CN1077792C - 用作治疗剂的吡啶基二膦酸酯 - Google Patents
用作治疗剂的吡啶基二膦酸酯 Download PDFInfo
- Publication number
- CN1077792C CN1077792C CN95193416A CN95193416A CN1077792C CN 1077792 C CN1077792 C CN 1077792C CN 95193416 A CN95193416 A CN 95193416A CN 95193416 A CN95193416 A CN 95193416A CN 1077792 C CN1077792 C CN 1077792C
- Authority
- CN
- China
- Prior art keywords
- methylene
- amino
- pyridine radicals
- diphosphonic acid
- ethyl
- 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 - Lifetime
Links
- 230000001225 therapeutic effect Effects 0.000 title description 2
- 208000001132 Osteoporosis Diseases 0.000 claims abstract description 9
- 201000011510 cancer Diseases 0.000 claims abstract description 6
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 69
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 68
- LFLCPWCZNJYHRD-UHFFFAOYSA-N C(C)P(=O)(O)OP(=O)O Chemical compound C(C)P(=O)(O)OP(=O)O LFLCPWCZNJYHRD-UHFFFAOYSA-N 0.000 claims description 46
- 239000000203 mixture Substances 0.000 claims description 28
- -1 ester compounds Chemical class 0.000 claims description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 125000002252 acyl group Chemical group 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229920006395 saturated elastomer Polymers 0.000 claims description 7
- YBHPRCXSMNLUID-UHFFFAOYSA-N N1=C(C=CC=C1)NC=CCP(=O)(O)OP(=O)O Chemical compound N1=C(C=CC=C1)NC=CCP(=O)(O)OP(=O)O YBHPRCXSMNLUID-UHFFFAOYSA-N 0.000 claims description 6
- SANVBGMJTJWZAY-UHFFFAOYSA-N N1=C(C=CC=C1)NOP(O)(=O)CP(O)(O)=O Chemical compound N1=C(C=CC=C1)NOP(O)(=O)CP(O)(O)=O SANVBGMJTJWZAY-UHFFFAOYSA-N 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical class [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- WQZCQSOBKLWIJW-UHFFFAOYSA-N N1=CC=C(C=C1)NC=CCP(=O)(O)OP(=O)O Chemical compound N1=CC=C(C=C1)NC=CCP(=O)(O)OP(=O)O WQZCQSOBKLWIJW-UHFFFAOYSA-N 0.000 claims description 4
- 125000004423 acyloxy group Chemical group 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 3
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- 239000004575 stone Substances 0.000 claims 1
- 150000002148 esters Chemical class 0.000 abstract description 13
- 208000010191 Osteitis Deformans Diseases 0.000 abstract description 2
- 208000027868 Paget disease Diseases 0.000 abstract description 2
- 208000027202 mammary Paget disease Diseases 0.000 abstract description 2
- 208000020084 Bone disease Diseases 0.000 abstract 2
- 206010028980 Neoplasm Diseases 0.000 abstract 1
- OEAFYMDEEMRBOS-UHFFFAOYSA-N [phosphono-(pyridin-2-ylamino)methyl]phosphonic acid Chemical class OP(O)(=O)C(P(O)(O)=O)NC1=CC=CC=N1 OEAFYMDEEMRBOS-UHFFFAOYSA-N 0.000 abstract 1
- 230000036210 malignancy Effects 0.000 abstract 1
- 230000000010 osteolytic effect Effects 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 29
- 241000700159 Rattus Species 0.000 description 14
- 210000000988 bone and bone Anatomy 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 229940122361 Bisphosphonate Drugs 0.000 description 9
- 208000006386 Bone Resorption Diseases 0.000 description 9
- 239000004098 Tetracycline Substances 0.000 description 9
