CA2118409A1 - Substituted phosphonates, the processes for their preparation and pharmaceutical compositions containing them - Google Patents
Substituted phosphonates, the processes for their preparation and pharmaceutical compositions containing themInfo
- Publication number
- CA2118409A1 CA2118409A1 CA002118409A CA2118409A CA2118409A1 CA 2118409 A1 CA2118409 A1 CA 2118409A1 CA 002118409 A CA002118409 A CA 002118409A CA 2118409 A CA2118409 A CA 2118409A CA 2118409 A1 CA2118409 A1 CA 2118409A1
- Authority
- CA
- Canada
- Prior art keywords
- butyl
- tert
- phosphonate
- hydroxyphenyl
- dimethyl
- 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 claims abstract 3
- 238000000034 method Methods 0.000 title claims description 14
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 title abstract description 14
- 238000002360 preparation method Methods 0.000 title abstract description 4
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 83
- 150000001875 compounds Chemical class 0.000 claims description 68
- -1 dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-buten-1-yl phosphonate Chemical compound 0.000 claims description 60
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 46
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 23
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims description 13
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 8
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 239000012312 sodium hydride Substances 0.000 claims description 8
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 201000001320 Atherosclerosis Diseases 0.000 claims description 7
- 150000002148 esters Chemical class 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 229910052744 lithium Inorganic materials 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 238000011282 treatment Methods 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 238000009835 boiling Methods 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 239000012279 sodium borohydride Substances 0.000 claims description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 125000005600 alkyl phosphonate group Chemical group 0.000 claims description 3
- 125000004429 atom Chemical group 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims description 3
- 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 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 150000008065 acid anhydrides Chemical class 0.000 claims description 2
- 125000004423 acyloxy group Chemical group 0.000 claims description 2
- 150000001299 aldehydes Chemical class 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- 150000004677 hydrates Chemical class 0.000 claims description 2
- 150000004678 hydrides Chemical class 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 7
- 238000004519 manufacturing process Methods 0.000 claims 5
- 101100006371 Arabidopsis thaliana CHX3 gene Proteins 0.000 claims 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 2
- UROWGOAGTNELKO-UHFFFAOYSA-N 4-(3,5-ditert-butyl-4-hydroxyphenyl)-1-(2-oxo-1,3,2$l^{5}-dioxaphosphinan-2-yl)but-3-en-2-one Chemical compound CC(C)(C)C1=C(O)C(C(C)(C)C)=CC(C=CC(=O)CP2(=O)OCCCO2)=C1 UROWGOAGTNELKO-UHFFFAOYSA-N 0.000 claims 1
- AEBUBTMTLKNUQB-UHFFFAOYSA-N CC(C)(C)C(C=C(C=C1C(C)(C)C)SC(C)(C)C(COP(O)=O)=O)=C1O Chemical compound CC(C)(C)C(C=C(C=C1C(C)(C)C)SC(C)(C)C(COP(O)=O)=O)=C1O AEBUBTMTLKNUQB-UHFFFAOYSA-N 0.000 claims 1
- 239000012448 Lithium borohydride Substances 0.000 claims 1
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 230000032050 esterification Effects 0.000 claims 1
- 238000005886 esterification reaction Methods 0.000 claims 1
- 238000011065 in-situ storage Methods 0.000 claims 1
- 150000002576 ketones Chemical group 0.000 claims 1
- 239000012453 solvate Substances 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 48
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 40
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 32
- 239000000203 mixture Substances 0.000 description 29
- 239000000243 solution Substances 0.000 description 20
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 18
- 229910052739 hydrogen Inorganic materials 0.000 description 17
- 239000003921 oil Substances 0.000 description 17
- 101150041968 CDC13 gene Proteins 0.000 description 16
- 229910052799 carbon Inorganic materials 0.000 description 15
- 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 description 15
- 229910052698 phosphorus Inorganic materials 0.000 description 15
- 239000000377 silicon dioxide Substances 0.000 description 14
- 235000012239 silicon dioxide Nutrition 0.000 description 14
- 229910052681 coesite Inorganic materials 0.000 description 13
- 238000004440 column chromatography Methods 0.000 description 13
- 229910052906 cristobalite Inorganic materials 0.000 description 13
- 229910052682 stishovite Inorganic materials 0.000 description 13
- 229910052905 tridymite Inorganic materials 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000012071 phase Substances 0.000 description 11
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 108010007622 LDL Lipoproteins Proteins 0.000 description 7
- 102000007330 LDL Lipoproteins Human genes 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 238000010626 work up procedure Methods 0.000 description 7
- 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 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 230000008602 contraction Effects 0.000 description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- 239000003963 antioxidant agent Substances 0.000 description 5
- 230000003078 antioxidant effect Effects 0.000 description 5
- 235000006708 antioxidants Nutrition 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- 235000019341 magnesium sulphate Nutrition 0.000 description 5
- 230000003647 oxidation Effects 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 235000012000 cholesterol Nutrition 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 102100022210 COX assembly mitochondrial protein 2 homolog Human genes 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- 239000007995 HEPES buffer Substances 0.000 description 3
- 101000900446 Homo sapiens COX assembly mitochondrial protein 2 homolog Proteins 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229930003427 Vitamin E Natural products 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 125000004464 hydroxyphenyl group Chemical group 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 239000008363 phosphate buffer Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 229960001866 silicon dioxide Drugs 0.000 description 3
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 3
- 235000019165 vitamin E Nutrition 0.000 description 3
- 229940046009 vitamin E Drugs 0.000 description 3
- 239000011709 vitamin E Substances 0.000 description 3
- GQBVFZDYDHGZPY-UHFFFAOYSA-N 1-diethoxyphosphorylbutan-2-one Chemical compound CCOP(=O)(OCC)CC(=O)CC GQBVFZDYDHGZPY-UHFFFAOYSA-N 0.000 description 2
- DOZRDZLFLOODMB-UHFFFAOYSA-N 3,5-di-tert-Butyl-4-hydroxybenzaldehyde Chemical compound CC(C)(C)C1=CC(C=O)=CC(C(C)(C)C)=C1O DOZRDZLFLOODMB-UHFFFAOYSA-N 0.000 description 2
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 2
- 101100225553 Caenorhabditis elegans epg-4 gene Proteins 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229910010066 TiC14 Inorganic materials 0.000 description 2
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 229960004217 benzyl alcohol Drugs 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- PBGGNZZGJIKBMJ-UHFFFAOYSA-N di(propan-2-yl)azanide Chemical compound CC(C)[N-]C(C)C PBGGNZZGJIKBMJ-UHFFFAOYSA-N 0.000 description 2
- 229940043279 diisopropylamine Drugs 0.000 description 2
- IPZJQDSFZGZEOY-UHFFFAOYSA-N dimethylmethylene Chemical compound C[C]C IPZJQDSFZGZEOY-UHFFFAOYSA-N 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- ALUDCPPKWVUVDT-UHFFFAOYSA-N ethyl 3-(3,5-ditert-butyl-4-hydroxyphenyl)prop-2-enoate Chemical compound CCOC(=O)C=CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 ALUDCPPKWVUVDT-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 230000000871 hypocholesterolemic effect Effects 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- YACKEPLHDIMKIO-UHFFFAOYSA-N methylphosphonic acid Chemical compound CP(O)(O)=O YACKEPLHDIMKIO-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 150000002978 peroxides Chemical class 0.000 description 2
- SONNWYBIRXJNDC-VIFPVBQESA-N phenylephrine Chemical compound CNC[C@H](O)C1=CC=CC(O)=C1 SONNWYBIRXJNDC-VIFPVBQESA-N 0.000 description 2
- 229960001802 phenylephrine Drugs 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 229960003912 probucol Drugs 0.000 description 2
- FYPMFJGVHOHGLL-UHFFFAOYSA-N probucol Chemical compound C=1C(C(C)(C)C)=C(O)C(C(C)(C)C)=CC=1SC(C)(C)SC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 FYPMFJGVHOHGLL-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229960002855 simvastatin Drugs 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000010936 titanium Substances 0.000 description 2
- 229910052719 titanium Inorganic materials 0.000 description 2
- NGSWKAQJJWESNS-ZZXKWVIFSA-N trans-4-coumaric acid Chemical compound OC(=O)\C=C\C1=CC=C(O)C=C1 NGSWKAQJJWESNS-ZZXKWVIFSA-N 0.000 description 2
- RSAFKRSMGOSHRK-UHFFFAOYSA-N 1-diethoxyphosphorylpropan-2-one Chemical compound CCOP(=O)(CC(C)=O)OCC RSAFKRSMGOSHRK-UHFFFAOYSA-N 0.000 description 1
- LQZCYXCHWNQBKX-UHFFFAOYSA-N 1-dimethoxyphosphorylheptan-2-one Chemical compound CCCCCC(=O)CP(=O)(OC)OC LQZCYXCHWNQBKX-UHFFFAOYSA-N 0.000 description 1
- JKMSDCYZHFMSIY-UHFFFAOYSA-N 3-diethoxyphosphoryl-3-methylbutan-2-one Chemical compound CCOP(=O)(OCC)C(C)(C)C(C)=O JKMSDCYZHFMSIY-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 229910014033 C-OH Inorganic materials 0.000 description 1
- OHMOPGZJYCOFJD-UHFFFAOYSA-N CC(C)(C)C(C=C(CCC(COP(O)=O)=O)C=C1C(C)(C)C)=C1O Chemical compound CC(C)(C)C(C=C(CCC(COP(O)=O)=O)C=C1C(C)(C)C)=C1O OHMOPGZJYCOFJD-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 108090001069 Chymopapain Proteins 0.000 description 1
- 229910014570 C—OH Inorganic materials 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 102000004286 Hydroxymethylglutaryl CoA Reductases Human genes 0.000 description 1
- 108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 101000913968 Ipomoea purpurea Chalcone synthase C Proteins 0.000 description 1
- WSMYVTOQOOLQHP-UHFFFAOYSA-N Malondialdehyde Chemical compound O=CCC=O WSMYVTOQOOLQHP-UHFFFAOYSA-N 0.000 description 1
- 101000907988 Petunia hybrida Chalcone-flavanone isomerase C Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 206010063493 Premature ageing Diseases 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- 208000034189 Sclerosis Diseases 0.000 description 1
- 241000906446 Theraps Species 0.000 description 1
- 229910003074 TiCl4 Inorganic materials 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000000879 anti-atherosclerotic effect Effects 0.000 description 1
- 210000002376 aorta thoracic Anatomy 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000000923 atherogenic effect Effects 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
- 230000000903 blocking effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- ZDQWVKDDJDIVAL-UHFFFAOYSA-N catecholborane Chemical compound C1=CC=C2O[B]OC2=C1 ZDQWVKDDJDIVAL-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940114081 cinnamate Drugs 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- BHFOAIMSKFAWOU-UHFFFAOYSA-N dimethoxy-methyl-sulfanylidene-$l^{5}-phosphane Chemical compound COP(C)(=S)OC BHFOAIMSKFAWOU-UHFFFAOYSA-N 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 125000002587 enol group Chemical group 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000003721 exogen phase Effects 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 210000000497 foam cell Anatomy 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 238000001030 gas--liquid chromatography Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- YWXYYJSYQOXTPL-SLPGGIOYSA-N isosorbide mononitrate Chemical compound [O-][N+](=O)O[C@@H]1CO[C@@H]2[C@@H](O)CO[C@@H]21 YWXYYJSYQOXTPL-SLPGGIOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 229940118019 malondialdehyde Drugs 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 108010071584 oxidized low density lipoprotein Proteins 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 150000003009 phosphonic acids Chemical class 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000008279 sol Substances 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 238000005199 ultracentrifugation Methods 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
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- 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
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
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- C07F9/657181—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom the ring phosphorus atom and, at least, one ring oxygen atom being part of a (thio)phosphonic acid derivative
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C07F9/40—Esters thereof
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- 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
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- 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
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Abstract
The present invention relates to novel phosphonates substituted by dialkylphenol group of formula (I), in which G, X1, X2, D, Y, Z1 and Z2 are defined in Claim 1, as well as their preparations and the pharmaceutical compositions comprising them.
Description
WO 94/19358 ~ 9 PCT/EP94/00520 SUBSTlTUTED PHOSPHONATES, THE PROCESSES FOR
THEIR PREPARATION AND PHARMACEUTICAL CO~IPOSlTIONS
CONTAINING THEM
5 This invention relatcs to novd phosphonates substituted with a dialkyl phenol moiety and the processes for their preparation. It further relates to pharmaceu~cal compositions containing these compounds and their therapeutic use in diseases inwhich reactive oxygen radicals have been implicated and more sp cifically in thetreatment of atherosclerosis.
Reactivc oxygen species are involved in a number of pathologies, pharmacologicaland clinical evidencc have been firmly established in the following cases (Halliwell, B. et al. "Role of Free Radicals and Catalytic Meta'l Ions in Human Disease: an Ovennew", Methods Enzymol. 1~6, 1-85, 1990):
"~
- inflammato~y and immunologic injuries (autoimmune diseases, rheumatoid arthrids), - ischemia/reperfusion injury, - radiadon injury, 20 - premature ageing, - Pa*inson's and Alzheimer's diseases, - cancer and and-cancer treatments, - condidons associated with impaired blood circuladon such as intermittent claudicatdon, excessive platelet aggregadon, myocardial infarction and 2s atherosclerosis.
In these pathological situadons andoxidant products would be useful as therapeudc agents. The tests perfo~med by the inventors show that the phosphonates of formula a) through their dialkyl phenol and phosphonate moiedes display potent andoxidant 30 activides and therefore offer this therapeudc potendal.
, In the particular case of atherosclerosis, it is now clearly proven that cholesterol camed in LDL is the most atherogenic form of plasma cholesterol. On the other hand current rçsearch shows that the uptake of oxidized LDL by macrophages leads35 to the formation of lipid-laden foam cells, which is the first step in the development of atherosclerosis. Numerous epidemiological studies have now firmly establishedthat high blood cholesterol is a major risk factor for coronary heart disease. Based on the above, it can be postulated that ~e combination of a cholesterol lowering Wo 94/19358 ~ pcTEwDoos2o regimen with an antioxidant treatment might be more effective than either one. Adrug which possesses the dual hypocholesterolemic and antioxidant property couldtherefore be highly effective in the treatment of atherosclerosis.
5 The phosphonate compounds (I) of this invention inhibit markedly the synthe~is of cholesterol in human cell lines similarly to the HMGCoA reductase enzyme inhibitors (lovætatin, simvastatin) which are potent hypocholesterolernic drugs in -man. The combination of their antioxidant and hypocholesterolemic activities confer to the phosphonates of this invention the potential for treating diseases associated 10 with elevated cholcsterol levels and pathological lipid oxidation. Furthermore, the lipophilicity of thcse compounds predicts that they will become incorporated in the LDL and protect these particles against the damages caused by oxidative species.
The generic structure of the compounds of the present invention is represented by 15 formula (I) ~D--P~ ( I ) where '' - Xl, x2 identical or different are straight or branched Cl to C6 alkyl groups, -YisOorS, zl, z2, identical or different~ are:
- OR where R is H, a straight or branched Cl-C6 alkyl group, - NRlR2 where Rl, R2, identical or different are H or a straight or branched Cl- C6 alkyl group, zl, z2 together may form a C2-Cg alkylidenedioxy group, - G is OH or a bioprecursor thereof;
THEIR PREPARATION AND PHARMACEUTICAL CO~IPOSlTIONS
CONTAINING THEM
5 This invention relatcs to novd phosphonates substituted with a dialkyl phenol moiety and the processes for their preparation. It further relates to pharmaceu~cal compositions containing these compounds and their therapeutic use in diseases inwhich reactive oxygen radicals have been implicated and more sp cifically in thetreatment of atherosclerosis.
Reactivc oxygen species are involved in a number of pathologies, pharmacologicaland clinical evidencc have been firmly established in the following cases (Halliwell, B. et al. "Role of Free Radicals and Catalytic Meta'l Ions in Human Disease: an Ovennew", Methods Enzymol. 1~6, 1-85, 1990):
"~
- inflammato~y and immunologic injuries (autoimmune diseases, rheumatoid arthrids), - ischemia/reperfusion injury, - radiadon injury, 20 - premature ageing, - Pa*inson's and Alzheimer's diseases, - cancer and and-cancer treatments, - condidons associated with impaired blood circuladon such as intermittent claudicatdon, excessive platelet aggregadon, myocardial infarction and 2s atherosclerosis.
In these pathological situadons andoxidant products would be useful as therapeudc agents. The tests perfo~med by the inventors show that the phosphonates of formula a) through their dialkyl phenol and phosphonate moiedes display potent andoxidant 30 activides and therefore offer this therapeudc potendal.
, In the particular case of atherosclerosis, it is now clearly proven that cholesterol camed in LDL is the most atherogenic form of plasma cholesterol. On the other hand current rçsearch shows that the uptake of oxidized LDL by macrophages leads35 to the formation of lipid-laden foam cells, which is the first step in the development of atherosclerosis. Numerous epidemiological studies have now firmly establishedthat high blood cholesterol is a major risk factor for coronary heart disease. Based on the above, it can be postulated that ~e combination of a cholesterol lowering Wo 94/19358 ~ pcTEwDoos2o regimen with an antioxidant treatment might be more effective than either one. Adrug which possesses the dual hypocholesterolemic and antioxidant property couldtherefore be highly effective in the treatment of atherosclerosis.
5 The phosphonate compounds (I) of this invention inhibit markedly the synthe~is of cholesterol in human cell lines similarly to the HMGCoA reductase enzyme inhibitors (lovætatin, simvastatin) which are potent hypocholesterolernic drugs in -man. The combination of their antioxidant and hypocholesterolemic activities confer to the phosphonates of this invention the potential for treating diseases associated 10 with elevated cholcsterol levels and pathological lipid oxidation. Furthermore, the lipophilicity of thcse compounds predicts that they will become incorporated in the LDL and protect these particles against the damages caused by oxidative species.
The generic structure of the compounds of the present invention is represented by 15 formula (I) ~D--P~ ( I ) where '' - Xl, x2 identical or different are straight or branched Cl to C6 alkyl groups, -YisOorS, zl, z2, identical or different~ are:
- OR where R is H, a straight or branched Cl-C6 alkyl group, - NRlR2 where Rl, R2, identical or different are H or a straight or branched Cl- C6 alkyl group, zl, z2 together may form a C2-Cg alkylidenedioxy group, - G is OH or a bioprecursor thereof;
2~
j WO 94/19358 PCT/EP94/00~20 D is a saturated or unsaturated Cl-Cl 1 alkylene chain in which one or more of the methylene groups can be replaced by a sulphur atom, an oxygen atom, a carbonyl group; optionally one or more methylene groups can be subs~tuted by one or more halogen atoms (F, Cl or Br), Cl-6 alkyl, phenyl, hydroxy or s acyl oxy groups, and salts, sohates and hydrates thereo Preferably, Xl and x2 are identical and are butyl gr~ups, in par~cular ~-butyl groups. .:
Prefe~ably, Y is oxygen.
Preferably Zl and z2 are identical, in particular O~ in which R is H, or a s~aight or 5 branched Cl 6alkyl group. More prefcrably, zl and z2 are idenacal OR groups inwhich R is Cl 6aLlcyl, in particular methyl, ethyl or i-propyl.
PreferaUy, G is OH.
20 Suitable bioprecu~sors of the group OH as defimed for G include, for example, oR3 groups where R3 is a straight or branched Cl-C6 alkyl group, a perfluorinated Cl-C6aL~yl group, a substituted or unsubsdtuted phenyl group, a subsntuted or unsubstituted benzyl group, suitable biopr~cursors can also be a R3-C(o)o- group, a R3O-C(o)o- group, a R3NH-C(o)o- group, a R3C(o)oCH20- group, a R3-So20-25 group wherc R3 is defined as abovc.
P~efo~bly, D is A-C(O)-B,A-CH(OH~-B,A-C~H2-B, (C~H2)r(CH=CH)n~(C~H2~t or S-(CH2)t, where - A is (CH2)t, (CH=CH)n-C~H=CX3, (CH2)t-CHX3, S-(CH2)t-(CH=CH)n, S-CX4X5, (CH~H)n-C~l=CH-C(O)-CHX3, (CH2)p-CH-~H-C(o)-CHX3, (CH2)t-C(o)-CHX3, S-(CH2)t-(CH-CH)n-C(o)-CHX3, S-CX4XS-C(o)-CHX3, (CH~H)n-CH=CH-C]H(oH)-CHX3, (CH2)p-CH=CH-CH(oH)-CHX3, 35 (CH2)rC]H(oH)-CHX3, S-(CH2)r(CH=CH)n-CH(oH)-CHX3, S-CX4XS-CH(oH)-CHX3 wo 94~9358 ~ PcT/EPs4lon~20 where n is zero, 1 or 2, t is a number f~m O to 4, p is a number ~om 1 to 3, - X3 is H, a s~aight ~r branched a~l Cl-C6 group, a substituted or unsubs~tuted 5 phenylgroup, - X4, XS identical or different are H, a s~ght or ~ranched Cl-C4 alkyl group, - B is CH2. CH-X6, X6-C-X7, where x6 and X7 identical or different are halogen 10 atoms (F,Cl, Br), straight Qr branched Cl-C6 alkyl groups, a substituted or unsubsatuted phenyl group;
when A is (CH2)t, (C~H-~H)n-CH=CX3. (CH2)t-CHX3, S-(CH2)t~ H) S-CX4~5, then B is also CH=CH-(CH2)p, ~H-CH-CHX6, CH=CH-CX15X7, 5 whe~e p and X6, X7 are defimed as above.
PrefeIably, D can also be A'-CH(O-C~X8~B' whe~e A' is (CH2)t, (CH~)n-~H=CX3, (CH2)rC~3X3, S-(CH2)r(CH=CH)n, S-CX4X5, B' is CH2, CH X6, X6-C-X7, CH~H-(CH2)p, CH~l CHX6, CH=CH-CX6X7 where t, n, p, 20 X3, X4, X5" x6 and X7 are as described above, and X8 is a sahlIated or unsa~ra~ed Cl-C6al~1 or alkenyl chain.
. :
Suitable sal~s included within the scope of formula (I) indude, for example, corresponding salts of the group OR (in z1/Z2), for examplc salts formed with aL~ali 2s metal atoms such as sodium or potassium.
~ .
The prescnt invention also relates to the processes used for prcpanng substituted 30 phosphonates (I).
D iS A C(O)-B
35 A is (CH2)t. (CH=CH)n-(~=CX3. (CH2)t-CHX3. S(C~H2)t-(CH=CH)n or s-cx4xS
.
~ ,,.. , . ,. ,. . . . . :
--~ wo 94/19358 ~ 4 ~ 9 PCT/EW4/00520 B is CH2, CH-X6 or C-X6X7 `
The proccdure described in Fig. 1 p. 10 consists in reacting the commercially available alkylphosphonate m with a suitable base such as n-butyllithium or ~ithium s diisopropylamide. The lithium anion of compound m thus formed is then reacted in sin.~ with the appropriate ester II to give the substituted phosphonates (I). The reaction is carried out in an ether solvent such as dimethoxyethane or tetrahydrofuran (1~:), preferably in THF, at a temperature between -78C and room temperature (25C).
