CA2096196A1 - Pharmaceutical compositions - Google Patents
Pharmaceutical compositionsInfo
- Publication number
- CA2096196A1 CA2096196A1 CA002096196A CA2096196A CA2096196A1 CA 2096196 A1 CA2096196 A1 CA 2096196A1 CA 002096196 A CA002096196 A CA 002096196A CA 2096196 A CA2096196 A CA 2096196A CA 2096196 A1 CA2096196 A1 CA 2096196A1
- Authority
- CA
- Canada
- Prior art keywords
- cis
- vitamin
- retinoic acid
- treatment
- cis retinoic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 239000008194 pharmaceutical composition Substances 0.000 title 1
- 229960001445 alitretinoin Drugs 0.000 claims abstract description 28
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- 150000003710 vitamin D derivatives Chemical class 0.000 claims abstract description 18
- 150000002148 esters Chemical class 0.000 claims abstract description 15
- 229960005339 acitretin Drugs 0.000 claims abstract description 13
- IHUNBGSDBOWDMA-AQFIFDHZSA-N all-trans-acitretin Chemical compound COC1=CC(C)=C(\C=C\C(\C)=C\C=C\C(\C)=C\C(O)=O)C(C)=C1C IHUNBGSDBOWDMA-AQFIFDHZSA-N 0.000 claims abstract description 13
- SHGAZHPCJJPHSC-NUEINMDLSA-N Isotretinoin Chemical compound OC(=O)C=C(C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-NUEINMDLSA-N 0.000 claims abstract description 12
- SHGAZHPCJJPHSC-UHFFFAOYSA-N Panrexin Chemical compound OC(=O)C=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229960005280 isotretinoin Drugs 0.000 claims abstract description 11
- 239000000825 pharmaceutical preparation Substances 0.000 claims abstract description 6
- 239000004480 active ingredient Substances 0.000 claims abstract 5
- 239000003937 drug carrier Substances 0.000 claims abstract 2
- 229960005084 calcitriol Drugs 0.000 claims description 18
- GMRQFYUYWCNGIN-NKMMMXOESA-N calcitriol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C GMRQFYUYWCNGIN-NKMMMXOESA-N 0.000 claims description 17
- SHGAZHPCJJPHSC-ZVCIMWCZSA-N 9-cis-retinoic acid Chemical compound OC(=O)/C=C(\C)/C=C/C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-ZVCIMWCZSA-N 0.000 claims description 16
- 235000020964 calcitriol Nutrition 0.000 claims description 16
- 239000011612 calcitriol Substances 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 16
- 206010028980 Neoplasm Diseases 0.000 claims description 7
- 201000004681 Psoriasis Diseases 0.000 claims description 6
- 230000008105 immune reaction Effects 0.000 claims description 6
- 208000001132 Osteoporosis Diseases 0.000 claims description 5
- 230000001575 pathological effect Effects 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims 1
- 239000011647 vitamin D3 Substances 0.000 description 17
- 229940021056 vitamin d3 Drugs 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 239000000203 mixture Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000013543 active substance Substances 0.000 description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- 239000002775 capsule Substances 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000001828 Gelatine Substances 0.000 description 5
- 229920000159 gelatin Polymers 0.000 description 5
- 235000019322 gelatine Nutrition 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
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 229960002061 ergocalciferol Drugs 0.000 description 4
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 4
- 238000003818 flash chromatography Methods 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- 239000011653 vitamin D2 Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- -1 alkaline earth metal salts Chemical class 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 229940093499 ethyl acetate Drugs 0.000 description 3
- 235000019439 ethyl acetate Nutrition 0.000 description 3
- 208000032839 leukemia Diseases 0.000 description 3
- 239000012266 salt solution Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 229940088594 vitamin Drugs 0.000 description 3
- 239000011782 vitamin Substances 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- 208000023275 Autoimmune disease Diseases 0.000 description 2
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 229920002774 Maltodextrin Polymers 0.000 description 2
- 239000005913 Maltodextrin Substances 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 208000009621 actinic keratosis Diseases 0.000 description 2
- 229940072107 ascorbate Drugs 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 210000000621 bronchi Anatomy 0.000 description 2
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 2
- 229940043253 butylated hydroxyanisole Drugs 0.000 description 2
- 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 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 239000011261 inert gas Substances 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 210000000867 larynx Anatomy 0.000 description 2
- 229940035034 maltodextrin Drugs 0.000 description 2
- 238000000034 method Methods 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
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- 210000000496 pancreas Anatomy 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229960001866 silicon dioxide Drugs 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 210000001685 thyroid gland Anatomy 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 description 2
- 235000005282 vitamin D3 Nutrition 0.000 description 2
- DCROKXXPZPPINM-YHJXBONMSA-N (1r,3z)-3-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-6-methylhept-5-en-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexan-1-ol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCC=C(C)C)C)=C\C=C1\C[C@H](O)CCC1=C DCROKXXPZPPINM-YHJXBONMSA-N 0.000 description 1
- GMRQFYUYWCNGIN-UHFFFAOYSA-N 1,25-Dihydroxy-vitamin D3' Natural products C1CCC2(C)C(C(CCCC(C)(C)O)C)CCC2C1=CC=C1CC(O)CC(O)C1=C GMRQFYUYWCNGIN-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 208000009137 Behcet syndrome Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 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
- 208000011231 Crohn disease Diseases 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- 235000001815 DL-alpha-tocopherol Nutrition 0.000 description 1
- 239000011627 DL-alpha-tocopherol Substances 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- YFPJFKYCVYXDJK-UHFFFAOYSA-N Diphenylphosphine oxide Chemical compound C=1C=CC=CC=1[P+](=O)C1=CC=CC=C1 YFPJFKYCVYXDJK-UHFFFAOYSA-N 0.000 description 1
- 206010058314 Dysplasia 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
- 206010015150 Erythema Diseases 0.000 description 1
- 208000001204 Hashimoto Disease Diseases 0.000 description 1
- 208000030836 Hashimoto thyroiditis Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 208000009525 Myocarditis Diseases 0.000 description 1
- 208000004179 Oral Leukoplakia Diseases 0.000 description 1
- 201000011152 Pemphigus Diseases 0.000 description 1
- 241000587784 Pemphis Species 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 description 1
- WFWLQNSHRPWKFK-UHFFFAOYSA-N Tegafur Chemical compound O=C1NC(=O)C(F)=CN1C1OCCC1 WFWLQNSHRPWKFK-UHFFFAOYSA-N 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- MECHNRXZTMCUDQ-UHFFFAOYSA-N Vitamin D2 Natural products C1CCC2(C)C(C(C)C=CC(C)C(C)C)CCC2C1=CC=C1CC(O)CCC1=C MECHNRXZTMCUDQ-UHFFFAOYSA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000005210 alkyl ammonium group Chemical group 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000002798 bone marrow cell Anatomy 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 210000003679 cervix uteri Anatomy 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- FNIATMYXUPOJRW-UHFFFAOYSA-N cyclohexylidene Chemical group [C]1CCCCC1 FNIATMYXUPOJRW-UHFFFAOYSA-N 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 231100000321 erythema Toxicity 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- HQMNCQVAMBCHCO-DJRRULDNSA-N etretinate Chemical compound CCOC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)C=C(OC)C(C)=C1C HQMNCQVAMBCHCO-DJRRULDNSA-N 0.000 description 1
- 229960002199 etretinate Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 208000024711 extrinsic asthma Diseases 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- LHGVFZTZFXWLCP-UHFFFAOYSA-N guaiacol Chemical compound COC1=CC=CC=C1O LHGVFZTZFXWLCP-UHFFFAOYSA-N 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 230000002489 hematologic effect Effects 0.000 description 1
- VBZWSGALLODQNC-UHFFFAOYSA-N hexafluoroacetone Chemical compound FC(F)(F)C(=O)C(F)(F)F VBZWSGALLODQNC-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 201000001976 pemphigus vulgaris Diseases 0.000 description 1
- 210000003800 pharynx Anatomy 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 229940113124 polysorbate 60 Drugs 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000001587 sorbitan monostearate Substances 0.000 description 1
- 235000011076 sorbitan monostearate Nutrition 0.000 description 1
- 229940035048 sorbitan monostearate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 235000001892 vitamin D2 Nutrition 0.000 description 1
- MECHNRXZTMCUDQ-RKHKHRCZSA-N vitamin D2 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)/C=C/[C@H](C)C(C)C)=C\C=C1\C[C@@H](O)CCC1=C MECHNRXZTMCUDQ-RKHKHRCZSA-N 0.000 description 1
- 150000003704 vitamin D3 derivatives Chemical class 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/203—Retinoic acids ; Salts thereof
-
- 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
- A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
-
- A—HUMAN NECESSITIES
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Abstract
Abstract Pharmaceutical preparation containing 9-cis- or 13-cis retinoic acid, or acitretin, a pharmaceutically usable salt or ester thereof and a vitamin D derivative as active ingredients, and usual pharmaceutical carriers.
