coagulant defect Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 208000007784 diverticulitis Diseases 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 231100001014 gastrointestinal tract lesion Toxicity 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 238000012153 long-term therapy Methods 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- 201000009240 nasopharyngitis Diseases 0.000 description 1
- 230000010309 neoplastic transformation Effects 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 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
- 229940100688 oral solution Drugs 0.000 description 1
- 229940100692 oral suspension Drugs 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- HJKYXKSLRZKNSI-UHFFFAOYSA-I pentapotassium;hydrogen sulfate;oxido sulfate;sulfuric acid Chemical group [K+].[K+].[K+].[K+].[K+].OS([O-])(=O)=O.[O-]S([O-])(=O)=O.OS(=O)(=O)O[O-].OS(=O)(=O)O[O-] HJKYXKSLRZKNSI-UHFFFAOYSA-I 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 231100000857 poor renal function Toxicity 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 208000026440 premature labor Diseases 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 201000007183 prothrombin deficiency Diseases 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 230000016160 smooth muscle contraction Effects 0.000 description 1
- 229910001467 sodium calcium phosphate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 201000004595 synovitis Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 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
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 208000004371 toothache Diseases 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000009385 viral infection Effects 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
Definitions
- This invention relates to pharmaceutical compositions for the treatment of cyclooxygenase-2 mediated diseases, methods of treatment thereof and the use of a compound in the manufacture of a medicament.
- this invention relates to a pharmaceutical composition for the treatment of cyclooxygenase-2 mediated diseases, said composition being suitable for once a day administration, said composition comprising
- Non-steroidal anti-inflammatory agents are normally administered 2 to 4 times daily.
- the relatively short half-life of most non-steroidal anti-inflammatory agents means that once a day administration is impractical and even twice a day administration is unusual.
- the relatively large doses needed to achieve once a day treatment of conventional non-steroidal anti-inflammatory agents would also lead to side effects so that there is a general understanding that once a day administration is unlikely to be achievable.
- active agent possesses a half-life in humans of sufficient length that a single oral dose of 2.5 to 250 mg of agent per day will provide effective safe anti-inflammatory treatment over a 24 hour period.
- active agents are particularly useful in the treatment of chronic indications, including arthritis, pain, Alzheimer's disease and the like.
- This invention is directed to a pharmaceutical composition for the treatment of cyclooxygenase-2 mediated diseases, said composition being suitable for once a day oral administration, said composition comprising 2.5 to 250 mgs of 5,5-dimethyl-3-(3- fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5//)-furanone.
- the invention is also directed to a method of treating cyclooxygenase-2 mediated diseases comprising the once a day oral administration of 2.5 to 250 mgs of 5,5-dimethyl-3-(3-fluorophenyl)-4-
- the invention is also directed to the use of 5,5-dimethyl-3-
- this invention is directed to a pharmaceutical composition for the treatment of cyclooxygenase-2 mediated diseases, said composition being suitable for once a day oral administration, said composition comprising 2.5 to 250 mg of 5,5- dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)- furanone, and a pharmaceutical carrier therefor.
- such a compound may inhibit cellular neoplastic transformations and metastic tumor growth and hence can be used in the treatment of cancer. It is also useful for the treatment of dementia including pre-senile and senile dementia, and in particular, dementia associated with Alzheimer's Disease (ie Alzheimer's dementia).
- dementia including pre-senile and senile dementia, and in particular, dementia associated with Alzheimer's Disease (ie Alzheimer's dementia).
- the compound will also inhibit prostanoid-induced smooth muscle contraction by preventing the synthesis of contractile prostanoids and hence may be of use in the treatment of dysmenorrhea, premature labor and asthma.
- the specified compound is also useful as an alternative to conventional non-steroidal antiinflammatory drugs (NSAID'S) particularly where such NSAIDS may be contra-indicated such as in patients with peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis or with a recurrent history of gastrointestinal lesions; GI bleeding, coagulation disorders including anemia such as hypoprothrombinemia, haemophilia or other bleeding problems (including those relating to reduced or impaired platelet function); kidney disease (eg impaired renal function); those prior to surgery or taking anticoagulants; and those susceptible to NSAID induced asthma.
- NSAID'S non-steroidal antiinflammatory drugs
- the compound may be administered orally.
- compositions for treating COX-2 mediated diseases as defined may optionally include one or more ingredients as listed above.
- compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
- the compositions are intended for oral use and may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
- excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc.
- inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate
- granulating and disintegrating agents for example, corn starch, or alginic acid
- binding agents for example starch, gelatin or acacia
- lubricating agents for example, magnesium stearate, stearic acid or talc.
- suitable formulations are set forth in U.S. Patent No. 5,474,995.
- Rapidisc® In view of the above mentioned characteristics, 5,5-dimethyl-3-(3-fluorophenyl)-4-(4- methylsulfonyl)phenyl)-2-(5//)-furanone is particularly well suited for a rapid dissolving sublingual formulation. For example, due to the lack of GI side-effects, the agent need not be taken with a large amount of water. Suitable Rapidisc® formulations and methods of making same are disclosed in US 4,305,502, US 4,371,516, US 4,470,202, US 4,758,598, US 4,754,597, US 5,046,618 and US 5,188,882, all of which are hereby incorporated by reference.
- Oral dosage levels for agents 5,5-dimethyl-3-(3- fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5/r)-furanone are of the order of from about 2.5 to 250 mg per patient per day.
- a formulation intended for oral administration to humans may contain from 2.5 to 250 mg of agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
- Dosage unit forms may typically contain 2.5, 5, 10, 12.5, 20, 25, 37.5, 50, 75, 100, 125, 150, 175 or 250 mg of active agent.
- the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination and the type and severity of the particular disease undergoing therapy. For many patients, a dosage range of 2.5 to 125 or 10 to 75 mg per day is preferred.
- a dosage of 10 to 75 or 5 to 125 mg per day is preferred. More particularly, for the treatment of osteoarthritis, a dosage of 10, 25 or 50 mg per day is preferred, whereas for the treatment of rheumatoid arthritis, 25, 50 or 75 mg per day is preferred.
- a dosage of 10 to 75 or 5 to 125 mg per day is preferred. More particularly, for the treatment of osteoarthritis, a dosage of 10, 25 or 50 mg per day is preferred, whereas for the treatment of rheumatoid arthritis, 25, 50 or 75 mg per day is preferred.
- non-chronic indications such as headache or post-operative swelling and pain, 5, 10, 25 or 50 mg per day is preferred.
- this invention is directed to a pharmaceutical composition for the treatment of COX-2 mediated diseases, said composition being suitable for once a day oral administration, said composition comprising a 2.5 to 250 mg of 5,5- dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5/ ⁇ r )- furanone, and a pharmaceutical carried therefor.
- a pharmaceutical composition for the treatment of COX-2 mediated diseases said composition being suitable for once a day oral administration, said composition comprising a 2.5 to 250 mg of 5,5- dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5/ ⁇ r )- furanone, and a pharmaceutical carried therefor.
- a first genus of compositions comprising 5, 10 or 25 mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4- methylsulfonyl)phenyl)-2-(
- compositions comprising 10 to 125 mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4- methylsulfonyl)phenyl)-2-(5/f)-furanone.
- compositions comprising 10 to 75 mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4- methylsulfonyl)phenyl)-2-(5H)-furanone.
- second class of compositions comprising 10, 25, or 50 mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4- methylsulfonyl)phenyl)-2-(5//)-furanone.
- compositions comprising 25, 50 or 75 mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4- methylsulfonyl)phenyl)-2-(5if)-furanone.
- the invention is directed to a unit dose oral form which comprises from 5 to 22.5 mg of 5,5-dimethyl-3-(3- fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone, for example, 12.5 or 20 mg.
- Tablet dose strengths of between 5 and 125 mg can be accomodated by varying total tablet weight, and the ratio of the first three ingredients.
- microcrystalline cellulose lactose monohydrate.
- Tablet dose strengths of between 5 and 125 mg can be accomodated by varying total tablet weight, and the ratio of the first three ingredients. Generally it is preferable to maintain a 1 : 1 ratio for microcrystalline cellulose : lactose monohydrate.
- Capsule dose strengths of between 1 and 50 mg can be accomodated by varying total fill weight, and the ratio of the first three ingredients. Generally it is preferable to maintain a 1 : 1 ratio for microcrystalline cellulose : lactose monohydrate.
- Solution dose strengths of between 1 and 50 mg/5mL can be accomodated by varying the ratio of the two ingredients.