A second procedure descnbed in Fig 2 p. 11 consists in condensing the unsaturated aldehyde IV with the starting compound ketophosphonate V using titanium tetrachloride and N-methyl morpholine as condensadon agents. The reaction is camed out in an ether solvent such as tetrahydrofuran, dioxane or dimethoxyethane, preferably 1~ at a temp~ure between -30C and the boiling point of the solvent (66C in the case of 1~;). A compound of formula (I) where A is (CH=CH)n-CH=CX3 is obtained. Compounds of formula (I) where A is (CH2)rCHX3 can be preparcd by reacting the starting compound ketophosphonate V with an excess of a base or combination of bases. The bases are sodium hydride, sodium allcoxides, n-buql lithium or lithium diisopropylamide. The anion of ketophosphonate V thus folmed is then reacted with the halide VI, where Hal = Br o~
Cl. The reacdon is ca~ied out in tetrahydrofuran, dimethoxyethane, dioxane,i benzene or toluene. The temperature of the reaction varies between 0C and the boiling point of the sol~ent.
:
Examples 1, 2, 3 and 4 further illustrate the expenmental aspects of the processdescribed in Fig 2. - ` - - `
Conceming condensation reactions, in the case where B is a CH2 group, i.e. when the carbon alpha ~o the phosphonate functional group has two protons, in addition to the main reaction pToduct formed by monocondensation at tho gamma positdon, a side pToduct is also formed by double condensation with the dialkyl phenol groups at the alpha and gamma positions (see cx 1 and 2). In the case where B - CHX6 or X6-C-X7, e.g. wben two p~tons are not a~ailable at the alpha position, the compoundfoTmed by monocondensadon at the Bamma posidon is the sole reaction p~duct (see ex 4 and 10).
WO 94/19358 ?,~Q0409 PCTIEP94/00520 Likewise, when the alpha position is completely unsubshtuted (B~H2), in additionto ~e ~ reac~on compound formed by monoaddi~:ion~ these is also formed a side product occ~g by double addi~ons at ~e alp)ta and gamma posiaons (see ex 3).
5 A is (CE~-CH)n-CH=CH-C(o)-C~X3f (CH2)p-CH=C~I-C(O)-CHX3, (CH2)rC(O)-CHx3~ S(cH2)r(cE~-cH)n-c(O)-c~EIx3 or S-CX4XS-~(o~ X3 10 B is CH2, CH-X6 or C-X6X7 The p~cess described in Fig. 3 p. 12 consists in condensing an ester of formula VII
with the dianion of ketophosphonate V as dle gamma position. The dianion is 5 generated by stepwise reaction of V with an equiYalent of sodium hydride and an excess o a stronger base, E.g. n-butyl lidlium or lithium diisopropylamide (IDA) in te~hydrof~an at a tempe~ature betwcen -30 and 30C. The excess of dianion is then reacted wi~ ~he este~ V~ at a tempe~ re between -70 and 30~C to yield dle ketophosphonate (I) according to ~ig. 3.
Compounds (I) which possess two ketonc groups in dleir strucnlres m~y in solution be in tautomcnc equilibrium with cnol forms. The di~etone and enol forms of compounds (I) are integral part of this invention.
A is (CH2)t, (CH~l)n-CH~3, (CH2)rCHX3 or S(CH2)t~ H CH)n or B is CH=CH-CX6X7 or CH~CH-(CH2)p Thc procedure for prepanng compounds of formuls (I) where D is A-C(O)-B, where A is ~CH2)t, (CH=CH)n-C~H=CX3, (CH2)t-CHX3, S(CH2)t-(CH=CH)n or S-CX4X5, B is CH=CH-CX6X7 or CH=CH-(CH2)p consists 35 irl reacting an aldehytle of formula VIIIa or VIIIb .
WO 94/1~3~8 ~ PCTtEP94t00520 OF1C--CX X--P ~, OHC--~C~2 ) p--P ~ 2 VIIIa VIIIb Y~dhapho~phorusreagent wh~ch may beaphosphonatecompound offornnular~ or aphosphoniu¢~s~t ~f fonnu~a X:
~ R
~A C--CH2--PO3 (Alkyl ) 2 IX
~ 8 +
~A--C--CH2--P ~C6 ~5 ) 3 Br X X
0 ~ ercac~io~iscamed outin an ethersolvent,such asd~nethoxyethane or tetrahydrofuranin presence ofa basesuch assodiurn hyd~de or~thium diis~propylannne. - :
.
D is A~C H(O H)-B
- -Thc kct~pho~phonatcs of fornnula ~ pleviously descr~bed can be seduced to the coqresponding hydroxyphosphonate delivatives. The reduction can be camed out with complex hydridc reagents such as sodium borohydride, lidlium borohydride, sodium bis (2-methoxyetlhoxy) alu~num hydride, sodi~m trime~hoxyborohydride~
20 sodium cyanoborohydride.
Suitable solvents include ether, tetrahydrofu~an, toluene, methanol, ethanol, isopropanol. ~Prefered reduction conditions are sodium borohydride in methanol at a tempcrature between -20C and 65C.
wo 94/193~82 ~ ~ ~ 4 0 ~ PCT/EP94/00520 -`, D IS A'-CH(O-CO-X8)-B' Thc above-mcntioned hydroxyphosphonates can bc esterified to the co2responding 5 acyloxj-phosphonatc dcrivativcs by employing known proccdurcs. Suitable reaction conditions involvc heating the hydroxyphosphonatcs with an appropriate acid anhydride (X8-CO)20 or an appropriatc acid chloride X8-CO-Cl in prescnce of a tertiary aminc, cg. triethyl aminc or pyridine. The reaction temperature can rangc betwccn 0C to the boiling point of the acylating agent.
~o D is A CH2-B, (cH2)t-(cH=cH)n-(cH2)t~ S-(CH2)t Thc kctophosphonates (I) can be rcduced to the corresponding alkylphosphonates and alkenylphosphonatcs by reduction of the p-toluenesulfonylhydrazone derivatives 15 with sodium borohydride, sodium cyanoborohydride or catechol borane.
Phosphonic acids of structure (I) where Zl=Z2=OH can be prepared from the co~responding phosphonate esters by reaction vith bromotrimethyl silane to produce bis (tnmcthylsilyl) phosphonates which are reacted in sin~ widl water or methanol.
The starting compounds allcylphosphonates m are commcrcially a~ailable. Thc starting compounds l~etaphosphonatcs V arc preparcd according to known literaturc mcthods: E. J. Corcy and G. T. Kwiatlcowsld, J. Am. Chem. Soc, 2Q. p. 6816-6821 (1968) and F. Mathey and P. Savignac, Tet~ahedron ~, p. 649-654 (1978).
j WO 94/19358 PCT/EP94/00~20 D is a saturated or unsaturated Cl-Cl 1 alkylene chain in which one or more of the methylene groups can be replaced by a sulphur atom, an oxygen atom, a carbonyl group; optionally one or more methylene groups can be subs~tuted by one or more halogen atoms (F, Cl or Br), Cl-6 alkyl, phenyl, hydroxy or s acyl oxy groups, and salts, sohates and hydrates thereo Preferably, Xl and x2 are identical and are butyl gr~ups, in par~cular ~-butyl groups. .:
Prefe~ably, Y is oxygen.
Preferably Zl and z2 are identical, in particular O~ in which R is H, or a s~aight or 5 branched Cl 6alkyl group. More prefcrably, zl and z2 are idenacal OR groups inwhich R is Cl 6aLlcyl, in particular methyl, ethyl or i-propyl.
PreferaUy, G is OH.
20 Suitable bioprecu~sors of the group OH as defimed for G include, for example, oR3 groups where R3 is a straight or branched Cl-C6 alkyl group, a perfluorinated Cl-C6aL~yl group, a substituted or unsubsdtuted phenyl group, a subsntuted or unsubstituted benzyl group, suitable biopr~cursors can also be a R3-C(o)o- group, a R3O-C(o)o- group, a R3NH-C(o)o- group, a R3C(o)oCH20- group, a R3-So20-25 group wherc R3 is defined as abovc.
P~efo~bly, D is A-C(O)-B,A-CH(OH~-B,A-C~H2-B, (C~H2)r(CH=CH)n~(C~H2~t or S-(CH2)t, where - A is (CH2)t, (CH=CH)n-C~H=CX3, (CH2)t-CHX3, S-(CH2)t-(CH=CH)n, S-CX4X5, (CH~H)n-C~l=CH-C(O)-CHX3, (CH2)p-CH-~H-C(o)-CHX3, (CH2)t-C(o)-CHX3, S-(CH2)t-(CH-CH)n-C(o)-CHX3, S-CX4XS-C(o)-CHX3, (CH~H)n-CH=CH-C]H(oH)-CHX3, (CH2)p-CH=CH-CH(oH)-CHX3, 35 (CH2)rC]H(oH)-CHX3, S-(CH2)r(CH=CH)n-CH(oH)-CHX3, S-CX4XS-CH(oH)-CHX3 wo 94~9358 ~ PcT/EPs4lon~20 where n is zero, 1 or 2, t is a number f~m O to 4, p is a number ~om 1 to 3, - X3 is H, a s~aight ~r branched a~l Cl-C6 group, a substituted or unsubs~tuted 5 phenylgroup, - X4, XS identical or different are H, a s~ght or ~ranched Cl-C4 alkyl group, - B is CH2. CH-X6, X6-C-X7, where x6 and X7 identical or different are halogen 10 atoms (F,Cl, Br), straight Qr branched Cl-C6 alkyl groups, a substituted or unsubsatuted phenyl group;
when A is (CH2)t, (C~H-~H)n-CH=CX3. (CH2)t-CHX3, S-(CH2)t~ H) S-CX4~5, then B is also CH=CH-(CH2)p, ~H-CH-CHX6, CH=CH-CX15X7, 5 whe~e p and X6, X7 are defimed as above.
PrefeIably, D can also be A'-CH(O-C~X8~B' whe~e A' is (CH2)t, (CH~)n-~H=CX3, (CH2)rC~3X3, S-(CH2)r(CH=CH)n, S-CX4X5, B' is CH2, CH X6, X6-C-X7, CH~H-(CH2)p, CH~l CHX6, CH=CH-CX6X7 where t, n, p, 20 X3, X4, X5" x6 and X7 are as described above, and X8 is a sahlIated or unsa~ra~ed Cl-C6al~1 or alkenyl chain.
. :
Suitable sal~s included within the scope of formula (I) indude, for example, corresponding salts of the group OR (in z1/Z2), for examplc salts formed with aL~ali 2s metal atoms such as sodium or potassium.
~ .
The prescnt invention also relates to the processes used for prcpanng substituted 30 phosphonates (I).
D iS A C(O)-B
35 A is (CH2)t. (CH=CH)n-(~=CX3. (CH2)t-CHX3. S(C~H2)t-(CH=CH)n or s-cx4xS
.
~ ,,.. , . ,. ,. . . . . :
--~ wo 94/19358 ~ 4 ~ 9 PCT/EW4/00520 B is CH2, CH-X6 or C-X6X7 `
The proccdure described in Fig. 1 p. 10 consists in reacting the commercially available alkylphosphonate m with a suitable base such as n-butyllithium or ~ithium s diisopropylamide. The lithium anion of compound m thus formed is then reacted in sin.~ with the appropriate ester II to give the substituted phosphonates (I). The reaction is carried out in an ether solvent such as dimethoxyethane or tetrahydrofuran (1~:), preferably in THF, at a temperature between -78C and room temperature (25C).
A second procedure descnbed in Fig 2 p. 11 consists in condensing the unsaturated aldehyde IV with the starting compound ketophosphonate V using titanium tetrachloride and N-methyl morpholine as condensadon agents. The reaction is camed out in an ether solvent such as tetrahydrofuran, dioxane or dimethoxyethane, preferably 1~ at a temp~ure between -30C and the boiling point of the solvent (66C in the case of 1~;). A compound of formula (I) where A is (CH=CH)n-CH=CX3 is obtained. Compounds of formula (I) where A is (CH2)rCHX3 can be preparcd by reacting the starting compound ketophosphonate V with an excess of a base or combination of bases. The bases are sodium hydride, sodium allcoxides, n-buql lithium or lithium diisopropylamide. The anion of ketophosphonate V thus folmed is then reacted with the halide VI, where Hal = Br o~
Cl. The reacdon is ca~ied out in tetrahydrofuran, dimethoxyethane, dioxane,i benzene or toluene. The temperature of the reaction varies between 0C and the boiling point of the sol~ent.
:
Examples 1, 2, 3 and 4 further illustrate the expenmental aspects of the processdescribed in Fig 2. - ` - - `
Conceming condensation reactions, in the case where B is a CH2 group, i.e. when the carbon alpha ~o the phosphonate functional group has two protons, in addition to the main reaction pToduct formed by monocondensation at tho gamma positdon, a side pToduct is also formed by double condensation with the dialkyl phenol groups at the alpha and gamma positions (see cx 1 and 2). In the case where B - CHX6 or X6-C-X7, e.g. wben two p~tons are not a~ailable at the alpha position, the compoundfoTmed by monocondensadon at the Bamma posidon is the sole reaction p~duct (see ex 4 and 10).
WO 94/19358 ?,~Q0409 PCTIEP94/00520 Likewise, when the alpha position is completely unsubshtuted (B~H2), in additionto ~e ~ reac~on compound formed by monoaddi~:ion~ these is also formed a side product occ~g by double addi~ons at ~e alp)ta and gamma posiaons (see ex 3).
5 A is (CE~-CH)n-CH=CH-C(o)-C~X3f (CH2)p-CH=C~I-C(O)-CHX3, (CH2)rC(O)-CHx3~ S(cH2)r(cE~-cH)n-c(O)-c~EIx3 or S-CX4XS-~(o~ X3 10 B is CH2, CH-X6 or C-X6X7 The p~cess described in Fig. 3 p. 12 consists in condensing an ester of formula VII
with the dianion of ketophosphonate V as dle gamma position. The dianion is 5 generated by stepwise reaction of V with an equiYalent of sodium hydride and an excess o a stronger base, E.g. n-butyl lidlium or lithium diisopropylamide (IDA) in te~hydrof~an at a tempe~ature betwcen -30 and 30C. The excess of dianion is then reacted wi~ ~he este~ V~ at a tempe~ re between -70 and 30~C to yield dle ketophosphonate (I) according to ~ig. 3.
Compounds (I) which possess two ketonc groups in dleir strucnlres m~y in solution be in tautomcnc equilibrium with cnol forms. The di~etone and enol forms of compounds (I) are integral part of this invention.
A is (CH2)t, (CH~l)n-CH~3, (CH2)rCHX3 or S(CH2)t~ H CH)n or B is CH=CH-CX6X7 or CH~CH-(CH2)p Thc procedure for prepanng compounds of formuls (I) where D is A-C(O)-B, where A is ~CH2)t, (CH=CH)n-C~H=CX3, (CH2)t-CHX3, S(CH2)t-(CH=CH)n or S-CX4X5, B is CH=CH-CX6X7 or CH=CH-(CH2)p consists 35 irl reacting an aldehytle of formula VIIIa or VIIIb .
WO 94/1~3~8 ~ PCTtEP94t00520 OF1C--CX X--P ~, OHC--~C~2 ) p--P ~ 2 VIIIa VIIIb Y~dhapho~phorusreagent wh~ch may beaphosphonatecompound offornnular~ or aphosphoniu¢~s~t ~f fonnu~a X:
~ R
~A C--CH2--PO3 (Alkyl ) 2 IX
~ 8 +
~A--C--CH2--P ~C6 ~5 ) 3 Br X X
0 ~ ercac~io~iscamed outin an ethersolvent,such asd~nethoxyethane or tetrahydrofuranin presence ofa basesuch assodiurn hyd~de or~thium diis~propylannne. - :
.
D is A~C H(O H)-B
- -Thc kct~pho~phonatcs of fornnula ~ pleviously descr~bed can be seduced to the coqresponding hydroxyphosphonate delivatives. The reduction can be camed out with complex hydridc reagents such as sodium borohydride, lidlium borohydride, sodium bis (2-methoxyetlhoxy) alu~num hydride, sodi~m trime~hoxyborohydride~
20 sodium cyanoborohydride.
Suitable solvents include ether, tetrahydrofu~an, toluene, methanol, ethanol, isopropanol. ~Prefered reduction conditions are sodium borohydride in methanol at a tempcrature between -20C and 65C.
wo 94/193~82 ~ ~ ~ 4 0 ~ PCT/EP94/00520 -`, D IS A'-CH(O-CO-X8)-B' Thc above-mcntioned hydroxyphosphonates can bc esterified to the co2responding 5 acyloxj-phosphonatc dcrivativcs by employing known proccdurcs. Suitable reaction conditions involvc heating the hydroxyphosphonatcs with an appropriate acid anhydride (X8-CO)20 or an appropriatc acid chloride X8-CO-Cl in prescnce of a tertiary aminc, cg. triethyl aminc or pyridine. The reaction temperature can rangc betwccn 0C to the boiling point of the acylating agent.
~o D is A CH2-B, (cH2)t-(cH=cH)n-(cH2)t~ S-(CH2)t Thc kctophosphonates (I) can be rcduced to the corresponding alkylphosphonates and alkenylphosphonatcs by reduction of the p-toluenesulfonylhydrazone derivatives 15 with sodium borohydride, sodium cyanoborohydride or catechol borane.
Phosphonic acids of structure (I) where Zl=Z2=OH can be prepared from the co~responding phosphonate esters by reaction vith bromotrimethyl silane to produce bis (tnmcthylsilyl) phosphonates which are reacted in sin~ widl water or methanol.
The starting compounds allcylphosphonates m are commcrcially a~ailable. Thc starting compounds l~etaphosphonatcs V arc preparcd according to known literaturc mcthods: E. J. Corcy and G. T. Kwiatlcowsld, J. Am. Chem. Soc, 2Q. p. 6816-6821 (1968) and F. Mathey and P. Savignac, Tet~ahedron ~, p. 649-654 (1978).
3 8 1l 1 ` 8 Il Zl ~
X - CH2--C--L + M CH2--P\ 2 ~ X --CH2--C--CH2--P\ 2 V
L = Cl or OEt M = Li or Cu 30 The structures of new compounds of formula (I) arc determincd by infrared (IR), mass (MS) ind nuclcar magnetic resonance (NMR) spcctroscopies. The purity of thecompounds is verificd by elcmental analysis and standard chromatographic methods: `
tilin layer chromatography, gas liquid chromatography or high performance liquidchromatography.
---) WO 94/19358 2 ~ 1 8 ~ O g PCTIEPs4/OOQO
The abbreviations used in this pa~ent application are as follows:
In the tables n- is normal, i- is iso-, sec is secondary-, t is terdary. In the NMR
spectra, s is singlet, d is doublet, t is triplet, m is muldplet. The temperatures are 5 measured in degree Celsius and the meldng points a~e unco~ected.
The present invendon will be further described by ~e examples 1 to 22 which are typical of the syndledc procedures used.
wo 94/19358 ~ 409 " PCT/EP94/00520 - ) O = V
~ ")X
'rX
X J3` N X C
V -- :
~>
I
h C ~ U~
~ ~ ~X X
C., C;
E- .L) ~1 :
_ O
C~
I ~
:> N N ~ 5 H X
_ :
0~
i~l H
-'X~X
V
--~ WO 94/19358 21 1 8 gl O 9 PCTIEP~4/00520 o X
:~
æ v ~ /
_~ ~ H
~=
m m i~ I o= I
C S \ /
X
Z =CI) , I ,~ + O
:I: V
C
m N
~o ~ ~ 1 5 ~ XJ~ x ~, xJ~ X
~X ~X
~X~
WO 94/19358~7'" ~ r~ ~ `! PCT/EP~4/00520 "
X - CH2--C--L + M CH2--P\ 2 ~ X --CH2--C--CH2--P\ 2 V
L = Cl or OEt M = Li or Cu 30 The structures of new compounds of formula (I) arc determincd by infrared (IR), mass (MS) ind nuclcar magnetic resonance (NMR) spcctroscopies. The purity of thecompounds is verificd by elcmental analysis and standard chromatographic methods: `
tilin layer chromatography, gas liquid chromatography or high performance liquidchromatography.
---) WO 94/19358 2 ~ 1 8 ~ O g PCTIEPs4/OOQO
The abbreviations used in this pa~ent application are as follows:
In the tables n- is normal, i- is iso-, sec is secondary-, t is terdary. In the NMR
spectra, s is singlet, d is doublet, t is triplet, m is muldplet. The temperatures are 5 measured in degree Celsius and the meldng points a~e unco~ected.
The present invendon will be further described by ~e examples 1 to 22 which are typical of the syndledc procedures used.
wo 94/19358 ~ 409 " PCT/EP94/00520 - ) O = V
~ ")X
'rX
X J3` N X C
V -- :
~>
I
h C ~ U~
~ ~ ~X X
C., C;
E- .L) ~1 :
_ O
C~
I ~
:> N N ~ 5 H X
_ :
0~
i~l H
-'X~X
V
--~ WO 94/19358 21 1 8 gl O 9 PCTIEP~4/00520 o X
:~
æ v ~ /
_~ ~ H
~=
m m i~ I o= I
C S \ /
X
Z =CI) , I ,~ + O
:I: V
C
m N
~o ~ ~ 1 5 ~ XJ~ x ~, xJ~ X
~X ~X
~X~
WO 94/19358~7'" ~ r~ ~ `! PCT/EP~4/00520 "
4~g , T
o= I .
~_X ~ ~X
o I
xJ~ X U
V :C :
~ ~, ~ . , T
O ¦N
. U ~
i- ~N ~
, = tt r X 3:
~C O
O O
C
X N X
l2 --~ WO 94/19358 ~118 ~ ~9 ~ PCT/EP94/00520 ~ ,.
Dimethvl 1.5-bis(35~i-tert-butvl-4-hvdrox~henvl)-3-ox~l~,oentadien-2-vl ~hosohonate and Dimethvl ~(3.5-di-tcrt-butvl~hvdrox~hen~1~-2-oxo-3-buten-1-Yl ~hos,ohona~
Titanium tctrachloride (114.5g, 0.6 mol) was added dropwise with stimng to 300 ml of dry tetrahydrofuran CTh~) kcpt under nitrogcn at -20C. Solid 3,5-di-tert-butyl-~
hydroxy benzaldebyde (58.7g, 0.25 mol) was added, followed by 200 ml THF then dimethyl 2-oxopropylphosphonatc (50 g, 0.3 mol) was added. Finally N-methyl morpholinc (121.7g, 1.2 mol) was introduced slowly and the reaction mixture was s~rred at room tempcrature for 1 h. Cold water (200 ml) was introduced and tbe mixture was extracted with 1000 ml diethyl ether. Thc ether fraction was washed with watcr until neutral pH, dried over magnesium sulfate and evaAoorated in vacuo.
Purification was carried out by chromatography on silica gel using a 98/2 chloroform/methanol mi~cturc.
~he first compound (5.5 g,4%) to dute from the column was identi~led as dimethyl1,5-bis(35~i-tert-butyl~hydroxyphenyl)-3-ox~l,~pentadien-2-yl phosphonate.
` t--Bu ~ t-Bu H~CEI=CEI--C--C=CH ,~OH
PO3Me2 t--Bu t--Bu C3sHslO6P Theor. %C 7Q21 %H 8.59 %P 5.17 25 Found %C0.96 %H8.55 ~` %P5.31 mp = 190-191C.
