CN1131669A - 光学活性苯并硫杂庚英衍生物,其制备方法和用途 - Google Patents
光学活性苯并硫杂庚英衍生物,其制备方法和用途 Download PDFInfo
- Publication number
- CN1131669A CN1131669A CN95121715A CN95121715A CN1131669A CN 1131669 A CN1131669 A CN 1131669A CN 95121715 A CN95121715 A CN 95121715A CN 95121715 A CN95121715 A CN 95121715A CN 1131669 A CN1131669 A CN 1131669A
- Authority
- CN
- China
- Prior art keywords
- optically active
- formula
- active compound
- compound
- oxo
- 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.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims description 17
- NIGNBCLEMMGDQP-UHFFFAOYSA-N 1-benzothiepine Chemical class S1C=CC=CC2=CC=CC=C12 NIGNBCLEMMGDQP-UHFFFAOYSA-N 0.000 title abstract description 8
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 17
- 230000000069 prophylactic effect Effects 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 76
- 230000011164 ossification Effects 0.000 claims description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 17
- 241000124008 Mammalia Species 0.000 claims description 13
- 230000009257 reactivity Effects 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 230000002265 prevention Effects 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 125000001118 alkylidene group Chemical group 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 239000000376 reactant Substances 0.000 claims description 3
- 230000035876 healing Effects 0.000 claims description 2
- 230000009471 action Effects 0.000 abstract description 4
- 208000020084 Bone disease Diseases 0.000 abstract description 3
- 229940043274 prophylactic drug Drugs 0.000 abstract 1
- 229940126585 therapeutic drug Drugs 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 63
- -1 sulfur heterocyclic compound Chemical class 0.000 description 47
- 239000000203 mixture Substances 0.000 description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 239000000243 solution Substances 0.000 description 22
- 238000001953 recrystallisation Methods 0.000 description 20
- 239000002904 solvent Substances 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 238000003756 stirring Methods 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 238000002425 crystallisation Methods 0.000 description 14
- 230000008025 crystallization Effects 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 239000010410 layer Substances 0.000 description 13
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 12
- YFNCATAIYKQPOO-UHFFFAOYSA-N thiophanate Chemical compound CCOC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OCC YFNCATAIYKQPOO-UHFFFAOYSA-N 0.000 description 12
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 9
- 210000000988 bone and bone Anatomy 0.000 description 9
- 229910052799 carbon Inorganic materials 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 238000009472 formulation Methods 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- ZVAYUUUQOCPZCZ-UHFFFAOYSA-N 4-(diethoxyphosphorylmethyl)aniline Chemical compound CCOP(=O)(OCC)CC1=CC=C(N)C=C1 ZVAYUUUQOCPZCZ-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 238000003810 ethyl acetate extraction Methods 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
- 230000003287 optical effect Effects 0.000 description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 5
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 5
- 208000001132 Osteoporosis Diseases 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical class C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 208000006386 Bone Resorption Diseases 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- 108090000445 Parathyroid hormone Chemical class 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 230000024279 bone resorption Effects 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- OQNGCCWBHLEQFN-UHFFFAOYSA-N chloroform;hexane Chemical compound ClC(Cl)Cl.CCCCCC OQNGCCWBHLEQFN-UHFFFAOYSA-N 0.000 description 4
- PGRHXDWITVMQBC-UHFFFAOYSA-N dehydroacetic acid Chemical compound CC(=O)C1C(=O)OC(C)=CC1=O PGRHXDWITVMQBC-UHFFFAOYSA-N 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 229940078581 Bone resorption inhibitor Drugs 0.000 description 3
- 108060001064 Calcitonin Proteins 0.000 description 3
- 102000055006 Calcitonin Human genes 0.000 description 3
- 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 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 150000008065 acid anhydrides Chemical class 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 235000019445 benzyl alcohol Nutrition 0.000 description 3
- 229960004217 benzyl alcohol Drugs 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000002950 deficient Effects 0.000 description 3
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 210000000689 upper leg Anatomy 0.000 description 3
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- 208000018083 Bone metabolism disease Diseases 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 206010009269 Cleft palate Diseases 0.000 description 2
- 239000004287 Dehydroacetic acid Substances 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 102000003982 Parathyroid hormone Human genes 0.000 description 2
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- CGIHPACLZJDCBQ-UHFFFAOYSA-N acibenzolar Chemical compound SC(=O)C1=CC=CC2=C1SN=N2 CGIHPACLZJDCBQ-UHFFFAOYSA-N 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000002617 bone density conservation agent Substances 0.000 description 2
- 239000000872 buffer Substances 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