- Suspension dose strengths of between 1 and 50 mg/5mL can be accomodated by varying the ratio of the first and last ingredients.
- Step 1 Methyl 2-trimethylsilyloxyisobutyrate
- Step 2 2-Trimethylsilyloxy-4'-(memylthioMsobutyrophenone A solution of 204 mg (1.0 mmol) of 4-bromothioanisole in 2.5 mL of THF was cooled to -78°C and treated with 0.42 mL of 2.5 M n-BuLi solution in hexane. After stirring at -78°C for 1 h, a solution of 380 mg (2.0 mmol) of methyl 2-trimethylsilyloxyisobutyrate (Step 1) in 2 mL of THF was added. The mixture was stirred at -78°C for 2 h and then quenched with NH4OAC buffer.
- Step 2 To a solution of 40 mg (0.14 mmol) of 2-trimethylsilyloxy- 4'-(methylthio)isobutyrophenone (Step 2) in 2 mL THF was added 0.2 mL of 1 M n-Bu4NF in THF. The resulting mixture was stirred for 30 min and then quenched with 10 mL of NH4OAC buffer. The product was extracted with EtOAc, dried over MgS ⁇ 4 and concentrated. The residue was purified by flash chromatography, eluting with 4: 1 hexane/EtOAc to give 25 mg of the title product.
- Step 5 3-Fluorophenylacetic acid, l,l-dimethyl-2-(4- (methylsulfonyl > ,phenylV2-oxo-ethyl ester
- 2-hydroxy-4'- (methylsulfonyl)isobutyrophenone (Step 4) (100 g), 3- fluorophenylacetic acid (83 g), l-cyclohexyl-3-(2- morpholinoethyl)carbodiimide metho-p-toluenesulfonate (225 g) and DMAP (25 g) in CH2CI2 (2 L) was mechanically stirred for 17 h at r.t..
- Step 6 5,5-Dimethyl-3-(3-fluorophenyl)-4-(4- fmethylsulfonyl>phenyl > ))-2-r5/r)-furanone
- DBU l,8-diazabicyclo[5.4.0]undec-7-ene
- DMAP 4-(dimethylamino)pyridine
- TLMSC1 trimethylsilyl chloride
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU31225/97A AU3122597A (en) | 1996-05-17 | 1997-05-13 | Compositions for a once a day treatment of cyclooxygenase-2 mediated diseases |
CA002254121A CA2254121A1 (fr) | 1996-05-17 | 1997-05-13 | Compositions de traitement journalier monodose de maladies a mediation cyclooxygenase-2 |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US1789196P | 1996-05-17 | 1996-05-17 | |
US60/017,891 | 1996-05-17 | ||
GBGB9612065.4A GB9612065D0 (en) | 1996-06-10 | 1996-06-10 | Compositions for a once a day treatment of cyclooxtgenase-2 mediated diseases |
GB9612065.4 | 1996-06-10 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1997044027A1 true WO1997044027A1 (fr) | 1997-11-27 |
Family
ID=26309473
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1997/007985 WO1997044027A1 (fr) | 1996-05-17 | 1997-05-13 | Compositions de traitement journalier monodose de maladies a mediation cyclooxygenase-2 |
Country Status (3)
Country | Link |
---|---|
AU (1) | AU3122597A (fr) |
CA (1) | CA2254121A1 (fr) |
WO (1) | WO1997044027A1 (fr) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1061908A4 (fr) * | 1998-03-13 | 2007-01-24 | Merck & Co Inc | Therapie associee destinee au syndrome ischemique coronarien aigu ainsi qu'a des troubles connexes |
CZ298484B6 (cs) * | 2000-02-02 | 2007-10-17 | Florida State University Research Foundation, Inc. | Taxan a farmaceutická kompozice s jeho obsahem |
US7320996B2 (en) | 2001-08-15 | 2008-01-22 | Sugen, Inc | Indolinone protein kinase inhibitors and cyclooxygenase inhibitors for use in combination therapy for the treatment of cancer |
US8541471B2 (en) | 2003-05-07 | 2013-09-24 | Osteologix A/S | Water-soluble strontium salts for use in treatment of cartilage and/or bone conditions |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5474995A (en) * | 1993-06-24 | 1995-12-12 | Merck Frosst Canada, Inc. | Phenyl heterocycles as cox-2 inhibitors |
-
1997
