CN1147497C - 亚甲基双膦酸类衍生物 - Google Patents
亚甲基双膦酸类衍生物Info
- Publication number
- CN1147497C CN1147497C CNB988103710A CN98810371A CN1147497C CN 1147497 C CN1147497 C CN 1147497C CN B988103710 A CNB988103710 A CN B988103710A CN 98810371 A CN98810371 A CN 98810371A CN 1147497 C CN1147497 C CN 1147497C
- Authority
- CN
- China
- Prior art keywords
- phosphonic acids
- methylene radical
- group
- formula
- methylene
- 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.)
- Expired - Fee Related
Links
- MBKDYNNUVRNNRF-UHFFFAOYSA-N medronic acid Chemical compound OP(O)(=O)CP(O)(O)=O MBKDYNNUVRNNRF-UHFFFAOYSA-N 0.000 title claims abstract description 26
- -1 ester anhydrides Chemical class 0.000 claims abstract description 142
- 150000001875 compounds Chemical class 0.000 claims abstract description 56
- 238000000034 method Methods 0.000 claims abstract description 26
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 12
- 239000000825 pharmaceutical preparation Substances 0.000 claims abstract description 3
- PFBUKDPBVNJDEW-UHFFFAOYSA-N dichlorocarbene Chemical group Cl[C]Cl PFBUKDPBVNJDEW-UHFFFAOYSA-N 0.000 claims description 94
- 239000002253 acid Substances 0.000 claims description 38
- 150000003839 salts Chemical class 0.000 claims description 23
- 238000006243 chemical reaction Methods 0.000 claims description 14
- 238000006460 hydrolysis reaction Methods 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 230000007062 hydrolysis Effects 0.000 claims description 10
- 150000008065 acid anhydrides Chemical class 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 6
- 229910052751 metal Inorganic materials 0.000 claims description 6
- 239000002184 metal Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 125000001419 myristoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 4
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 4
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 3
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 3
- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 125000005466 alkylenyl group Chemical group 0.000 claims 2
- 150000002431 hydrogen Chemical class 0.000 claims 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 230000008569 process Effects 0.000 abstract description 12
- 238000002360 preparation method Methods 0.000 abstract description 11
- 125000005843 halogen group Chemical group 0.000 abstract 1
- 238000004679 31P NMR spectroscopy Methods 0.000 description 63
- 229910052698 phosphorus Inorganic materials 0.000 description 52
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
- 239000000651 prodrug Substances 0.000 description 26
- 229940002612 prodrug Drugs 0.000 description 26
- 150000003009 phosphonic acids Chemical class 0.000 description 24
- 150000002148 esters Chemical class 0.000 description 18
- 239000000203 mixture Substances 0.000 description 18
- ACSIXWWBWUQEHA-UHFFFAOYSA-N clodronic acid Chemical compound OP(O)(=O)C(Cl)(Cl)P(O)(O)=O ACSIXWWBWUQEHA-UHFFFAOYSA-N 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- GTDPSWPPOUPBNX-UHFFFAOYSA-N ac1mqpva Chemical compound CC12C(=O)OC(=O)C1(C)C1(C)C2(C)C(=O)OC1=O GTDPSWPPOUPBNX-UHFFFAOYSA-N 0.000 description 13
- 239000002585 base Substances 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- 238000003756 stirring Methods 0.000 description 11
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 10
- 229910052799 carbon Inorganic materials 0.000 description 10
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 9
- 229940122361 Bisphosphonate Drugs 0.000 description 8
- 239000000872 buffer Substances 0.000 description 8
- 150000001721 carbon Chemical group 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 7
- 238000010306 acid treatment Methods 0.000 description 7
- 238000013459 approach Methods 0.000 description 7
- 150000004663 bisphosphonates Chemical class 0.000 description 7
- FJBFPHVGVWTDIP-UHFFFAOYSA-N dibromomethane Chemical group BrCBr FJBFPHVGVWTDIP-UHFFFAOYSA-N 0.000 description 7