- 230000024279 bone resorption Effects 0.000 description 9
- 235000019364 tetracycline Nutrition 0.000 description 9
- 150000003522 tetracyclines Chemical class 0.000 description 9
- 210000002700 urine Anatomy 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 8
- 229960002180 tetracycline Drugs 0.000 description 8
- 229930101283 tetracycline Natural products 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- JJJOZVFVARQUJV-UHFFFAOYSA-N 2-ethylhexylphosphonic acid Chemical compound CCCCC(CC)CP(O)(O)=O JJJOZVFVARQUJV-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 210000000689 upper leg Anatomy 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 150000004663 bisphosphonates Chemical class 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 239000003205 fragrance Substances 0.000 description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 239000011707 mineral Substances 0.000 description 4
- 238000010254 subcutaneous injection Methods 0.000 description 4
- 239000007929 subcutaneous injection Substances 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 108090000445 Parathyroid hormone Proteins 0.000 description 3
- 125000006295 amino methylene group Chemical group [H]N(*)C([H])([H])* 0.000 description 3
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical group OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 3
- 230000003203 everyday effect Effects 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 238000001819 mass spectrum Methods 0.000 description 3
- 230000002503 metabolic effect Effects 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 210000002997 osteoclast Anatomy 0.000 description 3
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 3
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 230000002269 spontaneous effect Effects 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- 102100036893 Parathyroid hormone Human genes 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000001054 cortical effect Effects 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- 210000003141 lower extremity Anatomy 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 230000002980 postoperative effect Effects 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 210000003497 sciatic nerve Anatomy 0.000 description 2
- 108010048734 sclerotin Proteins 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- UGBLISDIHDMHJX-UHFFFAOYSA-N 1-(4-fluorophenyl)-4-[4-(2-methoxyphenyl)piperazin-1-yl]butan-1-one;hydrochloride Chemical compound [Cl-].COC1=CC=CC=C1N1CC[NH+](CCCC(=O)C=2C=CC(F)=CC=2)CC1 UGBLISDIHDMHJX-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- JVVRJMXHNUAPHW-UHFFFAOYSA-N 1h-pyrazol-5-amine Chemical class NC=1C=CNN=1 JVVRJMXHNUAPHW-UHFFFAOYSA-N 0.000 description 1
- BMTSZVZQNMNPCT-UHFFFAOYSA-N 2-aminopyridin-3-ol Chemical compound NC1=NC=CC=C1O BMTSZVZQNMNPCT-UHFFFAOYSA-N 0.000 description 1
- NMCBWICNRJLKKM-UHFFFAOYSA-N 3-(benzyloxy)pyridin-2-amine Chemical compound NC1=NC=CC=C1OCC1=CC=CC=C1 NMCBWICNRJLKKM-UHFFFAOYSA-N 0.000 description 1
- LLWFWIZOFFLRKC-UHFFFAOYSA-N 3-phenylmethoxypyridine Chemical compound C=1C=CC=CC=1COC1=CC=CN=C1 LLWFWIZOFFLRKC-UHFFFAOYSA-N 0.000 description 1