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- SKCNIGRBPJIUBQ-UHFFFAOYSA-N chloroform;ethyl acetate Chemical compound ClC(Cl)Cl.CCOC(C)=O SKCNIGRBPJIUBQ-UHFFFAOYSA-N 0.000 description 2
- HYGYSIDIKIGPJA-UHFFFAOYSA-N chloroform;ethyl acetate;methanol Chemical compound OC.ClC(Cl)Cl.CCOC(C)=O HYGYSIDIKIGPJA-UHFFFAOYSA-N 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 235000008504 concentrate Nutrition 0.000 description 2
- 235000019258 dehydroacetic acid Nutrition 0.000 description 2
- 229940061632 dehydroacetic acid Drugs 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- OYJXTOVLKZDGFK-UHFFFAOYSA-N ethanol;2-propan-2-yloxypropane Chemical compound CCO.CC(C)OC(C)C OYJXTOVLKZDGFK-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- 239000012669 liquid formulation Substances 0.000 description 2
- 239000003589 local anesthetic agent Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 201000008482 osteoarthritis Diseases 0.000 description 2
- 230000001009 osteoporotic effect Effects 0.000 description 2
- 239000000199 parathyroid hormone Substances 0.000 description 2
- 229920000137 polyphosphoric acid Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical class [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 229940032147 starch Drugs 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 239000003826 tablet Substances 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
- 229960004418 trolamine Drugs 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- FCKJYANJHNLEEP-XRWYNYHCSA-N (24R)-24,25-dihydroxycalciol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CC[C@@H](O)C(C)(C)O)C)=C\C=C1\C[C@@H](O)CCC1=C FCKJYANJHNLEEP-XRWYNYHCSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- SNUSZUYTMHKCPM-UHFFFAOYSA-N 1-hydroxypyridin-2-one Chemical compound ON1C=CC=CC1=O SNUSZUYTMHKCPM-UHFFFAOYSA-N 0.000 description 1
- REGBHGBRYGEWFI-UHFFFAOYSA-N 1-oxo-3-benzothiepine-4-carboxylic acid Chemical compound O=C1CSC(=CC2=C1C=CC=C2)C(=O)O REGBHGBRYGEWFI-UHFFFAOYSA-N 0.000 description 1
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 1
- XYHKNCXZYYTLRG-UHFFFAOYSA-N 1h-imidazole-2-carbaldehyde Chemical compound O=CC1=NC=CN1 XYHKNCXZYYTLRG-UHFFFAOYSA-N 0.000 description 1
- PFRQBZFETXBLTP-RCIYGOBDSA-N 2-[(2e,6e,10e,14e,18e)-3,7,11,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaen-1-yl]-3-methyl-1,4-dihydronaphthalene-1,4-dione Chemical compound C1=CC=C2C(=O)C(C/C=C(C)/CC/C=C(C)/CC/C=C(C)/CC/C=C(C)/CC/C=C(C)/CCC=C(C)C)=C(C)C(=O)C2=C1 PFRQBZFETXBLTP-RCIYGOBDSA-N 0.000 description 1
- QHOINBKBMJLHPY-UHFFFAOYSA-N 2-chloroethyl formate Chemical compound ClCCOC=O QHOINBKBMJLHPY-UHFFFAOYSA-N 0.000 description 1
- AVZBOAGCVKEESJ-UHFFFAOYSA-O 2-ethyl-1,2-benzoxazol-2-ium-7-ol Chemical class C1=CC(O)=C2O[N+](CC)=CC2=C1 AVZBOAGCVKEESJ-UHFFFAOYSA-O 0.000 description 1
- CFMZSMGAMPBRBE-UHFFFAOYSA-N 2-hydroxyisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(O)C(=O)C2=C1 CFMZSMGAMPBRBE-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical class CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- SDXAWLJRERMRKF-UHFFFAOYSA-N 3,5-dimethyl-1h-pyrazole Chemical compound CC=1C=C(C)NN=1 SDXAWLJRERMRKF-UHFFFAOYSA-N 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-M 3-Methylbutanoic acid Natural products CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 1
- 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 1
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 description 1
- LPEKGGXMPWTOCB-UHFFFAOYSA-N 8beta-(2,3-epoxy-2-methylbutyryloxy)-14-acetoxytithifolin Natural products COC(=O)C(C)O LPEKGGXMPWTOCB-UHFFFAOYSA-N 0.000 description 1
- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 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
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- QDHHCQZDFGDHMP-UHFFFAOYSA-N Chloramine Chemical class ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 1
- 235000001258 Cinchona calisaya Nutrition 0.000 description 1
- DTDYFAZVXNSAGJ-UHFFFAOYSA-N ClC(O)C(O)CO.[Na] Chemical compound ClC(O)C(O)CO.[Na] DTDYFAZVXNSAGJ-UHFFFAOYSA-N 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- HDFFVHSMHLDSLO-UHFFFAOYSA-N Dibenzyl phosphate Chemical compound C=1C=CC=CC=1COP(=O)(O)OCC1=CC=CC=C1 HDFFVHSMHLDSLO-UHFFFAOYSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- ASMQGLCHMVWBQR-UHFFFAOYSA-N Diphenyl phosphate Chemical compound C=1C=CC=CC=1OP(=O)(O)OC1=CC=CC=C1 ASMQGLCHMVWBQR-UHFFFAOYSA-N 0.000 description 1
- ZQZFYGIXNQKOAV-OCEACIFDSA-N Droloxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=C(O)C=CC=1)\C1=CC=C(OCCN(C)C)C=C1 ZQZFYGIXNQKOAV-OCEACIFDSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- SFBODOKJTYAUCM-UHFFFAOYSA-N Ipriflavone Chemical compound C=1C(OC(C)C)=CC=C(C2=O)C=1OC=C2C1=CC=CC=C1 SFBODOKJTYAUCM-UHFFFAOYSA-N 0.000 description 1
- 206010023509 Kyphosis Diseases 0.000 description 1
- ITATYELQCJRCCK-UHFFFAOYSA-N Mandelic Acid, Methyl Ester Chemical compound COC(=O)C(O)C1=CC=CC=C1 ITATYELQCJRCCK-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Natural products C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- OJHYCVSSMDJYAK-UHFFFAOYSA-N O(O)O.O1N=CC=C1 Chemical compound O(O)O.O1N=CC=C1 OJHYCVSSMDJYAK-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241000009328 Perro Species 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- 102100036829 Probable peptidyl-tRNA hydrolase Human genes 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
