GB2079285A - Diphosphonate derivatives and pharmaceutical compositions containing them - Google Patents
Diphosphonate derivatives and pharmaceutical compositions containing them Download PDFInfo
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- GB2079285A GB2079285A GB8022463A GB8022463A GB2079285A GB 2079285 A GB2079285 A GB 2079285A GB 8022463 A GB8022463 A GB 8022463A GB 8022463 A GB8022463 A GB 8022463A GB 2079285 A GB2079285 A GB 2079285A
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- XQRLCLUYWUNEEH-UHFFFAOYSA-L diphosphonate(2-) Chemical class [O-]P(=O)OP([O-])=O XQRLCLUYWUNEEH-UHFFFAOYSA-L 0.000 title claims abstract description 12
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 69
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 28
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 3
- 150000002367 halogens Chemical class 0.000 claims abstract description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 3
- -1 Tetrabutyl 1 (p-chlorophenyl)methane Chemical compound 0.000 claims description 22
- PAXPHUUREDAUGV-UHFFFAOYSA-N OP(=O)OP(O)(O)=O Chemical class OP(=O)OP(O)(O)=O PAXPHUUREDAUGV-UHFFFAOYSA-N 0.000 claims description 5
- ISZIECUHZQGAPV-UHFFFAOYSA-N NP(O)(=O)OP(O)=O Chemical class NP(O)(=O)OP(O)=O ISZIECUHZQGAPV-UHFFFAOYSA-N 0.000 claims description 4
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- ZJXZSIYSNXKHEA-UHFFFAOYSA-N ethyl dihydrogen phosphate Chemical compound CCOP(O)(O)=O ZJXZSIYSNXKHEA-UHFFFAOYSA-N 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 abstract description 78
- 235000012000 cholesterol Nutrition 0.000 abstract description 37
- 230000000694 effects Effects 0.000 abstract description 16
- 108010010234 HDL Lipoproteins Proteins 0.000 abstract description 8
- 102000015779 HDL Lipoproteins Human genes 0.000 abstract description 8
- 230000000489 anti-atherogenic effect Effects 0.000 abstract description 4
- 230000002218 hypoglycaemic effect Effects 0.000 abstract description 4
- 102000004895 Lipoproteins Human genes 0.000 abstract description 3
- 108090001030 Lipoproteins Proteins 0.000 abstract description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 34
- 210000002966 serum Anatomy 0.000 description 20
- 241000700159 Rattus Species 0.000 description 18
- 239000000203 mixture Substances 0.000 description 16
- 150000002632 lipids Chemical class 0.000 description 15
- 239000002253 acid Substances 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 210000004185 liver Anatomy 0.000 description 12
- 238000000034 method Methods 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 201000001320 Atherosclerosis Diseases 0.000 description 11
- 125000003118 aryl group Chemical group 0.000 description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 11
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- 210000000709 aorta Anatomy 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 230000003247 decreasing effect Effects 0.000 description 9
- JQVDAXLFBXTEQA-UHFFFAOYSA-N dibutylamine Chemical compound CCCCNCCCC JQVDAXLFBXTEQA-UHFFFAOYSA-N 0.000 description 9
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 8
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 8
- 239000011575 calcium Substances 0.000 description 8
- 229910052791 calcium Inorganic materials 0.000 description 8
- 230000009102 absorption Effects 0.000 description 7
- 238000010521 absorption reaction Methods 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000013078 crystal Substances 0.000 description 7
- 230000037356 lipid metabolism Effects 0.000 description 7
- 238000001953 recrystallisation Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- 230000008021 deposition Effects 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 235000019198 oils Nutrition 0.000 description 6
- 230000000704 physical effect Effects 0.000 description 6
- 150000003839 salts Chemical group 0.000 description 6
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical class [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- 239000002285 corn oil Substances 0.000 description 5
- 235000005687 corn oil Nutrition 0.000 description 5
- 230000007423 decrease Effects 0.000 description 5
- CZHYKKAKFWLGJO-UHFFFAOYSA-N dimethyl phosphite Chemical compound COP([O-])OC CZHYKKAKFWLGJO-UHFFFAOYSA-N 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 150000003626 triacylglycerols Chemical class 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 208000024172 Cardiovascular disease Diseases 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 239000003524 antilipemic agent Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- KNHUKKLJHYUCFP-UHFFFAOYSA-N clofibrate Chemical compound CCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 KNHUKKLJHYUCFP-UHFFFAOYSA-N 0.000 description 4
- 229960001214 clofibrate Drugs 0.000 description 4
- 235000005911 diet Nutrition 0.000 description 4
- 230000037213 diet Effects 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 235000021588 free fatty acids Nutrition 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 150000003904 phospholipids Chemical class 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
- 206010002091 Anaesthesia Diseases 0.000 description 3
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000002159 abnormal effect Effects 0.000 description 3
- 230000037005 anaesthesia Effects 0.000 description 3
- 210000001367 artery Anatomy 0.000 description 3
- 230000003913 calcium metabolism Effects 0.000 description 3
- 239000012230 colorless oil Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 238000011835 investigation Methods 0.000 description 3
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 3
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- TUKCAVDKGXMEKW-UHFFFAOYSA-N (4-chlorophenyl)-dimethoxyphosphorylmethanone Chemical compound COP(=O)(OC)C(=O)C1=CC=C(Cl)C=C1 TUKCAVDKGXMEKW-UHFFFAOYSA-N 0.000 description 2
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 2
- OODRWLGKUBMFLZ-UHFFFAOYSA-N 2-(4-chlorophenoxy)-2-methylpropanoyl chloride Chemical compound ClC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 OODRWLGKUBMFLZ-UHFFFAOYSA-N 0.000 description 2
- NOWMMYCECIINPF-UHFFFAOYSA-N CC1=C(C(=C(C(=C1OC(C)(C)C)C)C)Cl)C Chemical compound CC1=C(C(=C(C(=C1OC(C)(C)C)C)C)Cl)C NOWMMYCECIINPF-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 241000700157 Rattus norvegicus Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- XEDLVIBRXVIWLS-UHFFFAOYSA-N benzoylphosphonic acid Chemical group OP(O)(=O)C(=O)C1=CC=CC=C1 XEDLVIBRXVIWLS-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000002308 calcification Effects 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 150000001793 charged compounds Chemical class 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229940126142 compound 16 Drugs 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- XPPKVPWEQAFLFU-UHFFFAOYSA-L diphosphate(2-) Chemical class OP([O-])(=O)OP(O)([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-L 0.000 description 2
- 239000003651 drinking water Substances 0.000 description 2
- 235000020188 drinking water Nutrition 0.000 description 2
- 238000006911 enzymatic reaction Methods 0.000 description 2
