CN1555356A - 作为nhe-3抑制剂的双酚衍生物 - Google Patents
作为nhe-3抑制剂的双酚衍生物 Download PDFInfo
- Publication number
- CN1555356A CN1555356A CNA008131600A CN00813160A CN1555356A CN 1555356 A CN1555356 A CN 1555356A CN A008131600 A CNA008131600 A CN A008131600A CN 00813160 A CN00813160 A CN 00813160A CN 1555356 A CN1555356 A CN 1555356A
- Authority
- CN
- China
- Prior art keywords
- compound
- xenyl
- group
- nhe
- phenyl
- 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.)
- Pending
Links
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- 239000003112 inhibitor Substances 0.000 title claims abstract description 24
- 102000046061 Sodium-Hydrogen Exchanger 3 Human genes 0.000 title claims abstract 5
- IISBACLAFKSPIT-UHFFFAOYSA-N bisphenol A Chemical class C=1C=C(O)C=CC=1C(C)(C)C1=CC=C(O)C=C1 IISBACLAFKSPIT-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 68
- 239000001257 hydrogen Substances 0.000 claims description 27
- 229910052739 hydrogen Inorganic materials 0.000 claims description 27
- 150000003839 salts Chemical class 0.000 claims description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 18
- 229910052760 oxygen Inorganic materials 0.000 claims description 17
- 239000012453 solvate Substances 0.000 claims description 16
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 15
- 239000001301 oxygen Substances 0.000 claims description 15
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- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 11
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 claims description 11
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 10
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 9
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 9
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
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- 239000011734 sodium Substances 0.000 abstract description 26
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- 229910052708 sodium Inorganic materials 0.000 abstract description 8
- -1 sec.-propyl Chemical group 0.000 description 73
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- 239000002253 acid Substances 0.000 description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 11
- 150000002148 esters Chemical class 0.000 description 11
- 238000000034 method Methods 0.000 description 11
- 238000012545 processing Methods 0.000 description 11
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 8
- 229910000564 Raney nickel Inorganic materials 0.000 description 8
- 102100030980 Sodium/hydrogen exchanger 1 Human genes 0.000 description 8
- 108010093115 growth factor-activatable Na-H exchanger NHE-1 Proteins 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 7
- 239000007868 Raney catalyst Substances 0.000 description 7
- 102100022897 Sodium/hydrogen exchanger 10 Human genes 0.000 description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 7
- 238000013016 damping Methods 0.000 description 7
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- 239000000463 material Substances 0.000 description 7
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
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- 229910001629 magnesium chloride Inorganic materials 0.000 description 6
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- 125000003368 amide group Chemical group 0.000 description 5
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
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- 230000008694 endothelial dysfunction Effects 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
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- 239000003889 eye drop Substances 0.000 description 1
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- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
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- 229950006191 gluconic acid Drugs 0.000 description 1
- 239000001087 glyceryl triacetate Substances 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- 150000005826 halohydrocarbons Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229960001008 heparin sodium Drugs 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000623 heterocyclic group Chemical group 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
