AU6205294A - 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
- AU6205294A AU6205294A AU62052/94A AU6205294A AU6205294A AU 6205294 A AU6205294 A AU 6205294A AU 62052/94 A AU62052/94 A AU 62052/94A AU 6205294 A AU6205294 A AU 6205294A AU 6205294 A AU6205294 A AU 6205294A
- Authority
- AU
- Australia
- 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 description 4
- 238000000034 method Methods 0.000 title description 22
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 title description 9
- 238000002360 preparation method Methods 0.000 title description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 94
- -1 dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-buten-1-yl phosphonate Chemical compound 0.000 claims description 83
- 150000001875 compounds Chemical class 0.000 claims description 71
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 71
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 47
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 29
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims description 19
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 17
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 9
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 9
- 239000012312 sodium hydride Substances 0.000 claims description 9
- 201000001320 Atherosclerosis Diseases 0.000 claims description 8
- 238000011282 treatment Methods 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 238000009835 boiling Methods 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 229910052744 lithium Inorganic materials 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 5
- 239000012279 sodium borohydride Substances 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000005600 alkyl phosphonate group Chemical group 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 3
- 150000001299 aldehydes Chemical class 0.000 claims description 3
- 238000011065 in-situ storage Methods 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
- 239000012448 Lithium borohydride Substances 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
- 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
- 229910052731 fluorine Inorganic materials 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
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 239000012453 solvate Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 6
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 claims 1
- 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
- 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
- 150000002576 ketones Chemical group 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 74
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 34
- 239000000243 solution Substances 0.000 description 33
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 31
- 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 31
- 239000000203 mixture Substances 0.000 description 31
- 238000005481 NMR spectroscopy Methods 0.000 description 25
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 23
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 22
- 229910052799 carbon Inorganic materials 0.000 description 21
- 229910052698 phosphorus Inorganic materials 0.000 description 21
- 229910052739 hydrogen Inorganic materials 0.000 description 20
- 238000004440 column chromatography Methods 0.000 description 17
- 229910052681 coesite Inorganic materials 0.000 description 14
- 229910052906 cristobalite Inorganic materials 0.000 description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 14
- 239000000377 silicon dioxide Substances 0.000 description 14
- 229910052682 stishovite Inorganic materials 0.000 description 14
- 229910052905 tridymite Inorganic materials 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 13
- 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 12
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 12
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 108010007622 LDL Lipoproteins Proteins 0.000 description 10
- 102000007330 LDL Lipoproteins Human genes 0.000 description 10
- 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
- 235000012000 cholesterol Nutrition 0.000 description 10
- 239000012071 phase Substances 0.000 description 10
- 238000010626 work up procedure Methods 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 230000003078 antioxidant effect Effects 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 239000003208 petroleum Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 238000007792 addition Methods 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 239000003963 antioxidant agent Substances 0.000 description 7
- 235000006708 antioxidants Nutrition 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 230000003647 oxidation Effects 0.000 description 7
- 238000007254 oxidation reaction 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
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 230000008602 contraction Effects 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 229960004756 ethanol Drugs 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 229960001866 silicon dioxide Drugs 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- RSAFKRSMGOSHRK-UHFFFAOYSA-N 1-diethoxyphosphorylpropan-2-one Chemical compound CCOP(=O)(CC(C)=O)OCC RSAFKRSMGOSHRK-UHFFFAOYSA-N 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 229940043279 diisopropylamine Drugs 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000012074 organic phase 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
- 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 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
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 239000007995 HEPES buffer Substances 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical class OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 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
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 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 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 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
- 230000000871 hypocholesterolemic effect Effects 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 150000002978 peroxides Chemical class 0.000 description 3
- SONNWYBIRXJNDC-VIFPVBQESA-N phenylephrine Chemical compound CNC[C@H](O)C1=CC=CC(O)=C1 SONNWYBIRXJNDC-VIFPVBQESA-N 0.000 description 3
- 229960001802 phenylephrine Drugs 0.000 description 3
- 239000008363 phosphate buffer Substances 0.000 description 3
- 229960003912 probucol Drugs 0.000 description 3
- 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 3
- 238000000746 purification Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 229940086542 triethylamine Drugs 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
- UOWIYNWMROWVDG-UHFFFAOYSA-N 1-dimethoxyphosphorylpropan-2-one Chemical compound COP(=O)(OC)CC(C)=O UOWIYNWMROWVDG-UHFFFAOYSA-N 0.000 description 2
- KMJCWEYBVMRBAX-UHFFFAOYSA-N 3-diethoxyphosphorylbutan-2-one Chemical compound CCOP(=O)(OCC)C(C)C(C)=O KMJCWEYBVMRBAX-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
- 229910014033 C-OH Inorganic materials 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 229910014570 C—OH Inorganic materials 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- WSMYVTOQOOLQHP-UHFFFAOYSA-N Malondialdehyde Chemical compound O=CCC=O WSMYVTOQOOLQHP-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
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [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
- 230000000903 blocking effect Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 230000003185 calcium uptake Effects 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 230000006378 damage Effects 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
- 238000001035 drying Methods 0.000 description 2
- 125000002587 enol group Chemical group 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 229940118019 malondialdehyde Drugs 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229960002855 simvastatin Drugs 0.000 description 2
- 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 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 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
- 238000003756 stirring Methods 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- XHTYQFMRBQUCPX-UHFFFAOYSA-N 1,1,3,3-tetramethoxypropane Chemical compound COC(OC)CC(OC)OC XHTYQFMRBQUCPX-UHFFFAOYSA-N 0.000 description 1
- XBRCCZCKPZJGEG-UHFFFAOYSA-N 1,3,2lambda5-dioxaphosphinane 2-oxide Chemical compound O=P1OCCCO1 XBRCCZCKPZJGEG-UHFFFAOYSA-N 0.000 description 1
- RXRNCFXUHIMALO-UHFFFAOYSA-N 1-diethoxyphosphoryl-3-phenylpropan-2-one Chemical compound CCOP(=O)(OCC)CC(=O)CC1=CC=CC=C1 RXRNCFXUHIMALO-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
- SKEMFEUSYWGOKR-UHFFFAOYSA-N 2-methyl-1,3,2$l^{5}-dioxaphosphinane 2-oxide Chemical compound CP1(=O)OCCCO1 SKEMFEUSYWGOKR-UHFFFAOYSA-N 0.000 description 1
- CTYWXRDQWMRIIM-UHFFFAOYSA-N 3-(3,5-ditert-butyl-4-hydroxyphenyl)prop-2-enoic acid Chemical compound CC(C)(C)C1=CC(C=CC(O)=O)=CC(C(C)(C)C)=C1O CTYWXRDQWMRIIM-UHFFFAOYSA-N 0.000 description 1
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- BHIXKCBGVBKTER-UHFFFAOYSA-N acetyl pent-4-enoate Chemical compound CC(=O)OC(=O)CCC=C BHIXKCBGVBKTER-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001340 alkali metals Chemical group 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
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- 238000003556 assay Methods 0.000 description 1
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- 239000012298 atmosphere Substances 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
- 230000017531 blood circulation 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
- 201000011510 cancer Diseases 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
- 238000005119 centrifugation Methods 0.000 description 1
- 230000002508 compound effect Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 210000002808 connective tissue Anatomy 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
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 125000005594 diketone group Chemical group 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
- VONWDASPFIQPDY-UHFFFAOYSA-N dimethyl methylphosphonate Chemical compound COP(C)(=O)OC VONWDASPFIQPDY-UHFFFAOYSA-N 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 239000012259 ether extract Substances 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
- 238000001030 gas--liquid chromatography Methods 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 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
- 238000010348 incorporation Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
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- 230000000968 intestinal effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 description 1
- 229910000359 iron(II) sulfate Inorganic materials 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
- 125000000468 ketone group Chemical group 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
- 229960004844 lovastatin Drugs 0.000 description 1
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 1
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 1
- 238000000464 low-speed centrifugation Methods 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L magnesium chloride Substances [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 108010071584 oxidized low density lipoprotein Proteins 0.000 description 1
- CJXMVKYNVIGQBS-UHFFFAOYSA-N p-hydroxycinnamaldehyde Natural products OC1=CC=C(C=CC=O)C=C1 CJXMVKYNVIGQBS-UHFFFAOYSA-N 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
- 238000005192 partition Methods 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000003009 phosphonic acids Chemical class 0.000 description 1
- 150000004714 phosphonium salts Chemical class 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229940096701 plain lipid modifying drug hmg coa reductase inhibitors Drugs 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000002035 prolonged effect Effects 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
- 239000003642 reactive oxygen metabolite Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 239000012419 sodium bis(2-methoxyethoxy)aluminum hydride Substances 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
- 238000000935 solvent evaporation Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- BGASRLNHTSXAIR-UHFFFAOYSA-N trimethyl(trimethylsilyloxyphosphonoyloxy)silane Chemical class C[Si](C)(C)OP(=O)O[Si](C)(C)C BGASRLNHTSXAIR-UHFFFAOYSA-N 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—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
- C07F9/6571—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
- C07F9/657163—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
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4015—Esters of acyclic unsaturated acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4056—Esters of arylalkanephosphonic acids
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4056—Esters of arylalkanephosphonic acids
- C07F9/4059—Compounds containing the structure (RY)2P(=X)-(CH2)n-C(=O)-(CH2)m-Ar, (X, Y = O, S, Se; n>=1, m>=0)
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/44—Amides thereof
- C07F9/4403—Amides thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4411—Amides of acyclic unsaturated acids
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Description
SUBSTITUTED PHOSPHONATES, THE PROCESSES FOR
THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS
CONTAINING THEM This invention relates to novel phosphonates substituted with a dialkyl phenol moiety and the processes for their preparation. It further relates to pharmaceutical compositions containing these compounds and their therapeutic use in diseases in which reactive oxygen radicals have been implicated and more specifically in the treatment of atherosclerosis.