- ZFUSXYNPPXGANH-UHFFFAOYSA-N ethyl 4-chloro-6-iminocyclohexa-2,4-diene-1-carboxylate Chemical compound N=C1C(C(=O)OCC)C=CC(=C1)Cl ZFUSXYNPPXGANH-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 2
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 description 2
- 238000005292 vacuum distillation Methods 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
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- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- GXZVJBYYRGAQQV-UHFFFAOYSA-N (4-chlorophenyl)-(4-dimethoxyphosphorylcarbonylphenyl)methanone Chemical compound C1=CC(C(=O)P(=O)(OC)OC)=CC=C1C(=O)C1=CC=C(Cl)C=C1 GXZVJBYYRGAQQV-UHFFFAOYSA-N 0.000 description 1
- OPCMVVKRCLOEDQ-UHFFFAOYSA-N 1-(4-chlorophenyl)-2-(methylamino)pentan-1-one Chemical compound ClC1=CC=C(C=C1)C(C(CCC)NC)=O OPCMVVKRCLOEDQ-UHFFFAOYSA-N 0.000 description 1
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 1
- BDKLKNJTMLIAFE-UHFFFAOYSA-N 2-(3-fluorophenyl)-1,3-oxazole-4-carbaldehyde Chemical compound FC1=CC=CC(C=2OC=C(C=O)N=2)=C1 BDKLKNJTMLIAFE-UHFFFAOYSA-N 0.000 description 1
- DNKCHGSCDQXXLE-UHFFFAOYSA-N 2-(4-chlorophenoxy)-1-dimethoxyphosphoryl-2-methylpropan-1-one Chemical compound COP(=O)(OC)C(=O)C(C)(C)OC1=CC=C(Cl)C=C1 DNKCHGSCDQXXLE-UHFFFAOYSA-N 0.000 description 1
- IHEFZWIFKNHUFJ-UHFFFAOYSA-N 2-(4-chlorophenyl)-1-dimethoxyphosphoryl-2-methylpropan-1-one Chemical compound COP(=O)(OC)C(=O)C(C)(C)C1=CC=C(Cl)C=C1 IHEFZWIFKNHUFJ-UHFFFAOYSA-N 0.000 description 1
- GQOLYABRQATDOI-UHFFFAOYSA-N 2-(4-chlorophenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)C1=CC=C(Cl)C=C1 GQOLYABRQATDOI-UHFFFAOYSA-N 0.000 description 1
- NDBFWVKQRKSULE-UHFFFAOYSA-N 2-(4-chlorophenyl)-2-methylpropanoyl chloride Chemical compound ClC(=O)C(C)(C)C1=CC=C(Cl)C=C1 NDBFWVKQRKSULE-UHFFFAOYSA-N 0.000 description 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 1
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- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
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- 239000012312 sodium hydride Substances 0.000 description 1
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- 238000012360 testing method Methods 0.000 description 1
- 125000003698 tetramethyl group Chemical group [H]C([H])([H])* 0.000 description 1
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- WVLBCYQITXONBZ-UHFFFAOYSA-N trimethyl phosphate Chemical compound COP(=O)(OC)OC WVLBCYQITXONBZ-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3839—Polyphosphonic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3882—Arylalkanephosphonic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4025—Esters of poly(thio)phosphonic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4056—Esters of arylalkanephosphonic acids
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
Abstract
This invention relates to new diphosphonate compounds of formula (I> <IMAGE> where X is H, OH, <IMAGE> or NH2, R and R' identical or different are H, CH3, C2H5 or C4H9-, m is zero or 1, and A is selected from the group comprising (CH3)3-C-, Y-C6H4-, Y-C6H4-O-C(CH3)2-, Y-C6H4-C(CH3)2-, Y-C6H4C(O)-C6H4 Y-C6H4-(CH2)n- and Y-C6H4-O-(CH2)n-, where n is an integer from 1 to 6 and Y is H, CH3, OCH3, or halogen. These compounds possess remarkable activity as hypoglycemic and/or antiatherogenic agents, and are usable in pharmaceutical compositions to alter lipoprotein profiles in favour of high density lipoproteins and to clear cholesterol from various tissues.
Description
SPECIFICATION
Diphosphonate derivatives and pharmaceutical compositions containing them
The present invention relates to diphosphonate derivatives, and more particularly to phenylalkyland phenoxylalkyl-diphosphonates and hydroxydiphosphonates, phosphonophospha,tes and aminodiphosphonates as well as antiatherogenic preparations containing said compounds for the treatment of human cardiovascular diseases.
Over the past few years, coronary heart prevention studies have been performed with common hypolipidemic agents such as clofibrate. More recently, the results of these studies have left the therapeutic effectiveness of these compounds in question (see for example New Engl. J. Med. 296, 1185-1190, 1970; Atherosclerosis Rev. 2, 113-153, 1977; The Lancet 8100, 1131-1132, 1978; and Brit. Med. J. 6152, 1585, 1978).
It is now desirable to make use of compounds which have a rapid and effective activity for decreasing cholesterol content directly in the tissues and not only in blood as it is the case for most common hypolipidemic agents.
Therefore, the present inventors have undertaken investigations on diphosphono compounds and have found that diphosphonates represented by general formula (I) possess a remarkable activity as antiatherogenic agents, as well as the ability to alter lipoprotein profiles in favour of high density lipoproteins and to directly clear cholesterol from various tissues.
This ability to remove cholesterol from tissues gives to these compounds (I) the potential of being used in diseases triggered by, or resulting from, abnormal cholesterol synthesis, metabolism and deposition. For example, cardiovascular diseases in general which are associated with cholesterol deposition in arterial walls (Atheromas), familial hypercholesterolemia and cholesterol deposition in subscutaneous tissues (Xanthomatosis), gallstones (cholesterol precipitated), cancer tissues in which cholesterol metabolism is impaired, thrombosis due to cholesterol rich-hypersensitive platelets (Shattil, S. J. et al The Journal of Clinical Investigation 55, 636-643, 1975), and deseases due to abnormal lipid content of red blood cells (Smith et al N. Engl. J. Med. 271, 396-398, 1963).
Since cholesterol is the precursor for steroid hormones (male and female sex hormones and for corticostern'(ds), abnormal synthesis of these hormones might be regulated by the use of such compounds. The possible uses of phosphonates in the fields described above are under investigation.
Some of these compounds of formula (I) further possess an activity as hypoglycemic agents.
In the above formula (I), X is H, OH,
or NH2; R and R' identical or different are H, CH C2H5 or C4H9; m is zero or 1; and A is selected from the group comprising
wherenis an integer from 1 to 6 and Y is H, CH3, OCH3, or an halogen, especially as Cl or F.
The hydroxydiphosphonate compounds of formula (la),
where R, R1 and A are as defined above, can be prepared according to the following scheme (with
R=R'=CH3 or C2H5):
The phosphonophosphates of formula (Ib):
where R, R' and A are as defined above, can be prepared according to the following scheme (with R = Rx = CH3 or C2H5):
The diphosphonate compounds of formula (Ic),
where R, R' and A are as defined can be prepared according to the following scheme:
where Z is Br or Cl.
The aminodiphosphonate compounds of formula (Id)
where R, R' and A are as described above can be prepared according to the following scheme, with
R=R'=C2H5 or C4H9, and
Y being as defined above.
The present invention will be now further described by reference to the following Examples 1 to 9 directed to the preparation of some of the compounds of formula (I).
