CN1151161C - 药物硝酸盐 - Google Patents
药物硝酸盐Info
- Publication number
- CN1151161C CN1151161C CNB998090212A CN99809021A CN1151161C CN 1151161 C CN1151161 C CN 1151161C CN B998090212 A CNB998090212 A CN B998090212A CN 99809021 A CN99809021 A CN 99809021A CN 1151161 C CN1151161 C CN 1151161C
- Authority
- CN
- China
- Prior art keywords
- called
- nitrate
- compound
- sodium
- acid
- 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
- 239000003814 drug Substances 0.000 title claims description 11
- 150000002823 nitrates Chemical class 0.000 title abstract description 3
- 229940079593 drug Drugs 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 40
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 34
- 229910002651 NO3 Inorganic materials 0.000 claims description 31
- 239000000243 solution Substances 0.000 claims description 20
- 229960002702 piroxicam Drugs 0.000 claims description 19
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 17
- KBOPZPXVLCULAV-UHFFFAOYSA-N mesalamine Chemical compound NC1=CC=C(O)C(C(O)=O)=C1 KBOPZPXVLCULAV-UHFFFAOYSA-N 0.000 claims description 16
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 15
- 229960004963 mesalazine Drugs 0.000 claims description 15
- 229910017604 nitric acid Inorganic materials 0.000 claims description 15
- 238000002360 preparation method Methods 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 13
- DCSBSVSZJRSITC-UHFFFAOYSA-M alendronate sodium trihydrate Chemical compound O.O.O.[Na+].NCCCC(O)(P(O)(O)=O)P(O)([O-])=O DCSBSVSZJRSITC-UHFFFAOYSA-M 0.000 claims description 11
- XVDXNSRMHBAVAX-UHFFFAOYSA-N 2-(4-methoxyphenyl)-3-propan-2-ylbenzo[e]benzimidazole Chemical compound C1=CC(OC)=CC=C1C(N1C(C)C)=NC2=C1C=CC1=CC=CC=C21 XVDXNSRMHBAVAX-UHFFFAOYSA-N 0.000 claims description 8
- -1 F2A compound Chemical class 0.000 claims description 8
- 229950007669 tomoxiprole Drugs 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 7
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims description 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000000463 material Substances 0.000 claims description 6
- 229960000485 methotrexate Drugs 0.000 claims description 6
- 239000011591 potassium Substances 0.000 claims description 6
- 229910052700 potassium Inorganic materials 0.000 claims description 6
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 claims description 6
- VVNCNSJFMMFHPL-VKHMYHEASA-N D-penicillamine Chemical compound CC(C)(S)[C@@H](N)C(O)=O VVNCNSJFMMFHPL-VKHMYHEASA-N 0.000 claims description 5
- ZJVFLBOZORBYFE-UHFFFAOYSA-N Ibudilast Chemical compound C1=CC=CC2=C(C(=O)C(C)C)C(C(C)C)=NN21 ZJVFLBOZORBYFE-UHFFFAOYSA-N 0.000 claims description 5
- UCHDWCPVSPXUMX-TZIWLTJVSA-N Montelukast Chemical compound CC(C)(O)C1=CC=CC=C1CC[C@H](C=1C=C(\C=C\C=2N=C3C=C(Cl)C=CC3=CC=2)C=CC=1)SCC1(CC(O)=O)CC1 UCHDWCPVSPXUMX-TZIWLTJVSA-N 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 229960002491 ibudilast Drugs 0.000 claims description 5
- 229960002202 lornoxicam Drugs 0.000 claims description 5
- OXROWJKCGCOJDO-JLHYYAGUSA-N lornoxicam Chemical compound O=C1C=2SC(Cl)=CC=2S(=O)(=O)N(C)\C1=C(\O)NC1=CC=CC=N1 OXROWJKCGCOJDO-JLHYYAGUSA-N 0.000 claims description 5