- 238000001704 evaporation Methods 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 238000005192 partition Methods 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical class C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 5
- 238000010521 absorption reaction Methods 0.000 description 5
- 210000000988 bone and bone Anatomy 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- XQRLCLUYWUNEEH-UHFFFAOYSA-L diphosphonate(2-) Chemical compound [O-]P(=O)OP([O-])=O XQRLCLUYWUNEEH-UHFFFAOYSA-L 0.000 description 5
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 239000002953 phosphate buffered saline Substances 0.000 description 5
- 210000002381 plasma Anatomy 0.000 description 5
- 230000009466 transformation Effects 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- 208000006386 Bone Resorption Diseases 0.000 description 4
- 102100036893 Parathyroid hormone Human genes 0.000 description 4
- 108090000445 Parathyroid hormone Proteins 0.000 description 4
- 230000024279 bone resorption Effects 0.000 description 4
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000013016 damping Methods 0.000 description 4
- 239000012530 fluid Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 239000011574 phosphorus Substances 0.000 description 4
- 150000003053 piperidines Chemical class 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- FPDNKWSQWXOPSC-UHFFFAOYSA-N 1-(methylamino)ethanol Chemical compound CNC(C)O FPDNKWSQWXOPSC-UHFFFAOYSA-N 0.000 description 3
- DPHWUQCXOBNREF-UHFFFAOYSA-N 1-propan-2-yl-2h-pyridine Chemical compound CC(C)N1CC=CC=C1 DPHWUQCXOBNREF-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 125000003710 aryl alkyl group Chemical group 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 230000003139 buffering effect Effects 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000004891 communication Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 230000000452 restraining effect Effects 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- 239000005695 Ammonium acetate Substances 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 239000005864 Sulphur Substances 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- SYKNUAWMBRIEKB-UHFFFAOYSA-N [Cl].[Br] Chemical compound [Cl].[Br] SYKNUAWMBRIEKB-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 229940043376 ammonium acetate Drugs 0.000 description 2
- 235000019257 ammonium acetate Nutrition 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 125000002393 azetidinyl group Chemical group 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 230000007073 chemical hydrolysis Effects 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 229960002286 clodronic acid Drugs 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical class [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 2
- 238000007599 discharging Methods 0.000 description 2
- 238000010494 dissociation reaction Methods 0.000 description 2
- 230000005593 dissociations Effects 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- PQLFROTZSIMBKR-UHFFFAOYSA-N ethenyl carbonochloridate Chemical compound ClC(=O)OC=C PQLFROTZSIMBKR-UHFFFAOYSA-N 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 125000002757 morpholinyl group Chemical group 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 2
- 125000004193 piperazinyl group Chemical group 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000010703 silicon Substances 0.000 description 2
- 229910052710 silicon Inorganic materials 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 150000003512 tertiary amines Chemical group 0.000 description 2
- 125000002769 thiazolinyl group Chemical group 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- RMNJMXHMWQGRQI-UHFFFAOYSA-N 2,2-bis(methylamino)ethanol Chemical class CNC(CO)NC RMNJMXHMWQGRQI-UHFFFAOYSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- AUFVJZSDSXXFOI-UHFFFAOYSA-N 2.2.2-cryptand Chemical compound C1COCCOCCN2CCOCCOCCN1CCOCCOCC2 AUFVJZSDSXXFOI-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