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- DKJJVAGXPKPDRL-UHFFFAOYSA-N Tiludronic acid Chemical compound OP(O)(=O)C(P(O)(O)=O)SC1=CC=C(Cl)C=C1 DKJJVAGXPKPDRL-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 1
- GBBBPWVJGMFZGX-UHFFFAOYSA-N [(cyclohexylamino)-phosphonomethyl]phosphonic acid Chemical compound OP(O)(=O)C(P(O)(O)=O)NC1CCCCC1 GBBBPWVJGMFZGX-UHFFFAOYSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229940062527 alendronate Drugs 0.000 description 1
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 125000006177 alkyl benzyl group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- WGQKYBSKWIADBV-UHFFFAOYSA-N aminomethyl benzene Natural products NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- MXBGIICVQSPJBU-UAUXSXORSA-N avicatonin Chemical compound C([C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](C)NC(=O)CCC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C1=CN=CN1 MXBGIICVQSPJBU-UAUXSXORSA-N 0.000 description 1
- 229950003605 avicatonin Drugs 0.000 description 1
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 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
- XIWFQDBQMCDYJT-UHFFFAOYSA-M benzyl-dimethyl-tridecylazanium;chloride Chemical compound [Cl-].CCCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 XIWFQDBQMCDYJT-UHFFFAOYSA-M 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N beta-methyl-butyric acid Natural products CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- RRKTZKIUPZVBMF-IBTVXLQLSA-N brucine Chemical compound O([C@@H]1[C@H]([C@H]2C3)[C@@H]4N(C(C1)=O)C=1C=C(C(=CC=11)OC)OC)CC=C2CN2[C@@H]3[C@]41CC2 RRKTZKIUPZVBMF-IBTVXLQLSA-N 0.000 description 1
- RRKTZKIUPZVBMF-UHFFFAOYSA-N brucine Natural products C1=2C=C(OC)C(OC)=CC=2N(C(C2)=O)C3C(C4C5)C2OCC=C4CN2C5C31CC2 RRKTZKIUPZVBMF-UHFFFAOYSA-N 0.000 description 1
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 description 1
- 229960003773 calcitonin (salmon synthetic) Drugs 0.000 description 1
- 229960005084 calcitriol Drugs 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 235000001465 calcium Nutrition 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Substances ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- KMPWYEUPVWOPIM-UHFFFAOYSA-N cinchonidine Natural products C1=CC=C2C(C(C3N4CCC(C(C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-UHFFFAOYSA-N 0.000 description 1
- KMPWYEUPVWOPIM-LSOMNZGLSA-N cinchonine Chemical compound C1=CC=C2C([C@@H]([C@H]3N4CC[C@H]([C@H](C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-LSOMNZGLSA-N 0.000 description 1
- 239000007979 citrate buffer Substances 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
- 238000007796 conventional method Methods 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 description 1
- XQRLCLUYWUNEEH-UHFFFAOYSA-L diphosphonate(2-) Chemical compound [O-]P(=O)OP([O-])=O XQRLCLUYWUNEEH-UHFFFAOYSA-L 0.000 description 1
- XQRLCLUYWUNEEH-UHFFFAOYSA-N diphosphonic acid Chemical class OP(=O)OP(O)=O XQRLCLUYWUNEEH-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 201000010099 disease Diseases 0.000 description 1
- 208000016097 disease of metabolism Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- AUZONCFQVSMFAP-UHFFFAOYSA-N disulfiram Chemical compound CCN(CC)C(=S)SSC(=S)N(CC)CC AUZONCFQVSMFAP-UHFFFAOYSA-N 0.000 description 1
- ODQWQRRAPPTVAG-GZTJUZNOSA-N doxepin Chemical compound C1OC2=CC=CC=C2C(=C/CCN(C)C)/C2=CC=CC=C21 ODQWQRRAPPTVAG-GZTJUZNOSA-N 0.000 description 1
- 229950004203 droloxifene Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 108700032313 elcatonin Proteins 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 229960005309 estradiol Drugs 0.000 description 1
- 229930182833 estradiol Natural products 0.000 description 1
- 230000001076 estrogenic effect Effects 0.000 description 1
- GCFHZZWXZLABBL-UHFFFAOYSA-N ethanol;hexane Chemical compound CCO.CCCCCC GCFHZZWXZLABBL-UHFFFAOYSA-N 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- WHQLQYRFIHPMNA-UHFFFAOYSA-N ethyl acetate;oxolane Chemical compound C1CCOC1.CCOC(C)=O WHQLQYRFIHPMNA-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- FWARNCMTCYKUBS-UHFFFAOYSA-N ethyl n-(ethoxycarbonylcarbamoyl)carbamate Chemical compound CCOC(=O)NC(=O)NC(=O)OCC FWARNCMTCYKUBS-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- XPYGGHVSFMUHLH-UUSULHAXSA-N falecalcitriol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(O)(C(F)(F)F)C(F)(F)F)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C XPYGGHVSFMUHLH-UUSULHAXSA-N 0.000 description 1
- 229950007545 falecalcitriol Drugs 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229940015043 glyoxal Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 210000002758 humerus Anatomy 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 229950006971 incadronic acid Drugs 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229940064880 inositol 100 mg Drugs 0.000 description 1
- 229960005431 ipriflavone Drugs 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012907 medicinal substance Substances 0.000 description 1
- DKHGMERMDICWDU-GHDNBGIDSA-N menaquinone-4 Chemical compound C1=CC=C2C(=O)C(C/C=C(C)/CC/C=C(C)/CC/C=C(C)/CCC=C(C)C)=C(C)C(=O)C2=C1 DKHGMERMDICWDU-GHDNBGIDSA-N 0.000 description 1
- 235000009491 menaquinone-4 Nutrition 0.000 description 1
- 239000011676 menaquinone-4 Substances 0.000 description 1
- 229960005481 menatetrenone Drugs 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- WVJKHCGMRZGIJH-UHFFFAOYSA-N methanetriamine Chemical compound NC(N)N WVJKHCGMRZGIJH-UHFFFAOYSA-N 0.000 description 1