Description
2096196 RAN_4051~2~
The present invention is coneerned with pharmaceutical preparations containing 9-cis- or 13-cis-retinoic acid or acitretin (all(E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid), a pharmaceutically usable salt or ester thereof 5 and a vitamin D derivative. it has been found that such preparations can be used for the treatrnent of psoriasis, of osteoporosis, of precanceroses and of tumours, as well as for the treatment of pathological or undesired immune reactions. The invention is therefore also concerned with the use of 9-cis-or 13-cis-retinoic 10 acid or acitretin9 pharmaceutically usable salts or esters thereof for the combined use with vitamin D derivatives in the treatment of the said diseases and anomalies. Finally, the invention is concerned with the use of 9-cis-or 13-cis-retinoic acid or acitretin, pharma-ceutically usable salts or esters thereof in the manufacture of ~5 pharmaceutical preparations for the combined use with vitamin D
derivatives in the treatment of ~he aforementioned diseases and anomalies.
Examples of pharmaceutically usable salts of 9-cis- or 13-ao cis-retinoic acid or acitretin are alkali salts such as the Na and K
salt, alkaline earth metal salts such as the Ca and Mg salt; as well as the ammonium salt and alkylammonium salts. Examples of esters are lower-alkyl esters such as the methyl and ethyl ester such as etretinate, and aromatic esters such as the benzyl es~er.
' Examples of vitamin D derivatives which can be used in accordance with the invention are hydroxylated vitamin D3 derivatives such as la-hydroxy-vitamin D3, 1,25-dihydroxy-vitamin D3 (calcitriol), la,25,26-trihydroxy-vitamin D3, la,23,25-30 trihydroxy-vitamin D3, 24-fluoro-1 a,25-dihydroxy-vitamin D3, 24,24-difluoro-1 a,25-dihydroxy-vitamin D3, 26,26,26-trifluoro-1 a,~5-dihydroxy-vitamin D3, 26,26,26,27,27,27-hexafluoro-1 a,25-dihydroxy-vitamin D3; 1a,Z5-dihydroxy-22,23-dehydro-vitamin D3, 26,26,26-trisdeutero-22,23-dehydro-1 a,25-dihydroxy-vi~amin D3, 35 26,26,26,27,27,27 hexakisdeutero-22,23-dehydro-1 a,25-dihydroxy-Grn/29.3.93 - - :
, .. . . . ... . . . . .
The present invention is coneerned with pharmaceutical preparations containing 9-cis- or 13-cis-retinoic acid or acitretin (all(E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid), a pharmaceutically usable salt or ester thereof 5 and a vitamin D derivative. it has been found that such preparations can be used for the treatrnent of psoriasis, of osteoporosis, of precanceroses and of tumours, as well as for the treatment of pathological or undesired immune reactions. The invention is therefore also concerned with the use of 9-cis-or 13-cis-retinoic 10 acid or acitretin9 pharmaceutically usable salts or esters thereof for the combined use with vitamin D derivatives in the treatment of the said diseases and anomalies. Finally, the invention is concerned with the use of 9-cis-or 13-cis-retinoic acid or acitretin, pharma-ceutically usable salts or esters thereof in the manufacture of ~5 pharmaceutical preparations for the combined use with vitamin D
derivatives in the treatment of ~he aforementioned diseases and anomalies.
Examples of pharmaceutically usable salts of 9-cis- or 13-ao cis-retinoic acid or acitretin are alkali salts such as the Na and K
salt, alkaline earth metal salts such as the Ca and Mg salt; as well as the ammonium salt and alkylammonium salts. Examples of esters are lower-alkyl esters such as the methyl and ethyl ester such as etretinate, and aromatic esters such as the benzyl es~er.
' Examples of vitamin D derivatives which can be used in accordance with the invention are hydroxylated vitamin D3 derivatives such as la-hydroxy-vitamin D3, 1,25-dihydroxy-vitamin D3 (calcitriol), la,25,26-trihydroxy-vitamin D3, la,23,25-30 trihydroxy-vitamin D3, 24-fluoro-1 a,25-dihydroxy-vitamin D3, 24,24-difluoro-1 a,25-dihydroxy-vitamin D3, 26,26,26-trifluoro-1 a,~5-dihydroxy-vitamin D3, 26,26,26,27,27,27-hexafluoro-1 a,25-dihydroxy-vitamin D3; 1a,Z5-dihydroxy-22,23-dehydro-vitamin D3, 26,26,26-trisdeutero-22,23-dehydro-1 a,25-dihydroxy-vi~amin D3, 35 26,26,26,27,27,27 hexakisdeutero-22,23-dehydro-1 a,25-dihydroxy-Grn/29.3.93 - - :
, .. . . . ... . . . . .
