JPH07507314A - カルシウム及びホスフェート代謝異常治療用ホスホノスルホネート化合物 - Google Patents
カルシウム及びホスフェート代謝異常治療用ホスホノスルホネート化合物Info
- Publication number
- JPH07507314A JPH07507314A JP6500721A JP50072194A JPH07507314A JP H07507314 A JPH07507314 A JP H07507314A JP 6500721 A JP6500721 A JP 6500721A JP 50072194 A JP50072194 A JP 50072194A JP H07507314 A JPH07507314 A JP H07507314A
- Authority
- JP
- Japan
- Prior art keywords
- substituted
- unsubstituted
- alkyl
- group
- hydrogen
- 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
- LQHYUUBBIJGBNR-UHFFFAOYSA-N OP(O)(=O)S(O)(=O)=O Chemical class OP(O)(=O)S(O)(=O)=O LQHYUUBBIJGBNR-UHFFFAOYSA-N 0.000 title claims abstract description 32
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 title claims abstract description 30
- 239000011575 calcium Substances 0.000 title claims abstract description 30
- 229910052791 calcium Inorganic materials 0.000 title claims abstract description 30
- 229910019142 PO4 Inorganic materials 0.000 title claims abstract description 25
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 title claims abstract description 24
- 239000010452 phosphate Substances 0.000 title claims abstract description 24
- 238000011282 treatment Methods 0.000 title claims abstract description 24
- 208000030159 metabolic disease Diseases 0.000 title claims description 3
- 150000003839 salts Chemical class 0.000 claims abstract description 27
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 23
- 150000002148 esters Chemical class 0.000 claims abstract description 22
- -1 pivaloyloxymethyl Chemical group 0.000 claims description 60
- 239000001257 hydrogen Substances 0.000 claims description 51
- 229910052739 hydrogen Inorganic materials 0.000 claims description 51
- 229920006395 saturated elastomer Polymers 0.000 claims description 42
- 125000000217 alkyl group Chemical group 0.000 claims description 41
- 125000004429 atom Chemical group 0.000 claims description 35
- 125000002950 monocyclic group Chemical group 0.000 claims description 31
- 125000003367 polycyclic group Chemical group 0.000 claims description 30
- 125000001424 substituent group Chemical group 0.000 claims description 30
- 229910052757 nitrogen Inorganic materials 0.000 claims description 28
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 27
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 26
- 125000000623 heterocyclic group Chemical group 0.000 claims description 24
- 125000004585 polycyclic heterocycle group Chemical group 0.000 claims description 23
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 19
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 18
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 17
- 229910052717 sulfur Inorganic materials 0.000 claims description 17
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 15
- 229910052760 oxygen Inorganic materials 0.000 claims description 15
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- 229910052799 carbon Inorganic materials 0.000 claims description 13
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 13
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
