JP4465193B2 - リン酸塩輸送インヒビター - Google Patents
リン酸塩輸送インヒビター Download PDFInfo
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- JP4465193B2 JP4465193B2 JP2003578384A JP2003578384A JP4465193B2 JP 4465193 B2 JP4465193 B2 JP 4465193B2 JP 2003578384 A JP2003578384 A JP 2003578384A JP 2003578384 A JP2003578384 A JP 2003578384A JP 4465193 B2 JP4465193 B2 JP 4465193B2
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- 229910019142 PO4 Inorganic materials 0.000 title claims abstract description 67
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 title claims abstract description 67
- 239000010452 phosphate Substances 0.000 title claims abstract description 67
- 239000003112 inhibitor Substances 0.000 title claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 80
- 125000003118 aryl group Chemical group 0.000 claims abstract description 54
- 150000001875 compounds Chemical class 0.000 claims abstract description 47
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 45
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 39
- 125000001183 hydrocarbyl group Chemical group 0.000 claims abstract description 37
- 125000003107 substituted aryl group Chemical group 0.000 claims abstract description 28
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 26
- 125000005647 linker group Chemical group 0.000 claims abstract description 24
- 150000001412 amines Chemical class 0.000 claims abstract description 19
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims abstract description 19
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims abstract description 17
- 150000003568 thioethers Chemical class 0.000 claims abstract description 16
- 125000006575 electron-withdrawing group Chemical group 0.000 claims abstract description 13
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 13
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims abstract description 12
- 125000006245 phosphate protecting group Chemical group 0.000 claims abstract description 11
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 7
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims abstract description 3
- -1 1,2-dibromo-ethyl group Chemical group 0.000 claims description 40
- 125000001246 bromo group Chemical group Br* 0.000 claims description 34
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 34
- 125000001424 substituent group Chemical group 0.000 claims description 33
- 125000001931 aliphatic group Chemical group 0.000 claims description 22
- 239000008194 pharmaceutical composition Substances 0.000 claims description 19
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 17
- 230000005764 inhibitory process Effects 0.000 claims description 13
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 9
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical group NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 claims description 7
- 101100439662 Arabidopsis thaliana CHR5 gene Proteins 0.000 claims description 7
- 229920006395 saturated elastomer Polymers 0.000 claims description 7