vitamin D3, 26,26,26-trifluoro-1 cc,25-dihydroxy-22,23-dehydro-vitamin D3, 26,26,26,27,27,27-hexafluoro-la,25-dihydroxy-22,23-dehydro-vitamin D3, 26,26,26,27,27,27-hexafluoro-1 a,25-dihydroxy-23,24-dehydro-vitamin D3, la,25-dihydroxy-vitamin D2, 5 26,26,26,27,27,27-hexakisdeutero-1oc,25-vitamin D2, la,25-dihydroxy-27-nor-vitamin Dz, 1a,25,26-trihydroxy-22,23-dehydro-vitamin D3, la,25,26-trihydroxy-vitamin D2, la,25-dihydroxy-23,24-didehydro-vi~amin D3, 1 oc,25-dihydroxy-16,17-dehydro-vitamin D3, 1 a,25-dihydroxy-16,17;23,24-bisdehydro-vitamin D3, 10 1 a,25-dihydroxy-16,17-dehydro-23,24-didehydro-vitamin D3, 26,26,26,27,27,27-hexafluoro-1 a,25-dihydroxy-16,17-dehydro-23,24-didehydro-vitamin D3,1a,26,26,26,27,27,27-heptafluoro-2~-hydroxy-23,24-didehydro-vitamin D3, 1 oc,25-dihydroxy-3-deoxy-23,24-didehydro-vitamin D3 and 25-hydroxy-23,24-didehydro-l5 vitamin D2-The aforementioned vitamin D derivatives and theirpreparation are known, see, e.g., the US patent specifications 3 993 675, 4 022 768, 4 407 7S4,4 421 690, 4 594 432, 2~ 4 594 346,4 612 308,4 613 ~94,4 6~2 405,4 749 710, 4 804 502,4 898 855,4 906 785,4 929 609, S 087 619 and 5 120 722.
26,26,Z6,27,27,Z7-Hexafluoro-l a,25-dihydroxy-16,17-25 dehydro-23,24-didehydro vitamin D3 has not yet been described and can be ob~ained as follows:
A. To 522 mg of [3aS-[3(S*),3aa,7a,7a~]]-[[3a,4,5,6,7,7a-hexahydro-3a-methyl-3-(1-methyl-3-butynyl~-1 H-inden-7-30 yl~oxy]trimethylsilane in 15 ml of anhydrous tetrahydrofuran,1.85 ml of 1.6M solution of n-butyllithium in hexane was added dropwise after cooling at -75C over 5 minutes and the mixture was stirred at -75C for 30 min. Then a stream of hexafluoroacetone was bubbled into the mixture for 15 min with temperature maintained at 35 -75C. The reaction mixture was stirred for one additional hour, and then quenched with 1 :1 mixture of 2M KHC03 and 1 M Roche!le salt added dropwise. The mixture was stirred at room temperature for one hour and then dilu~ed with 25 ml of the same salt solution. After .' . -.
- :
.... . .
2~9~6 extraction with CH2CI2, the organic phase was washed with 50 ml of the same salt solution, dried and evaporated. The residue was azeotroped with benzene to give 2.38 g of crude oily product.
Purification was performed by flash chromatography (EtOAc-hexane 5 1:9) to give 817 mg of [3aS-[3(S*),3[3aa,7a,7a~]]-1,1,1-trifluoro-6[3a,4,5,6,7,7a-hexahydro-3a-methyl-7-[(trimethylsilyl)oxy]-1 H-inden-3-yl]-2-(trifluoro-methyl)-3-heptyn-2-ol.
B. To a solution of 812 mg of [3aS-[3(S*),3aa,7a,7a~]3-1,1,1-10 trifluoro-6[3a,4,5,6,7,7a-hexahydro-3a-methyl-7-[(trimethylsilyl)-oxy]-1 H-inden-3-yl]-2-(trifluoromethyl)-3-heptin-2-ol in 18 ml of anhydrous tetrahydrofuran there was added 5.34 ml of tetra-butyl-ammonium fluoride in tetrahydrofuran, and the mixture was stirred at room temperature under argon for 8û min. The reaction was then 15 quenched by addition of 9 ml of half-saturated NaHC03 and stirred at room temperature for an additional 20 min. Excess of tetrahydro-furan was removed by evaporation and additional 9 ml of bicarbonate was added. The mixture was extracted with ethyl acetate, the ~-extract was washed with brine~ dried and evaporated. Af~er ao purification by flash chromatography (EtOAc-hexane 1:2), it gave 690 mg of [3aR-~1(R*),3aa,4~B,7a,B]]-3,3a,5,6,7,7a-hexahydro-7a-methyl-1 -[6,6,6-trifluoro-5-hydroxy-1 -methyl-5-(trifluoro-methyl~-3-hexynyl] -4H-inden-4-ol.
25 C. To a solution of 100 mg of [3aR,-[1(R*),3aa,4~,7a~]-3,3a,5,6,7,7a-hexahydro-7a-methyl-1 -[6,6,6-trifluoro-5-hydroxy-1-methyl-5-(trifluoromethyl)-3-hexynyl]-4H-inden-4-ol in 6 ml of anhydrous CH2CI2 there was added at room temperature, 176 mg of pyridinium chlorochromate, and the mixture was stirred at room 30 temperature for 50 min under argon. To this mixture there was added 9 ml of ether under stirring, then it was filtered and the filtrate evaporated to dryness. The crude product thus obtained was purified by chromatography on silicagel column with ethyl acetate-hexane 1:3 to give [3aR-[1(R*),3aa,7a~]]-3,3a,5,6,7,7a-hexahydro-7a-35 methyl-1-[6,6,6-trifluoro-5-hydroxy-1-methyl-5-(trifluoro-methyl)-3-hexinyl~-4H-inden-4-one.
.
.. , ~ , . ' . ,. ' .
... - ', '' ' . . , - ~ : : .-' .
.
209~
n To a solution of 333 mg of [35-(30c,5~,Z)]-2-~2-[2-methylene-3, 5 -bis [ [( 1 ,1 -dimethylethyl)dimethylsilyl]oxy~cyclohexylidene]-ethyl]diphenyl phosphine oxide in 7 ml anhydrous tetrahydrofuran there was added at -75C, 0.325 ml of 1.6M n-butyllithium in hexane 5 under argon. After stirring for 6 min, a solution of 73 mg of ~3aR-[1 (R*),3aa,7a~]]-3,3a,5,6,7,7a-hexahydro-7a-methyl-1-L6,6,6-trifluoro-5 -hydroxy- 1 -methyl-5-~trifluoromethyl)-3-hexiny]-4H-inden-4-one in 5 ml anhydrous tetrahydrofuran was added dropwise.
The reaction mixture was stirred for 1 hour at -75C, and then 10 quenched with 2.6 ml of 1:1 mixture of 2N Rochelle salt and 2N
K~C03 solutions and was allowed to warm to room temperature. It was then diluted with 10 ml of the same salt solution and extracted with Pthyl acetate. The extract was washed with brine, dried and evaporated. The crude intermediate was purified by flash chromato-graphy on silica gel column wi~h ethyl acetate-hexane 1:5 to give disilyl-protected 1 ,25-dihydroxy-1 6-ene-23-yne-26,27-hexafluoro-cholecalciferol.