EXAMPLE 1 Tetramethyj-1 (p-chlorophenyl)methane hydroxy 1, 1-diphosphonate (Compound 4) (Method adapted from D. A. Nicholson and H. Vaughn, Journal of Organic Chemistry 36, 3843, 1971)
Dimethyl phosphite (4.40 9, 40 mmol) and di(n-butyl)amine (0.24 g, 2 mmol) were dissolved in 90 ml ether and the resulting solution was cooled to OOC. Dimethyl p-chlorobenzoylphosphonate (9,96 g, 40 mmol) (prepared according to Journal of American Chemical Society 86,3862, 1964) was added dropwise with rapid stirring. A white solid separated out almost immediately. The mixture was stirred for one hour at 00, and filtration yielded 13.0 g (36 mmol) of the title compound.
Purification was done by dissolving the crude compound in acetone at room temperature and adding ether to crystallize it (acetone: ether ratio = 3:1). 7,9 g (22 mmol) of white crystals were obtained, with a yield (pure compound) of 55%.
yield (crude) = 90%
mp =119-1230C IR (KBr): 3260 cm- : OH
2880 : aliphatic C-H
1500 : aromatic C-C
1280 + 1240 :P=O
1060 :P-O-C
MS:m/e = 360 (M+2)+ :17%
358 (M)+ : 52% 251 (M+2-PO3Me2)+ :33%
249 (M-PO3Me2)+ :100%
NMR (CDCl3): 8= 7.90-7.20 (multiplet, 4H) : phenyl group.
4.50-4.20 (triplet, 1 H, J = 7Hz): H from hydroxyl group, removed through exchange with
deuterium oxide.
3.90-3.50 (multiplet, 12HO):H from methyl groups.
Analysis:C11H17C107P2 Calculated:C 36.84, H 4.78, P 17.27%
Found: C36.81, H4.78, P 17.26%
As verification of its structure, compound 4 was transformed into the corresponding hydroxydiphosphonic acid, mono sodium salt (compound 10), as follows:
A mixture of 3.59 g (10 mmol) of compound 4 and 15 g of 37% hydrochloric acid was refluxed for
3 hours. The evaporation of HCI and H2O left 3.2 g (10 mmol) of white solid.
mp: 192-1 940C (crude) yield: 100% (crude)
For purification purpose, hydroxy (p-chlorophenyl) methylenediphosphonic acid was transformed into its mono-sodium salt, according to the following purification method adapted from P. F. Pflaumer and J. P. Filcik, Chemical Abstracts 72, 55656 k, 1970: The solid obtained as described above was dissolved in a mixture of 4.8g (80 mmol) of acetic acid and 0.7 g (39 mmol) of water at 950. Sodium acetatetrihydrate (1.36 g, 10 mmol) was then added gradually. A voluminous precipitate appeared almost instantly. It was filtrated and washed copiously with ether until the smell of acetic acid disappeared.The rinsed precipitate was recrystallized in an ethanol : water (20 : 80) mixture to give 1.94 g (6 mmol) of white powder of 1 hydroxy 1 (pchlorophenyl)methane 1,1-diphosphonic acid, monosodium salt.
yield: 60%.
EXAMPLE 2
Tetramethyl 2,2-dimethyl 2(p-chlorophenoxy) ethane 1-hydroxy 1, 1-diphosphonate (Compound 7) (Method adapted from K. D. Berlin et al, Journal of Organic Chemistry 30, 1265. 1965, and D. A.
Nicholson and H. Vaughn, Journal of Organic Chemistry 36, 3843, 1971)
p-Chlorophenoxyisobutyryl chloride was first prepared by alkaline hydrolysis of ethyl pchlorophenoxyisobutyrate and refluxing the acid obtained in thionyl chloride, in following the standard procedures.
An amount of 10.6 g (86 mmol) of trimethyl phosphite was added dropwise to 20.0 g (86 mmol) of p-chlorophenoxyisobutyryl chloride cooled to OOC. As verification of the reaction, evolution of methyl chloride could be observed. Distillation under reduced pressure gave 19.0 g (62 mmol) of dimethyl pchlorophenoxyisobutyrylphosphonate as an almost colorless oil.
bp= 115-118 / 5.10-2 Torr yield = 72%
IR (film) : 3000 cm1 . aliphatic C-H
1740 :C=O
1500 : aromastic C-C
1250 :P=O
1050 :P-O-C
830 : 1,4-disubstituted phenyl
Then a solution of 2.86 g (26 mmol) dimethyl phosphite and 0.18 g (1.4 mmol) di(n-butyl)amine in 65 ml ether was cooled to OOC, and dimethyl p-chlorophenoxyisobutyrylphosphonate (7.97 g, 26 mmol) was introduced slowly with rapid stirring. A white solid began to form almost immediately. The reaction was left to stir at 0 C for one hour, then the solid was separated by filtration. Recrystallization in benzene: hexane (60 : 40) gave 7.18 g (1 7.2 mmol) of white feathery crystals of the title compound i.e. tetramethyl 2,2-dimethyl 2(p-chlorophenoxy) ethane 1-hydroxy 1,1diphosphonate.
mp = 137-1390C yield = 66%
IR (KBr): 3360 cm-': OH
3000 : aliphatic C-H
1500 :aromatic C-C 1250+1220 :p=O
1070 : P-0-C 860 : 1,4-dusubstituted phenyl
NMR (CDCl3): a = 7.4--7.0(multiplet, 4H) :phenylgroup.
4.0-3.70 (multiplet, 1 2H) : H from methyl groups bound to the phosphate moieties.
3.6-3.4 (hump, 1 H) : H from the hydroxyl group, removed through exchange with D20.
1.58 (singlet, 6H) : H from the branched methyl groups.
Analysis : C14H23 C108P2
Calculated:C 40.45 H 5.58 P 14.90%
Found: C40.29 H 5.94 P 14.93%
EXAMPLE 3
Tetramethyl 1[4(4'-chlorobenzoyl)-phenyl]methane 1-hydroxy 1,1-diphosphonate (Compound 8).
(Method adapted from D. A. Nicholson and H. Vaughn, Journal of Organic Chemistry 36, 3843, 1971).
The starting compound 4(4'-chlorobenzoyl)-benzoyl chloride was prepared according to G. E.
Robinson and J. M. Vernon, Journal of Chemical Society (C), 2586, 1970, and to E. Wertheim, Journal of American Chemical Society 55,2540, 1933.