- 238000004679 31P NMR spectroscopy Methods 0.000 description 1
- MNRPDCYOPOOILG-UHFFFAOYSA-N 6-chloro-n-(diethoxyphosphorylmethyl)pyridin-3-amine Chemical class CCOP(=O)(OCC)CNC1=CC=C(Cl)N=C1 MNRPDCYOPOOILG-UHFFFAOYSA-N 0.000 description 1
- QAJYCQZQLVENRZ-UHFFFAOYSA-N 6-chloropyridin-3-amine Chemical compound NC1=CC=C(Cl)N=C1 QAJYCQZQLVENRZ-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 102000003982 Parathyroid hormone Human genes 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 206010061363 Skeletal injury Diseases 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- 150000004075 acetic anhydrides Chemical class 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 150000003927 aminopyridines Chemical class 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 210000001229 azygos vein Anatomy 0.000 description 1
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 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
- 238000005574 benzylation reaction Methods 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 125000005997 bromomethyl group Chemical group 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- RMRJXGBAOAMLHD-IHFGGWKQSA-N buprenorphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)CN2CC1CC1 RMRJXGBAOAMLHD-IHFGGWKQSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- ACSIXWWBWUQEHA-UHFFFAOYSA-N clodronic acid Chemical compound OP(O)(=O)C(Cl)(Cl)P(O)(O)=O ACSIXWWBWUQEHA-UHFFFAOYSA-N 0.000 description 1
- 229960002286 clodronic acid Drugs 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000006310 cycloalkyl amino group Chemical group 0.000 description 1
- 238000011157 data evaluation Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- XQRLCLUYWUNEEH-UHFFFAOYSA-L diphosphonate(2-) Chemical class [O-]P(=O)OP([O-])=O XQRLCLUYWUNEEH-UHFFFAOYSA-L 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 150000002463 imidates Chemical class 0.000 description 1
- 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 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 210000002414 leg Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 229940102859 methylene diphosphonate Drugs 0.000 description 1
- 238000001531 micro-dissection Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 235000021590 normal diet Nutrition 0.000 description 1
- 239000000199 parathyroid hormone Substances 0.000 description 1
- 229960001319 parathyroid hormone Drugs 0.000 description 1
- 210000003455 parietal bone Anatomy 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003009 phosphonic acids Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229940040944 tetracyclines Drugs 0.000 description 1
- 230000036325 urinary excretion Effects 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Physical Education & Sports Medicine (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Rheumatology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Diabetes (AREA)
- Nutrition Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Detergent Compositions (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明涉及某些选择性环取代的吡啶基氨基亚甲基二膦酸四烷基酯(Ⅰ)以及其治疗诸如由于恶性肿瘤的溶骨病、佩吉特病和原发性及继发性骨质疏松症等骨病的用途。
Description