Reactive oxygen species are involved in a number of pathologies, pharmacological and clinical evidence have been firmly established in the following cases (Halliwell, B. et al. "Role of Free Radicals and Catalytic Metal Ions in Human Disease: an Overview", Methods Enzymol.186, 1-85, 1990):
- inflammatory and immunologic injuries (autoimmune diseases, rheumatoid arthritis),
- ischemia/reperfusion injury,
- radiation injury,
- premature ageing,
- Parkinson's and Alzheimer's diseases,
- cancer and anti-cancer treatments,
- conditions associated with impaired blood circulation such as intermittent claudication, excessive platelet aggregation, myocardial infarction and
atherosclerosis.
In these pathological situations antioxidant products would be useful as therapeutic agents. The tests performed by the inventors show that the phosphonates of formula (I) through their dialkyl phenol and phosphonate moieties display potent antioxidant activities and therefore offer this therapeutic potential.
In the particular case of atherosclerosis, it is now clearly proven that cholesterol carried in LDL is the most atherogenic form of plasma cholesterol. On the other hand current research shows that the uptake of oxidized LDL by macrophages leads to the formation of lipid-laden foam cells, which is the first step in the development of atherosclerosis. Numerous epidemiological studies have now firmly established that high blood cholesterol is a major risk factor for coronary heart disease. Based on the above, it can be postulated that the combination of a cholesterol lowering
regimen with an antioxidant treatment might be more effective than either one. A drug which possesses the dual hypocholesterolemic and antioxidant property could therefore be highly effective in the treatment of atherosclerosis. The phosphonate compounds (I) of this invention inhibit markedly the synthesis of cholesterol in human cell lines similarly to the HMGCoA reductase enzyme inhibitors (lovastatin, simvastatin) which are potent hypocholesterolemic drugs in man. The combination of their antioxidant and hypocholesterolemic activities confer to the phosphonates of this invention the potential for treating diseases associated with elevated cholesterol levels and pathological lipid oxidation. Furthermore, the lipophilicity of these 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 formula (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 more halogen atoms (F, Cl or Br), C1-6 alkyl, phenyl, hydroxy or
acyl oxy groups, and salts, solvates and hydrates thereof.
Preferably, X1 and X2 are identical and are butyl groups, in particular t-butyl groups.
Preferably, Y is oxygen.
Preferably Z1 and Z2 are identical, in particular OR in which R is H, or a straight or branched C1-6alkyl group. More preferably, Z1 and Z2 are identical OR groups in which R is C1-6alkyl, in particular methyl, ethyl or i-propyl.
Preferably, G is OH. Suitable bioprecursors of the group OH as defined for G include, for example, OR3 groups where R3 is a straight or branched C1-C6 alkyl group, a perfluorinated C1-C6alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzyl group, suitable bioprecursors can also be a R3-C(O)O- group, a R3O-C(O)O- group, a R3NH-C(O)O- group, a R3C(O)OCH2O- group, a R3-SO2O- group where R3 is defined as above.
Preferably, 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=CH-C(O)-CHX3,
(CH2)t-C(O)-CHX3, S-(CH2)r(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-C4 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.
Preferably, D can also be 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, 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 above, and X8 is a saturated or unsaturated C1-C6alkyl or alkenyl chain.
Suitable salts included within the scope of formula (I) include, for example, corresponding salts of the group OR (in Z1 / Z2), for example salts formed with alkali metal atoms such as sodium or potassium.
PROCESSES FOR PREPARING COMPOUNDS OF FORMULA (I)
The present invention also relates to the processes used for preparing substituted phosphonates (I).
D is A-C(O)-B
--------------------------- A is (CH2)t, (CH=CH)n-CH=CX3, (CH2)t-CHX3, S(CH2)t-(CH=CH)n or
S-CX4X5
-----------------------------------------------------------------------------------------------------
B is CH2, CH-X6 or C-X6X7
-------------------------------------------- The procedure described in Fig. 1 p. 10 consists in reacting the commercially available alkylphosphonate III with a suitable base such as n-butyllithium or lithium diisopropylamide. The lithium anion of compound HI thus formed is then reacted in situ 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 (THF), preferably in THF, at a temperature between -78°C and room temperature (25°C).
A second procedure described 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 condensation agents. The reaction is carried out in an ether solvent such as tetrahydrofuran, dioxane or dimethoxyethane, preferably THF, at a temperature between -30°C and the boiling point of the solvent (66°C in the case of THF). A compound of formula (I) where A is
(CH=CH)n-CH=CX3 is obtained. Compounds of formula (I) where A is
(CH2)t-CHX3 can be prepared by reacting the starting compound ketophosphonate V with an excess of a base or combination of bases. The bases are sodium hydride, sodium alkoxides, n-butyl lithium or lithium diisopropylamide. The anion of ketophosphonate V thus formed is then reacted with the halide VI, where Hal = Br or Cl. The reaction is carried out in tetrahydrofuran, dimethoxyethane, dioxane, benzene or toluene. The temperature of the reaction varies between 0°C and the boiling point of the solvent.
Examples 1, 2, 3 and 4 further illustrate the experimental aspects of the process described in Fig 2.
Concerning condensation reactions, in the case where B is a CH2 group, i.e. when the carbon alpha to the phosphonate functional group has two protons, in addition to the main reaction product formed by monocondensation at the gamma position, a side product is also formed by double condensation with the dialkyl phenol groups at the alpha and gamma positions (see ex 1 and 2). In the case where B = CHX6 or X6- C-X7, e.g. when two protons are not available at the alpha position, the compound formed by monocondensation at the gamma position is the sole reaction product (see ex 4 and 10).
Likewise, when the alpha position is completely unsubstituted (B=CH2), in addition to the main reaction compound formed by monoaddition, these is also formed a side product occurring by double additions at the alpha and gamma positions (see ex 3). A is (CH=CH)n-CH=CH-C(O)-CHX3, (CH2)p-CH=CH-C(O)-CHX3,
(CH2)t-C(O)-CHX3, S(CH2)r(CH=CH)n-C(O)-CHX3 or
S-CX4X5-C(O)-CHX3 ----------------------------------------------------------------------------------------------- B is CH2, CH-X6 or C-X6X7
--------------------------------------------
The process described in Fig. 3 p. 12 consists in condensing an ester of formula VII with the dianion of ketophosphonate V at the gamma position. The dianion is generated by stepwise reaction of V with an equivalent of sodium hydride and an excess of a stronger base, e.g. n-butyl lithium or lithium diisopropylamide (LDA) in tetrahydrofuran at a temperature between -30° and 30°C. The excess of dianion is then reacted with the ester VII at a temperature between -70° and 30°C to yield the ketophosphonate (I) according to Fig. 3.