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical group NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- KHBQMWCZKVMBLN-IDEBNGHGSA-N benzenesulfonamide Chemical group NS(=O)(=O)[13C]1=[13CH][13CH]=[13CH][13CH]=[13CH]1 KHBQMWCZKVMBLN-IDEBNGHGSA-N 0.000 claims description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 125000000466 oxiranyl group Chemical group 0.000 claims description 3
- 125000005543 phthalimide group Chemical group 0.000 claims description 3
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical group CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims 2
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 99
- 229920000642 polymer Polymers 0.000 description 72
- 239000000243 solution Substances 0.000 description 63
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 57
- 239000000203 mixture Substances 0.000 description 52
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- 239000007787 solid Substances 0.000 description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
- 238000006243 chemical reaction Methods 0.000 description 27
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 27
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 24
- 239000007788 liquid Substances 0.000 description 23
- 239000000725 suspension Substances 0.000 description 21
- 238000000034 method Methods 0.000 description 20
- 239000000047 product Substances 0.000 description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- 239000002253 acid Substances 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 14
- 238000002390 rotary evaporation Methods 0.000 description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 14
- 238000011282 treatment Methods 0.000 description 14
- 239000000872 buffer Substances 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 201000010099 disease Diseases 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- 239000006228 supernatant Substances 0.000 description 11
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 229910052791 calcium Inorganic materials 0.000 description 10
- 239000011575 calcium Substances 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 238000005119 centrifugation Methods 0.000 description 9
- 230000000968 intestinal effect Effects 0.000 description 9
- 239000000178 monomer Substances 0.000 description 9
- 229910052757 nitrogen Chemical group 0.000 description 9
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 9
- 125000005328 phosphinyl group Chemical group [PH2](=O)* 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- 210000002966 serum Anatomy 0.000 description 9
- 125000006850 spacer group Chemical group 0.000 description 9
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
- 208000001647 Renal Insufficiency Diseases 0.000 description 8
- 238000003556 assay Methods 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 8
- 201000005991 hyperphosphatemia Diseases 0.000 description 8
- 201000006370 kidney failure Diseases 0.000 description 8
- 239000012299 nitrogen atmosphere Substances 0.000 description 8
- 235000009518 sodium iodide Nutrition 0.000 description 8
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 7
- 229930195725 Mannitol Natural products 0.000 description 7
- PUWRRFJWMBAYMQ-UHFFFAOYSA-L [Na+].[Na+].[Na+].CP([O-])([O-])=O Chemical compound [Na+].[Na+].[Na+].CP([O-])([O-])=O PUWRRFJWMBAYMQ-UHFFFAOYSA-L 0.000 description 7