本发明涉及用作治疗剂，特别是用于骨病的特殊吡啶基二膦酸四酯。
二膦酸酯是用于治疗各种起源的病理性骨损伤的治疗剂，例如由于恶性肿瘤的溶骨病、佩吉特病(Paget’s disease)和骨质疏松症。它们是生理性无机焦磷酸酯的类似物。二膦酸酯的基本P-C-P结构使其可通过改变碳原子侧链或通过加到磷酸酯上而形成许多不同化合物。
一般而言，二膦酸酯可抑制破骨细胞，该细胞负责骨的吸收。已知的结合在骨质上的二膦酸酯可进入再吸收的破骨细胞并降低破骨细胞的活性。它们可于体外及体内抑制骨吸收。从胃肠道有限的吸收、于骨组织中迅速消失以及尿中恒定的排泄都是已知二膦酸酯的特性。
本发明基于提供具有高口服生物利用度和对骨的低亲合力的二膦酸酯衍生物。这为了避免副作用而不削减抗吸收活性。
美国专利4447256、德国专利2831578(Suzuki等)、日本专利55089210、日本专利55098105、日本专利55043054、日本专利55043055(Nissan Chemicalindustres)公开了制备某些吡啶基氨基亚甲基二膦酸四烷基酯的方法。根据这些专利，该化合物可用作除草剂。
欧洲专利337706(Isomura等)中公开了环基和杂环基取代的氨基亚甲基二膦酸四酯的制备，其中的环取代基为部分或全部饱和。四酯未经检测。
美国专利4973576(Sakamoto等)公开了某些异噁唑基取代的氨基亚甲基二膦酸四烷基酯，但是它们基本上是在关节炎中试验的。其口服生物利用度低。
欧洲专利282309公开了吡咯氨基亚甲基二膦酸及低级烷基酯。四酯未经检测。
欧洲专利325482公开了环烷基氨基亚甲基二膦酸及酯。四酯未经检测。
本发明涉及具有新药理和药代动力学特征的吡啶基二膦酸酯。这些新吡啶基二膦酸酯在体外不能抑制骨吸收，但是它们可抑制体内骨吸收。
吡啶基二膦酸酯不与骨质结合，它们似乎需要新陈代谢活化。
因此本发明涉及用作治疗活性药物的吡啶基氨基亚甲基二膦酸四烷基酯，其选择性在吡啶环上取代，具体为通式I的亚甲基二膦酸衍生物
通式中R1至R4各自为直链或支链饱和C1-C5烷基，X和Y各自独立地为氢、直链或支链饱和C1-C5烷基、卤素、羟基、C1-C5烷氧基、苄氧基、酰氧基、硝基、三氟甲基或NR5R6，其中R5和R6相同或不同，可为氢、C1-C5烷基或酰基。
亚甲基二膦酸酯骨架中的基团X和Y以及氨基可在吡啶环的2至6位任一上取代。基团X和Y优选为氢或羟基，后者优选为一或两个羟基。吡啶基优选为2-吡啶基。
卤素为氟、氯、溴或碘。
C1-C5烷基为直链或支链，例如甲基，乙基，正异丙基，正、异和叔丁基或者戊基，优选甲基或乙基。定义X和Y烷氧基中的烷基具有如上含义，优选甲基或乙基。
定义X和Y酰氧基中的酰基，或者定义R5和R6的酰基优选为低级烷基羰基，其中烷基含有1至5个碳原子并且具有如上含义，优选甲基和乙基。基团R1至R4优选都相同，乙基更好。
本发明优选的化合物如下：
[(2-吡啶基氨基)亚甲基]二膦酸四乙酯
[[(3-羟基-2-吡啶基)氨基]亚甲基]二膦酸四乙酯
[[(6-甲氧基-3-吡啶基)氨基]亚甲基]二膦酸四乙酯
[(4-吡啶基氨基)亚甲基]二膦酸四乙酯
[[(5-氯-2-吡啶基)氨基]亚甲基]二膦酸四乙酯
[[(5-甲氧基-2-吡啶基)氨基]亚甲基]二膦酸四乙酯
[[(6-氨基-2-吡啶基)氨基]亚甲基]二膦酸四乙酯
[[(3-硝基-2-吡啶基)氨基]亚甲基]二膦酸四乙酯
[[(3，5-二氯-2-吡啶基)氨基]亚甲基]二膦酸四乙酯
[[(6-羟基-3-吡啶基)氨基]亚甲基]二膦酸四乙酯
[[(5-羟基-2-吡啶基)氨基]亚甲基]二膦酸四乙酯
[[(3-氯-5-三氟甲基-吡啶基)氨基]亚甲基]二膦酸四乙酯
[[(2-氯-3-吡啶基)氨基]亚甲基]二膦酸四乙酯
[[(6-氯-3-吡啶基)氨基]亚甲基]二膦酸四乙酯
[[(3-苄氧基-2-吡啶基)氨基]亚甲基]二膦酸四乙酯
[[(5-硝基-2-吡啶基)氨基]亚甲基]二膦酸四乙酯
[[(5-苄氧基-2-吡啶基)氨基]亚甲基]二膦酸四乙酯
N-取代的(氨基亚烷基)二膦酸四酯可用已知方式制备，例如通过氨基取代的化合物与原甲酸烷基酯反应，然后将所得中间体亚氨醚衍生物与亚磷酸二烷基酯(如此或纯化形式)反应。
另一方法是首先将适当氨基吡啶与甲酸/乙酸酐混合物反应。然后将所得甲酰胺与三卤化磷和亚磷酸三烷基酯反应。
氨基亚烷基二膦酸四酯也可通过将氨基吡啶衍生物与膦酸卤代甲基酯反应，然后将所得化合物溴化后与亚磷酸三烷基酯反应(Schrader等，Synthesis(1986)，372)。
该化合物可用于治疗哺乳动物的骨病，例如由于恶性肿瘤的溶骨病、佩吉特病和原发性及继发性骨质疏松症。
该化合物的活性可通过动物及体外研究确证，以下为方法和结果。在正常发育的大鼠中，一种代表性化合物-[(2-吡啶基氨基)亚甲基]二膦酸四乙酯可降低自发性骨吸收，其可通过长期预标记大鼠的尿四环素排泄量评价。所述化合物也可有效抑制由切断大鼠坐骨神经骨诱导的实验性骨质疏松症中骨的丢失。对体外培养的小鼠颅盖的吸收没有影响，其通过钙释放分析。这可以说明该化合物在发挥药理作用前被代谢掉。母体化合物对体外羟磷灰石晶体未显示出任何结合作用。
在大鼠中研究化合物[(2-吡啶基氨基)亚甲基]二膦酸四乙酯的药代动力学。静脉内药量中少量在24小时中进入尿以母体化合物形式排泄，维持彻底的新陈代谢。所述化合物口服剂量中约有半量可在大鼠中吸收。
下述实施例阐明本发明，但不以任何方式限定本发明。
实施例1
[(2-吡啶基氨基)亚甲基]二膦酸四乙酯的合成
将2-氨基吡啶(0.2摩尔)与原甲酸三乙酯(0.8摩尔)和三氟化硼醚合物混合，将该混合物于150℃加热4小时，然后蒸馏掉反应中形成的乙醇。真空中蒸馏掉原甲酸三乙酯。将亚磷酸二乙酯(0.4摩尔)加到反应混合物中，于150℃加热该混合物同时蒸馏掉所形成的乙醇。冷却混合物，色谱纯化粗产物(洗脱液为二氯甲烷-甲醇1∶1)。产率29克(37％)。
该产物的理化性质如下：31P-NMR(CDCl3)15.52ppm1H-NMR(CDCl3)
| ppm | 质子 | 多重态 | 分配 |
| 1.27 | 12H | m | CH3 |
| 4.21 | 8H | m | CH2 |
| 4.78 | 1H | d | NH |
| 5.57 | 1H | dt | CH |
| 6.52 | 1H | d | CH(芳香) |
| 6.67 | 1H | m | CH(芳香) |
| 7.44 | 1H | m | CH(芳香) |
| 8.11 | 1H | d | CH(芳香) |
质谱(EIMass)
380M
334M-乙醇
243M-P(O)(OC2H5)2
实施例2
[[(5-氯-2-吡啶基)氨基]亚甲基]-二膦酸四乙酯的合成
将5-氯-2-吡啶(0.2摩尔)与原甲酸三乙酯(0.8摩尔)和三氟化硼醚合物混合，将该混合物于150℃加热4小时。反应过程中蒸馏掉所形成的乙醇。真空中蒸馏掉原甲酸三乙酯。将亚磷酸二乙酯(0.4摩尔)加到反应混合物中，于150℃加热该混合物同时蒸馏掉所形成的乙醇。冷却混合物，色谱纯化粗产物(洗脱液为二氯甲烷-甲醇1∶1)。产率26.5克(32％)。(31-P-MR15.20ppm；CDCl3)
按照相同的方式可制备下列化合物：
[[(3，5-二氯-2-吡啶基)氨基]亚甲基]-二膦酸四乙酯(31-P-NMR14.59ppm；CDCl3)
[[(3-氯-5-三氟甲基吡啶基)氨基]亚甲基]-二膦酸四乙酯(31-P-NMR 14.15ppm；CDCl3)