Trimethyl phosphate (10.9 g, 88 mmol, 10% excess) was added dropwise to the acid chloride (22.4 g, 80 mmol) heated to just below the melting point (about 100 ). The reaction was exothermic and the white crystals of acid chloride turned into a brown oil with considerable foaming. The reaction mixture was stirred at 1000 for thirty minutes. Upon standing and cooling the oily material was transformed into an orange solid. Recrystallization in a 60 :40 chloroform : petroleum ether mixture gave 20 g (56.7 mmol) of pure dimethyl 4(4'-chlorobenzoyl)benzoylphosphonate.
mp = 9597 (yellow powder) yield= 71%
IR (KBr) 2960 cm-1 : aliphatic C-H
1665+1650:C=O (pertaining to the benzoylphosphonate
and benzophenone moieties)
1590 : aromatic C-C
1250 + 1260:P=0 1050 + 1030:P-O-C Then a mixture of 2.20 g (20 mmol) of dimethyl phosphite and 0.144 g (1.10 mmol) di(n-butyl)
amide in 40 ml ether was cooled to OOC, and a filtered solution of 7.04 g (20 mmol) of di methyl 4(4'chlorobenzoyl) benzoylphosphonate in 40 ml dichloromethane was introduced dropwise. A white
precipitate soon separated out of the yellow mother liquor. The reaction mixture was stirred for one hour
at 0 C and the precipitate was filtrated and washed by ether.Recrystallization in acetone gave white
crystals (2.4 g, 5.2 mmol) of tetramethyl- 1 [4(4'-chlorobenzoyl)phenyl]methane 1 hydroxy 1,1
diphosphonate.
mp = 150-1530C yield= 26%
IR (KBr): 3280 cm-1 : OH 1670 :C=O 1600 : aromatic C-C
1260 + 1240 :P=O
1050+1030 :P-O-C
MS (m/e): 464 (M + 2)+: 14%
462 (M)+: 42%
355 (M + 2-PO3Me2)+ :32% 353 (M-PO3Me2)+ : 100% -NMR (CDCI3):
= 8.10-7.30 (multiplet, 8H): H from the two phenyl groups 4.5-4.3 (triplet, 1 H, J=Hz): H from hydroxyl group, removed through exchange with D2O
3.95-3.60 (multiplet, 1 2H) : H from the methyl groups.
EXAMPLE 4
Dimethyl 1(dimethoxyphosphinyl) p-chlorobenzyl phosphate (Compound 12)
Dimethyl p-chlorobenzoylphosphonate (9.96 g, 40 mmol) was introduced dropwise into a solution of equimolar amounts of dimethyl phosphite (4.40 g, 40 mmol) and di(n-butyl) amine (5.17 g, 40 mmol) that was cooled to 0 C prior to the addition. A white solid began to form almost immediately. After stirring for one hour at OOC, the solid was separated by filtration. Recrystallization performed at room temperature in a 1:3 dichloromethane : ether mixture gave 12.0 g (33 mmol) of white crystals.
mp=81-82 yield = 82%
IR (KBr) = 2980 cm-1 : aliphatic C-H
1500 : aromatic C-C
1290 + 1260 :P=O
1050 :P-O-C
NMR(CDCl3): #= 7.5-7.3(multiplet, 4H): phenyl group.
5.85-5.40 (multiplet, 1H):H from the methine group (non removable through exchange
with deuterium oxide)
3.95-3.50 (multiplet, 1 2H) : H from the methyl groups.
Elementary analysis: C11H17ClO7P2
Calculated :C 36.84 H 4.78 P 17.27%
Found: C36.71 H4.86 P 17.33%
EXAMPLE 5
Dimethyl [1-(dimethoxyphosphinyl)2,2-dimethyl 2(p-chlorophenyl)]ethylphosphate (Compound 16)
Dimethylation of p-chlorophenylacetonitrile by means of sodium amide and methyl iodide in ether gave dimethyl p-chlorophenylacetonitrile. Hydrolysis of this nitrile followed by reflux of the obtained acid in thionyl chloride yielded p-chlorophenylisobutyryl chloride.
Dimethyl p-chlorophenylisobutyrylphosphonate was prepared in 90% yield by adding an equimolar amount of trimethyl phosphite to the above described acid chloride cooled to 00.
bp = 108-11 1 00/5.1 0-2 Torr (white oil) IR (film): 1690 cm-1 :c=O
1270 :P-O 1070 + 1040 :P-0-C Then a solution of 3.30 g (30 mmol) of dimethylphosphite and 3.1 g (24 mmol) of di (n-butyl) amine was cooled to 0 and dimethyl p-chlorophenylisobutyryl phosphonate (8.72 g, 30 mmol) was introduced with rapid stirring. A white solid soon separated out. After stirring for one hour at 0 the solid was separated by filtration. Recrystallization in ether gave 9.0 g (75%) of white crystals of the title compound, di methyl [1 (dimethoxyphosphinyl)2,2-dimethyl 2(p-chlorophenyl)] ethylphosphate.
mp=62-63 pR(KBr) 2980 cm-1 : aliphatic C-H
1500 : aromatic C 1280+1260 :P=O
1080+1030 :P-O-C
MS(m/e) = 402 (M + 2)+ : 0.5% 400(M)+ :1.5%
248 +
NMR (CDCl3) = 7.5-7.25 (multiplet, 4H): phenyl group.
5.05-4.80 (multiplet, 1 H) : H from the methine group (non removable through exchange
with D20).
3.85-3.50 (multiplet, 12H): H from the four methyl groups bound to the phosphate and
phosphonate moieties
1.58 and 1.54 (two partially overlapped singlets, 6H) : H from the two branched methyl
groups.
EXAMPLE 6
Tetraethyl 4-phenylbutylidene 1,1 -diphosphonate (Compound 21) (Method adapted from H. R. Hays and T. J. Logan, Journal of Organic Chemistry 31,3391, 1966, and from 0. T. Quimby et al, Journal of Organometallic Chemistry 13, 199, 1968).
Tetraethyl methylenediphosphonate (23.06 g, 80 mmol) prepared according to Monatshefte
Chemie 81, 202, 1950 was added dropwise to a dispersion of sodium hydride (1.92 g, 80 mmol) in 30 ml toluene. When the evolution of hydrogen ceased, 3-phenyipropyl bromide (19.9 g, 100 mmol) was added and the mixture was heated to 900C for 14 hours and then to 11 00C for 2 more hours. After removal of the toluene under vacuum, the residue was dissolved in chloroform, washed repeatedly with a saturated sodium chloride solution and freed of water by passing through a silicone-treated filter.
Distillation under reduced pressure gave a colorless oil boiling at 135-1450/5.10-2Torr. A careful refractionation yielded 10.4 g (26 mmol) of tetraethyl 4 phenyl-butylidene 1,1-diphosphonate.
bp= 141-1430/5.10-2Torr yield = 32%
IR (film) : see Table Ill
MS (m/e): 406 (M)+ 61%
301 100% 269(M-po3Et2) : 23% NMR(CDCl3): #= 7.35-7.2:(multiplet, 5H): phenyl group.
4.45-3.90 : (quintet, 8H, J = 8Hz) H from the four methylene groups attached to the
phosphonate moieties.
2.80-1.70 : (multiplet, 7H) : H from the odd hydrogen and from the side-chain methylene
groups.
1.50-1.20: (triplet, 1 2H, J = 7Hz): H from the four methyl groups.
EXAMPLE 7 4-Phenylbutylidene 1, 1-diphosphonic acid (Compound 24)
A mixture of 8.1 5 g (20 mmol) of tetraethyl 4-phenylbutylidene 1,1 -diphosphonate and 40 g of 37% hydrochloric acid was refluxed for 1 5 hours. Evaporation to dryness of the clear acid solution gave a white sticky solid. The compound was repeatedly triturated with ether to remove its stickiness.