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- 206010007027 Calculus urinary Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- VBKKVDGJXVOLNE-UHFFFAOYSA-N Dioxation Chemical compound CCOP(=S)(OCC)SC1OCCOC1SP(=S)(OCC)OCC VBKKVDGJXVOLNE-UHFFFAOYSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- KGWDUNBJIMUFAP-KVVVOXFISA-N Ethanolamine Oleate Chemical compound NCCO.CCCCCCCC\C=C/CCCCCCCC(O)=O KGWDUNBJIMUFAP-KVVVOXFISA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010031149 Osteitis Diseases 0.000 description 1
- 208000010191 Osteitis Deformans Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 206010031299 Osteosis Diseases 0.000 description 1
- 208000027067 Paget disease of bone Diseases 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical class C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-O Pyrrolidinium ion Chemical compound C1CC[NH2+]C1 RWRDLPDLKQPQOW-UHFFFAOYSA-O 0.000 description 1
- 101001135767 Rattus norvegicus Parathyroid hormone Proteins 0.000 description 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical class OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- UOHUDFHWFDUDID-UHFFFAOYSA-N [Cl].C[SiH](C)C Chemical compound [Cl].C[SiH](C)C UOHUDFHWFDUDID-UHFFFAOYSA-N 0.000 description 1
- YUWBVKYVJWNVLE-UHFFFAOYSA-N [N].[P] Chemical compound [N].[P] YUWBVKYVJWNVLE-UHFFFAOYSA-N 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
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Abstract
本发明的目的是新的取代亚甲基双膦酸酐、酯酐、酰胺酐和酯酰胺酐,新化合物的制备方法,以及含有这些新化合物的药物制剂。
Description
本发明的目的在于新的亚甲基双膦酸类衍生物,具体涉及新的卤素取代的亚甲基双膦酸酐类化合物、酯酐类化合物、酰胺酐类化合物和酯酰胺酐类化合物,这些新化合物的制备方法,以及含有这些新化合物的药物制剂。
根据本发明的发现,新的亚甲基双膦酸酐、酯酐、酰胺酐、酯酰胺酐、偏酐及其在数种情况中的盐表现出明显优于相应的双膦酸、其偏酯、偏酰胺和偏酯酰胺衍生物的特性,这归因于酐类衍生物具有良好的动力学和使用性能,因此,它们对于机体的代谢和机能具有更可控的作用。
所有仅能用作四元酸盐形式的已知亚甲基双膦酸所存在的基本问题是,它们在口服给药中不易被吸收。因此需要较大剂量给药。
通过处理中间碳上的取代基或改变磷上所连接的基团可以影响吸收和有效性。从文献中可以检索出若干种通过改变中间碳上的取代基来改进双膦酸盐性质的例子(《骨骼上的双膦酸盐》(Bisfosfonate on Bones),Bijvoet编辑,F1eisch & Russel,Elsevier,Amsterdam 1995)。人们还尝试了利用配制方式来改善四元酸或盐形式的双膦酸的吸收或患者的依从性(CA 2120538,EP407345,EP 550385,EP 566535,US 5462932,WO9321907,WO9412200,WO 9426310,WO 9508331,WO 9528145,WO 9529679,WO 9531203),但是,对有效性的改进仅仅是最低限度地与给药剂量成正比。然而,迄今只有在极少的情况中对磷部分作了调整。通常,这种在磷部分中的调节剂是偏酯类化合物、酯酰胺类化合物和酰胺类化合物。作为本发明的主题,酐类衍生物的特征在于具有所需的选择性和可控作用,这就意味着治疗指数更好。
亚甲基双膦酸、其盐、四元酯、酰胺酯、偏酯和偏酯酰胺类化合物业已公开在某些出版物中,但作为本发明主题的酐类衍生物既未在文献中提及,也未描述它们的特性。
亚甲基双膦酸四元酯类化合物的制备方法业已公开在文献:US4447256;DE 2831578;EP 337706;EP 282320;EP 356866;《美国化学学会会志》78(1956)4450;《化学会志》1959,2272;《美国化学化学会志》84(1962)1876;《有机化学杂志》35(1970)3149;《有机化学杂志》36(1971)3843;《磷、硫和硅》42(1989)73;《中国化学会志》(北京译)2(1992)835;和《磷、硫和硅》70(1992)182(混合四元酯类化合物)。四元酰胺酯类化合物的制备方法业已公开在文献《有机金属化学杂志》304(1986)283;《四面体通讯》26(1985)4435;和《斯堪的那维亚化学学报》51(1997)932。
偏酯类化合物的制备方法公开在文献WO 9015806、WO 9211267、WO 9221169、《四面体通讯》34(1993)4551、《四面体》51(1995)6805和《四面体通讯》37(1996)3533;偏酰胺和偏酰胺酯的制备方法业已公开在专利申请公开WO 9211268中。
当用已知药物治疗骨骼疾病或用来提高低水溶性药物在水相中的溶解度时,可以将单或双膦酸部分作为必要部分加入到已知药用物质中或作为前体,由此来改进已知药物对骨骼靶向给药。已知某些膦酸占优势的膦酸和羧酸的混合酐也适用于此目的。
本发明所述的含有酸酐基团作为前体或具有活性的新分子极其适合于治疗与钙和其它金属,特别是二价金属代谢有关的疾病。它们可以有效地治疗骨骼性疾病(具体如骨形成)和吸收性疾病(如骨质疏松症和佩吉特氏病),以及软组织内的疾病,例如沉积、矿化性病症和骨化病。
另一方面,作为焦磷酸盐(酯)的类似物,新的亚甲基双膦酸的酐类衍生物适于治疗生物体的焦磷酸盐(酯)机能性疾病,这包括那些其中有活性但其失调倾向或不正确的机能有机部分与(焦)磷酸盐(酯)相关,或起金属复合物的作用或成为后者混合物的机能。
新的双膦酸衍生物直接或通过间接机制来调节阳离子和/或焦磷酸化合物的性质和水平,它们自由地存在于体液中或与机体结合,并且在组织中起活性作用并从其中释放出来,也就是可以形成、溶解、偶合和消除。因此,它们能够调整细胞的代谢、生长和破坏。因此,它们可有效地治疗例如骨癌及其转移、异位钙化、尿石病、类风湿关节炎、骨炎和骨变性。
本发明涉及新的如式I所示的亚甲基双膦酸衍生物:
其中基团Y1、Y2、Y3和Y4是OR1、NR2R3、OCOR1、OCNR2R3、O(CO)OR1、O(SO2)R1、O(SO2)OR1或OP(O)R2(OR3),其中R1、R2或R3彼此独立地表示氢、任选取代且任选不饱和的直链或支链C1-C22烷基,任选取代且任选不饱和的C3-C10环烷基、杂环基、芳基、杂芳基、芳烷基或甲硅烷基SiR3、其中R是指C1-C4烷基、苯基、取代苯基、C1-C4烷基和/或苯基类的混合基团;或基团R2或R3与相邻氮原子一起构成3-10元的饱和、部分饱和或芳香环,其中除了氮原子之外还可以含有一个或两个选自N、O或S的杂原子;或基团R2和R3与相邻O-PO-O基团一起构成5或6元环;
条件是在式I中至少一个Y1、Y2、Y3和Y4基团不是OR1或NR2R3;
Q1和Q2彼此独立地表示氢、氟、氯、溴或碘;
包括这些化合物的立体异构体,例如几何异构体和旋光异构体,及其可药用盐。
作为R1、R2和R3基团的任选不饱和C1-C22烷基是指烷基、链烯基或炔基,它们彼此独立地含有1-22个碳原子,分别含有2-22个碳原子;优选含有1-8个碳原子,分别含有2-8个碳原子;并且最优选含有1-5个碳原子,分别含有2-5个碳原子。
作为R1、R2和R3基团的任选不饱和C3-C10环烷基是指环烷基或环状烯基,其含有3-10个碳原子,优选5或6个碳原子,并且可以未被取代或被例如低级烷基(1-4C)取代。优选它是环丙基、环丁基、环戊基、环庚基或相应的环状烯基。杂环基在其环内含有一个或多个选自N、O和S的杂原子。