- 230000009102 absorption Effects 0.000 description 7
- 238000010521 absorption reaction Methods 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 208000020832 chronic kidney disease Diseases 0.000 description 7
- VONWDASPFIQPDY-UHFFFAOYSA-N dimethyl methylphosphonate Chemical compound COP(C)(=O)OC VONWDASPFIQPDY-UHFFFAOYSA-N 0.000 description 7
- 125000000524 functional group Chemical group 0.000 description 7
- 230000001771 impaired effect Effects 0.000 description 7
- 239000000594 mannitol Substances 0.000 description 7
- 235000010355 mannitol Nutrition 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 239000008188 pellet Substances 0.000 description 7
- 229920002451 polyvinyl alcohol Polymers 0.000 description 7
- 239000000377 silicon dioxide Substances 0.000 description 7
- 150000003384 small molecules Chemical class 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 239000003039 volatile agent Substances 0.000 description 7
- 208000020084 Bone disease Diseases 0.000 description 6
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical group OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000000539 dimer Substances 0.000 description 6
- 230000004060 metabolic process Effects 0.000 description 6
- 229920002401 polyacrylamide Polymers 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- SELHAAVPNZRCSB-UHFFFAOYSA-N 11-[dimethoxyphosphorylmethyl(ethoxy)phosphoryl]undec-1-ene Chemical compound COP(=O)(OC)CP(=O)(OCC)CCCCCCCCCC=C SELHAAVPNZRCSB-UHFFFAOYSA-N 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- 102000006335 Phosphate-Binding Proteins Human genes 0.000 description 5
- 108010058514 Phosphate-Binding Proteins Proteins 0.000 description 5
- 239000013543 active substance Substances 0.000 description 5
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 5
- 239000011230 binding agent Substances 0.000 description 5
- 230000000903 blocking effect Effects 0.000 description 5
- 230000002308 calcification Effects 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 208000022831 chronic renal failure syndrome Diseases 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 239000003937 drug carrier Substances 0.000 description 5
- 210000001035 gastrointestinal tract Anatomy 0.000 description 5
- 150000004676 glycans Chemical class 0.000 description 5
- 210000003734 kidney Anatomy 0.000 description 5
- 229920000083 poly(allylamine) Polymers 0.000 description 5
- 229920000058 polyacrylate Polymers 0.000 description 5
- 229920000728 polyester Polymers 0.000 description 5
- 229920001282 polysaccharide Polymers 0.000 description 5
- 239000005017 polysaccharide Substances 0.000 description 5
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 5
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 4
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- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
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- 125000002947 alkylene group Chemical group 0.000 description 4
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 4
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- 238000007152 ring opening metathesis polymerisation reaction Methods 0.000 description 4