- 229960005127 montelukast Drugs 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- 229960004583 pranlukast Drugs 0.000 claims description 5
- UAJUXJSXCLUTNU-UHFFFAOYSA-N pranlukast Chemical compound C=1C=C(OCCCCC=2C=CC=CC=2)C=CC=1C(=O)NC(C=1)=CC=C(C(C=2)=O)C=1OC=2C=1N=NNN=1 UAJUXJSXCLUTNU-UHFFFAOYSA-N 0.000 claims description 5
- 159000000000 sodium salts Chemical class 0.000 claims description 5
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims description 4
- 235000007164 Oryza sativa Nutrition 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 229940062527 alendronate Drugs 0.000 claims description 4
- LSNWBKACGXCGAJ-UHFFFAOYSA-N ampiroxicam Chemical compound CN1S(=O)(=O)C2=CC=CC=C2C(OC(C)OC(=O)OCC)=C1C(=O)NC1=CC=CC=N1 LSNWBKACGXCGAJ-UHFFFAOYSA-N 0.000 claims description 4
- 229950011249 ampiroxicam Drugs 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 229960001259 diclofenac Drugs 0.000 claims description 4
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 claims description 4
- 229960005293 etodolac Drugs 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 238000001556 precipitation Methods 0.000 claims description 4
- 235000009566 rice Nutrition 0.000 claims description 4
- 229960002871 tenoxicam Drugs 0.000 claims description 4
- WZWYJBNHTWCXIM-UHFFFAOYSA-N tenoxicam Chemical compound O=C1C=2SC=CC=2S(=O)(=O)N(C)C1=C(O)NC1=CC=CC=N1 WZWYJBNHTWCXIM-UHFFFAOYSA-N 0.000 claims description 4
- TVYLLZQTGLZFBW-ZBFHGGJFSA-N (R,R)-tramadol Chemical compound COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-ZBFHGGJFSA-N 0.000 claims description 3
- MNIPYSSQXLZQLJ-UHFFFAOYSA-N Biofenac Chemical compound OC(=O)COC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl MNIPYSSQXLZQLJ-UHFFFAOYSA-N 0.000 claims description 3
- SBDNJUWAMKYJOX-UHFFFAOYSA-N Meclofenamic Acid Chemical compound CC1=CC=C(Cl)C(NC=2C(=CC=CC=2)C(O)=O)=C1Cl SBDNJUWAMKYJOX-UHFFFAOYSA-N 0.000 claims description 3
- ZRVUJXDFFKFLMG-UHFFFAOYSA-N Meloxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=C(C)S1 ZRVUJXDFFKFLMG-UHFFFAOYSA-N 0.000 claims description 3
- JZFPYUNJRRFVQU-UHFFFAOYSA-N Niflumic acid Chemical compound OC(=O)C1=CC=CN=C1NC1=CC=CC(C(F)(F)F)=C1 JZFPYUNJRRFVQU-UHFFFAOYSA-N 0.000 claims description 3
- DRFDPXKCEWYIAW-UHFFFAOYSA-M Risedronate sodium Chemical compound [Na+].OP(=O)(O)C(P(O)([O-])=O)(O)CC1=CC=CN=C1 DRFDPXKCEWYIAW-UHFFFAOYSA-M 0.000 claims description 3
- 229910021607 Silver chloride Inorganic materials 0.000 claims description 3
- YEDTWOLJNQYBPU-UHFFFAOYSA-N [Na].[Na].[Na] Chemical compound [Na].[Na].[Na] YEDTWOLJNQYBPU-UHFFFAOYSA-N 0.000 claims description 3
- 229960004420 aceclofenac Drugs 0.000 claims description 3
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 claims description 3
- 229960000590 celecoxib Drugs 0.000 claims description 3
- 229960001850 droxicam Drugs 0.000 claims description 3
- OEHFRZLKGRKFAS-UHFFFAOYSA-N droxicam Chemical compound C12=CC=CC=C2S(=O)(=O)N(C)C(C2=O)=C1OC(=O)N2C1=CC=CC=N1 OEHFRZLKGRKFAS-UHFFFAOYSA-N 0.000 claims description 3
- LPEPZBJOKDYZAD-UHFFFAOYSA-N flufenamic acid Chemical compound OC(=O)C1=CC=CC=C1NC1=CC=CC(C(F)(F)F)=C1 LPEPZBJOKDYZAD-UHFFFAOYSA-N 0.000 claims description 3