Compounds (I) which possess two ketone groups in their structures may in solution be in tautomeric equilibrium with enol forms. The diketone and enol forms of compounds (I) are integral part of this invention. A is (CH2)t, (CH=CH)n-CH=CX3, (CH2)t-CHX3 or S(CH2)t-(CH=CH)n or S-CX4X5
--------------------------------------------------------------------------------------------------
B is CH=CH-CX6X7 or CH=CH-(CH2)p
--------------------------------------------
The procedure for preparing compounds of formula (I) where D is A-C(O)-B, where A is (CH2)t, (CH=CH)n-CH=CX3, (CH2)t-CHX3,
S(CH2)t-(CH=CH)n or S-CX4X5, B is CH=CH-CX6X7 or CH=CH-(CH2)p consists in reacting an aldehyde of formula VIlla or VIIIb
with a phosphorus reagent which may be a phosphonate compound of formula IX or a phosphonium salt of formula X:
CH2 - PO3 (Alkyl) 2
— CH2 -P (C6 H5 ) 3 Br
The reaction is carried out in an ether solvent, such as dimethoxyethane or tetrahydrofuran in presence of a base such as sodium hydride or lithium
diisopropylamine.
D is A-CH(OH)-B
------------------------
The ketophosphonates of formula (I) previously described can be reduced to the corresponding hydroxyphosphonate derivatives. The reduction can be carried out with complex hydride reagents such as sodium borohydride, lithium borohydride, sodium bis (2-methoxyethoxy) aluminum hydride, sodium trimethoxyborohydride, sodium cyanoborohydride.
Suitable solvents include ether, tetrahydrofuran, toluene, methanol, ethanol, isopropanol. Prefered reduction conditions are sodium borohydride in methanol at a temperature between -20°C and 65°C.
D is A'-CH(O-CO-X8)-B'
-------------------------------------
The above-mentioned hydroxyphosphonates can be esterified to the corresponding acyloxy-phosphonate derivatives by employing known procedures. Suitable reaction conditions involve heating the hydroxyphosphonates with an appropriate acid anhydride (X8-CO)2O or an appropriate acid chloride X8-CO-Cl in presence of a tertiary amine, eg. triethyl amine or pyridine. The reaction temperature can range between 0°C to the boiling point of the acylating agent.
D is A-CH2-B, (CH2)t-(CH=CH)n-(CH2)t, S-(CH2)t
-----------------------------------------------------------------------------------
The ketophosphonates (I) can be reduced to the corresponding alkylphosphonates and alkenylphosphonates by reduction of the p-toluenesulfonylhydrazone derivatives with sodium borohydride, sodium cyanoborohydride or catechol borane.
Phosphonic acids of structure (I) where Z1=Z2 =OH can be prepared from the corresponding phosphonate esters by reaction with bromotrimethyl silane to produce bis (trimethylsilyl) phosphonates which are reacted in situ with water or methanol.
The starting compounds alkylphosphonates III are commercially available. The starting compounds ketophosphonates V are prepared according to known literature methods: E. J. Corey and G. T. Kwiatkowski, J. Am. Chem. Soc.90, p. 6816-6821 (1968) and F. Mathey and P. Savignac, Tetrahedron 34, P- 649-654 (1978).
X3 - CH2 - C - L + M
L = Cl or OEt M = Li or Cu The structures of new compounds of formula (I) are determined by infrared (IR), mass (MS) and nuclear magnetic resonance (NMR) spectroscopies. The purity of the compounds is verified by elemental analysis and standard chromatographic methods: thin layer chromatography, gas liquid chromatography or high performance liquid chromatography.
The abbreviations used in this patent application are as follows:
In the tables n- is normal, i- is iso-, sec is secondary-, t is tertiary. In the NMR spectra, s is singlet, d is doublet, t is triplet, m is multiplet. The temperatures are measured in degree Celsius and the melting points are uncorrected.
The present invention will be further described by the examples 1 to 22 which are typical of the synthetic procedures used.
FIG 1: SYNTHETIC FRQCESS
A = (CH2)t, (CH=CH)n-CH=C-X3,(CH2)t-CHX3, S-(CH2)t- (CH=CH) n or S-CX4X5
B = CH2, CH-X6 or C-X6X7
FIG 3: SYNTHETIC PROCESS
where E is (CH=CH) n-CH=CH , (CH2)p-CH=CH , (CH2)t , S (CH2) t- (CH=CH) n or S-CX4X5
Example 1
Dimethyl 1.5-bis(3,5-di-tert-butyl-4-hydroxyphenyl)3-oxo-1,4-pentadien-2-yl phosphonate
and
Dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-buten-1-yl phosphonate
Titanium tetrachloride (114.5g, 0.6 mol) was added dropwise with stirring to 300 ml of dry tetrahydrofuran (THF) kept under nitrogen at -20°C. Solid 3,5-di-tert-butyl-4- hydroxy benzaldehyde (58.7g, 0.25 mol) was added, followed by 200 ml THF then dimethyl 2-oxopropylphosphonate (50 g, 0.3 mol) was added. Finally N-methyl morpholine (121.7g, 1.2 mol) was introduced slowly and the reaction mixture was stirred at room temperature for 1 h. Cold water (200 ml) was introduced and the mixture was extracted with 1000 ml diethyl ether. The ether fraction was washed with water until neutral pH, dried over magnesium sulfate and evaporated in vacuo. Purification was carried out by chromatography on silica gel using a 98/2
chloroform/methanol mixture.
The first compound (5.5 g, 4%) to elute from the column was identified as dimethyl 1,5-bis(3,5-di-tert-butyl-4-hydroxyphenyl)-3-oxo-1,4-pentadien-2-yl phosphonate.
C35H51O6P Theor. %C 70.21 %H 8.59 %P 5.17
Found %C 69.96 %H 8.55 %P 5.31 mp = 190-191°C.
IR (KBr): 3620 cm-1: OH, 1610: C=O, 1580: C=C, 1430 and 1420: t-Bu, 1240:
P=O, 1020: P-O-C
MS: m/e = 599: M++1, 598: M+, 488: M+-H-PO3Me2, 367 (100%)
NMR (CDCI3)
δ = 7.75 (d, J = 26 Hz, 1H): Ph-CH=C-P
7.57 (d, J = 16 Hz, 1H): Ph-CH=CH-
7.3 and 7.23 (2 s, 2H each): arom. H
6.60 (d, J= 16Hz, 1H): Ph-CH=CH
5.55 and 5.51 (2s, 1H each): OH
3.82 (d, J = 11Hz, 6H): P-O-CH3
1.40 and 1.34 (2 s, 18H each): t-C4H9 The second compound (36 g, 38 % yield) was identified by IR, MS and NMR as dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-buten- 1-yl phosphonate
CH=CH - CH2 -PO3Me2
mp = 107-109° (ligroin, 80-95 fraction)
IR (KBr): 3420 cm-1: OH, 1650: C=O, 1590: C=C, 1420: t-Bu, 1260: P=O and 1030: P-O-C MS (m/e): 382 M+, 367: M+-Me, 272: M+-HPO3Me2, 259:M+-CH2PO3Me2, 151: M+-CO-CH2-PO3Me2
NMR (CDCI3)
δ = 7.61 (d, J = 16Hz, 1H): Ph-CH=CH
7.42 (s, 2H): arom. H
6.73 (d, J = 16 Hz, 1H): Ph-CH=CH
5.62 (s, 1H): OH
3.81 (d, J = 11Hz, 6H): P-O-CH3
3.35 (d, J = 22Hz, 2H) CH2-P
1.40 (s, 18H): t-C4H9
C20H31O5P Theor. % C 62.81 % H 8.17 % P 8.10
Found. % C 62.63 % H 7.97 % P 8.24
Example 2
Diethyl 1 ,5-bis(3,5-di-tert-hutyl-4-hydroxyphenyl)-3-oxo-1,4-pentadien-2-yl phosphonate
and
Diethyl 4-( 3,5-di-tert-butyl-4-hydroxyphenyn-2-oxo-3-buten-1-yl phosphonate
Titanium tetrachloride (137.1 g, 0.72 mol) was added dropwise to 300 ml dry THF at -15°C. 3,5-Di-tert-butyl-4-hydroxybenzaldehyde (70.4 g, 0.30 mol) was added followed by diethyl 2-oxopropylphosphonate (70 g, 0.36 mol). N-methyl morpholine (145.8 g, 1.44 mol) was introduced and the reaction mixture was stirred at room temperature for 2 h. Work up was carried out by addition of 200 ml water and 800 ml diethyl ether. The ether phase was washed with water to neutral pH, dried over MgSO4 and evaporated. The residue was chromatographed on silicagel using 98/2 CHCl3/MeOH as eluent.
The first product (15 g, 8% yield) to elute was identified as diethyl 1,5-bis(3,5-di- tert-butyl-4-hydroxyphenyl)-3-oxo-1,4-pentadien-2-yl phosphonate.