- 1997-05-13 AU AU31225/97A patent/AU3122597A/en not_active Abandoned
- 1997-05-13 WO PCT/US1997/007985 patent/WO1997044027A1/fr active Application Filing
- 1997-05-13 CA CA002254121A patent/CA2254121A1/fr not_active Abandoned
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5474995A (en) * | 1993-06-24 | 1995-12-12 | Merck Frosst Canada, Inc. | Phenyl heterocycles as cox-2 inhibitors |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1061908A4 (fr) * | 1998-03-13 | 2007-01-24 | Merck & Co Inc | Therapie associee destinee au syndrome ischemique coronarien aigu ainsi qu'a des troubles connexes |
CZ298484B6 (cs) * | 2000-02-02 | 2007-10-17 | Florida State University Research Foundation, Inc. | Taxan a farmaceutická kompozice s jeho obsahem |
US7320996B2 (en) | 2001-08-15 | 2008-01-22 | Sugen, Inc | Indolinone protein kinase inhibitors and cyclooxygenase inhibitors for use in combination therapy for the treatment of cancer |
US8541471B2 (en) | 2003-05-07 | 2013-09-24 | Osteologix A/S | Water-soluble strontium salts for use in treatment of cartilage and/or bone conditions |
Also Published As
Publication number | Publication date |
---|---|
CA2254121A1 (fr) | 1997-11-27 |
AU3122597A (en) | 1997-12-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6063811A (en) | Compositions for a once day treatment of cyclooxygenase-2 mediated diseases | |
CZ288175B6 (en) | Phenyl heterocyclic derivatives, process of their preparation and pharmaceutical preparations in which they are comprised | |
JPH11501049A (ja) | イミダゾ〔1,2−a〕ピリジン誘導体 | |
CA2362675A1 (fr) | Formes polymorphes cristallines du celecoxibe | |
WO1997044027A1 (fr) | Compositions de traitement journalier monodose de maladies a mediation cyclooxygenase-2 | |
JPH0140009B2 (fr) | ||
NO315928B1 (no) | Anvendelse av en anilidforbindelse for fremstilling av et profylaktisk eller terapeutisk middel for behandling av type I allergiske sykdommer | |
EP0853481A1 (fr) | Compositions de traitement d'inflammations contenant certaines prostaglandines et un inhibiteur de cyclo-oxygenase-2 selectif | |
KR20130078147A (ko) | 일정한 입도를 갖는 4,5―디아릴―3(2h)―퓨라논 유도체를 포함하는 약학 조성물 | |
JP2001516750A (ja) | 新規な2−(3h)−オキサゾロン誘導体 | |
JPS5855423A (ja) | ベンゾグアナミン類を主成分としする医薬 | |
JPH10507445A (ja) | 神経変性障害の治療におけるシクロオキシゲナーゼ阻害剤の使用 | |
JP2006517561A (ja) | Cox−2阻害剤としての3−フェニルフラン−2−オン誘導体 | |
AU775030B2 (en) | Compositions for a once a day treatment of cyclooxygenase-2 mediated diseases | |
JP2024505912A (ja) | 連環を含むtyk2阻害剤化合物 | |
TW201818929A (zh) | 尿素衍生物 | |
TW536404B (en) | Compositions for a once a day treatment of cyclooxygenase-2 mediated diseases | |
RU2101011C1 (ru) | Средство, обладающее анальгетическим действием | |
AU774172C (en) | Polymorphic b form of 3-(cyclopropylmethoxy)-4-(4-(methylsulfonyl)phenyl)-5,5- dimethyl-5h-furan-2-one | |
UA51706C2 (uk) | Спосіб лікування запального захворювання за допомогою 3-феніл-4-(4-метилсульфоніл)феніл)-2-(5н)-фуранону | |
JPS6330410A (ja) | 抗潰瘍剤 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AL AM AU AZ BA BB BG BR BY CA CN CU CZ EE GE HU IL IS JP KG KR KZ LC LK LR LT LV MD MG MK MN MX NO NZ PL RO RU SG SI SK TJ TM 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 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: 2254121 Country of ref document: CA Ref country code: CA Ref document number: 2254121 Kind code of ref document: A Format of ref document f/p: F |
|
NENP | Non-entry into the national phase |
Ref country code: JP Ref document number: 97542472 Format of ref document f/p: F |
|
122 | Ep: pct application non-entry in european phase |