IR tKBr): 3620 cm-l: OH, 1610: C=O,1580: C=C, 1430 and 1420: t-Bu, 1240:
30P-O, 1020: P-O-C
MS: ~/e = 599: M++1,598: M+,488: M+-H-PO3Me2, 367 tl00%) WO g4/19358 PCT/EP94/00520 - `
NMR (CDC13) ;' = 7.75 (d, J = 26 Hz, lH): Ph-C~I=C-P
7.57 (d, J = 16 Hz, lH): Ph-C~
7.3 and 7.23 (2 s,2H cach): m. H
6.60 (d, J= 16Hz, lH): Ph-CH~
o= I .
~_X ~ ~X
o I
xJ~ X U
V :C :
~ ~, ~ . , T
O ¦N
. U ~
i- ~N ~
, = tt r X 3:
~C O
O O
C
X N X
l2 --~ WO 94/19358 ~118 ~ ~9 ~ PCT/EP94/00520 ~ ,.
Dimethvl 1.5-bis(35~i-tert-butvl-4-hvdrox~henvl)-3-ox~l~,oentadien-2-vl ~hosohonate and Dimethvl ~(3.5-di-tcrt-butvl~hvdrox~hen~1~-2-oxo-3-buten-1-Yl ~hos,ohona~
Titanium tctrachloride (114.5g, 0.6 mol) was added dropwise with stimng to 300 ml of dry tetrahydrofuran CTh~) kcpt under nitrogcn at -20C. Solid 3,5-di-tert-butyl-~
hydroxy benzaldebyde (58.7g, 0.25 mol) was added, followed by 200 ml THF then dimethyl 2-oxopropylphosphonatc (50 g, 0.3 mol) was added. Finally N-methyl morpholinc (121.7g, 1.2 mol) was introduced slowly and the reaction mixture was s~rred at room tempcrature for 1 h. Cold water (200 ml) was introduced and tbe mixture was extracted with 1000 ml diethyl ether. Thc ether fraction was washed with watcr until neutral pH, dried over magnesium sulfate and evaAoorated in vacuo.
Purification was carried out by chromatography on silica gel using a 98/2 chloroform/methanol mi~cturc.
~he first compound (5.5 g,4%) to dute from the column was identi~led as dimethyl1,5-bis(35~i-tert-butyl~hydroxyphenyl)-3-ox~l,~pentadien-2-yl phosphonate.
` t--Bu ~ t-Bu H~CEI=CEI--C--C=CH ,~OH
PO3Me2 t--Bu t--Bu C3sHslO6P Theor. %C 7Q21 %H 8.59 %P 5.17 25 Found %C0.96 %H8.55 ~` %P5.31 mp = 190-191C.
IR tKBr): 3620 cm-l: OH, 1610: C=O,1580: C=C, 1430 and 1420: t-Bu, 1240:
30P-O, 1020: P-O-C
MS: ~/e = 599: M++1,598: M+,488: M+-H-PO3Me2, 367 tl00%) WO g4/19358 PCT/EP94/00520 - `
NMR (CDC13) ;' = 7.75 (d, J = 26 Hz, lH): Ph-C~I=C-P
7.57 (d, J = 16 Hz, lH): Ph-C~
7.3 and 7.23 (2 s,2H cach): m. H
6.60 (d, J= 16Hz, lH): Ph-CH~
5.55 and 5.51 (2s, lH each): O~
3.82 (d, J = l lHz, 6H): P-O-C~13 1.40 and 1.34 (2 s, 18H each): t-C4~g The second compound (36 g, 38 % yield) was iden~fied by IR, MS and NMR as dimcthyl 4-(3,5-di-te~t-bu~14-hydroxyphenyl)-2-oxo-3-buten-1-yl phosphonate t--Bu EI~CEI=CEI--C --CEI2 --PO3 Me2 t-BU
mp = 107-109 (ligroin, 80-95 frac~on) IR (KBr): 3420 cm-l: OH, 1650: C=O, 1590: CzC, 1420: t-Bu,1260: P=O and 1030: P-O-C
MS (m~e): 382 M~, 367: M+-Me,272: M+-HP03Me2,259:M~-CH2P03Me2, 151: M+-co-cH2-po3Me2 .
N~ (CDC13) ' ~ = 7.61 (d, J z 16Hz, lH): Ph-C~lzCH
7.42 (s, 2H): m. H
3.82 (d, J = l lHz, 6H): P-O-C~13 1.40 and 1.34 (2 s, 18H each): t-C4~g The second compound (36 g, 38 % yield) was iden~fied by IR, MS and NMR as dimcthyl 4-(3,5-di-te~t-bu~14-hydroxyphenyl)-2-oxo-3-buten-1-yl phosphonate t--Bu EI~CEI=CEI--C --CEI2 --PO3 Me2 t-BU
mp = 107-109 (ligroin, 80-95 frac~on) IR (KBr): 3420 cm-l: OH, 1650: C=O, 1590: CzC, 1420: t-Bu,1260: P=O and 1030: P-O-C
MS (m~e): 382 M~, 367: M+-Me,272: M+-HP03Me2,259:M~-CH2P03Me2, 151: M+-co-cH2-po3Me2 .
N~ (CDC13) ' ~ = 7.61 (d, J z 16Hz, lH): Ph-C~lzCH
7.42 (s, 2H): m. H
6.73 (d, J = 16 Hz, lH): Ph-CH~l 5.62 (s, lH): O~l 3.81 (d, J = llHz, 6H): P-O-C~I3 3.35 (d> J = 22Hz, 2H) C~2-P
1.40 (s; 18H): t-C4~1g C2~H315P Theor % C 62.81 % H 8.17 % P 8.10 Found. 9Co C 62.63 % H 7.97 % P 8.24 --I Wo 94/19358 2 1 1 8 ~1 0 9 pcTlEp94loos2o ~2i~yLl.s-bi~ t~-hutvl~ ~x~1~4-Dentadie~-2-yl and Titanium tctrachl~ride (137.1 g, 0.72 mol) was added dropwise tO 300 ml dry THF
at -15C. 3,5-Di-tert-butyl 4 hydroxybenzaldehyde (70.4 g, 0.30 mol) was added 10 followed by died~yl 2-oxo~opylphosphonate (70 g, 0.36 mol). N-methyl morpholine (145.8 g, 1.44 mol) was introduced and the rcaction mixture was stirred at room temperature for 2 h. Work up was camed out by addition of 200 ml water and 800 ml diethyl ether. The etha phase was washed with water to neu~al pH, dried over MgSO4 and cvaporated. The residue was chromatographed on silicagel using 98/2 15 C~HC13/MeOH as duent.
The first product (15 g, 8% yield) to dute was identified as diethyl 1,5-bis(3,5-di-tert-butyl~hydroxyphenyl)-3-oxo-l,~pentadien-2-yl phosphonate.
t--Bu t--Bu H~CH=CH--C--C=CH ~OH
PO3 Et 2 t-~su t-Bu C37H5sO6P Thcor. % C 70.90 % H 8.84% P 4.94 Found 96 C 71.18 % H 8.67% P 4.75 25 mp - 174-175C
IR: (KBr): 3620 cm-l: OH, 1640: C=O, 1585: C=C, 1430 and 1415: t-Bu, 1230: P=O and 1030: P-O-C
30 MS: mle = 626: M~, 488: M+-HP03E~2, 395 (100%) i~8 ~9i ;
wo 94/19358 2 i PCT/EP94/00520 NMR (CDC13) = 7.7 (d, J - 26 Hz, 2H): Ph-~lCC-P
1.40 (s; 18H): t-C4~1g C2~H315P Theor % C 62.81 % H 8.17 % P 8.10 Found. 9Co C 62.63 % H 7.97 % P 8.24 --I Wo 94/19358 2 1 1 8 ~1 0 9 pcTlEp94loos2o ~2i~yLl.s-bi~ t~-hutvl~ ~x~1~4-Dentadie~-2-yl and Titanium tctrachl~ride (137.1 g, 0.72 mol) was added dropwise tO 300 ml dry THF
at -15C. 3,5-Di-tert-butyl 4 hydroxybenzaldehyde (70.4 g, 0.30 mol) was added 10 followed by died~yl 2-oxo~opylphosphonate (70 g, 0.36 mol). N-methyl morpholine (145.8 g, 1.44 mol) was introduced and the rcaction mixture was stirred at room temperature for 2 h. Work up was camed out by addition of 200 ml water and 800 ml diethyl ether. The etha phase was washed with water to neu~al pH, dried over MgSO4 and cvaporated. The residue was chromatographed on silicagel using 98/2 15 C~HC13/MeOH as duent.
The first product (15 g, 8% yield) to dute was identified as diethyl 1,5-bis(3,5-di-tert-butyl~hydroxyphenyl)-3-oxo-l,~pentadien-2-yl phosphonate.
t--Bu t--Bu H~CH=CH--C--C=CH ~OH
PO3 Et 2 t-~su t-Bu C37H5sO6P Thcor. % C 70.90 % H 8.84% P 4.94 Found 96 C 71.18 % H 8.67% P 4.75 25 mp - 174-175C
IR: (KBr): 3620 cm-l: OH, 1640: C=O, 1585: C=C, 1430 and 1415: t-Bu, 1230: P=O and 1030: P-O-C
30 MS: mle = 626: M~, 488: M+-HP03E~2, 395 (100%) i~8 ~9i ;
wo 94/19358 2 i PCT/EP94/00520 NMR (CDC13) = 7.7 (d, J - 26 Hz, 2H): Ph-~lCC-P
7.59 (d, J = 16Hz, 2H): Ph~C~
7.30 and 7.25 (2s, 2~I each): a~om. H
6.63 (d, J = 16 Hz, 2H): Ph-CH~
5.54 and 5.4812s. lH each): O~ -4 18 (q~int., J = iHz, 4H): P-O-C~I2-CH3 1.40 and 1.34 (2s, 18H each): t-C4~1g 1.34 (t, J= 7 Hz, 6H): P-aC~2-C~3 The second product was identified as diedlyl 4-(3,5-di-te~t-butyl~hydroxyphenyl) -2-oxo-3-buten-1-yl phosphonate (44 g, 36% yield) ;~
t--Bu O
~ 11 ' ,:
H~CH=C:H C --CH2 PO3Et2 t--Bu mp = 11~111C (rccrystallized from ligroin 80-95 fraction).
.
IR (KBr): 3620 cm~l: OH, 1680:C=O, 1590: C=C, 1430 and 1415: tl3u, 1240: P=O
and 1230: P-O-C
MS (m/e): 411: M+1, 410: M+, 272: M+-H-PO3Et2, 259: M+-CH2PO3Et2, 57 (100%) tBu+
Nl~ (CD(~3) ~ = 7.61 (d, J = 16 Hz, lH): Ph-~=CH
7.40 (s, 2H): arom. H
6.74 (d, J = 16Hz, lH): Ph-CH~
5.6 (s, lH): OEI.
4.16 (m, 4H): P-O-C~2-CH3 3.33 (d; J = 23 Hz, 2H): ~EI2-P
1.45 (s, 18H): t-C4~19 1.34 (t, J = 7Hz, 6H): P-O-CH2-C~3 -! wo 94/1935~ 8 4 D Y PCT/EPs4/oos20 C22H3sOsP ~eor% C 64.37 % H ~.S9 % P 7.55 ~ Found% C 64.52 % H 8.6S % P 7.36 s ~m~l~
and e~v~ 3.5-di-t~hvdrs~1~-2-Q2~1-~ts!l~bQsPh~l~
Sodium hydride (1.4~ g of a 60% dispersion in mineral`oil, 36.25 mmol) was suspended under nitrogen in hexane, this latt~r was pipe~ted out and replaced by 60 ml dry T~. Diethyl 2~xopropylphosphonate ~7.0 g, 36 mmol) was introcluced. The mixn~re was s~rred at room temperature for 30 min then was cooled to 0 ~C then n-bu~l lithium (37.5 ml of a 1.6 M solution, 60 mmol) was aclded. Finally a soluaon of 3,5-cli-tert-butyl~-hydroxybenzyl bromide (9.0 g, 30.1 mmol) in 40 ml THF wasadded and the reaction mixture was s~ed at room temperan~re ovemight. Work-up was ca~ied out by par~ti~n between 150 ml 15~c HCl and two fractions of 1~0 ml ether. The ether phase was washed with so~ium bicarbonate and satuIated sodium 20 chloride to ~eutral pH. After d~ying and solvent evap~ration, the crude mixture was purified by column chromatography (SiO2, 8/2 CHC13/AcOEt).
The first compound (1.~ g, 8% yield) to elute was die~hyl 1,5-bis(3,5-di-~ert-butyl-~hydroxy-phenyl)-3-oxo-2-pentyl phosphonate, mp = 60 61C.
t--Bu t-Bu )~ 8 ,~( HO~CH2--CH2 C--CH--CH2 ~OH
PO3 Et2 t--Bu t--Bu IR (KBr): 3620 cm-l: OH, 1710: C=O, 1430: t-Bu, 1230: P=O and 1010:
P-~C
MS:m/e= 630: M+, 493: M+-HP03Et2 8 ? '~ , ~ PCT/EP94100520 --NMR (C~DC13) o = 6.89 (2s, 2H each): arom. H
5.09 and 5.03 (2s): O~
4.1 (m,4H): P-O-C~2-CH
S 3.5 and 3.25 (2m,2H): Ph-(~I2-CH-P
3.04 (txd, lH): Ph-CH2-C~(P~CO
2.9 - 2.4 (2m,4H): Ph-c~a2-c~l2 1.14 and 1.39 (2s,18H cach): t-C4~1g 1.32 (2t, J=7Hz, 6H): P-O-CH2-The sccond compound was dicthyl 4-(3,5-di-tert-butyl 4- hydroxyphenyl)-2-oxo-1-butyl phosphonate: 2.2 g (18% yicld) of an oil was obtained which slowly solidified upon standing.
t--Bu ~CH2-CE12--C--C~2 PO3Et2 t--Bu IR (~m): 3620 cm~1: OH, 1710: C=O, 1430: t-Bu, 1250: P=O, 1010: P-O-C
MS m/c= 412: M+, 274: M-HPO3Et2 , ..................................... :
N~: (C~DC13) o = 6.98 (s, 2H): arom. H
5.1 (s, lH): oH
4.14 (m,4H): P-O-CH2CH
3.05 (d, J=25Hz, 2H): CEl2-p 2.94 (m,2H): Ph-C~I2-CH2 2.83 (m, 2H): Pb-cH2-c~l2 1.42 (s, 18H): t-C4Hg 1.32 (t, J=7Hz, 6H): P-O-CH2-C~13 -- I Wo 94/19358 21 1 8 4 ~ 9 PCT/EP94/~0~20 ~mQ~ ' Diethvl ~(3.5 di-tert-bd~-~b~h~-1 .l~im~hvl-2~ bu~n-l-vl-t--Bu o CH3 ~ 11 1 H~CH=CH - C--C--PO3 Et2 (~H3 ~--Bu Dicthyl 1,1-dimethyl-2-ox~pr~pylphosphonate (bp = 60~/0.2 mbar) was synthesized acco~ding to V. Roussis and D.F. Wiemer, J. Org. Chem. ~, p. 627-631 (1989).
To 20 ml dry THF kept at 0C were a~ed sequentially TiC14 (1.72 g, 9 mmol), 3,5-di-tert-buty1-4-hydroxybenzaldehyde (0.9 g, 3.8 mmol), diethyl 1,1 dimethyl-2-oxopropylphosphonate (1.0 g, 4.5 mmol), N-methyl mo~pholine (1.82 g, 18 mmol) then thc seaction mixt was s~rcd for 1 h at room temperan~re. Work up ca~ied out in the usual manner gave an oil which was purified by column chromatography (SiO2, 8/2 CHCl31AcOEt). An amount of 1.1 g (68% yield) of th~ atle compound was obtained. Mp = 91-92C (petroleum cther 40-60).
KBr): 3440 cm-1: OH, 1670: C=O, 1590: C=C, 1430 and 1410: t-Bu, 1210:
P~ and 1030: P-O-C
MS: mle= 439: M~ + 1, 259: M+-C(CH3)2-P03Et2, 57 (100%): tBu :~
N~: (CDC13) = 7.66 (d, J = l~Iz, lH): Ph-~=CH
7.43 (s, 2~I): aro~ H
7.26 (d, J = 16Hz, lH): Ph-CH~
5.55 (s, lH): OH
4.15 (m, 4H): P-O-~12-CH3 1.~0 (d, J = 17H~ 6H): -C(C~3)2-P
1.46 (s, 18H3: t-C4~19 1.32 (t, J = 7Hz, ~H): P-aCH2-~3 C24H39O5P ~alc. % C 65.73 % H 8.96 % P 7.06 Found % C 66.00 % H 8.98 % P 6.82 o9 , ~ t~ ~a~u~
Dho~
t-BU
~\ 11 .
HO~CH--C----C --C~2 PO3 Et2 t-Bu Diethyl 2-oxobutylphosphonate (bp = 90/0.6 mbar~ was prepared according to F.
Mathey and P. Savignac, Tetrahed-~n 34, p. 649-654 (1978).
To 20 ml dry T~IF ke~t at 0C were added successively TiC14 (1.82 g, 9.6 mmol), 3,~i-ter~-butyl~-hydroxybenzaldehyde (0.94 g, 4 mmol), diethyl 2-oxobutylphosphonate (1 g~ 4.~3 mmQl) and N-methyl morpholine (1.86 g, 18.4 mmol). The reacaon mixture was s~red at ~oom temperature for 30 min then was heated to reflux for 1 h. After the usual wor~-up and extraction ~e crude reacaon ~ture was purified by column c}~romatography (SiO2, 8/2 CHC13/AcOEt). A
small amount of unrcacted benzaldehyde was first collected ~en 0.35 g (21%) of ~e dtle compound was obtai~ed. Mp = 97-101C (petroleum e~er 4~60).
IR (KBr): 3400 cm-1: OH, 1680: C=O, 1610 and 1590: C=C, 1440: t-Bu, 12S0: P=O
and 1020: PO-C
MS: m/e = 424: M+, 409: M t-CH3~ 367: M+-tBu, 286: M~-HP03Et2, 57 (100%):
~Bu+
NMR (CDC13):
~ = 7.56 (s, lH): Ph-~l=C
2s 7.33 (s, 2~): arom. H
5.5 (s, lH): O~
4.16 (m, 4H): P-O-C~2-CH3 3.Sl (d, J=22Hz, 2H): ~2-P
2.1 (s, 3H): ~13 1.46 (s; 18H): t-C4~g 1.32 (t, J= 7HZ, 6H): P-O-CH2-~3 wo 94/19358 211~ 4 ~ 9 PCTIEPg4/00520 ~23~37O5P C alc. % C 65.07 ~O H 8.79 % P 7.30 Found % C 65.35 % H 8.58 ~ P 7.51 ~mu~
thyl9~i-tert-~utvl~c yll 3 (n ~Q~3-~
t--Bu HO~ CH=C C CH2 PO3 Me2 r n-C4 Hg t--Bu A mixture of 3,5-di-tert-butyl~hydroxybenzaldehyde ~3.65 g, 15 mmol), dimethyl 2-oxoheptylphosphonate ~4.0 g, 18 mmol), rlCl4 (6.84 g, 36 mmol) and N-methyl mospholine (7.27 g, 72 mmol) in 80 ml dry TH~ was refluxed as desc~ibed in example 7. Purification by column chromatography (SiO2, 8/2 CHCl3/AcOEt) gave 1.2 g (20% yield) of the tide compound. Mp - 82-85 (petrolcum ether 4~60) M~: m/c 439 M~ 1, 438 M+, 381 M+-C4Hg, 57 (100%): tl3u NMR (CDC13) 7.48 (s, lH): Ph~ =C(C4Hg) 7.32 (s, 2H): arom. H
5.5 (s, l~ O~
3.81 (d9 J = llHz, 6H): P-O-C~13 3.52 (d, J = 22Hz, 2H): ~2-P
2.~7 (m, 2~I): ~I2-C3H7 1.5-1.4 (m, 4H) CH2-~ )2-CH3 1.5 (s, 18H): t-C4~19 0,94 (t, J = 7Hz9 3~): (CH2)3-C~3 , ~ . - . .
WO 94/19358 sj~ ~ PCl'/EP94/00520 --Me~ 3.s~ u~l-~byd~henyL~-2~Q~ -3-bu~n PhQS~
t-BU
H~CH=C--g --CH2 --PO3 Et2 t-BU Ib The procedure desclibed in example S was employed, using as the phosphonate ~eagcnt diedlyl 2-oxo-3-phcnylpropylphosphonate (bp=150/0.5 mbar). The ~itle 10 compound was isolated ~y column chromatography under ~e usual condî~ons ~SiO2, 8/2 CHCl~/AcOEt) at ca 18% yqeld.
., mp=139-143C
15 IR (KBr): 3500: OH, 1640: C=O, 1610 and 1~90: C=C, 1430: t-Bu, 1230: P=O, 1020: P-~C.
MS: mlc=486 (100%) M~, 348: M+-HPQ3Et2, 335: M+-CH2P03Et2 20 N~:(CDC13) = 7.70 (s, lH): Ph-~~
7.45 - 7.25 (m, SH): (~6~5 6.97 (s, 2H): aro~ H
5.46 (s, lH): OH
4.15 (m, 4H): P-0-~2-CH3 3.33 (d, J=22Hz, 2H): C~12-P
1.32 (t, J=7Hz, 6H): P-O-C~H2-C~3 1.23 (S3 18H): C4~19 C2gH3g0sP Calc. % C 69.11 % H 8.08 % P 6.37 Found %C69.37 %H8.11 %P6.61 wO 94/19358 2 I I 8 4 0 9 PC rEW4/oos20 12is~hyL4 (~di-tcrt-~1-4~by=h~-l-methyl-2-oxQ 3-bu~n~
S ::
t-Bu HO~CH=CH ~ C--CH --PO3 Et2 t--Bu Diethyl l-methyl-2-oxopropylphosphonate was prepared according to Mathey and Savignac as cited as example S. ~
' '-A mixture of 3,5-di-test-butyl-~hydroxybenzaldehyde (7.19 g, 29 mmol), diethyl 1-methyl-2-oxopropylphosphorlate (8.20 g, 35 mmol), TiCl4 (13.47 g, 71 mmol), N- ::
methyl mo~pholine (14.34 g, 140 mmol) in 150 ml dry TH~ was reacted at room temperan~re for 1 h, then at reflux temperature for 18 h. After work up, column lS chromatog~aphy (SiO2, 8/2 CHC13/AcOEt) gave 4.7 g (38%) of the title compound.
mp~2-94C : i NMR (CDC13) : .
~ = 7.63 (d, J - 16Hz, lH): Ph-C~=CH .