[[(5-羟基-2-吡啶基)氨基]亚甲基]-二膦酸四乙酯(质谱(EIMass)：396M，350M-乙醇，259M-P(O)(OC2H5)2)
[[(5-硝基-2-吡啶基)氨基]亚甲基]-二膦酸四乙酯(31-P-NMR13.97ppm；CDCl3)
[[(5-苄氧基-2-吡啶基)氨基]亚甲基]-二膦酸四乙酯
[[(5-甲氧基-2-吡啶基)氨基]亚甲基]-二膦酸四乙酯
[[(3，5-二甲氧基-2-吡啶基)氨基]亚甲基]-二膦酸四乙酯
实施例3
[[(3-羟基-2-吡啶基)氨基]亚甲基]-二膦酸四乙酯的制备
将2-氨基-3-羟基吡啶与苄基氯在两相体系和相转移催化剂中进行o-苄化作用(Bristol等，Synthesis 1981，971)。将2-氨基-3-苄氧基吡啶(0.1摩尔)溶于二氯甲烷，将该溶液冷却至0℃，将50毫升甲酸/乙酸酐(5∶3)加到该溶液中，室温下搅拌该混合物过夜。浓缩反应混合物，残余物用二异丙醚洗涤而得11.4克6-甲氧基-3-甲酰胺。将10毫升三氯化磷和1.5毫升亚磷酸三乙酯于60-0℃加热1小时。将3-苄氧基吡啶基-2-甲酰胺(0.01摩尔)加到该溶液中，室温下搅拌混合物5小时。浓缩反应混合物，色谱纯化(洗脱液为二氯甲烷-甲醇，2∶1)得0.8克[[(3-苄氧基-2-吡啶基)氨基]亚甲基]-二膦酸四乙酯。将苄基氢化而得0.4克[[(3-羟基-2-吡啶基)氨基]亚甲基]-二膦酸四乙酯(质谱(EIMass)：396M，350M-乙醇，259M-P(O)(OC2H5)2)。
按照相同方式制备下列化合物：
[[(6-苄氧基-3-吡啶基)氨基]亚甲基]-二膦酸四乙酯
[[(6-羟基-3-吡啶基)氨基]亚甲基]-二膦酸四乙酯
实施例4
[[(6-氯-3-吡啶基)氨基]亚甲基]-二膦酸四乙酯的制备
按照Cade，J.Chem.Soc.1959；2266制备碘代甲基膦酸二乙酯。
用已知方法将6-氯-3-氨基吡啶与碘代甲基膦酸二乙酯烷基化，氨基钠作为碱。用200瓦灯照射所得6-氯-3-吡啶基氨基-甲基膦酸二乙酯(0.5摩尔)和N-溴琥珀酰亚胺(0.5摩尔)的无水四氯化碳溶液。滤除固体，用四氯化碳洗涤，真空浓缩溶液。将所得6-氯-3-吡啶基氨基(溴甲基)-膦酸二乙酯(0.1摩尔)在四氢呋喃中与亚磷酸三乙酯(0.1摩尔)50℃下保温4小时。真空浓缩反应混合物。色谱纯化产物(洗脱液为二氯甲烷∶甲醇，9∶1)。产率5.1克。
按照相同方式制备下列化合物：
[[(2-氯-3-吡啶基)氨基]亚甲基]-二膦酸四乙酯
[[(6-甲氧基-3-吡啶基)氨基]亚甲基]-二膦酸四乙酯
[(4-吡啶基氨基)亚甲基]-二膦酸四乙酯
[[(6-氨基-2-吡啶基)氨基]亚甲基]-二膦酸四乙酯
[[(3-硝基-2-吡啶基)氨基]亚甲基]-二膦酸四乙酯
[[(2-氯-3-吡啶基)氨基]亚甲基]-二膦酸四乙酯
[[(5-酰氧基-2-吡啶基)氨基]亚甲基]-二膦酸四乙酯
通过预标记大鼠的尿四环素排泄量评定对自发性骨吸收的作用
使用雄性Sprague-Dawley大鼠。从出生第一周起，将含有溶解在生理盐水中的10μCi/ml(7-3H(N)四环素)皮下注射给大鼠。每周注射两次，共6周。每只动物都接受总量为20μCi放射性标记的四环素。所有动物都给予动物生长的正常饮食和任意量的水。最后一次注射放射性标记的四环素一周后，将大鼠称重，喂以成年动物的饮食。第5天时，将大鼠随机分成小组，关在各自的代谢笼中。收集24小时的尿10天。自第二天起，将溶于生理盐水中的[(2-吡啶基氨基)亚甲基]二膦酸四乙酯(化合物I)在每日的不同剂量水平皮下注射6天。对照动物接受生理盐水。测量尿体积，通过液闪计数确定尿样中的放射性。以每日的治疗/对照比例计算数据以确定四环素排泄的最大抑制。
分泌到尿中未代谢的四环素反映了其在吸收过程中从骨中的消除，因此可连续监测骨吸收。如表1(化合物I)所示，剂量依赖性抑制放射性标记的四环素的排泄表明对骨吸收的抑制。
表1对大鼠自发性骨吸收的影响
| 四环素排泄的抑制％ | |||
| n | 平均(SE) | ||
| I | 1mg/kg10mg/kg100mg/kg200mg/kg | 5555 | 12.2(6.4)19.8(5.9)50.0(6.1)72.9(2.6) |
对固定术诱发大鼠骨质疏松症的影响
将雄性体重为200±25g的Sprague-Dawley大鼠按体重随机分成小组，用Hypnorm/Mebumat和Temgesic麻醉。在右或左髋部沿背外侧切口，暴露坐骨神经，切下0.5cm段。缝合肌肉和皮肤，将动物释放回笼。对侧腿保持完整。从术前两天直至神经切除术后第20天每日在不同剂量水平皮下注射溶于生理盐水的化合物I。对照动物接受生理盐水。在神经切除术后21天处死在标准时间点用荧光染料双标记的动物，除去其股骨。将股骨插入甲基丙烯酸甲酯中，切段，染色。将股骨的metphyseal第二松质(secondary spogiosa)和骨干皮质骨进行组织形态学分析。在对照大鼠中，不能移动腿的股骨总骨区域减少。如表2所示，化合物I剂量依赖性增加了不能移动腿的股骨区域。没有显示出对皮质骨的矿质增加率(mineral apposition rate)的有害影响(没有数据)。
表2对固定术诱发大鼠骨质疏松症的影响
| 不能移动腿股骨的总骨区％ | |||
| 对照 | n | 平均(SE) | |
| 20 | 5.3(0.6) | ||
| I | 1mg/kg37，5mg/kg75mg/kg200mg/kg | 4557 | 6.0(1.3)17.3(2.0)24.5(2.5)35.5(1.7) |
对体外骨的影响
处死新生鼠前4天通过皮下注射45Ca进行标记。从顶骨显微解剖下颅盖骨碎片，与消炎痛一起在培养基中预培养，洗涤，然后与化合物I或不含化合物I培养3天。通过甲状旁腺激素(PTH，10nM)刺激骨吸收，测定这种刺激性吸收的抑制作用。如表3所示，除了在非常高的非生理浓度外，没有显示出体外吸收的抑制。为测定化合物I与骨矿质的结合，于室温将14C-4水氯甲双磷酸二钠和羟基磷灰石晶体在生理pH值的巴比土酸缓冲液中在不含化合物I下培养以及与不同浓度的化合物I培养。培养2小时后，离心该混合物，从上清液中测量总特定结合放射性的百分数。直至500μM浓度都未发现化合物I与羟基磷灰石的结合(表3)。
表3对体外骨的影响
| 对PTH刺激的吸收的抑制100(PTH-X)抑制％(SE) | 与骨矿质的结合 | ||
| I | 1μmol/l5μmol/l10μmol/l100μmol/l200μmol/l500μmol/l1000μmol/l | 无抑制N.D无抑制无抑制N.DN.D12.9(1.3) | N.D无结合N.D无结合无结合无结合N.D |
N.D=未测定
药代动力学
从24小时排泄到尿中的化合物总量确定生物利用度或者从口服给药及静脉内给药后不同时间点的血清浓度数据确定生物利用度。用高压液相色谱法分析测试的尿样和血样的化合物I。24小时中低于10％的口服剂量和14％静脉内剂量以母体化合物排泄(表4，生物利用度58％)。通过血清浓度数据评价的化合物I生物利用度为44％。
表4单一静脉内或口服剂量后I的尿排泄量，
，以及生物利用度
剂量114mg/kg
F＝生物利用度
Claims (21)
1.一种药物组合物，其包含通式I的吡啶基氨基亚甲基二膦酸四酯化合物和可药用的载体：