Recrystallization from an ether : acetone : hexane (30 : 40 : 30) mixture gave 3.8 g (13 mmol of white powder.
mp = 190-1920C yield= 65%
IR (KBr) : see Table Ill
EXAMPLE 8
Tetramethyl 4-phenylbutylidene 1,1 -diphosphonate (Compound 27) (Method adpated from D. A. Nicholson et al., Journal of Organic Chemistry 35, 3149, 1970)
A suspension of 4.5 g (15 mmol) of 4-phenylbutylidene 1,1 -diphosphonic acid and 9.8 g (92
mmol) of trim ethyl orthoformate was heated to reflux for ninety minutes. Rapid stirring was necessary to assure intimate contact of the two phases. An excess of trimethyl orthoformate (9.8 g, 92 mmol) was then added and the mixture was refluxed for a further thirty minutes. The methanol and methyl formate that were formed were removed by distillation thereby allowing the reaction temperature to rise.
Heating was continued until one phase remained and trimethyl orthoformate began to distill. After removal of this reagent, the brown residue was submitted to vacuum distillation to give 3.3 g (9.3 mmol) of a colorless oil.
bp = 135138 (5.10-2 mmHg) yield= 62%
IR (film): see Table Ill
NMR (CDCIS): b = 7.35-7.20 (multiplet, 5 H) : phenyl group.
3.95-3.60 (doublet, 12H, J = 11 Hz) : H from the methyl groups attached to the
phosphonate moieties.
2.80-1.60 (multiplet, 7 H) : H from the odd hydrogen and from the side-chain methylene
groups.
EXAMPLE 9
Tetrabutyl 1-(p-chlorophenyl)methane 1-amino 1, 1-diphosphonate (Compound 31) (Method adapted from N. Kreutzkamp and G. Cordes, Annalen der Chemie 623, 103 (1959)
The hydrochloride of ethyl imino(p-chlorobenzoate) was prepared from p-chlorobenzonitrile by the procedure of C. Grundmann and G. Ottmann, Chemical Abstracts 49, 3271 h, 1955 and the free base was liberated with potassium carbonate and ether.
Dibutyl phosphite (14.60 g, 75 mmol) was added dropwise to 0.57 g of sodium lumps (25 mmol)
in 25 ml of dry benzene. Ethyl imino(p-chlorobenzoate) (3.67 g, 20 mmol) was then added and the
reaction mixture was refluxed for five hours. The benzene solution was neutralized with acetic acid, washed repeatedly with a saturated sodium chloride solution and dried over sodium sulfate. The solvent was evaporated and the mixture submitted to vacuum distillation to remove the excess of reagent.
The residue was submitted to column chromatography (eluent = chloroform), 3.4 g of a white viscous oil were obtained which slowly solidified. Recrystallization in n-pentane gave white crystals (2.6 9,4.9 mmol) of tetrabutyl 1 (p-chlorophenyl)methane 1-amino 1,1-diphosphonate.
yield = 25% mp = 6768 IR = see Table IV
MS= m/e=527 (M+2)+ : 1.8%
525 M+ : 5.5%
334 (M + 2-PO3Bu2)+: 35%
332 (M-PO3Bu2)+ : 100%
Other compounds of formula (I) were prepared according to similar processes as above, and the physical properties of the compounds (I) prepared are shown on the following Tables I, II, III and IV.
NMR spectra of the hydroxy diphosphonate ester compounds (la) (Compounds 1 to 8) all displayed the characteristic absorptions of a hydroxy group : a sharp peak (for compounds 1 and 7), or a triplet (compounds 2, 3, 4, 5, 6, and 8), that all were removed through exchange with deuterium oxide.
The NMR spectra of phosphonophosphate compounds (lb) also displayed a characteristic pattern - # 7.5-7.3 multiplet, phenyl group.
= 5.8-5.4 (Compounds 11, 12, 13, and 14).
5.1-4.8 (Compound 15, 16, and 17) multiplet corresponding to the absorption of the odd
hydrogen atom, non removable through exchange with deuterium oxide.
8 ~ 3.9-3.5 multiplet, methyl ester groups.
a = 1.60-1.55 (only for compounds 1 5, 16, and 17) two singlets, branched methyl group
The MS spectra of all diphosphonate ester compounds (la-Id) showed a characteristic pattern : a molecular ion (M+) in significant intensity (1030%) and a base peak (100%) corresponding to the loss of a phosphonate ester group (M-PO3R2)+.
The sole exception is the mass spectrum of compound 7 which did not show the molecular ion but peaks corresponding to the beakdown of the molecule. The structure of the compounds was established without ambiguity by micro-analysis.
TABLE I
Physical properties of hydroxydiphosphonates of formula (Ia)
Com- Formula (Ia) pound No. A R, R' mp ( C) IR absorptions (cm-1) 1 (CH3)3C- CH3 110-112 2 #- CH3 129-131 3250 : OH 2980 aliphatic C-H 3 H3C-#- CH3 110-113 4 Cl-#- CH3 119-123 # 1260 + 1240 : P = O 5 F-#- CH3 118-122 1050 : P-O-C CH3O 6 CH3O-#- CH3 120-123 CH3 7 Cl-#-O-C- CH3 137-138 3340, 1500, 1260, 1240, 1070 CH3 Cl 8 # # CH3 150-153 3280, 1670 (C=O) 1600, 1260 + 1240 O 1050 + 1030 3/4 H 9 #- > 300 3460 1/4 Na 3000 (broad) P-O-H # 10 Cl-#- 3/4 H 1200 - 1080 - 950 > 300 1/4 Na TABLE II
Physical properties of phosphonophosphates of formula (Ib)
Compound Formula (Ib) No. A R, R' mp ( C) IR absorptions (cm-1) 11 #- CH3 oil * 12 Cl-#- CH3 81-82 2980 : aliphatic C-H 1500 : aromatic C-C 1290 + 1260 : P=O 1050 : P-O-C 13 F-#- CH3 48-49 # CH3 14 #- CH3 oil CH3 CH3 15 #-C- CH3 47-48 CH3 CH3 2980 : aliphatic C-C 16 Cl-#-C- CH3 62-63 # 1500 : aromatic C-C 1280 + 1260 : P=O CH3 1200 + 1180 : -C- group CH3 CH3 17 CH3O-#-C- CH3 1050 : P-O-C CH3 * bp = 152 - 155 (5.10-2 Torr) TABLE III
Physical properties of diphosphonates of formula (Ic)
Formula (Ic) Compound No. A R, R' bp ( C/Torr) mp ( C) IR absorptions (cm-1) 18 #-CH2- C2H5 135-138/5.10-2 2980 : aliphatic C-H 1500: aromatic C-C 19 Cl-#-CH2- C2H5 153-156/5.10-2 # 1260 : P=O 1170 : P-O-C2H5 20 #-(CH2)2- C2H5 137-140/5.10-2 1050 : P-O-C21 #-(CH2)3 - C2H5 141-143/5.10-2 22 #-CH2- H 210-212 3400-3200 (broad):OH 1500 : aromatic C-C 23 Cl-#-CH2 - H 237-239 1230 : P=O 1040 : P-O24 #-(CH2)3- H 190-192 1040 : P-O (to be cont.) TABLE III (Cont.)