E. To 92 mg of the disilyl protected 1,25-dihydroxy 16-ene-23-ao yne-26,27-hexafluoro-cholecalciferol in 5 ml anhydrous ~etrahydro-furan in a dark wall flask there was added 0.89 ml of lM tetrabutyl-ammonium fluoride in tetrahydrofuran, and the mixture was stirred for 16 hrs under argon. The reaction was then quenched with 3 ml of half-saturated NaHC03 and stirred at room temperature. It was then 25 extracted with ethyl acetate. The extract was washed with half-saturated NaHC03 and brine, then dried and evaporated. The crude product was purified by flash chromatography with ethyl-acetate 4:1, to give 1 ,25-dihydroxy-1 6-ene-23-yne-26,27-hexafluoro-cholecalciferol as a foamy glass; [a]25 = +59.1 (c 0.11, CH30H).
In accordance with the invention the 9-cis- or 13-cis-retinoic acid or acitretin or a salt or ester thereof can be used in the form of pharmaceutical preparations which also contain a vitamin D
derivative or as preparations which contain an ad hoc combination 35 with vitamin D derivatives.
2~9~196 The use o~ 9-cis-retinoic acid, pharrnaceutically usable salts or esters thereof and vitamin D derivatives, especially 9-cis-retinoic acid and calciferol is preferred.
The active substances can be administered ~opically or orally for the treatment of psoriasis. Topical prepara~ions can be present as creams, ointments, lotions, tinctures or gels which contain the ac~ive substances together with carriers which are usual in such preparations. The content of 9-cis- or 13-cis-retinoic acid or 10 acitretin, salts or esters thereof in these preparations can be about 0.001-0.1 wt.%, preferably 0.003-0.03 wt.%. The content of vitamin D derivative in such preparations can be about 1 ~lg/g to about 100 llg/g. These preparations are applied to ~he diseased site on the skin according to the requirements of the patien~, e.g. once or twice per day.
Preparations for oral administration can be present in the form of tablets, capsules, solutions or emulsions. For the treatment of psoriasis, such preparations can be administered in dosages of ao about 0.01 mg to about 3 m~ of 9-cis-or 13-cis-re~inoic acid or acitretin or salt or ester thereof per kg body weight per day, preferably about 0.025 mg/kg to about 1.5 mg/kg per day; and about 0.001 ~lg/kg to about 0.1 llg/kg of vitamin D derivative, preferably about O.OOS ~lg/kg to about 0.05 ~lg/kg, per day. Solid dosage forms 25 such as tablets and capsules conveniently contain per dosage unit about 1 mg to about 50 rng of 9-cis- or 13-cis-retinoic acid or acitretin and, respectively, about 0.1 1l9 to about 1 1l9 of vitamin D
derivative.
For the treatment and prevention of tumours, the active substances or the preparations in accordance with the invention can be administered enterally, parenterally or topically. Fxamples of tumours which can be treated with the preparations in accordance with the invention or the active substance combination in 35 accordance with the invention are haematological tumours such as leukaemia, especially acute promyelocy~aric leukaemia and Iymphomas. Furthermore precancerous lesions of the epitheliai tissue such as actinic keratoses of the skin, oral leukoplakias, - , . ~ .. ..
,, ~, . - . . ~ . .. -. . .
2~6~6 dysplasias of the larynx, bronchi and cervix; as well as carcinornas of the skin, buccal cavity, the bronchi, the larynx, pharynx, stomach, colon, uterus, pancreas, the bladder, breast and pros~ate can be treated by the administration of an effective amount of the 5 preparations or active substance combination in accordance with the invention.
Examples of pathological or undesired immune reactions are autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, insulin-dependent diabetes, ~upus erythematosus, pemphigus vulgaris, pemphi~us foliaceus, myasthenia gravis, ankylosing spondylitis, autoimmune diseases of the thyroid gland such as Hashimoto's disease and primary thyroid gland failure;
scleroderma, uveitis, Behcet's disease, Crohn's disease, auto-immune-conditioned myocarditis and autoimmune-conditioned poly-glandular syndrome; as well as allergies such as ailergic rhinitis, atopic dermatitis, asthma and celiaca. Other indications are undesired immune reactions in organ or cell transplants suoh as kidney, heart, pancreas beta-islet cell, bone marrow and liver ao transplants.
A further aspect of the invention is concerned with the use of the preparations and, respectively, active substance combination in accordance with the invention for the preferably emeral or 25 parenteral treatrnent and prevention of osteoporosis. In all of these indications the active substances can be used in the dosage ranges given above, whereby the individual dosage will depend on the nature of the disease to be treated and on the age and condi~ion of the patient and can be determined within the framework of medical 30 expertise. The invention is illustrated in more detail by the following Examples.
- - ' - . . .
.
. , : . . - ~, . - , .
.
:, : -, 2 0 ~ 6 Example ~
Ca~ules containing 9-cis-retinoic_~$id ~ -9-cis-Retinoic acid 20.0 mg Gelatine ~BIoom number 30) 70.0 mg Maltodextrin 108.0 mg dl-a-Tocopherol 2.0 mg Na ascorbate 10.0 mg Microcrystalline cellulose 48.0 mg Mg stearate 2.0 mg Total 260 mg -The active substance is wet-ground in a soiution of gelatine, 5 maltodextrin, tocopherol and Na ascorbate and the suspension obtained is spray-dried. Thereafter, the cellulose and the Mg stearate are admixed and 260 mg aliquots of the mixture are filled into hard gelatine capsules.
Capsules cQntainina calcitriol Calcitriol 0.25 ~lg Butylated hydroxytoluene 0.016 mg Buylated hydroxyanisole 0.016 mg Fractionated coconut oil ad 160.0 mg The ingredients are mixed and the oily solution is filled under an inert gas into soft gelatine capsules each containing 160 mg.
,5 .. . - - .. - . - , . ~
. .: . . - : ' . . '' . . :-, , . . - - . . . . . . .
... . ~ . . :
,. - . .... : .
- . . ~ . .. . .
2~9~1~6 Ex~le 3 Capsules ~ontaining 9-cis-retinoic acid and calcitri~!
Calcitriol 0.25 ~g 9-cis-Retinoic acid 20 mg Polyethylene glycol 400 200 mg Butylated hydroxyanisole 0~1 mg The ingredients are mixed and filled under an inert gas into s soft gelatine capsules having a fill weight of 220 mg.
Example 4 Cre~m ~on~i~ing ~-cis-retinoic acid and calci~riol Calcitriol 2 mg 9-cis-Retinoic acid 30 mg Cetyl alcohol 1.5 mg Stearyl alcohol 2.5 mg Sorbitan monostearate 2.0mg Glyceryl monostearate and polyoxyethylene glycolsteara~e 4.0 mg Polysorbate 60 l.Omg Mineral oil 4.0 mg Propylene glycol 5.0mg Propylparaben 0.05 mg Butylated hydroxyanisole 0.05 mg Sorbitol solution 2.0 mg Na EDTA 0.01 mg Methylparaben 0.18 mg Dist. water q.s. ad 100 9 Example 5 The activity of the combination in accordance with the invention of 9-cis-retinoic acid and calcitriol on the differentiation of hurnan promyelocytic leukaemia cells (HL-60) can be . . .