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- ZNSIZMQNQCNRBW-UHFFFAOYSA-N sevelamer Chemical compound NCC=C.ClCC1CO1 ZNSIZMQNQCNRBW-UHFFFAOYSA-N 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
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- AXNUIYKEVMRMOZ-UHFFFAOYSA-N 1-[dimethoxyphosphorylmethyl(ethoxy)phosphoryl]decane Chemical compound CCCCCCCCCCP(=O)(OCC)CP(=O)(OC)OC AXNUIYKEVMRMOZ-UHFFFAOYSA-N 0.000 description 3
- NYYLZXREFNYPKB-UHFFFAOYSA-N 1-[ethoxy(methyl)phosphoryl]oxyethane Chemical compound CCOP(C)(=O)OCC NYYLZXREFNYPKB-UHFFFAOYSA-N 0.000 description 3
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- GAWKYKJKVOFTMK-UHFFFAOYSA-N [11-aminoundecyl(hydroxy)phosphoryl]methylphosphonic acid Chemical compound NCCCCCCCCCCCP(O)(=O)CP(O)(O)=O GAWKYKJKVOFTMK-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 229910052782 aluminium Inorganic materials 0.000 description 3
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- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 3
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- NPGFXTQYCCQUPB-UHFFFAOYSA-N 11-[dimethoxyphosphorylmethyl(ethoxy)phosphoryl]undecan-1-ol Chemical compound COP(=O)(OC)CP(=O)(OCC)CCCCCCCCCCCO NPGFXTQYCCQUPB-UHFFFAOYSA-N 0.000 description 2
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- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- QVCZFLCDKXOIBB-UHFFFAOYSA-N C=CCCCCCCCCCCl(O)(P(O)(O)=O)(=O)=O Chemical compound C=CCCCCCCCCCCl(O)(P(O)(O)=O)(=O)=O QVCZFLCDKXOIBB-UHFFFAOYSA-N 0.000 description 2
- UQXHVIYQCBZGBU-UHFFFAOYSA-N CC(C)OOP(C)(=O)OOC(C)C Chemical compound CC(C)OOP(C)(=O)OOC(C)C UQXHVIYQCBZGBU-UHFFFAOYSA-N 0.000 description 2
- NGYDLKSGFTWXNL-UHFFFAOYSA-N CCOP(Cl)=O Chemical compound CCOP(Cl)=O NGYDLKSGFTWXNL-UHFFFAOYSA-N 0.000 description 2
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- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
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- 108010078791 Carrier Proteins Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
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Classifications
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- 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
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Description
本願は、2002年3月19日に出願された米国仮出願第60/365,940号の利益を請求する。上記出願の全教示は参考として本明細書中に援用される。
不適当な腎機能、副甲状腺機能低下症、または所定の他の医学的状態を有する人々は、しばしば、高リン酸塩血症、または上昇した血清リン酸塩レベル(6mg/dLを超える)を有する。特に長期間にわたり存在する場合、高リン酸塩血症は、副甲状腺機能亢進症、骨疾患および関節、肺、目および脈管構造における石灰化によりしばしば明らかになるカルシウムおよびリン代謝における重篤な異常性を導く。腎不全を示す患者に関して、正常範囲内の血清リンの上昇は、腎不全の進行および心血管系事象の危険性の増大に関連する。腎疾患の進行は、リン酸塩保持を低減させることにより緩徐になりうる。従って、高リン酸塩血症である腎不全患者に関して、および血清リン酸塩が正常範囲内であるか、わずかだけ上昇している慢性腎疾患患者に関して、リン酸塩保持を低減させる治療は有益である。
所定のホスフィニルホスホネート(phosphinyl phosphonate)化合物がリン酸塩輸送タンパク質の有効なインヒビターであることが今や見出された。例えば、表1に示されるホスフィニルホスホネート化合物はリン酸塩輸送を阻害し、多くはインビトロウサギ腸刷毛縁膜(Brush Border Membrane)アッセイにおいて50μM未満のIC50を有する(実施例28参照)。この発見に基づいて、慢性腎疾患、リン酸塩代謝の障害に関連する疾患または損傷したリン酸塩輸送機能により媒介される疾患を有する被験体を処置する方法が開示される。また、新規リン酸塩輸送阻害ポリマーおよび化合物が開示される。