C37H55O6P Theor. % C 70.90 % H 8.84 % P 4.94
Found % C 71.18 % H 8.67 % P 4.75 mp = 174-175°C
IR: (KBr): 3620 cm-1: OH, 1640: C=O, 1585: C=C, 1430 and 1415: t-Bu,
1230: P=O and 1030: P-O-C MS: m/e = 626: M+, 488: M+-HPO3Et2, 395 (100%)
NMR (CDCI3)
δ = 7.7 (d, J = 26 Hz, 2H): Ph-CH=C-P
7.59 (d, J = 16Hz, 2H): Ph-CH=CH
7.30 and 7.25 (2s, 2H each): arom. H
6.63 (d, J = 16 Hz, 2H): Ph-CH=CH
5.54 and 5.48 (2s, 1H each): OH
4.18 (quint, J = 7Hz, 4H): P-O-CH2-CH3
1.40 and 1.34 (2s, 18H each): t-C4H9
1.34 (t, J= 7 Hz, 6H): P-O-CH2-CH3
The second product was identified as diethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)- 2-oxo-3-buten-1-yl phosphonate (44 g, 36% yield)
mp = 110-111°C (recrystallized from ligroin 80-95 fraction).
IR (KBr): 3620 cm-1: OH, 1680:C=O, 1590: C=C, 1430 and 1415: tBu, 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+
NMR (CDCI3)
δ = 7.61 (d, J = 16 Hz, 1H): Ph-CH=CH
7.40 (s, 2H): arom. H
6.74 (d, J = 16Hz, 1H): Ph-CH=CH
5.6 (s, 1H): OH
4.16 (m, 4H): P-O-CH2-CH3
3.33 (d, J = 23 Hz, 2H): CH2-P
1.45 (s, 18H): t-C4H9
1.34 (t, J = 7Hz, 6H): P-O-CH2-CH3
C22H35O5P Theor % C 64.37 % H 8.59 % P 7.55
Found % C 64.52 % H 8.65 % P 7.36 Example 3
Diethyl 1 ,5-bis(3,5-di-tert-butyl-4-hydroxyphenyl)-3-oxo-2-pentyl phosphonate
and
Diethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-1-butyl phosphonate
Sodium hydride (1.45 g of a 60% dispersion in mineral oil, 36.25 mmol) was suspended under nitrogen in hexane, this latter was pipetted out and replaced by 60 ml dry THF. Diethyl 2-oxopropylphosphonate (7.0 g, 36 mmol) was introduced. The mixture was stirred at room temperature for 30 min then was cooled to 0° C then n- butyl lithium (37.5 ml of a 1.6 M solution, 60 mmol) was added. Finally a solution of 3,5-di-tert-butyl-4-hydroxybenzyl bromide (9.0 g, 30.1 mmol) in 40 ml THF was added and the reaction mixture was stiιτed at room temperature overnight. Work-up was carried out by partition between 150 ml 15% HCl and two fractions of 150 ml ether. The ether phase was washed with sodium bicarbonate and saturated sodium chloride to neutral pH. After drying and solvent evaporation, the crude mixture was purified by column chromatography (SiO2, 8/2 CHCl3/AcOEt).
The first compound (1.5 g, 8% yield) to elute was diethyl 1,5-bis(3,5-di-tert-butyl-4- hydroxy-phenyl)-3-oxo-2-pentyl phosphonate, mp = 60-61°C.
IR (KBr): 3620 cm-1: OH, 1710: C=O, 1430: t-Bu, 1230: P=O and 1010:
P-O-C
MS:m/e= 630: M+, 493: M+-HPO3Et2
NMR (CDCI3)
δ = 6.89 (2s, 2H each): arom. H
5.09 and 5.03 (2s): OH
4.1 (m, 4H): P-O-CH2-CH3
3.5 and 3.25 (2m, 2H): Ph-CH2-CH-P
3.04 (txd, 1H): Ph-CH2-CH(P)-CO
2.9 - 2.4 (2m, 4H): Ph-CH2-CH2-CO- 1.14 and 1.39 (2s, 18H each): t-C4H9
1.32 (2t, J=7Hz, 6H): P-O-CH2-CH3
The second compound was diethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-1- butyl phosphonate: 2.2 g (18% yield) of an oil was obtained which slowly solidified upon standing.
IR (film): 3620 cm-1: OH, 1710: C=O, 1430: t-Bu, 1250: P=O, 1010: P-O-C MS m/e= 412: M+, 274: M-HPO3Et2
NMR : (CDCI3)
δ = 6.98 (s, 2H): arom. H
5.1 (s, 1H): OH
4.14 (m, 4H): P-O-CH2CH3
3.05 (d, J=25Hz, 2H): CH2-P
2.94 (m, 2H): Ph-CH2-CH2
2.83 (m, 2H): Ph-CH2-CH2
1.42 (s, 18H): t-C4H9
1.32 (t, J=7Hz, 6H): P-O-CH2-CH3
Example 4
Diethyl 4-(3,5-di-tert-butyl-4-hydroxyρhenyl)-1,1-dimethyl-2-oxo-3-buten-1-yl- phosphonate
Diethyl 1,1-dimethyl-2-oxo-propylphosphonate (bp = 60º/0 .2 mbar) was synthesized according to V. Roussis and D.F. Wiemer, J. Org. Chem.54, p. 627-631 (1989). To 20 ml dry THF kept at 0°C were added sequentially ΗCI4 (1.72 g, 9 mmol), 3,5- di-tert-butyl-4-hydroxybenzaldehyde (0.9 g, 3.8 mmol), diethyl 1,1-dimethyl-2- oxopropylphosphonate (1.0 g, 4.5 mmol), N-methyl morpholine (1.82 g, 18 mmol) then the reaction mixture was stirred for 1 h at room temperature. Work up carried out in the usual manner gave an oil which was purified by column chromatography (SiO2, 8/2 CHCI3/ACOEt). An amount of 1.1 g (68% yield) of the title compound was obtained. Mp = 91-92°C (petroleum ether 40-60).
IR: (KBr): 3440 cm-1: OH, 1670: C=O, 1590: C=C, 1430 and 1410: t-Bu, 1210: P=O and 1030: P-O-C
MS: m/e= 439: M+ + 1, 259: M+-C(CH3)2-PO3Et2, 57 (100%): tBu
NMR: (CDCI3)
δ = 7.66 (d, J = 16Hz, 1H): Ph-CH=CH
7.43 (s, 2H): arom. H
7.26 (d, J = 16Hz, 1H): Ph-CH=CH
5.55 (s, 1H): OH
4.15 (m, 4H): P-O-CH2-CH3
1.50 (d, J = 17Hz, 6H): -C(CH3)2-P
1.46 (s, 18H): t-C4H9
1.32 (t, J = 7Hz, 6H): P-O-CH2-CH3
C24H39O5P Calc. % C 65.73 % H 8.96 % P 7.06
Found % C 66.00 % H 8.98 % P 6.82
Example 5 Diethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-methyl-2-oxo-3-buten-1-yl phosphonate
Diethyl 2-oxobutylphosphonate (bp = 90º/0.6 mbar) was prepared according to F. Mathey and P. Savignac, Tetrahedron 34, P- 649-654 (1978).
To 20 ml dry THF kept at 0°C were added successively TiCI4 (1.82 g, 9.6 mmol), 3,5-di-tert-butyl-4-hydroxybenzaldehyde (0.94 g, 4 mmol), diethyl 2- oxobutylphosphonate (1 g, 4.8 mmol) and N-methyl morpholine (1.86 g, 18.4 mmol). The reaction mixture was stirred at room temperature for 30 min then was heated to reflux for 1 h. After the usual work-up and extraction the crude reaction mixture was purified by column chromatography (SiO2, 8/2 CHCl3/AcOEt). A small amount of unreacted benzaldehyde was first collected then 0.35 g (21%) of the title compound was obtained. Mp = 97-101°C (petroleum ether 40-60).