,. , . . ~
-..
.. ~.. . ~.
209~96 g demonstrated in vitro in the tes~ procedure described in Cancer Research 45, 4244 (1985). The effects obtained with various concentrations of the active substances on cell differentiation (measured by detecting the reduction effect on nitroblue-tetra-5 zolium, NBT) can be concluded from Figure 1. The measurement ofthe NBT reduction was effected according to a modified method of Pick et al. in J. Reticul. Soc. 30, 581 (1981). In each case, 3.104 cells in 200 ,ul were incubated for 48 hours with the active substances. The cells were centrifuged off and treated with in each 10 case 100 1ll of pre-warmed NBT solution (1 mg~ml, diluted with Dulbeccos PBS) and PMA (123 mg/ml in DMSO) and incubated at 37~C
for 1 hour. After cen~rifugation, 100 1ll of 90% DMF, diluted with 10% SDS, were added, the mixture was incubated at 37C and the extinction (OD) was measured at 550 mm.
The curves in Fig. 1 show the effect of calcitriol alone and of combinations of varying amounts of calcitriol with (from above downwards) 80 nM, 16 nM and 3.2 nM 9-cis-retinoic acid.
ExamplQ 6 Patients with multiple actinic keratoses were treated -topically with 9-cis-retinoic acid and calcitriol. 9-cis-retinoic acid was applied as a 0.01% (v/v) solution in ethanol/propylene glycol 2s (50:50). Calcitriol was applied as a 0.0025% (w/w) cream.
Treatment was carried out for 4-16 weeks with adminis~ration of the preparations to the skin once daily. 9-cis-retinoic acid was applied first, followed, after drying (3 minutes~, by calcitriol cream.
Occlusive dressing was not used.
The following results were obtained with various patient groups:
, .- . :
.
2 ~
- lo -A. Patient group: 16 patients Duration of treatment: 4 weeks Result of treatment:
6 patients: slight improvement 5 patients: moderate improvement 5 patients: marked irnprovement B. Patient group: 16 pa~ients Duration of treatment: 8 weeks Result of treatment:
3 patients: slight improvement 4 patients: moderate improvement 9 patients: marked improvement C. Patient group: 7 patients Duration of treatment: 1Z weeks Result of treatment:
in all 7 patients: marked improYement ao D. Patient group: 3 patients Duration of treatment: 16 weeks Result of treatment:
in all 3 patients: marksd improvement In all cases, slight erythema but no disturbing symptoms (burning, itching) developed.
.
- : : .:
. . . .
, , . ~ .
26,26,Z6,27,27,Z7-Hexafluoro-l a,25-dihydroxy-16,17-25 dehydro-23,24-didehydro vitamin D3 has not yet been described and can be ob~ained as follows:
A. To 522 mg of [3aS-[3(S*),3aa,7a,7a~]]-[[3a,4,5,6,7,7a-hexahydro-3a-methyl-3-(1-methyl-3-butynyl~-1 H-inden-7-30 yl~oxy]trimethylsilane in 15 ml of anhydrous tetrahydrofuran,1.85 ml of 1.6M solution of n-butyllithium in hexane was added dropwise after cooling at -75C over 5 minutes and the mixture was stirred at -75C for 30 min. Then a stream of hexafluoroacetone was bubbled into the mixture for 15 min with temperature maintained at 35 -75C. The reaction mixture was stirred for one additional hour, and then quenched with 1 :1 mixture of 2M KHC03 and 1 M Roche!le salt added dropwise. The mixture was stirred at room temperature for one hour and then dilu~ed with 25 ml of the same salt solution. After .' . -.
- :
.... . .
2~9~6 extraction with CH2CI2, the organic phase was washed with 50 ml of the same salt solution, dried and evaporated. The residue was azeotroped with benzene to give 2.38 g of crude oily product.
Purification was performed by flash chromatography (EtOAc-hexane 5 1:9) to give 817 mg of [3aS-[3(S*),3[3aa,7a,7a~]]-1,1,1-trifluoro-6[3a,4,5,6,7,7a-hexahydro-3a-methyl-7-[(trimethylsilyl)oxy]-1 H-inden-3-yl]-2-(trifluoro-methyl)-3-heptyn-2-ol.
B. To a solution of 812 mg of [3aS-[3(S*),3aa,7a,7a~]3-1,1,1-10 trifluoro-6[3a,4,5,6,7,7a-hexahydro-3a-methyl-7-[(trimethylsilyl)-oxy]-1 H-inden-3-yl]-2-(trifluoromethyl)-3-heptin-2-ol in 18 ml of anhydrous tetrahydrofuran there was added 5.34 ml of tetra-butyl-ammonium fluoride in tetrahydrofuran, and the mixture was stirred at room temperature under argon for 8û min. The reaction was then 15 quenched by addition of 9 ml of half-saturated NaHC03 and stirred at room temperature for an additional 20 min. Excess of tetrahydro-furan was removed by evaporation and additional 9 ml of bicarbonate was added. The mixture was extracted with ethyl acetate, the ~-extract was washed with brine~ dried and evaporated. Af~er ao purification by flash chromatography (EtOAc-hexane 1:2), it gave 690 mg of [3aR-~1(R*),3aa,4~B,7a,B]]-3,3a,5,6,7,7a-hexahydro-7a-methyl-1 -[6,6,6-trifluoro-5-hydroxy-1 -methyl-5-(trifluoro-methyl~-3-hexynyl] -4H-inden-4-ol.
25 C. To a solution of 100 mg of [3aR,-[1(R*),3aa,4~,7a~]-3,3a,5,6,7,7a-hexahydro-7a-methyl-1 -[6,6,6-trifluoro-5-hydroxy-1-methyl-5-(trifluoromethyl)-3-hexynyl]-4H-inden-4-ol in 6 ml of anhydrous CH2CI2 there was added at room temperature, 176 mg of pyridinium chlorochromate, and the mixture was stirred at room 30 temperature for 50 min under argon. To this mixture there was added 9 ml of ether under stirring, then it was filtered and the filtrate evaporated to dryness. The crude product thus obtained was purified by chromatography on silicagel column with ethyl acetate-hexane 1:3 to give [3aR-[1(R*),3aa,7a~]]-3,3a,5,6,7,7a-hexahydro-7a-35 methyl-1-[6,6,6-trifluoro-5-hydroxy-1-methyl-5-(trifluoro-methyl)-3-hexinyl~-4H-inden-4-one.
.
.. , ~ , . ' . ,. ' .
... - ', '' ' . . , - ~ : : .-' .
.
209~
n To a solution of 333 mg of [35-(30c,5~,Z)]-2-~2-[2-methylene-3, 5 -bis [ [( 1 ,1 -dimethylethyl)dimethylsilyl]oxy~cyclohexylidene]-ethyl]diphenyl phosphine oxide in 7 ml anhydrous tetrahydrofuran there was added at -75C, 0.325 ml of 1.6M n-butyllithium in hexane 5 under argon. After stirring for 6 min, a solution of 73 mg of ~3aR-[1 (R*),3aa,7a~]]-3,3a,5,6,7,7a-hexahydro-7a-methyl-1-L6,6,6-trifluoro-5 -hydroxy- 1 -methyl-5-~trifluoromethyl)-3-hexiny]-4H-inden-4-one in 5 ml anhydrous tetrahydrofuran was added dropwise.