Physical properties of diphosphonates of formula (Ic)
Compound Formula (Ib) No. A R, R' bp ( C/Torr) mp ( C) Ir absorptions (cm-1) 25 #-CH2- CH3 130-132/5.10-2 2980 : aliphatic C-H 1500 : aromatic C-C 26 Cl-#-CH2- CH3 141-144/5.10-2 # 1270 : P=O 1195 : P=O-CH3 27 #-(CH2)3- CH3 135-138/5.10-2 1050 : P-O-C TABLE IV
Physical properties of aminodiphosphonates of formula (Id)
Cpd Formula (Id) No A R, R' bp ( C Torr) mp ( C) IR absorptions (cm-1) 28 #- C2H5 170-172/5.10-2 58.5-59.5 3240 : NH2 29 Cl-#- C2H5 185-188/5.10-2 79-80 2980 : aliphatic C-H 1460 : Phenyl group # 1240 : P=O 30 #- C4H9 180-185/5.10-2 10-15 1030 : P-O-C 31 Cl-#- C4H9 67-68 *Partial decomposition occured during the distillation, subsequent purification was carried out by column chromatography yielding the pure compound (white oil which solidified at 10 ).
MS : m/e:491 (M)+: 7%, 298 (M-PO3Bu2)+: 100% The present invention will be now further illustrated through the following Examples 11 to 1 3 concerning the pharmocological activity of the compounds of formula (I).
EXAMPLE 10
Effects of diphosphonates of formula (I) on lipid metabolism in normal rats
Method used:
Groups of 4 or 5 normal male Wistare rats, weighing about 200 g were treated with diphosphonates (200 mg/kg/day) p.o. for 4 to 21 days. Water soluble compounds were given in water or in solution in 24 mM dicarbonate buffer. Lipid soluble compounds were given in corn oil. The rats were weighed, sacrificed by decapitation (under light ether anesthesia) after overnight fasting. Blood was collected and serum used for analysis. The following blood parameter reflecting changes in lipid metabolism are reported - free fatty acids measured according to W. G. Duncombe (Clin.Acta 9, 122, 1964) - triglycerides enzymatic method (Boehringer Mannheim Kit 126 012)
- phospholipids : moiybdate/vandate reaction (Boehringer Mannheim Kit 124 974) - -lipoproteins cholesterol was measured after heparin, CaCI2 precipitation according to M.
Burnstein et al. (La Presse Médicale 43, 974, 1958) and to D. Watson (Clin. Chim. Acta 5, 637, 1960).
Results obtained:
With the exception of compounds 1 and 3, all the diphosphonates (I) tested lowered serum free fatty acids when measured in normal rats or in cholesterol fed rats. This activity seems to be a rather general property of these diphosphonates which possess a p-chlorophenyl moiety and shows their involvement in lipid metabolism. Similar properties have been described for several hypolipidemic agents ("Hypolipidemic Agents", ed. David Kritchevsky, vol. 41, Handbook of Experimental
Pharmacology, Springer-Verlag, 349-408, 1 975). Significant decreases in serum triglycerides were measured with compounds 2, 4, 7, 8, 10 and 1 9 and the acid form of compound 4. In several cases, compounds 2, 4, 7 and 8, 11, 12, 1 5, 1 6, 21, 27 and 28, serum phospholipid was found to increase.In particular, compound 4 was found to be at least two fold the most active. Cholesterol present in the ,B- lipoprotein fraction (very low density lipoproteins VLDL, and low density lipoproteins LDL) decreased whereas sx-liprotein (high density lipoproteins HDL) cholesterol increased thus leading to a favorable augmentation of the a-cholesterol/j3-cholesterol ratio. This effect was associated in long term therapy with a decreased liver and aorta cholesterol content. Clofibrate was tested for comparison purposes and in our hands decreased phospholipids by 33.6% and the alp ratio decreased by 52.2%. The results are in agreement with those pubiished by C. E. Day et al (Artery 5, 90--109. 1979) and by K. R. Miller and G.
G. Cortesi (Artery 4, 564-577, 1 978) demonstrating that clofibrate decreases HDL cholesterol in rats.
The results described above show that these diphosphonates have the property to change lipid metabolism especially to increase the amount of lipid (mainly cholesterol) carried by a-lipoproteins and decrease the amount of lipids carried by s-lipoproteins (mainly triglycerides). Since it has been shown that the amount of HDL-cholesterol inversely correlates with the risk of cardiovascular disease (see N. E.
Miller, Lipids 13, 914--919, 1978),diphosphonates having the property to increase HDL levels might be useful in the potential treatment of atherosclerosis. It is important to note that the acid or salt form of compound 4 and the rather simple diphosphonate compound 1, do not have these properties. It is also important to note that diphosphonates which are structurally different from compounds 2, 4, 7, 8 and tested by others do not have the property to act on lipid metabolism (see W.Hollander et al.,
Atherosclerosis 31,307--325, 1978 and Mellies et al., Artery 6, 38, 1979) EXAMPLE 11
Effects of diphosphonates of formula (I) in cholesterol fed rats
Method used:
In order to increase tissue cholesterol, especially liver, rats were fed a high fat-high cholesterol diet for 10 days to 3 months, with the following diet composition : casein 20%, butter 37%, cellulose 9,1%, dextrose 18.9%, cholesterol 4.5%, sodium cholate 1.8%, minerals 7.3%, vitamins 1%, choline 0.4%.
The rats were then fed normal food and were treated for 10 days to 3 months with different compounds (200 mg/kg/day). Serum parameters described above were measured. Liver and aorta lipids were extracted according to J. Folch et al (J. Biochem. 226, 497, 1957). Total lipids were determined by the sulfophosphovanillic reaction (see N. Zölner and K. Kirsch, Z. Ges. exp. Med. 135, 545, 1962) and cholesterol by the Liebermann-Burchard reaction.
Results obtained The diet described above increased liver total lipids, especially triglycerides and cholesterol, 8 to
10 folds. Treatment with compounds 2, 4, 7, 8, 11, 12, 1 6 and 1 9 decreased significantly liver total lipids and/or liver cholesterol. When tested, the same effect was measured in the aortic tissue, This shows that these particular diphosphonates tested have the property to remove tissue cholesterol.
Since it is well established that cholesterol deposition is an important step in the initiation and/or development of atherosclerosis, these compounds might be useful in the prevention or treatment of atherosclerotic lesions, by preventing cholesterol deposition in tissues such as the aorta.