- 125000006413 ring segment Chemical group 0.000 claims description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 9
- 150000002431 hydrogen Chemical group 0.000 claims description 8
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical group C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 125000004945 acylaminoalkyl group Chemical group 0.000 claims description 6
- 125000002619 bicyclic group Chemical group 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 238000006467 substitution reaction Methods 0.000 claims description 6
- 229910052720 vanadium Inorganic materials 0.000 claims description 6
- 125000005041 acyloxyalkyl group Chemical group 0.000 claims description 5
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 claims description 5
- 229960001231 choline Drugs 0.000 claims description 5
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical group C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000005256 alkoxyacyl group Chemical group 0.000 claims description 3
- 125000002837 carbocyclic group Chemical group 0.000 claims description 3
- 125000005429 oxyalkyl group Chemical group 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical group C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 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 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-O hydron;pyrimidine Chemical group C1=CN=C[NH+]=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-O 0.000 claims description 2
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 claims description 2
- 125000006732 (C1-C15) alkyl group Chemical group 0.000 claims 6
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 claims 3
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-O hydron;quinoline Chemical compound [NH+]1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-O 0.000 claims 2
- CEKSPMMCISUSTR-UHFFFAOYSA-N 1,2,3,4,4a,5,6,7-octahydroquinoline Chemical compound C1CCC2CCCNC2=C1 CEKSPMMCISUSTR-UHFFFAOYSA-N 0.000 claims 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-O 1H-indol-1-ium Chemical compound C1=CC=C2[NH2+]C=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-O 0.000 claims 1
- 125000001054 5 membered carbocyclic group Chemical group 0.000 claims 1
- VNHBYKHXBCYPBJ-UHFFFAOYSA-N 5-ethynylimidazo[1,2-a]pyridine Chemical compound C#CC1=CC=CC2=NC=CN12 VNHBYKHXBCYPBJ-UHFFFAOYSA-N 0.000 claims 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims 1
- 125000001041 indolyl group Chemical group 0.000 claims 1
- KDXKERNSBIXSRK-YFKPBYRVSA-O lysinium group Chemical group [NH3+][C@@H](CCCCN)C(=O)O KDXKERNSBIXSRK-YFKPBYRVSA-O 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 125000006187 phenyl benzyl group Chemical group 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 89
- 238000000034 method Methods 0.000 abstract description 72
- 239000000203 mixture Substances 0.000 abstract description 52
- 208000001132 Osteoporosis Diseases 0.000 abstract description 31
- 230000002159 abnormal effect Effects 0.000 abstract description 21
- 239000000546 pharmaceutical excipient Substances 0.000 abstract description 16
- 230000004060 metabolic process Effects 0.000 abstract description 15