- ITATYELQCJRCCK-MRVPVSSYSA-N methyl (2r)-2-hydroxy-2-phenylacetate Chemical compound COC(=O)[C@H](O)C1=CC=CC=C1 ITATYELQCJRCCK-MRVPVSSYSA-N 0.000 description 1
- ITATYELQCJRCCK-QMMMGPOBSA-N methyl (2s)-2-hydroxy-2-phenylacetate Chemical compound COC(=O)[C@@H](O)C1=CC=CC=C1 ITATYELQCJRCCK-QMMMGPOBSA-N 0.000 description 1
- LPEKGGXMPWTOCB-GSVOUGTGSA-N methyl (R)-lactate Chemical compound COC(=O)[C@@H](C)O LPEKGGXMPWTOCB-GSVOUGTGSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 229940057867 methyl lactate Drugs 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- VKHAHZOOUSRJNA-GCNJZUOMSA-N mifepristone Chemical compound C1([C@@H]2C3=C4CCC(=O)C=C4CC[C@H]3[C@@H]3CC[C@@]([C@]3(C2)C)(O)C#CC)=CC=C(N(C)C)C=C1 VKHAHZOOUSRJNA-GCNJZUOMSA-N 0.000 description 1
- 229960003248 mifepristone Drugs 0.000 description 1
- VMMKGHQPQIEGSQ-UHFFFAOYSA-N minodronic acid Chemical compound C1=CC=CN2C(CC(O)(P(O)(O)=O)P(O)(O)=O)=CN=C21 VMMKGHQPQIEGSQ-UHFFFAOYSA-N 0.000 description 1
- ACTNHJDHMQSOGL-UHFFFAOYSA-N n',n'-dibenzylethane-1,2-diamine Chemical class C=1C=CC=CC=1CN(CCN)CC1=CC=CC=C1 ACTNHJDHMQSOGL-UHFFFAOYSA-N 0.000 description 1
- HOGDNTQCSIKEEV-UHFFFAOYSA-N n'-hydroxybutanediamide Chemical compound NC(=O)CCC(=O)NO HOGDNTQCSIKEEV-UHFFFAOYSA-N 0.000 description 1
- UHAAFJWANJYDIS-UHFFFAOYSA-N n,n'-diethylmethanediimine Chemical compound CCN=C=NCC UHAAFJWANJYDIS-UHFFFAOYSA-N 0.000 description 1
- VMESOKCXSYNAKD-UHFFFAOYSA-N n,n-dimethylhydroxylamine Chemical compound CN(C)O VMESOKCXSYNAKD-UHFFFAOYSA-N 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
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 230000000399 orthopedic effect Effects 0.000 description 1
- ZLLOIFNEEWYATC-XMUHMHRVSA-N osaterone Chemical compound C1=C(Cl)C2=CC(=O)OC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)C)(O)[C@@]1(C)CC2 ZLLOIFNEEWYATC-XMUHMHRVSA-N 0.000 description 1
- 229950006466 osaterone Drugs 0.000 description 1
- 210000002997 osteoclast Anatomy 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 210000003049 pelvic bone Anatomy 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 208000028169 periodontal disease Diseases 0.000 description 1
- 230000003239 periodontal effect Effects 0.000 description 1
- 201000001245 periodontitis Diseases 0.000 description 1
- 210000004261 periodontium Anatomy 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940067107 phenylethyl alcohol Drugs 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- IVRIRQXJSNCSPQ-UHFFFAOYSA-N propan-2-yl carbonochloridate Chemical compound CC(C)OC(Cl)=O IVRIRQXJSNCSPQ-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 1
- 229960004622 raloxifene Drugs 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 229940089617 risedronate Drugs 0.000 description 1
- 108010068072 salmon calcitonin Proteins 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229950004400 secalciferol Drugs 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 235000013024 sodium fluoride Nutrition 0.000 description 1
- 239000011775 sodium fluoride Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- DHCDFWKWKRSZHF-UHFFFAOYSA-N sulfurothioic S-acid Chemical compound OS(O)(=O)=S DHCDFWKWKRSZHF-UHFFFAOYSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- OGBMKVWORPGQRR-UMXFMPSGSA-N teriparatide Chemical compound C([C@H](NC(=O)[C@H](CCSC)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)C(C)C)[C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CNC=N1 OGBMKVWORPGQRR-UMXFMPSGSA-N 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- WZDGZWOAQTVYBX-XOINTXKNSA-N tibolone Chemical compound C([C@@H]12)C[C@]3(C)[C@@](C#C)(O)CC[C@H]3[C@@H]1[C@H](C)CC1=C2CCC(=O)C1 WZDGZWOAQTVYBX-XOINTXKNSA-N 0.000 description 1
- 229960001023 tibolone Drugs 0.000 description 1
- 229940019375 tiludronate Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 229940038773 trisodium citrate Drugs 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 229920001567 vinyl ester resin Polymers 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 235000005282 vitamin D3 Nutrition 0.000 description 1
- 239000011647 vitamin D3 Substances 0.000 description 1
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 description 1
- 229940021056 vitamin d3 Drugs 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms
- C07F9/655363—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a six-membered ring
- C07F9/655372—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a six-membered ring condensed with carbocyclic rings or carbocyclic ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- 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
- A61K31/67—Phosphorus compounds having sulfur as a ring hetero atom
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
- C07F9/657163—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom
- C07F9/657181—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom the ring phosphorus atom and, at least, one ring oxygen atom being part of a (thio)phosphonic acid derivative
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Physical Education & Sports Medicine (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Rheumatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Abstract
本发明涉及上式代表的光学活性苯并硫杂庚英衍生物,其中R代表低级烷基;R1和R2独立地代表低级烷基,或一起代表低级亚烷基。这些化合物显示良好的骨生成促进作用,可用作骨疾病的预防或治疗药物。
Description
本发明涉及具有骨生成促进活性、骨吸收抑制活性和其他活性的光学活性苯并硫杂庚英衍生物,和含有其作为活性成分的骨疾病预防或治疗药物。