- 229960004369 flufenamic acid Drugs 0.000 claims description 3
- 229960003803 meclofenamic acid Drugs 0.000 claims description 3
- 229960003464 mefenamic acid Drugs 0.000 claims description 3
- 229960001929 meloxicam Drugs 0.000 claims description 3
- 229960000916 niflumic acid Drugs 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 229960000759 risedronic acid Drugs 0.000 claims description 3
- HKZLPVFGJNLROG-UHFFFAOYSA-M silver monochloride Chemical compound [Cl-].[Ag+] HKZLPVFGJNLROG-UHFFFAOYSA-M 0.000 claims description 3
- 229910001961 silver nitrate Inorganic materials 0.000 claims description 3
- 229960004380 tramadol Drugs 0.000 claims description 3
- TVYLLZQTGLZFBW-GOEBONIOSA-N tramadol Natural products COC1=CC=CC([C@@]2(O)[C@@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-GOEBONIOSA-N 0.000 claims description 3
- 239000000010 aprotic solvent Substances 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 238000006386 neutralization reaction Methods 0.000 claims description 2
- 239000012047 saturated solution Substances 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- LXLBEOAZMZAZND-UHFFFAOYSA-M sodium;hydroxy-[1-hydroxy-3-[methyl(pentyl)amino]-1-phosphonopropyl]phosphinate Chemical compound [Na+].CCCCCN(C)CCC(O)(P(O)(O)=O)P(O)([O-])=O LXLBEOAZMZAZND-UHFFFAOYSA-M 0.000 claims description 2
- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 claims 1
- 240000007594 Oryza sativa Species 0.000 claims 1
- 125000001118 alkylidene group Chemical group 0.000 claims 1
- HYYBABOKPJLUIN-UHFFFAOYSA-N mefenamic acid Chemical compound CC1=CC=CC(NC=2C(=CC=CC=2)C(O)=O)=C1C HYYBABOKPJLUIN-UHFFFAOYSA-N 0.000 claims 1
- WRUUGTRCQOWXEG-UHFFFAOYSA-N pamidronate Chemical compound NCCC(O)(P(O)(O)=O)P(O)(O)=O WRUUGTRCQOWXEG-UHFFFAOYSA-N 0.000 claims 1
- 229940046231 pamidronate Drugs 0.000 claims 1
- 230000001225 therapeutic effect Effects 0.000 abstract description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 230000000694 effects Effects 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 11
- 102000003896 Myeloperoxidases Human genes 0.000 description 10
- 108090000235 Myeloperoxidases Proteins 0.000 description 10
- 241001465754 Metazoa Species 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- 230000002496 gastric effect Effects 0.000 description 7
- 210000002784 stomach Anatomy 0.000 description 7
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 230000006378 damage Effects 0.000 description 6
- 238000001291 vacuum drying Methods 0.000 description 6
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 5
- 239000001768 carboxy methyl cellulose Substances 0.000 description 5
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 5
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 210000000988 bone and bone Anatomy 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 241000209094 Oryza Species 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229960001138 acetylsalicylic acid Drugs 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 238000000151 deposition Methods 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 3