- 241000282412 Homo Species 0.000 abstract description 13
- 206010003246 arthritis Diseases 0.000 abstract description 11
- 201000008482 osteoarthritis Diseases 0.000 abstract description 11
- 206010039073 rheumatoid arthritis Diseases 0.000 abstract description 11
- 241000124008 Mammalia Species 0.000 abstract description 8
- 230000001575 pathological effect Effects 0.000 abstract description 7
- 241000282414 Homo sapiens Species 0.000 abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 67
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 52
- 239000000243 solution Substances 0.000 description 45
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 39
- 239000007858 starting material Substances 0.000 description 38
- 235000021317 phosphate Nutrition 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- 230000015572 biosynthetic process Effects 0.000 description 20
- 239000011541 reaction mixture Substances 0.000 description 19
- 238000003786 synthesis reaction Methods 0.000 description 19
- 239000002253 acid Substances 0.000 description 18
- 210000000988 bone and bone Anatomy 0.000 description 18
- 239000004480 active ingredient Substances 0.000 description 17
- 238000003756 stirring Methods 0.000 description 17
- 239000003054 catalyst Substances 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- 208000024891 symptom Diseases 0.000 description 14
- 201000010099 disease Diseases 0.000 description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 230000002829 reductive effect Effects 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 11
- 239000002775 capsule Substances 0.000 description 11
- 150000002430 hydrocarbons Chemical group 0.000 description 11
- 230000000694 effects Effects 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 241001465754 Metazoa Species 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000012141 concentrate Substances 0.000 description 9
- 239000012153 distilled water Substances 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 238000002560 therapeutic procedure Methods 0.000 description 9
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- 239000007924 injection Substances 0.000 description 8
- 238000002347 injection Methods 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 8
- 210000001519 tissue Anatomy 0.000 description 8
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 7
- 206010065687 Bone loss Diseases 0.000 description 7
- 238000010521 absorption reaction Methods 0.000 description 7
- 229960000583 acetic acid Drugs 0.000 description 7
- 235000011054 acetic acid Nutrition 0.000 description 7
- 239000000284 extract Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- BBFCIBZLAVOLCF-UHFFFAOYSA-N pyridin-1-ium;bromide Chemical compound Br.C1=CC=NC=C1 BBFCIBZLAVOLCF-UHFFFAOYSA-N 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-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
- 208000002193 Pain Diseases 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- 125000003277 amino group Chemical group 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 239000003729 cation exchange resin Substances 0.000 description 6