通式中R1至R4各自为直链或支链饱和C1-C5烷基，X和Y各自独立地为氢、直链或支链饱和C1-C5烷基、卤素、羟基、C1-C5烷氧基、苄氧基、酰氧基、硝基、三氟甲基或NR5R6，其中R5和R6相同或不同，为氢、C1-C5烷基或酰基。
2.根据权利要求1的组合物，其中C1-C5烷基，包括烷氧基以及酰基中的烷基，为甲基或乙基，卤素为氯。
3.根据权利要求1的组合物，其中R1至R4都相同。
4.根据权利要求2的组合物，其中R1至R4都相同。
5.根据权利要求3的组合物，其中R1至R4为乙基。
6.根据权利要求4的组合物，其中R1至R4为乙基。
7.根据权利要求3-6中任一项的组合物，其中吡啶基是2-吡啶基。
8.根据权利要求1的组合物，其中所述吡啶基氨基亚甲基二膦酸四酯化合物为：
[(2-吡啶基氨基)亚甲基]二膦酸四乙酯，
[[(3-羟基-2-吡啶基)氨基]亚甲基]二膦酸四乙酯，
[[(6-甲氧基-3-吡啶基)氨基]亚甲基]二膦酸四乙酯，
[(4-吡啶基氨基)亚甲基]二膦酸四乙酯，
[[(5-氯-2-吡啶基)氨基]亚甲基]二膦酸四乙酯，
[[(5-甲氧基-2-吡啶基)氨基]亚甲基]二膦酸四乙酯，
[[(6-氨基-2-吡啶基)氨基]亚甲基]二膦酸四乙酯，
[[(3-硝基-2-吡啶基)氨基]亚甲基]二膦酸四乙酯，
[[(3，5-二氯-2-吡啶基)氨基]亚甲基]二膦酸四乙酯，
[[(6-羟基-3-吡啶基)氨基]亚甲基]二膦酸四乙酯，
[[(5-羟基-2-吡啶基)氨基]亚甲基]二膦酸四乙酯，
[[(3-氯-5-三氟甲基-吡啶基)氨基]亚甲基]二膦酸四乙酯，
[[(2-氯-3-吡啶基)氨基]亚甲基]二膦酸四乙酯，
[[(6-氯-3-吡啶基)氨基]亚甲基]二膦酸四乙酯，
[[(3-苄氧基-2-吡啶基)氨基]亚甲基]二膦酸四乙酯，
[[(5-硝基-2-吡啶基)氨基]亚甲基]二膦酸四乙酯，或者
[[(5-苄氧基-2-吡啶基)氨基]亚甲基]二膦酸四乙酯。
9.根据权利要求1-6和8中任一项的组合物，其中所述组合物为治疗骨病的组合物。
10.根据权利要求7的组合物，其中所述组合物为治疗骨病的组合物。
11.根据权利要求9的组合物，其中所述骨病为由于恶性肿瘤的溶骨病、佩吉特病和原发性及继发性骨质疏松症。
12.根据权利要求10的组合物，其中所述骨痛为由于恶性肿瘤的溶骨病、佩吉特病和原发性及继发性骨质疏松症。
13.通式I的吡啶基氨基亚甲基二膦酸四酯化合物在制备治疗骨病的药物组合物中的用途.
通式中R1至R4各自为直链或支链饱和C1-C5烷基，X和Y各自独立地为氢、直链或支链饱和C1-C5烷基、卤素、羟基、C1-C5烷氧基、苄氧基、酰氧基、石D基、三氟甲基或NR5R6其中R5和R6相同或不同，为氢、C1-C5烷基或酰基。
14.根据权利要求13的用途，其中所述骨病为由于恶性肿瘤的溶骨病、佩吉特病和原发性及继发性骨质疏松症。
15.根据权利要求13的用途，其中C1-C5烷基，包括烷氧基以及酰基中的烷基，为甲基或乙基，卤素为氯。
16.根据权利要求14的用途，其中C1-C5烷基，包括烷氧基以及酰基中的烷基，为甲基或乙基，卤素为氯。
17.根据权利要求13-16中任一项的用途，其中R1至R4都相同。
18.根据权利要求17的用途，其中R1至R4为乙基。
19.根据权利要求17的用途，其中吡啶基是2-吡啶基。
20.根据权利要求18的用途，其中吡啶基是2-吡啶基。
21.根据权利要求13或14的用途，其中所述吡啶基氨基亚甲基二膦酸四酯化合物为：
[(2-吡啶基氨基)亚甲基]二膦酸四乙酯，
[[(3-羟基-2-吡啶基)氨基]亚甲基]二膦酸四乙酯，
[[(6-甲氧基-3-吡啶基)氨基]亚甲基]二膦酸四乙酯，
[(4-吡啶基氨基)亚甲基]二膦酸四乙酯，
[[(5-氯-2-吡啶基)氨基]亚甲基]二膦酸四乙酯，
[[(5-甲氧基-2-吡啶基)氨基]亚甲基]二膦酸四乙酯，
[[(6-氨基-2-吡啶基)氨基]亚甲基]二膦酸四乙酯，
[[(3-硝基-2-吡啶基)氨基]亚甲基]二膦酸四乙酯，
[[(3，5-二氯-2-吡啶基)氨基]亚甲基]二膦酸四乙酯，
[[(6-羟基-3-吡啶基)氨基]亚甲基]二膦酸四乙酯，
[[(5-羟基-2-吡啶基)氨基]亚甲基]二膦酸四乙酯，
[[(3-氯-5-三氟甲基-吡啶基)氨基]亚甲基]二膦酸四乙酯，
[[(2-氯-3-吡啶基)氨基]亚甲基]二膦酸四乙酯，
[[(6-氯-3-吡啶基)氨基]亚甲基]二膦酸四乙酯，
[[(3-苄氧基-2-吡啶基)氨基]亚甲基]二膦酸四乙酯，
[[(5-硝基-2-吡啶基)氨基]亚甲基]二膦酸四乙酯，或者
[[(5-苄氧基-2-吡啶基)氨基]亚甲基]二膦酸四乙酯。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9402001-3 | 1994-06-09 | ||
| SE9402001A SE9402001D0 (sv) | 1994-06-09 | 1994-06-09 | Pyridylbisphosphonates for use as a therapeutical agent |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1149830A CN1149830A (zh) | 1997-05-14 |
| CN1077792C true CN1077792C (zh) | 2002-01-16 |
Family
ID=20394303
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN95193416A Expired - Lifetime CN1077792C (zh) | 1994-06-09 | 1995-06-02 | 用作治疗剂的吡啶基二膦酸酯 |
Country Status (27)
| Country | Link |
|---|---|
| US (2) | US5866556A (zh) |
| EP (1) | EP0762883B1 (zh) |
| JP (1) | JP3883137B2 (zh) |
| KR (1) | KR100363692B1 (zh) |
| CN (1) | CN1077792C (zh) |
| AT (1) | ATE208622T1 (zh) |
| AU (1) | AU691616B2 (zh) |
| BG (1) | BG63104B1 (zh) |
| BR (1) | BR9508185A (zh) |
| CZ (1) | CZ291477B6 (zh) |
| DE (1) | DE69523914T2 (zh) |
| DK (1) | DK0762883T3 (zh) |
| EE (1) | EE03475B1 (zh) |
| ES (1) | ES2162919T3 (zh) |
| HK (1) | HK1012572A1 (zh) |
| HU (1) | HU228618B1 (zh) |
| IS (1) | IS1801B (zh) |
| NO (1) | NO311069B1 (zh) |
| NZ (1) | NZ287094A (zh) |
| PL (1) | PL180705B1 (zh) |
| PT (1) | PT762883E (zh) |
| RO (1) | RO119433B1 (zh) |