The reaction mixture was stirred for 1 hour at -75C, and then 10 quenched with 2.6 ml of 1:1 mixture of 2N Rochelle salt and 2N
K~C03 solutions and was allowed to warm to room temperature. It was then diluted with 10 ml of the same salt solution and extracted with Pthyl acetate. The extract was washed with brine, dried and evaporated. The crude intermediate was purified by flash chromato-graphy on silica gel column wi~h ethyl acetate-hexane 1:5 to give disilyl-protected 1 ,25-dihydroxy-1 6-ene-23-yne-26,27-hexafluoro-cholecalciferol.
E. To 92 mg of the disilyl protected 1,25-dihydroxy 16-ene-23-ao yne-26,27-hexafluoro-cholecalciferol in 5 ml anhydrous ~etrahydro-furan in a dark wall flask there was added 0.89 ml of lM tetrabutyl-ammonium fluoride in tetrahydrofuran, and the mixture was stirred for 16 hrs under argon. The reaction was then quenched with 3 ml of half-saturated NaHC03 and stirred at room temperature. It was then 25 extracted with ethyl acetate. The extract was washed with half-saturated NaHC03 and brine, then dried and evaporated. The crude product was purified by flash chromatography with ethyl-acetate 4:1, to give 1 ,25-dihydroxy-1 6-ene-23-yne-26,27-hexafluoro-cholecalciferol as a foamy glass; [a]25 = +59.1 (c 0.11, CH30H).
In accordance with the invention the 9-cis- or 13-cis-retinoic acid or acitretin or a salt or ester thereof can be used in the form of pharmaceutical preparations which also contain a vitamin D
derivative or as preparations which contain an ad hoc combination 35 with vitamin D derivatives.
2~9~196 The use o~ 9-cis-retinoic acid, pharrnaceutically usable salts or esters thereof and vitamin D derivatives, especially 9-cis-retinoic acid and calciferol is preferred.
The active substances can be administered ~opically or orally for the treatment of psoriasis. Topical prepara~ions can be present as creams, ointments, lotions, tinctures or gels which contain the ac~ive substances together with carriers which are usual in such preparations. The content of 9-cis- or 13-cis-retinoic acid or 10 acitretin, salts or esters thereof in these preparations can be about 0.001-0.1 wt.%, preferably 0.003-0.03 wt.%. The content of vitamin D derivative in such preparations can be about 1 ~lg/g to about 100 llg/g. These preparations are applied to ~he diseased site on the skin according to the requirements of the patien~, e.g. once or twice per day.
Preparations for oral administration can be present in the form of tablets, capsules, solutions or emulsions. For the treatment of psoriasis, such preparations can be administered in dosages of ao about 0.01 mg to about 3 m~ of 9-cis-or 13-cis-re~inoic acid or acitretin or salt or ester thereof per kg body weight per day, preferably about 0.025 mg/kg to about 1.5 mg/kg per day; and about 0.001 ~lg/kg to about 0.1 llg/kg of vitamin D derivative, preferably about O.OOS ~lg/kg to about 0.05 ~lg/kg, per day. Solid dosage forms 25 such as tablets and capsules conveniently contain per dosage unit about 1 mg to about 50 rng of 9-cis- or 13-cis-retinoic acid or acitretin and, respectively, about 0.1 1l9 to about 1 1l9 of vitamin D
derivative.
For the treatment and prevention of tumours, the active substances or the preparations in accordance with the invention can be administered enterally, parenterally or topically. Fxamples of tumours which can be treated with the preparations in accordance with the invention or the active substance combination in 35 accordance with the invention are haematological tumours such as leukaemia, especially acute promyelocy~aric leukaemia and Iymphomas. Furthermore precancerous lesions of the epitheliai tissue such as actinic keratoses of the skin, oral leukoplakias, - , . ~ .. ..
,, ~, . - . . ~ . .. -. . .
2~6~6 dysplasias of the larynx, bronchi and cervix; as well as carcinornas of the skin, buccal cavity, the bronchi, the larynx, pharynx, stomach, colon, uterus, pancreas, the bladder, breast and pros~ate can be treated by the administration of an effective amount of the 5 preparations or active substance combination in accordance with the invention.
Examples of pathological or undesired immune reactions are autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, insulin-dependent diabetes, ~upus erythematosus, pemphigus vulgaris, pemphi~us foliaceus, myasthenia gravis, ankylosing spondylitis, autoimmune diseases of the thyroid gland such as Hashimoto's disease and primary thyroid gland failure;
scleroderma, uveitis, Behcet's disease, Crohn's disease, auto-immune-conditioned myocarditis and autoimmune-conditioned poly-glandular syndrome; as well as allergies such as ailergic rhinitis, atopic dermatitis, asthma and celiaca. Other indications are undesired immune reactions in organ or cell transplants suoh as kidney, heart, pancreas beta-islet cell, bone marrow and liver ao transplants.
A further aspect of the invention is concerned with the use of the preparations and, respectively, active substance combination in accordance with the invention for the preferably emeral or 25 parenteral treatrnent and prevention of osteoporosis. In all of these indications the active substances can be used in the dosage ranges given above, whereby the individual dosage will depend on the nature of the disease to be treated and on the age and condi~ion of the patient and can be determined within the framework of medical 30 expertise. The invention is illustrated in more detail by the following Examples.
- - ' - . . .
.
. , : . . - ~, . - , .
.
:, : -, 2 0 ~ 6 Example ~
Ca~ules containing 9-cis-retinoic_~$id ~ -9-cis-Retinoic acid 20.0 mg Gelatine ~BIoom number 30) 70.0 mg Maltodextrin 108.0 mg dl-a-Tocopherol 2.0 mg Na ascorbate 10.0 mg Microcrystalline cellulose 48.0 mg Mg stearate 2.0 mg Total 260 mg -The active substance is wet-ground in a soiution of gelatine, 5 maltodextrin, tocopherol and Na ascorbate and the suspension obtained is spray-dried. Thereafter, the cellulose and the Mg stearate are admixed and 260 mg aliquots of the mixture are filled into hard gelatine capsules.
Capsules cQntainina calcitriol Calcitriol 0.25 ~lg Butylated hydroxytoluene 0.016 mg Buylated hydroxyanisole 0.016 mg Fractionated coconut oil ad 160.0 mg The ingredients are mixed and the oily solution is filled under an inert gas into soft gelatine capsules each containing 160 mg.
,5 .. . - - .. - . - , . ~
. .: . . - : ' . . '' . . :-, , . . - - . . . . . . .
... . ~ . . :
,. - . .... : .
- . . ~ . .. . .
2~9~1~6 Ex~le 3 Capsules ~ontaining 9-cis-retinoic acid and calcitri~!