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
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- 206010020718 hyperplasia Diseases 0.000 description 1
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- 125000006303 iodophenyl group Chemical group 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 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
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- 210000004185 liver Anatomy 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
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- 239000002184 metal Substances 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 125000006216 methylsulfinyl group Chemical group [H]C([H])([H])S(*)=O 0.000 description 1
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- 239000011259 mixed solution Substances 0.000 description 1
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- 229940045641 monobasic sodium phosphate Drugs 0.000 description 1
- 230000002969 morbid Effects 0.000 description 1
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- 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
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- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 125000005245 nitryl group Chemical group [N+](=O)([O-])* 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([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])[H] 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000011368 organic material Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical group C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
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- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
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- 150000003053 piperidines Chemical class 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
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- 230000002062 proliferating effect Effects 0.000 description 1
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- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-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
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 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
- 239000011541 reaction mixture Substances 0.000 description 1
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- 238000011160 research Methods 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
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- 238000000926 separation method Methods 0.000 description 1
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- 210000003491 skin Anatomy 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 229940083466 soybean lecithin Drugs 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
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- 150000003462 sulfoxides Chemical class 0.000 description 1
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- 239000000725 suspension Substances 0.000 description 1
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- 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
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003556 thioamides Chemical class 0.000 description 1
- 230000009424 thromboembolic effect Effects 0.000 description 1
- 125000005425 toluyl group Chemical group 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 238000002525 ultrasonication Methods 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
- C07C279/22—Y being a hydrogen or a carbon atom, e.g. benzoylguanidines
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- C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
- C07C257/18—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
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Abstract
本发明涉及通式(I)的化合物,其中X、R1、R2、R3、R4和R5具有权利要求1指出的含义。本发明化合物代表亚型3钠/质子交换剂(NHE-3)的抑制剂。
Description
本发明涉及通式I的化合物,
其中
R1、R4每种情况均彼此独立地是-C(=NH)-NH2,其上还可单取代上-COA、-CO-[C(R6)2]n-Ar、-COOA、-OH或传统氨基保护基团NH-C(=NH)-NH2、-CO-N=C(NH2)2,
或
R2、R3、R5每种情况均彼此独立地是
H,A,OR6,N(R6)2,NO2,CN,Hal,NHCOA,
NHCOAr,NHSO2A,NHSO2Ar,COOR6,CON(R6)2,
CONHAr,COR6,COAr,S(O)nA,S(O)nAr,
-O-[C(R6)2]m-COOR6,-[C(R6)2]p-COOR6,
-O-[C(R6)2]m-CON(R6)2,-[C(R6)2]p-CON(R6)2,
-O-[C(R6)2]m-CONHAr或-[C(R6)2]p-CONHAr,