| RU (1) | RU2154482C2 (zh) |
| SE (1) | SE9402001D0 (zh) |
| SK (1) | SK282650B6 (zh) |
| UA (1) | UA43918C2 (zh) |
| WO (1) | WO1995033466A1 (zh) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1178810B8 (en) * | 1999-05-21 | 2005-07-27 | Novartis AG | Use of bisphosphonic acids for treating angiogenesis |
| EP1246829A1 (en) * | 1999-12-17 | 2002-10-09 | Ariad Pharmaceuticals, Inc. | Novel heterocycles |
| US7115589B2 (en) | 1999-12-17 | 2006-10-03 | Ariad Pharmaceuticals, Inc. | Purine derivatives |
| AU2583901A (en) | 1999-12-17 | 2001-06-25 | Ariad Pharmaceuticals, Inc. | Proton pump inhibitors |
| PT1328277E (pt) * | 2000-10-27 | 2007-05-31 | Schering Ag | Compostos bisfosfónicos para o fortalecimento do osso cortical. |
| US7208481B2 (en) * | 2002-02-19 | 2007-04-24 | Ilex Products, Inc. | Aminodiphosphonate apolipoprotein E modulators |
| TW200413381A (en) * | 2002-11-04 | 2004-08-01 | Hoffmann La Roche | Novel amino-substituted dihydropyrimido [4,5-d]pyrimidinone derivatives, their manufacture and use as pharmaceutical agents |
| US20050010305A1 (en) * | 2003-01-28 | 2005-01-13 | Lee Francis Y. | Novel bone graft composite |
| US20050065171A1 (en) * | 2003-06-25 | 2005-03-24 | Shakespeare William C. | Substituted purine derivatives |
| JP2005060303A (ja) * | 2003-08-12 | 2005-03-10 | Sutaagen:Kk | 不動性骨粗鬆の治療または予防剤 |
| US7862552B2 (en) * | 2005-05-09 | 2011-01-04 | Boston Scientific Scimed, Inc. | Medical devices for treating urological and uterine conditions |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US447256A (en) * | 1891-02-24 | Apparatus for flashing and exhausting incandescent electric lamps | ||
| EP0186405A2 (en) * | 1984-12-21 | 1986-07-02 | The Procter & Gamble Company | Pharmaceutical compositions containing geminal diphosphonates |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| DK126888A (da) * | 1987-03-10 | 1988-09-11 | Yamanouchi Pharma Co Ltd | Bisphosphonsyrederivater og terapeutiske praeparater indeholdende disse forbindelser |
| KR880011136A (ko) * | 1987-03-11 | 1988-10-26 | 모리오까 시게오 | 아졸- 아미노메틸렌 비스포스폰산 유도체 |
-
1994
- 1994-06-09 SE SE9402001A patent/SE9402001D0/xx unknown
-
1995
- 1995-02-06 UA UA97010075A patent/UA43918C2/uk unknown
- 1995-06-02 SK SK1572-96A patent/SK282650B6/sk not_active IP Right Cessation
- 1995-06-02 AU AU25698/95A patent/AU691616B2/en not_active Expired
- 1995-06-02 RU RU97100161/14A patent/RU2154482C2/ru active
- 1995-06-02 EE EE9600191A patent/EE03475B1/xx unknown
- 1995-06-02 CZ CZ19963561A patent/CZ291477B6/cs not_active IP Right Cessation
- 1995-06-02 DE DE69523914T patent/DE69523914T2/de not_active Expired - Lifetime
- 1995-06-02 US US08/750,355 patent/US5866556A/en not_active Expired - Lifetime
- 1995-06-02 KR KR1019960706991A patent/KR100363692B1/ko not_active IP Right Cessation
- 1995-06-02 DK DK95920122T patent/DK0762883T3/da active
- 1995-06-02 RO RO96-02286A patent/RO119433B1/ro unknown
- 1995-06-02 CN CN95193416A patent/CN1077792C/zh not_active Expired - Lifetime
- 1995-06-02 PT PT95920122T patent/PT762883E/pt unknown
- 1995-06-02 HU HU9603375A patent/HU228618B1/hu unknown
- 1995-06-02 JP JP50040096A patent/JP3883137B2/ja not_active Expired - Lifetime