リン酸塩輸送の小分子およびポリマーインヒビターが本明細書中に開示される。これらの化合物は、好ましくは、胃腸管においてリン酸塩輸送を阻害する(すなわち、全体または部分的に減少または防止する)ために好適に使用され、それ故、上昇したリン酸塩レベルにより特徴付けられる状態および疾患、例えば、高リン酸塩血症、腎不全および副甲状腺機能低下症を処置するのに有用である。小分子インヒビターの多くは、胃腸管により吸収されることが予想され、それゆえ全身に利用可能である。結果として、それらは、腎臓等の他の器官においてリン酸塩輸送を阻害し得、慢性腎不全を処置するために有利に使用されうる。小分子インヒビターは、構造式(I)により表わされ、ホスフィニルホスホネート基を含有する。ポリマーインヒビターはまた、ホスフィニルホスホネート基を含有し、これは、ポリマー骨格から下垂するかまたは統合(integral)される。
の一部である。ジオールは2つの水酸基を有し、一方、ポリオールは3つ以上の水酸基を有する。ジオールおよびポリオールの例としては、ポリビニルアルコール、ポリアリルアルコール、ポリエチレングリコール、ポリピロピレングリコール、ポリサッカリド、および分枝ポリサッカリドが挙げられる。
ホスフェートトランスポーター阻害インビトロ試験
以下の例は、ウサギ腸刷子縁膜小嚢(BBMV)によるホスフェートの取り込み阻害のインビトロ測定に必要とされる手法の概要を説明する。
300MET 50mL
300mM マンニトール 2.73g
5mM EGTA 117mg
12mM トリス塩基 73mg
pH7.1(w/HCl)
60MET 250mL
60mM マンニトール 2.73g
5mM EGTA 585mg
12mM トリス塩基 363mg
pH7.1(w/HCl)
Na取り込みバッファー 50mL
100mM NaCl 292mg
50mM HEPES 596mg
100mM マンニトール 911mg
100μM KH2PO4 50mL0.1Mストック
pH7.4(w/NaOH)
停止バッファー 1000mL
100mM マンニトール 18.22g
20mM HEPES:トリス 20mL 全量の1Mストック
20mM MgSO4 4.93g
100mM コリンCl 13.96g
5mM KH2PO4 681mg
280MH 250mL
280mM マンニトール 12.75g
20mM HEPES 5mLの1Mストック
pH7.4(w/KOH)
K取り込みバッファー 50mL
100mM KCl 373mg
50mM HEPES 596mg
100mM マンニトール 911mg
100mM KH2PO4 50mL0.1Mストック
pH7.4(w/KOH)
ウサギ腸刷毛縁膜小胞(BBMV)を、雄ニュージーランドシロウサギの上部小腸(十二指腸)の粘膜小片から単離した。該小片を凍結保存バイアル中で2 gの部分に分け、液体窒素中で凍結させ、-80℃で保存した。
以下の実験を、ベックマンマルチメック(Beckman Multimek)96チップ自動(robotic)ピペッターを使用して行った。以下は化合物の1つの96ウェルプレートをスクリーニングするために必要な調製の概要である。しかしながら、複数のプレートが1回の実験においてスクリーニングされ得る。
a.最大活性(MAX)- Na取り込みバッファー+200,000 CPM/19μLでの33PO4
b.中度活性(MID)- MAX+100μM KH2PO4、pH 7.4
c.最小活性(MIN)- K取り込みバッファー+200,000 CPM/19μLでの33PO4
を調製し、ポリプロピレン、96ウェル V底プレート(「ホットストックプレート」)の適切なウェルに入れた。化合物を含む反応物に使用される、残りのウェルに、MAX対照バッファーを入れた。ホットストックプレートを室温で貯蔵した。適切な96ウェルフィルタープレートの各ウェルにおよそ200μLの停止バッファーを加え、アッセイ前に少なくとも15分間、フィルターを前もって湿らせた。「化合物プレート」を、96ウェル、ポリプロピレン、V底プレートの適切なウェルに化合物溶液をローディングすることによりセットアップした。これは単一「スクリーニング」濃度での阻害を試験するためか、または適切な濃度での用量応答分析による化合物の潜在力を測定するためであり得る。「BBMVプレート」を、96ウェル、ポリプロピレン、V底プレートに0.5〜2.0 mg/mLのBBMV(上記のように調製)をローディングすることによりセットアップした。BBMVプレートをアッセイの直前まで氷上に保持した。反応を、ホットストックプレートからの熱い取り込みバッファー(19μL)、および化合物プレートからの化合物溶液(2μL)のアスピレーションにより開始させ、空の96ウェルV底プレート(アッセイプレート)へ分配し、次いで直ぐにBBMVプレートからBBMV(19μL)を吸引し、同じアッセイプレートに分配した。アッセイプレートへのBBMVの添加により、反応開始時間を記録した。15分後、200μLの停止バッファーをリザーバーから添加することにより、反応を停止させた。停止バッファーを、フィルタープレート装置を使用して前もって湿らせたフィルタープレートのウェルからフィルターを通して、バキュームにより吸引した。停止した反応物を吸引し、真空下でフィルタープレートに移した。フィルターを、200μLの停止バッファーで2回、真空下で洗浄した。フィルタープレートを除去し、乾燥させ、フィルタープレートの底を密封した。フィルタープレートの各ウェルに、50μLのシンチラント(scintillant)(Microscint-20)を加えた。次いでフィルタープレートの上部に封をした。プレートを、33P CPMを読む前にシンチレーションカウンター(すなわち、TopCount-Packard Instruments)上でおよそ20分間インキュベートした。以下の式
1-((CPM-MIN)/(MAX-MIN))
を使用して、同じプレート上で、化合物を含むウェルからのCPM値をMAXおよびMIN対照と比較することによって、阻害率を計算した。適切なソフトウエアパッケージ(すなわち、Prism GraphPad)内での非直線回帰分析からIC50値を計算した。結果を以下、表1に示す。
Claims (22)
- 以下の構造式:
R1およびR2は独立して-H、電子吸引基またはC1〜C10アルキル基であり;
Yは、-CHX;ハロゲン、-NO 2 、-CN、-CF 3 および-OCF 3 から選択される電子吸引基で置換されたメチレン基;または-CR1R2P(O)(OH)-であり、ここで、Xは、低級アルキル基であり、
R3は任意に1以上のアミン、アンモニウム、エーテル、チオエーテルもしくはフェニレン結合基を含むヒドロカルビル基;任意に1以上のアミン、アンモニウム、エーテル、チオエーテルもしくはフェニレン結合基を含む置換ヒドロカルビル基;ヘテロアリール基;置換ヘテロアリール基;または-Cl、-Br、-F、-CN、-NO2、-ORa、-N(Ra)2、-COOR a 、-CON(Ra)2、-CORa、-S(O)Ra、-S(O)2Ra、-S(O)2N(Ra)2、-NRaS(O)2Ra、-NRaCORa、ハロゲン化低級アルキル基、アリール基、置換アリール基、もしくはハロゲン化アルコキシ基から選択される1以上の基で置換されたフェニル基である、ここで、置換ヒドロカルビル基、置換ヘテロアリール基、または置換アリール基は、-OH、-Br、-Cl、-I、-F、-O(R12)、-O-CO-(R12)、-CN、-NO 2 、-COOH、=O、-NH 2 、-NH(R12)、-N(R12) 2 、-COO(R12)、-CONH 2 、-CONH(R12)、-CON(R12) 2 、-SH、-S(R12)、脂肪族基、アリール基およびヘテロアリール基から選択される1つ以上の置換基で置換され、各R12は、独立して-H、アルキル基またはアリール基であり;あるいは