- 210000004027 cell Anatomy 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
- 239000002552 dosage form Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 239000012299 nitrogen atmosphere Substances 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 125000004103 aminoalkyl group Chemical group 0.000 description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 5
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- 238000006243 chemical reaction Methods 0.000 description 5
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 5
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- ROFVJSWBDQUQGW-UHFFFAOYSA-N piperidin-1-ium;bromide Chemical compound Br.C1CCNCC1 ROFVJSWBDQUQGW-UHFFFAOYSA-N 0.000 description 5
- 239000011591 potassium Substances 0.000 description 5
- 229910052700 potassium Inorganic materials 0.000 description 5
- BJDYCCHRZIFCGN-UHFFFAOYSA-N pyridin-1-ium;iodide Chemical compound I.C1=CC=NC=C1 BJDYCCHRZIFCGN-UHFFFAOYSA-N 0.000 description 5
- 125000004076 pyridyl group Chemical group 0.000 description 5
- 239000011347 resin Substances 0.000 description 5
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- 229910052708 sodium Inorganic materials 0.000 description 5
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- XJLMJCCXKHCVDN-UHFFFAOYSA-N 1-hydroxy-1-phosphono-2-pyridin-3-ylethanesulfonic acid Chemical compound OP(=O)(O)C(S(O)(=O)=O)(O)CC1=CC=CN=C1 XJLMJCCXKHCVDN-UHFFFAOYSA-N 0.000 description 4
- DXHNTXMADHTMPT-UHFFFAOYSA-N 1-phosphono-2-pyridin-2-ylethanesulfonic acid Chemical compound OP(O)(=O)C(S(O)(=O)=O)CC1=CC=CC=N1 DXHNTXMADHTMPT-UHFFFAOYSA-N 0.000 description 4
- CNQCWYFDIQSALX-UHFFFAOYSA-N 3-(chloromethyl)pyridine Chemical compound ClCC1=CC=CN=C1 CNQCWYFDIQSALX-UHFFFAOYSA-N 0.000 description 4
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- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 4
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 4
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 4
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- 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 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
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- 150000003863 ammonium salts Chemical class 0.000 description 4
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- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 3
- 208000037147 Hypercalcaemia Diseases 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
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- 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 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 210000001188 articular cartilage Anatomy 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
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Abstract
Description
Claims (1)