作为R1、R2或R3基团的芳基或芳烷基是指任选地被C1-C4-烷基、C1-C4烷氧基或卤素取代的单环芳基或芳烷基,例如苯基或苄基,但首选未取代的苯基或苄基。
当存在于甲硅烷基SiR3中时基团R是含有1-4个碳原子的低级烷基,该基团具体为甲基、乙基、异丙基、丁基或叔丁基。当甲硅烷基中的R基团是指C1-C4烷基或苯基的混合基团时,它可例如是二甲基叔丁基、甲基二异丙基、二甲基苯基、二乙基苯基、甲基叔丁基苯基或二异丙基-(2,6-二甲基苯基)。
当R2和R3与氮原子一起构成饱和杂环时,该环一般可例如(2-或3-)吗啉基、硫吗啉基、哌啶基、哌嗪基、氮杂环丁烷基(azetidinyl)、氮杂环丙烯基(azirdinyl)或吡咯烷基;当它们构成一个部分饱和的或芳香环时,该环例如是吡咯基、咪唑基、三唑基、四唑基、噁唑基、噻唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基或氮杂基(azepinyl)。该基团可以被定义环烷基的上述取代基所取代,但优选未经取代,例如吡咯烷基、吗啉基或哌嗪基。
当R2和R3与相邻O-PO-O基团一起构成5或6元环时,优选该环是氧化二噁磷杂环戊烷(dioxaphospholaneoxide)和dioxaphosphaneoxide。
Q1和Q2首选均为氯。
具体的式I化合物的盐是其与可药用碱形成的盐,例如:金属盐,如碱金属盐,具体如锂盐、钠盐和钾盐,如碱土金属盐,具体如钙盐或镁盐,铜、铝或锌盐;以及与氨或伯胺、仲胺或叔胺形成的铵盐,包括脂肪族、脂环族和芳香族胺,以及脂肪族或芳香族季铵盐;与氨基醇类化合物形成的盐,例如乙醇胺、二乙醇胺和三乙醇胺类化合物,三(羟甲基)氨基甲烷,1-和2-甲基及1,1-、1,2-和2,2-二甲基氨基乙醇类化合物,N-单-或N,N-二烷氨基乙醇,N-(羟甲基和乙基)-N,-N-乙二胺以及氨基冠醚和穴状化合物;和杂环铵盐,例如氮杂环丁烷鎓盐、吡咯烷鎓盐、哌啶鎓盐、哌嗪鎓盐、吗啉鎓盐、吡咯鎓盐、咪唑鎓盐、吡啶鎓盐和喹啉鎓盐;多种四烷基铵盐,例如四甲基铵、甲基三丁基铵和苄基二甲基高级烷基铵盐。
优选的本发明化合物是式I所示的亚甲基双膦酸类衍生物,其中基团Y1、Y2、Y3和Y4中的两个基团是OCOR1,其中R1定义如上。在这些化合物中,更优选的是其中R1是直链或支链C1-C22烷基或苯基的化合物。
优选的本发明化合物还有式I所示的亚甲基双膦酸类衍生物,其中基团Y1、Y2、Y3和Y4中的两个基团是OR1,其中R1定义如上。在这些化合物中,更优选的是那些其中R1是直链或支链C1-C22烷基或苯基的化合物。
在其中基团Y1、Y2、Y3和Y4中的两个基团是OCOR1或OR1的式I化合物中,更优选的本发明化合物是基团Y1、Y2、Y3和Y4中的第三个基团选自烷基磺酰基、低级烷基羧基、苯甲酰基、芳基磺酰基、单-或二-低级烷基磷酰基。
本发明优选化合物的例子例如是:
P,P’-二乙酰基(二氯亚甲基)双膦酸二钠盐及游离酸,
P,P’-二丁酰基(二氯亚甲基)双膦酸二钠盐及游离酸,
P,P’-二(新戊酰基)(二氯亚甲基)双膦酸二钠盐及游离酸
P,P’-二(苯甲酰基)(二氯亚甲基)双膦酸二钠盐及游离酸,
P,P’-二(异丁酰基)(二氯亚甲基)双膦酸二钠盐及游离酸,
P,P’-二(十四烷酰基)(二氯亚甲基)双膦酸二钠盐及游离酸,
P,P’-二(十八烷酰基)(二氯亚甲基)双膦酸二钠盐及游离酸。
本发明所述的衍生物可以通过多种不同的途径来制备,这取决于所要制备的亚甲基双膦酸酐。用亚甲基双膦酸作为起始原料,通过已知方法可以制得其盐、四元酯、四元酯酰胺、偏酯和偏酰胺酯(参见,例如WO 92/11267和WO 92/11268)。所以,例如通过有选择地水解亚甲基双膦酸四元酯、通过选择性地酯化双膦酸或由其它偏酯通过分子内或分子间的反应均可以制备偏酯类化合物。另一方面,通过选择性地水解双膦酸四(酰胺酯)或从其它偏酯酰胺通过分子内或分子间的反应可以制备偏酰胺酯。
根据合成路线1中的a)从相应的亚甲基双膦酸或其盐通过逐级取代反应来制备那些其中部分(1-3个基团)或全部的Y1、Y2、Y3和Y4基团是除了OR1或NR2R3以外的上述取代基的本发明化合物。起始原料(II)(其中至少一个或全部的基团X1-X4彼此独立地是OH或OM且M可以是金属或铵)选择性地与指定的酸衍生物(Z-A)反应,例如与酰氯反应。
当X1-X4中至少一个基团或全部基团分别为卤素或卤素类似物(如磺酰氧基)时,合成路线1中的b)可以采用相同的方法,该方法通过该化合物与选定的酸(A-OH)或其金属盐(A-OM)反应并最终除去附加基团X和可能有的附加基团Y,例如用水水解。若向混合物中加入醇、硫醇或胺来改变附加基团,特别是含卤素基团时,由此得到混合酯、酯酰胺或酰胺酯酐。
合成路线1:
a)Xn(n=1-4)=OH或OM,其中M是金属或铵;Q1和Q2具有如上所述的含义;Z是卤素或类似基团;A是指OCOR1、OCNR2R3、O(CO)OR1、O(SO2)R1、O(SO2)OR1或OP(O)R2(OR3),其中R1、R2和R3是指上述相同的基团;或
b)Xn(n=1-4)=卤素或类似基团;Z是OH或OM,其中M是金属或铵;和A、Q1和Q2具有与上述相同的含义。
从按照上述方法制备的四元衍生物I,还可以进一步按照合成路线2、通过选择性地水解三-、二-或单偏酐衍生物I来制备c):
合成路线2
c)Yn(n=4)=A--→Yn(n=1-3),其中A具有与合成路线1中相同的含义。
可以根据色谱法或借助于31P-NMR光谱来判断水解的进程。当预期的偏酐(Y中至少一个基团=OH或OM)的浓度达到最高时,反应可以被中止,并从反应物中通过沉淀法、萃取法或层析法将酸或盐形式的产物分离出来。
混合酯、酯酰胺或酰胺酯酐类化合物具体可以由式I所示的分子开始制备,其中Y1、Y2、Y3或Y4基团表示选定量的上述基团X或上述除OR1或NR2R3以外所定义的Y基团。这是按照方法a与适当的酰卤反应,或按照方法b与酸或其金属盐反应。
本发明的新化合物可以经肠道或非肠道给药。所有常规给药形式,例如片剂、胶囊、颗粒剂、糖浆剂、溶液、植入物和混悬剂均被采用。另外,可以采用所有可药用的制药辅料、溶解辅剂和给药辅料,以及稳定剂、粘度调节剂、分散剂和缓冲剂。
适当的辅料包括:酒石酸盐和柠檬酸盐缓冲剂、醇、EDTA和其它非毒性络合剂、固体和液体聚合物和其它灭菌底物、淀粉、乳糖、甘露糖醇、甲基纤维素、滑石、硅酸、脂肪酸、明胶、琼脂、磷酸钙、硬脂酸镁、动物或植物脂肪,以及根据需要加入的矫味剂和甜味剂。
所用剂量取决于若干因素,例如给药方式、种属、年龄和个体状况。日剂量约为1-1000mg/人,通常是10-200mg/人,可以采取单剂量给药,或分成若干剂量给药。
在下文中,给出代表性胶囊和片剂的组成:
胶囊
mg/个胶囊
活性物质 100.0mg
淀粉 20.0mg
硬脂酸镁 1.0mg
片剂
mg/片
活性物质 400.0mg
微晶纤维素 20.0mg
乳糖 67.0mg
淀粉 10.0mg
滑石 4.0mg
硬脂酸镁 1.0mg
本发明的化合物还可以被制成肌肉内或非肠道给药的制剂,例如输注浓缩物,其中作为辅料的例如是灭菌水、磷酸盐缓冲剂、氯化钠、氢氧化钠、盐酸,或者采用其它适当的可药用辅料。
本发明将以下列实施例来举例说明,但是它们不以任何方式限定本发明。
实施例1:P,P-二甲基-P′-甲磺酰基(二氯亚甲基)双膦酸甲基三丁基铵盐和游离酸
将12.2g(0.025mol)三甲基(二氯亚甲基)双膦酸甲基三丁基铵盐和2.9g(0.025mol)甲磺酰氯(mesyl chloride)溶解在150ml无水乙腈中并在回流下将该溶液搅拌约20分钟。反应的进程用31P-NMR来监测。真空蒸发溶剂,得到约13.2g(理论值的96%)的黄色、油状P,P-二甲基-P’-甲磺酰基(二氯亚甲基)双膦酸甲基三丁基铵盐(31P-NMR(CDCl3):13.12ppm(P),-2.42ppm(P’),2Jpp’=20.3Hz,3Jph=10.7Hz),浓度为99.5%,用酸处理可以从其中释放出相应的酸。
例如,可以按照类似方法制备下列亚甲基双膦酸P,P-二酯-P’-单酐类化合物及其季铵盐:
P,P-二甲基-P’-新戊酰基(二氯亚甲基)双膦酸甲基三丁基铵盐,31P-NMR(CDCl3):15.13ppm(P),-0.63ppm(P’),2Jpp’=18.9Hz,3JpH=10.7Hz;
P,P-二甲基-P’-戊基(二氯亚甲基)双膦酸甲基三丁基铵盐,31P-NMR(CDCl3):15.12ppm(P),-1.04ppm(P’),2Jpp’=18.6Hz,3JpH=10.6Hz;
P,P-二甲基-P’-苯甲酰基(二氯亚甲基)双膦酸甲基三丁基铵盐,31P-NMR(CDCl3):14.87ppm(P),-0.79ppm(P’),2Jpp’=23.0Hz,3JpH=10.7Hz;
P,P-二甲基-P’-三氯乙酰基(二氯亚甲基)双膦酸甲基三丁基铵盐,31P-NMR(CDCl3):14.03ppm(P),-1.04ppm(P’),2Jpp’=19.9Hz,3JpH=10.8Hz;
P,P-二异丙基-P’-新戊酰基(二氯亚甲基)双膦酸N-异丙基吡啶鎓盐,31P-NMR(CDCl3):8.99ppm(P),0.24ppm(P’),2Jpp’=24.5Hz,3JpH=6.6Hz;