Yは非置換メチレン基であり、
R3はC7〜C18飽和非置換ヒドロカルビル基または置換基が末端位置にあるC7〜C18飽和一置換ヒドロカルビル基であり、該末端位置にある置換基は、シクロヘキシル基、オキシラン基、置換もしくは非置換ベンゼンスルホンアミド基、置換もしくは非置換のベンズアミド基、プロピオンアミド基、アクリルアミド基、置換もしくは非置換のナフサアミド基、フタルイミド基、1,2-ジブロモ-エチル基、1-ヒドロキシ-2-ブロモ-エチル基、置換もしくは非置換のフェニル基、置換もしくは非置換のヘテロアリール基、CH 2 =CH-、-M-CR4=CHR5、-N(R7) 2 、-OR7、-COOR7、-Br、-Cl、-Iまたは-N + (R7) 3 であり、ここで、置換ベンゼンスルホンアミド基、置換ベンズアミド基、置換ナフサアミド基、置換フェニル基、および置換ヘテロアリール基は、-OH、-Br、-Cl、-I、-F、-O(R12)、-O-CO-(R12)、-CN、-NO 2 、-COOH、=O、-NH 2 、-NH(R12)、-N(R12) 2 、-COO(R12)、-CONH 2 、-CONH(R12)、-CON(R12) 2 、-SH、-S(R12)、脂肪族基、アリール基およびヘテロアリール基から選択される1つ以上の置換基で置換され;
Mは、-NR6-、-O-、-C(O)-、-C(O)O-、-C(O)NR6-、-NR6C(O)-、-(CH 2 ) q -、またはフェニレンであり;
各R4およびR5は、独立して-HまたはC1〜C5アルキル基であり;
各R6は、独立して-H、低級アルキルまたはアリールであり;
各R7は、独立して-HまたはC1〜C3低級アルキル基であり;
qは0または1であり;
各Rbは独立して-H、低級アルキル基またはリン酸塩保護基であり;
各Raは独立して-H、低級アルキル、置換低級アルキル、アリールまたは置換アリールであり、ここで、置換低級アルキルまたは置換アリールは、-OH、-Br、-Cl、-I、-F、-O(R12)、-O-CO-(R12)、-CN、-NO 2 、-COOH、=O、-NH 2 、-NH(R12)、-N(R12) 2 、-COO(R12)、-CONH 2 、-CONH(R12)、-CON(R12) 2 、-SH、-S(R12)、脂肪族基、アリール基およびヘテロアリール基から選択される1つ以上の置換基で置換される
により表される化合物またはその薬学的に許容され得る塩を含む医薬組成物であって、該医薬組成物は、リン酸塩輸送阻害を必要とする被験体においてリン酸塩輸送を阻害するために使用される、医薬組成物。 - R1およびR2が独立して-Hまたは-Fである、請求項1記載の医薬組成物。
- Yが-CH2-、-CHF-または-CF2-であり、R3が以下の構造式:
nは7から18の整数であり;
R4は-HまたはC1〜C5アルキル基であり;
R5は-HまたはC1〜C5アルキル基であり;
Qは共有結合、-CH2-、1,3-フェニレン、1,4-フェニレン、-C(O)O-、-C(O)NR6-、-C(O)-、-O-、-NR6-、-CH2NR6-または-CH2O-であり;
各R6は独立して-H、低級アルキル、置換低級アルキル、アリールまたは置換アリールであり、ここで、置換低級アルキルまたは置換アリールは、-OH、-Br、-Cl、-I、-F、-O(R12)、-O-CO-(R12)、-CN、-NO 2 、-COOH、=O、-NH 2 、-NH(R12)、-N(R12) 2 、-COO(R12)、-CONH 2 、-CONH(R12)、-CON(R12) 2 、-SH、-S(R12)、脂肪族基、アリール基およびヘテロアリール基から選択される1つ以上の置換基で置換され、各R12は、独立して-H、アルキル基またはアリール基である
により表される、請求項2記載の医薬組成物。 - R3が以下の構造式:
- Yが-CHF-または-CF2-である、請求項2記載の医薬組成物。
- Yが-CHX-であり、Xが低級アルキル基である、請求項2記載の医薬組成物。
- R3が、任意に1以上のアミン、アンモニウム、エーテル、チオエーテルまたはフェニレン結合基を含み、末端が-M-CR4=CHR5、-CH=CH2、-N(R7)2、-OR7、-COOR7、-Br、-Cl、-Iまたは-N+(R7)3で置換されたヒドロカルビル基であり;
Mは-NR6-、-O-、-C(O)-、-C(O)O-、-C(O)NR6-、-NR6C(O)-、-(CH2)q-、またはフェニレンであり;
R4およびR5は独立して-HまたはC1〜C5アルキル基であり;
各R6は独立して-H、低級アルキル、置換低級アルキル、アリールまたは置換アリールであり、ここで、置換低級アルキルまたは置換アリールは、-OH、-Br、-Cl、-I、-F、-O(R12)、-O-CO-(R12)、-CN、-NO 2 、-COOH、=O、-NH 2 、-NH(R12)、-N(R12) 2 、-COO(R12)、-CONH 2 、-CONH(R12)、-CON(R12) 2 、-SH、-S(R12)、脂肪族基、アリール基およびヘテロアリール基から選択される1つ以上の置換基で置換され、各R12は、独立して-H、アルキル基またはアリール基であり;
各R7は独立して-HまたはC1〜C3直鎖低級アルキル基であり;qは0または1である、請求項6記載の医薬組成物。 - R3が、任意に1以上のアミン、アンモニウム、エーテル、チオエーテルまたはフェニレン結合基を含み、末端が-CH=CH2、-N(R7)2、-OR7、-COOR7、-Br、-Cl、-Iまたは-N+(R7)3で置換されたヒドロカルビル基であり、各R7は独立して-HまたはC1〜C3直鎖低級アルキル基である、請求項5記載の医薬組成物。
- R3が、-Cl、-Br、-F、-CN、-NO2、-ORa、-N(Ra)2、-COOR a 、-CON(Ra)2、-CORa、-S(O)Ra、-S(O)2Ra、-S(O)2N(Ra)2、-NRaS(O)2Ra、-NRaCORa、ハロゲン化低級アルキル基、アリール基、置換アリール基、またはハロゲン化アルコキシ基から選択される1以上の基で置換されたフェニル基であり、ここで、置換アリール基は、-OH、-Br、-Cl、-I、-F、-O(R12)、-O-CO-(R12)、-CN、-NO 2 、-COOH、=O、-NH 2 、-NH(R12)、-N(R12) 2 、-COO(R12)、-CONH 2 、-CONH(R12)、-CON(R12) 2 、-SH、-S(R12)、脂肪族基、アリール基およびヘテロアリール基から選択される1つ以上の置換基で置換され、各R12は、独立して-H、アルキル基またはアリール基である、請求項6記載の医薬組成物。
- Yが-CHF-または-CF2-であり、R3が-(CH2)m-R8であり、R8は置換または非置換ヘテロアリール基であり、mは0から20の整数であり、ここで、置換ヘテロアリール基は、-OH、-Br、-Cl、-I、-F、-O(R12)、-O-CO-(R12)、-CN、-NO 2 、-COOH、=O、-NH 2 、-NH(R12)、-N(R12) 2 、-COO(R12)、-CONH 2 、-CONH(R12)、-CON(R12) 2 、-SH、-S(R12)、脂肪族基、アリール基およびヘテロアリール基から選択される1つ以上の置換基で置換され、各R12は、独立して-H、アルキル基またはアリール基である、請求項2記載の医薬組成物。