- 125000006850 spacer group Chemical group 0.000 description 3
- QAYDBLPDKAGEFQ-UHFFFAOYSA-N 2-hydroxy-5-[(2-methylpropan-2-yl)oxycarbonylamino]benzoic acid Chemical compound CC(C)(C)OC(=O)NC1=CC=C(O)C(C(O)=O)=C1 QAYDBLPDKAGEFQ-UHFFFAOYSA-N 0.000 description 2
- PJJGZPJJTHBVMX-UHFFFAOYSA-N 5,7-Dihydroxyisoflavone Chemical compound C=1C(O)=CC(O)=C(C2=O)C=1OC=C2C1=CC=CC=C1 PJJGZPJJTHBVMX-UHFFFAOYSA-N 0.000 description 2
- ZXLODOLKPLQYSK-UHFFFAOYSA-N BrCCCCOC(C1=C(C(=CC(=C1)C(=O)OC(C)(C)C)N)O)=O Chemical compound BrCCCCOC(C1=C(C(=CC(=C1)C(=O)OC(C)(C)C)N)O)=O ZXLODOLKPLQYSK-UHFFFAOYSA-N 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 210000000936 intestine Anatomy 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
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- 210000000664 rectum Anatomy 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- QLSWIGRIBOSFMV-UHFFFAOYSA-N 1h-pyrrol-2-amine Chemical compound NC1=CC=CN1 QLSWIGRIBOSFMV-UHFFFAOYSA-N 0.000 description 1
- JRBJSXQPQWSCCF-UHFFFAOYSA-N 3,3'-Dimethoxybenzidine Chemical compound C1=C(N)C(OC)=CC(C=2C=C(OC)C(N)=CC=2)=C1 JRBJSXQPQWSCCF-UHFFFAOYSA-N 0.000 description 1
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 1
- PQCAUHUKTBHUSA-UHFFFAOYSA-N 7-nitro-1h-indazole Chemical compound [O-][N+](=O)C1=CC=CC2=C1NN=C2 PQCAUHUKTBHUSA-UHFFFAOYSA-N 0.000 description 1
- 208000006386 Bone Resorption Diseases 0.000 description 1
- 208000020084 Bone disease Diseases 0.000 description 1
- CSJZHKCMQUYTMR-UHFFFAOYSA-N C1(=CC=CC=C1)S(=O)(=O)O.[N+](=O)(O)[O-] Chemical class C1(=CC=CC=C1)S(=O)(=O)O.[N+](=O)(O)[O-] CSJZHKCMQUYTMR-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- MPBVHIBUJCELCL-UHFFFAOYSA-N Ibandronate Chemical compound CCCCCN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O MPBVHIBUJCELCL-UHFFFAOYSA-N 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- IIDJRNMFWXDHID-UHFFFAOYSA-N Risedronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CC1=CC=CN=C1 IIDJRNMFWXDHID-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
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- 230000003110 anti-inflammatory effect Effects 0.000 description 1
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- 230000002785 anti-thrombosis Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
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- 230000037396 body weight Effects 0.000 description 1
- 230000024279 bone resorption Effects 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- GPOGKMPXBDGPJH-UHFFFAOYSA-N butan-2-yl acetate hydrochloride Chemical compound Cl.CCC(C)OC(C)=O GPOGKMPXBDGPJH-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 210000001612 chondrocyte Anatomy 0.000 description 1
- 206010009887 colitis Diseases 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- XQRLCLUYWUNEEH-UHFFFAOYSA-L diphosphonate(2-) Chemical compound [O-]P(=O)OP([O-])=O XQRLCLUYWUNEEH-UHFFFAOYSA-L 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229940015872 ibandronate Drugs 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- HWYHZTIRURJOHG-UHFFFAOYSA-N luminol Chemical compound O=C1NNC(=O)C2=C1C(N)=CC=C2 HWYHZTIRURJOHG-UHFFFAOYSA-N 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- FJQXCDYVZAHXNS-UHFFFAOYSA-N methadone hydrochloride Chemical compound Cl.C=1C=CC=CC=1C(CC(C)N(C)C)(C(=O)CC)C1=CC=CC=C1 FJQXCDYVZAHXNS-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