7.42 (s, 2~1): a~om. H
6.87 (d, J = 16Hz, lH): Ph-CH~
5.6 (s, lH): O~ ::
4.15 (m, 4H): P-O-C~2-CH3 3.~3 and 3.46 (n~o q, J = 24Hz and 7Hz, lH): C~I-P
1.5~1.43 (two d, J = 7Hz~: ~-(P)-~3 1.46 (s, 18H): C4~g 1.32 (two ~, J ~ 7Hz): P-~CH2C~3 WO 94/1s358 PCT/EP94/00520 Dimethyl q-(3.~ tert-butvl-~hvd~ )-2-Q2~-bute~-1-yl ~ ,ahQn~
t--Bu H(~CH CH --C CH2--PO3 Me2 t--Bu S Under ni~gen ahnosphere dime~yl methylphosphonate (3.17 g, 25.6 mmol) was added at -60 to a solution of n-butyllithium (16 ml of a 1.6 M solution in hexane, 25.6 mmol) in 1~ ml anhydrous THF. The reac~on mixturc was stirred at -50 for 30 min to allow fo~ complcte fo~mation of the lithium anion (slight ~rbidity~. The m~ix~e was again cooled to -60 and a solution of e~yl 3,5-di-tert-butyI-~hydroxycinnamate (2.6 10 g, 8.5 mmol) in 20 ml dry THF was added. The resulhng orange-colored mixture was left to stir at room temperanlIe (25C) for 18 h. Hydrolysis was caIIied out by adding 10 ml of a lO~o HCl sc~ludon and the produc~ was extracted into ether. After ~ngove~ MgSO4, e~e~ was evapor~ed to yield a yellow solid. RecIystallization in 40 - 60 petroleum ether gave 3.0 g (92% yield) of dimethyl ~(3,~ te~-bu~yl~
15 hydroxyphenyl)-2-ox~3-buten-1-yl phosphonate.
mp=107-109C
The ~de compound can also be obtained by using as the bases a mixture of n-BuLi and 20 LDA ~ithium diisopropylamide). To a solu~on of n-butyllithium (16ml of a 1.6 M
solution, 25.6 mmol) in 20 ml dry l~ was added at -60C diisopropyl amine (0.86 g, 8.5 mmol). The resulting mixture was st~red at 40 for 15min, then dime~yl methylphosphonate (2.11 g, 17 mmol) was added. After 15 min, ethyl 3,5-di-tert-butyl-4-hydroxycinnamate (2.6 g, 8.5 mmol) was added and the rea~tion mixture was stirred 25 at room temperat~e (25C) fo~ 15 h. Work up by addition of 10% HCl and extraction into ether gave 3.10 g (95%) of dimethyl ~(3,5-di-tert-butyl~hydroxyphenyl)-2-ox~
3-butcn-1-yl phosphonate.
mp=107-109C
30 The compound p~epared by dther of these n~o variant p~ocesses has spectroscopic data idenical to thiose of the same product described in example 1.
, i1 ' . ~
~) WO 94/19358 2I 18 4 09 PCT/EPg4/00520 C2bH3105P Theor. 9~oC 62.81 %H 8.17 96P 8.10 Pound %C 62.56 %H 8.21 %P 8.24 ; 5 ~ ~m~ll~
Diethv! ~f3 S-di-tert-butvl~hvdroxv~henvl)-l.l-dime~vl-2-oxo-3.5-hexadien-1-vl ~hos~hona~e `
..
t--Bu ~ `
)~ 8 1CH3 ~; HG~CH=CH--CH=CH C C--PO3Et2 CH3 `
t--Bu : ' ~`.
To 15 ml dry THF kcpt at 0 were added rlcl4 (1.23 g, 6.47 mmol), 3,5-di-tert-butyl-4hydm~ cinnamaldehydc (0.7 g, 2.67 mmol), diethyl 1,1 dimethyl-2-~; ~io~_ (0.72 g, 3.24 mmol) and N-methylmorpholine (1.31 g, 12.97 ~ . Thc leaction mixture was sti~rcd for 1 h at 20C then 1 h at 30C. Work-up gare a da~ oil which was purified by column chromatography (SiO2, 8/2 C~IC13/AcOEt). 650 mg (52%) of yellow crystals werc obtained, mp = 13~133C
:
NMR (CDC13) o = 7.40 (d x d, J = 11 and 15Hz, lH): Ph-CH~-CH=CH
7.2 (s, 2H): arom. H - ~- ` ` `
6.87 and 6.85 (2 d, J = 15Hz, 2H): Ph-~=CH-CH~
6.75 (d x d, J = 11.5 and 16Hz, lH): Ph-CH=CH-C~H
- 5.4(s, lH): OH
4.1 (m, 4H): P-O-C~12-CH3 1.40 (d, J = 16Hz, 6 H): C(C~I3)2 1.39 (s. 18H): t-C4Hg 1.24 (t, J = 7Hz, 6 H): P-O-CH2-C~3 MS: tn/e~: M+, 326: M+- HP03Et2, 285 (100*): M+- CMe2-P03Et2 C26H41SP Calc- % C 67.22 % H 8.90 % P 6.67 Found % C 66.68 % H 8.56 % P 6.21 wO 94/19358 ~Q~ 4~9 ; PCT/EP94l00520 -~ ~
`:
t--Bu ~ 11 .
H~CH2-CH2- C --CH2 PO3Me2 ;~
t--Bu A solution of dimethyl lithiomethylphosphonate was prepared under nitrogcn by adding dimethyl mcthylphosphona~c (3.2 g,25.6 mmol) to a solution of n-butyllithium (16 ml of a 1.6 M soludon in hexane, 25.6 mmol) in 15 ml dry THF at - `
60C. To this solution was added at -60 a solution of ethyl 3,5-di-tert-butyl-~hydroxyhydrocinnamate (2.6 g, 8.5 mmol) in 20ml THF. The resulting solution was stirrcd at -60 for 30 min and then was allowed to reach r~om temperature (25C)ovemight. 25 ml 10% HCl was addcd and the mixture was ex~racted into ether. The ;~
residue of the eth~ phase was purified by column chromatography (SiO2,8/2 - CHC13/AcOEt) to yield a white solid. Recrystallizadon in petroleum ether gave 2.1 g (64% yield) of thc dde compound.
mp=78-79C
MS: m/e=384: M+, 284: M+-HP03Mc2,57 (100%): tBu+
N~ (CDC13) ~ = 6.98 (s, 2H): arom. H
5.06 (s, lH): OH
3.75 (d, J = 11.5Hz, 6H): P-O-C~I3 3.08 (d, J = 22.5Hz,2H): (~12-P
2.90 (m, 2H): Ph-c~2-cH2 2.81 (m, 2H): Ph-CH2-C~12 1.41 (s~ 18H): t-C4~1g WO 94/19358 21 18 ~ ~ 9 PCT/EP94/00520 ~2, :
Diethvl ~(3~-di-tert-butvl-4-hv~henyl~-æ4-di~-s-hex~n-l-vl ~ho~hon~
t Bu )~\ i~) ~) .' HO~\ /)--CH=CH C --CH2 C -- CH2 PO3 Et2 ~ `:
t-Bu Diethyl 2-oxopr~pylphosphonate (3.4 g, 17 mmol) was added at room temperan~re under nitrogen to a suspension of sodium hydride (0.82 g of a 60% dispension, 201~ mmol) in 35 ml dry T~IF. The mixture was sti~ at room temperature for 60 min,then diisopropylan~ine (1.71 g, 17 mmol) was added at 0, followed by n-butyllithium (21 ml of a 1.6 M solution, 34 mm~l). After 30 min at 0, the mixture was cooled to -60 and a solution of ethyl 3,5~ tert-butyl-~hydroxycinnamate (2.6 g, 8.5 mmol) in 25 ml T~ was induced dropwise. The resulting mixture was sdrred at 0 fc~r 2 h, at 25C for 1 h, hydrolyæd with 60 ml H20 whereupon it separatedinto two phases. Thc aqueous phase was acidified with 10% HCl and was extracted wi~ two 100 ml po~ons of ether. The ether extracts were pooled with the T~
phase, dried and cvaporated. The residue was purified by column ch~omatography (SiO2, 8/2 C~HC13/AcOEt) to yield a viscous olange oil. Recrystallizadon in ligroin gave 2.25 g ~60% yield) of the title compound, mp=109-1 10C
NI~ (CDC13) = 7.60 (d, J=16Hz, lH): Ph-C~=CH
7.37 (s, 2H): arom. H
6.35 ~d, J= 16Hz, lH): Ph-CH~
5.83 (s, lH): CO-(~=C-OH
5.54 (s, lH): phenol O~
4.17 (m, 4H): P-O-C~12-CH3 3.02 (d, J = 22Hz, 2H): C;~12-P
1.46 (s, i8H): t-C4~g 1.34 (t, J = 7Hz, 3H): P-O-CH2-~3 MS: m/e 452 M+, 314 M+ - HP03Et2, 57 (100%) tBu ~ -~~ . .
WO 94/19358 . PCT/EPg4/00520 - `~
E~ ..
t~BU
O O
~\ ~1 il ~
HO~C:H2 -CH2--C--CH2 C CH~--PO3 Et2 /
t Bu Diethyl 2-oxopropylphosphonate (2.02 g, lO mmol) was added at room temperature to sodium hydride (0.48 g of a 60% dispersion, 12 mmol) suspended ~ 30 ml T~.
10 Aftc~ 30 min the mixn~re was cooled to 0 and diisopropylamine (1.01 g~ 10 mmol) and n-butyllithium (13 ml of a 1.~ M solution, 21 mmol) we~e added. After 30 min, the mixture was cooled to -60 snd ethyl 3,5~i-tert-butyl-4-hydroxy hydrocinnamate (1.6 g, 5.2 mmol) dissolved in 15 ml THF was added. The ~h~re was left to react at -60 for 15 min then at 0 fo¢ 2 h and 25C for 1 h and was hydrolyzed with 10%
5 HCl and ex~wted with e~er. Column chromatography (SiO2, 8/2 CHCl3/AcOEt) gave 1.0 g (42%) of ~he tide compound as a colorless oil.
. ~ ................................ .
(CDC13) ~ ; r ~ ~ 6.98 (m, 2H): arom. H
5.70 (s, lH): CO-C~CC-OH
5.09 (s, lH): phenol OH
4.15 (m, 4H~: P-O~ 2-CH3 2.92 (d, J = æ.~ 2H): ~I2-P
2.85 (m, 2H): Ph-~2-CH2 2.59 (m, 2H): Ph-cH2-(~I2 1.43 (s, 18H): t-C4~Ig 1.33 (t, J = 7Hz, 6H): P-~CH2-C~3 MS: 455 M+ +1, 454 M+, 436 M+ -H20, 57 (100%) t:Bu wo 94/193~8 21 I 8 4 0 9 PCT/EP94/00520 E~l!l .
Dimethvl ~f3~$ di-te~-~u~l-~h~drox~henvl2-~d~oxo-~-h~n-1-vl ~b~ na~
:
t--Bu O O
/~\ 11 11 HO~ ~CH=CH C CH2 ~ C --CH2 PO3 Me2 r t--Bu The procedure ~s~ibed in example 12 was followed using dime~yl 2-ox~
pr~pylphosphnnate to give the title compound at ?9% yield, yellow solid with lo mp = 14~-146C.
~ .
,2-r4-(3 5-~-butvl~-hvdrox~nyl~2-ox~3-bu~n-1-vU
15 f2-ox~1.3.2~ioxaDhosphorinan) t -Bu 11~~
H~CH=CH--C --CH2 P
t-Bu Under nitrogen atmosphe~e, 2-methyl-2-ox~1,3,2-dioxaphosphorinan (2.62g, 19.2 mmol) dissolved in THF~dioxane (30ml each) was added to an equimolar amount of n-butyllithium in 35ml TH~ at -60C. The mixture was stirred at -60C for 30 minthen a solu~on of ethyl 3,5-di-tert-butyl-4-hydroxycinnamate (2g, 6.4 mmol) in 20ml TH~ was added. The resulting mixture was sti~Ted at -60C for 30 min and left to attain room temperature (25C) over 16 h. After the usual work up, column chrornatogra~hy (silicagel, 98/2 CHC13~MeOH) gave 0.76g of the title compound (30%).
mp = 158-161C
MS: m/e = 394 M+, 57 (100%): tBu WQ 94/19358 . PCT/EP94/00520 -" ~
4~ ~
. ~ ' Nl~ (CD~13): , - 7.65 (d, J= 16Hz, lH): Ph~
7.42 (s, 2H): arom. H
6.74 ( d, J = 16Hz, lH): Ph-CH~
5.7 (s, lH): QH
4.5-4.4 (largc m, 2H): P-O-C~2 3.4~ (d, J = 22~z): ~I2-P
2.1 and 2.0 (2m, 2H): P-~CH2-C~2 1.45 (s, 18H): t-C4Hg ~am~2~
t--Bu )~ 8 HO~ C CH=CH CH2 --PO3 Et2 t--Bu To a suspcnsion of 730mg 60% sodium hydride (18 mmol) in 20ml THF was added 3;0g t8.4 mmol) of dimethyl 2-(3,5-di-tèrt-butyl-4-hydroxyphenyl)-2-oxo-1 20 e~ylphosphonatc in 25ml THF. Thc mixture was s~ed for 30 min then it was cooled to 0 and 3.1g tl8 mmol) die~hyl foqmylmethylphosphonate was added. The resulting mixture was sti~red at 0C for 1 h then at 25C for 16h, par~tioned into cther and watcr and the o~ganic phasc was evaporated. Purificadon by means of column chromatography (silicagd 98/2 dichlo~omethane/methyl t-butyl ethcr) gave 25 550mg (16%) of the dde compound.
mp = 68-70C
MS=m/e: 410 M+, 39~: M+-CH3, 272: M+-HP03E~2, 233 (1~0%) M+-CH=CH-CH2P03Et2 -! W094/l9358 21I8~09 PCTIEP~4/00520 NMR: CDC13 = 7.83 (m, 2H): arom. H, 7.1 (dd, 1=15 and 4.5Hz, lH), Ph-CO~
6.9 (m, 2H): Ph-CO-CH~
5.7 (s, lH): OH
4.15 (m, 4H): P-O-C~2-CH3 2.86 (dd, J=23 and 7Hz): C~2-P
1.48 (s, 18H): t-C4Hg 1.34(t, 6H): P-O-CH2-C~3 ~ime~vl ~(3.5-di-~ert-butvl~hy~roxv ~henvl)-2-hvdroxv-3-buten-1-vl ~ ~.
lS
t-Bu )~ f HO~ CH=CH CH CH2 PO3Me2 r t--Bu To 100 ml of a methanol solution of dimethyl 4-(3,5-di-tert-butyl~hydroxyphenyl)-2-oxo-3-buten-1-yl phosphonate (19g, 5 mmol) cooled to -10C were added 0.75g 20 sodium borohydride. The reacting mixture was stirred at -10C for 1 h then at room - temperature (2SC) for 2 h. Wor~ up was carried out by addi~on of 100ml ether and 60ml sodium bicarbonate soludon. Thc ether phase was washed with brine, dried over MgSO4 and e~raporated to yield 1.6g (85%) of ~e tide compound.
.;!-25 mp = 122-123C -MS (m/e)= 384:M+, 366: M+-H20, 256: M+-H2~HP03Me2 Wo 94l19358~ ~ 3 PCTEP94/0052U
NMR (C~DC~3): .
7.21 (s, 2H): arom.;H
6.59 (d, J = 16Hz, i`H): Ph-C~H, 6.08 ~dd, J = 16 and 6Hz, lH): Ph-CH-{~
5.26 (s, lH): OH (phenol) 4.7 (rn, lH): C~-OH
3.78 (2xd, 6H): PO3~2 3.4 (hump, lH): CH-O~
2.15 (distorted dd, 2H): C~2-P
1.44 (t, 18H): t-C4Hg Dimethvl ~r3.s di-tert-blltvl~hvdrox~henvl~-2-ox~3^butcn-1-vl .~iono~ho~honate t--Bu O S
/=\ 11 11 , HO--~\ /; CH=CH C --CH2 P (OMe) 2 :
~~ .
t--Bu Undcr nitrogcn atmosphcrc dimethyl methylthionophosphonate (3. lg, 25 rnmol) was20 added at -60C to a soludon of n-butyllithium (16ml of a 1.6M soludon, 25.6 rnmol) in 50ml lL~. Thc mixture was st~ed at -60C for 15 rnin then a solution of ethyl3,5~-tert-butyl 4 hydro~cy cinnamate (2.5g, 8.2 mmol) in 20 ml T~ was added.
Thc resulting mi~cture was sturcd at -60C for 30 min and at room temperature (25C) for 2 h. After the usual hydrolysis and wo~ up, the compound was purified25 by column chromatography (SiO2, 9/1 CHCl3/AcOEt) and rec~ystallization in CHC131petro1eum ether to yield 1.7g (52%) of a yellow solid, mp = 88-90C
MS: mle = 398: M+, 259: M+-CH2P(S)(OMe)2, 125: P(S)(OMe)2, 57 (100%) ~. ~.. .
`` WO 94/19358 2118 4 09 PCTIEP94/00520 NMR (CDC13~
~= 7.60 (d, J - 16Hz, lH): Ph-C~=CH
7.42 (s, 2H): aro~ H
6.75 (d, J = 16Hz, lH): Ph-CH=C~
5.6 (s~ lH): O~
3.78 (d, J = 14Hz, 6H): P(S)-~3 3.56 (d, J = 20Hz, 2H~ 2-P
1.46 (s, lg~ t-C~g ~ ~2(iH31O4PS Theor. %C 60.28 %H 7.84 %P 7.77 %S 8.04 Pound %C60.58 %H 8.04 %P8.05 %S 8.30 ~m~2 t--Bu HO~5 CH2 C--CH2 PO3 Me2 t--BU : :
To a T~ solu~on o~ dimethyl lidliomethylphosphonate (24.6 mmol) kept at -60C
20 was added a solu~on of e~yl 3,5 di-tert-bu~rl~hydroxyphenyl ~ioacetate (2g, 6.2 mmol) in l5ml T~. The resul~ng mixnIre was stim2d at -60C for 30 min and was allowed to reach r~om tempe~re (25C) over 4 h. Afte~ addition of l~ml 10% HM~
thç reaction mix~e wæ pardtioned between ether and water. The residue after evapo~don OI the orgal~ic phase was purified by column chromatography (SiO2, ~/22s CHC13/AcOEt) and re~ystallization in petroleum e~er to give O.95g of dle dtle compound (38%).
mp = 63-65C
MS: m/e 402: M+, 251: M+-(CO-CH2-P03Me2), 57 WO 94/19358 ?,~,~,Q~ 4~3 PCT/EP94/00520 -`
NMR (CDCl3~
= 7.21 (s, 2H): arom H
5.3 (s, lH): OH
3.75 (d, J ~ 1 lHz, 6H): P-O-C~13 3.72 (s, 2H): S-C~2-CO
3.33 (d, J = 22Hz, 2H): C~2-P
1.41 (s, 18H): t-C4~1g ~m~2Q
,Dimethvl 3-f ~di~:~l~hvdrox~henvlthio)-3~imç~d-~ 1-~l ~hos~hona~
t-Bu )~ CH3 8 H~S--C--C - CH2 PO3 2 t-Bu '. 15 i, To 10ml of a T~ solutioD of dimethyl lithiomethylphosphonate (68.2 mmol) kept at 60C was added a solution of e~yl 2-(3,5-di-lcrt-butyl~hydroxyphcnyl-thio-2-mcthylpropionate (6g 17.1 mmol) in 15ml THF. The resulthg mixture was sti~ed at -60C for 30 min and was allowed to reach room temperature (25C) over 4 h. After addition of 15ml 1096 HCI, the reaction mi1cture was partitioned between ether and water. The residue after evaporadon of thc organic phase was purified by column chromatography (SiO2, 8n CHC13/AcOEt). Rec~ystallization in pe~leum ether gave 4.16g of the title compound (57%).
mp = 105-106C ~ ~
2s MS: m/e 430: M+, 279: M+-(CO-CH2-P03Me2), 194 (100%), 57 N~ (CDC13) ~ = 7.15 (s, 2H): arom H
5.38 (s, lH): OH
3.80 (d; J = 1 lHz, 6H): P-O-C~13 3.46 (d, J = 22Hz. 2H): C~2-P
1.41 (m, 24H):t-C4~1g + C(C~13)2 - WO 94/19358 21 1 ~ 4 0 9 - ~CT~P94/00~20 ~mR~
t-Bu ~, HO~CH=CH-CH~CH PO3Me2 t-Bu A mix~ure of dimethyl ~(3,5-di-tert-butyl~hydroxyphenyl) 2-hydroxy-3-buten-1-yl phosphor~ate ~2.3g, 6 mmol) in 1.70ml acetic anhydride and 1.26ml triethylamine was stirred at 60C for 3h. Following hydrolysis with lOml H20, the reac:tion lo mixture was ex~acted with 20ml diethyl ethcr. The e~her phase was extracted with 10% HCl and d~ied over MgSO4. The residue after evaporation was purifiled by column chromatography to give l.Og (46%) o~ the title compound.
mp= 113-115C
MS: m/e: 366 M~, 351 M+-Me, 57 (tBu) NMR (~DC13) = 7.32-720 (m, 3H): arom H + CH~H-~ P
6.82 (lH,d)~ ~-CH~I-P
6.74-6.66 (lH, m) C~H~-CH=CH-P
5.67 (lH, dd, J = 16.6 and l9.~Hz): CH=CH-CH~-P
3.75 (d, 6H): Po-(~EI3 1.46 (19H, s): t-C4~g WO 94/19358 , . PCT/EP94/00520 `"`, 12im~h~4 (3.5~ tert-butvl ~ hvdrox~ 2-f4 ~en~n~vln~ u~l ~QS~hopate 0 :~
t-Bu 1 ¦
)~ o--C--CH2-CH2-CH~CH2 H~cH2 -CH2 CH -cH2--Po3 Me2 t--~u To a mixture of acetyl~pentcnoate (0.66g, 4.6 mmol) and triethylamine (0.24ml, 1.7 mmol) was added 0.50g (1.37 mmol) of dimethyl ~(3,S-di-tert-butyl~
10 hydroxyphenyl)-2-hydroxy- l-butyl phosphonate. The reaction mixture was kept at 60C for 6 h, cooled and extracted in~o diethyl ethe~ and water. The residue of the dried organic phase was purified by column chromatography (SiO2, 7/3 CHC13~Mc~yl-tert-butyl ethcr) to yield OAg of a colorless oil (62%).