X是-[C(R6)2]n-,-CR6=CR6-,-[C(R6)2]n-O-,
-O-[C(R6)2]n-,-COO-,-OOC-,-CONR6-或
-NR6CO-,
R6是氢、A或苄基,
A是1~20个碳原子的烷基,其中一或两个CH2基团可被O或S原子代替或被-CR6=CR6-基团代替,和/或1~7个氢原子可被F代替,
Ar是苯基或萘基,它们可以是未取代的或者取代上一个、两个或三个取代基A,Ar′,
OR6,OAr′,N(R6)2,NO2,CN,Hal,NHCOA,
NHCOAr′,NHSO2A,NHSO2Ar′,COOR6,CON(R6)2,
CONHAr′,COR6,COAr′,S(O)nA或S(O)nAr′,
Ar’是苯基或萘基,它们可以是未取代的或者取代上一个、两个或三个取代基A,OR6,
N(R6)2,NO2,CN,Hal,NHCOA,COOR6,CON(R6)2,
COR6或S(O)nA,
Hal是F、Cl、Br或I,
n是0、1或2,
m是1或2,
p是1或2,
及其盐和溶剂合物,作为NHE-3抑制剂。
钠/质子交换剂亚型3的其他抑制剂,例如描述在EP 0 825 178中。
本发明的主要目的是找到具有宝贵性能,特别是可用于生产药剂的性能的新化合物。
DE 198 19548提到,通式I化合物及其盐具有因子Xa抑制性能,因此可用于控制和预防血栓栓塞疾病,例如血栓形成、心肌梗塞、动脉硬化、发炎、中风、心绞痛胸闷、血管成形术后的再狭窄、间歇性跛行。
现已惊奇地发现,通式I的化合物及其盐显示对钠/质子交换剂亚型3的抑制作用并具有良好耐受性。通式I化合物可用作人和兽医学中的药物活性化合物。
已知,Na+/H+交换剂是包括至少六种不同同种型(NHE-1~NHE-6)的一个族,现已全部被克隆。虽然亚型NHE-1遍布于整个身体的所有组织中,但是其他NHE亚型则选择性地表达在特定器官中,例如肾中或小肠的内腔壁和对腔壁中。此种分布反映不同同种型所起到的特定功能,即,一方面亚型NHE-1起到对细胞内pH和细胞体积的调节,另一方面同种型NHE-2和NHE-3在肠和肾脏起到钠离子吸收和再吸收作用。同种型NHE-4主要存在于胃中。NHE-5的表达则局限于脑和神经组织。NHE-6是一种在线粒体中形成钠/质子交换剂的同种型。
同种型NHE-3尤其表达于近中肾小管的顶膜中;NHE-3抑制剂因而尤其起到一种肾保护作用。
NHE-3同种型选择性抑制剂的治疗用途有各种各样。NHE-3抑制剂能抑制或减轻因病理学缺氧和缺血事件导致NHE活性激活之后的组织受损和细胞坏死,例如在肾缺血期间或肾移植中肾的取出、运输和再灌注期间的情况。
通式I的化合物具有降血压作用,因此适合作为治疗高血压的药物活性化合物。它们也适合作利尿剂。
通式I的化合物本身,或者与不同特定亚型的NHE抑制剂配合,具有抗局部缺血作用,因此可用于治疗血栓形成、动脉硬化、血管痉挛以保护器官,例如术前及手术期间保护肾和肝,以及慢性和急性肾衰竭。
它们还可用于治疗中风、脑水肿、神经系统局部缺血、各种形式休克乃至用于改善呼吸驱动,例如下列情况:中枢睡眠呼吸暂停、婴儿猝死、术后缺氧以及其他呼吸疾病。与碳脱水酶(carboanhydrase)抑制剂配合还可进一步改善呼吸活动。
通式I化合物具有对细胞增殖的抑制作用,例如对成纤维细胞增殖和血管平滑肌细胞的增殖,因此可用于治疗细胞增殖作为主要或次要病因的疾病。
通式I化合物可用于对抗糖尿病晚期并发症,恶性肿瘤疾病、纤维化疾病、内皮机能障碍、器官肥大以及增生,特别是前列腺增生或前列腺肥大。
它们也适合用于诊断,以确定和区分高血压、动脉硬化、糖尿病和增殖性疾病的特定形式。
鉴于通式I化合物也能有利地影响血清脂蛋白水平,因此它们可单独或者配合其他药物用于治疗高血脂。
本发明涉及权利要求1的通式I化合物及其生理可接受盐和/或溶剂合物用于生产治疗血栓形成、心肌局部缺血、外周及中枢神经系统以及中风、外周器官局部和手足局部缺血,以及处理休克状态等药物的应用。
本发明还涉及权利要求1的通式I化合物及其生理可接受盐和/或溶剂合物用于生产外科手术和器官移植用药剂以及用于保存和贮藏外科措施移植物的应用。
本发明还涉及权利要求1的通式I化合物及其生理可接受盐和/或溶剂合物用于生产治疗细胞增殖作为主要或次要病因的疾病,治疗或预防脂代谢疾病或呼吸驱动受干扰的药物的应用。
本发明还涉及权利要求1的通式I化合物及其生理可接受盐和/或溶剂合物用于生产治疗肾脏缺血、缺血性肠道疾病或用于预防急性或慢性肾疾病等药物的应用。
抑制钠/质子交换剂亚型3的物质的鉴别方法描述在,例如,US5,871,919中。
对于通式I化合物中的所有基团,凡是出现多次的,例如R6,其条件是它们的含义彼此独立。
水合物和溶剂合物应理解为,例如半-、单-或二水合物;溶剂合物理解为,例如,醇的加成化合物,例如与甲醇或乙醇的。
在上式中,A是烷基,是线型或支化的,并且具有1~20,优选1、2、3、4、5、6、7、8、9、10、11或12个碳原子。A优选是甲基,还有乙基、丙基、异丙基、丁基、异丁基、仲丁基或叔丁基,另外还有戊基、1-、2-、3-甲基丁基,1,1-、1,2-或2,2-二甲基丙基、1-乙基丙基、己基、1-、2-、3-或4-甲基戊基、1,1-、1,2-、1,3-、2,2-、2,3-或3,3-二甲基丁基、1-或2-乙基丁基、1-乙基-1-甲基丙基、1-乙基-2-甲基丙基、1,1,2-或1,2,2-三甲基丙基、庚基、辛基、壬基或癸基。
A还可以是,例如,三氟甲基、五氟乙基、烯丙基或巴豆基。
COR6是酰基,优选是甲酰、乙酰、丙酰,还有丁酰、戊酰或己酰基。
COOR6优选是甲氧基羰基、乙氧基羰基、丙氧基羰基或丁氧基羰基。
Hal优选是F、Cl或Br,但也可以是I。
R2、R3和R5每种情况各自独立地优选是氢、氟、氯、溴、碘、羟基、甲氧基、乙氧基、丙氧基、硝基、氨基、甲氨基、二甲氨基、乙氨基、二乙氨基、乙酰氨基、亚磺酰氨基、甲基亚磺酰氨基、苯基亚磺酰氨基、甲硫基、乙硫基、甲基亚磺酰基、乙基亚磺酰基、甲磺酰基、乙磺酰基、苯亚磺酰基、苯磺酰基、氰基、羧基、甲氧羰基、乙氧羰基、羧甲氧基、甲氧羰基甲氧基、羧甲基、甲氧羰基甲基、氨基羰基甲氧基、氨基羰基甲基、N-苯基氨基羰基甲氧基、N-苯基氨基羰基甲基,还有酰基或苯甲酰基。
特别是,R2、R5是氢。
R3,具体地说例如是氢、COOA或-OCH2COOR6,其中R6是氢或1~4个碳原子烷基。
R6是氢、A或苄基,然而特别是氢或1~4个碳原子烷基。
X优选地例如是-CH2-、-CH=CH-、-CH2O-、-O-CH2-、-COO-、-OOC-、-CONH-或-NHCO-;而-CH2O-、-O-CH2-或-CH2-CH2-是尤其优选的。
Ar优选是未取代的苯基或萘基,还优选例如是取代上下列基团的单-、二-或三取代的苯基或萘基:A、氟、氯、溴、碘、羟基、甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、己氧基、苄氧基、苯乙氧基、甲硫基、乙硫基、甲亚磺酰基、乙亚磺酰基、甲磺酰基、乙磺酰基、苯亚磺酰基、苯磺酰基、硝基、氨基、甲氨基、乙氨基、二甲氨基、二乙氨基、甲酰氨基、乙酰氨基、丙酰氨基、丁酰氨基、甲亚磺酰氨基、乙亚磺酰氨基、丙亚磺酰氨基、丁亚磺酰氨基、苯亚磺酰氨基、(4-甲基苯基)亚磺酰氨基、羧甲氧基、羧乙氧基、甲氧羰基甲氧基、甲氧羰基乙氧基、羟甲氧基、羟乙氧基、甲氧基乙氧基、羧基、甲氧羰基、乙氧羰基、氰基、苯氨基羰基、酰基或苯甲酰基,还有联苯基。
因此Ar优选,例如是邻-、间-或对-甲苯基、邻-、间-或对-乙基苯基,邻-、间-或对-丙基苯基,邻-、间-或对-异丙基苯基,邻-、间-或对-叔丁基苯基,邻-、间-或对-羟苯基、,邻-、间-或对-硝基苯基,邻-、间-或对-氨基苯基,邻-、间-或对-(N-甲基氨基)苯基,邻-、间-或对-乙酰氨基苯基,邻-、间-或对-甲氧基苯基,邻-、间-或对-乙氧基苯基,邻-、间-或对-羧基苯基,邻-、间-或对-甲氧羰基苯基,邻-、间-或对-(N,N-二甲氨基)苯基,邻-、间-或对-(N-乙氨基)苯基,邻-、间-或对-(N,N-二乙氨基)苯基,邻-、间-或对-乙酰苯基,邻-、间-或对-甲酰苯基,邻-、间-或对-氟代苯基,邻-、间-或对-溴代苯基,邻-、间-或对-氯代苯基,邻-、间-或对-甲磺酰基苯基,邻-、间-或对-(苯磺酰氨基)苯基,邻-、间-或对-(甲磺酰氨基)苯基,邻-、间-或对-甲硫基苯基,另一些优选的是,2,3-、2,4-、2,5-、2,6-、3,4-或3,5-二氟苯基,2,3-、2,4-、2,5-、2,6-、3,4-或3,5-二氯苯基,2,3-、2,4-、2,5-、2,6-、3,4-或3,5-二溴苯基,2,4-或2,5-二硝基苯基、2,5-或3,4-二甲氧基苯基、3-硝基-4-氯苯基、3-氨基-4-氯-、2-氨基-3-氯-、2-氨基-4-氯-、2-氨基-5-氯-或2-氨基-6-氯苯基、2-硝基-4-N,N-二甲氨基或3-硝基-4-N,N-二甲氨基苯基、2,3-二氨基苯基-、2,3,4-、2,3,5-、2,3,6-、2,4,6-或3,4,5-三氯苯基、2,4,6-三甲氧基苯基、2-羟基-3,5-二氯苯基、对碘苯基、3,6-二氯-4-氨基苯基、4-氟代-3-氯苯基、2-氟代-4-溴苯基、2,5-二氟-4-溴苯基、3-溴代-6-甲氧基苯基、3-氯代-6-甲氧基苯基、3-氯代-4-乙酰氨基苯基、3-氟代-4-甲氧基苯基、3-氨基-6-甲基苯基、3-氯代-4-乙酰氨基苯基或2,5-二甲基-4-氯代-苯基。
Ar’具体地说例如是,苯基或萘基,还优选例如是邻-、间-或对-甲苯基、邻-、间-或对-乙基苯基,邻-、间-或对-丙基苯基,邻-、间-或对-异丙基苯基,邻-、间-或对-叔丁基苯基,邻-、间-或对-羟苯基,邻-、间-或对-硝基苯基,邻-、间-或对-氨基苯基,邻-、间-或对-(N-甲基氨基)苯基,邻-、间-或对-乙酰氨基苯基,邻-、间-或对-甲氧基苯基,邻-、间-或对-乙氧基苯基,邻-、间-或对-羧基苯基,邻-、间-或对-甲氧羰基苯基,邻-、间-或对-(N,N-二甲氨基)苯基,邻-、间-或对-(N-乙氨基)苯基,邻-、间-或对-(N,N-二乙氨基)苯基,邻-、间-或对-乙酰苯基,邻-、间-或对-甲酰苯基,邻-、间-或对-氟代苯基,邻-、间-或对-溴代苯基,邻-、间-或对-氯代苯基或邻-、间-或对-甲磺酰基苯基。