EXAMPLE 12
Effects of acid and salt form of diphosphonates of formula (I) in hypercalceamic rats
Method used:
In recent years, diphosphonic acids have been shown to be effective in the hypercalceamic animal model in which they inhibit aorta and kidney calcification (see M. Potokar and M. Schmidt-Dunker,
Atherosclerosis 30, 313-320, 1 978). They have also been shown to prevent the vitamin D-induced rise in plasma calcium. This activity might be useful for the regression of preestablished atherosclerosis (see I. Y. Rosenblum et al., Atherosclerosis 22,411-424, 1975). Since diphosphonates have these activities when given as acids or sodium salts the acid and monosodium forms of compound 4 were also tested by using a protocol similar two the one described by Potokar (see above).Briefly, groups of 4 male Wistar rats received acid or salt form of compound 4 as 0.05% solution in drinking water corresponding to about 50 mg/kg/day. The rats were treated with the compounds for 1 5 days. From the 5th day to the 10th day hypercalceamia was produced by giving to control and treated rats 75000 U vitamin Dkg/day. Diphosphonate treatment continued from the 10th to the 15th day. The animals were then sacrificed under light ether anesthesia and serum calcium determined according to B. C. Ray
Sarkar and U. P. S. Chanham (Anal. Biochem. 20, 155, 1967).
Results obtained Calcium deposition has been considered to play a role in the late stages of the development of atherosclerotic plaques (see W. Hollander, Exp. Mol. Path. 25, 106, 1976), and it has been shown that some diphosphonate acids or salts act on calcium metabolism and that this property by itself might be useful in the treatment of the late stages of atherosclerosis. The fact that none of the esterified forms but the acid and salt forms of compound 4 decrease serum calcium by 20 and 14% respectively indicates that the non-esterified diphosphonates act on calcium metabolism and might decrease calcification of atheromas.
Some results of the above described pharmacological activity tests of diphosphonates of formula (I) according to the present invention are shown in the following Tables V and VI.
TABLE V: Pharmacological activity of diphosphonates of formula (I)
Serum Liver Aorta Compounds Serum Free Serum Serum Cholesterol Tot. Liver Tot. Aorta Serum No. Fatty Acids Triglycerides Phospholipids α;/ss Lipids Cholesterol Lipids Chlolesterol Calcium N C.F N C.F N C.F N C.F C.F C.F C.F C.F 2 NS -56 -21 -15 +25 NS +88 -24 -50 -30 NS NS 4 -48 -67 -24 -21 +43 +21 +220 -31 -58 -47 NS NS 7 +28 -40 -33 NS +26 NS +27 NS -25 -27 -19 NS 8 -38 -52 -16 -17 NS +36 +51 -25 NS NS -39 NS 5 - +27 - +64 - - - - 3 NS NS NS NS - - - - NS 1 NS +24 -43 NS - - - - NS 4 Acid -17 -29 NS NS NS NS NS NS -20 10 -27 -17 NS NS NS NS NS NS -14 Clofibrate NS +19 -34 NS - NS - - TABLE VI
Serum Liver Aorta Compounds Serum Free Serum Serum Cholesterol Total Liver Total Aorta Serum No. Fatty Acids Triglycerides Phospholipids α/ss Lipids Chol. Lipids Chol. Calcium N CF N CF N CF N CF CF CF CF CF 12 -50 NS +26 +169 -32 -57 -37 -30 NS 11 -21 +32 +21 +25 -18 -51 - - 15 - +38 +15 +25 - - - - 16 - - +28 - +24 -32 -36 -46 - - 13 - NS NS +81 - - - - 14 - NS NS +15 - - - - 26 -44 +36 -18 NS - - - - NS 19 -44 -65 -16 -24 NS NS -35 NS NS -60 NS NS 21 - +46 +17 +33 - - - - 27 - +42 +33 +49 - - - - 28 - +41 +30 +15 - - - - Note: - In above Tables V and VI, results are given as % control values. Except for serum calcium, values which differ from control values by less than 15% are considered as non significant (NS).
- Serum free fatty acids, triglycerides and phospholipids were measured in normal rats (N) and in rats fed cholesterol for 10 days (C.F.) - Serum α/ss cholesterol, total lipids and cholesterol of liver and aorta were determined normal and in rats which had previously been fed a high cholesterol diet.
- Serum calcium was measured in hypercalceamic rats.
The pharmacological screening of diphosphonate derivatives of formula (I) according to the present invention has shown that said compounds possess specific properties and activities upon lipids and lipid metabolism, and that they have the potential of being used in the treatment of cardiovascular disease for the following reasons -They act on lipid metabolism in normal rats by decreasing serum free fatty acids, decreasing triglycerides and increasing phospholipids. The later might be linked to the increased HDL lipids, especially HDL cholesterol, observed most dramatically with compounds 2, 4, 5, 12 and 1 3.
-They possess the important property of decreasing and removing significantly liver and aorta lipids, especially cholesterol, in high fat high cholesterol fed rats. Experiments not reported here have also shown that compounds such as 2 and 4 increase bile and fecal cholesterol excretion leading to a net loss of tissue cholesterol.
It should be thus noted that the primary actions of said diphosphonates (I) are different and novel in comparison to the classical hypolipidemic compounds. The specificity of these activities (increased
HDL and tissue clearance of cholesterol) strongly suggest a potential pharmaceutical use in atherosclerosis. Experiments done on rabbits in which experimental atherosclerosis had been induced by cholesterol feeding confirmed the previous observations, that compound 4 which has the p-CI moiety is the most active.
In addition, the fact that the acid and salt forms of compound 4 act on calcium metabolism suggests that all the non-esterified forms of these diphosphonates described have the potential of being used also to treat the late stages of atherosclerosis.
EXAMPLE 13
Hypoglycemic activity of diphosphonates of formula {IJ Male Wistar rats (5/group) weighing between 150200 g were treated for 4 days with prescreened phosphonates. They were fasted overnight and sacrificed the 5th day by decapitation under light ether anesthesia. Blood samples were collected using EDTA as anticoagulant. Results are given as means value + sem. The results as seen in Table VII indicate that the p-chloro-phenyl diphosphonate was most potent and especially when given i.p.
TABLE VII HYPOGLYCEMIC ACTIVITY
Plasma glucose (mg/100 ml) Treated Route of administration dosage, and vehicle Controls Cpd 4 Cpd 2 Cpd 21 Cpd 27 i.p. 50 mg/kg aq. buffer 87 j 3 36 t 1 p.o. 50 mg/kg aq. buffer 132 + 8 100 + 12 p.o. 50 mg/kg corn oil 125 + 10 90i 5 p.o. 100 mg/kg aq. buffer 111 + 7 93 + 12 p.o. 50 mg/kg corn oil 125j10 110i10 p.o. 200 mg/kg aq. buffer 131 + 4 88 + 5 p.o. 200 mg/kg aq. buffer 131 + 4 ~ 102 + 9 Glucose concentration was determined by the enzymatic method of W. Werner and H. G. Wielinger (Z.
Analyt. Chem. 252, 224, 1970) (obtained from Boehringer Mannheim, Kit No. 124036).
The present invention further includes in its scope hypoglycemic and antiatherogenic preparations.
which comprise as active ingredient a pharmaceutically effective amount of one or more diphosphonate derivatives of formula (I).
Safe and effective amounts of phosphonate compound are prepared in sufficient amounts to produce a desirable effect at a reasonable benefit/risk ratio attendant with any medical treatment.
Within the scope of acceptable and sound medical judgment, the dosage of phosphonate compound will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, and the specific phosphonate compound employed.
The phosphonates are prepared as pharmaceutically acceptable products which include all
ingredients used in the compositions employed and are suitable for use in contact with the tissues of
humans and animals without undue toxicity, irritation, allergic response commensurate with a
reasonable benefit/risk ratio.