IR (KBr): 3400 cm-1: OH, 1680: C=O, 1610 and 1590: C=C, 1440: t-Bu, 1250: P=O and 1020: PO-C
MS: m/e = 424: M+, 409: M+-CH3, 367: M+-tBu, 286: M+-HPO3Et2, 57 (100%): tBu+
NMR (CDCI3):
δ = 7.56 (s, 1H): Ph-CH=C
7.33 (s, 2H): arom. H
5.5 (s, 1H): OH
4.16 (m, 4H): P-O-CH2-CH3
3.51 (d, J=22Hz, 2H): CH2-P
2.1 (s, 3H): CH3
1.46 (s, 18H): t-C4H9
1.32 (t, J= 7Hz, 6H): P-O-CH2-CH3
C23H37O5P Calc. % C 65.07 % H 8.79 % P 7.30
Found % C 65.35 % H 8.58 % P 7.51
Example 6
Dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-(n-butyl)-2-oxo-3-buten-1-yl phosphonate
A mixture of 3,5-di-tert-butyl-4-hydroxybenzaldehyde (3.65 g, 15 mmol), dimethyl 2-oxoheptylphosphonate (4.0 g, 18 mmol), TiCI4 (6.84 g, 36 mmol) and N-methyl morpholine (7.27 g, 72 mmol) in 80 ml dry THF was refluxed as described in example 7. Purification by column chromatography (SiO2, 8/2 CHCl3/AcOEt) gave 1.2 g (20% yield) of the title compound. Mp = 82-85° (petroleum ether 40-60)
MS: m/e 439 M++ 1, 438 M+, 381 M+-C4H9, 57 (100%): tBu
NMR (CDCI3)
δ = 7.48 (s, 1H): Ph-CH=C(C4H9)
7.32 (s, 2H): arom. H
5.5 (s, 1H): OH
3.81 (d, J = 11Hz, 6H): P-O-CH3
3.52 (d, J = 22Hz, 2H): CH2-P
2.57 (m, 2H): CH2-C3H7
1.5-1.4 (m, 4H) CH2-(CH2)2-CH3
1.5 (s, 18H): t-C4H9
0.94 (t, J = 7Hz, 3H): (CH2)3-CH3
Example 7
Diethyl 4-(3,5-di-tert-hutyl-4-hydroxyphenyl)-2-oxo-3-phenyl-3-buten-1-yl phosphonate
The procedure described in example 5 was employed, using as the phosphonate reagent diethyl 2-oxo-3-phenylpropylphosphonate (bp= 15070.5 mbar). The title compound was isolated by column chromatography under the usual conditions (SiO2, 8/2 CHCl3/AcOEt) at ca 18% yield. mp=139-143°C IR (KBr): 3500: OH, 1640: C=O, 1610 and 1590: C=C, 1430: t-Bu, 1230: P=O, 1020: P-O-C.
MS: m/e=486 (100%) M+, 348: M+-HPO3Et2, 335: M+-CH2PO3Et2 NMR: (CDCI3)
δ = 7.70 (s, 1H): Ph-CH=C
7.45 - 7.25 (m, 5H): C6H5
6.97 (s, 2H): arom. H
5.46 (s, 1H): OH
4.15 (m, 4H): P-O-CH2-CH3
3.33 (d, J=22Hz, 2H): CH2-P
1.32 (t, J=7Hz, 6H): P-O-CH2-CH3
1.23 (s, 18H): C4H9 C28H39O5P Calc. % C 69.11 % H 8.08 % P 6.37
Found % C 69.37 % H 8.11 % P 6.61
Example 8 Diethyl 4-( 3,5-di-tert-butyl-4-hydroxyphenyl)-1-methyl-2-oxo-3-huten-1-yl phosphonate
Diethyl 1-methyl-2-oxopropylphosphonate was prepared according to Mathey and Savignac as cited as example 5.
A mixture of 3,5-di-tert-butyl-4-hydroxybenzaldehyde (7J9 g, 29 mmol), diethyl 1- methyl-2-oxopropylphosphonate (8.20 g, 35 mmol), TiCI4 (13.47 g, 71 mmol), N- methyl morpholine (14.34 g, 140 mmol) in 150 ml dry THF was reacted at room temperature for 1 h, then at reflux temperature for 18 h. After work up, column chromatography (SiO2, 8/2 CHCl3/AcOEt) gave 4.7 g (38%) of the title compound. mp=92-94°C
NMR (CDCI3)
δ = 7.63 (d, J = 16Hz, 1H): Ph-CH=CH
7.42 (s, 2H): arom. H
6.87 (d, J = 16Hz, 1H): Ph-CH=CH
5.6 (s, 1H): OH
4J5 (m, 4H): P-O-CH2-CH3
3.53 and 3.46 (two q, J = 24Hz and 7Hz, 1H): CH-P
1.50-1.43 (two d, J = 7Hz): CH-(P)-CH3
1.46 (s, 18H): C4H9
1.32 (two t, J = 7Hz): P-O-CH2CH3
Example 9 Dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-buten-1-yl phosphonate
Under nitrogen atmosphere dimethyl 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 15 ml anhydrous THF. The reaction mixture was stirred at -50° for 30 min to allow for complete formation of the lithium anion (slight turbidity). The mixture was again cooled to -60° and a solution of ethyl 3,5-di-tert-butyl-4-hydroxycinnamate (2.6 g, 8.5 mmol) in 20 ml dry THF was added. The resulting orange-colored mixture was left to stir at room temperature (25°C) for 18 h. Hydrolysis was carried out by adding 10 ml of a 10% HCl solution and die product was extracted into ether. After drying over MgSO4, ether was evaporated to yield a yellow solid. Recrystallization in 40 - 60 petroleum ether gave 3.0 g (92% yield) of dimethyl 4-(3,5-di-tert-butyl-4- hydroxyphenyl)-2-oxo-3-buten-1-yl phosphonate. mp=107-109°C
The title compound can also be obtained by using as the bases a mixture of n-BuLi and LDA (lithium diisopropylamide). To a solution of n-butyllithium (16ml of a 1.6 M solution, 25.6 mmol) in 20 ml dry THF was added at -60°C diisopropyl amine (0.86 g, 8.5 mmol). The resulting mixture was stirred at -40° for 15min, then dimethyl memylphosphonate (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 die reaction mixture was stirred at room temperature (25°C) for 15 h. Work up by addition of 10% HCl and extraction into ether gave 3J0 g (95%) of dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo- 3-buten-1-yl phosphonate.
mp=107-109°C The compound prepared by either of these two variant processes has spectroscopic data identical to those of the same product described in example 1.
C20H31O5P Theor. %C 62.81 %H 8.17 %P 8.10
Found %C 62.56 %H 8.21 %P 8.24
Example 10
Diethyl 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,1-dimethyl-2-oxo-3,5-hexadien-1-yl phosphonate
To 15 ml dry THF kept at 0° were added ΗCI4 (1.23 g, 6.47 mmol), 3,5-di-tert-butyl- 4-hydroxy cinnamaldehyde (0.7 g, 2.67 mmol), diethyl 1,1-dimethyl-2- oxopropylphosphonate (0.72 g, 3.24 mmol) and N-methylmorpholine (1.31 g, 12.97 mmol). The reaction mixture was stirred for 1 h at 20°C then 1 h at 30°C. Work-up gave a dark oil which was purified by column chromatography (SiO2, 8/2
CHCl3/AcOEt). 650 mg (52%) of yellow crystals were obtained, mp = 130-133°C.