P,P-二乙基-P’-甲磺酰基(二氯亚甲基)双膦酸乙基三丁基铵盐,31P-NMR(CDCl3):9.90ppm(P),-1.29ppm(P’),2Jpp’=22.8Hz,3JpH=7.9Hz;
P,P-二异丙基-P’-甲磺酰基(二氯亚甲基)双膦酸N-异丙基吡啶鎓盐,31P-NMR(CDCl3):7.79ppm(P),-1.45ppm(P’),2Jpp’=23.3Hz,3JpH=6.4Hz;
P-甲基-P-异丙基-P’-甲磺酰基(二氯亚甲基)双膦酸甲基三丁基铵盐,31P-NMR(CDCl3):10.80ppm(P),-2.21ppm(P’),2Jpp’=21.2Hz,3JpH=6.5Hz,3Jp’H=10.5Hz;
P,P-二甲基-P’-苯磺酰基(二氯亚甲基)双膦酸甲基三丁基铵盐,31P-NMR(CDCl3):13.07ppm(P),-2.28ppm(P’),2Jpp’=21.0Hz,3JpH=10.7Hz;
P,P-二甲基-P’-p-甲苯磺酰基(二氯亚甲基)双膦酸甲基三丁基铵盐,31P-NMR(CDCl3):13.27ppm(P),-2.54ppm(P’),2Jpp’=20.2Hz,3JpH=10.3Hz;
P,P-二甲基-P’-2,4,6-三甲基苯磺酰基(二氯亚甲基)双膦酸甲基三丁基铵盐,31P-NMR(CDCl3):13.53ppm(P),-2.81ppm(P’),2Jpp’=22.0Hz,3JpH=10.8Hz;
P,P-二甲基-P’-2,4,6-三异丙基苯磺酰基(二氯亚甲基)双膦酸甲基三丁基铵盐,31P-NMR(CDCl3):13.54ppm(P),-2.83ppm(P’),2Jpp’=21.9Hz,3JpH=10.8Hz;
P,P-二甲基-P’-d-10-樟脑磺酰基(二氯亚甲基)双膦酸甲基三丁基铵盐,31P-NMR(CDCl3):13.06ppm(P),-2.82ppm(P’),2Jpp’=20.7Hz,3JpH=10.7Hz;
P,P-二甲基-P’-新戊酰基(二溴亚甲基)双膦酸甲基三丁基铵盐,31P-NMR(CDCl3):15.16ppm(P),-0.90ppm(P’),2Jpp’=14.5Hz,3JpH=10.9Hz;
P,P-二甲基-P’-甲磺酰基(二溴亚甲基)双膦酸甲基三丁基铵盐,31P-NMR(CDCl3):12.99ppm(P),-2.83ppm(P’),2Jpp’=15.7Hz,3JpH=10.6Hz;
P, P-二甲基-P’-三氯甲磺酰基(二溴亚甲基)双膦酸甲基三丁基铵盐,31P-NMR(CDCl3):13.12ppm(P),-2.98ppm(P’),2Jpp’=15.4Hz;
P,P-二甲基-P’-p-甲苯磺酰基(二氯亚甲基)双膦酸甲基三丁基铵盐,31P-NMR(CDCl3):13.13ppm(P),-2.95ppm(P’),2Jpp’=15.1Hz,3JpH=10.8Hz;
P,P-二甲基-P’-新戊酰基(一溴亚甲基)双膦酸甲基三丁基铵盐,31P-NMR(CDCl3):20.51ppm(P),0.95ppm(P’),2Jpp=6.0Hz,2JpH=16.5Hz,3JpH=10.9Hz;
P,P-二甲基-P’-甲磺酰基(一溴亚甲基)双膦酸甲基三丁基铵盐,31P-NMR(CDCl3):17.46ppm(P),1.19ppm(P’),2Jpp=7.3Hz,2JpH=17.3Hz,3JpH=11.0Hz;
P,P-二甲基-P’-乙酰基(二氯亚甲基)双膦酸甲基三丁基铵盐,31P-NMR(CDCl3):13.71ppm(P),-4.10ppm(P’),2Jpp’=18.9Hz;
P,P-二甲基-P’-丙酰基(二氯亚甲基)双膦酸甲基三丁基铵盐,31P-NMR(CDCl3):14.57ppm(P),-1.61ppm(P’),2Jpp’=19.1Hz,3JpH=10.7Hz;
P,P-二甲基-P’-异戊酰基(二氯亚甲基)双膦酸甲基三丁基铵盐,31P-NMR(CDCl3):14.17ppm(P),-1.18ppm(P’),2Jpp’=18.3Hz,3JpH=10.7Hz;
P,P-二甲基-P’-二甲基氨基甲酰基(二氯亚甲基)双膦酸甲基三丁基铵盐,31P-NMR(CDCl3):14.80ppm(P),-1.62ppm(P’),2Jpp’=18.2Hz,3JpH=10.6Hz;
P,P-二甲基-P’-乙酰基(二溴亚甲基)双膦酸甲基三丁基铵盐,31P-NMR(CDCl3):14.73ppm(P),-2.00ppm(P’),2Jpp’=13.7Hz,3JpH=10.8Hz;
P,P-二甲基-P’-丙酰基(二溴亚甲基)双膦酸甲基三丁基铵盐,31P-NMR(CDCl3):14.17ppm(P),-1.40ppm(P’),2Jpp’=14.0Hz,3JpH=10.7Hz;
P,P-二甲基-P’-二甲基氨基甲酰基(二溴亚甲基)双膦酸甲基三丁基铵盐,31P-NMR(CDCl3):14.92ppm(P),-1.92ppm(P’),2Jpp’=14.0Hz;
P,P-二异丙基-P’-乙酰基(一氯亚甲基)双膦酸N-异丙基吡啶鎓盐,31P-NMR(CDCl3):14.49ppm(P),3.07ppm(P’),2Jpp=8.4Hz,2JpH=17.1Hz,3JpH=7.7Hz;
P,P-二异丙基-P’-新戊酰基(一氯亚甲基)双膦酸N-异丙基吡啶鎓盐,31P-NMR(CDCl3):15.02ppm(P),3.02ppm(P’),2Jpp=9.8Hz,2JpH=17.4Hz,3JpH=7.1Hz;
P,P-二异丙基-P’-新戊酰基(溴氯亚甲基)双膦酸N-异丙基吡啶鎓盐和P,P-二异丙基-P’-甲磺酰基(溴氯亚甲基)双膦酸N-异丙基吡啶鎓盐。
起始原料的制备
用作起始原料的一氯、二氯、一溴或(二溴亚甲基)双膦酸三酯类化合物可以通过例如用一当量的叔铵在无水的惰性溶剂中在约25-100℃的温度下处理相应的四元酯来制备,该反应的进程根据31P-NMR来判断。
下列实施例举例说明起始原料的制备:
将30.1g(0.1mol)(二氯亚甲基)双膦酸四甲酯溶解在60ml无水氯仿中并加入18.6g(0.1mol)无水三丁基胺。将该溶液回流混合4小时并在真空下蒸发溶剂。得到约为50g(理论值的100%)的几乎无色的油状三甲基(二氯亚甲基)双膦酸甲基三丁基铵盐,其浓度为98%(31P-NMR(CDCl3):15.50ppm(P),4.25ppm(P’),2Jpp=16.6Hz)。
实施例2:P,P-二甲基-P’-二甲基磷酰基(二氯亚甲基)双膦酸甲基三丁基铵盐及游离酸
将4.86g(0.01mol)三甲基(二氯亚甲基)双膦酸甲基三丁基铵盐溶解在50ml无水乙腈中并加入1.45g(0.01mole)二甲基氯亚磷酸盐,在回流下将该溶液搅拌约1小时(反应的进程根据31P-NMR来判断)。真空下蒸发溶剂,由此得到约5.6g(理论值的96%)褐色油状的P,P-二甲基-P’-二甲基磷酰基(二氯亚甲基)双膦酸甲基三丁基铵盐(31P-NMR(CDCl3):13.90ppm(P),-4.84ppm(P’),10.23(P”),2Jpp’=20.3Hz,2Jp’p”=27.7Hz,3JPH=10.7Hz,3JP”H=11.7Hz),其浓度约为90%且用酸处理该化合物可释放出相应的酸。
例如,可以按照类似方法制备下列磷酰基(二氯亚甲基)双膦酸及其季铵盐:
P,P-二甲基-P’-二异丙基磷酰基(二氯亚甲基)双膦酸甲基三丁基铵盐,31P-NMR(CDCl3):14.95ppm(P),-4.84ppm(P’),-13.98(P”),2Jpp’=20.6Hz,2Jp’p”=26.1Hz,3JPH=10.6Hz,3JP”H=7.8Hz;
P,P-二异丙基-P’-二甲基磷酰基(二氯亚甲基)双膦酸N-异丙基吡啶鎓盐,31P-NMR(CDCl3):9.22ppm(P),-3.74ppm(P’),-9.25(P”),2Jpp’=22.3Hz,2Jp’p”=27.4Hz;
P,P-二(三甲基甲硅烷基)-P’-二(三甲基甲硅烷基)磷酰基(二氯亚甲基)双膦酸甲基三丁基铵盐,31P-NMR(CDCl3):-7.38ppm(P),-4.51ppm(P’),-29.00(P”),2Jpp’=24.2Hz,2Jp’p”=22.6Hz。
实施例3:P,P,P’-三甲基-P’-新戊酰基(二氯亚甲基)双膦酸酯
将2.9g(0.01mol)P,P,P’-三甲基(二氯亚甲基)双膦酸酯和1.7g(0.014mol)新戊酰氯溶解在50ml无水乙腈中并将该溶液在回流下搅拌约1.5小时(反应的进程根据31P-NMR来判断)。在真空下蒸发溶剂和过量的试剂,由此得到约3.3g(理论值的90%)褐色油状的P,P,P’-三甲基-P’-新戊酰基(二氯亚甲基)双膦酸盐(31P-NMR(CDCl3):10.41ppm(P),9.17ppm(P’),2Jpp’=23.7Hz,3JPH=10.9Hz,3JP’H=10.9Hz)。
例如,可以采用类似方法制备下列(二氯亚甲基)双膦酸P,P,P’-三酯-P-单酐类化合物:
P,P,P’-三异丙基-P’-新戊酰基(二氯亚甲基)双膦酸酯(31P-NMR(CDCl3):6.40ppm(P),4.71ppm(P’),2Jpp’=26.2Hz,3JPH=6.5Hz,3JP’H=6.7Hz)。
P,P,P’-三异丙基-P’-甲磺酰基(二氯亚甲基)双膦酸酯(31P-NMR(CDCl3):5.32ppm(P),0.39ppm(P’),2Jpp’=24.8Hz,3JPH=6.4Hz,3JP’H=6.8Hz).