Preparation of the pharmaceutical compositions according to the present invention for oral unit
dosage forms can be a mixture with a solid vehicle containing iactose, saccharose, sorbitol, mannitol, amidon, amylopectine, cellulose derivative, and/or gelatine which can be prepared with the lubricants
such as magnesium stearate, calcium stearate, forms of "carbowax" and/or polyethylene glycol. It can
be preferable in some cases to use a capsule, and the ingredients can then consist of a mixture
containing concentrated sugar, arabic gum, talc, and/or titan bioxide.
In some cases particular phosphonates can be mixed in buffer solution, corn oil, olive oil, glycerol
commercial fillers, and administered in a closed hard gelatin capsule, as drops, or sirop forms.
In addition, the phosphonates can be fabricated with "Imhausen H" to produce suitable
suppositories.
For example, compounds 4 to 9 were compressed in tablet form with magnesium stearate 10%
and amidon 25% to obtain a final concentration of about 100 to 300 mg active agent. In addition compounds of formula (I) were made up in solution of drinking water or corn oil at concentrations
between about 2 mg/ml and 100 mg/ml.
In conciusion, it should be pointed out that many of the compounds disclosed herein are also
disclosed in our copending U.K. Application No. 79331 57, as is their use as antiatheriogenetic agents.
Broadly speaking, the compounds disclosed and claimed in that application are of the formula
where X is H or OH, R and R' which may be the same or different are H, CH3 or C2H5, m is zero or 1; A is
where n is 1, 2 or 3 and Y is H, CH3 or CI.
Accordingly we make no claim herein to the compounds disclosed and claimed in our copending
U.K. application No. 7933157, their preparation or pharmaceutical compositions containing them.
Claims (10)
1. Diphosphonate compounds of the formula
where X is H, OH,
R and R' which may be the same or different are H, OH3, C2H5 or C4Hg; m is zero or 1; and A is
where n is an integer from 1 to 6 and Y is H, CH3, OCH3 or halogen.
2. Compounds according to claim 1, being hydroxydiphosphonates of the formula:
where R, R' and A are as defined in claim 1.
3. Compounds according to claim 1, being phosphonophosphates of the formula:
where R, R' and A are as defined in claim 1.
4. Compounds according to claim 1 being disphosphonates of the formula:
where R, R' and A are as defined in claim 1.
5. Compounds according to claim 1 being aminodiphosphonates of the formula:
where R, R' and A are as defined in claim 1.
6. Compounds according to any one of claims 1 to 5 in which Y is H or a chlorine atom in para position.
7. Dimethyl [1 (dimethoxyphosphonyl) 2,2-dimethyl 2-phenyl]-ethyl phosphate.
8. Dimethyl [1 (dimethoxyphosphonyl)2,2-dimethyl 2-phenyl] ethyl phosphate.
9. Tetrabutyl 1 (p-chlorophenyl)methane 1-amino 1,1 -diphosphonate.
10. A pharmaceutical composition comprising a compound as claimed in any one of claims 1-9 in admixture with a pharmaceutically acceptable diluent or carrier.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB8022463A GB2079285B (en) | 1980-07-09 | 1980-07-09 | Dipthosphonate derivatives and pahrmaceutical compositions containing them |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB8022463A GB2079285B (en) | 1980-07-09 | 1980-07-09 | Dipthosphonate derivatives and pahrmaceutical compositions containing them |
Publications (2)
Publication Number | Publication Date |
---|---|
GB2079285A true GB2079285A (en) | 1982-01-20 |
GB2079285B GB2079285B (en) | 1984-05-23 |
Family
ID=10514643
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB8022463A Expired GB2079285B (en) | 1980-07-09 | 1980-07-09 | Dipthosphonate derivatives and pahrmaceutical compositions containing them |
Country Status (1)
Country | Link |
---|---|
GB (1) | GB2079285B (en) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2118042A (en) * | 1982-04-15 | 1983-10-26 | Gentili Ist Spa | Pharmaceutical compositions containing biphosphonic acids |
US4503049A (en) * | 1982-01-27 | 1985-03-05 | Schering Aktiengesellschaft | Diphosphonic acid derivatives and pharmaceutical preparations containing them |
DE3500670A1 (en) * | 1984-01-12 | 1985-07-18 | Istituto Gentili S.P.A., Pisa | MEDICINAL PRODUCTS CONTAINING DIPHOSPHONATES |
EP0173041A1 (en) * | 1984-07-18 | 1986-03-05 | Symphar S.A. | 2-Substituted-1,3-propylidenediphosphonate derivatives, the process for their preparation and pharmaceutical compositions containing them |
EP0513760A2 (en) * | 1991-05-13 | 1992-11-19 | E.R. SQUIBB & SONS, INC. | Use of biphosphonate squalene synthetase inhibitors in pharmaceutical compositions useful in lowering cholesterol |
EP0514124A2 (en) * | 1991-05-13 | 1992-11-19 | E.R. SQUIBB & SONS, INC. | Use of phosphonomethylphosphinate squalene synthetase inhibitors for the manufacture of a medicament for the lowering cholesterol |
-
1980
- 1980-07-09 GB GB8022463A patent/GB2079285B/en not_active Expired
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4503049A (en) * | 1982-01-27 | 1985-03-05 | Schering Aktiengesellschaft | Diphosphonic acid derivatives and pharmaceutical preparations containing them |
GB2118042A (en) * | 1982-04-15 | 1983-10-26 | Gentili Ist Spa | Pharmaceutical compositions containing biphosphonic acids |
DE3500670A1 (en) * | 1984-01-12 | 1985-07-18 | Istituto Gentili S.P.A., Pisa | MEDICINAL PRODUCTS CONTAINING DIPHOSPHONATES |
EP0173041A1 (en) * | 1984-07-18 | 1986-03-05 | Symphar S.A. | 2-Substituted-1,3-propylidenediphosphonate derivatives, the process for their preparation and pharmaceutical compositions containing them |
EP0513760A2 (en) * | 1991-05-13 | 1992-11-19 | E.R. SQUIBB & SONS, INC. | Use of biphosphonate squalene synthetase inhibitors in pharmaceutical compositions useful in lowering cholesterol |
EP0514124A2 (en) * | 1991-05-13 | 1992-11-19 | E.R. SQUIBB & SONS, INC. | Use of phosphonomethylphosphinate squalene synthetase inhibitors for the manufacture of a medicament for the lowering cholesterol |
EP0514124A3 (en) * | 1991-05-13 | 1992-12-16 | E.R. Squibb & Sons, Inc. | Use of phosphonomethylphosphinate squalene synthetase inhibitors for the manufacture of a medicament for the lowering cholesterol |
EP0513760A3 (en) * | 1991-05-13 | 1992-12-23 | E.R. Squibb & Sons, Inc. | Use of biphosphonate squalene synthetase inhibitors in pharmaceutical compositions useful in lowering cholesterol |
Also Published As
Publication number | Publication date |
---|---|
GB2079285B (en) | 1984-05-23 |
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PCNP | Patent ceased through non-payment of renewal fee |