NMR (CDCI3)
δ = 7.40 (d x d, J = 11 and 15Hz, 1H): Ph-CH=CH-CH=CH
7.2 (s, 2H): arom. H
6.87 and 6.85 (2 d, J = 15Hz, 2H): Ph-CH=CH-CH=CH
6.75 (d x d, J = 11.5 and 16Hz, 1H): Ph-CH=CH-CH=CH
5.4 (s, 1H): OH
4.1 (m, 4H): P-O-CH2-CH3
1.40 (d, J = 16Hz, 6 H): C(CH3)2
1.39 (s, 18H): t-C4H9
1.24 (t, J = 7Hz, 6 H): P-O-CH2-CH3 MS: m/e=464: M+, 326: M+- HPO3Et2, 285 (100%): M+- CMe2-PO3Et2
C26H41O5P Calc. % C 67.22 % H 8.90 % P 6.67
Found % C 66.68 % H 8.56 % P 6.21
Example 11
Dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-1-butyl phosphonate
A solution of dimethyl lithi omethylphosphonate was prepared under nitrogen by adding dimethyl memylphosphonate (3.2 g, 25.6 mmol) to a solution of n- butyllithium (16 ml of a 1.6 M solution in hexane, 25.6 mmol) in 15 ml dry THF at - 60°C. To this solution was added at -60° a solution of eth yl 3,5-di-tert-butyl-4- hydroxyhydrocinnamate (2.6 g, 8.5 mmol) in 20ml THF. The resulting solution was stirred at -60° for 30 min and then was allowed to reach room temperature (25°C) overnight. 25 ml 10% HCl was added and the mixture was extracted into ether. The residue of the ether phase was purified by column chromatography (SiO2, 8/2
CHCl3/AcOEt) to yield a white solid. Recrystallization in petroleum ether gave 2.1 g (64% yield) of the title compound. mp=78-79°C
MS: m/e=384: M+, 284: M+-HPO3Me2, 57 (100%): tBu+
NMR (CDCI3)
δ = 6.98 (s, 2H): arom. H
5.06 (s, 1H): OH
3.75 (d, J = 11.5Hz, 6H): P-O-CH3
3.08 (d, J = 22.5Hz, 2H): CH2-P
2.90 (m, 2H): Ph-CH2-CH2
2.81 (m, 2H): Ph-CH2-CH2
1.41 (s, 18H): t-C4H9
Example 12 Diethyl 6-( 3,5-di-tert-hutyl-4-hydroxyphenyl-2,4-dioxo-5-hexen-1-yl phosphonate
Diethyl 2-oxopropylphosphonate (3.4 g, 17 mmol) was added at room temperature under nitrogen to a suspension of sodium hydride (0.82 g of a 60% dispension, 20 mmol) in 35 ml dry THF. The mixture was stirred at room temperature for 60 min, then diisopropylamine (1.71 g, 17 mmol) was added at 0°, followed by n- butyllithium (21 ml of a 1.6 M solution, 34 mmol). After 30 min at 0°, the mixture was cooled to -60° and a solution of etiiyl 3,5-di-tert-butyl-4-hydroxycinnamate (2.6 g, 8.5 mmol) in 25 ml THF was induced dropwise. The resulting mixture was stirred at 0° for 2 h, at 25°C for 1 h, hydrolyzed with 60 ml H2O whereupon it separated into two phases. The aqueous phase was acidified with 10% HCl and was extracted with two 100 ml portions of ether. The ether extracts were pooled with the THF phase, dried and evaporated. The residue was purified by column chromatography (SiO2, 8/2 CHCl3/AcOEt) to yield a viscous orange oil. Recrystallization in ligroin gave 2.25 g (60% yield) of the title compound, mp=109- 110°C
NMR (CDCI3)
δ = 7.60 (d, J=16Hz, 1H): Ph-CH=CH
7.37 (s, 2H): arom. H
6.35 (d, J= 16Hz, 1H): Ph-CH=CH
5.83 (s, 1H): CO-CH=C-OH
5.54 (s, 1H): phenol OH
4.17 (m, 4H): P-O-CH2-CH3
3.02 (d, J = 22Hz, 2H): CH2-P
1.46 (s, 18H): t-C4H9
1.34 (t, J = 7Hz, 3H): P-O-CH2-CH3
MS: m/e 452 M+, 314 M+ - HPO3Et2, 57 (100%) tBu
Example 13
Diethyl 6-(3,5-di-tert-butyI-4-hydroxyphenyl)-2,4-dioxo-1-hexyl phosphonate
Diethyl 2-oxopropylphosphonate (2.02 g, 10 mmol) was added at room temperature to sodium hydride (0.48 g of a 60% dispersion, 12 mmol) suspended in 30 ml THF. After 30 min the mixture was cooled to 0° and diisopropylamine (1.01 g, 10 mmol) and n-butyllithium (13 ml of a 1.6 M solution, 21 mmol) were added. After 30 min, the mixture was cooled to -60° and eth yl 3,5-di-tert-butyl-4-hydroxy hydrocinnamate (1.6 g, 5.2 mmol) dissolved in 15 ml THF was added. The mixture was left to react at -60° for 15 min then at 0° for 2 h and 25°C for 1 h and was hydrolyzed with 10% HCl and extracted widi ether. Column chromatography (SiO2, 8/2 CHCl3/AcOEt) gave 1.0 g (42%) of the title compound as a colorless oil.
NMR (CDCI3)
δ = 6.98 (m, 2H): arom. H
5.70 (s, 1H): CO-CH=C-OH
5.09 (s, 1H): phenol OH
4J5 (m, 4H): P-O-CH2-CH3
2.92 (d, J = 22.5Hz, 2H): CH2-P
2.85 (m, 2H): Ph-CH2-CH2
2.59 (m, 2H): Ph-CH2-CH2
1.43 (s, 18H): t-C4H9
1.33 (t, J = 7Hz, 6H): P-O-CH2-CH3
MS: 455 M+ +1, 454 M+, 436 M+ -H2O, 57 (100%) tBu
Example 14
Dimethyl 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,4-dioxo-5-hexen-1-yl
phosphonate
The procedure described in example 12 was followed using dimethyl 2-oxo- propylphosphonate to give the tide compound at 79% yield, yellow solid with mp = 145-146°C.
Example 15
2-[4-(3,5-di-tert-hutyl-4-hydroxyphenyl)-2-oxo-3-buten-1-yl]
(2-oxo-1,3,2-dioxaphosphorinan)
Under nitrogen atmosphere, 2-methyl-2-oxo-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 THF at -60°C. The mixture was stirred at -60°C for 30 min then a solution of ethyl 3,5-di-tert-butyl-4-hydroxycinnamate (2g, 6.4 mmol) in 20ml THF was added. The resulting mixture was stirred at -60°C for 30 min and left to attain room temperature (25°C) over 16 h. After the usual work up, column chromatography (silicagel, 98/2 CΑCl3/M eOH) gave 0.76g of the title compound (30%).
mp = 158-161°C
MS: m/e = 394 M+, 57 (100%): tBu
NMR (CDCI3):
δ = 7.65 (d, J= 16Hz, 1H): Ph-CH=CH
7.42 (s, 2H): arom. H
6.74 ( d, J = 16Hz, 1H): Ph-CH=CH
5.7 (s, 1H): OH
4.5-4.4 (large m, 2H): P-O-CH2
3.45 (d, J = 22Hz): CH2-P
2.1 and 2.0 (2m, 2H): P-O-CH2-CH2
1.45 (s, 18H): t-C4H9
Example 16
Diethy] 4-(3,5-di-tert-butyl-4-hydroxy)-4-oxo-2-buten-1-yl phosphonate
To a suspension of 730mg 60% sodium hydride (18 mmol) in 20ml THF was added 3.0g (8.4 mmol) of dimethyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-1 ethylphosphonate in 25ml THF. The mixture was stirred for 30 min then it was cooled to 0° and 3.1 g (18 mmol) dieth yl formylmethylphosphonate was added. The resulting mixture was stirred at 0°C for 1 h then at 25°C for 16h, partitioned into ether and water and the organic phase was evaporated. Purification by means of column chromatography (silicagel 98/2 dichloromethane/methyl t-butyl ether) gave 550mg (16%) of the title compound.