Calcitriol 0.25 ~g 9-cis-Retinoic acid 20 mg Polyethylene glycol 400 200 mg Butylated hydroxyanisole 0~1 mg The ingredients are mixed and filled under an inert gas into s soft gelatine capsules having a fill weight of 220 mg.
Example 4 Cre~m ~on~i~ing ~-cis-retinoic acid and calci~riol Calcitriol 2 mg 9-cis-Retinoic acid 30 mg Cetyl alcohol 1.5 mg Stearyl alcohol 2.5 mg Sorbitan monostearate 2.0mg Glyceryl monostearate and polyoxyethylene glycolsteara~e 4.0 mg Polysorbate 60 l.Omg Mineral oil 4.0 mg Propylene glycol 5.0mg Propylparaben 0.05 mg Butylated hydroxyanisole 0.05 mg Sorbitol solution 2.0 mg Na EDTA 0.01 mg Methylparaben 0.18 mg Dist. water q.s. ad 100 9 Example 5 The activity of the combination in accordance with the invention of 9-cis-retinoic acid and calcitriol on the differentiation of hurnan promyelocytic leukaemia cells (HL-60) can be . . .
,. , . . ~
-..
.. ~.. . ~.
209~96 g demonstrated in vitro in the tes~ procedure described in Cancer Research 45, 4244 (1985). The effects obtained with various concentrations of the active substances on cell differentiation (measured by detecting the reduction effect on nitroblue-tetra-5 zolium, NBT) can be concluded from Figure 1. The measurement ofthe NBT reduction was effected according to a modified method of Pick et al. in J. Reticul. Soc. 30, 581 (1981). In each case, 3.104 cells in 200 ,ul were incubated for 48 hours with the active substances. The cells were centrifuged off and treated with in each 10 case 100 1ll of pre-warmed NBT solution (1 mg~ml, diluted with Dulbeccos PBS) and PMA (123 mg/ml in DMSO) and incubated at 37~C
for 1 hour. After cen~rifugation, 100 1ll of 90% DMF, diluted with 10% SDS, were added, the mixture was incubated at 37C and the extinction (OD) was measured at 550 mm.
The curves in Fig. 1 show the effect of calcitriol alone and of combinations of varying amounts of calcitriol with (from above downwards) 80 nM, 16 nM and 3.2 nM 9-cis-retinoic acid.
ExamplQ 6 Patients with multiple actinic keratoses were treated -topically with 9-cis-retinoic acid and calcitriol. 9-cis-retinoic acid was applied as a 0.01% (v/v) solution in ethanol/propylene glycol 2s (50:50). Calcitriol was applied as a 0.0025% (w/w) cream.
Treatment was carried out for 4-16 weeks with adminis~ration of the preparations to the skin once daily. 9-cis-retinoic acid was applied first, followed, after drying (3 minutes~, by calcitriol cream.
Occlusive dressing was not used.
The following results were obtained with various patient groups:
, .- . :
.
2 ~
- lo -A. Patient group: 16 patients Duration of treatment: 4 weeks Result of treatment:
6 patients: slight improvement 5 patients: moderate improvement 5 patients: marked irnprovement B. Patient group: 16 pa~ients Duration of treatment: 8 weeks Result of treatment:
3 patients: slight improvement 4 patients: moderate improvement 9 patients: marked improvement C. Patient group: 7 patients Duration of treatment: 1Z weeks Result of treatment:
in all 7 patients: marked improYement ao D. Patient group: 3 patients Duration of treatment: 16 weeks Result of treatment:
in all 3 patients: marksd improvement In all cases, slight erythema but no disturbing symptoms (burning, itching) developed.
.
- : : .:
. . . .
, , . ~ .
Claims (14)
1. Pharmaceutical preparation containing 9-cis- or 13-cis retinoic acid, or acitretin, a pharmaceutically usable salt or ester thereof and a vitamin D derivative as active ingredients, and usual pharmaceutical carriers.
2. A preparation according to claim 1, wherein the active ingredients are 9-cis retinoic acid, a pharmaceutically usable salt or ester thereof and a vitamin D derivative.
3. A preparation according to claim 2, wherein the active ingredients are 9-cis retinoic acid and calcitriol.
4. A product containing 9-cis- or 13-cis retinoic acid or acitretin, a pharmaceutically usable salt or ester thereof and a vitamin D derivative as a combination preparation for the simultaneous, separate or sequential use in the treatment of psoriasis, osteoporosis or tumours.
5. A product according to claim 4 for use in the treatment of pathological or undesired immune reactions.
6. A product according to claim 4 or 5 containing 9-cis retinoic acid and calcitriol.
7. A commercial pack containing 9-cis- or 13-cis retinoic acid, or acitretin, a pharmaceutically usable salt or ester thereof as active ingredients, together with instructions for the use thereof in combination with a vitamin D derivative for the simultaneous, separate or sequential use in the treatment of psoriasis, osteoporosis or tumours.
8. A commercial pack according to claim 7 for use in the treatment of pathological or undesired immune reactions.
9. A commercial pack according to claim 7 or 8 containing 9-cis retinoic acid together with instructions for the combined use with calcitriol.
10. 9-cis- or 13-cis retinoic acid or acitretin, a pharma-ceutically usable salt or ester thereof and a vitamin D derivative for use as a medicament.
11. 9-cis retinoic acid and calcitriol for use according to claim 10.
12. The use of 9-cis- or 13-cis retinoic acid, or acitretin, a pharmaceutically usable salt or ester thereof in the manufacture of pharmaceutical preparations for the combined application with a vitamin D derivative in the treatment of psoriasis, osteoporosis or tumours.