P,P,P’-二甲基-P’-三甲基甲硅烷-P’-新戊酰基(二氯亚甲基)双膦酸酯(31P-NMR(CDCl3):12.59ppm(P),-2.10ppm(P’),2Jpp’=22.7Hz,3JPH=11.0Hz)。
实施例4:P-甲基-P’-单甲基磷酰基(二氯亚甲基)双膦酸二哌啶鎓-甲基三丁基铵盐和游离酸
将2.9g(0.005mo1)P,P-二甲基-P’-二甲基磷酰基(二氯亚甲基)双膦酸甲基三丁基铵盐和12ml无水哌啶在约80℃下混合约1小时(反应进程根据31P-NMR判断),在真空下将过量的哌啶蒸发,由此得到3.5g(理论值的97%)褐色P-甲基-P’-甲基磷酰基(二氯亚甲基)双膦酸二哌啶鎓-甲基三丁基铵盐(31P-NMR(CDCl3):7.00ppm(P),-0.89ppm(P’),-7.51(P”),2Jpp’=16.7Hz,2JP’P”=28.9Hz,3JPH=10.0Hz,3JP”H=11.5Hz),其浓度约为90%且用酸处理该化合物释放出相应的酸。
实施例5:P,P-二甲基-P,P’-双(三氯乙酰基)(二氯亚甲基)双膦酸酯
将4.86g(0.01mol)P,P,P-三甲基(二氯亚甲基)双膦酸甲基三丁基铵盐和3.64g(0.02mol)三氯乙酰氯在50ml无水乙腈中、于回流下搅拌2小时并真空下蒸发溶剂,由此得到约8g的油状蒸发残余物,该残余物中含有约1∶1的P,P-二甲基-P’,P’-双(三氯乙酰基)(二氯亚甲基)双膦酸(31P-NMR(CDCl3):14.25ppm(P),0.11ppm(P’),2Jpp’=20.3Hz,3JPH=10.6Hz)和P,P-二甲基-P’-三氯乙酰基(二氯亚甲基)双膦酸甲基三丁基铵盐(参见实施例1)。
实施例6:P-甲基-P’-乙酰基(二氯亚甲基)双膦酸二钠盐和游离酸
将3.9g(0.01mol)P-甲基(二氯亚甲基)双膦酸二钠-哌啶鎓盐和40ml乙酸酐在室温下搅拌约2天。将混合物在冰水中冷却并过滤出沉淀,用丙酮洗涤并干燥,由此得到3.3g(理论值的96%)无色结晶状的P-甲基-P’-乙酰基(二氯亚甲基)双膦酸二钠盐(31P-NMR(DO2):9.03ppm(P),4.01ppm(P’),2Jpp’=16.5Hz,3JPH=10.4Hz),其浓度约为100%且用酸处理该化合物释放出相应的酸。
例如,可以按照类似方法制备下列对称(二氯亚甲基)双膦酸酯酐及其盐:
P-甲基-P’-新戊酰基(二氯亚甲基)双膦酸二(二乙基铵)盐(31P-NMR(CDCl3):5.68ppm(P),1.78ppm(P’),2Jpp’=25.1Hz,3JPH=9.9Hz)。
实施例7:P,P’-二乙酰基(二氯亚甲基)双膦酸二钠盐和游离酸
将6.7g(0.02mol)(二氯亚甲基)双膦酸四钠盐和220ml乙酸酐在约60℃下搅拌约60小时(反应的进程用31P-NMR判断)并冷却。过滤出沉淀并用丙酮洗涤,在水-乙醇中重结晶。干燥后,得到7.1g(理论值的95%)无色结晶状的P,P’-二乙酰基(二氯亚甲基)双膦酸二钠盐(31P-NMR(D2O):2.84ppm(P和P’)),其浓度约为100%且用酸处理可释放出相应的酸。
例如,按照类似方法可以制备下列对称的(二氯亚甲基)双膦酸二酐类混合物:
P,P’-二丁酰基(二氯亚甲基)双膦酸二钠盐,31P-NMR(D2O):2.90ppm(P和P’);
P,P’-二戊酰基(二氯亚甲基)双膦酸二钠盐,31P-NMR(D2O):3.13ppm(P和P’);
P,P’-二(新戊酰基)(二氯亚甲基)双膦酸二钠盐,31P-NMR(D2O):3.74ppm(P和P’);
P,P’-二(苯甲酰基)(二氯亚甲基)双膦酸二钠盐,31P-NMR(D2O):3.85ppm(P和P’);
P,P’-二(异丁酰基)(二氯亚甲基)双膦酸二钠盐,31P-NMR(D2O):2.75ppm(P和P’);
P,P’-二己酰基(二氯亚甲基)双膦酸二钠盐,31P-NMR(D2O):3.03ppm(P和P’)。
实施例8:P,P-双(二乙基酰氨基)-P’-乙氧基羰基(二氯亚甲基)双膦酸甲基三丁基铵盐和游离酸
将1.895g(0.003mol)P,P-双(二乙基酰氨基)-P’-甲基(二氯亚甲基)双膦酸甲基三丁基铵盐溶解在11ml无水乙腈中。用夹套将混合物加热并搅拌直至内温达到80℃为止。在15分钟内向混合物中滴加80℃的溶液,该溶液在11ml无水乙腈中含有355mg(0.003mol)氯甲酸乙酯(ethylchloroformate)。将混合物在内温为80-82℃的同时搅拌3小时45分钟并蒸发至千。放置结晶过夜,由此得到2.1g的P,P-双(二乙基酰氨基)-P’-乙氧基羰基(二氯亚甲基)双膦酸甲基三丁基铵盐(31P-NMR(D2O):27.11ppm(P),0.73ppm(P’),2Jpp=22.3Hz),其浓度约为90%且用酸处理该化合物释放出相应的酸。
实施例9:P,P-二(乙氧基羰基)(二氯亚甲基)双膦酸二(甲基三丁基铵)盐和游离酸
将3.36g(0.05mol)P,P’-二甲基(二氯亚甲基)双膦酸双(甲基三丁基铵)盐溶解在20ml无水乙腈中,向该溶液中加入217g(0.02mol)氯甲酸乙酯并在约75℃下混合30分钟。真空下蒸发溶剂,由此得到约5.03g(理论值的95%)油状的P,P’-二(乙氧基羰基)(二氯亚甲基)双膦酸二(甲基三丁基铵)盐(31P-NMR(CDCl3):0.40ppm(P和P’)),其浓度约为85%且用酸处理可释放出相应的酸。
例如,按照类似方法可以制备下列对称的(二氯亚甲基)双膦酸二酐:
P,P’-双(二甲基羰基)(二氯亚甲基)双膦酸二钠盐(31P-NMR(D2O):2.53ppm(P和P’))。
实施例10:P,P’-二甲基-P’-新戊酰基-P-三甲基甲硅烷基(二氯亚甲基)双膦酸酯
将2.2g(0.004mol)P,P-二甲基-P’-新戊酰基(二氯亚甲基)双膦酸甲基三丁基铵盐溶解在20ml无水乙腈中并将该溶液冷却至0℃,在搅拌和0-5℃的条件下加入0.45g(0.0042mol)氯三甲基硅烷的5ml无水乙腈溶液。加入完毕后,在0-5℃下将该混合物搅拌10分钟,撤去冷却继续搅拌1小时,真空下蒸发溶剂,由此得到褐色油状的所需产物,其纯度约为80%(31P-NMR(CDCl3):12.59ppm(P),-2.10ppm(P’),2Jpp’=22.7Hz,3JPH=11.0Hz)。
实施例11:P,P’-二(十四碳酰基)(二氯亚甲基)双膦酸二吡啶鎓盐
将1.0g(4.08mmol)(二氯亚甲基)双膦酸和10ml无水四氢呋喃混合并在约23℃下加入2.0g(8.16mmol)十四碳酰氯和1.3g(16.32mmol)无水吡啶。在约23℃下将该灰色混悬液搅拌3小时并真空下蒸发至干。产量为4.3g(理论值的100%),其中3.4g是P,P’-二(十四碳酰基)(二氯亚甲基)双膦酸二吡啶鎓盐(31P-NMR(CDCl3):1.65ppm(P和P’)),其浓度约为100%(32P-NMR),和0.9g盐酸吡啶鎓盐。
实施例12:单己酰氧基(二氯亚甲基)双膦酸三钠盐
将5.0g(15.0mmol)的(二氯亚甲基)双膦酸四钠盐和23.1g(108.2mmol)己酸酐在约85℃下混合7小时并在室温下混合约18小时(反应的进程由31P-NMR判断)。过滤该混合物并用2ml丙酮洗涤且在真空下干燥,由此得到约5.4g(理论值的88%)结晶状的单己酰氧基(二氯亚甲基)双膦酸三钠盐(31P-NMR(D2O):7.57ppm(P),4.59ppm(P),2Jpp=17.6Hz),其浓度约为81%,起始原料的浓度为16%,同时P,P’-二己酰氧基(二氯亚甲基)双膦酸二钠盐的浓度是3%(31P-NMR)。
实施例13:前药分子的体外试验
体外试验中采用的HPLC法
用反相/离子对HPLC法(对于氯甲双磷酸盐(clodronate)的测定是无梯度过程;在同时测定氯甲双磷酸盐及其前药分子时是梯度过程)试验氯甲双磷酸盐和氯甲双磷酸盐的前药分子,其中对化合物的测定是基于为未蒸发化合物所引起的光散射量。
试验设备:Merck LaChrom HPLC(Merck Hitachi Ltd.日本)Kromasil 100RP-C8(250×4.6内径,5μm)(Higgins Analytical Inc.USA)。
洗脱剂:
无梯度过程:加醇/乙酸铵缓冲液(3:97,pH4.6),其中含有2.25%丁胺作为离子对试剂,流速1.2ml/min。
梯度过程:甲醇(在1-3分钟3%-→40-60%,乙酸铵(pH4.6),其中含有2.25%丁胺作为离子对试剂,流速为1.2ml/min。
检测器:Sedex 55光散射检测器(Sedere,法国)
设定:检测器温度70℃,蒸气压(过滤空气)2.Bar
前药分子的水溶性
在室温下测定前药分子在磷酸盐缓冲液中的水溶解度。
将待测过量的化合物溶解于约5ml磷酸盐缓冲液。将悬浮液搅拌2小时,过滤悬浮液,滤液的前药浓度并用HPLC测定。用同样的方法来测定氯甲双磷酸盐在水中的溶解度。表1中列出测定的化合物的水溶解度。
表1:氯甲双磷酸盐及其前药分子在pH7.4下的水溶解度
前药 水溶解性
(mg/ml)
氯甲双磷酸盐 397
乙酸二酐(实施例7) 190
丁酸二酐(实施例7) 172
新戊酸二酐(实施例7) 23.5
苯甲酸二酐(实施例7) 6.0