- Yが-CH2-であり、R3が-(CH2)m-R8であり、R8は置換または非置換フェニル基であり、mは7から18の整数であり、ここで、置換フェニル基は、-OH、-Br、-Cl、-I、-F、-O(R12)、-O-CO-(R12)、-CN、-NO 2 、-COOH、=O、-NH 2 、-NH(R12)、-N(R12) 2 、-COO(R12)、-CONH 2 、-CONH(R12)、-CON(R12) 2 、-SH、-S(R12)、脂肪族基、アリール基およびヘテロアリール基から選択される1つ以上の置換基で置換され、各R12は、独立して-H、アルキル基またはアリール基である、請求項2記載の医薬組成物。
- 以下の構造式:
R1およびR2は独立して-H、電子吸引基またはC1〜C10アルキル基であり;
Yは、-CHX;ハロゲン、-NO 2 、-CN、-CF 3 および-OCF 3 から選択される電子吸引基で置換されたメチレン基;または-CR1R2P(O)(OH)-であり、ここで、Xは、低級アルキル基であり、
R3は任意に1以上のアミン、アンモニウム、エーテル、チオエーテルもしくはフェニレン結合基を含むヒドロカルビル基;任意に1以上のアミン、アンモニウム、エーテル、チオエーテルもしくはフェニレン結合基を含む置換ヒドロカルビル基;ヘテロアリール基;置換ヘテロアリール基;または-Cl、-Br、-F、-CN、-NO 2 、-OR a 、-N(R a ) 2 、-COOR a 、-CON(R a ) 2 、-COR a 、-S(O)R a 、-S(O) 2 R a 、-S(O) 2 N(R a ) 2 、-NR a S(O) 2 R a 、-NR a COR a 、ハロゲン化低級アルキル基、アリール基、置換アリール基、もしくはハロゲン化アルコキシ基から選択される1以上の基で置換されたフェニル基である、ここで、置換ヒドロカルビル基、置換ヘテロアリール基、または置換アリール基は、-OH、-Br、-Cl、-I、-F、-O(R12)、-O-CO-(R12)、-CN、-NO 2 、-COOH、=O、-NH 2 、-NH(R12)、-N(R12) 2 、-COO(R12)、-CONH 2 、-CONH(R12)、-CON(R12) 2 、-SH、-S(R12)、脂肪族基、アリール基およびヘテロアリール基から選択される1つ以上の置換基で置換され、各R12は、独立して-H、アルキル基またはアリール基であり;あるいは
Yは非置換メチレン基であり、
R3はC7〜C18飽和非置換ヒドロカルビル基または置換基が末端位置にあるC7〜C18飽和一置換ヒドロカルビル基であり、該末端位置にある置換基は、シクロヘキシル基、オキシラン基、置換もしくは非置換ベンゼンスルホンアミド基、置換もしくは非置換のベンズアミド基、プロピオンアミド基、アクリルアミド基、置換もしくは非置換のナフサアミド基、フタルイミド基、1,2-ジブロモ-エチル基、1-ヒドロキシ-2-ブロモ-エチル基、置換もしくは非置換のフェニル基、置換もしくは非置換のヘテロアリール基、CH 2 =CH-、-M-CR4=CHR5、-N(R7) 2 、-OR7、-COOR7、-Br、-Cl、-Iまたは-N + (R7) 3 であり、ここで、置換ベンゼンスルホンアミド基、置換ベンズアミド基、置換ナフサアミド基、置換フェニル基、および置換ヘテロアリール基は、-OH、-Br、-Cl、-I、-F、-O(R12)、-O-CO-(R12)、-CN、-NO 2 、-COOH、=O、-NH 2 、-NH(R12)、-N(R12) 2 、-COO(R12)、-CONH 2 、-CONH(R12)、-CON(R12) 2 、-SH、-S(R12)、脂肪族基、アリール基およびヘテロアリール基から選択される1つ以上の置換基で置換され;
Mは、-NR6-、-O-、-C(O)-、-C(O)O-、-C(O)NR6-、-NR6C(O)-、-(CH 2 ) q -、またはフェニレンであり;
各R4およびR5は、独立して-HまたはC1〜C5アルキル基であり;
各R6は、独立して-H、低級アルキルまたはアリールであり;
各R7は、独立して-HまたはC1〜C3低級アルキル基であり;
qは0または1であり;
各Rbは独立して-H、低級アルキル基またはリン酸塩保護基であり;
各R a は独立して-H、低級アルキル、置換低級アルキル、アリールまたは置換アリールであり、ここで、置換低級アルキルまたは置換アリールは、-OH、-Br、-Cl、-I、-F、-O(R12)、-O-CO-(R12)、-CN、-NO 2 、-COOH、=O、-NH 2 、-NH(R12)、-N(R12) 2 、-COO(R12)、-CONH 2 、-CONH(R12)、-CON(R12) 2 、-SH、-S(R12)、脂肪族基、アリール基およびヘテロアリール基から選択される1つ以上の置換基で置換される
により表される化合物またはその薬学的に許容され得る塩の、リン酸塩輸送阻害を必要とする被験体においてリン酸塩輸送を阻害するための医薬の製造における使用。 - R1およびR2が独立して-Hまたは-Fである、請求項12記載の使用。
- Yが-CH 2 -、-CHF-または-CF 2 -であり、R3が以下の構造式:
nは7から18の整数であり;
R4は-HまたはC1〜C5アルキル基であり;
R5は-HまたはC1〜C5アルキル基であり;
Qは共有結合、-CH 2 -、1,3-フェニレン、1,4-フェニレン、-C(O)O-、-C(O)NR6-、-C(O)-、-O-、-NR6-、-CH 2 NR6-または-CH 2 O-であり;
各R6は独立して-H、低級アルキル、置換低級アルキル、アリールまたは置換アリールであり、ここで、置換低級アルキルまたは置換アリールは、-OH、-Br、-Cl、-I、-F、-O(R12)、-O-CO-(R12)、-CN、-NO 2 、-COOH、=O、-NH 2 、-NH(R12)、-N(R12) 2 、-COO(R12)、-CONH 2 、-CONH(R12)、-CON(R12) 2 、-SH、-S(R12)、脂肪族基、アリール基およびヘテロアリール基から選択される1つ以上の置換基で置換され、各R12は、独立して-H、アルキル基またはアリール基である
により表される、請求項13記載の使用。 - R3が以下の構造式:
- Yが-CHF-または-CF 2 -である、請求項13記載の使用。
- Yが-CHX-であり、Xが低級アルキル基である、請求項13記載の使用。
- R3が、任意に1以上のアミン、アンモニウム、エーテル、チオエーテルまたはフェニレン結合基を含み、末端が-M-CR4=CHR5、-CH=CH 2 、-N(R7) 2 、-OR7、-COOR7、-Br、-Cl、-Iまたは-N + (R7) 3 で置換されたヒドロカルビル基であり;
Mは-NR6-、-O-、-C(O)-、-C(O)O-、-C(O)NR6-、-NR6C(O)-、-(CH 2 ) q -、またはフェニレンであり;
R4およびR5は独立して-HまたはC1〜C5アルキル基であり;