MS: m/e: 468: M+, 368: M+- CH22H-CH2-COOH, 258: 368 - HP03Me2 N~ (CDC13) t' = 6.94 (s, 2~: arom H
5.85 (m, lH): C~H2~-CH2-CH2-COO
5.18 (m, lH): Ph-CH2-CH2-~-CH2-P
5.0 - S.l (m, 2H): C~I2-cH-cH2-cH2-coo 5.15 (s, lH): OH (phenol) 3.72 (2xd, 6H): P3~2 2.55 (m, 2H~: Ph-cH2-cH2-cH-c~2-p 2s 2.41 (m, 4H): CH2~-c~2-c~l2 1.43 (s, 18H): t-C4Hg `) wo 94/19358 21 1 8 4 0 9 PCT/EP94tO0520 I:a}2~L PHC)SPHONATES OF FORMULA (I) X~ y )~ ,I,Z
~D--P~ ( I ) Comp G xl, x2 D _ zl z2 mp ~C) I~Jcroar;lysi5 1 HO ~BuCH=C~-C(0~ 2 O OMe 107-109 C20H3105P
2 HO ~BuCH=~H~(0~H2 OEt 110~111 C22H3505P
3 HO ~BuC~H_C~H-C(~)~C~H2 O O~Pr121 - 122 C24H390sp 4 HO tBuC~H=~H-C~O)~C iH2 ChiBu6~i7 C26H4305P
HO ~BuC~H=~H-C(O)-C(cH3)2 O OMe 125-126 cæH3sosp 6 HO ~BuC~H=c~H-c(o)-c(c~H3)2 O OEt 91 -92 ~24H3905P
7 ~IO ~BuC3H=CH-C(O~C(C~3)2 O O~Pr138-139 C26H4305p 8 HO ~BuC~H=C~H-C(03-CH(C~H3) O OMe 144-145 C21H330sp 9 HO ~BuCH=C~H-C(O)IC~H(C~H3) O OEt 92-94 C23H3705P
EK~ tBuC~H=dC~C~H3~C(~)~ClH2 O OMe 131-133 C21H3305p11 HC) ~BuC~=d~(C~H3)~(0~5~H2 O OEt 97-101 C23H3705P
12 H~ tBuCH=C(nC4Hg~C(O) CH2 O OMe 82-85 C24H3905P
13 HO tBuCH=C(nCsH1 l)-C(O)~H2 O OMe 67-72 C25H4105P
14 HO tBuCH=C~Ph~C(O) CH2 O OMe 147-149 C26H3505P
HO tBuCH=C(Ph) C(O) CH2 O OEt139-143 C2gH3905P16 HO ~uCH2 CH2~(0) CH2 o OMe 78-79 C20H3305P
17 HO tBuCH2-CH2~(0~CH2 O OEt oil C22H3705P
18 HO tBuCH2-CEI2~(0) C(CH3)2 O OMe 85-87 C22H3705P
19. HO IBuCH2~ -C(O~C(cH3)2 O OEt 64 66 C24H4105P
HO IBuCH~H-CH=CH~(O) CH2 C) OEt oil 21 HO tBuCH=CH-CH=CH~(O~C(CH3)2 O OMe142-146 22 HO tBuCH=CH-CH=CH-C(O)-C(CH3)2 O OEt130-133 C26H4105 23 HO tBu C(O~CH2 O OMe108-111 C18H2905 24 HO tBuCH=CH-C(O)-CH2 O NMe2178-179 C22H3703 HO IBuC(O)-CH2-C(O)-cH2 O OMe108-109 C20H3106 26 HO tBuCH=CH-C(O~CH2~(0)-CH2 O OMe145-146 C22H3306 27 HO tBuCH=C~-C(O~CH2-C(O)-CH2 O OEt109-110 C24H3706 28 HO lliuCH2-CH2-C(O) CH2-C(O)-CH2 O OEl oil C24H3906 wo s4tls3s8 PCT/EP94/00520 f- ~ ~
4~9 . I
I:ak~ PH(:)SPHONAl'ES O~; FORMULA (I) (cont.) x P~ ( I ~
Comp. G xl,x2 y zl z2mp(C) M~c~analysu .. . __ .... . " . _ _ .......... . .
29 HO ~BuCH2~2~(0) CH2~(o)~H2 O OMe oil C22H3506P
HO tBuCH=C(C2Hs)-C(O~CH~ O OMe 128-132 C22H3505P
31 HO sBuCH=CH-C(O)-CH2 O OMe oil C20H3 l 5P
32 HO s~uCH=CH-C(O~H2 O OEt oil C22H350'iP
33 MeO tBuCH=CH-C(O)-CH2 O OMe 73 75 C21H335P
34 HO tBuCH=CH-C(O)~H2 S OMe 88-90 C20H3104P
HO tBuCH=CH-C(O)-CH2 O-(~H2)30 156-lfil C21H3l05 36 HO lBuC(O)-CH=CH~H2 O OMe oil C20H3los 37 HO tBuC(O) CH=CH~H2 O OE~ 65-70 C22H3505 38 HO tBuC(O)-CH2 C)OEt 112-115 C20H3305 39 HO tBuC(O)-CH2 OOiPr 127-131 C20H3705 HO tBuS-CH2-C(O)-CH2 O OMe 62~5 C19H3105 41 HO tBuS-CH2-C(O)-CH2 (~OEt 76-78 C21 H3505 42 HO tBuS-C(CH3)2-C(O) CH2 o OMe 105-106 C21H3505 43 HO tBuS-C(CH3)2-C(O~cH2 O OEt 8~81 C23H3gOs 44 HO tBuS-CH2-C(~CH2-C(o)-cH2 O OMe oil C21H3306 HO tBuS-CH2~(0) CH2-c(o)-cH2 O OEl oil C23H3706 46 HO tBuCH-CH-CH(OH)-CH2 O OMe 122- 123 C20~335 47 HO tBuCH2-CH~H(OH) CH2 o OMe 88-91 C20H3505 48 HO IBuCH(0H) CH2 O OMe 128-133 C18H310s 49 HO IBuCH(OH)-CH2 CH(OH)-CH2 OOMe 129-132 C20H3506 HO tBuS-CH2-cH(OH) CH2 oOMe 1~108 Cl9H335 51 HO ~uCH=CH-CH=CH OOMe 113- 115 C22H3506 52 HO tBu(CH~)2-CH(O-CO-cH3) CH2 OOMe oil C22H370 53 HO tBu(cH2)2-cH(o-co-ncsHl l)~H2 OOMe oil C26H450 54 HO ~u(CH2)2-cHlo-co-(cH2)2~H=cH23-cH2 oOMe oil C25H416 HO SBuS-CH2-CH(O-CO~H3)-CH2 OOMe oil C21H3506 56 HO ~BuS-CH2 CH(O-CO-nC5Hll)-cH2 OOMe l~il C25H430 `) WO 94/193~8 PCT/EW4/00520 2118~og A. ~i:~=~
I
1) lron i,nduced,~eroxide fo~mation in rat li~hQm~en~
Wis~r raes were euthanasied by cthe~ inhiala~on. The liversi were dissected out and ', homogenised with a poeter homogeneiser in 4 volumes of phosphate buffer (4C, pH 7.4). After cen~ifugation at 2000 ~pm for 10 min the supema~ant obtained was o kept ae 4C.
A mixeure containing 0.2 ml of liver homogenate, 1.7 ml of phosphate buffer was incubated with 0.1 ml of a 2mM PeS04 soludon to induce peroxide foImaeion according to the method descnbed by A. T. Quintanilha et al., Ann. N. Y. Acad. ,:
lS Sci., ~, 32~7, 1982.
Compounds to be tested for antioxidant ac~vity were dissolved in DMSO or cehanol and added iLn a volume of 5 111 to the incubation mixture. Stock solu~ion of the compounds were diluted scquen~ally to obtain final concen~ation of 0.5, 1, 2, - 20 5 and 5 pM. Oxidation was pe~fon~ed at 37C for 2 hours and was stopped by the addition of 20 pl of a 2* ethanolic solution of BHT. The generated peroxides meas~d as malondialdehydc fonnjation were quantitated according to the method of Yagi ("Iipid Pe~xidcs in Biology and Medicine" p. 223-242, 1982, Ed. K.
Yagi, Academic Press ~c.) u~g dle Thioba~bituric Acid Reaction and with 2s 1,1,3,3,-telrame~oxy~ropa~ie as standard. Results aIe given as concentranon in pmoUI which inhibits malondialdehyde formation by 50% (IC50).
..,. ~ . .... ..
All ~e tested compounds have IC50's between 0.5 and 5 ~M and are more active ~an Probucol, vitamin E and Vitamin C Bu~l hydroxytoluene (13HT) has an IC50 of 3.3 ~M in ~is assay. Compound of foImula (I) are thus useful for the treatment of disease sta~es jD which oxygeD re~c~ve species ale involved.
wo 94/19358 Q~ ~9 PCT/EP~4/00520 --!
T~ble 2 . ...... ~
Compound lC50 (pM)_ Probucol ~ 25 ~ita~n E _ > 25 Yitam~n C _ ~ 25 BHT _ 3.3 , , _l, ~.01 2 _ 3~20 _ 3 _ _ 1~37 4 1~41 _ _ 1~0__ _ 16 4~89 17 3~03 _ 1 2~85 3 ~ _ 1~88 ~ ~ 3~18 ~ ~38 7 . ~ . . t ^ ' ' 2 06 18 3~56 i9~ ~ 2~49 _ 12 ~ 1~71 3~48 4 3~07 20 ~ 2~44 24 ~ 4~55 25 ` ~_ 2~71 26 0~68 27 0.70 28 1.0 32 2~78 33_ 5~0 34 2~91 2~84 `~ WO 94/19358 21 1 810 9 PCTIEP94/00~20 2)~
Plasma was obtained after low speed centrifuga~on of blood from donors. I,DL
(d=1.006 1.C63 glml) were isolated by preparative ultracentrifugation in a salt s solu~on (NaBr, KBr). The isolated LDL fraction was dialysed against phosphate buffer.
LDL oxida~on was pe$fo~med a~eording to Ester~auer et al. (Continuous Monit~g of in Vitro Oxidation of Human Low Density Lipoprotein, Free Rad.
Res. Commun. ~, 67-75, 1989). Briefly the LDL suspension (50-2001~g protein/ml) was distributed in quartz cuvettes and kep~ at 37C then a solution of CuC12 wasadd~d at a final concentration of 511M. The increase in optical density at 235 nm was recorded using a W-visible spec~ophotometer. The time course of oxidation was recorded over a penod of 8 hours at 10 min intervals. Compouncls to be tested we~e dissolved in ethanol and added at the final concentraaon of 0.1 ~M. Controls ~eceived ethanol only. The lag phase is pr~longed by the p~esence of antioxidants.
This medlod was validated with Probueol and vi~-E as reference antioxiclants.
The prolongation of the lag phase was uscd to quantify ~e antioxidant activity of the compounds tcsted, this pr~longation W2~ expressed in percent of ~e value measured in absence of exogen an~oxidant (controls).
` ~,,, J` , ,`
The phosphonates of Formula (I) as noted in TaUe 3 prolong the lag phase compared to control. An inhibitoIy activi~ on LDL oxidation is thus demonstrated2~ which is clearly supe~ior to that of Prt)bucol and vitamin E. Since these two antioxidants have been shown to be anti-atherosclerotic in animal models, the therap~utic poten~ial of phosphonates of Fo~mula (I) is ob~rious.
wo 94/193~ 9 PCT/EP94100~20 .--Table 3 C~-: _nll Lag pbase % con~ol . ~ . . _ _ ~obuccl _+ 7 Vitamin E _ 0 1 _ ~ 1 45 ~ _ _ 7 3_ ~ + 172 4 _ _ ~ 74 _ ~ 233 16 _ l 159 17 ~195 11 _ _+212 13 _ + 191 ~ 147 6 . + 129 `~. . . ~ ~
18 _ ~ 223 19 ~ 157 : . 9 __ + 1 12 :~ 10 + 126 : 20 ~- + 38 + 1 18 26 ~
27 + 42 28 ~
32 + 80 33 + 14 ~ 8 + 118 - ~ wo 94/193~8 PCT/E:Pg4/00520 B. ~
The human intes~nal cell line CaCo~ cells (ATCC HTB37) was used to study the effect of compounds of formula (I) on choles~erol syndlesis. The cells were grown S in 6 wells dishes (Falcon) in 2 ml of Dulbecco's m~dified Eagle cult~re medium (I:)MEM) supplemented with 20% fetal calf serum (Flow). Cells were maintained at 3PC in a 5% CO2 a~nosphe~e and the labelling expenment was done 8 days after cell pla~ng. To ~e culture were added lû pl of ~e ethanol solu~on of the compounds to be tested. Control wells ~eived lOpl of ethanol alone. One hour later 0.7 yCi of 14 C-acetate 53.4 mCilmmol was added, labelling was connnued for 4 hours and w~s stopped by washing ~e ccll layer with chilled P~3S. The cells wcre collected in 2ml of O.O1 N NaOH and 1 ml of PBS. Lipids were extracted by the Folch method and separated on silica gd TLC plates developed in petroleum ethes: diethyl ether: acetic acid (70:30: O.5). After exposition to iodine vapors, ~e bands coiTespondiT~g to cholesterol and choleste~yl esters were scrapped off and~dio~ctivity was measur~d in a liquid scin~llator countcr.
l~ne amount of radioactivity inco~ted in cholestcrol and cholesteryl esters in presence of compounds to be tested was compared to that of the control cells.
HMGCoA r~ductase inhibito~s such as simvastatin (lyM) s~ved to validate the measuremcnt of 14C-acetate inco~poration in ~holestcrol and cholesteryl csters.
All thc compounds tcstcd inhibited cholestcrol and cholesteryl est~s synthesis.
-- Most of the compou~ds inhibi~ed choles~e~yl ès~ers synthesis by more than 50%
CTablc 4~. Phosphonates of fo~mula (I) display an inhibitory activity on choleste~ol and cholestayl estcrs and can be considcrd as therapcutic agcnts in thc treatmcnt of hgpe~lipidania and ather~sclerosis.
WO ~4lls35B , PCTIEPg4/00~20 --~
Table 4 _ ~
Choleteryl (::ompounds Choleterol ester~
% %
Simvasta~in 96_ __ 70.
_ _ _ _ _ _ ~ _ -5? - __ ___ 3 _ -i55 -84 . 4_ _ _ 21 80 __ __ .. .
_13 ~9 _ 84 . --26 j _ -22 _ -75 19_ _~46 -83 9 _ -49 _ 81_ .
i - 14 26 ~ 84 _ _ 1 ~ 24 ` ` 1 1 5 r ~l ~ -60 _ _ 33 - 54~ ; ~ -34 ~0 wo 94/1g358 2 I 1 8 4 0 9 PCT/EPs4/00520 C. ~alci~ Fntr~ Rlockin~ activitv of ketoDhosDhonates Expenments were performed on aor~c nngs from rnale Sprague -Dawley rats (28~350g body weight) which were killed by stunning and exsan~nation.
Thoracic aortas were cleared of connective tissues and cut into ~ings of approximately 2mm in length. Each ring was mounted under a resting tension of 2g and was equilibrated for 1 hour at 37C in a lO ml organ bath containing a HEPES bufferRinger soludon (Buffer composition (mM): NaCl 139.0, KCl 5.0, MgC12 3-7. ~Glucose 11.0, HEPES 5.0, pH 7.4) acrated with 95% 2:5% CO2.
~' Maximal contractions we~e produced within 5-lO min exposure to 10pM
Phenylephnne. The dssues were then washed with a Ca+2 free HEPES buffer.
After 30 min the dssue was depolarised with KCl (60~I).One hundred ~ of the vehicle (10% DMSO) or compound solution (1 yM) werc added S min later. The final concentra~on of DMSO was 1%. The tissues ~n=2 per compound) were further equili~ated for 15 min in the presence of compounds prior to cumulative ` -addition of Ca+2 (0.1-30 mM). The contractions to cach concentration of calcium are calculated as a percentage of the second phenylephrine contraction and the EC30 (concentration of Ca2+ producing a contraction 30% of the phenylephrine contraction) calculated. Thè potericy index of cach compound is expressed as theconcentration ~io (calcium drug EC30hehicle EC30), where a potency index ~1 indicates a c~npound effect.
The compounds of formula (~ are thus potentially useful in the treatment of cardiovascular discases via their calcium eritry blocking activity. The pnmary indicadons of these compounds would be the t~ent of atherosclerosis, angina pocto~is, congesdve heart failure and hypertension.
Tabae 5 -Effect`of compounds (I) on Ca+2 induccd contraction of K+ depolarizcd rat aoqta .
Compound EC30Ratio .` 6 21.8 7 9.2 16 4.2 26 4.7 28 5.~ ~-
7.30 and 7.25 (2s, 2~I each): a~om. H
6.63 (d, J = 16 Hz, 2H): Ph-CH~
5.54 and 5.4812s. lH each): O~ -4 18 (q~int., J = iHz, 4H): P-O-C~I2-CH3 1.40 and 1.34 (2s, 18H each): t-C4~1g 1.34 (t, J= 7 Hz, 6H): P-aC~2-C~3 The second product was identified as diedlyl 4-(3,5-di-te~t-butyl~hydroxyphenyl) -2-oxo-3-buten-1-yl phosphonate (44 g, 36% yield) ;~
t--Bu O
~ 11 ' ,:
H~CH=C:H C --CH2 PO3Et2 t--Bu mp = 11~111C (rccrystallized from ligroin 80-95 fraction).
.
IR (KBr): 3620 cm~l: OH, 1680:C=O, 1590: C=C, 1430 and 1415: tl3u, 1240: P=O
and 1230: P-O-C
MS (m/e): 411: M+1, 410: M+, 272: M+-H-PO3Et2, 259: M+-CH2PO3Et2, 57 (100%) tBu+
Nl~ (CD(~3) ~ = 7.61 (d, J = 16 Hz, lH): Ph-~=CH
7.40 (s, 2H): arom. H
6.74 (d, J = 16Hz, lH): Ph-CH~
5.6 (s, lH): OEI.
4.16 (m, 4H): P-O-C~2-CH3 3.33 (d; J = 23 Hz, 2H): ~EI2-P
1.45 (s, 18H): t-C4~19 1.34 (t, J = 7Hz, 6H): P-O-CH2-C~3 -! wo 94/1935~ 8 4 D Y PCT/EPs4/oos20 C22H3sOsP ~eor% C 64.37 % H ~.S9 % P 7.55 ~ Found% C 64.52 % H 8.6S % P 7.36 s ~m~l~
and e~v~ 3.5-di-t~hvdrs~1~-2-Q2~1-~ts!l~bQsPh~l~
Sodium hydride (1.4~ g of a 60% dispersion in mineral`oil, 36.25 mmol) was suspended under nitrogen in hexane, this latt~r was pipe~ted out and replaced by 60 ml dry T~. Diethyl 2~xopropylphosphonate ~7.0 g, 36 mmol) was introcluced. The mixn~re was s~rred at room temperature for 30 min then was cooled to 0 ~C then n-bu~l lithium (37.5 ml of a 1.6 M solution, 60 mmol) was aclded. Finally a soluaon of 3,5-cli-tert-butyl~-hydroxybenzyl bromide (9.0 g, 30.1 mmol) in 40 ml THF wasadded and the reaction mixture was s~ed at room temperan~re ovemight. Work-up was ca~ied out by par~ti~n between 150 ml 15~c HCl and two fractions of 1~0 ml ether. The ether phase was washed with so~ium bicarbonate and satuIated sodium 20 chloride to ~eutral pH. After d~ying and solvent evap~ration, the crude mixture was purified by column chromatography (SiO2, 8/2 CHC13/AcOEt).
The first compound (1.~ g, 8% yield) to elute was die~hyl 1,5-bis(3,5-di-~ert-butyl-~hydroxy-phenyl)-3-oxo-2-pentyl phosphonate, mp = 60 61C.
t--Bu t-Bu )~ 8 ,~( HO~CH2--CH2 C--CH--CH2 ~OH
PO3 Et2 t--Bu t--Bu IR (KBr): 3620 cm-l: OH, 1710: C=O, 1430: t-Bu, 1230: P=O and 1010:
P-~C
MS:m/e= 630: M+, 493: M+-HP03Et2 8 ? '~ , ~ PCT/EP94100520 --NMR (C~DC13) o = 6.89 (2s, 2H each): arom. H
5.09 and 5.03 (2s): O~
4.1 (m,4H): P-O-C~2-CH
S 3.5 and 3.25 (2m,2H): Ph-(~I2-CH-P
3.04 (txd, lH): Ph-CH2-C~(P~CO
2.9 - 2.4 (2m,4H): Ph-c~a2-c~l2 1.14 and 1.39 (2s,18H cach): t-C4~1g 1.32 (2t, J=7Hz, 6H): P-O-CH2-The sccond compound was dicthyl 4-(3,5-di-tert-butyl 4- hydroxyphenyl)-2-oxo-1-butyl phosphonate: 2.2 g (18% yicld) of an oil was obtained which slowly solidified upon standing.
t--Bu ~CH2-CE12--C--C~2 PO3Et2 t--Bu IR (~m): 3620 cm~1: OH, 1710: C=O, 1430: t-Bu, 1250: P=O, 1010: P-O-C
MS m/c= 412: M+, 274: M-HPO3Et2 , ..................................... :
N~: (C~DC13) o = 6.98 (s, 2H): arom. H
5.1 (s, lH): oH
4.14 (m,4H): P-O-CH2CH
3.05 (d, J=25Hz, 2H): CEl2-p 2.94 (m,2H): Ph-C~I2-CH2 2.83 (m, 2H): Pb-cH2-c~l2 1.42 (s, 18H): t-C4Hg 1.32 (t, J=7Hz, 6H): P-O-CH2-C~13 -- I Wo 94/19358 21 1 8 4 ~ 9 PCT/EP94/~0~20 ~mQ~ ' Diethvl ~(3.5 di-tert-bd~-~b~h~-1 .l~im~hvl-2~ bu~n-l-vl-t--Bu o CH3 ~ 11 1 H~CH=CH - C--C--PO3 Et2 (~H3 ~--Bu Dicthyl 1,1-dimethyl-2-ox~pr~pylphosphonate (bp = 60~/0.2 mbar) was synthesized acco~ding to V. Roussis and D.F. Wiemer, J. Org. Chem. ~, p. 627-631 (1989).
To 20 ml dry THF kept at 0C were a~ed sequentially TiC14 (1.72 g, 9 mmol), 3,5-di-tert-buty1-4-hydroxybenzaldehyde (0.9 g, 3.8 mmol), diethyl 1,1 dimethyl-2-oxopropylphosphonate (1.0 g, 4.5 mmol), N-methyl mo~pholine (1.82 g, 18 mmol) then thc seaction mixt was s~rcd for 1 h at room temperan~re. Work up ca~ied out in the usual manner gave an oil which was purified by column chromatography (SiO2, 8/2 CHCl31AcOEt). An amount of 1.1 g (68% yield) of th~ atle compound was obtained. Mp = 91-92C (petroleum cther 40-60).
KBr): 3440 cm-1: OH, 1670: C=O, 1590: C=C, 1430 and 1410: t-Bu, 1210:
P~ and 1030: P-O-C
MS: mle= 439: M~ + 1, 259: M+-C(CH3)2-P03Et2, 57 (100%): tBu :~
N~: (CDC13) = 7.66 (d, J = l~Iz, lH): Ph-~=CH
7.43 (s, 2~I): aro~ H
7.26 (d, J = 16Hz, lH): Ph-CH~
5.55 (s, lH): OH
4.15 (m, 4H): P-O-~12-CH3 1.~0 (d, J = 17H~ 6H): -C(C~3)2-P
1.46 (s, 18H3: t-C4~19 1.32 (t, J = 7Hz, ~H): P-aCH2-~3 C24H39O5P ~alc. % C 65.73 % H 8.96 % P 7.06 Found % C 66.00 % H 8.98 % P 6.82 o9 , ~ t~ ~a~u~
Dho~
t-BU
~\ 11 .
HO~CH--C----C --C~2 PO3 Et2 t-Bu Diethyl 2-oxobutylphosphonate (bp = 90/0.6 mbar~ was prepared according to F.
Mathey and P. Savignac, Tetrahed-~n 34, p. 649-654 (1978).
To 20 ml dry T~IF ke~t at 0C were added successively TiC14 (1.82 g, 9.6 mmol), 3,~i-ter~-butyl~-hydroxybenzaldehyde (0.94 g, 4 mmol), diethyl 2-oxobutylphosphonate (1 g~ 4.~3 mmQl) and N-methyl morpholine (1.86 g, 18.4 mmol). The reacaon mixture was s~red at ~oom temperature for 30 min then was heated to reflux for 1 h. After the usual wor~-up and extraction ~e crude reacaon ~ture was purified by column c}~romatography (SiO2, 8/2 CHC13/AcOEt). A
small amount of unrcacted benzaldehyde was first collected ~en 0.35 g (21%) of ~e dtle compound was obtai~ed. Mp = 97-101C (petroleum e~er 4~60).