- 【特許請求の範囲】 1.下記式(I)で表される構造を有するホスホノスルホネート並びにそれらの 薬学的に許容される塩及びエステル: ▲数式、化学式、表等があります▼(I)(式中、 (A) (1)Aは水素;ハロゲン;SR1;R2SR1;アミノ;ヒドロキシ;及び置 換又は未置換のC1−C8アルキルからなる群から選択され;(2)Bは (a)−NH2; (b)−R3N(R4)2;−R3[−N(R5)3]+;−R3N(R4)C (O)R4;−R3N(R4)C(S)R4;−R3N(R4)C(N)R4; 及び−R3C(O)N(R4)2からなる群から選択される1個以上の置換基で 置換された飽和又は不飽和のC1−C15アルキル鎖; (c)鎖原子数2〜15の置換又は未置換、飽和又は不飽和のヘテロアルキル鎖 (但し、前記鎖原子の1個以上は窒素原子である); (d)鎖原子数2〜15の飽和又は不飽和のヘテロアルキル鎖(但し、前記鎖原 子の1個以上はS又はOから選択され;及び前記ヘテロアルキル鎖は−R3N( R4)2;−R3〔−N(R5)3]+;,−R3N(R4)C(O)R4;− R3N(R4)C(S)R4;−R3N(R4)C(N)R4;及び−R3C( O)N(R4)2からなる群から選択される1個以上の置換基で置換されている );又は (e)R6−L−(式中、 (i)Lは、存在しない;N;−N(R5)3+;S;O;置換又は未置換、飽 和又は不飽和のC1〜C15アルキル鎖;及び鎖原子数2〜15の置換又は未置 換、飽和又は不飽和のヘテロアルキル鎖(但し、前記鎖原子の1個以上がN、S 又はOである)からなる群から選択され;そして (ii)R6は、飽和単環又は多環炭素環;不飽和単環又は多環炭素環;飽和単 環又は多環複素環;及び不飽和単環又は多環複素環からなる群から選択され;但 し、R6は、水素、−R3SR1;置換又は未置換のC1〜C8アルキル;−R 3OR4;−R3CO2R4;−R3O2CR4;−R3N(R4)2;R3[ −N(R5)3]+;−R3N(R4)C(O)R4;−R3N(R4)C(S )R4;−R3N(R4)C(N)R4;−R3C(O)N(R4)2;ハロゲ ン;−R3C(O)R4;アリールアルキル;ニトロ;置換又は未置換のアリー ル;及びヒドロキシからなる群からそれぞれ独立して選択される1個以上の置換 基で置換されていてもよい;そして (3) (a)R1は水素、−C(O)R7;−C(S)R7;−C(O)N(R7)2 ;−C(O)OR7;−C(S)N(R7)2;汲び−C(S)OR7(式中、 R7は、水素又は置換若しくは未置換のC1〜C8アルキルである)からなる群 がらそれぞれ独立して選択され; (b)R2は置換又は未置換のC1〜C8アルキルであり、 (c)R3は存在しない及び置換又は未置換のC1〜C8アルキルからなる群か ら選択され;(d)R4は、水素;置換又は未置換のC1〜C8アルキル;及び −R2SR1からなる群からそれぞれ独立して選択され;そして (e)R5は置換又は未置換のC1〜C15アルキル;置換又は未置換のフェニ ル;ベンジル;及び−R2SR1からなる群からそれぞれ独立して選択され: 又は (B)A及びBはC*と共有結合して以下の構造を有する単環又は二環構造を形 成する。 ▲数式、化学式、表等があります▼ (式中、 (1)WはC*、X及びX′を含んでなる置換又は未置換、飽和又は不飽和炭素 環であり、前記炭素環は合計3〜6個の環炭素原子を有するか;C*、X及びX ′を含んでなる置換又は未置換、飽和又は不飽和複素環であり、前記複素環は合 計4〜6個の環原子を有し、前記環原子の1個以上はN、O又はSであり; (2)Vは存在しない;X及びX′を含んでなる置換又は未置換、飽和又は不飽 和炭素環であって、前記炭素環は合計3〜8個の環炭素原子を有するか;又はX 及びX′を含んでなる置換又は未置換、飽和又は不飽和複素環であって、前記複 素環が合計3〜8個の環原子を有し、前記環原子の1個以上がN、O又はSであ り;そして(3)X及びX′はそれぞれ独立してN又はCであるが;但し、Vと Wのどちらも窒素含有複素環でない場合には、VとWの少なくとも一方は−R3 N(R4)2;R3〔−N(R5)3]+;−R3N(R4)C(O)R4;− R3N(R4)C(S)R4;−R3N(R4)C(N)R4;及び−R3C( O)N(R4)2からなる群から選択される一個以上の置換基によって置換され ている); そして、Rは水素、低級アルキル、低級アシルオキシァルキル、アミノカルボニ ルオキシアルキル、ピバロイルオキシメチル、ラクトニル、低級アルコキシアシ ロキシアルキル、アルコキシアルキル、コリン及びアシルアミノアルキルからか らなる群から選択される。)2.Aがヒドロキシであり;そしてBが鎖原子数2 〜15の置換又は未置換、飽和又は不飽和ヘテロアルキル鎖であって、前記鎖原 子の一個以上が窒素であるか、又はR6−L−(式中、LはN;N(R5)3+ 、C1〜C15アルキル鎖若しくは鎖原子数2〜15の窒素含有ヘテロアルキル であり、そしてR6は単環又は多環複素環若しくは炭素環である)である請求項 1に記載のホスホノスルホネート。 3.BがR6−L−(式中、LはN;C1〜C15アルキル鎖であって、前記ア ルキル鎖が−R3SR1、水素、置換又は未置換のC1〜C8アルキル、−R3 OR4及び−R3CO2R4からなる群から選択される少なくとも1以上の置換 基で置換されている);又は鎖原子数2〜15のヘテロアルキル鎖(前記ヘテロ アルキル鎖は−R3SR1、水素、−R3N(R4)2;−R3〔N(R5)3 +]及び−R3N(R4)C(O)R4からなる群から選択される1個以上の置 換基によって置換されている)である、請求項2に記載のホスホノスルホネート 。 4.R6が、ピリジン、ピリミジン、ピペリジン、ピリジニウム、ピリミジニウ ム及びピペリジニウムからなる群から選択される置換又は未置換6員単環複素環 ;イミダゾール、ピロール、ピロリジン、イミダゾリウム、ピロリウム及びピロ リジニウムからなる群から選択される置換又は未置換5員単環複素環;シクロヘ プチル及びシクロヘキシルからなる群から選択される置換又は未置換単環炭素環 ;6員環を5貫環に縮合して有している置換又は未置換多環複素環であって、前 記多環複素環がインドール、インドリウム、ピリジン、イミダゾール−(1,2 −a−)ピリジン、イミダゾール−(1,2−a−)ビリジニウム及びピリジニ ウムからなる群から選択されるものであり;又は6員環を6員環に縮合して有し ている置換又は未置換多環複素環であって、前記多環複素環がキノリン、イソキ ノリン、テトラヒドロキノリン、オクタヒドロキノリン、キノリニウム、インキ ノリニウム、テトラヒドロキノリニウム及びオクタヒドロキノリニウムからなる 群から選択されるものである、請求項3に記載のホスホノスルホネート。 5.R6が、−SR1、水素、−R3N(R4)2、−R3[N(R5)3]及 び−R3N(R4)からなる群から選択される一個以上の置換基で置換されてお り;そしてR1が−C(O)R7、C(S)R7;C(O)N(R7)2又は好 ましくは水素であり、R3が存在せず、そしてR4が水素である、請求項4に記 載のホスホノスルホネート。 6.Bが置換又は未置換、飽和又は不飽和の鎖原子数2〜15のヘテロアルキル 鎖であって、前記鎖原子の一つ以上が窒素原子であり、前記ヘテロアルキル鎖が −R3SR1;水素;置換又は未置換のC1〜C8アルキル;−R3OR4;− R3CO2R4;−R3N(R4)2;−R3[N(R5)3+];汲び−R3 N(R4)C(O)R4からなる群から選択される1個以上の置換基によって置 換されている、請求項2に記載のホスホノスルホネート。 7.A及びBはC*と一緒に二環を形成するが、但し、Wは5員環炭素環であり ;そしてVは少なくとも一個の環窒素原子を含有する5員環複素環か、好ましく は少なくとも一個の環窒素原子を含有する6員複素環である、請求項1に記載の ホスホノスルホネート。 8.