据此,本发明尤其涉及这样的通式I化合物的应用,其中至少一个提到的基团具有上述优选的含义之一。化合物的某些优选基团可表示为下列子式Ia~Ii,它们对应于通式I,且其中没有详细指定的基团则具有通式I给出的含义,不过其中,
在Ia中,R1、R4每种情况均彼此独立地是-C(=NH)-NH2,后者也可被OH或-CO-N=C(NH2)2单取代;
在Ib中,R2、R5是氢;
在Ic中,R1、R4每种情况均彼此独立地是-C(=NH)-NH2,后者也可被OH或-CO-N=C(NH2)2单取代,
R2、R5是氢,并且
R3是氢或COOR6;
在Id中,R1、R4每种情况均彼此独立地是-C(=NH)-NH2,后者也可被OH或-CO-N=C(NH2)2单取代,
R2、R5是氢,并且
R3是氢或COOR6或-O-(CH2)COOR6;
在Ie中,X是-CH2-O-或-O-CH2-;
在If中,R1、R4每种情况均彼此独立地是-C(=NH)-NH2,后者也可被OH或-CO-N=C(NH2)2单取代,
R2、R5是氢,
R3是氢或COOR6,并且
X是-CH2-O-或-O-CH2-;
在Ig中,R1、R4每种情况均彼此独立地是-C(=NH)-NH2,后者也可被OH或-CO-N=C(NH2)2单取代,
R2、R5是氢,
R3是氢或COOR6或-O-(CH2)COOR6,并且
X是-CH2-O-或-O-CH2-或-CH2-CH2-;
在Ih中,R1、R4每种情况均彼此独立地是-C(=NH)-NH2,后者也可被OH或-CO-N=C(NH2)2单取代,
R2、R5是氢,
R3是氢或COOR6、-O-(CH2)-COOR6、CH2-COOR6、-O-CH2-CON(R6)2、CH2-CON(R6)2-O-CH2-CONHAr或CH2-CONHAr,
X是-CH2-O-或-O-CH2-或-CH2-CH2-,
R6是氢或A,
A是1~4个碳原子的烷基;
在Ii中,R1、R4每种情况均彼此独立地是-C(=NH)-NH2,后者也可被OH或-CO-N=C(NH2)2单取代,
R2、R5是氢,
R3是氢或COOR6、-O-(CH2)-COOR6、CH2-COOR6、-O-CH2-CON(R6)2或CH2-CON(R6)2,
X是-CH2-O-或-O-CH2-或-CH2-CH2-,
R6是氢或A,
A是1~4个碳原子的烷基。
通式I化合物及制备它们的原料,在其他方面则按照本身已知的方法来制备,例如按文献中所述(例如,在标准著作,例如Houben-Weyl,《有机化学方法》(Methoden der organischen Chemie),Georg-Thieme出版社,斯图加特),即,在已知并且适合所述反应的反应条件下实施。在这种情况下,还可采用本身已知但这里并未详细提及的各种不同方案。
希望的话,原料也可就地生成,以便不需将它们从反应混合物中分离出来,而是立即进一步反应以生成通式I的化合物。
通式I化合物可优选地通过,以溶剂分解剂或氢解剂处理而由其官能衍生物之一中释放出通式I化合物,这样来制取。
溶剂分解或氢解用的优选原料是那些其他方面均与通式I相对应,然而,不是含有一个或多个游离氨基和/或羟基基团,而是含有对应的被保护氨基和/或羟基基团,优选那些,在N原子上不是键合着氢原子,而是带有氨基保护基团,特别是那些,替代HN基团而带有R’-N-基团者,其中R’是氨基保护基团,和/或那些,代替羟基基团的氢原子而带有羟基保护基团者,例如对应于通式I的那些但代替基团-COOH的是基团-COOR”,其中R”是羟基保护基团。优选的原料还有可转化为相应脒基化合物的噁二唑衍生物。
噁二唑基团的引入例如可通过氰基化合物与羟基胺的反应,以及与光气、碳酸二烷基酯、氯代甲酸酯、N,N’-羰基-二咪唑或乙酸酐的反应来实现。
也可以有许多相同或不同的被保护氨基和/或羟基基团存在于原料物质的分子中。如果存在的保护基团彼此不同,则许多情况下它们可选择性地脱除。
术语“氨基保护基团”是普遍已知的,指的是适合用于保护(或封闭)氨基基团以免发生化学反应,然而在要求的化学反应在分子的其他部位完成以后又很容易脱除的基团。典型的此类型基团尤其是未取代或取代的酰基、芳基、芳烷氧基甲基或芳烷基基团。由于氨基保护基团在要求的反应(或反应序列)之后将脱除,它们的大小和性质除此之外便无关紧要;然而,优选1~20,尤其是1~8个碳原子的那些。术语“酰基基团”涉及本发明方法时应按最广的意义来解释。它包括由脂族、芳脂族、芳族和杂环羧酸或磺酸衍生的酰基基团,特别是烷氧羰基、芳氧羰基以及,特别是芳烷氧羰基基团。此种类型酰基基团的例子是链烷酰基,如乙酰基、丙酰基、丁酰基;芳烷酰基,例如苯乙酰基;芳酰基,例如苯甲酰基或甲苯酰基;芳氧烷酰基,如POA;烷氧羰基如甲氧羰基、乙氧羰基、2,2,2-三氯乙氧羰基、BOC(叔丁氧基羰基)、2-碘代乙氧羰基;芳烷氧羰基如CBZ(苄酯基)、4-甲氧基苄氧羰基、FMOC;芳基磺酰基,如Mtr。优选的氨基保护基团是BOC和Mtr,还有CBZ、Fmoc、苄基和乙酰基。
术语“羟基保护基团”同样也是普遍已知的,涉及适合用于保护羟基基团以免化学反应,然而要求的化学反应在分子其他部位完成之后又容易脱除的基团。典型的此类型基团是上面提到的未取代或取代的芳基、芳烷基或酰基基团,还有烷基基团。羟基保护基团的性质和大小并不严格要求,因为它们在要求的化学反应或反应序列之后将再次脱除;优选1~20,尤其是1~10个碳原子的基团。羟基保护基团的例子特别是苄基、对硝基苯甲酰基、对甲苯磺酰基、叔丁基和乙酰基,尤其优选苄基和叔丁基。
通式I化合物是这样(视所用保护基团而定)从其官能衍生物中释放的:例如采用强酸,最好采用TFA或高氯酸,但也可采用其他强无机酸如盐酸或硫酸,强有机羧酸如三氯乙酸或磺酸如苯-或对甲苯磺酸。附加惰性溶剂的存在是可以的但并非总是必须。合适的惰性溶剂优选是有机溶剂,例如羧酸如乙酸,醚如四氢呋喃或二氧杂环己烷,酰胺如DMF、卤代烃如二氯甲烷,还有醇如甲醇、乙醇或异丙醇,以及还有水。另外,上述溶剂的混合物也是可以的。TFA优选以过量使用而不再加入其他溶剂;高氯酸以乙酸与70%高氯酸按9∶1比例的混合物形式使用。该裂解反应温度以介于约0~约50℃为佳;反应优选在15~30℃(室温)实施。
基团BOC、OBut和Mtr的脱除优选地采用,例如TFA的二氯甲烷溶液或者采用约3~5N氯化氢在二氧杂环己烷中的溶液,在15~30℃实现;Fmoc基团采用约5~50%二甲胺、二乙胺或哌啶在DMF中的溶液在15~30℃来实施。
可氢解脱除的保护基团的脱除(例如,CBZ、苄基的脱除,或脒基基团从其恶二唑衍生物中的释放)例如可通过以氢在催化剂(例如,贵金属催化剂如钯,方便地在诸如碳之类的载体上,或者如湿阮内镍外加,例如乙酸)存在下的处理来实现。这里,适合的溶剂是上面给出的那些,尤其是,例如醇如甲醇或乙醇,或者酰胺如DMF。一般而言,氢解在约0~100℃和约1~200bar,优选在20~30℃的温度和1~10bar的压力下进行。CBZ基团的氢解可方便地在例如,用5~10%Pd/C在甲醇中,或者用Pd/C在甲醇/DMF中以及20~30℃采用甲酸铵(替代氢气)来实施。
通式I化合物,其中R1和R4是-C(=NH)-NH2,优选可以由对应的氰基化合物获得。
氰基基团通过与,例如羟基胺起反应,随后以氢气在诸如Pd/C或阮内镍之类的催化剂存在下还原N-羟基脒而转化为脒基基团。
为制备通式I(R1=-C(=NH)-NH2)的脒,也可在通式I(R1=CN)的腈上加成氨。该加成反应优选分多个阶段实施,即,按照本身已知的方式,a)利用H2S将腈转化为硫代酰胺,后者再利用烷基化剂如CH3I,转化为对应的S-烷基亚氨硫代酯,它本身再与氨起反应生成脒,b)利用醇,如乙醇在HCl存在下将腈转化为对应的亚氨酸酯,然后用氨处理它,或者c)腈与双(三甲基甲硅烷基)酰胺锂起反应,然后将产物氢解。
氰基化合物是采用本身已知的方法制备的。
通式I化合物,其中R1和R4是-CON(=NH)-NH2,优选可以由对应的烷氧羰基化合物通过与胍起反应来制取。
此外,通式I化合物可能转化为另一种通式I化合物,只需将一或多个基团R1、R2、R3、R4和/或R5转变为一或多个基团R1、R2、R3、R4和/或R5,例如通过将氨基酰化或将硝基基团还原为氨基基团(例如通过在阮内镍或Pd/C上在惰性溶剂如甲醇或乙醇中的氢化)。
酯的水解例如可以借助乙酸或者氢氧化钠或氢氧化钾水溶液、水/THF或水/二氧杂环己烷在0~100℃的温度实施。
另一种可能是按传统方式采用酰氯或酸酐将游离氨基基团酰化,或者利用未取代的或取代的烷基卤化物,最好在惰性溶剂如二氯甲烷或THF和/或在诸如三乙胺或吡啶之类的碱存在下在-60~+30℃的温度将它们烷基化。
一般而言,该反应在惰性溶剂中,在酸结合剂,优选碱金属或碱土金属氢氧化物、碳酸盐或碳酸氢盐,或者碱金属或碱土金属,优选钾、钠、钙或铯的另一种弱酸盐存在下进行。
也可能有利的是加入有机碱,如三乙胺、二甲基苯胺、吡啶或喹啉,或者过量的通式II的胺组分或通式III的烷基化衍生物。依所采用条件而定,反应时间介于几分钟到14天,反应温度介于约0℃~150℃,一般在20℃~130℃之间。
合适的惰性溶剂例如是烃类,例如己烷、石油醚、苯、甲苯或二甲苯;氯代烃如三氯乙烯、1,2-二氯乙烷、四氯化碳、氯仿或二氯甲烷;醇如甲醇、乙醇、异丙醇、正丙醇、正丁醇或叔丁醇;醚,例如乙醚、二异丙醚、四氢呋喃(THF)或二氧杂环己烷;二醇醚,例如乙二醇单甲醚或单乙醚、乙二醇二甲醚;酮,例如丙酮或丁酮;酰胺,例如乙酰胺、二甲基乙酰胺、N-甲基吡咯烷酮(NMP)或二甲基甲酰胺(DMF);腈,例如乙腈;亚砜,例如二甲基亚砜(DMSO);二硫化碳;羧酸,例如甲酸或乙酸;硝基化合物,例如硝基甲烷或硝基苯;酯,例如乙酸乙酯或者上述溶剂的混合物。