13. The use according to claim 12 in the treatment of pathological or undesired immune reactions.
14. The use of 9-cis retinoic acid for the combined application with calcitriol according to claims 12 or 13.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
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CH1619/92 | 1992-05-20 | ||
CH161992 | 1992-05-20 | ||
CH92693 | 1993-03-26 | ||
CH926/93 | 1993-03-26 |
Publications (1)
Publication Number | Publication Date |
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CA2096196A1 true CA2096196A1 (en) | 1993-11-21 |
Family
ID=25686129
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CA002096196A Abandoned CA2096196A1 (en) | 1992-05-20 | 1993-05-13 | Pharmaceutical compositions |
Country Status (12)
Country | Link |
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EP (1) | EP0579915A1 (en) |
JP (1) | JPH0632740A (en) |
KR (1) | KR940005278A (en) |
CN (1) | CN1080525A (en) |
AU (1) | AU3716193A (en) |
CA (1) | CA2096196A1 (en) |
CZ (1) | CZ83293A3 (en) |
HU (1) | HUT66864A (en) |
IL (1) | IL105700A0 (en) |
NO (1) | NO931831L (en) |
NZ (1) | NZ247630A (en) |
TW (1) | TW272187B (en) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5837728A (en) * | 1995-01-27 | 1998-11-17 | Molecular Design International | 9-cis retinoic acid esters and amides and uses thereof |
US6242435B1 (en) | 1998-07-16 | 2001-06-05 | Gentrix Llc | Compositions and methods of treating abnormal cell proliferation |
AU739440B2 (en) * | 1997-08-23 | 2001-10-11 | Basilea Pharmaceutica Ag | Treatment of cell-mediated immune diseases |
US6479474B2 (en) | 1999-07-08 | 2002-11-12 | Wisconsin Alumni Research Foundation | Dietary calcium as a supplement to vitamin D compound treatment of multiple sclerosis |
US6552009B2 (en) | 1998-07-16 | 2003-04-22 | Gentrix Llc | Compositions and methods of treating abnormal cell proliferation |
US8541469B2 (en) | 1997-08-23 | 2013-09-24 | Glaxo Group Limited | Treatment of cell-mediated immune diseases |
Families Citing this family (19)
Publication number | Priority date | Publication date | Assignee | Title |
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US6461622B2 (en) * | 1994-09-07 | 2002-10-08 | Johnson & Johnson Consumer Companies, Inc. | Topical compositions |
DK128494A (en) * | 1994-11-08 | 1996-05-09 | Edel K Seidenschnur | Treatment of keratinous and psoriatic disease states with nail polish containing vitamin D metabolite, or derivative, and / or vitamin A derivative |
AU6944796A (en) * | 1995-09-28 | 1997-04-17 | Teijin Limited | Preventive or remedy for hyperthyreosis |
US5716946A (en) * | 1996-02-13 | 1998-02-10 | Wisconsin Alumni Research Foundation | Multiple sclerosis treatment |
DK0815858T3 (en) * | 1996-07-01 | 2001-10-08 | Nisshin Flour Milling Co | Pharmaceutical composition containing 9-cis-retinoic acid alpha-tocopherol ester for the treatment of leukemia |
US5891865A (en) * | 1996-10-04 | 1999-04-06 | Wisconsin Alumni Research Foundation | Treatment of arthritic disease induced by infectious agents |
FR2767058B1 (en) * | 1997-08-05 | 2000-05-05 | Centre Nat Rech Scient | USE OF A RETINOID-LIKE COMPOUND, IN PARTICULAR RETINOIC ACID FOR THE PREPARATION OF A MEDICINAL PRODUCT FOR THE TREATMENT OF OBESITY. |
US6833373B1 (en) | 1998-12-23 | 2004-12-21 | G.D. Searle & Co. | Method of using an integrin antagonist and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia |
US6858598B1 (en) | 1998-12-23 | 2005-02-22 | G. D. Searle & Co. | Method of using a matrix metalloproteinase inhibitor and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia |
US6733779B2 (en) * | 1999-08-26 | 2004-05-11 | L. Dean Parks | Method of treating benign prostatic hyperplasia and other benign prostate conditions |
FR2807662A1 (en) * | 2000-04-12 | 2001-10-19 | Cll Pharma | PROCESS FOR STABILIZING THE SIZE OF AN ACTIVE INGREDIENT DISPERSE IN A LIQUID AND ITS APPLICATIONS |
US6339107B1 (en) | 2000-08-02 | 2002-01-15 | Syntex (U.S.A.) Llc | Methods for treatment of Emphysema using 13-cis retinoic acid |
JP2002104995A (en) * | 2000-09-29 | 2002-04-10 | Masahiko Hosaka | Telomerase activity inhibitor |
JP4326159B2 (en) | 2001-02-09 | 2009-09-02 | 株式会社ジェイテクト | Ball bearing |
WO2004098612A2 (en) * | 2003-05-07 | 2004-11-18 | Ab Science | Calcitriol analogs of uses thereof |
US20070099996A1 (en) * | 2003-05-20 | 2007-05-03 | Shashikanth Isloor | Pharmaceutical compositions of acitretin |
WO2005102296A2 (en) * | 2004-04-23 | 2005-11-03 | Heptagen Limited | Combinations for the treatment of immunoproliferative skin disorders such as psoriasis |
CN102727476B (en) * | 2012-06-14 | 2014-05-14 | 合肥博太医药生物技术发展有限公司 | Application of retinoic acid and its derivatives in preparation of drugs preventing and treating osteoporosis |
JP2019014676A (en) * | 2017-07-06 | 2019-01-31 | 東海カプセル株式会社 | Capsule agent |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6360910A (en) * | 1986-09-01 | 1988-03-17 | Shiseido Co Ltd | Skin drug for external use |
-
1993
- 1993-04-14 TW TW082102845A patent/TW272187B/zh active
- 1993-04-23 AU AU37161/93A patent/AU3716193A/en not_active Abandoned
- 1993-05-06 CZ CZ93832A patent/CZ83293A3/en unknown
- 1993-05-08 EP EP93107492A patent/EP0579915A1/en not_active Withdrawn
- 1993-05-13 CA CA002096196A patent/CA2096196A1/en not_active Abandoned
- 1993-05-14 NZ NZ247630A patent/NZ247630A/en unknown
- 1993-05-14 HU HU9301404A patent/HUT66864A/en unknown
- 1993-05-14 IL IL105700A patent/IL105700A0/en unknown
- 1993-05-17 JP JP5114777A patent/JPH0632740A/en active Pending
- 1993-05-18 KR KR1019930008442A patent/KR940005278A/en not_active Application Discontinuation
- 1993-05-19 CN CN93106248A patent/CN1080525A/en active Pending
- 1993-05-19 NO NO931831A patent/NO931831L/en unknown
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5837728A (en) * | 1995-01-27 | 1998-11-17 | Molecular Design International | 9-cis retinoic acid esters and amides and uses thereof |
AU739440B2 (en) * | 1997-08-23 | 2001-10-11 | Basilea Pharmaceutica Ag | Treatment of cell-mediated immune diseases |
US8541469B2 (en) | 1997-08-23 | 2013-09-24 | Glaxo Group Limited | Treatment of cell-mediated immune diseases |
US6242435B1 (en) | 1998-07-16 | 2001-06-05 | Gentrix Llc | Compositions and methods of treating abnormal cell proliferation |
US6552009B2 (en) | 1998-07-16 | 2003-04-22 | Gentrix Llc | Compositions and methods of treating abnormal cell proliferation |
US6479474B2 (en) | 1999-07-08 | 2002-11-12 | Wisconsin Alumni Research Foundation | Dietary calcium as a supplement to vitamin D compound treatment of multiple sclerosis |
Also Published As
Publication number | Publication date |
---|---|
AU3716193A (en) | 1993-11-25 |
NO931831D0 (en) | 1993-05-19 |
CN1080525A (en) | 1994-01-12 |
HU9301404D0 (en) | 1993-09-28 |
NZ247630A (en) | 1995-12-21 |
CZ83293A3 (en) | 1993-12-15 |
TW272187B (en) | 1996-03-11 |
IL105700A0 (en) | 1993-09-22 |
KR940005278A (en) | 1994-03-21 |
HUT66864A (en) | 1995-01-30 |
JPH0632740A (en) | 1994-02-08 |
EP0579915A1 (en) | 1994-01-26 |
NO931831L (en) | 1993-11-22 |
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