前药分子的分配系数
通过测定化合物在pH7.4和2.0下的分配系数来研究试验化合物的脂溶性。试验是在辛醇和缓冲液的混合物中进行。
当采用辛醇/缓冲液测定法时,将混合物搅拌过夜使所用1-辛醇和磷酸盐缓冲液(50mM,pH7.40,μ=0.15)相互饱和。分离各相并在缓冲相中配制所需浓度的前药标准溶液。将适当体积的1-辛醇和标准的磷酸盐缓冲溶液混合并将混合物剧烈振摇60分钟。振摇后,分离各相,根据上述HPLC方法测定缓冲相中化合物在分配前后的浓度。根据下式计算出分配系数P:
其中
Ci=被测化合物在分配前的浓度
Ca=被测化合物在分配后的浓度
Va=缓冲相的体积
Vo=辛醇相的体积
前药分子的分配系数值(logP)如表2所示:
表2:被测前药分子的分配系数
前药 log P(pH7.4) LogP(pH2.0)
乙酸二酐(实施例7) -2.2 -1.4
丁酸二酐(实施例7) -2.4 -1.9
新戊酸二酐(实施例7) -2.3 -2.0
苯甲酸二酐(实施例7) -2.4 -1.5
注意:氯甲双磷酸盐的分配系数无法用所述方法测定,因为该化合物极易溶于水(氯甲双磷酸盐单乙酯的LogP值是-5.4(《医学和化学杂志》34:2338-2343,1991))。
前药分子的化学水解
在磷酸盐缓冲液(50mM,μ=0.15)中测定前药分子在pH2.0和7.4及37℃下时的化学水解。
将试验化合物溶解在10.0ml磷酸盐缓冲液中。在水浴中用磁搅拌器将该溶液搅拌24-1000小时,在规定时间取样并用HPLC进行分析。根据结果绘制出假性I级的曲线图,其中将残余化合物的量表示为时间的函数。由得到的线性图形的斜率(kk),计算出解离常数k(K=2.303×-kk),由此计算出前药分子在所述环境中的半衰期T1/2(T1/2=0.693/k)。被测化合物的半衰期如表3所示。
前药分子的酶促水解(在血浆中)
在血浆/缓冲液混合物(80%-20%)中,在pH7.40和37℃下测定前药分子的酶促水解率。
将被测化合物溶解在缓冲液中,溶解后,加入37℃的血浆。用磁搅拌器搅拌该溶液并在1-360分钟的时间间隔(取决于被测的分子)从该混合物中取0.25ml样品,向样品中加入0.25ml甲醇(变性蛋白)。将样品离心,使澄清的上清液蒸发至干,将残余物溶解在HPLC法的洗脱剂中,用HPLC测定残余前药的浓度和氯甲双磷酸盐的含量。由所得的浓度绘制出一级曲线(残余前药量表示为时间的函数),由此测定出解离常数和半衰期(T1/2)。被测化合物的半衰期如表3所示。
表3:被测前药分子在缓冲液(pH2.0和7.4)和80%
血浆(pH7.4)、于37℃下的半衰期
前药 T1/2 T1/2 T1/2
pH2.0 pH7.4 血浆
乙酸二酐(实施例7) 0.7h 15.2h 1)
丁酸二酐(实施例7) 0.8h 31.3h 2)
新戊酸二酐(实施例7) 8.6h 790h 3.3±0.6h
苯甲酸二酐(实施例7) 286h 235h 3)
1)在第一个样品(1分钟)中,释放出101.6±1.2%(平均值±SE,n=3)的氯甲双磷酸盐;
2)在第一个样品(1分钟)中,释放出98.0±6.9%(平均值±SE,n=3)的氯甲双磷酸盐;
3)在第一个样品(1分钟)中,释放出91.4±8.6%(平均值±SE,n=3)的氯甲双磷酸盐。
实施例14:对PTH诱发性骨吸收的体外作用或其化合物在体内的吸收和水解
对小鼠颅盖的PTH诱发性骨吸收的影响
在处死前4天时皮下注射45Ca来标记新生小鼠。从顶骨显微解剖得到颅盖骨碎片,将培养基用消炎痛预保温,洗涤,随后在含有前药或不含有前药的条件下培养3天。用甲状旁腺激素(PTH,10nM)刺激骨吸收,测定化合物对这种受刺激的骨吸收的影响。如表4所示,化合物对吸收作用起抑制作用。双膦酸前药的抑制作用甚至高于母体药物。
化合物 浓度 对于吸收的抑制作用
μmol/l 100(PTH-X)/PTH,%
1 100 48.7
2 100 64.8
3 100 50.5
4 100 53.9
氯甲双磷酸 100 43.2
(母体药物)
化合物1=乙酸二酐(P,P’-二乙酰基(二氯亚甲基)双膦酸二钠盐)
化合物2=P,P’-二(异丁酰基)(二氯亚甲基)双膦酸二钠盐
化合物3=P,P’-二(十四碳酰基)(二氯亚甲基)双膦酸二钠盐
化合物4=P,P’-二(十八碳酰基)(二氯亚甲基)双膦酸二钠盐
氯甲双磷酸盐=二氯亚甲基双膦酸二钠盐
在体内的吸收和水解
在禁食大鼠中研究化合物在体内的吸收和水解。从给药后72小时内排泄到尿中的总量来测定化合物的吸收作用。为了测试口服给药的生物利用度,将口服给药后的排出量与静脉内给药后的排出量进行比较。用质谱-选择或氮磷检测的气相色谱来分析尿样的母体药物。结果如表5所示,双膦酸盐前药的生物利用度比母体化合物的高。
表5:双膦酸盐前药的的吸收
化合物,剂量100μmol/kg 生物利用度,%
1 4.5
2 8.78
3 4.18
4 23.37
氯甲双磷酸盐 2.17
(母体药物)
所述化合物与表4相同。
Claims (11)
1.如通式I所示的亚甲基双膦酸酐衍生物,包括这些化合物的立体异构体,例如几何异构体和旋光异构体,以及这些化合物的可药用盐:
其中基团Y1、Y2、Y3和Y4是OR1、NR2R3、OCOR1、OCONR2R3、O(CO)OR1、O(SO2)R1、O(SO2)OR1或OP(O)R2(OR3),其中R1、R2和R3彼此独立地表示氢、任选取代且任选不饱和的直链或支链C1-C22烷基,芳基、或甲硅烷基SiR3、其中R是指C1-C4烷基、苯基、取代苯基、C1-C4烷基和/或苯基类的混合基团;条件是在式I中至少一个Y1、Y2、Y3和Y4基团不是OR1或NR2R3;
Q1和Q2彼此独立地表示氢、氟、氯、溴或碘。
2.如权利要求1所述的亚甲基双膦酸酐类衍生物,其特征在于式I中的Q1和Q2均为氯。
3.如权利要求1或2中的亚甲基双膦酸酐衍生物,其特征在于式I的Y1、Y2、Y3和Y4中的两个基团是OCOR1,其中R1如权利要求1所述定义。
4.如权利要求3所述的亚甲基双膦酸酐类衍生物,其特征在于R1是直链或支链C1-C22烷基或苯基。
5.如权利要求1或2所述的亚甲基双膦酸酐类衍生物,其特征在于式I的Y1、Y2、Y3和Y4中的两个基团是OR1,其中R1如权利要求1所述定义。
6.如权利要求5所述的亚甲基双膦酸酐类衍生物,其特征在于R1是直链或支链C1-C22烷基或苯基。
7.如权利要求3所述的亚甲基膦酸酐类衍生物,其特征在于式I的Y1、Y2、Y3和Y4中的第三个基团是选自烷基磺酰基、低级烷基羧基、苯甲酰基、芳基磺酰基、单-和二-低级烷基磷酰基。
8.如权利要求5所述的亚甲基膦酸酐类衍生物,其特征在于式I的Y1、Y2、Y3和Y4中的第三个基团是选自烷基磺酰基、低级烷基羧基、苯甲酰基、芳基磺酰基、单-和二-低级烷基磷酰基。
9.如权利要求1所述的亚甲基膦酸酐类衍生物,其特征在于它是:
P,P’-二乙酰基(二氯亚甲基)双膦酸二钠盐或游离酸;
P,P’-二丁酰基(二氯亚甲基)双膦酸二钠盐或游离酸;
P,P’-二(新戊酰基)(二氯亚甲基)双膦酸二钠盐或游离酸;
P,P’-二(苯甲酰基)(二氯亚甲基)双膦酸二钠盐或游离酸;
P,P’-二(异丁酰基)(二氯亚甲基)双膦酸二钠盐或游离酸;
P,P’-二(十四碳酰基)(二氯亚甲基)双膦酸二钠盐或游离酸;或
P,P’-二(十八碳酰基)(二氯亚甲基)双膦酸二钠盐或游离酸。
10.一种制备如权利要求1所述的亚甲基双膦酸酐类衍生物的方法,其特征在于:
a)将如式II所示的起始化合物选择性地与指定的酸衍生物(Z-A)反应,式II中至少一个或全部的X1-X4基团彼此独立地为OH或OM,其中M可以是金属或铵,和Q1和Q2是氢或卤素,式Z-A中A是指OCOR1、OCONR2R3、O(CO)OR1、O(SO2)R1、O(SO2)OR1或OP(O)R2(OR3)并且Z是卤素或类似基团;或
b)将如式II所示的起始化合物与选定的酸(A-OH)(Z=OH)或其金属盐(A-OM)(Z=OM)反应,随后例如通过用水水解脱去附加基团X和任选的附加基团Y;式II中至少一个或全部的X1-X4基团彼此独立地为卤素或卤素类似基团,其中A和M具体与a)相同的含义,或
c)为了制备三-、二-或单偏酐衍生物I,将上述a)或b)所得的四元酐选择性水解。
11.药物制剂,其特征在于它含有作为活性药物的如权利要求1所述的式I的亚甲基双膦酸酐类衍生物。
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FI974001A FI104901B (fi) | 1997-10-20 | 1997-10-20 | Uudet metyleenibisfosfonihappojohdannaiset |
FI974001 | 1997-10-20 |
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US (1) | US6326363B1 (zh) |
EP (1) | EP1032578A1 (zh) |
JP (1) | JP2001520232A (zh) |
KR (1) | KR20010031269A (zh) |
CN (1) | CN1147497C (zh) |
AU (1) | AU740355B2 (zh) |
BG (1) | BG104452A (zh) |