通式I的碱可用酸转化为相关酸的加成盐,例如通过等当量碱与酸在诸如乙醇之类的惰性溶剂中反应,随后蒸发。适合该反应使用的酸尤其是能生成生理可接受盐的那些。因此,可使用无机酸,例如硫酸、硝酸、氢卤酸如盐酸或氢溴酸,磷酸如正磷酸、氨基磺酸,还有有机酸,特别是脂族、脂环族、芳脂族、芳族或杂环单-或多元羧酸、磺酸或硫酸,例如:甲酸、乙酸、丙酸、新戊酸、二乙基乙酸、丙二酸、琥珀酸、庚二酸、富马酸、马来酸、乳酸、酒石酸、苹果酸、柠檬酸、葡糖酸、抗坏血酸、烟酸、异烟酸、甲烷-或乙烷磺酸、乙烷二磺酸、2-羟基乙烷磺酸、苯磺酸、对甲苯磺酸、萘单-和-二磺酸以及月桂基硫酸。与生理可接受酸所生成的盐,例如苦味酸盐,可用于分离和/或提纯通式I化合物。
另一方面,通式I化合物利用碱(例如,钠或钾的氢氧化物或碳酸盐)可转化为相应的金属盐,特别是碱金属盐或碱土金属盐,或者转化为相应的铵盐。
生理可接受的有机碱,例如乙醇胺,也可使用。
本发明还涉及通式1化合物作为NHE-3抑制剂和/或其生理可接受盐用于生产药物制剂的应用,尤其是通过非化学路线。就此而论,它们可连同至少一种固体、液体和/或半液体载体或赋形剂一起制成适宜的剂量形式,并且适当的话与一种或多种其他活性化合物组合使用。
本发明还涉及包含至少一种通式I的NHE-3抑制剂和/或其生理可接受盐和溶剂合物之一的药物制剂。
此类制剂可用作人或兽医用药剂。可能的载体是适合经肠(例如口服)或不经肠服用的或者局部施用并且不与该新化合物起反应的有机或无机物质,例如水、植物油、苯甲醇、链烷二醇、聚乙二醇、甘油三乙酸酯、明胶、诸如乳糖或淀粉之类的碳水化合物、硬脂酸镁、滑石和凡士林。具体地说,片剂、丸剂、包衣片剂、胶囊、粉末、粒剂、糖浆、汁液或滴剂,用于口服;栓剂用于直肠给药;溶液,优选油状或水溶液,还有悬浮体、乳剂或植入物,可用于不经肠给药;油膏、霜或粉末用于局部施用,或者经皮用于膏药。该新化合物还可进行冷冻干燥,获得的冻干物可用于,例如生产注射制剂。上面提到的制剂可进行消毒和/或可包含赋形剂,例如润滑剂、防腐剂、稳定剂和/或润湿剂、乳化剂、用于影响渗透压的盐、缓冲物质、着色剂、香料和/或一种或多种其他活性化合物,例如一种或多种维生素。适合以气溶胶或喷雾形式给药的药物制剂例如是通式I活性化合物在药理学可接受溶剂中的溶液、悬浮体或乳液。
通式I化合物及其生理可接受盐和溶剂合物可用于治疗和/或预防上面指出的疾病或疾病状态。
就此而论,本发明物质一般优选的给药剂量介于约0.1~100mg,尤其是1~10mg,每剂量单位。日剂量优选介于约0.001~10mg/kg体重。然而,每个患者的具体剂量则取决于各种各样的因素,例如具体使用的化合物的效力、年龄、体重、一般健康状况、性别、日常饮食、给药时间和途径、排泄速率、药物组合以及施治对象具体疾病的严重程度。优选口服给药。
上面以及下文,所有温度均指℃而言。在下面的实施例中,“常规处理”,适用的话是指加水,需要的话再根据最终产物的组成调节混合物至pH介于2~10,并以乙酸乙酯或二氯甲烷萃取,分离掉有机相,用硫酸钠干燥,蒸发,然后残余物采用硅胶色谱术和/或通过结晶进行提纯。质谱术(MS):EI(电子撞击电离)M+
FAB(快速原子轰击)(M+H)+
实例1
2.06g3-溴苄腈和1.50g3-甲苯基硼酸在50mL二甲氧基乙烷中的溶液,以247mg乙酸钯(II)、335mg三-邻-甲苯基膦、20mL水和954mg无水碳酸钠处理,然后在100℃、搅拌下加热18h。混合物常规处理,残余物利用石油醚/乙酸乙酯(9∶1)在硅胶柱上进行色谱提纯,结果获得3’-甲基联苯基-3-腈,呈无色固体(“A”),EI193。
1.17g“A”在10mL四氯化碳中的溶液,以1.09g N-溴代琥珀酰亚胺(NBS)和60mg偶氮二异丁腈处理,然后在70℃加热18h。混合物常规处理,残余物利用石油醚/乙酸乙酯(9∶1)在硅胶柱上进行色谱提纯,结果获得3’-溴甲基联苯基-3-腈,呈无色固体(“B”)。
500mg“B”和238mg3-羟基苄腈在10mL乙腈中的溶液,以625mg碳酸铯处理,并在室温下搅拌40h。常规处理之后,残余物在反相柱上采用乙腈/水(65∶35)进行色谱提纯。获得3’-(3-氰基苯氧基甲基)联苯基-3-腈(“C”),呈无色固体,FAB 311。
90mg“C”和125mg羟基氯化铵在10mL乙醇中的溶液,以1.2g聚合物结合的二甲氨基吡啶(DMAP)处理,并在室温下搅拌18h。滤掉聚合物,赶出溶剂,于是获得N-羟基-3’-[3-(N-羟基carbamimidoyl)苯氧基甲基]联苯基-3-羰基脒(carboxamidine)(“D”),呈无色固体,FAB 377。
76mg“D”在10mL甲醇中的溶液,以100mg水湿阮内镍和30mg乙酸处理,并在室温和常压下氢化18h。滤除催化剂,赶出溶剂,于是获得3’-(3-carbamimidoyl苯氧基甲基)联苯基-3-羰基脒(carboxamidine)的乙酸酯,EI 327(M+-NH3),310(M+-2NH3)
类似地制取到下列化合物
3’-(3-carbamimidoyl苯氧基甲基)联苯基-4-羰基脒(carboxamidine)的二乙酸酯,FAB 345;
3’-(4-carbamimidoyl苯氧基甲基)联苯基-4-羰基脒(carboxamidine)的二乙酸酯,FAB 345;
3’-(4-carbamimidoyl苯氧基甲基)联苯基-3-羰基脒(carboxamidine)的二乙酸酯,FAB 345;
4’-(4-carbamimidoyl苯氧基甲基)联苯基-4-羰基脒(carboxamidine),
4’-(4-carbamimidoyl苯氧基甲基)联苯基-3-羰基脒(carboxamidine),
4’-(3-carbamimidoyl苯氧基甲基)联苯基-3-羰基脒(carboxamidine),以及
4’-(3-carbamimidoyl苯氧基甲基)联苯基-4-羰基脒(carboxamidine)。
实例2
类似于实例1,利用3-溴苄腈与3-甲氧基苯基硼酸起反应而制成化合物3’-甲氧基联苯基-3-腈。随后通过在乙腈中利用三碘化铝使醚裂解,然后与3-溴甲基苄腈起反应,获得3’-(3-氰基苄氧基)联苯基-3-腈。
通过与羟胺起反应,并以氢气在阮内镍催化剂作用下还原,获得3’-(3-carbamimidoyl-苯甲酸基)联苯基-3-羰基脒(carboxamidine)
类似地制取下列化合物,
4’-(4-carbamimidoyl苄氧基)联苯基-4-羰基脒(carboxamidine)的二乙酸酯,FAB 345;
4’-(3-carbamimidoyl苄氧基)联苯基-4-羰基脒(carboxamidine)的二乙酸酯,FAB 345;
实例3
类似于实例1,化合物3’-氰基-5-甲基联苯基-3-羧酸甲酯,通过3-氰基苯基硼酸与3-溴-5-甲基苯甲酸甲酯起反应而制成。通过用NBS溴化并与3-羟基苄腈反应,而获得3’-氰基-5-(3-氰基苯氧基甲基)联苯基-3-羧酸甲酯。与羟胺起反应并以H2/阮内镍还原获得化合物3’-carbamimidoyl-5-(3-carbamimidoyl苯氧基甲基)联苯基-3-羧酸甲酯。该酯利用氢氧化钠水溶液水解,结果获得3’-carbamimidoyl-5-(3-carbamimidoyl苯氧基甲基)联苯基-3-羧酸。
在反相柱上采用乙腈/水/TFA混合物进行色谱提纯,获得3’-carbamimidoyl-5-(3-carbamimidoyl苯氧基甲基)联苯基-3-羧酸的双三氟乙酸酯。
类似地制取下列化合物,
4’-carbamimidoyl-4-(4-carbamimidoyl苯氧基甲基)联苯基-3-羧酸甲酯,FAB 403;
4’-carbamimidoyl-4-(3-carbamimidoyl苯氧基甲基)联苯基-2-羧酸甲酯,FAB 403;
3’-carbamimidoyl-4-(4-carbamimidoyl苯氧基甲基)联苯基-2-羧酸甲酯,FAB 403;
3’-carbamimidoyl-4-(3-carbamimidoyl苯氧基甲基)联苯基-2-羧酸甲酯,FAB 403;
4’-carbamimidoyl-5-(3-carbamimidoyl苯氧基甲基)联苯基-4-羧酸甲酯,FAB 403;
3’-carbamimidoyl-5-(3-carbamimidoyl苯氧基甲基)联苯基-4-羧酸甲酯,FAB 403。
实例4
类似于实例1,3’-甲基联苯基-3-羧酸甲酯,利用3-溴代苯甲酸甲酯与3-甲苯基硼酸起反应而制成。通过用NBS溴化并与3-羟基苯甲酸甲酯起反应,而获得3’-(3-甲氧羰基苯氧基甲基)联苯基-3-羧酸甲酯。与胍的盐酸盐在甲醇钠的甲醇溶液中起反应,便获得化合物N-[3’-(3-胍基羰基苯氧基甲基)联苯基-3-羰基]胍,
类似地获得化合物N-[4’-(4-胍基羰基苯氧基甲基)联苯基-4-羰基]胍。
实例5
7.0g3-溴-5-甲基苯酚和5.97g溴乙酸甲酯,还有13g碳酸铯在100mL乙腈中的溶液,在室温下搅拌过夜。常规处理之后,获得9.70g(3-溴-5-甲基苯氧基)乙酸甲酯(“AB”)。
2.0g“AB”、100mg四(三苯基膦)钯和0.85g碳酸钠在50mL甲苯中的悬浮体,加热至沸腾。随后滴加2.94g3-氰基苯基硼酸在30mL甲醇中的溶液,然后混合物在回流下加热14h。将其常规处理,便获得2.17g(3’-氰基-5-甲基联苯基-3-基氧基)乙酸甲酯(“AC”)。
1.2g“AC”和0.765g NBS在50mL四氯化碳中的溶液在室温利用紫外线进行辐照。常规处理之后,获得1.54g(3’-氰基-5-溴甲基联苯基-3-基氧基)乙酸甲酯(“AD”)。
185mg“AD”、63.1mg4-羟基-苄腈和172.7mg碳酸铯在10mL乙腈中的溶液在室温下搅拌4日。常规处理之后,获得[3’-氰基-5-(4-氰基苯氧基甲基)联苯基-3-基氧基]乙酸甲酯(“AE”)。