各R6は独立して-H、低級アルキル、置換低級アルキル、アリールまたは置換アリールであり、ここで、置換低級アルキルまたは置換アリールは、-OH、-Br、-Cl、-I、-F、-O(R12)、-O-CO-(R12)、-CN、-NO 2 、-COOH、=O、-NH 2 、-NH(R12)、-N(R12) 2 、-COO(R12)、-CONH 2 、-CONH(R12)、-CON(R12) 2 、-SH、-S(R12)、脂肪族基、アリール基およびヘテロアリール基から選択される1つ以上の置換基で置換され、各R12は、独立して-H、アルキル基またはアリール基であり;
各R7は独立して-HまたはC1〜C3直鎖低級アルキル基であり;qは0または1である、請求項17記載の使用。 - R3が、任意に1以上のアミン、アンモニウム、エーテル、チオエーテルまたはフェニレン結合基を含み、末端が-CH=CH 2 、-N(R7) 2 、-OR7、-COOR7、-Br、-Cl、-Iまたは-N + (R7) 3 で置換されたヒドロカルビル基であり、各R7は独立して-HまたはC1〜C3直鎖低級アルキル基である、請求項16記載の使用。
- R3が、-Cl、-Br、-F、-CN、-NO 2 、-OR a 、-N(R a ) 2 、-COOR a 、-CON(R a ) 2 、-COR a 、-S(O)R a 、-S(O) 2 R a 、-S(O) 2 N(R a ) 2 、-NR a S(O) 2 R a 、-NR a COR a 、ハロゲン化低級アルキル基、アリール基、置換アリール基、またはハロゲン化アルコキシ基から選択される1以上の基で置換されたフェニル基であり、ここで、置換アリール基は、-OH、-Br、-Cl、-I、-F、-O(R12)、-O-CO-(R12)、-CN、-NO 2 、-COOH、=O、-NH 2 、-NH(R12)、-N(R12) 2 、-COO(R12)、-CONH 2 、-CONH(R12)、-CON(R12) 2 、-SH、-S(R12)、脂肪族基、アリール基およびヘテロアリール基から選択される1つ以上の置換基で置換され、各R12は、独立して-H、アルキル基またはアリール基である、請求項17記載の使用。
- Yが-CHF-または-CF 2 -であり、R3が-(CH 2 ) m -R8であり、R8は置換または非置換ヘテロアリール基であり、mは0から20の整数であり、ここで、置換ヘテロアリール基は、-OH、-Br、-Cl、-I、-F、-O(R12)、-O-CO-(R12)、-CN、-NO 2 、-COOH、=O、-NH 2 、-NH(R12)、-N(R12) 2 、-COO(R12)、-CONH 2 、-CONH(R12)、-CON(R12) 2 、-SH、-S(R12)、脂肪族基、アリール基およびヘテロアリール基から選択される1つ以上の置換基で置換され、各R12は、独立して-H、アルキル基またはアリール基である、請求項13記載の使用。
- Yが-CH 2 -であり、R3が-(CH 2 ) m -R8であり、R8は置換または非置換フェニル基であり、mは7から18の整数であり、ここで、置換フェニル基は、-OH、-Br、-Cl、-I、-F、-O(R12)、-O-CO-(R12)、-CN、-NO 2 、-COOH、=O、-NH 2 、-NH(R12)、-N(R12) 2 、-COO(R12)、-CONH 2 、-CONH(R12)、-CON(R12) 2 、-SH、-S(R12)、脂肪族基、アリール基およびヘテロアリール基から選択される1つ以上の置換基で置換され、各R12は、独立して-H、アルキル基またはアリール基である、請求項13記載の使用。
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US5508342A (en) * | 1994-02-01 | 1996-04-16 | The United States Of America As Represented By The Secretary Of Commerce | Polymeric amorphous calcium phosphate compositions |
US5618851A (en) * | 1995-02-06 | 1997-04-08 | Arch Development Corp. | Grafted methylenediphosphonate ion exchange resins |
EP1485391B1 (en) | 2002-03-19 | 2006-08-23 | Genzyme Corporation | Phosphate transport inhibitors |
-
2003
- 2003-03-19 EP EP03714264A patent/EP1485391B1/en not_active Expired - Lifetime
- 2003-03-19 AT AT03714264T patent/ATE337326T1/de not_active IP Right Cessation
- 2003-03-19 JP JP2003578384A patent/JP4465193B2/ja not_active Expired - Fee Related
- 2003-03-19 AU AU2003218270A patent/AU2003218270A1/en not_active Abandoned
- 2003-03-19 US US10/392,280 patent/US7109184B2/en not_active Expired - Lifetime
- 2003-03-19 DE DE60307799T patent/DE60307799T2/de not_active Expired - Lifetime
- 2003-03-19 WO PCT/US2003/008449 patent/WO2003080630A2/en active IP Right Grant
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2006
- 2006-05-22 US US11/438,679 patent/US7754200B2/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
ATE337326T1 (de) | 2006-09-15 |
US20040019020A1 (en) | 2004-01-29 |
WO2003080630A2 (en) | 2003-10-02 |
US7754200B2 (en) | 2010-07-13 |
EP1485391A2 (en) | 2004-12-15 |
AU2003218270A8 (en) | 2003-10-08 |
EP1485391B1 (en) | 2006-08-23 |
JP2005520864A (ja) | 2005-07-14 |
DE60307799D1 (de) | 2006-10-05 |
DE60307799T2 (de) | 2007-08-16 |
WO2003080630A3 (en) | 2003-12-11 |
AU2003218270A1 (en) | 2003-10-08 |
US20060280719A1 (en) | 2006-12-14 |
US7109184B2 (en) | 2006-09-19 |
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