BR (1) | BR9813102A (zh) |
CA (1) | CA2306080A1 (zh) |
EE (1) | EE04061B1 (zh) |
FI (1) | FI104901B (zh) |
HU (1) | HUP0004386A3 (zh) |
IL (1) | IL135639A0 (zh) |
NO (1) | NO20002006L (zh) |
NZ (1) | NZ504390A (zh) |
PL (1) | PL340055A1 (zh) |
RU (1) | RU2205833C2 (zh) |
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NO313180B1 (no) * | 2000-07-04 | 2002-08-26 | Anticancer Therapeutic Inv Sa | Bensökende alfapartikkel emitterende radiofarmasöytika |
US7862552B2 (en) | 2005-05-09 | 2011-01-04 | Boston Scientific Scimed, Inc. | Medical devices for treating urological and uterine conditions |
WO2008024169A1 (en) * | 2006-07-21 | 2008-02-28 | Glsynthesis, Inc. | Reactive pyrophosphoric and bisphosphonic acid derivatives and methods of their use |
WO2010059215A1 (en) | 2008-11-20 | 2010-05-27 | Glsynthesis Inc. | Novel antithrombotic diadenosine tetraphosphates and related analogs |
CN107011380A (zh) * | 2016-01-28 | 2017-08-04 | 臧伟 | 一种二膦酸衍生物及含二膦酸衍生物的组合物治疗骨折的应用 |
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US4447256A (en) | 1977-07-20 | 1984-05-08 | Nissan Chemical Industries, Ltd. | N-(Unsubstituted or substituted pyridyl)aminomethylene-diphosphonic acids, herbicidal compositions containing same, their use for herbicides, and process for preparing same |
DE2758580A1 (de) | 1977-12-29 | 1979-07-05 | Hoechst Ag | Verfahren zur herstellung von phosphin- und phosphonsaeure-anhydriden |
US4973576A (en) | 1987-03-10 | 1990-11-27 | Yamanouchi Pharmaceutical Co., Ltd. | Bisphophonic acid derivatives and pharmaceutical compositions containing the same |
US4933472A (en) | 1988-04-08 | 1990-06-12 | Yamanouchi Pharmaceutical Co., Ltd. | Substituted aminomethylenebis(phosphonic acid) derivatives |
EP0356866A3 (en) | 1988-08-29 | 1991-03-27 | E.R. SQUIBB & SONS, INC. | Phosphorus-containing squalene synthetase inhibitors and method |
FI83421C (fi) * | 1989-06-21 | 1991-07-10 | Huhtamaeki Oy | Foerfarande foer framstaellning av farmakologiskt anvaendbara metylenbisfosfonsyraderivat. |
EP0416689B1 (en) * | 1989-09-06 | 1995-11-29 | Merck & Co. Inc. | Acyloxymethyl esters of bisphosphonic acids as bone resorption inhibitors |
FI89365C (fi) * | 1990-12-20 | 1993-09-27 | Leiras Oy | Foerfarande foer framstaellning av nya farmakologiskt anvaendbara metylenbisfosfonsyraderivat |
FI89366C (fi) | 1990-12-20 | 1993-09-27 | Leiras Oy | Foerfarande foer framstaellning av nya farmakologiskt anvaendbara metylenbisfosfonsyraderivat |
FI89364C (fi) * | 1990-12-20 | 1993-09-27 | Leiras Oy | Foerfarande foer framstaellning av nya, farmakologiskt anvaendbara metylenbisfosfonsyraderivat |
ATE127808T1 (de) | 1991-04-06 | 1995-09-15 | Fisons Plc | Atp-analogen. |
TW237386B (zh) | 1992-04-15 | 1995-01-01 | Ciba Geigy | |
TW326045B (en) * | 1993-02-10 | 1998-02-01 | Astra Pharma Prod | N-alkyl-2-substituted ATP analogues the invention relates to a compound of formula (I) and its pharmaceutically acceptable salt which can be used for inhibition of platelet aggregation. |
US5462932A (en) | 1994-05-17 | 1995-10-31 | Merck & Co., Inc. | Oral liquid alendronate formulations |
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HUP0004386A2 (hu) | 2001-04-28 |
JP2001520232A (ja) | 2001-10-30 |
CN1276793A (zh) | 2000-12-13 |
FI974001A0 (fi) | 1997-10-20 |
FI104901B (fi) | 2000-04-28 |
AU9543798A (en) | 1999-05-10 |
US6326363B1 (en) | 2001-12-04 |
CA2306080A1 (en) | 1999-04-29 |
KR20010031269A (ko) | 2001-04-16 |
NO20002006L (no) | 2000-06-15 |
AU740355B2 (en) | 2001-11-01 |
WO1999020634A1 (en) | 1999-04-29 |
BR9813102A (pt) | 2000-08-22 |
TR200001055T2 (tr) | 2000-09-21 |
FI974001A (fi) | 1999-04-21 |
EE200000239A (et) | 2001-08-15 |
EE04061B1 (et) | 2003-06-16 |
NZ504390A (en) | 2001-10-26 |
EP1032578A1 (en) | 2000-09-06 |
NO20002006D0 (no) | 2000-04-17 |
HUP0004386A3 (en) | 2002-08-28 |
RU2205833C2 (ru) | 2003-06-10 |
PL340055A1 (en) | 2001-01-15 |
IL135639A0 (en) | 2001-05-20 |
BG104452A (en) | 2000-12-29 |
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