60mg“AE”、69.5mg羟基氯化铵和101mg三乙胺在10mL乙醇中的溶液在回流下加热14h。赶出溶剂后,残余物用水调配。分离掉固体,获得70mg[3’-N-羟基脒基-5-(4-N-羟基脒基苯氧基-甲基)联苯基-3-基氧基]乙酸甲酯(“AF”)。通过采用H2/阮内镍还原,获得[3’-脒基-5-(4-脒基苯氧基甲基)联苯基-3-基氧基]乙酸甲酯,FAB 433。
类似地,制取下列化合物
[4’-脒基-5-(4-脒基苯氧基甲基)联苯基-3-基氧基]乙酸甲酯,FAB 433
[3’-脒基-5-(3-脒基苯氧基甲基)联苯基-3-基氧基]乙酸甲酯,FAB 433
[4’-脒基-5-(3-脒基苯氧基甲基)联苯基-3-基氧基]乙酸甲酯,FAB 433
倘若在第一阶段将溴乙酸甲酯换成溴乙酸叔丁酯,则在最后阶段获得的叔丁酯可采用三氟乙酸和对应的羧酸进行裂解,结果获得:
[3’-脒基-5-(4-脒基苯氧基甲基)联苯基-3-基氧基]乙酸的双三氟乙酸酯,FAB 419;
[4’-脒基-5-(4-脒基苯氧基甲基)联苯基-3-基氧基]乙酸;
[3’-脒基-5-(3-脒基苯氧基甲基)联苯基-3-基氧基]乙酸;
[4’-脒基-5-(3-脒基苯氧基甲基)联苯基-3-基氧基]乙酸。
实例6
5.0g3’-溴甲基联苯基-3-腈的溶液和5mL亚磷酸三乙酯混合并慢慢加热到150℃。混合物在150℃搅拌6h,常规处理后获得6.05g(3’-氰基-联苯基-3-基甲基)膦酸二乙酯(“BA”)。
150mg氢化钠在冰水冷却和氮气保护下加入到1.0g“BA”和3-氰基苯甲醛在20mL乙二醇二甲醚的溶液中。随后,混合物搅拌4h,常规处理后获得0.93g3’-[2-(3-氰基苯基)乙烯基]联苯基-3-腈(“BB”)。
360mg“ BB”用5%Pd-C的甲醇溶液氢化之后,获得360mg3’-[2-(3-氰基苯基)乙基]-联苯基-3-腈(“BC”)。与羟基氯化铵起反应并以阮内镍氢化之后,类似于实例1那样获得化合物3’-[2-(3-脒基苯基)乙基]联苯基-3-羰基脒(carboxamidine),FAB 343
类似地制取化合物3’-[2-(4-脒基苯基)乙基]联苯基-3-羰基脒(carboxamidine),FAB 343。
实例7
化合物N-[3’-(4-胍基羰基苄氧基)联苯基-3-羰基]胍的二盐酸盐,FAB 431,
按例如以下反应顺序制取:
类似地制取化合物,
N-[3’-(3-胍基羰基苄氧基)联苯基-3-羰基]胍,FAB 431;
N-[3’-(4-胍基羰基苄氧基)联苯基-4-羰基]胍,FAB 431;
N-[3’-(3-胍基羰基苄氧基)联苯基-4-羰基]胍,FAB 431;
药理学试验
用来表征作为NHE-3抑制剂的通式I化合物的方法学如下。
通式I化合物,就其对同种型NHE-1~NHE-3的选择性做了鉴定。这三种同种型均稳定地表达于鼠的成纤维细胞细胞系中。该化合物的抑制作用,通过确定在胞内酸中毒以后EIPA敏感的22Na+在细胞内的吸收来评估。为鉴定Na+/H+交换抑制剂的同种型选择性,我们考察了这些化合物对能稳定表达于鼠成纤维细胞细胞系中的NHE同种型,包括NHE-1、-2和-3的抑制作用(见操作方法一节),即确定在胞内酸中毒之后EIPA敏感的22Na+在细胞内的吸收。
材料和方法
表达不同NHE同种型的LAP1细胞系
表达NHE同种型NHE-1、-2和-3的LAP1细胞系(鼠成纤维细胞细胞系)由J.Pouyssegur教授(Nice,法国)取得。转染是按照Franchi等人的方法(1986)实施的。细胞培养在加有10%灭活胚胎小牛血清(FCS)的DMEM培养基中。为挑选NHE-表达细胞,采用Sardet等人的所谓“酸破坏方法”(1989)。细胞首先通过用无碳酸氢根、无氯化铵和无钠离子的缓冲液洗涤,被移到含氯化铵的无碳酸氢根和无钠离子的缓冲液中,然后用无碳酸氢根、含氯化钠的缓冲液进行孵育。只有那些具有表达NHE功能的细胞才能在它们所处的胞内酸化的条件下存活。
NHE抑制剂对同种型选择性的鉴定
采用上述表达同种型NHE-1、NHE-2和NHE-3的鼠成纤维细胞细胞系,按照Counillon等人(1993)和Scholz等人(1995)所描述的方法测试了化合物对各种同种型的选择性。细胞的胞内酸化是通过氯化铵prepulse方法,然后在无碳酸氢根的含22Na+的缓冲液中孵育来完成的。由于胞内酸化,致使NHE激活,于是钠被吸收到细胞内。试验化合物的效果用对EIPA乙基异丙基氨氯吡嗪脒敏感的22Na+吸收的抑制程度来表示。表达NHE-1、NHE-2和NHE-3的细胞以5~7.5×104个细胞/孔的密度进行接种,转移到24孔细胞培养板中并集中培养24~48h。吸去培养基,细胞在37℃于氯化铵缓冲液(50mM氯化铵,70mM氯化胆碱、15mM MOPS,pH7.0)中孵育60min。然后,去掉缓冲液,细胞迅速用氯化胆碱洗涤缓冲液(120mM氯化胆碱、15mMPIPES/tris,0.1mM G毒毛旋花苷、1mM氯化镁、2mM氯化钙,pH7.4)洗涤2次;细胞在此缓冲液中孵育6min。孵育时间结束后,吸去孵育缓冲液。为除去细胞外的放射活性,细胞用冰冷却的磷酸盐缓冲溶液(PBS)迅速洗涤4次。然后,通过每孔加入0.3mL 0.1N的氢氧化钠使细胞增溶。含细胞碎片的溶液转移到闪烁管中。每孔另外再用0.3mL 0.1N氢氧化钠洗涤两次,洗涤溶液也加入到相应闪烁管中。装有细胞裂解产物的闪烁管与闪烁混合液混合在一起,然后通过测定β-辐射来确定吸收到细胞内的放射活性。
在兔子红细胞中22Na+吸收的抑制
Na+/H+的交换活性还可以通过观察在酸化后的兔子红细胞中22Na+离子的吸收加以确定。兔子红细胞已广泛应用在关于Na+/H+交换活性的研究中(Escobales & Fugueroa,1991:Morgan & Canessa,1990)。在酸化红细胞中22Na+吸收的EIPA敏感部分被视为Na+/H+依赖的22Na+吸收。
细胞制备
红细胞的制备以及红细胞的内部酸化,严格按照Morgan和Canessa(1990)的方法进行。
血液取自兔子(例如,新西兰白兔)。将其收集在装有5mL肝素钠溶液(250U/ml)的50mL Falcon离心管中。血液和肝素溶液充分混合。通过在4℃、2000xg条件下离心回收红细胞;血浆和buffy coat则去掉。剩余溶液通过200μm纱布进行过滤。滤液再次悬浮在原来体积的洗涤缓冲液(140mM氯化钾,0.15mM氯化镁、10mMTRIS/MOPS,pH7.4)中。再次离心(2000xg,4℃)分离回收红细胞。该洗涤过程重复两次。
胞内酸化
为实现胞内酸化,5mL沉淀并收集的红细胞再次悬浮在45mL酸化缓冲液(170mM氯化钾,0.15mM氯化镁,0.1mM G毒毛旋花苷,10mM葡糖,10mM蔗糖,20mMtris/Mes,pH6.2)中。红细胞悬浮体在37℃孵育10min(偶尔搅拌)。为固定内部pH值,用最高200μM到1mM的DIDS或DIAMOX(乙酰唑胺)进行处理。混合物另外再在37℃孵育30min。
然后,通过离心回收红细胞(4min,2000xg,4℃);再次将它们悬浮在冰冷却的未缓冲洗涤溶液(170mM氯化钾,40mM蔗糖,0.15mM氯化镁)中并用其洗涤四次。
孵育及22Na+吸收的测定
在规格8×12的多孔培养管中进行孵育。孵育随着200μL孵育缓冲液(160mM氯化钾,22NaCl(37MBq/孔),10mM氯化钠,0.15mM氯化镁,0.1mM G毒毛旋花苷,10mM葡糖,40mM蔗糖,10mMtris/MOPS,pH8.0,0.5mM Diamox,1%DMSO)与20μL(预热的)红细胞酸化溶液的混合而开始。试验物质首先用100%DMSO溶解,然后溶液采用孵育缓冲液稀释到相应浓度。孵育在37℃进行5min。(在初步实验中发现,在这样的孵育条件下,22Na吸收速率在5min孵育期间内呈线性)。孵育通过加入800μL冰冷却的终止溶液(112mM氯化镁,0.1mMG毒毛旋花苷)而终止。试管短时间存放在冰中。然后用封口膜覆盖试管,并通过2000xg和4℃下离心7min来回收红细胞。上层清液以自制吸取装置吸去,使用它可同时吸取彼此相邻的4个试管;吸管远端的间隔环防止吸管过深地插入到试管和吸取的红细胞粒子中。所有含22Na的上层清液和洗涤溶液全部作为放射活性废液贮存和处理。
红细胞以900μL冰冷却的终止溶液洗涤三次,即,重复上面所述悬浮/离心步骤。最后一次洗涤之后,红细胞粒子与200μL水混合。然后,试管用超声波处理2×30min。然后,拆开多孔培养管,然后将每一试管头朝下放入到单个闪烁管中;红细胞的溶血处理溶液,借助轻轻摇动而全部倒入到闪烁管中。每个管以3mL闪烁液Aquasafe 300 PS处理,然后给管盖上盖子并充分混合。被吸收到红细胞内的放射活性,借助监测β分解从闪烁计数器上读取。每种物质浓度,做一式三份测定。将在10μM EIPA存在下的计数器读数的平均值从每个数值中扣除,以便将非Na+/H+依赖的22Na+吸收包括在红细胞中。无物质时的剩余读数的平均值被当作100%对照例;试验化合物存在下的平均值则被表示为该对照值的百分数。吸收数据的百分数在半对数座标上进行标绘;采用等式(插入34页圈内),通过将数据拟会为非线性曲线,获得IC50数值。
Counillon et al.(1993) Mol.Pharmacol.44:1041-1045Escobales and Figueroa(1991)J.Membrane Biol.120,41-49
Franchi et al.(1986)Proc.Natl.Acad.Sci.USA 83:9388-9392
Morgan and Canessa(1990) J.Membrane Biol.118,193-214
Sardet et al.(1989) Cell 56:271-280
Scholz et al.(1995) Cardiovasc.Res.29:260-268
试验结果
1.