- 1995-06-02 NZ NZ287094A patent/NZ287094A/en not_active IP Right Cessation
- 1995-06-02 PL PL95317612A patent/PL180705B1/pl unknown
- 1995-06-02 BR BR9508185A patent/BR9508185A/pt not_active IP Right Cessation
- 1995-06-02 AT AT95920122T patent/ATE208622T1/de active
- 1995-06-02 ES ES95920122T patent/ES2162919T3/es not_active Expired - Lifetime
- 1995-06-02 EP EP95920122A patent/EP0762883B1/en not_active Expired - Lifetime
- 1995-06-02 WO PCT/FI1995/000315 patent/WO1995033466A1/en active IP Right Grant
-
1996
- 1996-12-02 IS IS4392A patent/IS1801B/is unknown
- 1996-12-06 NO NO19965228A patent/NO311069B1/no not_active IP Right Cessation
-
1997
- 1997-01-06 BG BG101116A patent/BG63104B1/bg unknown
-
1998
- 1998-12-17 HK HK98113970A patent/HK1012572A1/xx not_active IP Right Cessation
- 1998-12-23 US US09/219,692 patent/US6083938A/en not_active Expired - Lifetime
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US447256A (en) * | 1891-02-24 | Apparatus for flashing and exhausting incandescent electric lamps | ||
| EP0186405A2 (en) * | 1984-12-21 | 1986-07-02 | The Procter & Gamble Company | Pharmaceutical compositions containing geminal diphosphonates |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1077792C (zh) | 用作治疗剂的吡啶基二膦酸酯 | |
| US3683080A (en) | Compositions for inhibiting anomalous deposition and mobilization of calcium phosphate in animal tissue | |
| WO2008131024A1 (en) | Iodo-hexose compounds useful to treat cancer | |
| GB2096889A (en) | Pharmaceutical composition containing 6-amino-1-hydroxyhexane-1,1-diphosphonic acid | |
| JPS63239290A (ja) | 新規の二環式ジホスホネート化合物、医薬組成物、および異常なカルシウムおよびホスフェート代謝の治療法 | |
| CN1161363C (zh) | 用于治疗骨质疏松症的双膦酸盐 | |
| US20030153533A1 (en) | Novel phospholipid derivatives | |
| CN1151793C (zh) | 多发性骨髓瘤的骨病变治疗用医药组合物 | |
| CN110124053B (zh) | 一种肝素阿伦磷酸钠偶联物的合成方法及其药物 | |
| AU2002346888B2 (en) | Process for reacting alkaloids and use of the reaction products in the preparation of medicaments | |
| CN1164603C (zh) | 1，6－二磷酸果糖锶盐系列化合物及其制备方法和在医药中的应用 | |
| US6207655B1 (en) | Bis-phosphonate confugates with alkylating moieties having antitumor activity | |
| CA2192456C (en) | Pyridylbisphosphonates for use as a therapeutical agent | |
| JP7354246B2 (ja) | ピロロピリミジン骨格を有する新規なリン酸エステル化合物又はその薬学的に許容可能な塩 | |
| WO1997008178A1 (en) | Novel bisphosphonates, process for their preparation and pharmaceutical compositions containing them | |
| FI117053B (fi) | Pyridyylibisfosfonaatit käytettäväksi terapeuttisena aineena | |
| MXPA96006180A (en) | Piridilbisphosphonates to be used as a therapist agent | |
| CN108815117A (zh) | 一种镇痛药物组合物及其制备方法 | |
| CA2281937A1 (en) | Drug for treating abnormalities in bone marrow | |
| AU2018291757A1 (en) | Ibandronate conjugates of nucleoside antimetabolites | |
| CN106456610A (zh) | 用于疼痛的破骨细胞抑制剂 | |
| TW201625615A (zh) | 含有乙內醯脲衍生物之醫藥組合物 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| C10 | Entry into substantive examination | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C17 | Cessation of patent right | ||
| CX01 | Expiry of patent term |
Expiration termination date: 20150602 Granted publication date: 20020116 |