IR (KBr): 3400 cm-1: OH, 1680: C=O, 1610 and 1590: C=C, 1440: t-Bu, 12S0: P=O
and 1020: PO-C
MS: m/e = 424: M+, 409: M t-CH3~ 367: M+-tBu, 286: M~-HP03Et2, 57 (100%):
~Bu+
NMR (CDC13):
~ = 7.56 (s, lH): Ph-~l=C
2s 7.33 (s, 2~): arom. H
5.5 (s, lH): O~
4.16 (m, 4H): P-O-C~2-CH3 3.Sl (d, J=22Hz, 2H): ~2-P
2.1 (s, 3H): ~13 1.46 (s; 18H): t-C4~g 1.32 (t, J= 7HZ, 6H): P-O-CH2-~3 wo 94/19358 211~ 4 ~ 9 PCTIEPg4/00520 ~23~37O5P C alc. % C 65.07 ~O H 8.79 % P 7.30 Found % C 65.35 % H 8.58 ~ P 7.51 ~mu~
thyl9~i-tert-~utvl~c yll 3 (n ~Q~3-~
t--Bu HO~ CH=C C CH2 PO3 Me2 r n-C4 Hg t--Bu A mixture of 3,5-di-tert-butyl~hydroxybenzaldehyde ~3.65 g, 15 mmol), dimethyl 2-oxoheptylphosphonate ~4.0 g, 18 mmol), rlCl4 (6.84 g, 36 mmol) and N-methyl mospholine (7.27 g, 72 mmol) in 80 ml dry TH~ was refluxed as desc~ibed in example 7. Purification by column chromatography (SiO2, 8/2 CHCl3/AcOEt) gave 1.2 g (20% yield) of the tide compound. Mp - 82-85 (petrolcum ether 4~60) M~: m/c 439 M~ 1, 438 M+, 381 M+-C4Hg, 57 (100%): tl3u NMR (CDC13) 7.48 (s, lH): Ph~ =C(C4Hg) 7.32 (s, 2H): arom. H
5.5 (s, l~ O~
3.81 (d9 J = llHz, 6H): P-O-C~13 3.52 (d, J = 22Hz, 2H): ~2-P
2.~7 (m, 2~I): ~I2-C3H7 1.5-1.4 (m, 4H) CH2-~ )2-CH3 1.5 (s, 18H): t-C4~19 0,94 (t, J = 7Hz9 3~): (CH2)3-C~3 , ~ . - . .
WO 94/19358 sj~ ~ PCl'/EP94/00520 --Me~ 3.s~ u~l-~byd~henyL~-2~Q~ -3-bu~n PhQS~
t-BU
H~CH=C--g --CH2 --PO3 Et2 t-BU Ib The procedure desclibed in example S was employed, using as the phosphonate ~eagcnt diedlyl 2-oxo-3-phcnylpropylphosphonate (bp=150/0.5 mbar). The ~itle 10 compound was isolated ~y column chromatography under ~e usual condî~ons ~SiO2, 8/2 CHCl~/AcOEt) at ca 18% yqeld.
., mp=139-143C
15 IR (KBr): 3500: OH, 1640: C=O, 1610 and 1~90: C=C, 1430: t-Bu, 1230: P=O, 1020: P-~C.
MS: mlc=486 (100%) M~, 348: M+-HPQ3Et2, 335: M+-CH2P03Et2 20 N~:(CDC13) = 7.70 (s, lH): Ph-~~
7.45 - 7.25 (m, SH): (~6~5 6.97 (s, 2H): aro~ H
5.46 (s, lH): OH
4.15 (m, 4H): P-0-~2-CH3 3.33 (d, J=22Hz, 2H): C~12-P
1.32 (t, J=7Hz, 6H): P-O-C~H2-C~3 1.23 (S3 18H): C4~19 C2gH3g0sP Calc. % C 69.11 % H 8.08 % P 6.37 Found %C69.37 %H8.11 %P6.61 wO 94/19358 2 I I 8 4 0 9 PC rEW4/oos20 12is~hyL4 (~di-tcrt-~1-4~by=h~-l-methyl-2-oxQ 3-bu~n~
S ::
t-Bu HO~CH=CH ~ C--CH --PO3 Et2 t--Bu Diethyl l-methyl-2-oxopropylphosphonate was prepared according to Mathey and Savignac as cited as example S. ~
' '-A mixture of 3,5-di-test-butyl-~hydroxybenzaldehyde (7.19 g, 29 mmol), diethyl 1-methyl-2-oxopropylphosphorlate (8.20 g, 35 mmol), TiCl4 (13.47 g, 71 mmol), N- ::
methyl mo~pholine (14.34 g, 140 mmol) in 150 ml dry TH~ was reacted at room temperan~re for 1 h, then at reflux temperature for 18 h. After work up, column lS chromatog~aphy (SiO2, 8/2 CHC13/AcOEt) gave 4.7 g (38%) of the title compound.
mp~2-94C : i NMR (CDC13) : .
~ = 7.63 (d, J - 16Hz, lH): Ph-C~=CH .
7.42 (s, 2~1): a~om. H
6.87 (d, J = 16Hz, lH): Ph-CH~
5.6 (s, lH): O~ ::
4.15 (m, 4H): P-O-C~2-CH3 3.~3 and 3.46 (n~o q, J = 24Hz and 7Hz, lH): C~I-P
1.5~1.43 (two d, J = 7Hz~: ~-(P)-~3 1.46 (s, 18H): C4~g 1.32 (two ~, J ~ 7Hz): P-~CH2C~3 WO 94/1s358 PCT/EP94/00520 Dimethyl q-(3.~ tert-butvl-~hvd~ )-2-Q2~-bute~-1-yl ~ ,ahQn~
t--Bu H(~CH CH --C CH2--PO3 Me2 t--Bu S Under ni~gen ahnosphere dime~yl methylphosphonate (3.17 g, 25.6 mmol) was added at -60 to a solution of n-butyllithium (16 ml of a 1.6 M solution in hexane, 25.6 mmol) in 1~ ml anhydrous THF. The reac~on mixturc was stirred at -50 for 30 min to allow fo~ complcte fo~mation of the lithium anion (slight ~rbidity~. The m~ix~e was again cooled to -60 and a solution of e~yl 3,5-di-tert-butyI-~hydroxycinnamate (2.6 10 g, 8.5 mmol) in 20 ml dry THF was added. The resulhng orange-colored mixture was left to stir at room temperanlIe (25C) for 18 h. Hydrolysis was caIIied out by adding 10 ml of a lO~o HCl sc~ludon and the produc~ was extracted into ether. After ~ngove~ MgSO4, e~e~ was evapor~ed to yield a yellow solid. RecIystallization in 40 - 60 petroleum ether gave 3.0 g (92% yield) of dimethyl ~(3,~ te~-bu~yl~
15 hydroxyphenyl)-2-ox~3-buten-1-yl phosphonate.
mp=107-109C
The ~de compound can also be obtained by using as the bases a mixture of n-BuLi and 20 LDA ~ithium diisopropylamide). To a solu~on of n-butyllithium (16ml of a 1.6 M
solution, 25.6 mmol) in 20 ml dry l~ was added at -60C diisopropyl amine (0.86 g, 8.5 mmol). The resulting mixture was st~red at 40 for 15min, then dime~yl methylphosphonate (2.11 g, 17 mmol) was added. After 15 min, ethyl 3,5-di-tert-butyl-4-hydroxycinnamate (2.6 g, 8.5 mmol) was added and the rea~tion mixture was stirred 25 at room temperat~e (25C) fo~ 15 h. Work up by addition of 10% HCl and extraction into ether gave 3.10 g (95%) of dimethyl ~(3,5-di-tert-butyl~hydroxyphenyl)-2-ox~
3-butcn-1-yl phosphonate.
mp=107-109C
30 The compound p~epared by dther of these n~o variant p~ocesses has spectroscopic data idenical to thiose of the same product described in example 1.
, i1 ' . ~
~) WO 94/19358 2I 18 4 09 PCT/EPg4/00520 C2bH3105P Theor. 9~oC 62.81 %H 8.17 96P 8.10 Pound %C 62.56 %H 8.21 %P 8.24 ; 5 ~ ~m~ll~
Diethv! ~f3 S-di-tert-butvl~hvdroxv~henvl)-l.l-dime~vl-2-oxo-3.5-hexadien-1-vl ~hos~hona~e `
..
t--Bu ~ `
)~ 8 1CH3 ~; HG~CH=CH--CH=CH C C--PO3Et2 CH3 `
t--Bu : ' ~`.
To 15 ml dry THF kcpt at 0 were added rlcl4 (1.23 g, 6.47 mmol), 3,5-di-tert-butyl-4hydm~ cinnamaldehydc (0.7 g, 2.67 mmol), diethyl 1,1 dimethyl-2-~; ~io~_ (0.72 g, 3.24 mmol) and N-methylmorpholine (1.31 g, 12.97 ~ . Thc leaction mixture was sti~rcd for 1 h at 20C then 1 h at 30C. Work-up gare a da~ oil which was purified by column chromatography (SiO2, 8/2 C~IC13/AcOEt). 650 mg (52%) of yellow crystals werc obtained, mp = 13~133C
:
NMR (CDC13) o = 7.40 (d x d, J = 11 and 15Hz, lH): Ph-CH~-CH=CH
7.2 (s, 2H): arom. H - ~- ` ` `
6.87 and 6.85 (2 d, J = 15Hz, 2H): Ph-~=CH-CH~
6.75 (d x d, J = 11.5 and 16Hz, lH): Ph-CH=CH-C~H
- 5.4(s, lH): OH
4.1 (m, 4H): P-O-C~12-CH3 1.40 (d, J = 16Hz, 6 H): C(C~I3)2 1.39 (s. 18H): t-C4Hg 1.24 (t, J = 7Hz, 6 H): P-O-CH2-C~3 MS: tn/e~: M+, 326: M+- HP03Et2, 285 (100*): M+- CMe2-P03Et2 C26H41SP Calc- % C 67.22 % H 8.90 % P 6.67 Found % C 66.68 % H 8.56 % P 6.21 wO 94/19358 ~Q~ 4~9 ; PCT/EP94l00520 -~ ~
`:
t--Bu ~ 11 .
H~CH2-CH2- C --CH2 PO3Me2 ;~
t--Bu A solution of dimethyl lithiomethylphosphonate was prepared under nitrogcn by adding dimethyl mcthylphosphona~c (3.2 g,25.6 mmol) to a solution of n-butyllithium (16 ml of a 1.6 M soludon in hexane, 25.6 mmol) in 15 ml dry THF at - `
60C. To this solution was added at -60 a solution of ethyl 3,5-di-tert-butyl-~hydroxyhydrocinnamate (2.6 g, 8.5 mmol) in 20ml THF. The resulting solution was stirrcd at -60 for 30 min and then was allowed to reach r~om temperature (25C)ovemight. 25 ml 10% HCl was addcd and the mixture was ex~racted into ether. The ;~
residue of the eth~ phase was purified by column chromatography (SiO2,8/2 - CHC13/AcOEt) to yield a white solid. Recrystallizadon in petroleum ether gave 2.1 g (64% yield) of thc dde compound.
mp=78-79C
MS: m/e=384: M+, 284: M+-HP03Mc2,57 (100%): tBu+
N~ (CDC13) ~ = 6.98 (s, 2H): arom. H
5.06 (s, lH): OH
3.75 (d, J = 11.5Hz, 6H): P-O-C~I3 3.08 (d, J = 22.5Hz,2H): (~12-P
2.90 (m, 2H): Ph-c~2-cH2 2.81 (m, 2H): Ph-CH2-C~12 1.41 (s~ 18H): t-C4~1g WO 94/19358 21 18 ~ ~ 9 PCT/EP94/00520 ~2, :
Diethvl ~(3~-di-tert-butvl-4-hv~henyl~-æ4-di~-s-hex~n-l-vl ~ho~hon~
t Bu )~\ i~) ~) .' HO~\ /)--CH=CH C --CH2 C -- CH2 PO3 Et2 ~ `:
t-Bu Diethyl 2-oxopr~pylphosphonate (3.4 g, 17 mmol) was added at room temperan~re under nitrogen to a suspension of sodium hydride (0.82 g of a 60% dispension, 201~ mmol) in 35 ml dry T~IF. The mixture was sti~ at room temperature for 60 min,then diisopropylan~ine (1.71 g, 17 mmol) was added at 0, followed by n-butyllithium (21 ml of a 1.6 M solution, 34 mm~l). After 30 min at 0, the mixture was cooled to -60 and a solution of ethyl 3,5~ tert-butyl-~hydroxycinnamate (2.6 g, 8.5 mmol) in 25 ml T~ was induced dropwise. The resulting mixture was sdrred at 0 fc~r 2 h, at 25C for 1 h, hydrolyæd with 60 ml H20 whereupon it separatedinto two phases. Thc aqueous phase was acidified with 10% HCl and was extracted wi~ two 100 ml po~ons of ether. The ether extracts were pooled with the T~
phase, dried and cvaporated. The residue was purified by column ch~omatography (SiO2, 8/2 C~HC13/AcOEt) to yield a viscous olange oil. Recrystallizadon in ligroin gave 2.25 g ~60% yield) of the title compound, mp=109-1 10C
NI~ (CDC13) = 7.60 (d, J=16Hz, lH): Ph-C~=CH
7.37 (s, 2H): arom. H
6.35 ~d, J= 16Hz, lH): Ph-CH~
5.83 (s, lH): CO-(~=C-OH
5.54 (s, lH): phenol O~
4.17 (m, 4H): P-O-C~12-CH3 3.02 (d, J = 22Hz, 2H): C;~12-P
1.46 (s, i8H): t-C4~g 1.34 (t, J = 7Hz, 3H): P-O-CH2-~3 MS: m/e 452 M+, 314 M+ - HP03Et2, 57 (100%) tBu ~ -~~ . .
WO 94/19358 . PCT/EPg4/00520 - `~
E~ ..
t~BU
O O
~\ ~1 il ~
HO~C:H2 -CH2--C--CH2 C CH~--PO3 Et2 /
t Bu Diethyl 2-oxopropylphosphonate (2.02 g, lO mmol) was added at room temperature to sodium hydride (0.48 g of a 60% dispersion, 12 mmol) suspended ~ 30 ml T~.
10 Aftc~ 30 min the mixn~re was cooled to 0 and diisopropylamine (1.01 g~ 10 mmol) and n-butyllithium (13 ml of a 1.~ M solution, 21 mmol) we~e added. After 30 min, the mixture was cooled to -60 snd ethyl 3,5~i-tert-butyl-4-hydroxy hydrocinnamate (1.6 g, 5.2 mmol) dissolved in 15 ml THF was added. The ~h~re was left to react at -60 for 15 min then at 0 fo¢ 2 h and 25C for 1 h and was hydrolyzed with 10%
5 HCl and ex~wted with e~er. Column chromatography (SiO2, 8/2 CHCl3/AcOEt) gave 1.0 g (42%) of ~he tide compound as a colorless oil.
. ~ ................................ .
(CDC13) ~ ; r ~ ~ 6.98 (m, 2H): arom. H
5.70 (s, lH): CO-C~CC-OH
5.09 (s, lH): phenol OH
4.15 (m, 4H~: P-O~ 2-CH3 2.92 (d, J = æ.~ 2H): ~I2-P
2.85 (m, 2H): Ph-~2-CH2 2.59 (m, 2H): Ph-cH2-(~I2 1.43 (s, 18H): t-C4~Ig 1.33 (t, J = 7Hz, 6H): P-~CH2-C~3 MS: 455 M+ +1, 454 M+, 436 M+ -H20, 57 (100%) t:Bu wo 94/193~8 21 I 8 4 0 9 PCT/EP94/00520 E~l!l .
Dimethvl ~f3~$ di-te~-~u~l-~h~drox~henvl2-~d~oxo-~-h~n-1-vl ~b~ na~
:
t--Bu O O
/~\ 11 11 HO~ ~CH=CH C CH2 ~ C --CH2 PO3 Me2 r t--Bu The procedure ~s~ibed in example 12 was followed using dime~yl 2-ox~
pr~pylphosphnnate to give the title compound at ?9% yield, yellow solid with lo mp = 14~-146C.
~ .
,2-r4-(3 5-~-butvl~-hvdrox~nyl~2-ox~3-bu~n-1-vU
15 f2-ox~1.3.2~ioxaDhosphorinan) t -Bu 11~~
H~CH=CH--C --CH2 P
t-Bu Under nitrogen atmosphe~e, 2-methyl-2-ox~1,3,2-dioxaphosphorinan (2.62g, 19.2 mmol) dissolved in THF~dioxane (30ml each) was added to an equimolar amount of n-butyllithium in 35ml TH~ at -60C. The mixture was stirred at -60C for 30 minthen a solu~on of ethyl 3,5-di-tert-butyl-4-hydroxycinnamate (2g, 6.4 mmol) in 20ml TH~ was added. The resulting mixture was sti~Ted at -60C for 30 min and left to attain room temperature (25C) over 16 h. After the usual work up, column chrornatogra~hy (silicagel, 98/2 CHC13~MeOH) gave 0.76g of the title compound (30%).
mp = 158-161C
MS: m/e = 394 M+, 57 (100%): tBu WQ 94/19358 . PCT/EP94/00520 -" ~
4~ ~
. ~ ' Nl~ (CD~13): , - 7.65 (d, J= 16Hz, lH): Ph~
7.42 (s, 2H): arom. H
6.74 ( d, J = 16Hz, lH): Ph-CH~
5.7 (s, lH): QH
4.5-4.4 (largc m, 2H): P-O-C~2 3.4~ (d, J = 22~z): ~I2-P
2.1 and 2.0 (2m, 2H): P-~CH2-C~2 1.45 (s, 18H): t-C4Hg ~am~2~
t--Bu )~ 8 HO~ C CH=CH CH2 --PO3 Et2 t--Bu To a suspcnsion of 730mg 60% sodium hydride (18 mmol) in 20ml THF was added 3;0g t8.4 mmol) of dimethyl 2-(3,5-di-tèrt-butyl-4-hydroxyphenyl)-2-oxo-1 20 e~ylphosphonatc in 25ml THF. Thc mixture was s~ed for 30 min then it was cooled to 0 and 3.1g tl8 mmol) die~hyl foqmylmethylphosphonate was added. The resulting mixture was sti~red at 0C for 1 h then at 25C for 16h, par~tioned into cther and watcr and the o~ganic phasc was evaporated. Purificadon by means of column chromatography (silicagd 98/2 dichlo~omethane/methyl t-butyl ethcr) gave 25 550mg (16%) of the dde compound.
mp = 68-70C
MS=m/e: 410 M+, 39~: M+-CH3, 272: M+-HP03E~2, 233 (1~0%) M+-CH=CH-CH2P03Et2 -! W094/l9358 21I8~09 PCTIEP~4/00520 NMR: CDC13 = 7.83 (m, 2H): arom. H, 7.1 (dd, 1=15 and 4.5Hz, lH), Ph-CO~
6.9 (m, 2H): Ph-CO-CH~
5.7 (s, lH): OH
4.15 (m, 4H): P-O-C~2-CH3 2.86 (dd, J=23 and 7Hz): C~2-P
1.48 (s, 18H): t-C4Hg 1.34(t, 6H): P-O-CH2-C~3 ~ime~vl ~(3.5-di-~ert-butvl~hy~roxv ~henvl)-2-hvdroxv-3-buten-1-vl ~ ~.
lS
t-Bu )~ f HO~ CH=CH CH CH2 PO3Me2 r t--Bu To 100 ml of a methanol solution of dimethyl 4-(3,5-di-tert-butyl~hydroxyphenyl)-2-oxo-3-buten-1-yl phosphonate (19g, 5 mmol) cooled to -10C were added 0.75g 20 sodium borohydride. The reacting mixture was stirred at -10C for 1 h then at room - temperature (2SC) for 2 h. Wor~ up was carried out by addi~on of 100ml ether and 60ml sodium bicarbonate soludon. Thc ether phase was washed with brine, dried over MgSO4 and e~raporated to yield 1.6g (85%) of ~e tide compound.
.;!-25 mp = 122-123C -MS (m/e)= 384:M+, 366: M+-H20, 256: M+-H2~HP03Me2 Wo 94l19358~ ~ 3 PCTEP94/0052U
NMR (C~DC~3): .
7.21 (s, 2H): arom.;H
6.59 (d, J = 16Hz, i`H): Ph-C~H, 6.08 ~dd, J = 16 and 6Hz, lH): Ph-CH-{~
5.26 (s, lH): OH (phenol) 4.7 (rn, lH): C~-OH
3.78 (2xd, 6H): PO3~2 3.4 (hump, lH): CH-O~
2.15 (distorted dd, 2H): C~2-P
1.44 (t, 18H): t-C4Hg Dimethvl ~r3.s di-tert-blltvl~hvdrox~henvl~-2-ox~3^butcn-1-vl .~iono~ho~honate t--Bu O S
/=\ 11 11 , HO--~\ /; CH=CH C --CH2 P (OMe) 2 :
~~ .
t--Bu Undcr nitrogcn atmosphcrc dimethyl methylthionophosphonate (3. lg, 25 rnmol) was20 added at -60C to a soludon of n-butyllithium (16ml of a 1.6M soludon, 25.6 rnmol) in 50ml lL~. Thc mixture was st~ed at -60C for 15 rnin then a solution of ethyl3,5~-tert-butyl 4 hydro~cy cinnamate (2.5g, 8.2 mmol) in 20 ml T~ was added.
Thc resulting mi~cture was sturcd at -60C for 30 min and at room temperature (25C) for 2 h. After the usual hydrolysis and wo~ up, the compound was purified25 by column chromatography (SiO2, 9/1 CHCl3/AcOEt) and rec~ystallization in CHC131petro1eum ether to yield 1.7g (52%) of a yellow solid, mp = 88-90C
MS: mle = 398: M+, 259: M+-CH2P(S)(OMe)2, 125: P(S)(OMe)2, 57 (100%) ~. ~.. .