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- 150000002825 nitriles Chemical class 0.000 description 1
- OSDZHDOKXGSWOD-UHFFFAOYSA-N nitroxyl;hydrochloride Chemical group Cl.O=N OSDZHDOKXGSWOD-UHFFFAOYSA-N 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
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Abstract
本发明公开了在骨疾病中具有药物活性的硝酸盐。
Description
本发明涉及用于治疗和预防骨疾病,例如骨组织和关节的疾病的组合物,更具体地说,本发明涉及具有改善的治疗活性和改善的胃肠忍受能力的组合物。
现有技术中,人们已知骨疾病的药物治疗意味着涉及控制病理生理学过程,例如与骨组织和关节有关的过程的治疗。
EP186405公开了用于治疗异常钙和磷酸盐代谢的含有成对的二膦酸化合物的药物组合物。
EP210728公开了采用无周期性制度治疗或预防骨质疏松的方法,其包括交替进行两个或多个给药骨吸收抑制多膦酸盐的周期和非治疗周期。
WO95/30641公开了式A-X1-NO2化合物,其中基团-NO2共价连接于二价连接桥X1,WO95/30641的化合物有消炎、止痛和抗血栓形成活性。
在现有技术中用于治疗肌骨骼和关节系统疾病的化合物中,可提到如下化合物(参见“New Guide to Medicine & Drugs”,Brit.Med.Association 1997,115页;“Martindale,The ExtraPharmacopeia”31卷,1996,11-13页):
-二膦酸盐(阿仑特罗、帛米酸盐、risedronate等);
-“昔康”(oxicam),例如吡罗昔康、替诺昔康、氨基吡林、托莫普罗、青霉胺、甲氨蝶呤等。
它们是具有有限功效和导致胃肠导管,尤其是胃损害的困难的药物,二膦酸盐还引起食管的损害。
用于骨疾病治疗的其它化合物是抗白三烯药物,例如异丁地特、Pranlukast等;氨基水杨酸盐。这些药物的功效和胃肠忍受能力不是最佳的。
在本领域中,尚没有适于克服在骨疾病治疗中所用的药物表现出的缺点的化合物。
感到有必要得到用于骨疾病治疗的、具有改善的治疗特征的耐受性和/或具有高效率的化合物。
申请人出乎意料地和惊奇地发现具有改善的治疗性质的化合物和它们的组合物。
本发明的目的是具有骨疾病治疗活性的化合物的硝酸盐或它们的药物组合物,所述化合物的特征在于它们具有至少一个能够用硝酸盐化的反应基团,所述化合物选自如下种类:
种类F1):
称为二钠阿仑特罗
称为钠Ibandronate
(F1c)称为二钠帛米昔康;(F1d)称为钠Risedronate;
种类F2A:
称为替诺昔康;
称为安吡昔康;
称为芬诺昔康(Lornoxicam);
称为吡罗昔康;
称为美洛昔康;
称为氟芬那酸;
称为甲氯芬那酸;
称为甲芬那酸;
称为尼氟灭酸;
称为醋氯芬酸;
称为双氯芬酸(钠盐);
称为依托度酸;
称为美沙拉嗪(mesalamine)
称为甲氨蝶呤;
称为青霉胺;
称为曲马朵;
种类F2B:
称为托莫普罗;
称为屈噁昔康;
称为Celecoxib;
种类F3:
称为Pranlukast;
称为异丁地特;
称为钠盐Montelukast。
本发明的硝酸盐还可以通过使用上述种类的上述化合物得到,它选择性地含有通过如下二价连接桥之一共价键合到分子的一个或多个-ONO2基团
-YO,其中Y是直链或支链C1-C20亚烷基,如果可能,优选2-5个碳原子,或选择性地取代的5-7个碳原子的亚环烷基;
-Y1选自:
其中n3是0-3的整数;
其中nf’是1-6的整数,优选2-4;
其中R1f=H、CH3和nf是1-6的整数;优选2-4。
含有通过一个或多个所述二价连接桥或间隔基共价键合到分子的-ONO2基团的所述化合物的制备如以申请人名义申请的EP759899中描述,列为本文参考文献。
含有通过所述间隔基共价键合到分子的-ONO2基团的这些化合物优选选自种类F2A化合物(在安吡昔康(F2AII)情况下,通过预先水解乙酯)和种类F3的Montelukast。
申请人发现含有至少一个通过一种或多种上述间隔基共价键合到分子的硝酸盐基团的化合物的硝酸盐显示较高的药理学活性。例如,含有通过丁基间隔基共价键合到分子的硝酸盐基团的5-氨基水杨酸衍生物(美沙拉嗪)的硝酸盐比未盐化的化合物在实施例中所示的药理学模型中产生更高的活性。
得到本发明的盐的前体优选选自如下:
-种类F1:阿仑特罗;
-种类F2A:吡罗昔康、双氯芬酸、依托度酸、氟芬昔康;
-种类F2B:托莫普罗;
-种类F3:Pranlukast。
在本发明的组合物中,还可以使用属于上述种类的化合物的可能的异构体,异构体的实例是顺-、反-、旋光异构体D和L或外消旋体、对映体。通常一种异构体形式相对于其它的形式,例如D型相对于L型具有较高活性,反之亦然。
属于上述种类的化合物盐含有每摩尔化合物至少一摩尔硝酸盐离子,硝酸盐离子摩尔与前体摩尔之间的比率优选是归一的。当在分子中存在其它其碱性足以被盐化的氨基时,得到具有较高摩尔比率的盐。
本发明的盐根据本领域已知的方法,与常用赋形剂一起配制在相应药物组合物中,参见例如“Remington’s Pharmaceutical Sciences15a Ed.”卷。
在其药物组合物中的本发明盐的剂量是相同的,通常低于所述种类的母体的剂量,然而,由于它们通常是更可忍受的,因此人们也可以以高于母体的剂量使用盐,而不会产生使用高剂量母体时出现的副作用。
属于上述种类的盐的母体根据如下参考文献中提到的方法制备:
种类F1:
二钠阿仑特罗、二钠帛米酸盐;钠Risedronate:参见“IndexMerck 14a Ed.”卷,列为本文参考文献;二钠Ibandronate:EP252502,式(F1e)化合物:EP325842、式(F1f)化合物:EP531253、式(F1g)化合物:EP592488、式(F1h)化合物:EP522576、式(F1i)化合物:EP546548、式(F1l)化合物:EP561296、式(F1m)化合物:JP93032684(C.A.ref.119卷,226194d)、式(F1n)化合物:JP93222073(C.A.ref.120卷,134926m)、式(F1o)化合物:JP92356496(C.A.ref.119卷,095828p)、式(F1p)化合物:WO93/12122;
种类F2A:
替诺昔康、安吡昔康、芬诺昔康、吡罗昔康、美洛昔康、氟芬那酸、甲氯芬那酸、甲芬那酸、尼氟灭酸、醋氯芬酸、双氯芬酸、依托度酸、美沙拉嗪、甲氨蝶呤、青霉胺、曲马朵:参见参见“Index Merck14a Ed.”卷,列为本文参考文献;