骨疾病是一种涉及由骨量减少超过某一程度引起的某些症状或倾向的病理状态或疾病。骨质疏松(一种骨疾病)的主要症状是脊柱后凸,和背腰骨、椎骨体、股骨颈、桡骨下端、肋骨、肱骨上端和其他部位的骨折。在健康的骨组织中,骨破坏持续发生,在骨形成和吸收之间有良好的平衡;成骨细胞和破骨细胞分别在骨形成和吸收中起关键作用。破坏它们之间的平衡造成骨量减少。传统的骨吸收抑制剂如***、降钙素和双膦酸盐已用于预防和治疗骨质疏松。但由于治疗对象的限制或疗效不确切,这些骨吸收抑制剂在某些情况下不能取得满意的效果。
另一方面,本发明者已发现具有优异的骨吸收抑制活性的含硫杂环化合物,即由通式(A)或(B)代表的化合物或其盐(日本未市查专利公开232880/1991和364179/1992)。其中A环为可被取代的苯环;R代表氢原子或可被取代的烃基;B代表可被酯化或酰胺化的羧基;X代表-CH(OH)-或-CO-;k代表0或1,k’和n代表0、1或2。
需要开发具有临床药学(特别是口服制剂)的改进特性(稳定性、可吸收性、生物利用度等)的预防或治疗药物。
因此,本发明涉及:(1)式(I)的光学活性化合物:其中R代表低级烷基;R1和R2独立地代表低级烷基,或一起代表低级亚烷基,
(2)根据上述(1)的化合物,其中R、R1和R2独立地为C1-4烷基,
(3)根据上述(1)的化合物,其为(2 R,4 S)-(-)-N-[4-(二乙氧基磷酰基甲基)苯基]-1,2,4,5-四氢-4-甲基-7,8-亚甲二氧基-5-氧代-3-苯并硫杂庚英-2-甲酰胺,
(4)式(I)光学活性化合物的制备方法:其中R代表低级烷基;R1和R2独立地代表低级烷基,或一起代表低级亚烷基,其中式(II)光学活性化合物或其羧基处的反应活性衍生物或盐:其中R同上所定义,与式(III)化合物或其氨基处的反应活性衍生物或盐反应:其中R1和R2同上所定义,
(6)含有以上(1)的式(I)光学活性化合物的骨生成促进剂,
(7)根据以上(6)的骨生成促进剂,它是口服可吸收的,
(8)含有以上(1)的式(I)光学活性化合物的骨疾病预防或治疗药物,
(9)含有以上(1)的式(I)光学活性化合物的骨折愈合促进剂,
(10)一种促进哺乳动物骨生成的方法,它包括给予需要治疗的所述哺乳动物有效量的以上(1)的式(I)光学活性化合物,
(11)一种预防或治疗哺乳动物骨疾病的方法,它包括给予需要治疗的所述哺乳动物有效量的以上(1)的式(1)光学活化合物,
(12)一种促进哺乳动物骨折愈合的方法,它包括给予需要治疗的所述哺乳动物有效量的以上(1)的式(1)光学活性化合物,
(13)以上(1)的式(I)光学活性化合物在制备骨生成促进剂中的用途,
(14)以上(1)的式(I)光学活性化合物在制备骨疾病治疗或预防药物中的用途,
(15)以上(1)的式(I)光学活性化合物在制备骨折愈合促进剂中的用途。
对于以上结构式,R、R1或R2代表的低级烷基的实例为具有1-6个碳原子的直链或支链烷基,如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基和己基。R1和R2可一起代表低级亚烷基,此时(n代表2到4的整数)。
优选地,R、R1和R2各自为具有1-4个碳原子的烷基,如甲基或乙基。
本发明的化合物(I),即(2R,4S)构型的光学活性化合物,优选基本不含(2S,4R)构型的化合物,具有近100%的光学纯度。
式(I)化合物中,优选(2R,4S)-(-)-N-[4-(二乙氧基磷酰基甲基)苯基]-1,2,4,5-四氢-4-甲基-7,8-亚甲二氧基-5-氧代-3-苯并硫杂庚英-2-甲酰胺等。
通过式(II)代表的光学活性化合物或其羧基处的反应活性衍生物或盐与式(III)代表的光学活性化合物或其氨基处的反应活性衍生物或盐反应,制备化合物(I)。
其氨基处具有反应活性的式(III)化合物的优选衍生物包括:式(III)化合物与羰基化合物如醛(如乙醛)或酮(如丙酮)反应形成的Schiff’s碱型的氨基或烯氨形式互变异构体;式(III)化合物与甲硅烷基化合物如二(三甲基甲硅烷基)乙酰胺、单(三甲基甲硅烷基)乙酰胺或二(三甲基甲硅烷基)脲反应形成的甲硅烷基衍生物;和式(III)化合物与三氯化磷或光气反应生成的衍生物。
其羧基处具有反应活性的式(II)化合物的优选衍生物包括酰卤、酸酐、活化酰胺和活化酯,所有这些都按常规方法获得。更具体地讲,这种优选的反应活性衍生物包括酰氯;酸叠氮化物;混合酸酐如与取代磷酸如二烷基磷酸、苯基磷酸、二苯基磷酸、二苄基磷酸或卤代磷酸,或与二烷基亚磷酸、亚硫酸、硫代硫酸或硫酸,或与磺酸如甲磺酸,或与脂肪羧酸如乙酸、丙酸、丁酸、异丁酸、新戊酸、戊酸、异戊酸或三氯乙酸,或与芳香羧酸如苯甲酸形成的混合酸酐;对称酸酐;与咪唑、4-取代咪唑、二甲基吡唑、***或四唑形成的活化酰胺;活化酯如氰基甲基酯、甲氧基甲基酯、二甲基亚氨基甲基酯、乙烯基酯、炔丙基酯、对硝基苯基酯、三氯苯基酯、五氯苯基酯、甲磺酰苯基酯、苯基偶氮苯基酯、苯硫基酯、对硝基苯基酯、对甲苯硫基酯、羧基甲硫基酯、吡喃基酯、吡啶基酯、哌啶基酯和8-喹啉硫基酯;和与N-羟基化合物如N,N-二甲基羟基胺、1-羟基-2-(1H)-吡啶酮,N-羟基琥珀酰亚胺、N-羟基邻苯二甲酰亚胺、1-羟基-1H-苯并***和N-羟基-5-降冰片烷-2,3-二甲酰胺的酯。这些反应活性衍生物可根据所用式(II)化合物的种类任意选择。
化合物(II)或(III)的反应活性衍生物的优选盐包括与碱的盐,例如碱金属盐如钠盐和钾盐,碱土金属盐如钙盐和镁盐,铵盐,和有机碱盐如三甲胺盐、三乙胺盐、吡啶盐、甲基吡啶盐、二环己基胺盐和N,N-二苄基-乙二胺盐。
该反应一般在常规溶剂中进行,例如水,醇如甲醇或乙醇,丙酮,二恶烷,乙腈,氯仿,二氯甲烷,二氯乙烷,四氢呋喃,乙酸乙酯,N,N-二甲基甲酰胺或吡啶,但也可以在任何其他有机溶剂中进行,只要它不干扰反应。这些溶剂可与水混合使用。当使用游离形式的式(II)或(III)化合物或其盐时,该反应优选在常规缩合剂存在下进行,例如N,N’-二环己基碳化二亚胺;N-环己基-N’-吗啉代乙基碳化二亚胺;N-环己基-N’-(4-二乙氨基己基)碳化二亚胺;N,N’-二乙基碳化二亚胺;N,N’-二异丙基碳化二亚胺;N-乙基-N’-(3-二甲氨基丙基)碳化二亚胺;N,N’-羰基二(2-甲基咪唑);五亚甲基乙烯酮-N-环己基亚胺;二苯基乙烯酮-N-环己基亚胺;乙氧基乙炔;1-烷氧基-1-氯乙烯;亚磷酸三烷酯;多聚磷酸乙酯;多聚磷酸异丙酯;***;二苯基磷酰基叠氮;亚硫酰氯;草酰氯;卤代甲酸低级烷基酯如氯代甲酸乙酯或氯代甲酸异丙酯;三苯膦;2-乙基-7-羟基苯并异噁唑鎓盐,2-乙基-5-(间磺基苯基)异噁唑鎓氢氧化物分子内盐;N-羟基苯并***;1-(对氯苯磺酰氧基)-6-氯-1H-苯并***;或N,N’-二甲基甲酰胺与亚硫酰氯、光气、氯代甲酸三氯甲基酯、***或其它反应制备的所谓Vilsmeier’s试剂。还优选在N-羟基苯并***或N-羟基-5-降冰片烷-内-2,3-二甲酰胺存在下使用缩合剂如N,N’-二环己基碳化二亚胺。该反应也可以在无机或有机碱存在下进行,例如碱金属碳酸氢盐、三(低级)烷基胺、吡啶、N-(低级)烷基吗啉或N,N-二(低级)烷基苄基胺。虽然反应温度不受限制,但该反应一般在冷却到加热条件下(-10到120℃)进行。反应时间一般为0.5到100小时,优选约1至50小时。
这样得到的化合物(I)可通过已知的分离纯化方法分离和纯化,例如浓缩、减压浓缩、溶剂萃取、结晶、重结晶、拆分和层析。
例如通过拆分日本未市查专利公开346179/1992中公开的化合物(II)的外消旋物可产生起始化合物(II)。具体讲,通过制备化合物(II)的外消旋物与光学活性碱(如光学活性α-甲基苄基胺、番木鳖碱、奎宁、辛可宁)的盐,利用所形成的非对映异构体之间的溶解度差异重复进行分部结晶得到纯的微溶盐,然后进行酸处理,从而制得光学活性化合物。另一方法是,通过用光学活性醇(如光学活性乳酸甲酯、扁桃酸甲酯)酯化化合物(II)的外消旋物,利用非对映异构体之间的物理性质差异,从形成的非对映异构体酯中制备一种纯异构体,然后进行水解,从而制得光学活性化合物。可将本发明目标化合物-化合物(I)-制成固态制剂如片剂、胶囊、颗粒和粉剂,或液态制剂如糖浆和注射制剂,如与药学上可接受载体用常规方法配制,可口服或非口服给药。化合物(I)的含量一般为整个制剂重量的约0.01到95%,优选约0.1到20%。化合物(I)优选以口服制剂使用。
药学上可接受载体是一般用作药用物质的各种有机或无机载体物质,包括用于固态制剂的赋形剂、润滑剂、粘合剂和崩解剂,和用于液态制剂的溶剂、助溶剂、悬浮剂、等渗调节剂、缓冲剂和局部麻醉剂。需要时可使用其他药物添加剂如防腐剂、扰氧基、着色剂和甜味剂。优选的赋形剂包括乳糖、蔗糖、D-甘露糖、淀粉、结晶纤维素和轻硅酸酐。优选的润滑剂包括硬脂酸镁、硬脂酸钙、滑石和硅胶。优选的粘合剂包括结晶纤维素、蔗糖、D-甘露糖、葡萄糖、羟丙基纤维素、羟丙基甲基纤维素和聚乙烯吡咯烷酮。优选的崩解剂包括淀粉、羧甲基纤维素、羧甲基纤维素钙、交联羧甲基纤维素钠和羧甲基淀粉钠。优选的溶剂包括注射用水、乙醇、丙二醇、聚氧乙烯二醇、芝麻油和玉米油。优选的助溶剂包括聚乙二醇、丙二醇、D-甘露糖、苯甲酸苄酯、乙醇、三氨基甲烷、胆固醇、三乙醇胺、碳酸钠和柠檬酸钠。优选的悬浮剂包括表面活性剂如硬脂基三乙醇胺、月桂基硫酸钠、月桂基氨基丙酸、卵磷脂、苯扎氯胺、苄索氯胺和甘油单硬脂酸酯;和亲水聚合物如聚乙烯醇、聚乙烯吡咯烷酮、羧甲基纤维素钠、甲基纤维素、羟甲基纤维素、羟乙基纤维素、和羟丙基纤维素。优选的等渗调节剂包括氯化钠、甘油和D-甘露糖。优选的缓冲剂包括磷酸盐、醋酸盐、碳酸盐和柠檬酸盐缓冲溶液。优选的局部麻醉剂包括苯甲醇。优选的防腐剂包括对羟基苯甲酸酯、氯代丁醇、苯甲醇、苯乙醇、脱氢乙酸和山梨酸。优选的抗氧基包括亚硫酸和抗坏血酸。
因为通式(I)代表的化合物具有强骨吸收抑制活性和骨生成促进活性、具有更好的与临床应用相关的特性如稳定性、可吸收性和生物利用度,它可用作骨生成促进剂用于预防或治疗各种哺乳动物(如人、大鼠、小鼠、猫、狗、兔、牛、猪)骨疾病,如骨质疏松和骨折。本发明化合物(I)的毒性低,可安全使用。例如,当以500mg/kg/天的剂量将化合物(I)口服给予大鼠2周,没有发现异常。当口服给药时,化合物(I)的可吸收性比相应的外消旋化合物优越,因此可用于口服给药制剂。
更具体讲,本发明涉及的通式(I)代表的光学活性苯并硫杂庚英衍生物具有极好的碱性磷酸酶诱导活性,因此显示极佳的骨生成促进作用,可作为药物用于预防或治疗骨代谢疾病,包括骨质疏松。含有本发明具有这种活性的化合物(1)的任何骨生成促进剂,可用丁治疗骨折、骨缺陷、和骨疾病如矫正外科领域的骨关节炎和牙周疾病。这种促进剂还可望在牙科领域中有效,用于修复山牙周炎引起的牙周组织缺陷、稳定人工牙根、嵴形成和腭裂修复等。
当用作骨质疏松预防和治疗药时,根据病人状态和体重及给药方法,通式(I)代表的化合物作为活性成分(I)口服给药时,对每个成人(体重50kg)以日剂量5-1000mg、优选30-600mg给药,每天1-3次。
本发明的化合物(I)可与其他骨吸收抑制剂和骨生成促进剂联合使用,如维生素D类(如1α-基维生素D3、1α,25-二羟基维生素D3、Flocalcitriol、Secalciferol等),降钙素(如鳗降钙素、鲑降钙素、猪降钙素、Avicatonin等),二膦酸衍生物(如羟乙二膦酸盐、Cimadronate,Alendronate,Tiludronate,Risedronate,Clodronate,YH-529等),性激素相关化合物(如替勃龙、***、Osaterone,雷洛昔芬、屈洛昔芬、奥美洛昔芬、他莫昔芬、米非司酮等),异丙氧黄酮,维生素K2(如四烯甲萘醌),氟化钠和PTH衍生物(如PTH(1-34),PTH(1-84),PTH(1-36)等)。
通过以下实验实施例、参考实施例和实施例将更详细地描述本发明,但这些实施例并不限制本发明。实验实施例1骨生成促进作用
用从正常大鼠股骨髓制备的基质细胞测定骨生成指数碱性磷酸酶活性。具体讲,用Maniatopoulos等[Cell Tissue Research,Vol.254,p.317(1988)]的方法从7周龄雄性Sprague-Dawley大鼠的股骨髓制备基质细胞,在含有***(10-7M)和β-甘油磷酸(10-2M)的α-MEM溶液(最小基础培养基)中培养以得到矿化骨样组织。一周后向连片生长的细胞中加入实验化合物(10-6M或10-5M),在上述培养液中继续培养10-14天。用磷酸盐缓冲液洗涤后,细胞用0.2% Nonidet P-40匀化并以3000rpm离心10分钟。用Lowry等[Journal of Biological Chemistry,Vol.207,p.19(1954)]的方法检测上清液的碱性磷酸酶活性。所得值以平均值±SE的形式列于表1中。表1化合物 浓度(M) 碱性磷酸酶活性
(nmol对硝基苯酚/分/孔)对照 未加 113.7±8.1实施例1中所得化合物 10-5 1635.5±169.7**实施例1中所得化合物 10-6 682.5±123.2**与对照相比*p<0.05;**p<0.01