`` WO 94/19358 2118 4 09 PCTIEP94/00520 NMR (CDC13~
~= 7.60 (d, J - 16Hz, lH): Ph-C~=CH
7.42 (s, 2H): aro~ H
6.75 (d, J = 16Hz, lH): Ph-CH=C~
5.6 (s~ lH): O~
3.78 (d, J = 14Hz, 6H): P(S)-~3 3.56 (d, J = 20Hz, 2H~ 2-P
1.46 (s, lg~ t-C~g ~ ~2(iH31O4PS Theor. %C 60.28 %H 7.84 %P 7.77 %S 8.04 Pound %C60.58 %H 8.04 %P8.05 %S 8.30 ~m~2 t--Bu HO~5 CH2 C--CH2 PO3 Me2 t--BU : :
To a T~ solu~on o~ dimethyl lidliomethylphosphonate (24.6 mmol) kept at -60C
20 was added a solu~on of e~yl 3,5 di-tert-bu~rl~hydroxyphenyl ~ioacetate (2g, 6.2 mmol) in l5ml T~. The resul~ng mixnIre was stim2d at -60C for 30 min and was allowed to reach r~om tempe~re (25C) over 4 h. Afte~ addition of l~ml 10% HM~
thç reaction mix~e wæ pardtioned between ether and water. The residue after evapo~don OI the orgal~ic phase was purified by column chromatography (SiO2, ~/22s CHC13/AcOEt) and re~ystallization in petroleum e~er to give O.95g of dle dtle compound (38%).
mp = 63-65C
MS: m/e 402: M+, 251: M+-(CO-CH2-P03Me2), 57 WO 94/19358 ?,~,~,Q~ 4~3 PCT/EP94/00520 -`
NMR (CDCl3~
= 7.21 (s, 2H): arom H
5.3 (s, lH): OH
3.75 (d, J ~ 1 lHz, 6H): P-O-C~13 3.72 (s, 2H): S-C~2-CO
3.33 (d, J = 22Hz, 2H): C~2-P
1.41 (s, 18H): t-C4~1g ~m~2Q
,Dimethvl 3-f ~di~:~l~hvdrox~henvlthio)-3~imç~d-~ 1-~l ~hos~hona~
t-Bu )~ CH3 8 H~S--C--C - CH2 PO3 2 t-Bu '. 15 i, To 10ml of a T~ solutioD of dimethyl lithiomethylphosphonate (68.2 mmol) kept at 60C was added a solution of e~yl 2-(3,5-di-lcrt-butyl~hydroxyphcnyl-thio-2-mcthylpropionate (6g 17.1 mmol) in 15ml THF. The resulthg mixture was sti~ed at -60C for 30 min and was allowed to reach room temperature (25C) over 4 h. After addition of 15ml 1096 HCI, the reaction mi1cture was partitioned between ether and water. The residue after evaporadon of thc organic phase was purified by column chromatography (SiO2, 8n CHC13/AcOEt). Rec~ystallization in pe~leum ether gave 4.16g of the title compound (57%).
mp = 105-106C ~ ~
2s MS: m/e 430: M+, 279: M+-(CO-CH2-P03Me2), 194 (100%), 57 N~ (CDC13) ~ = 7.15 (s, 2H): arom H
5.38 (s, lH): OH
3.80 (d; J = 1 lHz, 6H): P-O-C~13 3.46 (d, J = 22Hz. 2H): C~2-P
1.41 (m, 24H):t-C4~1g + C(C~13)2 - WO 94/19358 21 1 ~ 4 0 9 - ~CT~P94/00~20 ~mR~
t-Bu ~, HO~CH=CH-CH~CH PO3Me2 t-Bu A mix~ure of dimethyl ~(3,5-di-tert-butyl~hydroxyphenyl) 2-hydroxy-3-buten-1-yl phosphor~ate ~2.3g, 6 mmol) in 1.70ml acetic anhydride and 1.26ml triethylamine was stirred at 60C for 3h. Following hydrolysis with lOml H20, the reac:tion lo mixture was ex~acted with 20ml diethyl ethcr. The e~her phase was extracted with 10% HCl and d~ied over MgSO4. The residue after evaporation was purifiled by column chromatography to give l.Og (46%) o~ the title compound.
mp= 113-115C
MS: m/e: 366 M~, 351 M+-Me, 57 (tBu) NMR (~DC13) = 7.32-720 (m, 3H): arom H + CH~H-~ P
6.82 (lH,d)~ ~-CH~I-P
6.74-6.66 (lH, m) C~H~-CH=CH-P
5.67 (lH, dd, J = 16.6 and l9.~Hz): CH=CH-CH~-P
3.75 (d, 6H): Po-(~EI3 1.46 (19H, s): t-C4~g WO 94/19358 , . PCT/EP94/00520 `"`, 12im~h~4 (3.5~ tert-butvl ~ hvdrox~ 2-f4 ~en~n~vln~ u~l ~QS~hopate 0 :~
t-Bu 1 ¦
)~ o--C--CH2-CH2-CH~CH2 H~cH2 -CH2 CH -cH2--Po3 Me2 t--~u To a mixture of acetyl~pentcnoate (0.66g, 4.6 mmol) and triethylamine (0.24ml, 1.7 mmol) was added 0.50g (1.37 mmol) of dimethyl ~(3,S-di-tert-butyl~
10 hydroxyphenyl)-2-hydroxy- l-butyl phosphonate. The reaction mixture was kept at 60C for 6 h, cooled and extracted in~o diethyl ethe~ and water. The residue of the dried organic phase was purified by column chromatography (SiO2, 7/3 CHC13~Mc~yl-tert-butyl ethcr) to yield OAg of a colorless oil (62%).
MS: m/e: 468: M+, 368: M+- CH22H-CH2-COOH, 258: 368 - HP03Me2 N~ (CDC13) t' = 6.94 (s, 2~: arom H
5.85 (m, lH): C~H2~-CH2-CH2-COO
5.18 (m, lH): Ph-CH2-CH2-~-CH2-P
5.0 - S.l (m, 2H): C~I2-cH-cH2-cH2-coo 5.15 (s, lH): OH (phenol) 3.72 (2xd, 6H): P3~2 2.55 (m, 2H~: Ph-cH2-cH2-cH-c~2-p 2s 2.41 (m, 4H): CH2~-c~2-c~l2 1.43 (s, 18H): t-C4Hg `) wo 94/19358 21 1 8 4 0 9 PCT/EP94tO0520 I:a}2~L PHC)SPHONATES OF FORMULA (I) X~ y )~ ,I,Z
~D--P~ ( I ) Comp G xl, x2 D _ zl z2 mp ~C) I~Jcroar;lysi5 1 HO ~BuCH=C~-C(0~ 2 O OMe 107-109 C20H3105P
2 HO ~BuCH=~H~(0~H2 OEt 110~111 C22H3505P
3 HO ~BuC~H_C~H-C(~)~C~H2 O O~Pr121 - 122 C24H390sp 4 HO tBuC~H=~H-C~O)~C iH2 ChiBu6~i7 C26H4305P
HO ~BuC~H=~H-C(O)-C(cH3)2 O OMe 125-126 cæH3sosp 6 HO ~BuC~H=c~H-c(o)-c(c~H3)2 O OEt 91 -92 ~24H3905P
7 ~IO ~BuC3H=CH-C(O~C(C~3)2 O O~Pr138-139 C26H4305p 8 HO ~BuC~H=C~H-C(03-CH(C~H3) O OMe 144-145 C21H330sp 9 HO ~BuCH=C~H-C(O)IC~H(C~H3) O OEt 92-94 C23H3705P
EK~ tBuC~H=dC~C~H3~C(~)~ClH2 O OMe 131-133 C21H3305p11 HC) ~BuC~=d~(C~H3)~(0~5~H2 O OEt 97-101 C23H3705P
12 H~ tBuCH=C(nC4Hg~C(O) CH2 O OMe 82-85 C24H3905P
13 HO tBuCH=C(nCsH1 l)-C(O)~H2 O OMe 67-72 C25H4105P
14 HO tBuCH=C~Ph~C(O) CH2 O OMe 147-149 C26H3505P
HO tBuCH=C(Ph) C(O) CH2 O OEt139-143 C2gH3905P16 HO ~uCH2 CH2~(0) CH2 o OMe 78-79 C20H3305P
17 HO tBuCH2-CH2~(0~CH2 O OEt oil C22H3705P
18 HO tBuCH2-CEI2~(0) C(CH3)2 O OMe 85-87 C22H3705P
19. HO IBuCH2~ -C(O~C(cH3)2 O OEt 64 66 C24H4105P
HO IBuCH~H-CH=CH~(O) CH2 C) OEt oil 21 HO tBuCH=CH-CH=CH~(O~C(CH3)2 O OMe142-146 22 HO tBuCH=CH-CH=CH-C(O)-C(CH3)2 O OEt130-133 C26H4105 23 HO tBu C(O~CH2 O OMe108-111 C18H2905 24 HO tBuCH=CH-C(O)-CH2 O NMe2178-179 C22H3703 HO IBuC(O)-CH2-C(O)-cH2 O OMe108-109 C20H3106 26 HO tBuCH=CH-C(O~CH2~(0)-CH2 O OMe145-146 C22H3306 27 HO tBuCH=C~-C(O~CH2-C(O)-CH2 O OEt109-110 C24H3706 28 HO lliuCH2-CH2-C(O) CH2-C(O)-CH2 O OEl oil C24H3906 wo s4tls3s8 PCT/EP94/00520 f- ~ ~
4~9 . I
I:ak~ PH(:)SPHONAl'ES O~; FORMULA (I) (cont.) x P~ ( I ~
Comp. G xl,x2 y zl z2mp(C) M~c~analysu .. . __ .... . " . _ _ .......... . .
29 HO ~BuCH2~2~(0) CH2~(o)~H2 O OMe oil C22H3506P
HO tBuCH=C(C2Hs)-C(O~CH~ O OMe 128-132 C22H3505P
31 HO sBuCH=CH-C(O)-CH2 O OMe oil C20H3 l 5P
32 HO s~uCH=CH-C(O~H2 O OEt oil C22H350'iP
33 MeO tBuCH=CH-C(O)-CH2 O OMe 73 75 C21H335P
34 HO tBuCH=CH-C(O)~H2 S OMe 88-90 C20H3104P
HO tBuCH=CH-C(O)-CH2 O-(~H2)30 156-lfil C21H3l05 36 HO lBuC(O)-CH=CH~H2 O OMe oil C20H3los 37 HO tBuC(O) CH=CH~H2 O OE~ 65-70 C22H3505 38 HO tBuC(O)-CH2 C)OEt 112-115 C20H3305 39 HO tBuC(O)-CH2 OOiPr 127-131 C20H3705 HO tBuS-CH2-C(O)-CH2 O OMe 62~5 C19H3105 41 HO tBuS-CH2-C(O)-CH2 (~OEt 76-78 C21 H3505 42 HO tBuS-C(CH3)2-C(O) CH2 o OMe 105-106 C21H3505 43 HO tBuS-C(CH3)2-C(O~cH2 O OEt 8~81 C23H3gOs 44 HO tBuS-CH2-C(~CH2-C(o)-cH2 O OMe oil C21H3306 HO tBuS-CH2~(0) CH2-c(o)-cH2 O OEl oil C23H3706 46 HO tBuCH-CH-CH(OH)-CH2 O OMe 122- 123 C20~335 47 HO tBuCH2-CH~H(OH) CH2 o OMe 88-91 C20H3505 48 HO IBuCH(0H) CH2 O OMe 128-133 C18H310s 49 HO IBuCH(OH)-CH2 CH(OH)-CH2 OOMe 129-132 C20H3506 HO tBuS-CH2-cH(OH) CH2 oOMe 1~108 Cl9H335 51 HO ~uCH=CH-CH=CH OOMe 113- 115 C22H3506 52 HO tBu(CH~)2-CH(O-CO-cH3) CH2 OOMe oil C22H370 53 HO tBu(cH2)2-cH(o-co-ncsHl l)~H2 OOMe oil C26H450 54 HO ~u(CH2)2-cHlo-co-(cH2)2~H=cH23-cH2 oOMe oil C25H416 HO SBuS-CH2-CH(O-CO~H3)-CH2 OOMe oil C21H3506 56 HO ~BuS-CH2 CH(O-CO-nC5Hll)-cH2 OOMe l~il C25H430 `) WO 94/193~8 PCT/EW4/00520 2118~og A. ~i:~=~
I
1) lron i,nduced,~eroxide fo~mation in rat li~hQm~en~
Wis~r raes were euthanasied by cthe~ inhiala~on. The liversi were dissected out and ', homogenised with a poeter homogeneiser in 4 volumes of phosphate buffer (4C, pH 7.4). After cen~ifugation at 2000 ~pm for 10 min the supema~ant obtained was o kept ae 4C.
A mixeure containing 0.2 ml of liver homogenate, 1.7 ml of phosphate buffer was incubated with 0.1 ml of a 2mM PeS04 soludon to induce peroxide foImaeion according to the method descnbed by A. T. Quintanilha et al., Ann. N. Y. Acad. ,:
lS Sci., ~, 32~7, 1982.
Compounds to be tested for antioxidant ac~vity were dissolved in DMSO or cehanol and added iLn a volume of 5 111 to the incubation mixture. Stock solu~ion of the compounds were diluted scquen~ally to obtain final concen~ation of 0.5, 1, 2, - 20 5 and 5 pM. Oxidation was pe~fon~ed at 37C for 2 hours and was stopped by the addition of 20 pl of a 2* ethanolic solution of BHT. The generated peroxides meas~d as malondialdehydc fonnjation were quantitated according to the method of Yagi ("Iipid Pe~xidcs in Biology and Medicine" p. 223-242, 1982, Ed. K.
Yagi, Academic Press ~c.) u~g dle Thioba~bituric Acid Reaction and with 2s 1,1,3,3,-telrame~oxy~ropa~ie as standard. Results aIe given as concentranon in pmoUI which inhibits malondialdehyde formation by 50% (IC50).
..,. ~ . .... ..
All ~e tested compounds have IC50's between 0.5 and 5 ~M and are more active ~an Probucol, vitamin E and Vitamin C Bu~l hydroxytoluene (13HT) has an IC50 of 3.3 ~M in ~is assay. Compound of foImula (I) are thus useful for the treatment of disease sta~es jD which oxygeD re~c~ve species ale involved.
wo 94/19358 Q~ ~9 PCT/EP~4/00520 --!
T~ble 2 . ...... ~
Compound lC50 (pM)_ Probucol ~ 25 ~ita~n E _ > 25 Yitam~n C _ ~ 25 BHT _ 3.3 , , _l, ~.01 2 _ 3~20 _ 3 _ _ 1~37 4 1~41 _ _ 1~0__ _ 16 4~89 17 3~03 _ 1 2~85 3 ~ _ 1~88 ~ ~ 3~18 ~ ~38 7 . ~ . . t ^ ' ' 2 06 18 3~56 i9~ ~ 2~49 _ 12 ~ 1~71 3~48 4 3~07 20 ~ 2~44 24 ~ 4~55 25 ` ~_ 2~71 26 0~68 27 0.70 28 1.0 32 2~78 33_ 5~0 34 2~91 2~84 `~ WO 94/19358 21 1 810 9 PCTIEP94/00~20 2)~
Plasma was obtained after low speed centrifuga~on of blood from donors. I,DL
(d=1.006 1.C63 glml) were isolated by preparative ultracentrifugation in a salt s solu~on (NaBr, KBr). The isolated LDL fraction was dialysed against phosphate buffer.
LDL oxida~on was pe$fo~med a~eording to Ester~auer et al. (Continuous Monit~g of in Vitro Oxidation of Human Low Density Lipoprotein, Free Rad.
Res. Commun. ~, 67-75, 1989). Briefly the LDL suspension (50-2001~g protein/ml) was distributed in quartz cuvettes and kep~ at 37C then a solution of CuC12 wasadd~d at a final concentration of 511M. The increase in optical density at 235 nm was recorded using a W-visible spec~ophotometer. The time course of oxidation was recorded over a penod of 8 hours at 10 min intervals. Compouncls to be tested we~e dissolved in ethanol and added at the final concentraaon of 0.1 ~M. Controls ~eceived ethanol only. The lag phase is pr~longed by the p~esence of antioxidants.
This medlod was validated with Probueol and vi~-E as reference antioxiclants.
The prolongation of the lag phase was uscd to quantify ~e antioxidant activity of the compounds tcsted, this pr~longation W2~ expressed in percent of ~e value measured in absence of exogen an~oxidant (controls).
` ~,,, J` , ,`
The phosphonates of Formula (I) as noted in TaUe 3 prolong the lag phase compared to control. An inhibitoIy activi~ on LDL oxidation is thus demonstrated2~ which is clearly supe~ior to that of Prt)bucol and vitamin E. Since these two antioxidants have been shown to be anti-atherosclerotic in animal models, the therap~utic poten~ial of phosphonates of Fo~mula (I) is ob~rious.
wo 94/193~ 9 PCT/EP94100~20 .--Table 3 C~-: _nll Lag pbase % con~ol . ~ . . _ _ ~obuccl _+ 7 Vitamin E _ 0 1 _ ~ 1 45 ~ _ _ 7 3_ ~ + 172 4 _ _ ~ 74 _ ~ 233 16 _ l 159 17 ~195 11 _ _+212 13 _ + 191 ~ 147 6 . + 129 `~. . . ~ ~
18 _ ~ 223 19 ~ 157 : . 9 __ + 1 12 :~ 10 + 126 : 20 ~- + 38 + 1 18 26 ~
27 + 42 28 ~
32 + 80 33 + 14 ~ 8 + 118 - ~ wo 94/193~8 PCT/E:Pg4/00520 B. ~
The human intes~nal cell line CaCo~ cells (ATCC HTB37) was used to study the effect of compounds of formula (I) on choles~erol syndlesis. The cells were grown S in 6 wells dishes (Falcon) in 2 ml of Dulbecco's m~dified Eagle cult~re medium (I:)MEM) supplemented with 20% fetal calf serum (Flow). Cells were maintained at 3PC in a 5% CO2 a~nosphe~e and the labelling expenment was done 8 days after cell pla~ng. To ~e culture were added lû pl of ~e ethanol solu~on of the compounds to be tested. Control wells ~eived lOpl of ethanol alone. One hour later 0.7 yCi of 14 C-acetate 53.4 mCilmmol was added, labelling was connnued for 4 hours and w~s stopped by washing ~e ccll layer with chilled P~3S. The cells wcre collected in 2ml of O.O1 N NaOH and 1 ml of PBS. Lipids were extracted by the Folch method and separated on silica gd TLC plates developed in petroleum ethes: diethyl ether: acetic acid (70:30: O.5). After exposition to iodine vapors, ~e bands coiTespondiT~g to cholesterol and choleste~yl esters were scrapped off and~dio~ctivity was measur~d in a liquid scin~llator countcr.
l~ne amount of radioactivity inco~ted in cholestcrol and cholesteryl esters in presence of compounds to be tested was compared to that of the control cells.
HMGCoA r~ductase inhibito~s such as simvastatin (lyM) s~ved to validate the measuremcnt of 14C-acetate inco~poration in ~holestcrol and cholesteryl csters.
All thc compounds tcstcd inhibited cholestcrol and cholesteryl est~s synthesis.
-- Most of the compou~ds inhibi~ed choles~e~yl ès~ers synthesis by more than 50%
CTablc 4~. Phosphonates of fo~mula (I) display an inhibitory activity on choleste~ol and cholestayl estcrs and can be considcrd as therapcutic agcnts in thc treatmcnt of hgpe~lipidania and ather~sclerosis.
WO ~4lls35B , PCTIEPg4/00~20 --~
Table 4 _ ~
Choleteryl (::ompounds Choleterol ester~
% %
Simvasta~in 96_ __ 70.
_ _ _ _ _ _ ~ _ -5? - __ ___ 3 _ -i55 -84 . 4_ _ _ 21 80 __ __ .. .
_13 ~9 _ 84 . --26 j _ -22 _ -75 19_ _~46 -83 9 _ -49 _ 81_ .
i - 14 26 ~ 84 _ _ 1 ~ 24 ` ` 1 1 5 r ~l ~ -60 _ _ 33 - 54~ ; ~ -34 ~0 wo 94/1g358 2 I 1 8 4 0 9 PCT/EPs4/00520 C. ~alci~ Fntr~ Rlockin~ activitv of ketoDhosDhonates Expenments were performed on aor~c nngs from rnale Sprague -Dawley rats (28~350g body weight) which were killed by stunning and exsan~nation.
Thoracic aortas were cleared of connective tissues and cut into ~ings of approximately 2mm in length. Each ring was mounted under a resting tension of 2g and was equilibrated for 1 hour at 37C in a lO ml organ bath containing a HEPES bufferRinger soludon (Buffer composition (mM): NaCl 139.0, KCl 5.0, MgC12 3-7. ~Glucose 11.0, HEPES 5.0, pH 7.4) acrated with 95% 2:5% CO2.
~' Maximal contractions we~e produced within 5-lO min exposure to 10pM
Phenylephnne. The dssues were then washed with a Ca+2 free HEPES buffer.
After 30 min the dssue was depolarised with KCl (60~I).One hundred ~ of the vehicle (10% DMSO) or compound solution (1 yM) werc added S min later. The final concentra~on of DMSO was 1%. The tissues ~n=2 per compound) were further equili~ated for 15 min in the presence of compounds prior to cumulative ` -addition of Ca+2 (0.1-30 mM). The contractions to cach concentration of calcium are calculated as a percentage of the second phenylephrine contraction and the EC30 (concentration of Ca2+ producing a contraction 30% of the phenylephrine contraction) calculated. Thè potericy index of cach compound is expressed as theconcentration ~io (calcium drug EC30hehicle EC30), where a potency index ~1 indicates a c~npound effect.
The compounds of formula (~ are thus potentially useful in the treatment of cardiovascular discases via their calcium eritry blocking activity. The pnmary indicadons of these compounds would be the t~ent of atherosclerosis, angina pocto~is, congesdve heart failure and hypertension.
Tabae 5 -Effect`of compounds (I) on Ca+2 induccd contraction of K+ depolarizcd rat aoqta .
Compound EC30Ratio .` 6 21.8 7 9.2 16 4.2 26 4.7 28 5.~ ~-
Claims (15)
1. A compound of formula (I) ( I ) where - X1, X2 identical or different are straight or branched C1 to C6 alkyl groups, -Y is O or S, Z1, Z2, identical or different, are:
- OR where R is H, a straight or branched C1-C6 alkyl group, - NR1R2 where R1, R2, identical or different are H or a straight or branched C1-C6 alkyl group, - Z1, Z2 together may form a C2-C8 alkylidenedioxy group, - G is OH or a bioprecursor thereof;
D is a saturated or unsaturated C1-C11 alkylene chain in which one or more of the methylene groups can be replaced by a sulphur atom, an oxygen atom, a carbonyl group; optionally one or more methylene groups can be substituted by one or morehalogen atoms (F, Cl or Br), C1-6 alkyl, phenyl, hydroxy or acyloxy groups, and salts, solvates and hydrates thereof.
- OR where R is H, a straight or branched C1-C6 alkyl group, - NR1R2 where R1, R2, identical or different are H or a straight or branched C1-C6 alkyl group, - Z1, Z2 together may form a C2-C8 alkylidenedioxy group, - G is OH or a bioprecursor thereof;
D is a saturated or unsaturated C1-C11 alkylene chain in which one or more of the methylene groups can be replaced by a sulphur atom, an oxygen atom, a carbonyl group; optionally one or more methylene groups can be substituted by one or morehalogen atoms (F, Cl or Br), C1-6 alkyl, phenyl, hydroxy or acyloxy groups, and salts, solvates and hydrates thereof.
2. A compound of formula (I) according to claim 1 where:
D is A-C(O)-B, A-CH(OH)-B, A-CH2-B, (CH2)t-(CH=CH)n-(CH2)t or S-(CH2)t, where A is (CH2)t, (CH=CH)n-CH=CX3, (CH2)t-CHX3. S-(CH2)t-(CH=CH)n, S-CX4X5, , (CH=CH)n-CH=CH-C(O)-CHX3, (CH2)p-CH=H-C(O)-CHX3, (CH2)t-C(O)CHX3, S-(CH2)t-(CH=CH)n-C(O)CHX3, S-CX4X5-C(O)-CHX3, (CH=CH)n-CH=CH-CH(OH)-CHX3, (CH2)p-CH=CH-CH(OH)-CHX3, (CH2)t-CH(OH)-CHX3, S-(CH2)t-(CH=CH)n-CH(OH)-CHX3, S-CX4X5-CH(OH)-CHX3, where n is zero, 1 or 2, t is a number from 0 to 4, p is a number from 1 to 3, - X3 is H, a straight or branched alkyl C1-C6 group, a substituted or unsubstituted phenyl group, - X4, X5 identical or different are H, a straight or branched C1-4 alkyl group, - B is CH2, CH-X6, X6-C-X7, where X6 and X7 identical or different are halogen atoms (F, Cl, Br), straight or branched C1-C6 alkyl groups, a substituted or unsubstituted phenyl group;
when A is (CH2)t, (CH=CH)n-CH=CX3, (CH2)t-CHX3. S-(CH2)t-(CH=CH)n, S-CX4X5, then B is also CH=CH-(CH2)p, CH=CH-CHX6, CH=CH-CX6X7, where p and X6, X7 are defined as above.