种类F2B:
托莫普罗:EP12866;屈噁昔康:“Index Merck 14a Ed.”;Celecoxib:WO94/2798、式(F2BIV)化合物:WO95/15315、式F2BV化合物(7-硝基吲唑)和F2BVI(1,2-(三氟甲基苯基)imydazol)由Lancaster Synthesis,Morecam-England商业化。
种类F3:
钠盐Pranlukast、异丁地特、Montelukast:参见“Index Merck14a Ed.”。
本发明的盐可根据如下方法中的一种得到。
如果被盐化的物质作为溶解于优选不含有羟基的有机溶剂,例如乙腈、乙酸乙酯、四氢呋喃等的游离碱或相应的盐得到,盐通过将物质以优选等于或高于10%w/v的浓度溶解在溶剂中,加入相应于化合物中存在的可盐化的氨基的数量的浓硝酸制备。硝酸优选在同一溶剂中稀释,优选在加入过程中和加完后,将混合物冷却至20℃-0℃的温度,产物通常通过过滤和用溶剂洗涤回收。
相反,当在上述溶剂中物质不很溶解时,或它作为不很溶解的盐得到时,可使用与羟基溶剂的相应混合物。该溶剂的实例是甲醇、乙醇和水。在加完硝酸后,用非质子溶剂稀释所得到的混合物可加速沉淀。
当起始产物用盐酸盐化时,可以将硝酸银直接加入化合物溶液制备硝酸盐,在过滤氯化银后,浓缩溶液和冷却以回收硝酸盐。
当起始产物是盐时,它可以通过用碳酸氢钠或钾或碳酸钠或钾饱和溶液,或用氢氧化钠或钾稀溶液处理以游离相应的碱。该碱随后用合适的有机溶剂(例如卤代溶剂、酯、醚)提取,随后干燥。蒸发有机溶剂,随后根据上述制备方法,通过将碱溶解在腈中或在其它上述溶剂中进行的方法。
给出如下实施例以举例说明本发明,它们不是限制本发明。
实施例1
吡罗昔康硝酸盐制备
在4℃,用溶解在乙腈(5ml)中的65%硝酸(0.63ml)处理在乙腈(30ml)和四氢呋喃(50ml)中的吡罗昔康溶液(3g,9.05mmol),搅拌混合物,然后静置。在4℃下30分钟后,将其过滤,收集沉淀,用乙醚洗涤并真空干燥。
得到白色固体(3.23g),熔点:120-123℃。
元素分析:
计算值(%):C 45.68 H 3.58 N 14.12 S 8.13
实验值(%):C 45.76 H 3.54 N 14.11 S 8.16
实施例2
阿仑特罗硝酸盐制备
在4℃的温度下将在50%硝酸(2ml)中的阿仑特罗溶液(0.92g,3.7mmol)滴加到乙醚(30ml)中,搅拌混合物,随后静置。在4℃下40分钟后,过滤,用乙醚洗涤,并真空干燥。得到白色无定形固体。
计算值(%):C 15.39 H 4.52 N 9.01
实验值(%):C 15.41 H 4.50 N 8.99
实施例3
青霉胺硝酸盐制备
在4℃,用溶解在乙腈(7ml)中的65%硝酸(2.5ml)处理在甲醇(50ml)中的(L)-青霉胺溶液(5g,33.5mmol),搅拌混合物,然后静置。在4℃下15分钟后,加入乙醚,过滤沉淀并真空干燥,得到无定形固体(3.2g)。
元素分析:
计算值(%):C 28.30 H 5.65 N 13.19 S 15.11
实验值(%):C 28.29 H 5.66 N 13.22 S 15.08
实施例4
甲氨蝶呤硝酸盐制备
在4℃及搅拌下,用溶解在乙腈(5ml)中的65%硝酸(0.82ml)处理在甲醇(60ml)中的甲氨蝶呤溶液(5g,11.00mmol)。
在4℃下30分钟后,溶液用乙醚处理。过滤沉淀,用乙醚洗涤。将其真空干燥,得到无定形固体(2..2g)。
元素分析:
计算值(%):C 46.42 H 4.44 N 24.35
实验值(%):C 46.44 H 4.40 N 24.39
实施例5
托莫普罗硝酸盐制备
在4℃,用溶解在乙腈(10ml)中的65%硝酸(0.432ml)处理在乙腈(50ml)和甲醇(18ml)中的托莫普罗溶液(2g,6.32mmol)。搅拌混合物,然后在4℃下静置。30分钟后,溶液用乙醚处理。
过滤形成的沉淀,用乙醚洗涤并真空干燥,得到白色固体,熔点:197-199℃。
元素分析:
计算值(%):C 65.81 H 5.52 N 11.01
实验值(%):C 65.78 H 5.59 N 11.02
实施例6
5-氨基-2-羟基苯甲酸(4-硝酰基)-丁酯(5-ASA-NO2)制备
实施例6a
5-叔丁氧基羰基氨基-2-羟基苯甲酸制备
向5-氨基-2-羟基苯甲酸(15g,98mmol)在二噁烷(105ml)和水(150ml)中的悬浮液中加入三乙胺(24.6ml,176mmol),向得到的溶液中加入二叔丁基焦碳酸酯(25.65g,118mmol)。将反应混合物在室温下搅拌4天,最终真空浓缩溶液至约150ml的体积,用冰冷却,用5%盐酸酸化,用乙酸乙酯提取。回收有机相,用水洗涤,有机相用硫酸钠脱水,真空蒸发溶剂,得到产物,为无定形固体(20.8g)。
实施例6b
5-叔丁氧基羰基氨基-2-羟基苯甲酸(4-溴丁基)酯酸制备
向5-叔丁氧基羰基氨基-2-羟基苯甲酸(20g,85.7mmol)在四氢呋喃(200ml)中的溶液中加入三苯膦(44.9g,171mmol),随后加入四溴化碳(56.7g,171mmol)。反应混合物在室温下搅拌24小时,真空蒸发。得到的残余物用硅胶柱色谱法(洗脱液:正己烷/乙酸乙酯8/2v/v)纯化,用薄层色谱法监测收集馏分的含量。在用于合成的四溴化碳从柱中洗脱后,通过收集头馏分得到产物。收集馏分并干燥,回收白色固体(21.16g),熔点:108-111℃。
实施例6c
5-叔丁氧基羰基氨基-2-羟基苯甲酸(4-硝酰丁基)酯酸制备
5-叔丁氧基羰基氨基-2-羟基苯甲酸(4-溴丁基)酯(21.16g,57.6mmol)在乙腈(150ml)中的溶液在80℃下在黑暗中加热5小时。在冷却至室温后,过滤固体,回收溶剂,蒸发至干得到残余物,残余物用硅胶柱色谱法(洗脱液:正己烷/乙酸乙酯7/3v/v)纯化,用薄层色谱法监测收集馏分的含量。蒸发含有化合物的头馏分至干得到12.6g白色固体,熔点:107-109℃。
实施例7(比较例)
5-氨基水杨酸-(4-硝酰基)丁基酯的盐酸盐(5-ASA-NO2.HCl)制备
将5-叔丁氧基羰基氨基-2-羟基苯甲酸-(4-硝酰基-丁基)酯(10g,28.6mmol)溶解在乙酸乙酯(8ml)中,冷却到0℃。在搅拌下加入通过在乙酸乙酯中鼓泡气态HCl制备的乙酸乙酯/HCl 3M(30ml)直至得到所需的HCl摩尔浓度。使混合物达到温室,搅拌2小时。过滤形成的固体,用乙醚洗涤并真空。得到白色固体产物7.1g,熔点:136-140℃。
元素分析:
计算值(%):C 43.09 H 4.89 N 9.13 Cl 11.56
实验值(%):C 43.005 H 4.88 N 9.10 Cl 11.54
实施例8
5-氨基-2-羟基苯甲酸(4-硝酰基)丁酯的硝酸盐(5-ASA-NO2.HNO3)制备
向在乙腈(50ml)和四氢呋喃(15ml)的混合物中的5-氨基水杨酸4-硝酰基丁酯盐酸盐(2g,7mmol)溶液中加入硝酸银(1.19g,7mmol)。10分钟后,过滤形成的盐(AgCl),使溶液在室温下静置30分钟,过滤沉淀,用乙醚洗涤并真空干燥。得到盐(1.27g)白色固体,熔点:123-128℃。
元素分析:
计算值(%):C 39.66 H 4.50 N 12.61
实验值(%):C 39.70 H 4.53 N 12.67
药理学试验
实施例9
急性毒性