mp = 68-70°C
MS=m/e: 410 M+, 395: M+-CH3, 272: M+-HPO3Et2,
233 (100%) M+-CH=CH-CH2PO3Et2
NMR: CDCI3
δ = 7.83 (m, 2H): arom. H,
7.1 (dd, J=15 and 4.5Hz, 1H), Ph-CO-CH=CH
6.9 (m, 2H): Ph-CO-CH=CH
5.7 (s, 1H): OH
4.15 (m, 4H): P-O-CH2-CH3
2.86 (dd, J=23 and 7Hz): CH2-P
1.48 (s, 18H): t-C4H9
1.34 (t, 6H): P-O-CH2-CH3
Example 17
Dimethyl 4-(3,5-di-tert-butyl-4-hydroxy phenyl)-2-hydroxy-3-huten-1-yl
phosphonate
To 100 ml of a methanol solution of dimeth yl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)- 2-oxo-3-buten-1-yl phosphonate (1.9g, 5 mmol) cooled to -10°C were added 0.75g sodium borohydride. The reacting mixture was stirred at -10°C for 1 h then at room temperature (25°C) for 2 h. Work up was carried out by addition of 100ml ether and 60ml sodium bicarbonate solution. The ether phase was washed with brine, dried over MgSO4 and evaporated to yield 1.6g (85%) of the title compound. mp = 122-123°C
MS (m/e)= 384:M+, 366: M+-H2O, 256: M+-H2O-HPO3Me2
NMR (CDCI3):
δ= 7.21 (s, 2H): arom. H
6.59 (d, J = 16Hz, 1H): Ph-CH=CH,
6.08 (dd, J = 16 and 6Hz, 1H): Ph-CH=CH
5.26 (s, 1H): OH (phenol)
4.7 (m, 1H): CH-OH
3.78 (2xd, 6H): PO3Me2
3.4 (hump, 1H): CH-OH
2.15 (distorted dd, 2H): CH2-P
1.44 (t, 18H): t-C4H9
Example 18
Dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-buten-1-yl
thionophosphonate
Under nitrogen atmosphere dimethyl methylthionophosphonate (3.1 g, 25 mmol) was added at -60°C to a solution of n-butyllithium (16ml of a 1.6M solution, 25.6 mmol) in 50ml THF. The mixture was stirred at -60°C for 15 min then a solution of ethyl 3,5-di-tert-butyl-4-hydroxy cinnamate (2.5g, 8.2 mmol) in 20 ml THF was added. The resulting mixture was stirred at -60°C for 30 min and at room temperature (25°C) for 2 h. After the usual hydrolysis and work up, the compound was purified by column chromatography (SiO2, 9/1 CHCl3/AcOEt) and recrystallization in CHCl3/petroleum ether to yield 1.7g (52%) of a yellow solid, mp = 88-90°C
MS: m/e = 398: M+, 259: M+-CH2P(S)(OMe)2, 125: P(S)(OMe)2,
57 (100%)
NMR (CDCI3)
δ= 7.60 (d, J = 16Hz, 1H): Ph-CH=CH
7.42 (s, 2H): arom. H
6.75 (d, J = 16Hz, 1H): Ph-CH=CH
5.6 (s, 1H): OH
3.78 (d, J = 14Hz, 6H): P(S)-OCH3
3.56 (d, J = 20Hz, 2H): CH2-P
1.46 (s, 18H): t-C4H9 C20H31O4PS Theor. %C 60.28 %H 7.84 %P 7.77 %S 8.04
Found %C 60.58 %H 8.04 %P 8.05 %S 8.30
Example 19 Dimethyl 3-(3,5-di-tert-butyl-4-hydroxyphenylthio)-2-oxo-1-propyl phosphonate
To a THF solution of dimethyl lithiomethylphosphonate (24.6 mmol) kept at -60°C was added a solution of ethyl 3,5-di-tert-butyl-4-hydroxyphenyl thioacetate (2g, 6.2 mmol) in 15ml THF. The resulting mixture was stirred at -60°C for 30 min and was allowed to reach room temperature (25°C) over 4 h. After addition of 15ml 10% HCl, the reaction mixture was partitioned between ether and water. The residue after evaporation of the organic phase was purified by column chromatography (SiO2, 8/2 CHCl3/AcOEt) and recrystallization in petroleum ether to give 0.95g of the title compound (38%).
mp = 63-65°C
MS: m/e 402: M+, 251: M+-(CO-CH2-PO3Me2), 57
NMR (CDCI3)
δ = 7.21 (s, 2H): arom H
5.3 (s, 1H): OH
3.75 (d, J = 11Hz, 6H): P-O-CH3
3.72 (s, 2H): S-CH2-CO
3.33 (d, J = 22Hz, 2H): CH2-P
1.41 (s, 18H): t-C4H9
Example 20
Dimethyl 3-(3,5-di-tert-butyl-4-hydroxyphenylthio)-3,3-dimethyl-2-oxo-1-propyl phosphonate
To 10ml of a THF solution of dimethyl lithiomethylphosphonate (68.2 mmol) kept at -60°C was added a solution of eth yl 2-(3,5-di-tert-butyl-4-hydroxyphenyl-thio-2- methylpropionate (6g 17.1 mmol) in 15ml THF. The resulting mixture was stirred at -60°C for 30 min and was allowed to reach room temperature (25°C) over 4 h. After addition of 15ml 10% HCl, the reaction mixture was partitioned between ether and water. The residue after evaporation of the organic phase was purified by column chromatography (SiO2, 8/2 CHCl3AcOEt). Recrystallization in petroleum ether gave 4.16g of the title compound (57%).
mp = 105-106°C
MS: m/e 430: M+, 279: M+-(CO-CH2-PO3Me2), 194 (100%), 57
NMR (CDCI3)
δ = 7.15 (s, 2H): arom H
5.38 (s, 1H): OH
3.80 (d, J = 11Hz, 6H): P-O-CH3
3.46 (d, J = 22Hz, 2H): CH2-P
1.41 (m, 24H):t-C4H9 + C(CH3)2
Example 21 Dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-butadien-1-yl phosphonate
CH=CH-CH=CH - PO3Me2
A mixture of dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl) 2-hydroxy-3-buten-1- yl phosphonate (2.3g, 6 mmol) in 1.70ml acetic anhydride and 1.26ml triethylamine was stirred at 60°C for 3h. Following hydrolysis with 10ml H2O, the reaction mixture was extracted with 20ml diethyl ether. The ether phase was extracted with 10% HCl and dried over MgSO4. The residue after evaporation was purified by column chromatography to give 1.0g (46%) of the title compound.
mp = 113-115°C MS : m/e: 366 M+, 351 M+-Me, 57 (tBu)
NMR (CDCl3)
δ = 7.32-7.20 (m, 3H): arom H + CH=CH-CH=CH-P
6.82 (1H,d): -CH=CH-CH=CH-P
6.74-6.66 (1H, m) CH=CH-CH=CH-P
5.67 (1H, dd, J = 16.6 and 19.5Hz): CH=CH-CH=CH-P
3.75 (d, 6H): PO-CH3
1.46 (19H, s): t-C4H9
Example 22 Dimethyl 4-( 3,5-di-tert-buty l-4-hydroxyphenyn-2-(4-pentenoyloxy)-1-butyl phosphonate
To a mixture of acetyl-4-pentenoate (0.66g, 4.6 mmol) and triethylamine (0.24ml, 1.7 mmol) was added 0.50g (1.37 mmol) of dimethyl 4-(3,5-di-tert-butyl-4- hydroxyphenyl)-2-hydroxy-1-butyl phosphonate. The reaction mixture was kept at 60°C for 6 h, cooled and extracted into diediyl etiier and water. The residue of the dried organic phase was purified by column chromatography (SiO2, 7/3
CHCl3/Methyl-tert-butyl ether) to yield 0.4g of a colorless oil (62%). MS: m/e: 468: M+, 368: M+- CH2=CH-CH2-COOH, 258: 368 - HPO3Me2
NMR (CDCI3)
δ = 6.94 (s, 2H): arom H
5.85 (m, 1H): CH2=CH -CH2-CH2-COO
5.18 (m, 1H): Ph-CH2-CH2-CH-CH2-P
5.0 - 5.1 (m, 2H): CH2=CH-CH2-CH2-COO
5.15 (s, 1H): OH (phenol)
3.72 (2xd, 6H): PO3Me2
2.55 (m, 2H): Ph-CH2-CH2-CH-CH2-P
2.41 (m, 4H): CH2=CH-CH2-CH2-COO-
1.43 (s, 18H): t-C4H9
BIOLOGICAL ACTIVITIES
A. Antioxidant Activity
1) Iron induced peroxide formation in rat liver homogenate
Wistar rats were euth anasied by ether inhalation. The livers were dissected out and homogenised with a potter homogeneiser in 4 volumes of phosphate buffer (4°C, pH 7.4). After centrifugation at 2000 rpm for 10 min the supernatant obtained was kept at 4°C.
A mixture containing 0.2 ml of liver homogenate, 1.7 ml of phosphate buffer was incubated with 0.1 ml of a 2mM FeSO4 solution to induce peroxide formation according to the method described by A. T. Quintanilha et al., Ann. N. Y. Acad. Sci., 393, 32-47, 1982.
Compounds to be tested for antioxidant activity were dissolved in DMSO or ethanol and added in a volume of 5 μl to the incubation mixture. Stock solution of the compounds were diluted sequentially to obtain final concentration of 0.5, 1, 2, 5 and 5 μM. Oxidation was performed at 37°C for 2 hours and was stopped by the addition of 20 μl of a 2% ethanolic solution of BHT. The generated peroxides measured as malondialdehyde formation were quantitated according to the method of Yagi ("Lipid Peroxides in Biology and Medicine" p. 223-242, 1982, Ed. K. Yagi, Academic Press Inc.) using the Thiobaibituric Acid Reaction and with 1,1,3,3,-tetramethoxypropane as standard. Results are given as concentration in μmol/l which inhibits malondialdehyde formation by 50% (IC50).
All the tested compounds have IC50's between 0.5 and 5 μM and are more active man Probucol, vitamin E and Vitamin C. Butyl hydroxytoluene (BHT) has an IC50 of 3.3 μM in this assay. Compound of formula (I) are thus useful for the treatment of disease states in which oxygen reactive species are involved.