D is A-C(O)-B, A-CH(OH)-B, A-CH2-B, (CH2)t-(CH=CH)n-(CH2)t or S-(CH2)t, where A is (CH2)t, (CH=CH)n-CH=CX3, (CH2)t-CHX3. S-(CH2)t-(CH=CH)n, S-CX4X5, , (CH=CH)n-CH=CH-C(O)-CHX3, (CH2)p-CH=H-C(O)-CHX3, (CH2)t-C(O)CHX3, S-(CH2)t-(CH=CH)n-C(O)CHX3, S-CX4X5-C(O)-CHX3, (CH=CH)n-CH=CH-CH(OH)-CHX3, (CH2)p-CH=CH-CH(OH)-CHX3, (CH2)t-CH(OH)-CHX3, S-(CH2)t-(CH=CH)n-CH(OH)-CHX3, S-CX4X5-CH(OH)-CHX3, where n is zero, 1 or 2, t is a number from 0 to 4, p is a number from 1 to 3, - X3 is H, a straight or branched alkyl C1-C6 group, a substituted or unsubstituted phenyl group, - X4, X5 identical or different are H, a straight or branched C1-4 alkyl group, - B is CH2, CH-X6, X6-C-X7, where X6 and X7 identical or different are halogen atoms (F, Cl, Br), straight or branched C1-C6 alkyl groups, a substituted or unsubstituted phenyl group;
when A is (CH2)t, (CH=CH)n-CH=CX3, (CH2)t-CHX3. S-(CH2)t-(CH=CH)n, S-CX4X5, then B is also CH=CH-(CH2)p, CH=CH-CHX6, CH=CH-CX6X7, where p and X6, X7 are defined as above.
3. A compound of formula (I) according to claim 1 in which D is A-C(O)-B in which A is (CH2)t, (CH=CH)n-CH=CX3, (CH2)t-CHX3. S-(CH2)t-(CH=CH)n, S-CX4X5, , (CH=CH)n-CH=CH-C(O)-CHX3, (CH2)p-CH=H-C(O)-CHX3, (CH2)t-C(O)CHX3, S-(CH2)t-(CH=CH)n-C(O)CHX3, S-CX4X5-C(O)-CHX3, (CH=CH)n-CH=CH-CH(OH)-CHX3, (CH2)p-CH=CH-CH(OH)-CHX3, (CH2)t-CH(OH)-CHX3, S-(CH2)t-(CH=CH)n-CH(OH)-CHX3, S-CX4X5-CH(OH)-CHX3, and where n is zero, 1 or 2, t is a number from 0 to 4, p is a number from 1 to 3, - X3 is H, a straight or branched alkyl C1-C6 group, a substituted or unsubstituted phenyl group, - X4, X5 identical or different are H, a straight or branched C1-C4 alkyl group, and B is CH2, CH-X6, X6-C-X7, where x6 and X7 identical or different are halogen atoms (F,Cl, Br), straight are branched C1-C6 alkyl groups, a substituted or unsubstituted phenyl group;
when A is (CH2)t, (CH=CH)n-CH=CX3, (CH2)t-CHX3. S-(CH2)t-(CH=CH)n, S-CX4X5, then B is also CH=CH-(CH2)p, CH=CH CHX6, CH=CH-CX6X7, where p and X6, X7 are as defined in claim 1.
when A is (CH2)t, (CH=CH)n-CH=CX3, (CH2)t-CHX3. S-(CH2)t-(CH=CH)n, S-CX4X5, then B is also CH=CH-(CH2)p, CH=CH CHX6, CH=CH-CX6X7, where p and X6, X7 are as defined in claim 1.
4. A compound of formula (I) according to claim 1 in which D is -ACH(OH)-B-in which A and B are as described in claim 2.
5. A compound of formula (I) according to claim 1 in which D is A'-CH(O-CO-X8)-B' where A' is (CH2)t, (CH=CH)n-CH=CX3, (CH2)t-CHX3. S-(CH2)t-(CH=CH)n, S-CX4X5. and B' is CH2, CH-X6, X6-C-X7, CH=CH-(CH2)p, CH=CH-CHX6, CH=CH-CX6X7 where t, n, p, X3, X4, X5, X6 and X7 are as described in claim 2, and X8 is a saturated or unsaturated C1-C6alkyl or alkenyl chain.
6. A compound of formula (I) according to claim 1 selected from the group comprising:
dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-buten-1-yl phosphonate, diethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-buten-1-yl phosphonate, diisopropyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-buten-1-yl phosphonate, dibutyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-buten-1-yl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,1-dimethyl-2-oxo-3-buten-1-yl phosphonate, diethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,1-dimethyl-2-oxo-3-buten-1-yl phosphonate, diisopropyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,1-dimethyl-2-oxo-3-buten-1-yl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-methyl-2-oxo-3-buten-1-yl phosphonate, diethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-methyl-2-oxo-3-buten-1-yl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4hydroxyphenyl)-3-methyl-2-oxo-3-buten-1-yl phosphonate, diethyl 4-(3,5 di-tert-butyl-4-hydroxyphenyl)-3-methyl-2-oxo-3-buten-1-yl phosphonate, dimethyl 4-(3,5 di-tert-butyl-4-hydroxyphenyl)-3-(n-butyl)-2-oxo-3-buten-1-yl phosphonate, dimethyl 4-(3,5 di-tert-butyl-4-hydroxyphenyl)-3-(n-pentyl)-2-oxo-3-buten-1-yl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-phenyl-3-buten-1-yl phosphonate, diethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-phenyl-3-buten-1-yl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-1-butylphosphonate, diethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-1-butylphosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,1-dimethyl-2-oxo-1-butyl phosphonate, diethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,1-dimethyl-2-oxo-1-butyl phosphonate, diethyl 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3,5-hexadien-1-yl phosphonate dimethyl 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,1-dimethyl-2-oxo-3,5-hexadien-1-yl phosphonate diethyl 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,1-dimethyl-2-oxo-3,5-hexadien-1-yl-phosphonate, dimethyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-1-ethyl phosphonate, N,N,N',N'-tetramethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-buten-1-yl phosphonamide, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,4-dioxo-1-butyl phosphonate, dimethyl 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,4-dioxo-5-hexen-1-yl phosphonate, diethyl 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,4-dioxo-5-hexen-1-yl phosphonate, diethyl 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,4-dioxo-1-hexyl phosphonate, dimethyl 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,4-dioxo-hexyl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)3-ethyl-2-oxo-3-buten-1-yl phosphonate dimethyl 4-(3,5-di-sec-butyl-4-hydroxyphenyl)-2-oxo-3-buten-1-yl phosphonate, diethyl 4-(3,5-di-sec-butyl-4-hydroxyphenyl)-2-oxo-3-buten-1-yl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-methoxyphenyl)-2-oxo-3-buten-1-yl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-buten-1-yl thionophosphonate, 2-[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-buten-1-yl](2-oxo-1,3,2-dioxaphosphorinan), dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-oxo-2-buten-1-yl phosphonate, diethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-oxo-2-buten-1-yl phosphonate, diethyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-1-ethyl phosphonate, diisopropyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-1-ethyl phosphonate, dimethyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl thio)-2-oxo-1-propyl phosphonate, diethyl 3-(3,5-di-tert-butyl-4-hydroxyphcnyl thio)-2-oxo-1-propyl phosphonate, dimethyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl thio)-3,3-dimethyl-2-oxo-1-propyl phosphonate dicthyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl thio)-3,3-dimethyl-2-oxo-1-propyl phosphonate dimethyl 5-(3,5-di-tert-butyl-4-hydroxyphenylthio)-2,4-dioxo-1-pentyl phosphonate, diethyl 5-(3,5-di-tert-butyl-4-hydroxyphenylthio)-2,4-dioxo-1-pentyl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-hydroxy-3-buten-1-yl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-hydroxy-1-butyl phosphonate, dimethyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-hydroxy-1-ethyl phosphonate, dimethyl 4-(3,5-di-tert-butyl-hydroxyphenyl)-2,4-dihydroxy-1-butyl phosphonate, dimethyl 3-(3,5-di-tert-buty1-4-hydroxyphenylthio)-2-hydroxy-1-propyl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-butadien-1-yl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(acetyl oxy)-1-butyl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(hexanoyl oxy)-1-butyl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(4-pentenoyl oxy)-1-butyl phosphonate, dimethyl 3-(3,5 di-tert-butyl-4-hydroxyphenyl thio)-2-(acetyl oxy)-1-propyl phosphonate, dimethyl 3-(3,5-di-tert-butyl 4-hydroxyphenyl thio)-2-(hexanoyl oxy)-1-propyl phosphonate.
dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-buten-1-yl phosphonate, diethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-buten-1-yl phosphonate, diisopropyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-buten-1-yl phosphonate, dibutyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-buten-1-yl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,1-dimethyl-2-oxo-3-buten-1-yl phosphonate, diethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,1-dimethyl-2-oxo-3-buten-1-yl phosphonate, diisopropyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,1-dimethyl-2-oxo-3-buten-1-yl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-methyl-2-oxo-3-buten-1-yl phosphonate, diethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-methyl-2-oxo-3-buten-1-yl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4hydroxyphenyl)-3-methyl-2-oxo-3-buten-1-yl phosphonate, diethyl 4-(3,5 di-tert-butyl-4-hydroxyphenyl)-3-methyl-2-oxo-3-buten-1-yl phosphonate, dimethyl 4-(3,5 di-tert-butyl-4-hydroxyphenyl)-3-(n-butyl)-2-oxo-3-buten-1-yl phosphonate, dimethyl 4-(3,5 di-tert-butyl-4-hydroxyphenyl)-3-(n-pentyl)-2-oxo-3-buten-1-yl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-phenyl-3-buten-1-yl phosphonate, diethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-phenyl-3-buten-1-yl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-1-butylphosphonate, diethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-1-butylphosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,1-dimethyl-2-oxo-1-butyl phosphonate, diethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,1-dimethyl-2-oxo-1-butyl phosphonate, diethyl 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3,5-hexadien-1-yl phosphonate dimethyl 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,1-dimethyl-2-oxo-3,5-hexadien-1-yl phosphonate diethyl 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,1-dimethyl-2-oxo-3,5-hexadien-1-yl-phosphonate, dimethyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-1-ethyl phosphonate, N,N,N',N'-tetramethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-buten-1-yl phosphonamide, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,4-dioxo-1-butyl phosphonate, dimethyl 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,4-dioxo-5-hexen-1-yl phosphonate, diethyl 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,4-dioxo-5-hexen-1-yl phosphonate, diethyl 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,4-dioxo-1-hexyl phosphonate, dimethyl 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,4-dioxo-hexyl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)3-ethyl-2-oxo-3-buten-1-yl phosphonate dimethyl 4-(3,5-di-sec-butyl-4-hydroxyphenyl)-2-oxo-3-buten-1-yl phosphonate, diethyl 4-(3,5-di-sec-butyl-4-hydroxyphenyl)-2-oxo-3-buten-1-yl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-methoxyphenyl)-2-oxo-3-buten-1-yl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-buten-1-yl thionophosphonate, 2-[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-buten-1-yl](2-oxo-1,3,2-dioxaphosphorinan), dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-oxo-2-buten-1-yl phosphonate, diethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-oxo-2-buten-1-yl phosphonate, diethyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-1-ethyl phosphonate, diisopropyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-1-ethyl phosphonate, dimethyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl thio)-2-oxo-1-propyl phosphonate, diethyl 3-(3,5-di-tert-butyl-4-hydroxyphcnyl thio)-2-oxo-1-propyl phosphonate, dimethyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl thio)-3,3-dimethyl-2-oxo-1-propyl phosphonate dicthyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl thio)-3,3-dimethyl-2-oxo-1-propyl phosphonate dimethyl 5-(3,5-di-tert-butyl-4-hydroxyphenylthio)-2,4-dioxo-1-pentyl phosphonate, diethyl 5-(3,5-di-tert-butyl-4-hydroxyphenylthio)-2,4-dioxo-1-pentyl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-hydroxy-3-buten-1-yl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-hydroxy-1-butyl phosphonate, dimethyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-hydroxy-1-ethyl phosphonate, dimethyl 4-(3,5-di-tert-butyl-hydroxyphenyl)-2,4-dihydroxy-1-butyl phosphonate, dimethyl 3-(3,5-di-tert-buty1-4-hydroxyphenylthio)-2-hydroxy-1-propyl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-butadien-1-yl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(acetyl oxy)-1-butyl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(hexanoyl oxy)-1-butyl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(4-pentenoyl oxy)-1-butyl phosphonate, dimethyl 3-(3,5 di-tert-butyl-4-hydroxyphenyl thio)-2-(acetyl oxy)-1-propyl phosphonate, dimethyl 3-(3,5-di-tert-butyl 4-hydroxyphenyl thio)-2-(hexanoyl oxy)-1-propyl phosphonate.
7. A process for prepanng compounds of formula (I) according to claim 3, where A is (CH2)t, (CH=CH)n-CH-=CX3, (CH2)t-CHX3, S-(CH2)t-(CH=CH)n, S-CX4X5 where n, t, X3, X4 and X5 are as described in claim 1 which consists in reacting the alkylphosphonates III
III
where B is CH2, CHX6, CX6X7 and X6, X7, Y, Z1 and Z2 are as described in claim 1, with n-butyllithium or lithium diisopropylamide at a temperature between -78°
and -40°, then reacting in situ the lithium anion of III thus formed with the ester II
II
where X1, X2, G are as described in claim 1 and A is (CH2)t, (CH=CH)n-CH=CX3, (CH2)t-CHX3, S-(CH2)t-(CH=CH)n or S-CX4X5 in tetrahydrofuran at a temperature between -78° C and 25°C.
III
where B is CH2, CHX6, CX6X7 and X6, X7, Y, Z1 and Z2 are as described in claim 1, with n-butyllithium or lithium diisopropylamide at a temperature between -78°
and -40°, then reacting in situ the lithium anion of III thus formed with the ester II
II
where X1, X2, G are as described in claim 1 and A is (CH2)t, (CH=CH)n-CH=CX3, (CH2)t-CHX3, S-(CH2)t-(CH=CH)n or S-CX4X5 in tetrahydrofuran at a temperature between -78° C and 25°C.
8. A process for preparing compounds of formula (I) according to claim 3 where Ais (CH=CH)n-CH=CX3 which consists in reacting an aldehyde of formula IV
IV
where G, X1, X2, n are as described in claim 1, with a ketophosphonate of formula V
V
where X3, B, Y, Z1, Z2 are as described in claim 1, in tetrahydrofuran in presence of titanium tetrachloride and N-methyl morpholine at a temperature between -20°C and 66°C.
IV
where G, X1, X2, n are as described in claim 1, with a ketophosphonate of formula V
V
where X3, B, Y, Z1, Z2 are as described in claim 1, in tetrahydrofuran in presence of titanium tetrachloride and N-methyl morpholine at a temperature between -20°C and 66°C.
9. A process for preparing compounds of formula (I) according to claim 3 in which A is (CH2)t-CHX3, which consists in reacting the compound V
V
where X3. B, Y, Z1 and Z2 are as described in claim 1 first with sodium hydride and n-butyl lithium, then with the halide of formula VI
VI, Hal = Br or Cl where G, X1, X2, t are as described in claim 1, in tetrahydrofuran at a temperature between -30° and the boiling point oftetrahydrofuran (66°C).
V
where X3. B, Y, Z1 and Z2 are as described in claim 1 first with sodium hydride and n-butyl lithium, then with the halide of formula VI
VI, Hal = Br or Cl where G, X1, X2, t are as described in claim 1, in tetrahydrofuran at a temperature between -30° and the boiling point oftetrahydrofuran (66°C).
10. A process for preparing compounds of formula (I) according to claim 3 where A is (CH=CH)n-CH=CH-C(O)-CHX3, (CH2)p-CH=CH-C(O)-CHX3, (CH2)t-C(O)-CHX3, S-(CH2)t-(CH=CH)n-C(O)-CHX3 or S-CX4X5-C(O)-CHX3 where n, p, t, X3, X4 and X5 are as described in claim 1 which consists in reacting compound V
V
where X3, B, Y, Z1, Z2 are as described in claim 1, first with sodium hydride then with n-butyl lithium or lithium diisopropylamide at a temperature between -78° and 0°, then with ester VII
VII
where E is (CH=CH)n-CH=CH, (CH2)p-CH=CH, (CH2)t or S(CH2)t-(CH=CH)n, S-CX4X5, n, p, t, X4, X5 are as described in claim 1, in tetrahydrofuran at a temperature between -60° and 25°C°.
V
where X3, B, Y, Z1, Z2 are as described in claim 1, first with sodium hydride then with n-butyl lithium or lithium diisopropylamide at a temperature between -78° and 0°, then with ester VII
VII
where E is (CH=CH)n-CH=CH, (CH2)p-CH=CH, (CH2)t or S(CH2)t-(CH=CH)n, S-CX4X5, n, p, t, X4, X5 are as described in claim 1, in tetrahydrofuran at a temperature between -60° and 25°C°.
11. A process for preparing compounds of formula (I) according to claim 4 which consists in reducing the ketone functional group by a complex hydride, which is sodium borohydride or lithium borohydride in methanol, ethanol or isopropanol ata temperature between -20°C and the boiling point of the solvent.
12. A process for preparing compounds of formula (I) according to claim 5 which consists of esterification of the corresponding acyloxy-phosphonate compound, with an appropriate acid anhydride (X8CO)2O or acid chloride X8-CO'-Cl.
13. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to claim 1 in combination with a pharmaceutically acceptable carrier.
14. A compound of formula (I) as claimed in claim 1 for use in therapy.
15. A compound of formula (I) as claimed in claim 1 for use in the treatment of atherosclerosis.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH00521/93-1 | 1993-02-19 | ||
CH52193 | 1993-02-19 |
Publications (1)
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CA2118409A1 true CA2118409A1 (en) | 1994-09-01 |
Family
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CA002118409A Abandoned CA2118409A1 (en) | 1993-02-19 | 1994-02-21 | Substituted phosphonates, the processes for their preparation and pharmaceutical compositions containing them |
Country Status (8)
Country | Link |
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EP (1) | EP0638084A1 (en) |
JP (1) | JPH07506121A (en) |
CN (1) | CN1106611A (en) |
AU (1) | AU6205294A (en) |
CA (1) | CA2118409A1 (en) |
MX (1) | MX9401295A (en) |
WO (1) | WO1994019358A1 (en) |
ZA (1) | ZA941088B (en) |
Families Citing this family (11)
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DE4433244A1 (en) * | 1994-09-19 | 1996-03-28 | Hoechst Ag | Aminomethylphosphonic and aminomethylphosphinic acid derivatives and their use for the treatment of degenerative joint diseases |
DE19502209A1 (en) * | 1995-01-25 | 1996-08-01 | Hoechst Ag | Phosphonoacetic acid derivatives and their use for the treatment of degenerative joint diseases |
JP3588734B2 (en) * | 1996-07-26 | 2004-11-17 | コニカミノルタホールディングス株式会社 | Electrophotographic photoreceptor |
WO2004026243A2 (en) * | 2002-09-19 | 2004-04-01 | Ilex Oncology Research, Sarl | Therapeutic uses of linear ketophosphonates |
AU2003299029A1 (en) * | 2002-09-19 | 2004-04-08 | Ilex Oncology Research, Sarl | Substituted phosphonate compounds having bone anabolic activity |
FR2876104B1 (en) | 2004-10-04 | 2007-02-23 | Centre Nat Rech Scient | FLUOROPHOSPHONOCINNAMIC COMPOUNDS, SYSTEM AND APLICATIONS |
GB0613518D0 (en) | 2006-07-06 | 2006-08-16 | Phytopharm Plc | Chemical compounds |
BRPI0922089B1 (en) * | 2008-11-13 | 2017-05-16 | Basf Se | use of compounds and cosmetic preparation |
EP2270021A1 (en) * | 2009-06-18 | 2011-01-05 | Centre National de la Recherche Scientifique | Phosphonates synthons for the synthesis of phosphonates derivatives showing better bioavailability |
WO2018227940A1 (en) * | 2017-12-29 | 2018-12-20 | 邦泰生物工程(深圳)有限公司 | Method for preparing ursodeoxycholic acid via chemical-enzymatic process |
CN108794559A (en) * | 2018-07-31 | 2018-11-13 | 重庆波克底科技开发有限责任公司 | A method of using hyodesoxycholic acid as Material synthesis lithocholic acid |
Family Cites Families (7)
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DE2024030A1 (en) * | 1970-05-16 | 1971-12-02 | Deutsche Advance Produktion GmbH, 6141 Lautern | 2,6-dialkyl phenols |
JPS5921889B2 (en) * | 1975-06-02 | 1984-05-23 | 帝人株式会社 | Polyester manufacturing method |
JPS5782828A (en) * | 1980-11-11 | 1982-05-24 | Canon Inc | Heat developing photosensitive material |
DE3362618D1 (en) * | 1982-10-07 | 1986-04-24 | Ciba Geigy Ag | Phenols and their preparation |
CH675422A5 (en) * | 1988-03-31 | 1990-09-28 | Symphar Sa | |
JPH0377894A (en) * | 1989-08-18 | 1991-04-03 | Toray Ind Inc | Methylene diphosphonic acid compound |
US5300687A (en) * | 1991-07-18 | 1994-04-05 | Ortho Pharmaceutical Corporation | Trifluoromethylbenzylphosphonates useful in treating osteoporosis |
-
1994
- 1994-02-17 ZA ZA941088A patent/ZA941088B/en unknown
- 1994-02-18 MX MX9401295A patent/MX9401295A/en unknown
- 1994-02-21 EP EP94909033A patent/EP0638084A1/en not_active Withdrawn
- 1994-02-21 JP JP6518667A patent/JPH07506121A/en active Pending
- 1994-02-21 CA CA002118409A patent/CA2118409A1/en not_active Abandoned
- 1994-02-21 AU AU62052/94A patent/AU6205294A/en not_active Abandoned
- 1994-02-21 WO PCT/EP1994/000520 patent/WO1994019358A1/en not_active Application Discontinuation
- 1994-02-21 CN CN94190122A patent/CN1106611A/en active Pending
Also Published As
Publication number | Publication date |
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ZA941088B (en) | 1995-09-27 |
WO1994019358A1 (en) | 1994-09-01 |
MX9401295A (en) | 1994-08-31 |
EP0638084A1 (en) | 1995-02-15 |
AU6205294A (en) | 1994-09-14 |
CN1106611A (en) | 1995-08-09 |
JPH07506121A (en) | 1995-07-06 |
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