通过插管向10只体重20g的一组鼠口服给药单一剂量为在2%w/v羧甲基纤维素含水悬浮液的100mg/kg的吡罗昔康硝酸盐(实施例1)。
动物保持观察14天,该组中没有1只动物观察到中毒症状出现。
实施例10
与吡罗昔康相比吡罗昔康硝酸盐(实施例1)的胃毒性
向3组每组10只空腹24小时的鼠口服给药如下药物:
-5ml/kg2%羧甲基纤维素含水悬浮液。
-在5ml/kg2%羧甲基纤维素含水悬浮液中的数量相当于100mg/kg的吡罗昔康的吡罗昔康硝酸盐。
-在5ml/kg2%羧甲基纤维素含水悬浮液中的数量相当于100mg/kg的吡罗昔康的吡罗昔康盐酸盐。
6小时后,杀死动物,评价胃损害发生率。结果在表I中报导,结果显示与用吡罗昔康盐酸盐处理相比,用吡罗昔康硝酸盐处理的鼠显示改善的胃忍受能力。
实施例11
在急性结肠炎模型中与相应盐酸盐和硝酸盐相比5-氨基水杨酸(4-
硝酰基)丁酯的髓过氧化物酶活性
将动物分成4组,每组6只,各组分别用载体(1%羧甲基纤维素水溶液)、100mg/kg 5-ASA、数量相当于100mg/kg 5-ASA的5-ASA-NO2.HCl、数量相当于100mg/kg 5-ASA的5-ASA-NO2.HNO3处理。
动物在零时间用上述化合物通过直肠途径处理。1小时后,动物用0.5ml的2,4,6-三硝酸苯磺酸在乙醇50%中的60mg/ml溶液处理,在2小时后再次通过直肠途径用相同的化合物以12小时的间隔处理动物,直至共给药6次。
测量髓过氧化物酶(MPO)的组织含量,它是在不同组织中的炎性过程标志,骨关节是其中之一(C.Rathakrishnan等,“关节软骨细胞的氧基释放:与鲁米诺有关的化学荧光和过氧化氢分泌的研究”
J. Bone Miner.Res.7/10 1138-1148 1992)。
髓过氧化物酶活性用Bradley等J.Invest.Dermatol.78,206-209,1982描述的实验模型的改进方式测量。由每个动物中取出肠组织的样品,将其悬浮在pH6的0.1%十六烷基三甲基溴化铵(50mg/ml),均化15秒(PolytronPT-7发生器)。将样品冷冻和解冻三次,随后在Eppendorf Benchtop离心机中离心(9000g)2分钟。通过向200μl联茴香胺(Sigma)反应物中加入7μl上清液(surnatant)和在2分钟时间内在Microtitre Multiscan中在450nm下测量光密度变化,测量髓过氧化物酶活性。反应物含有0.0005%过氧化氢,用作髓过氧化物酶的酶解物。1个单位的髓过氧化物酶活性定义为在22℃下在1分钟内能够将1微摩尔过氧化氢转化为水的单位。结果在表II中报导,表示为髓过氧化物酶活性/组织mg(wet)的单位数。
由表格中看出,用5-ASA-NO2.HNO3处理的组髓过氧化物酶活性低于其它组。
实施例12
与阿仑特罗硝酸盐相比,通过给药阿仑特罗对由阿司匹林引起的胃损
害的防止作用
三组每组5只鼠通过口服如下所示的胃试样处理:
-I组:以80mg/kg的剂量用阿仑特罗(Alen)处理。
-II组:在80mg/kg剂量的阿仑特罗之前1小时,以125mg/kg的剂量口服阿司匹林(Asp)。
-III组:在相当于80mg/kg剂量的阿仑特罗的阿仑特罗硝酸盐(Alen-.HNO3)之前1小时,以125mg/kg的剂量口服阿司匹林。
在用阿仑特罗或阿仑特罗硝酸盐处理后3小时,杀死动物进行胃损害评价。
结果在表III中报导,其显示与提供阿仑特罗后观察的结果相比给药阿仑特罗硝酸盐降低了胃损害程度4-5倍。
表I
处理 | 剂量mg/kg/口服 | 胃损害(发生率) |
对照吡罗昔康盐酸盐吡罗昔康硝酸盐 | -100100 | 010020 |
表II
处理 | 髓过氧化物酶活性(单位/mg 组织) |
载体5-ASA5-ASA-NO2.HCl5-ASA-NO2.HNO3 | 111±1972±15111±2035±13 |
表III
处理 | 剂量阿仑特罗mg/kg/口服 | 胃损害(发生率) |
Alen.Alen.+Asp.Alen.HNO3+Asp. | 808080 | 1.8±2.236.2±4.18.6±1.6 |
Claims (13)
1.选自如下种类的化合物的硝酸盐:
种类F1):
称为二钠阿仑特罗(Alendronate)
称为钠Ibandronate
(F1c)称为二钠帛米昔康(Pamidronate);(F1d)称为钠Risedronate;
种类F2A:
称为替诺昔康;
称为安吡昔康;
称为芬诺昔康(Lornoxicam);
称为吡罗昔康;
称为美洛昔康;
称为氟芬那酸;
称为甲氯芬那酸;
称为甲芬那酸;
称为尼氟灭酸;
称为醋氯芬酸;
双氯芬酸(钠盐);
称为依托度酸;
称为美沙拉嗪(Mesalamine);
称为甲氨蝶呤(Metotrexate);
称为青霉胺;
种类F2B:
称为曲马朵;
称为托莫普罗;
称为屈噁昔康;
称为Celecoxib;
种类F3:
称为Pranlukast;
称为异丁地特(Ibudilast);
称为钠盐Montelukast。
2.权利要求1的硝酸盐,其中化合物选自阿仑特罗、吡罗昔康和托莫普罗。
4.权利要求3的硝酸盐,其中亚烷基含有2-5个碳原子。
5.权利要求3的硝酸盐,其中nf是2-4的整数。
6.权利要求3的硝酸盐,其中含有通过二价连接桥共价键合到分子的-ONO2基团的化合物选自种类F2A化合物和种类F3的Montelukast。
7.权利要求1-6中任何一项的硝酸盐,含有所述化合物的一个或多个异构体。
8.含有权利要求1-7中任何一项的硝酸盐的药物组合物。
9.权利要求1-7中任何一项的硝酸盐及其组合物用于制备治疗骨疾病的药物中的应用。
10.一种制备权利要求1-7中任何一项的硝酸盐的方法,其中当被盐化的物质可作为溶解于不含有羟基的有机溶剂的游离碱或相应的盐得到时,该盐通过将物质以等于或高于10%w/v的浓度溶解在溶剂中,加入相应于化合物中存在的可盐化的氨基的数量的浓硝酸,在加入过程中和加完后,冷却至20℃-0℃的温度,和通过过滤回收产物制备。
11.权利要求10的方法,其中当物质在上述溶剂中不很溶解时,或它作为不很溶解的盐得到时,可使用与羟基化溶剂的相应混合物,在加完硝酸后,用非质子溶剂稀释所得到的混合物以加速沉淀。
12.权利要求10或11的方法,其中当起始产物用盐酸盐化时,可以将硝酸银直接加入化合物溶液制备硝酸盐,在过滤氯化银后,浓缩溶液和冷却以回收硝酸盐。
13.制备权利要求1-7中任何-项的硝酸盐的方法,其中当起始产物是盐时,它可以通过用碳酸氢钠或钾或碳酸钠或钾饱和溶液,或用氢氧化钠或钾稀溶液处理以游离相应的碱,用合适的有机溶剂提取碱,随后根据权利要求10或11制备硝酸盐的方法。
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ITMI98A001744 | 1998-07-28 | ||
IT1998MI001744A IT1303672B1 (it) | 1998-07-28 | 1998-07-28 | Sali nitrati di farmaci attivi nei disordini ossei |
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CN1310721A CN1310721A (zh) | 2001-08-29 |
CN1151161C true CN1151161C (zh) | 2004-05-26 |