2) Copper Oxidation of human low density lipoproteins (LDL) Plasma was obtained after low speed centrifugation of blood from donors. LDL
(d= 1.006- 1.063 g/ml) were isolated by preparative ultracentrifugation in a salt solution (NaBr, KBr). The isolated LDL fraction was dialysed against phosphate buffer.
LDL oxidation was performed according to Esterbauer et al. (Continuous
Monitoring of in Vitro Oxidation of Human Low Density Lipoprotein, Free Rad. Res. Commun.6, 67-75, 1989). Briefly the LDL suspension (50-200μg protein/ml) was distributed in quartz cuvettes and kept at 37°C then a solution of CuCI2 was added at a final concentration of 5μM. The increase in optical density at 235 nm was recorded using a UV- visible spectrophotometer. The time course of oxidation was recorded over a period of 8 hours at 10 min intervals. Compounds to be tested were dissolved in ethanol and added at the final concentration of 0.1 μM. Controls received ethanol only. The lag phase is prolonged by the presence of antioxidants. This method was validated with Probucol and vitamin-E as reference antioxidants.
The prolongation of the lag phase was used to quantify the antioxidant activity of the compounds tested, this prolongation was expressed in percent of the value measured in absence of exogen antioxidant (controls).
The phosphonates of Formula (I) as noted in Table 3 prolong the lag phase compared to control. An inhibitory activity on LDL oxidation is thus demonstrated which is clearly superior to that of Probucol and vitamin E. Since these two antioxidants have been shown to be anti-atherosclerotic in animal models, the therapeutic potential of phosphonates of Formula (I) is obvious.
B. Inhibition of Cholesterol and Cholesteryl Esters Synthesis
The human intestinal cell line CaCo2 cells (ATCC HTB37) was used to study the effect of compounds of formula (I) on cholesterol synthesis. The cells were grown in 6 wells dishes (Falcon) in 2 ml of Dulbecco's modified Eagle culture medium
(DMEM) supplemented with 20% fetal calf serum (Flow). Cells were maintained at 37°C in a 5% CO2 atmosphere and the labelling experiment was done 8 days after cell plating. To the culture were added 10 μl of the eth anol solution of the compounds to be tested. Control wells received 10μl of ethanol alone. One hour later 0.7 μCi of 14-C-acetate 53.4 mCi/mmol was added, labelling was continued for 4 hours and was stopped by washing the cell layer with chilled PBS. The cells were collected in 2ml of 0.01 N NaOH and 1 ml of PBS. Lipids were extracted by the Folch method and separated on silica gel TLC plates developed in petroleum ether: diethyl ether: acetic acid (70:30: 0.5). After exposition to iodine vapors, the bands corresponding to cholesterol and cholesteryl esters were scrapped off and radioactivity was measured in a liquid scintillator counter.
The amount of radioactivity incorporated in cholesterol and cholesteryl esters in presence of compounds to be tested was compared to that of the control cells.
HMGCoA reductase inhibitors such as simvastatin (1μM) served to validate the measurement of 14C-acetate incorporation in cholesterol and cholesteryl esters.
All the compounds tested inhibited cholesterol and cholesteryl esters synthesis.
Most of the compounds inhibited cholesteryl esters synthesis by more than 50%
(Table 4). Phosphonates of formula (I) display an inhibitory activity on cholesterol and cholesteryl esters and can be considered as therapeutic agents in the treatment of hyperlipidemia and ath erosclerosis.
C. Calcium Entry Blocking activity of ketophosphonates
Experiments were performed on aortic rings from male Sprague -Dawley rats (280-350g body weight) which were killed by stunning and exsanguination.
Thoracic aortas were cleared of connective tissues and cut into rings of approximately 2mm in length. Each ring was mounted under a resting tension of 2g and was equilibrated for 1 hour at 37°C in a 10 ml organ bath containing a HEPES buffer Ringer solution (Buffer composition (mM): NaCl 139.0, KC15.0, MgCl23.7, D-Glucose 11.0, HEPES 5.0, pH 7.4) aerated with 95% O2:5% CO2.
Maximal contractions were produced within 5-10 min exposure to 10μM
Phenylephrine. The tissues were then washed with a Ca+2 free HEPES buffer. After 30 min the tissue was depolarised with KCl (60mM).One hundred μl of the vehicle (10% DMSO) or compound solution (1 μM) were added 5 min later. The final concentration of DMSO was 1%. The tissues (n=2 per compound) were further equilibrated for 15 min in the presence of compounds prior to cumulative addition of Ca+2 (0.1-30 mM). The contractions to each 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. The potency index of each compound is expressed as the concentration ratio (calcium drug EC30/vehicle EC30), where a potency index >1 indicates a compound effect.
The compounds of formula (I) are thus potentially useful in the treatment of cardiovascular diseases via their calcium entry blocking activity. The primary indications of these compounds would be the treatment of atherosclerosis, angina pectoris, congestive heart failure and hypertension.
Table 5
Effect of compounds (I) on Ca+2 induced contraction of K+ depolarized rat aorta
Claims (1)
1. A compound of formula (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 more halogen 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=CH-C(O)-CHX3,
(CH2)t-C(O)-CHX3, S-(CH2)t-(CH=CH)n-C(O)-CΗX3, 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-C4 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=CH-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 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 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-4-hydroxyphenyl)-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-butyl phosphonate, diethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-1-butyl phosphonate,
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-dimethy l-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-edιyl phosphonate, dimethyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl thio )-2-oxo-1-propyl phosphonate, diethyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl thio)-2-oxo-1-propyl phosphonate, dimethyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl thio)-3,3-dimethyl-2-oxo-1-propyl phosphonate diethyl 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-hydrox yphenylthio)-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-4-hydroxyphenyl)-2,4-dihydroxy-1-butyl phosphonate,
dimethyl 3-(3,5-di-tert-butyl-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. A process for preparing 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
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
where X1 , X2, G are as described in claim 1 and A is (CH2)t,
(CH=CH)n-CH=CX3, (CΗ2)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 A is (CH=CH)n-CH=CX3 which consists in reacting an aldehyde of formula IV
where G, X1, X2, n are as described in claim 1,
with a ketophosphonate of formula 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
where X3, B, Y, Z1 and Z2 are as described in claim 1 first with sodium hydride and n-butyl lithium, men with the halide of formula VI
where G, X1, X2, t are as described in claim 1,
in tetrahydrofuran at a temperature between -30° and the boiling point of tetrahydrofuran (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
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
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 at a 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 (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH52193 | 1993-02-19 | ||
| CH521/93 | 1993-02-19 | ||
| PCT/EP1994/000520 WO1994019358A1 (en) | 1993-02-19 | 1994-02-21 | Substituted phosphonates, the processes for their preparation and pharmaceutical compositions containing them |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| AU6205294A true AU6205294A (en) | 1994-09-14 |
Family
ID=4188911
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU62052/94A Abandoned AU6205294A (en) | 1993-02-19 | 1994-02-21 | Substituted phosphonates, the processes for their preparation and pharmaceutical compositions containing them |
Country Status (8)
| Country | Link |
|---|---|
| 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)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| AU2003270693A1 (en) * | 2002-09-19 | 2004-04-08 | Ilex Oncology Research, Sarl | Substituted ketophosphonate compounds having bone anabolic activity |
| AU2003272513A1 (en) * | 2002-09-19 | 2004-04-08 | Ilex Oncology Research, Sarl | Substituted ketophosphonate inhibitors of tumor cell proliferation |
| 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 |
| CN102281862B (en) * | 2008-11-13 | 2015-04-15 | 巴斯夫欧洲公司 | Benzylidene compounds comprising phosphono-groups |
| 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 |
| CN109154016B (en) * | 2017-12-29 | 2021-11-16 | 邦泰生物工程(深圳)有限公司 | Method for preparing ursodeoxycholic acid by chemical-enzymatic method |
| 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)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| EP0106799B1 (en) * | 1982-10-07 | 1986-03-19 | 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 CA CA002118409A patent/CA2118409A1/en not_active Abandoned
- 1994-02-21 JP JP6518667A patent/JPH07506121A/en active Pending
- 1994-02-21 CN CN94190122A patent/CN1106611A/en active Pending
- 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 EP EP94909033A patent/EP0638084A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
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| WO1994019358A1 (en) | 1994-09-01 |
| MX9401295A (en) | 1994-08-31 |
| CN1106611A (en) | 1995-08-09 |
| CA2118409A1 (en) | 1994-09-01 |
| JPH07506121A (en) | 1995-07-06 |
| ZA941088B (en) | 1995-09-27 |
| EP0638084A1 (en) | 1995-02-15 |
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