从表1可以看出本发明的通式(1)代表的光学活性苯并硫杂庚英衍生物具有良好的碱性磷酸酶诱导活性,因而显示良好的骨生成促进作用,可作为药物预防或治疗包括骨质疏松的骨代谢疾病。
参考实施例1
将(2R,4S)-(-)-1,2,4,5-四氢-4-甲基-7,8-亚甲二氧基-5-氧代-3-苯并硫杂庚英-2-羧酸的(R)-α-甲氧羰基苄基酯(4.18g)、乙酸(45ml)和浓盐酸(30ml)的混合物在回流下搅拌30分钟。将反应混合物倾入水中(800ml);过滤收集形成的结晶,溶于乙酸乙酯(150ml)中。乙酸乙酯层用水洗涤,用硫酸镁干燥,然后蒸去溶剂;过滤收集残余的结晶,用己烷洗涤,然后在乙酸乙酯-己烷中重结晶,得到(2R,4S)-(-)-1,2,4,5-四氢-4-甲基-7,8-亚甲二氧基-5-氧代-3-苯并硫杂庚英-2-羧酸(1.62g,59%)。无色针状。熔点194-195℃。旋光[α]D(23℃)-210.8(c=0.50,CH3OH)。参考实施例2
将1-乙基-3-(3-二甲氨基丙基)碳化二亚胺盐酸盐(12.59g)于二氯甲烷(200ml)中的溶液加到(±)-反-1,2,4,5-四氢-4-甲基-7,8-亚甲二氧基-5-氧代-3-苯并硫杂庚英-2-羧酸(15.34g)和(R)-(-)-扁桃酸甲酯(18.19)于N,N-二甲基甲酰胺(DMF)(200ml)中的溶液中,然后于0℃加入4-二甲氨基吡啶(DMAP)(3.34g)。混合物于0℃搅拌1小时,于室温搅拌15小时,然后将其倾入水中,用乙酸乙酯萃取。乙酸乙酯层用水洗涤并用硫酸镁干燥,然后蒸去溶剂;过滤收集残余的结晶,用***-己烷洗涤,然后在乙酸乙酯-己烷中重结晶两次,得到(2R,4S)-(-)-1,2,4,5-四氢-4-甲基-7,8-亚甲二氧基-5-氧代-3-苯并硫杂庚英-2-羧酸的(R)-α-甲氧羰基苄基酯(4.09g,17%)。无色针状。熔点140-141℃。旋光[α]D(23℃)-244.2°(c=0.50,CHCl3)。实施例1
将1-乙基-3-(3-二甲氨基丙基)碳化二亚胺盐酸盐(0.39g)于二氯甲烷中的溶液加入(2R,4S)-(-)-1,2,4,5-四氢-4-甲基-7,8-亚甲二氧基-5-氧代-3-苯并硫杂庚英-2-羧酸(0.47g)和4-氨基苄基膦酸二乙酯(0.41g)于N,N-二甲基甲酰胺(DMF)(7ml)中的0℃溶液中,然后加入1-羟基苯并***(HOBt)(0.28)。混合物于0℃搅拌1小时,于室温(25℃)搅拌15小时,然后将其倾入水中,用乙酸乙酯萃取。乙酸乙酯层用水洗涤并用硫酸镁干燥,然后蒸去溶剂;过滤收集残余的结晶,然后在乙酸乙酯-己烷中重结晶,再在甲醇-己烷中重结晶,得到(2R,4S)-(-)-N-[4-(二乙氧基磷酰基甲基)苯基]-1,2,4,5-四氢-4-甲基-7,8-亚甲二氧基-5-氧代-3-苯并硫杂庚英-2-甲酰胺(0.37g,44%)。无色棱晶。熔点181-182℃。旋光[α]D(23℃)-197.4°(c=0.50,CHCl3)。
实施例2
(2R,4S)-(-)-N-[4-(二甲氧基磷酰基甲基)苯基]-1,2,4,5-四氢-4-甲基-7,8-亚甲二氧基-5-氧代-3-苯并硫杂庚英-2-甲酰胺
将1-羟基苯并***(HOBt)(0.51g)和1-乙基-3-(3-二甲氨基丙基)碳化二亚胺盐酸盐(0.69g)加入到(2R,4S)-(-)-1,2,4,5-四氢-4-甲基-7,8-亚甲二氧基-5-氧代-3-苯并硫杂庚英-2-羧酸(0.84g)和4-氨基苄基膦酸二甲酯(0.65g)于N,N-二甲基甲酰胺(DMF)(10ml)中的0℃溶液中。该混合物于0℃搅拌1小时,于室温搅拌15小时,然后将其倾入水中,用乙酸乙酯-四氢呋喃(3∶1)萃取。乙酸乙酯层用1N HCl、水、饱相碳酸氢钠溶液洗涤,并用硫酸镁干燥,然后蒸去溶剂。过滤收集残余的固体,然后在乙醇-己烷中重结晶,得到(2R,4S)-(-)-N-[4-(二甲氧基磷酰基甲基)苯基]-1,2,4,5-四氢-4-甲基-7,8-亚甲二氧基-5-氧代-3-苯并硫杂庚英-2-甲酰胺(0.92g,64%)。无色针晶。熔点198-199℃。旋光[α]D(23℃)-198.8°(c=0.50,CHCl3)。
实施例3
按实施例2的相同步骤,制备了(2R,4S)-(-)-N-[4-(四亚甲基二氧基磷酰基甲基)苯基]-1,2,4,5-四氢-4-甲基-7,8-亚甲二氧基-5-氧代-3-苯并硫杂庚英-2-甲酰胺。无色棱晶。熔点139-140℃。旋光[α]D(23)-176.2°(c=0.50,CHCl3)。制剂实施例
例如可用下列配方制备含式(I)光学活性化合物作为活性成分的骨生成促进剂:1.胶囊(1)(2R,4S)-(-)-N-[4-(二乙氧基磷酰基甲基)苯基]-1,2,4,5-四氢-4-甲基-7,8-亚甲二氧基-5-氧代-3-苯并硫杂庚英-2-甲酰胺 10mg(2)乳糖 90mg(3)微晶纤维素 70mg(4)硬脂酸镁 10mg
共计 180mg/胶囊
将成分(1)、(2)和(3)及成分(4)的一半混合并制粒。向这些颗粒中加入成分(4)的剩余部分,将整个混合物装入明胶胶囊中。2.片剂(1)(2R,4S)-(-)-N-[4-(二乙氧基磷酰基甲基)苯基]-1,2,4,5-四氢-4-甲基-7,8-亚甲二氧基-5-氧代-3-苯并硫杂庚英-2-甲酰胺 10mg(2)乳糖 35mg(3)玉米淀粉 150mg(4)微晶纤维素 30mg(5)硬脂酸镁 5mg
共计 230mg/片
将成分(1)、(2)和(3)及成分(4)的三分之二和成分(5)的一半混合并制粒。向这些颗粒中加入成分(4)和(5)的剩余部分,将整个混合物压制成片。3.注射制剂(1)(2R,4S)-(-)-N-[4-(二乙氧基磷酰基甲基)苯基]-1,2,4,5-四氢-4-甲基-7,8-亚甲二氧基-5-氧代-3-苯并硫杂庚英-2-甲酰胺 10mg(2)肌醇 100mg(3)苯甲醇 20mg
共计 130mg/安瓿
将成分(1)、(2)和(3)溶于注射用蒸馏水中,终体积2ml,将此溶液装入安瓿中。整个操作在无菌条件下进行。参考实施例3
向(±)-3,4-二氢-6,7-二甲基-4-氧代-1H-2-苯并硫代吡喃-1-羧酸(27.5g)于氯仿(200ml)中的悬液中加入(S)-(-)-α-甲基苄基胺(14.1g)。于室温搅拌30分钟后,减压浓缩反应混合物。形成的残余物溶于乙酸乙酯(200ml)中,于室温静置2小时。过滤收集形成的结晶,然后在氯仿-乙酸乙酯中重结晶,再在氯仿-己烷中重结晶,得到(-)-3,4-二氢-6,7-二甲基-4-氧代-1H-2-苯并硫代吡喃-1-羧酸的(S)-(-)-α-甲基苄基胺盐(15.5g,37%)。无色棱晶。熔点162-163℃。旋光[α]D(23℃)-43°(c=0.50,CHCl3)。参考实施例4
向(±)-3,4-二氢-6,7-二甲基-4-氧代-1H-2-苯并硫代吡喃-1-羧酸(35.0g)于氯仿(300ml)中的悬液中加入(R)-(+)-α-甲基苄基胺(17.9g)。于室温搅拌30分钟后,减压浓缩反应混合物。形成的残余物溶于乙酸乙酯(200ml)中,于室温静置2小时。过滤收集形成的结晶,然后在氯仿-乙酸乙酯中重结晶,再在氯仿-己烷中重结晶,得到(+)-3,4-二氢-6,7-二甲基-4-氧代-1H-2-苯并硫代吡喃-1-羧酸的(R)-(+)-α-甲基苄基胺盐(17.9g,34%)。无色棱晶。熔点162-163℃。旋光[α]D(23℃)+42.2°(c=0.51,CHCl3)。参考实施例5
向(-)-3,4-二氢-6,7-二甲基-4-氧代-1H-2-苯并硫代吡喃-1-羧酸的(S)-(-)-α-甲基苄基胺盐于乙酸乙酯(100ml)中的悬液中加入2N盐酸(100ml)。室温搅拌此混合物30分钟后,收集乙酸乙酯层。乙酸乙酯层用水洗涤并干燥(硫酸镁),然后蒸去溶剂,在乙酸乙酯-己烷中重结晶,得到(-)-3,4-二氢-6,7-二甲基-4-氧代-1H-2-苯并硫代吡喃-1-羧酸(9.1g,95%)。无色棱晶。熔点177-178℃。旋光[α]D(23℃)-135.0°(c=0.50,CHCl3)。
参考实施例6
向(+)-3,4-二氢-6,7-二甲基-4-氧代-1H-2-苯并硫代吡喃-1-羧酸的(R)-(+)-α-甲基苄基胺盐(8.0g)于乙酸乙酯(100ml)中的悬液中加入2N盐酸(50ml)。室温搅拌此混合物30分钟后,收集乙酸乙酯层。乙酸乙酯层用水洗涤并干燥(硫酸镁),然后蒸去溶剂,在乙酸乙酯-己烷中重结晶,得到(+)-3,4-二氢-6,7-二甲基-4-氧代-1H-2-苯并硫代吡喃-1-羧酸(4.55g,86%)。无色棱晶。熔点177-178℃。旋光[α]D(23℃)+136.0°(c=0.50,CHCl3)。
参考实施例7
将1-乙基-3-(3-二甲氨基丙基)碳化二亚胺盐酸盐(4.89g)在二氯甲烷(80ml)中的溶液加至(±)-1,2,4,5-四氢-7,8-二甲氧基-5-氧代-3-苯并硫杂庚英-2-羧酸(6.0g)和(R)-(+)-乳酸甲酯(4.43g)于N,N-二甲基甲酰胺(DMF)(80ml)中的0℃溶液中,然后加入4-二甲氨基吡啶(DMAP)(1.3g)。将混合物在0℃搅拌1小时,在于室温搅拌15小时,减压浓缩。向残余物中加入乙酸乙酯(500ml)和水(500ml),然后收集有机层。用水洗涤有机层并干燥(硫酸镁),然后蒸去溶剂;过滤收集残余固体并用***洗涤,然后在乙酸乙酯-己烷中重结晶2次,得到(2R)-(-)-1,2,4,5-四氢-7,8-二甲氧基-5-氧代-3-苯并硫杂庚英-2-羧酸的(R)-1-甲氧羰基乙基酯(2.2g,28%)。无色针状。熔点161-162℃。旋光[α]D(16℃)-194.1°(c=0.50,CHCl3)。浓缩上述固体的滤液,过滤收集形成的结晶并用***-己烷洗涤,然后在乙酸乙酯-己烷中重结晶2次,得到(2S)-(+)-1,2,4,5-四氢-7,8-二甲氧基-5-氧代-3-苯并硫杂庚英-2-羧酸的(R)-1-甲氧羰基乙基酯(1.6g,20%)。无色片状。熔点121-122℃。旋光[α]D(16℃)+234.3°(c=0.50,CHCl3)。参考实施例8
将(2R)-(-)-1,2,4,5-四氢-7,8-二甲氧基-、5-氧代-3-苯并硫杂庚英-2-羧酸的(R)-1-甲氧羰基乙基酯(0.5g)、乙酸(2.5ml)和浓盐酸(2.5ml)的混合物于回流温度下搅拌30分钟。将反应混合物倾入水(50ml)中;过滤收集形成的结晶,相继用水、乙醇和***洗涤,得到(2R)-(-)-1,2,4,5-四氢-7,8-二甲氧基-5-氧代-3-苯并硫杂庚英-2-羧酸(0.2g,53%)。无色粉末。熔点223-224℃。旋光[α]D(23℃)-190.0°(c=0.50,DMSO)。参考实施例9
将(2S)-(+)-1,2,4,5-四氢-7,8-二甲氧基-5-氧代-3-苯并硫杂庚英-2-羧酸的(R)-1-甲氧羰基乙基酯(0.7g)、乙酸(3.5ml)和浓盐酸(3.5ml)的混合物于回流温度下搅拌30分钟。将反应混合物倾入水(70ml)中;过滤收集形成的结晶,相继用水、乙醇和***洗涤,得到(2S)-(+)-1,2,4,5-四氢-7,8-二甲氧基-5-氧代-3-苯并硫杂庚英-2-羧酸(0.3g,56%)。无色粉末。熔点223-224℃。旋光[α]D(22℃)+196.7°(c=0.50,DMSO)。参考实施例10
将1-乙基-3-(3-二甲氨基丙基)碳化二亚胺盐酸盐(12.5g)在二氯甲烷(200ml)中的溶液加至(±)-反-1,2,4,5-四氢-7,8-亚甲二氧基-5-氧代-3-苯并硫杂庚英-2-羧酸(15.34g)和(S)-(+)-扁桃酸甲酯(18.19g)于N,N-二甲基甲酰胺(DMF)(200m1)中的0℃溶液中,然后加入4-二甲氨基吡啶(DMAP)(3.34g)。将混合物在0℃搅拌1小时,再于室温搅拌15小时,然后将其倾入水中,用乙酸乙酯萃取。乙酸乙酯层用水洗涤并用硫酸镁干燥,然后蒸去溶剂;过滤收集残余的结晶,并用***-己烷洗涤,然后在乙酸乙酯-己烷中重结晶2次,得到(2S,4R)-(+)-1,2,4,5-四氢-4-甲基-7,8-亚甲二氧基-5-氧代-3-苯并硫杂庚英-2-羧酸的(S)-α-甲氧羰基苄基酯(4.57g,19%)。无色针状。熔点141-142℃。旋光[α]D(23℃)+239.7°(c=0.50,CHCl3)。参考实施例11
将(2S,4R)-(+)-1,2,4,5-四氢-4-甲基-7,8-亚甲二氧基-5-氧代-3-苯并硫杂庚英-2-羧酸的(S)-α-甲氧羰基苄基酯(4.37g)、乙酸(45ml)和浓盐酸(30ml)的混合物于回流温度下搅拌30分钟。将反应混合物倾入水(800ml)中;过滤收集形成的结晶,并溶于乙酸乙酯(150ml)。乙酸乙酯层用水洗涤并干燥(硫酸镁),然后蒸去溶剂;过滤收集残余结晶并用己烷洗涤,然后在乙酸乙酯-己烷中重结晶,得到(2S,4R)-(+)-1,2,4,5-四氢-4-甲基-7,8-亚甲二氧基-5-氧代-3-苯并硫杂庚英-2-羧酸(1.38g,48%)。无色针晶。熔点192-193℃。旋光[α]D(23℃)+212.9°(c=0.50,CH3OH)。参考实施例12