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US (1) | US6573252B1 (zh) |
EP (1) | EP1100805B1 (zh) |
JP (1) | JP2002521487A (zh) |
KR (1) | KR20010071962A (zh) |
CN (1) | CN1151161C (zh) |
AT (1) | ATE229533T1 (zh) |
AU (1) | AU756440B2 (zh) |
BR (1) | BR9912376A (zh) |
CA (1) | CA2338912A1 (zh) |
DE (1) | DE69904483T2 (zh) |
DK (1) | DK1100805T3 (zh) |
ES (1) | ES2189464T3 (zh) |
HU (1) | HUP0102866A3 (zh) |
IL (1) | IL140684A0 (zh) |
IT (1) | IT1303672B1 (zh) |
PT (1) | PT1100805E (zh) |
RU (1) | RU2238932C2 (zh) |
WO (1) | WO2000006585A1 (zh) |
ZA (1) | ZA200100453B (zh) |
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WO2003105752A2 (en) * | 2002-05-02 | 2003-12-24 | Osteoscreen, Inc. | Methods and compositions for stimulating bone growth using nitric oxide releasing bisphosphonate conjugates (no-bisphosphonate) |
ES2532393T3 (es) * | 2002-05-10 | 2015-03-26 | F. Hoffmann-La Roche Ag | Acidos bisfosfónicos para tratamiento y prevención de osteoporosis |
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1998
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1999
- 1999-07-20 WO PCT/EP1999/005170 patent/WO2000006585A1/en not_active Application Discontinuation
- 1999-07-20 BR BR9912376-2A patent/BR9912376A/pt not_active IP Right Cessation
- 1999-07-20 HU HU0102866A patent/HUP0102866A3/hu unknown
- 1999-07-20 DE DE69904483T patent/DE69904483T2/de not_active Expired - Fee Related
- 1999-07-20 AT AT99940026T patent/ATE229533T1/de not_active IP Right Cessation
- 1999-07-20 ES ES99940026T patent/ES2189464T3/es not_active Expired - Lifetime
- 1999-07-20 JP JP2000562382A patent/JP2002521487A/ja active Pending
- 1999-07-20 DK DK99940026T patent/DK1100805T3/da active
- 1999-07-20 RU RU2001102263A patent/RU2238932C2/ru not_active IP Right Cessation
- 1999-07-20 CA CA002338912A patent/CA2338912A1/en not_active Abandoned
- 1999-07-20 AU AU54120/99A patent/AU756440B2/en not_active Ceased
- 1999-07-20 CN CNB998090212A patent/CN1151161C/zh not_active Expired - Fee Related
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- 1999-07-20 US US09/743,801 patent/US6573252B1/en not_active Expired - Fee Related
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Also Published As
Publication number | Publication date |
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HUP0102866A3 (en) | 2002-12-28 |
AU5412099A (en) | 2000-02-21 |
RU2238932C2 (ru) | 2004-10-27 |
BR9912376A (pt) | 2001-04-17 |
DE69904483D1 (de) | 2003-01-23 |
PT1100805E (pt) | 2003-03-31 |
ITMI981744A1 (it) | 2000-01-28 |
AU756440B2 (en) | 2003-01-16 |
ES2189464T3 (es) | 2003-07-01 |
HUP0102866A2 (hu) | 2001-12-28 |
ZA200100453B (en) | 2002-01-16 |
JP2002521487A (ja) | 2002-07-16 |
KR20010071962A (ko) | 2001-07-31 |
EP1100805B1 (en) | 2002-12-11 |
CN1310721A (zh) | 2001-08-29 |
ATE229533T1 (de) | 2002-12-15 |
DK1100805T3 (da) | 2003-03-31 |
DE69904483T2 (de) | 2003-10-23 |
EP1100805A1 (en) | 2001-05-23 |
ITMI981744A0 (it) | 1998-07-28 |
US6573252B1 (en) | 2003-06-03 |
IL140684A0 (en) | 2002-02-10 |
IT1303672B1 (it) | 2001-02-23 |
WO2000006585A1 (en) | 2000-02-10 |
CA2338912A1 (en) | 2000-02-10 |
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