Code EMD 221960
IC50(NHE-3)=1-2μM
2.
Code EMD 221963
IC50(NHE-3)=1μM
3.
二乙酸酯;
Code EMD 246326
IC50(NHE-3)=3μM
4.
二乙酸酯;
Code EMD 246327
IC50(NHE-3)=3-4μM.
下面是关于药物制剂的实施例:
实例A:注射管形瓶
100g通式I的NHE-3抑制剂和5g磷酸氢二钠的溶液利用2N盐酸,在3L二次蒸馏水中调节到pH6.5,无菌过滤,分配到注射管形瓶中,在无菌条件下冷冻干燥,然后无菌密封。每个注射管形瓶装有5mg活性化合物。
实例B:栓剂
20g通式I的NHE-3抑制剂的混合物与100g大豆卵磷脂和1400g可可脂熔融混合,倒入到模具中并使其冷却。每个栓剂包含20mg活性化合物。
实例C:溶液
由1g通式I的NHE-3抑制剂、9.38g磷酸二氢钠合二水、28.48g磷酸氢二钠合十二水以及0.1g苯扎氯铵,在940mL二次蒸馏水中制备成溶液。将其调节到pH6.8,注满至1L,然后通过辐照灭菌。该溶液可以眼睛滴剂的形式使用。
实例D:油膏
500mg通式I的NHE-3抑制剂与99.5g凡士林在无菌条件下进行混合。
实例E:片剂
1kg通式I的NHE-3抑制剂、4kg乳糖、1.2g马铃薯淀粉、0.2kg滑石粉和0.1kg硬脂酸镁的混合物按照惯用方式压制成为片剂,每片含有10mg活性化合物。
实例F:包衣片剂
片剂按照类似于实例E那样压制,然后按照惯用方式涂以蔗糖、马铃薯淀粉、滑石粉、西黄蓍胶和着色剂的涂层。
实例G:胶囊
2kg通式I的NHE-3抑制剂按照惯用方式充填到硬明胶胶囊中,每个胶囊含有20mg活性化合物。
实例H:安瓿
1kg通式I的NHE-3抑制剂在60L二次蒸馏水中的溶液进行无菌过滤,分配到安瓿瓶中,在无菌条件下冷冻干燥然后无菌密封。每个安瓿含有10mg活性化合物。
Claims (7)
1.通式I的化合物,
其中
R1、R4每种情况均彼此独立地是-C(=NH)-NH2,其上还可单取代上-COA、-CO-[C(R6)2]n-Ar、-COOA、-OH或传统氨基保护基团NH-C(=NH)-NH2、-CO-N=C(NH2)2,
R2、R3、R5每种情况均彼此独立地是
H,A,OR6,N(R6)2,NO2,CN,
Hal,NHCOA,NHCOAr,NHSO2A,NHSO2Ar,
COOR6,CON(R6)2,CONHAr,COR6,COAr,
S(O)nA,S(O)nAr,-O-[C(R6)2]m-COOR6,
-[C(R6)2]p-COOR6,-O-[C(R6)2]m-CON(R6)2,
-[C(R6)2]p-CON(R6)2,-O-[C(R6)2]m-CONHAr或
-[C(R6)2]p-CONHAr,
X是-[C(R6)2]n-,-CR6=CR6-,-[C(R6)2]n-O-,
-O-[C(R6)2]n-,-COO-,-OOC-,-CONR6-或
-NR6CO-,
R6是氢、A或苄基,
A是1~20个碳原子的烷基,其中一或两个CH2基团可被O或S原子代替或被-CR6=CR6-基团代替,和/或1~7个氢原子可被F代替,
Ar是苯基或萘基,它们是未取代的或者取代上一个、两个或三个
取代基A,Ar′,OR6,OAr′,
N(R6)2,NO2,CN,Hal,NHCOA,NHCOAr′,
NHSO2A,NHSO2Ar′,COOR6,CON(R6)2,
CONHAr′,COR6,COAr′,S(O)nA或S(O)nAr′,
Ar’是苯基或萘基,它们是未取代的或者取代上一个、两个或三个取代基A,OR6,N(R6)2,NO2,
CN,Hal,NHCOA,COOR6,CON(R6)2,COR6或
S(O)nA,
Hal是F、Cl、Br或I,
n是0、1或2,
m是1或2,
p是1或2,
及其盐和溶剂合物,作为NHE-3抑制剂。
2.权利要求1的化合物
a)3’-(3-carbamimidoyl苯氧基甲基)联苯基-3-羰基脒(carboxamidine);
b)3’-(3-carbamimidoyl苄氧基)联苯基-3-羰基脒(carboxamidine);
c)3’-carbamimidoyl-5-(3-carbamimidoyl苯氧基甲基)联苯基-3-羧酸;
d)N-[3’-(3-胍基羰基苯氧基甲基)联苯基-3-羰基]胍;
e)[3’-脒基-5-(4-脒基苯氧基甲基)联苯基-3-基氧基]乙酸甲酯;
f)[3’-脒基-5-(4-脒基苯氧基甲基)联苯基-3-基氧基]乙酸,及其盐和溶剂合物,作为NHE-3抑制剂。
3.权利要求1的通式I化合物及其生理可接受盐和/或溶剂合物用于生产治疗血栓形成、心肌局部缺血、外周及中枢神经系统以及中风、外周器官局部和手足局部缺血,以及处理休克状态的药物的应用。
4.权利要求1的通式I化合物及其生理可接受盐和/或溶剂合物用于生产外科手术和器官移植用药物以及用于保存和贮藏外科手术移植物的应用。
5.权利要求1的通式I化合物及其生理可接受盐和/或溶剂合物用于生产治疗细胞增殖作为主要或次要病因的疾病,治疗或预防脂代谢疾病或呼吸驱动受干扰的药物的应用。
6.权利要求1的通式I化合物及其生理可接受盐和/或溶剂合物用于生产治疗肾脏缺血、肠缺血疾病或用于预防急性或慢性肾疾病的药物的应用。
7.药物制剂,其特征在于,它含有至少一种权利要求1的NHE-3抑制剂和/或其生理可接受盐和/或溶剂合物之一。
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CZ (1) | CZ2002815A3 (zh) |
DE (1) | DE19945302A1 (zh) |
HU (1) | HUP0202891A3 (zh) |
MX (1) | MXPA02003087A (zh) |
NO (1) | NO20021407L (zh) |
PL (1) | PL355097A1 (zh) |
SK (1) | SK3342002A3 (zh) |
WO (1) | WO2001021582A1 (zh) |
ZA (1) | ZA200203095B (zh) |
Families Citing this family (22)
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DE10163239A1 (de) * | 2001-12-21 | 2003-07-10 | Aventis Pharma Gmbh | Substituierte Imidazolidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie enthaltendes Medikament |
US7049333B2 (en) | 2002-06-04 | 2006-05-23 | Sanofi-Aventis Deutschland Gmbh | Substituted thiophenes: compositions, processes of making, and uses in disease treatment and diagnosis |
DE10304374A1 (de) | 2003-02-04 | 2004-08-05 | Aventis Pharma Deutschland Gmbh | Neue substituierte 2-Aminoimidazole, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
US20050054705A1 (en) | 2003-02-04 | 2005-03-10 | Aventis Pharma Deutschland Gmbh | N-substituted (benzoimidazol-2-yl) phenylamines, process for their preparation, their use as medicament or diagnostic aid, and medicament comprising them |
DE10341240A1 (de) | 2003-09-08 | 2005-04-07 | Aventis Pharma Deutschland Gmbh | Substituierte Thienoimidazole, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
US7534894B2 (en) | 2003-09-25 | 2009-05-19 | Wyeth | Biphenyloxy-acids |
DE102005001411A1 (de) | 2005-01-12 | 2006-07-27 | Sanofi-Aventis Deutschland Gmbh | Substituierte 4-Phenyltetrahydroisochinoline, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament, sowie sie enthaltendes Medikament |
EP2170872B1 (en) | 2007-06-28 | 2010-09-01 | Sanofi-Aventis U.S. LLC | Process for the preparation of the n-(2-chloro-4-methyl-3-thienyl)-1h- benzimidazol-2-amine hydrochloride and intermediates thereof |
MX2011001821A (es) * | 2008-09-02 | 2011-03-25 | Sanofi Aventis | Aminoindanos sustituidos y sus analogos, y el uso farmaceutico de los mismos. |
MX345283B (es) | 2008-12-31 | 2017-01-24 | Ardelyx Inc | Compuestos y metodos para inhibir el antiporte mediado por intercambiador de iones de sodio/iones de hidrogeno (nhe) en el tratamiento de trastornos asociados con retencion de fluido o sobrecarga de sal y trastornos del tracto gastrointestinal. |