将(-)-3,4-二氢-6,7-二甲基-4-氧代-1H-2-苯并硫代吡喃-1-羧酸(8.6g)溶于四氢呋喃(100ml)后,加入草酰氯(5.0g),然后加入N,N-二甲基甲酰胺(1滴)。于室温搅拌3小时后,减压浓缩反应混合物。将残余物溶于二氯甲烷(30ml),并在冰冷却下向此溶液中滴加4-氨基苄基膦酸二乙酯(8.8g)、碳酸氢钠(10.0g)和二氯甲烷(100ml)的混合物。在冰冷却下搅拌30分钟后,用水洗涤反应混合物并干燥(硫酸镁),然后蒸去溶剂,在氯仿-己烷中重结晶,得到(-)-N-[4-(二乙氧基磷酰基甲基)苯基]-3,4-二氢-6,7-二甲基-4-氧代-1H-2-苯并硫代吡喃-1-甲酰胺(15.4g,92%)。无色针晶。熔点175-176℃。旋光[α]D(23℃)-152.0°(c=0.10,CH3OH)。
参考实施例13
将(+)-3,4-二氢-6,7-二甲基-4-氧代-1H-2-苯并硫代吡喃-1-羧酸(8.4g)溶于四氢呋喃(100ml)后,加入草酰氯(5.0g),然后加入N,N-二甲基甲酰胺(1滴)。于室温搅拌3小时后,减压浓缩反应混合物。将残余物溶于二氯甲烷(30ml),并在冰冷却下向此溶液中滴加4-氨基苄基膦酸二乙酯(8.6g)、碳酸氢钠(8.0g)和二氯甲烷(100ml)的混合物。在冰冷却下搅拌30分钟后,用水洗涤反应混合物并干燥(硫酸镁),然后蒸去溶剂,在氯仿-己烷中重结晶,得到(+)-N-[4-(二乙氧基磷酰基甲基)苯基]-3,4-二氢-6,7-二甲基-4-氧代-1H-2-苯并硫代吡喃-1-甲酰胺(15.8g,96%)。无色针晶。熔点175-176℃。旋光[α]D(23℃)+155.0°(c=1.0,CH3OH)。
参考实施例14
将1-乙基-3-(3-二甲氨基丙基)碳化二亚胺盐酸盐(0.149g)在二氯甲烷(3ml)中的溶液加至(R)-(-)-1,2,4,5-四氢-7,8-二甲氧基-5-氧代-3-苯并硫杂庚英-2-羧酸(0.183g)和4-氨基苄基膦酸二乙酯(0.158g)于N,N-二甲基甲酰胺(DMF)(3ml)中的0℃溶液中,然后加入1-羟基苯并***(HOBt)(0.109g)。将混合物在0℃搅拌1小时,再于室温搅拌15小时,然后将其倾入水中,用乙酸乙酯萃取。乙酸乙酯层用水洗涤并用硫酸镁干燥,然后蒸去溶剂;残余物用乙醇-异丙基醚处理,并过滤除去固体。浓缩滤液,残余油进行硅胶柱层析。从用乙酸乙酯-氯仿-甲醇(15∶15∶1,V/V)洗脱的流份得到(2R)-(-)-N-[4-(二乙氧基磷酰基甲基)苯基]-1,2,4,5-四氢-7,8-二甲氧基-5-氧代-3-苯并硫杂庚英-2-甲酰胺(0.136g,41%)。无色无定形固体。熔点96-98℃。旋光[α]D(23℃)-155.0°(c=0.50,CHCl3)。
参考实施例15
将1-乙基-3-(3-二甲氨基丙基)碳化二亚胺盐酸盐(0.228g)在二氯甲烷(5ml)中的溶液加至(S)-(+)-1,2,4,5-四氢-7,8-二甲氧基-5-氧代-3-苯并硫杂庚英-2-羧酸(0.28g)和4-氨基苄基膦酸二乙酯(0.241g)于N,N-二甲基甲酰胺(DMF)(5ml)中的0℃溶液中,然后加入1-羟基苯并***(HOBt)(0.167g)。将混合物在0℃搅拌1小时,再于室温搅拌15小时,然后将其倾入水中,用乙酸乙酯萃取。乙酸乙酯层用水洗涤并用硫酸镁干燥,然后蒸去溶剂;残余物用乙醇-异丙基醚处理,并过滤除去固体。浓缩滤液,残余油进行硅胶柱层析。从用乙酸乙酯-氯仿-甲醇(15∶15∶1,V/V)洗脱的流份得到(2S)-(+)-N-[4-(二乙氧基磷酰基甲基)苯基]-1,2,4,5-四氢-7,8-二甲氧基-5-氧代-3-苯并硫杂庚英-2-甲酰胺(0.202g,40%)。无色无定形固体。熔点97-99℃。旋光[α]D(23℃)+155.3°(c=0.50,CHCl3)。参考实施例16
将1-乙基-3-(3-二甲氨基丙基)碳化二亚胺盐酸盐(0.69g)在二氯甲烷(12ml)中的溶液加至(2S,4R)-(+)-1,2,4,5-四氢-4-甲基-7,8-亚甲二氧基-5-氧代-3-苯并硫杂庚英-2-羧酸(0.84g)和4-氨基苄基膦酸二乙酯(0.73g)于N,N-二甲基甲酰胺(DMF)(12ml)中的0℃溶液中,然后加入1-羟基苯并***(HOBt)(0.51g)。将混合物在0℃搅拌1小时,再于室温搅拌15小时,然后将其倾入水中,用乙酸乙酯萃取。乙酸乙酯层用水洗涤并用硫酸镁干燥,然后蒸去溶剂;过滤收集残余结晶,然后在乙酸乙酯-己烷中重结晶,再在甲醇-己烷中重结晶,得到(2S,4R)-(+)-N-[4-(二乙氧基磷酰基甲基)苯基]-1,2,4,5-四氢-4-甲基-7,8-亚甲二氧基-5-氧代-3-苯并硫杂庚英-2-甲酰胺(0.62g,41%)。无色棱晶。熔点183-184℃。旋光[α]D(23℃)+190.5°(c=0.50,CHCl3)。
工业应用
本发明化合物(I)显示良好的骨生成促进作用,可用作骨疾病(包括骨质疏松的骨代谢疾病、骨折、骨缺陷、和诸如骨关节炎的矫形外科领域骨疾病)的预防或治疗药物;它还在牙科领域对牙周组织缺陷的修复、人工牙根的稳定化、嵴形成和腭裂修复等有用。
Claims (15)
2.根据权利要求1的化合物,其中R、R1和R2独立地代表C1-4烷基。
3.根据权利要求1的化合物,其为(2R,4S)-(-)-N-4-(二乙氧基磷酰基甲基)苯基]-1,2,4,5-四氢-7,8-亚甲二氧基-5-氧代-3-苯并硫杂庚英-2-甲酰胺。
5.式(II)光学活性化合物或其羧基处的反应活性衍生物或盐:其中R代表低级烷基。
6.含有权利要求1的式(I)光学活性化合物的骨生成促进剂。
7.根据权利要求6的骨生成促进剂,它是口服可吸收的。
8.含有权利要求1的式(I)光学活性化合物的骨疾病预防或治疗药物。
9.含有权利要求1的式(I)光学活性化合物的骨折愈合促进剂。
10.一种促进哺乳动物骨生成的方法,它包括给予需要治疗的所述哺乳动物有效量的权利要求1的式(I)光学活性化合物。
11.一种预防或治疗哺乳动物骨疾病的方法,它包括给予需要治疗的所述哺乳动物有效量的权利要求1的式(1)光学活性化合物。
12.一种促进哺乳动物骨折愈合的方法,它包括给予需要治疗的所述哺乳动物有效量的权利要求1的式(I)光学活性化合物。
13.权利要求1的式(I)光学活性化合物在制备骨生成促进剂中的用途。
14.权利要求1的式(I)光学活性化合物在制备骨疾病治疗或预防药中的用途。
15.权利要求1的式(1)光学活性化合物在制备骨折愈合促进剂中的用途。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP327275/94 | 1994-12-28 | ||
JP327275/1994 | 1994-12-28 | ||
JP32727594 | 1994-12-28 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1131669A true CN1131669A (zh) | 1996-09-25 |
CN1058718C CN1058718C (zh) | 2000-11-22 |
Family
ID=18197308
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN95121715A Expired - Fee Related CN1058718C (zh) | 1994-12-28 | 1995-12-28 | 光学活性苯并硫杂庚英衍生物,其制备方法和用途 |
Country Status (20)
Country | Link |
---|---|
US (2) | US6346521B1 (zh) |
EP (1) | EP0719782B1 (zh) |
KR (1) | KR960022542A (zh) |
CN (1) | CN1058718C (zh) |
AR (1) | AR002018A1 (zh) |
AT (1) | ATE202782T1 (zh) |
AU (1) | AU689004B2 (zh) |
BR (1) | BR9506098A (zh) |
CA (1) | CA2166152A1 (zh) |
DE (1) | DE69521595T2 (zh) |
DK (1) | DK0719782T3 (zh) |
ES (1) | ES2158034T3 (zh) |
FI (1) | FI956273A (zh) |
GR (1) | GR3036757T3 (zh) |
HU (1) | HUT74562A (zh) |
NO (1) | NO303641B1 (zh) |
NZ (1) | NZ280745A (zh) |
PT (1) | PT719782E (zh) |
RU (1) | RU2162083C2 (zh) |
TW (1) | TW403757B (zh) |
Families Citing this family (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
RU2188011C2 (ru) * | 1995-06-05 | 2002-08-27 | Такеда Кемикал Индастриз, Лтд. | Активирующая остеогенез фармацевтическая композиция |
US5910492A (en) * | 1995-06-05 | 1999-06-08 | Takeda Chemical Industries, Ltd. | Osteogenic promoting pharmaceutical composition |
US5952512A (en) * | 1995-07-24 | 1999-09-14 | Takeda Chemical Industries, Ltd. | Production of optically active benzothiepin salts |
CA2264131A1 (en) * | 1996-08-26 | 1998-03-05 | Takeda Chemical Industries, Ltd. | Pharmaceutical composition containing osteogenesis-promoting substance |
AU4571097A (en) * | 1996-10-09 | 1998-05-05 | Takeda Chemical Industries Ltd. | A method for producing a microparticle |
AU4165699A (en) * | 1998-06-15 | 2000-01-05 | Takeda Chemical Industries Ltd. | Composition for treating cartilage disease |
WO2000008018A1 (fr) | 1998-08-07 | 2000-02-17 | Takeda Chemical Industries, Ltd. | Derives de benzothiepine, leur procede de preparation et leurs utilisations |
CA2340165A1 (en) * | 1998-08-12 | 2000-02-24 | Haruhiko Makino | Enhancer of cell differentiation induction factor |
EP1120122A1 (en) * | 1998-09-30 | 2001-08-01 | Takeda Chemical Industries, Ltd. | Bone repair materials/artificial bone compositions |
AU2001240115A1 (en) * | 2000-03-10 | 2001-09-24 | Pharmacia Corporation | Method for the preparation of tetrahydrobenzothiepines |
US20030158154A1 (en) * | 2001-07-17 | 2003-08-21 | Moshe Fleshner-Barak | Dosage forms for immediate gastric release of a calcium transport stimulator coupled with delayed gastric release of a bis-phosphonate |