前記二環が置換又は未置換のC1〜C8アルキル、−R3OR4、−R3O 2CR4、−R3N(R4)C(S)R4、−R3N(R4)C(N)R4、− R3C(O)N(R4)2、−R3SR1・水素、−R3CO2R4、−R3N (R4)2、−R3〔N(R5)3+]及び−R3N(R4)C(O)R4から なる群から選択される一個以上の置換基で置換されており;R3が存在せず;R 4が−R3SR1又は水素であり;そしてR1がC(O)R7、C(S)R7; C(O)N(R7)2又は好ましくは水素である、請求項7に記載のホスホノス ルホネート。 9.下式(I)で表されるホスホノスルホネート並びにそれらの薬学的に許容さ れる塩又はエステル;▲数式、化学式、表等があります▼(I)(式中、 (A) (1)Aはヒドロキシであり;そして (2)Bは、 ▲数式、化学式、表等があります▼ (式中、 (a)mは0から10の整数;nは0から10の整数;及びm+nは0から10 の整数であり;(b)R8は、存在しない;−R3SR1;水素1置換着しくは 未置換のC1〜C8アルキル;−R3OR4;−R3CO2R4;−R3O2C R4;−R3N(R4)2;−R3[N(R5)3]+;−R3N(R4)C( O)R4;−R3N(R4)C(S)R4;−R3N(R4)C(N)R4;− R3C(O)N(R4)2;ハロゲン;−R3C(O)R4;ニトロ;ヒドロキ シ;置換又は未置換飽和単環若しくは多環炭素環;置換又は未置換不飽和単環若 しくは多環炭素環;置換又は未置換飽和単環若しくは多環複素環;及び置換又は 未置換不飽和単環若しくは多環複素環からなる群からそれぞれ独立して選択され ; (c)R1は、水素;−C(O)R7;−C(S)R7;−C(O)N(R7) 2;−C(O)OR7;−C(S)N(R7)2;及び−C(S)OR7(但し 、R7は、水素、又は置換若しくは未置換のC1〜C8アルキルである)からな る群からそれぞれ独立して選択され; (d)R3は、存在しない及び置換又は置換のC1〜C8アルキルからなる群か ら選択され;(e)R4は、水素;置換又は未置換のC1〜C8アルキル;及び −R2SR1からなる群からそれぞれ独立して選択され; (f)R5は置換又は未置換のC1〜C35アルキル;置換又は未置換のフェニ ル;ベンジル;及び−R2SR1からなる群からそれぞれ独立して選択され; (g)Lは存在しない;−N(R8)−;[−N(R5)2−]+;−S−;− O−;及び−D−C(−E)−S−(式中、Dは共有結合、O又はSからなる群 から選択され、EはO又はSである)からなる群から選択され;そして (i)Lが−N(R8)−であるとき、又はLが[−N(R5)2−]+であり 及びmが1から10の整数であるとき、R9は存在しない;水素;置換又は未置 換のC1〜C15アルキル;R2SR1;及びR10からなる群からそれぞれ独 立して選択され; (ii)Lが[−N(R5)2−]+であり及びmが0であるとき、R9は置換 又は未置換のC1〜C15アルキル;R2SR1;及びR10からなる群から選 択され;又は (iii)Lが存在しない;−S−、−O−又は−D−C(=E)−S−のとき 、R9はR10であり; (h)R10は飽和、不飽和又は芳香族単環若しくは多環炭素環又は1個以上の ヘテロ原子を有する飽和、不飽和又は芳香族単環若しくは多環複素環であり;但 し、前記炭素環又は複素環は、1個以上のR11置換基で置換されており;そし て (j)各R11は、−R3SR1;水素;置換若しくは未置換のC1〜C8アル キル;−R3R4;−R3COR4;−R3O2CR4;−R3N(R4)2; −R3[−N(R5)3〕+;−R3N(R4)C(O)R4;−R3N(R4 )C(S)R4;−R3N(R4)C(N)R4;−R3C(O)N(R4)2 ;ハロゲン;−R3C(O)R4;ヒドロキシ;置換又は未置換のアリールアル キル;ニトロ;及び置換又は未置換のアリールからなる群からそれぞれ独立して 選択される); 又は (B)A及びBは、C*と一緒に共有結合して下記の構造を有する単環又は二環 を形成する: ▲数式、化学式、表等があります▼ (式中、 (a)A及びBは存在しない、−O−、−S−及び−NR10−からなる群から それぞれ独立して選択され; (b)Qは存在しない;−NR12−;及び[−N(R13)2−]+からなる 群から選択され;(c)X及びX′はC又はNからそれぞれ独立して選択され; (d)各R12は存在しない;−R3SR1;水素;置換若しくは未置換のC1 〜C8アルキル;−R3OR4;−R3CO2R4;−R3O2CR4;−R3 N(R4)2;R3[−N(R5)3]+;−R3N(R4)C(O)R4;− R3C(O)N(R4)2;ハロゲン;−R3C(O)R4;ヒドロキシ;置換 又は未置換のアリールアルキル;ニトロ;及び未置換又は置換のアリールからな る群からそれぞれ独立して選択され;そして (c)各R13は存在しない;置換又は未置換のC1〜C35アルキル;置換又 は未置換のフェニル;ベンジル;及び−R2SR1からなる群から選択され; (f)Qが存在しない場合以外のときには、k、j及びk+jは0から5の整数 であり;Qが存在しないときには、k、j及びk+jは0から6の整数であり; 並びに (g)p、q及びp+qは0から3のそれぞれ独立した整数であり;但し、Qが 存在しないときには、R11又はR12の少なくとも1個は、−R3N(R4) 2;R3[−N(R5)3〕+;−R3N(R4)C(O)R4;−R3N(R 4)C(S)R4;−R3N(R4)C(N)R4;及び−R3C(O)N(R 4)2からなる群から選択される); そしてRは、水素、低級アルキル、低級アシルオキシアルキル、アミノカルボニ ルオキシアルキル、ピバロイルオキシメチル、ラクトニル、低級アルコキシアシ ルオキシアルキル、アルコキシアルキル、コリン及びアシルアミノアルキルから なる群から選択される)。 10.(a)安全で効果的な量の請求項1、2、3、4、5、6、7、8又は9 に記載のホスホノスルホネートと; (b)薬学的に許容される担体とを含んでなる、医薬組成物。 11.カルシウム及びリン酸代謝異常の治療用医薬の製造のための、請求項1、 2、3、4、5、6、7、8又は9に記載のホスホノスルホネートの使用。
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AT352142B (de) * | 1977-03-29 | 1979-09-10 | Benckiser Knapsack Gmbh | Verfahren zur herstellung von neuen n- sulfoalkan-aminoalkanphosphonsaeuren und deren alkalisalzen |
DE3434667A1 (de) * | 1984-09-21 | 1986-04-03 | Henkel KGaA, 4000 Düsseldorf | 4-dimethylamino-1-hydroxybutan-1,1-diphosphonsaeure, deren wasserloesliche salze, verfahren zu ihrer herstellung sowie ihre verwendung |
IL77243A (en) * | 1984-12-21 | 1996-11-14 | Procter & Gamble | Pharmaceutical compositions containing geminal diphosphonic acid compounds and certain such novel compounds |
IL86951A (en) * | 1987-07-06 | 1996-07-23 | Procter & Gamble Pharma | Methylene phosphonoalkylphosphinates and pharmaceutical preparations containing them |
IL86095A0 (ja) * | 1987-09-30 | 1988-09-30 | Lilly Co Eli | |
KR900011782A (ko) * | 1989-01-03 | 1990-08-02 | 추후보정 | 불화 포스포노술폰산 및 그의 유도체 |
US5731299A (en) * | 1992-05-29 | 1998-03-24 | The Procter & Gamble Company | Phosphonosulfonate compounds, pharmaceutical compositions, and methods for treating abnormal calcium and phosphate metabolism |
-
1993
- 1993-05-26 AU AU43916/93A patent/AU659565B2/en not_active Ceased
- 1993-05-26 CZ CZ942958A patent/CZ295894A3/cs unknown
- 1993-05-26 ES ES93914150T patent/ES2123057T3/es not_active Expired - Lifetime
- 1993-05-26 HU HU9403411A patent/HUT71907A/hu unknown
- 1993-05-26 WO PCT/US1993/004976 patent/WO1993024495A1/en not_active Application Discontinuation
- 1993-05-26 DK DK93914150T patent/DK0642518T3/da active
- 1993-05-26 SG SG9607956A patent/SG90009A1/en unknown
- 1993-05-26 NZ NZ253523A patent/NZ253523A/en unknown
- 1993-05-26 AT AT93914150T patent/ATE169302T1/de not_active IP Right Cessation
- 1993-05-26 DE DE69320187T patent/DE69320187T2/de not_active Expired - Fee Related
- 1993-05-26 SK SK1455-94A patent/SK145594A3/sk unknown
- 1993-05-26 CA CA002136823A patent/CA2136823C/en not_active Expired - Fee Related
- 1993-05-26 JP JP50072194A patent/JP3781769B2/ja not_active Expired - Fee Related
- 1993-05-26 EP EP93914150A patent/EP0642518B1/en not_active Expired - Lifetime
- 1993-05-28 IL IL10583993A patent/IL105839A/xx not_active IP Right Cessation
- 1993-05-29 CN CN93108418A patent/CN1087640A/zh active Pending
- 1993-05-31 MX MX9303242A patent/MX9303242A/es not_active IP Right Cessation
-
1994
- 1994-11-24 NO NO944498A patent/NO305958B1/no not_active IP Right Cessation
- 1994-11-28 FI FI945592A patent/FI945592A0/fi unknown
-
1999
- 1999-01-20 CN CN99101270A patent/CN1229083A/zh active Pending
- 1999-09-06 CN CN99118825A patent/CN1255501A/zh active Pending
Also Published As
Publication number | Publication date |
---|---|
FI945592A (fi) | 1994-11-28 |
ATE169302T1 (de) | 1998-08-15 |
CN1229083A (zh) | 1999-09-22 |
FI945592A0 (fi) | 1994-11-28 |
CN1255501A (zh) | 2000-06-07 |
NO944498D0 (no) | 1994-11-24 |
AU659565B2 (en) | 1995-05-18 |
IL105839A (en) | 2001-08-26 |
HU9403411D0 (en) | 1995-02-28 |
CN1087640A (zh) | 1994-06-08 |
CA2136823C (en) | 1998-05-26 |
EP0642518A1 (en) | 1995-03-15 |
NZ253523A (en) | 1997-01-29 |
CA2136823A1 (en) | 1993-12-09 |
JP3781769B2 (ja) | 2006-05-31 |
DE69320187T2 (de) | 1999-02-11 |
SK145594A3 (en) | 1995-07-11 |
MX9303242A (es) | 1994-05-31 |
SG90009A1 (en) | 2002-07-23 |
EP0642518B1 (en) | 1998-08-05 |
AU4391693A (en) | 1993-12-30 |
NO944498L (no) | 1995-01-26 |
HUT71907A (en) | 1996-02-28 |
CZ295894A3 (en) | 1995-10-18 |
DK0642518T3 (da) | 1998-12-14 |
IL105839A0 (en) | 1993-09-22 |
DE69320187D1 (de) | 1998-09-10 |
ES2123057T3 (es) | 1999-01-01 |
WO1993024495A1 (en) | 1993-12-09 |
NO305958B1 (no) | 1999-08-23 |
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