WO2018129556A1 (en) | 2017-01-09 | 2018-07-12 | Ardelyx, Inc. | Compounds and methods for inhibiting nhe-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders |
HUE028394T2 (en) | 2011-03-15 | 2016-12-28 | Astellas Pharma Inc | Guanidin Compound |
CN103012200B (zh) * | 2011-09-20 | 2014-12-17 | 北京大学 | 具有β-分泌酶抑制功能的化合物及其制备方法与应用 |
US10376481B2 (en) | 2012-08-21 | 2019-08-13 | Ardelyx, Inc. | Compounds and methods for inhibiting NHE-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders |
MX366293B (es) | 2012-08-21 | 2019-07-04 | Ardelyx Inc | Compuestos y metodos para inhibir al antipuerto mediado por nhe en el tratamiento de trastornos asociados con la retencion de fluidos o la sobrecarga de sal y trastornos del tracto gastrointestinal. |
JP6377132B2 (ja) | 2013-04-12 | 2018-08-22 | アーデリクス,インコーポレーテッド | Nhe3結合化合物およびリン酸輸送の阻害方法 |
BR112017000691B1 (pt) | 2014-07-25 | 2023-02-14 | Taisho Pharmaceutical Co., Ltd | Feniltetra-hidroisoquinolina substituído com heteroari-la, seu uso, medicamento, inibidores de nhe3, de absorção de sódio e de absorção de fósforo, promotor de secre-ção de água intestinal e fármaco profilático ou terapêu-tico para constipação |
EP3565808A1 (en) | 2017-01-09 | 2019-11-13 | Ardelyx, Inc. | Compounds useful for treating gastrointestinal tract disorders |
EA201991676A1 (ru) | 2017-01-09 | 2020-01-30 | Арделикс, Инк. | Ингибиторы nhe-опосредованного антипорта |
AU2018335130B2 (en) | 2017-08-04 | 2023-02-16 | Ardelyx, Inc. | Glycyrrhetinic acid derivatives for treating hyperkalemia |
EP3921327B1 (en) | 2019-02-07 | 2023-04-05 | Ardelyx, Inc. | Glycyrrhetinic acid derivatives for use in treating hyperkalemia |
US20200368223A1 (en) | 2019-05-21 | 2020-11-26 | Ardelyx, Inc. | Methods for inhibiting phosphate transport |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE19548812A1 (de) * | 1995-12-27 | 1997-07-03 | Hoechst Ag | Verwendung von Inhibitoren des zellulären Na·+·/H·+·-Exchangers (NHE) zur Herstellung eines Medikaments zur Atemstimulation |
DE19622222A1 (de) * | 1996-06-03 | 1997-12-04 | Hoechst Ag | Verwendung von Inhibitoren des zellulären Na·+·/H·+·-Exchangers (NHE) zur Herstellung eines Medikament zur Normalisierung der Serumlipide |
DE19737224A1 (de) * | 1997-08-27 | 1999-03-18 | Hoechst Marion Roussel De Gmbh | Pharmazeutisches Kombinationspräparat aus einem Inhibitor des Natrium-Wasserstoff-Austauschers und einem Arzneimittel zur Behandlung von Herz-Kreislauferkrankungen |
DE19819548A1 (de) * | 1998-04-30 | 1999-11-04 | Merck Patent Gmbh | Biphenylderivate |
-
1999
- 1999-09-22 DE DE19945302A patent/DE19945302A1/de not_active Withdrawn
-
2000
- 2000-09-04 WO PCT/EP2000/008616 patent/WO2001021582A1/de not_active Application Discontinuation
- 2000-09-04 KR KR1020027003735A patent/KR20020033818A/ko not_active Application Discontinuation
- 2000-09-04 EP EP00965915A patent/EP1214291A1/de not_active Withdrawn
- 2000-09-04 HU HU0202891A patent/HUP0202891A3/hu unknown
- 2000-09-04 JP JP2001524962A patent/JP2004500338A/ja active Pending
- 2000-09-04 SK SK334-2002A patent/SK3342002A3/sk not_active Application Discontinuation
- 2000-09-04 BR BR0014199-2A patent/BR0014199A/pt not_active IP Right Cessation
- 2000-09-04 AU AU76497/00A patent/AU7649700A/en not_active Abandoned
- 2000-09-04 CA CA002387529A patent/CA2387529A1/en not_active Abandoned
- 2000-09-04 MX MXPA02003087A patent/MXPA02003087A/es unknown
- 2000-09-04 PL PL00355097A patent/PL355097A1/xx unknown
- 2000-09-04 CN CNA008131600A patent/CN1555356A/zh active Pending
- 2000-09-04 CZ CZ2002815A patent/CZ2002815A3/cs unknown
-
2002
- 2002-03-21 NO NO20021407A patent/NO20021407L/no unknown
- 2002-04-18 ZA ZA200203095A patent/ZA200203095B/xx unknown
Also Published As
Publication number | Publication date |
---|---|
WO2001021582A1 (de) | 2001-03-29 |
CZ2002815A3 (cs) | 2002-08-14 |
AU7649700A (en) | 2001-04-24 |
PL355097A1 (en) | 2004-03-22 |
ZA200203095B (en) | 2003-09-23 |
EP1214291A1 (de) | 2002-06-19 |
HUP0202891A3 (en) | 2003-11-28 |
NO20021407D0 (no) | 2002-03-21 |
MXPA02003087A (es) | 2003-08-20 |
DE19945302A1 (de) | 2001-03-29 |
BR0014199A (pt) | 2002-05-21 |
SK3342002A3 (en) | 2002-07-02 |
KR20020033818A (ko) | 2002-05-07 |
HUP0202891A2 (hu) | 2003-02-28 |
CA2387529A1 (en) | 2001-03-29 |
NO20021407L (no) | 2002-03-21 |
JP2004500338A (ja) | 2004-01-08 |
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