US20050026871A1 (en) * | 2002-07-17 | 2005-02-03 | Moshe Flashner-Barak | Method of increasing bioavailability of alendronate or other bis-phosphonate by predose administration of vitamin D derivative |
US20060173009A1 (en) * | 2003-01-07 | 2006-08-03 | Hiroyuki Kanoh | Agent inducing increase in bone mass |
WO2009006226A1 (en) * | 2007-06-29 | 2009-01-08 | Kci Licensing Inc. | Activation of bone and cartilage formation |
JP5630868B2 (ja) | 2009-01-19 | 2014-11-26 | 第一三共株式会社 | ヘテロ原子を有する環状化合物 |
MX2011010523A (es) | 2009-04-06 | 2011-10-28 | Daiichi Sankyo Co Ltd | Compuesto ciclico que tiene grupo fenilo sustituido. |
JPWO2011136264A1 (ja) | 2010-04-28 | 2013-07-22 | 第一三共株式会社 | [5,6]複素環化合物 |
EP3040329B1 (en) | 2013-08-29 | 2018-10-10 | Kyoto Pharmaceutical Industries, Ltd. | Aromatic compound and use thereof in the treatment of disorders associated with bone metabolism |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5158943A (en) * | 1988-11-21 | 1992-10-27 | Takeda Chemical Industries, Ltd. | Sulfur-containing heterocyclic compounds |
NZ231939A (en) | 1988-12-28 | 1991-07-26 | Takeda Chemical Industries Ltd | Benzothiopyran derivatives and medicaments |
ATE203020T1 (de) * | 1990-05-30 | 2001-07-15 | Takeda Chemical Industries Ltd | Schwefel enthaltende heterocyclische verbindungen |
JP3165866B2 (ja) * | 1990-06-06 | 2001-05-14 | 武田薬品工業株式会社 | 含硫黄複素環化合物 |
-
1995
- 1995-12-20 TW TW084113629A patent/TW403757B/zh not_active IP Right Cessation
- 1995-12-21 NZ NZ280745A patent/NZ280745A/en unknown
- 1995-12-22 DE DE69521595T patent/DE69521595T2/de not_active Expired - Fee Related
- 1995-12-22 PT PT95120444T patent/PT719782E/pt unknown
- 1995-12-22 EP EP95120444A patent/EP0719782B1/en not_active Expired - Lifetime
- 1995-12-22 DK DK95120444T patent/DK0719782T3/da active
- 1995-12-22 AU AU40693/95A patent/AU689004B2/en not_active Ceased
- 1995-12-22 AT AT95120444T patent/ATE202782T1/de not_active IP Right Cessation
- 1995-12-22 ES ES95120444T patent/ES2158034T3/es not_active Expired - Lifetime
- 1995-12-27 RU RU95122478/04A patent/RU2162083C2/ru active
- 1995-12-27 CA CA002166152A patent/CA2166152A1/en not_active Abandoned
- 1995-12-27 BR BR9506098A patent/BR9506098A/pt unknown
- 1995-12-27 NO NO955305A patent/NO303641B1/no not_active IP Right Cessation
- 1995-12-27 HU HU9503802A patent/HUT74562A/hu unknown
- 1995-12-27 FI FI956273A patent/FI956273A/fi unknown
- 1995-12-28 US US08/579,731 patent/US6346521B1/en not_active Expired - Fee Related
- 1995-12-28 AR ARP950100805A patent/AR002018A1/es unknown
- 1995-12-28 KR KR1019950061545A patent/KR960022542A/ko not_active Application Discontinuation
- 1995-12-28 CN CN95121715A patent/CN1058718C/zh not_active Expired - Fee Related
-
2000
- 2000-08-09 US US09/635,067 patent/US6632807B1/en not_active Expired - Fee Related
-
2001
- 2001-09-28 GR GR20010401614T patent/GR3036757T3/el not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
AU4069395A (en) | 1996-07-04 |
CA2166152A1 (en) | 1996-06-29 |
AU689004B2 (en) | 1998-03-19 |
EP0719782B1 (en) | 2001-07-04 |
HUT74562A (en) | 1997-01-28 |
GR3036757T3 (en) | 2001-12-31 |
AR002018A1 (es) | 1998-01-07 |
NO955305D0 (no) | 1995-12-27 |
CN1058718C (zh) | 2000-11-22 |
DE69521595D1 (de) | 2001-08-09 |
RU2162083C2 (ru) | 2001-01-20 |
DE69521595T2 (de) | 2002-05-23 |
ATE202782T1 (de) | 2001-07-15 |
NO303641B1 (no) | 1998-08-10 |
US6632807B1 (en) | 2003-10-14 |
PT719782E (pt) | 2001-10-31 |
US6346521B1 (en) | 2002-02-12 |
ES2158034T3 (es) | 2001-09-01 |
HU9503802D0 (en) | 1996-02-28 |
EP0719782A1 (en) | 1996-07-03 |
FI956273A0 (fi) | 1995-12-27 |
FI956273A (fi) | 1996-06-29 |
NO955305L (no) | 1996-07-01 |
DK0719782T3 (da) | 2001-09-24 |
TW403757B (en) | 2000-09-01 |
NZ280745A (en) | 1997-09-22 |
BR9506098A (pt) | 1997-12-23 |
KR960022542A (ko) | 1996-07-18 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1058718C (zh) | 光学活性苯并硫杂庚英衍生物,其制备方法和用途 | |
US7915303B2 (en) | Glycopyrronium salts and their therapeutic use | |
ES2386851T3 (es) | Alquil (C2-C5)-imidazol-bisfosfonatos | |
JP4621659B2 (ja) | [2−(8,9−ジオキソ−2,6−ジアザビシクロ[5.2.0]ノナ−1(7)−エン−2−イル)アルキル]ホスホン酸の誘導体およびn−メチル−d−アスパルテート(nmda)受容体アンタゴニストとしてのその使用 | |
EP0409881B1 (en) | N-heterocyclic propylidene-1,1-bisphosphonic acids, their production and a pharmaceutical composition | |
JPS58210097A (ja) | ホスフイニルアルカノイル置換イミノ酸類 | |
WO1987003598A1 (en) | Novel bisphosphonic derivatives, a method for their production and a pharmaceutical composition | |
CN102143967A (zh) | 阿德福韦酯的纯化方法 | |
US5618964A (en) | Prodrug esters of phosphonosulfonate squalene synthetase inhibitors and method | |
CN1034574C (zh) | 5-氧取代的(rs)-2-(2,3-二氢-4,6,7-三甲基苯并呋喃基)乙酸衍生物的制备方法 | |
AU2003206755A1 (en) | Solid salts benzazepine compounds and their use in the preparation of pharmaceuticals compounds | |
JPH04316557A (ja) | 6−アリール環状アントラニル酸誘導体 | |
PT97281A (pt) | Processo para a preparacao de novos derivados contendo fosforo | |
JP2946298B2 (ja) | 光学活性ベンゾチエピン誘導体、その製造法および剤 | |
JP3178070B2 (ja) | ラクトンおよびラクタム化合物 | |
JPS62292788A (ja) | 置換アミノアルカノイルアミノアルキルホスホネ−トアンギオテンシン変換酵素抑制剤 | |
JPH08208672A (ja) | ホスホノスルホネート塩スクアレンシンセターゼ抑制剤 | |
JPH09183784A (ja) | 光学活性ベンゾチエピン誘導体、その製造法および剤 | |
CN1222153A (zh) | 哌啶乙酸衍生物及其在血栓性疾病治疗中的用途 | |
JPH1180177A (ja) | ホウ素含有ビスホスホン酸化合物、その製造方法、およびその医薬用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C19 | Lapse of patent right due to non-payment of the annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |