CN1784235A - 增强剂 - Google Patents
增强剂 Download PDFInfo
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- CN1784235A CN1784235A CNA2004800125995A CN200480012599A CN1784235A CN 1784235 A CN1784235 A CN 1784235A CN A2004800125995 A CNA2004800125995 A CN A2004800125995A CN 200480012599 A CN200480012599 A CN 200480012599A CN 1784235 A CN1784235 A CN 1784235A
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- 208000017169 kidney disease Diseases 0.000 claims abstract description 48
- GHOSNRCGJFBJIB-UHFFFAOYSA-N Candesartan cilexetil Chemical compound C=12N(CC=3C=CC(=CC=3)C=3C(=CC=CC=3)C3=NNN=N3)C(OCC)=NC2=CC=CC=1C(=O)OC(C)OC(=O)OC1CCCCC1 GHOSNRCGJFBJIB-UHFFFAOYSA-N 0.000 claims abstract description 29
- 150000003180 prostaglandins Chemical class 0.000 claims abstract description 29
- 229960004349 candesartan cilexetil Drugs 0.000 claims abstract description 16
- 230000003449 preventive effect Effects 0.000 claims abstract description 14
- 239000003112 inhibitor Substances 0.000 claims abstract description 11
- 229960002890 beraprost Drugs 0.000 claims abstract description 3
- CTPOHARTNNSRSR-APJZLKAGSA-N beraprost Chemical compound O([C@H]1C[C@@H](O)[C@@H]([C@@H]21)/C=C/[C@@H](O)C(C)CC#CC)C1=C2C=CC=C1CCCC(O)=O CTPOHARTNNSRSR-APJZLKAGSA-N 0.000 claims abstract description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 72
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 70
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 claims description 64
- 239000003814 drug Substances 0.000 claims description 60
- -1 Alpha-Naphthyl Chemical group 0.000 claims description 50
- 230000000694 effects Effects 0.000 claims description 47
- 125000000217 alkyl group Chemical group 0.000 claims description 44
- 150000001875 compounds Chemical class 0.000 claims description 38
- RMMXLENWKUUMAY-UHFFFAOYSA-N telmisartan Chemical compound CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O RMMXLENWKUUMAY-UHFFFAOYSA-N 0.000 claims description 36
- 239000001257 hydrogen Substances 0.000 claims description 34
- 229910052739 hydrogen Inorganic materials 0.000 claims description 34
- 239000012744 reinforcing agent Substances 0.000 claims description 30
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 28
- 210000002966 serum Anatomy 0.000 claims description 24
- 229940109239 creatinine Drugs 0.000 claims description 23
- 239000005541 ACE inhibitor Substances 0.000 claims description 19
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 19
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 claims description 19
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 claims description 19
- 239000005537 C09CA07 - Telmisartan Substances 0.000 claims description 18
- 229960005187 telmisartan Drugs 0.000 claims description 18
- 239000002083 C09CA01 - Losartan Substances 0.000 claims description 17
- 229960004773 losartan Drugs 0.000 claims description 17
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 16
- 208000033679 diabetic kidney disease Diseases 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 16
- 150000002431 hydrogen Chemical class 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 14
- 239000002053 C09CA06 - Candesartan Substances 0.000 claims description 13
- 108010061435 Enalapril Proteins 0.000 claims description 13
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- 108010007859 Lisinopril Proteins 0.000 claims description 12
- 229960002394 lisinopril Drugs 0.000 claims description 12
- RLAWWYSOJDYHDC-BZSNNMDCSA-N lisinopril Chemical compound C([C@H](N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 RLAWWYSOJDYHDC-BZSNNMDCSA-N 0.000 claims description 12
- IPVQLZZIHOAWMC-QXKUPLGCSA-N perindopril Chemical compound C1CCC[C@H]2C[C@@H](C(O)=O)N(C(=O)[C@H](C)N[C@@H](CCC)C(=O)OCC)[C@H]21 IPVQLZZIHOAWMC-QXKUPLGCSA-N 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 11
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 10
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 10
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 10
- 125000001118 alkylidene group Chemical group 0.000 claims description 10
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 10
- 229910052794 bromium Inorganic materials 0.000 claims description 10
- 239000000460 chlorine Substances 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 10
- 229960000873 enalapril Drugs 0.000 claims description 10
- GBXSMTUPTTWBMN-XIRDDKMYSA-N enalapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 GBXSMTUPTTWBMN-XIRDDKMYSA-N 0.000 claims description 10
- 229910052731 fluorine Inorganic materials 0.000 claims description 10
- 239000011737 fluorine Substances 0.000 claims description 10
- AXTCRUUITQKBAV-KBPBESRZSA-N libenzapril Chemical compound OC(=O)CN1C(=O)[C@@H](N[C@@H](CCCCN)C(O)=O)CCC2=CC=CC=C21 AXTCRUUITQKBAV-KBPBESRZSA-N 0.000 claims description 10
- 229950001218 libenzapril Drugs 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
- 229960002582 perindopril Drugs 0.000 claims description 10
- 239000002080 C09CA02 - Eprosartan Substances 0.000 claims description 9
- 239000004072 C09CA03 - Valsartan Substances 0.000 claims description 9
- 239000002947 C09CA04 - Irbesartan Substances 0.000 claims description 9
- 229960004563 eprosartan Drugs 0.000 claims description 9
- OROAFUQRIXKEMV-LDADJPATSA-N eprosartan Chemical compound C=1C=C(C(O)=O)C=CC=1CN1C(CCCC)=NC=C1\C=C(C(O)=O)/CC1=CC=CS1 OROAFUQRIXKEMV-LDADJPATSA-N 0.000 claims description 9
- 229960002198 irbesartan Drugs 0.000 claims description 9
- YCPOHTHPUREGFM-UHFFFAOYSA-N irbesartan Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C=2[N]N=NN=2)C(CCCC)=NC21CCCC2 YCPOHTHPUREGFM-UHFFFAOYSA-N 0.000 claims description 9
- 229960004699 valsartan Drugs 0.000 claims description 9
- FIKYECRHLXONOX-UHFFFAOYSA-N zolasartan Chemical compound CCCCC1=NC(Cl)=C(C(O)=O)N1CC1=CC=C(OC(=C2Br)C=3C(=CC=CC=3)C3=NNN=N3)C2=C1 FIKYECRHLXONOX-UHFFFAOYSA-N 0.000 claims description 9
- 229950004433 zolasartan Drugs 0.000 claims description 9
- 239000002081 C09CA05 - Tasosartan Substances 0.000 claims description 8
- 239000002051 C09CA08 - Olmesartan medoxomil Substances 0.000 claims description 8
- UQGKUQLKSCSZGY-UHFFFAOYSA-N Olmesartan medoxomil Chemical compound C=1C=C(C=2C(=CC=CC=2)C2=NNN=N2)C=CC=1CN1C(CCC)=NC(C(C)(C)O)=C1C(=O)OCC=1OC(=O)OC=1C UQGKUQLKSCSZGY-UHFFFAOYSA-N 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 239000004615 ingredient Substances 0.000 claims description 8
- 229960001199 olmesartan medoxomil Drugs 0.000 claims description 8
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 8
- 229960000651 tasosartan Drugs 0.000 claims description 8
- ADXGNEYLLLSOAR-UHFFFAOYSA-N tasosartan Chemical compound C12=NC(C)=NC(C)=C2CCC(=O)N1CC(C=C1)=CC=C1C1=CC=CC=C1C=1N=NNN=1 ADXGNEYLLLSOAR-UHFFFAOYSA-N 0.000 claims description 8
- 229960005227 delapril Drugs 0.000 claims description 7
- WOUOLAUOZXOLJQ-MBSDFSHPSA-N delapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N(CC(O)=O)C1CC2=CC=CC=C2C1)CC1=CC=CC=C1 WOUOLAUOZXOLJQ-MBSDFSHPSA-N 0.000 claims description 7
- YONOBYIBNBCDSJ-UHFFFAOYSA-N forasartan Chemical compound N1=C(CCCC)N=C(CCCC)N1CC1=CC=C(C=2C(=CC=CC=2)C2=NNN=N2)N=C1 YONOBYIBNBCDSJ-UHFFFAOYSA-N 0.000 claims description 7
- 229950003641 forasartan Drugs 0.000 claims description 7
- ZEUXAIYYDDCIRX-UHFFFAOYSA-N losartan carboxylic acid Chemical compound CCCCC1=NC(Cl)=C(C(O)=O)N1CC1=CC=C(C=2C(=CC=CC=2)C2=NNN=N2)C=C1 ZEUXAIYYDDCIRX-UHFFFAOYSA-N 0.000 claims description 7
- LPUDGHQMOAHMMF-JBACZVJFSA-N (2s)-2-[[[(2s)-6-amino-2-(methanesulfonamido)hexanoyl]amino]methyl]-3-[1-[[(1s)-1-carboxy-2-(4-hydroxyphenyl)ethyl]carbamoyl]cyclopentyl]propanoic acid Chemical compound N([C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C(=O)C1(C[C@@H](CNC(=O)[C@H](CCCCN)NS(=O)(=O)C)C(O)=O)CCCC1 LPUDGHQMOAHMMF-JBACZVJFSA-N 0.000 claims description 6
- FTYVYAGWBXTWTN-ZVZYQTTQSA-N (2s)-5-tert-butyl-3-[(2s)-2-[[(2s)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino]propanoyl]-2h-1,3,4-thiadiazole-2-carboxylic acid Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](SC(=N1)C(C)(C)C)C(O)=O)CC1=CC=CC=C1 FTYVYAGWBXTWTN-ZVZYQTTQSA-N 0.000 claims description 6
- FHHHOYXPRDYHEZ-COXVUDFISA-N Alacepril Chemical compound CC(=O)SC[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 FHHHOYXPRDYHEZ-COXVUDFISA-N 0.000 claims description 6
- 108050000824 Angiotensin II receptor Proteins 0.000 claims description 6
- 102000008873 Angiotensin II receptor Human genes 0.000 claims description 6
- IFYLTXNCFVRALQ-OALUTQOASA-N Ceronapril Chemical compound O([C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(O)=O)P(O)(=O)CCCCC1=CC=CC=C1 IFYLTXNCFVRALQ-OALUTQOASA-N 0.000 claims description 6
- 206010018364 Glomerulonephritis Diseases 0.000 claims description 6
- 239000005478 Saprisartan Substances 0.000 claims description 6
- DUEWVPTZCSAMNB-UHFFFAOYSA-N Saprisartan Chemical compound NC(=O)C=1N(CC=2C=C3C(Br)=C(OC3=CC=2)C=2C(=CC=CC=2)NS(=O)(=O)C(F)(F)F)C(CC)=NC=1C1CC1 DUEWVPTZCSAMNB-UHFFFAOYSA-N 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 229950007884 alacepril Drugs 0.000 claims description 6
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 6
- 229960000830 captopril Drugs 0.000 claims description 6
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 claims description 6
- 150000001768 cations Chemical class 0.000 claims description 6
- 229950005749 ceronapril Drugs 0.000 claims description 6
- 229960005025 cilazapril Drugs 0.000 claims description 6
- HHHKFGXWKKUNCY-FHWLQOOXSA-N cilazapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H]1C(N2[C@@H](CCCN2CCC1)C(O)=O)=O)CC1=CC=CC=C1 HHHKFGXWKKUNCY-FHWLQOOXSA-N 0.000 claims description 6
- 229950006127 embusartan Drugs 0.000 claims description 6
- 230000002401 inhibitory effect Effects 0.000 claims description 6
- LYVGOAYMIAQLHI-UHFFFAOYSA-N methyl 2-butyl-1-[[2-fluoro-4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]-6-oxopyridine-4-carboxylate Chemical compound CCCCC1=CC(C(=O)OC)=CC(=O)N1CC1=CC=C(C=2C(=CC=CC=2)C2=NNN=N2)C=C1F LYVGOAYMIAQLHI-UHFFFAOYSA-N 0.000 claims description 6
- FLSLEGPOVLMJMN-YSSFQJQWSA-N quinaprilat Chemical compound C([C@H](N[C@@H](C)C(=O)N1[C@@H](CC2=CC=CC=C2C1)C(O)=O)C(O)=O)CC1=CC=CC=C1 FLSLEGPOVLMJMN-YSSFQJQWSA-N 0.000 claims description 6
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- HDACQVRGBOVJII-JBDAPHQKSA-N ramipril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](C[C@@H]2CCC[C@@H]21)C(O)=O)CC1=CC=CC=C1 HDACQVRGBOVJII-JBDAPHQKSA-N 0.000 claims description 6
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- HRWCVUIFMSZDJS-SZMVWBNQSA-N spirapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CC2(C1)SCCS2)C(O)=O)CC1=CC=CC=C1 HRWCVUIFMSZDJS-SZMVWBNQSA-N 0.000 claims description 6
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- FIQOFIRCTOWDOW-BJLQDIEVSA-N temocapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H]1C(N(CC(O)=O)C[C@H](SC1)C=1SC=CC=1)=O)CC1=CC=CC=C1 FIQOFIRCTOWDOW-BJLQDIEVSA-N 0.000 claims description 6
- 238000012360 testing method Methods 0.000 claims description 6
- 229950005696 utibapril Drugs 0.000 claims description 6
- OLJAPHMBAMBVKL-UHFFFAOYSA-N 5-methyl-7-propyl-8-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]-3h-[1,2,4]triazolo[1,5-c]pyrimidin-2-one Chemical compound CCCC=1N=C(C)N2NC(=O)N=C2C=1CC(C=C1)=CC=C1C1=CC=CC=C1C=1N=NNN=1 OLJAPHMBAMBVKL-UHFFFAOYSA-N 0.000 claims description 5
- 239000005479 Ripisartan Substances 0.000 claims description 5
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
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- IAIDUHCBNLFXEF-MNEFBYGVSA-N zofenopril Chemical compound C([C@@H](C)C(=O)N1[C@@H](C[C@@H](C1)SC=1C=CC=CC=1)C(O)=O)SC(=O)C1=CC=CC=C1 IAIDUHCBNLFXEF-MNEFBYGVSA-N 0.000 claims description 5
- XPCFTKFZXHTYIP-PMACEKPBSA-N Benazepril Chemical compound C([C@@H](C(=O)OCC)N[C@@H]1C(N(CC(O)=O)C2=CC=CC=C2CC1)=O)CC1=CC=CC=C1 XPCFTKFZXHTYIP-PMACEKPBSA-N 0.000 claims description 4
- 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 claims description 4
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- UWWDHYUMIORJTA-HSQYWUDLSA-N Moexipril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CC2=CC(OC)=C(OC)C=C2C1)C(O)=O)CC1=CC=CC=C1 UWWDHYUMIORJTA-HSQYWUDLSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 230000008485 antagonism Effects 0.000 claims description 4
- 125000003435 aroyl group Chemical group 0.000 claims description 4
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 208000020832 chronic kidney disease Diseases 0.000 claims description 4
- 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 4
- 150000002460 imidazoles Chemical class 0.000 claims description 4
- 201000006334 interstitial nephritis Diseases 0.000 claims description 4
- QVFVAKQHELFATN-UHFFFAOYSA-N methyl 2-[[4-butyl-2-methyl-6-oxo-5-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]pyrimidin-1-yl]methyl]thiophene-3-carboxylate Chemical compound O=C1C(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C2=NNN=N2)=C(CCCC)N=C(C)N1CC=1SC=CC=1C(=O)OC QVFVAKQHELFATN-UHFFFAOYSA-N 0.000 claims description 4
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- LVRLSYPNFFBYCZ-VGWMRTNUSA-N omapatrilat Chemical compound C([C@H](S)C(=O)N[C@H]1CCS[C@H]2CCC[C@H](N2C1=O)C(=O)O)C1=CC=CC=C1 LVRLSYPNFFBYCZ-VGWMRTNUSA-N 0.000 claims description 4
- 229950000973 omapatrilat Drugs 0.000 claims description 4
- LWBGIHXLGBYBNG-UHFFFAOYSA-N potassium;1-ethoxycarbonyloxyethyl 2-butyl-5-chloro-3-[[4-[2-(1,2,3-triaza-4-azanidacyclopenta-2,5-dien-5-yl)phenyl]phenyl]methyl]imidazole-4-carboxylate Chemical compound [K+].CCCCC1=NC(Cl)=C(C(=O)OC(C)OC(=O)OCC)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N-]N=NN=2)C=C1 LWBGIHXLGBYBNG-UHFFFAOYSA-N 0.000 claims description 4
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
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- NHOWDZOIZKMVAI-UHFFFAOYSA-N (2-chlorophenyl)(4-chlorophenyl)pyrimidin-5-ylmethanol Chemical compound C=1N=CN=CC=1C(C=1C(=CC=CC=1)Cl)(O)C1=CC=C(Cl)C=C1 NHOWDZOIZKMVAI-UHFFFAOYSA-N 0.000 claims description 2
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 2
- 208000009304 Acute Kidney Injury Diseases 0.000 claims description 2
- 208000033626 Renal failure acute Diseases 0.000 claims description 2
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- 208000012998 acute renal failure Diseases 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 125000004799 bromophenyl group Chemical group 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 claims 2
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Abstract
本发明公开了坎地沙坦酯等肾素-血管紧张素系统抑制剂的肾病治疗或预防效果增强剂。该增强剂含有贝雷普罗钠等特定的前列腺素I衍生物作为有效成分。
Description
技术领域
本发明涉及用于治疗或预防肾病的药物,特别是涉及肾素-血管紧张素系统抑制剂的肾病治疗或预防效果的增强剂。
背景技术
近年来肾病患者的数量呈不断增加的趋势。作为其原因可列举生活环境的变化、高龄化以及近年来糖尿病患者的增加引起的糖尿病性肾病的增加等。由于肾机能的衰退而导致肾衰竭不得不进行透析的患者每年都在增加。透析疗法除了每2至3周必须去一次医院外,还有红血球的生成、成熟障碍、与长期的透析伴随的铝或β2微球蛋白等的蓄积导致的并发症、心血管病变的增加等诸多尚未解决的课题。特别是原患糖尿病性肾病发展至透析的患者的5年生存率仅为不超过50%。因此,迫切需要研制可抑制肾病的恶化,有效延长其发展至透析的时间的药物。
为抑制肾病的恶化,除了例如低蛋白饮食等饮食疗法之外,一般采用降压疗法。另外,除为抑制肾小球肾炎的炎症反应施用甾体制剂或免疫抑制剂外,对于糖尿病性肾病患者则为严格控制血糖而使用胰岛素或其它口服糖尿病药物的处方。
另外,对于发展至肾衰竭的患者,除降压疗法之外,可施用抑制血液中电解质升高的药物,进行低蛋白饮食。导致肾性贫血时则施用促红细胞生成素。为延缓病情的恶化及改善尿毒症症状,有时也使用口服活性炭制剂。
但现况是即使进行了上述的治疗,也不能充分抑制病情的恶化。
肾炎、糖尿病性肾病以及肾衰竭等肾病多伴随高血压,而高血压又被认为是肾病恶化的主要原因之一,因此为抑制肾病的恶化可施用降压剂。其中最受瞩目的是肾素-血管紧张素系统抑制剂。具有强升压作用的血管紧张素II是血管紧张素I经血管紧张素转换酶(ACE)作用生成的。因此可抑制ACE的物质具有降压作用,作为降压剂被广泛使用。但是ACE抑制剂有干咳等共同的副作用。作为其它的肾素-血管紧张素系统抑制剂有血管紧张素II受体拮抗剂。已知血管紧张素II受体有AT1及AT2两种亚型,其中AT1受体拮抗剂作为比ACE的副作用少的降压剂被广泛应用着。
有关于ACE抑制剂及血管紧张素II受体拮抗剂对于动物模型或在临床上抑制慢性肾小球肾炎或糖尿病性肾病的恶化的报道(Am J Med1995 Nov;99(5):497-504、Diabetologia 1996 May;39(5):587-93、N Engl J Med 2001 Sep 20;345(12):861-9、J Hypertens1993 Sep;11(9):969-75)。ACE抑制剂或血管紧张素II受体拮抗剂还具有非基于降压作用的肾保护作用,如有报道指出厄贝沙坦的糖尿病性肾病的恶化抑制效果与通过钙拮抗剂控制血压相比具有优越性(N Engl J Med 2001 Sep 20;345(12):851-60)。因此特别是对于糖尿病性肾病患者,即使血压在正常范围,ACE抑制剂或血管紧张素II受体拮抗剂也被广泛使用。
综上所述,可以说以ACE抑制剂或血管紧张素II受体拮抗剂为代表的肾素-血管紧张素系统抑制剂对于肾病的临床效果是被广泛认可的。
但是,ACE抑制剂或血管紧张素II受体拮抗剂的肾病恶化抑制效果的限度也明确起来。例如,血管紧张素II受体拮抗剂的代表药氯沙坦以糖尿病性肾病患者为对象的临床试验证明其可减轻肌酸酐的倍增、减少向透析的发展、死亡的复合风险。但是该风险降低率只有16.1%(N Engl J Med 2001 Sep 20;345(12):861-9)。ACE抑制剂或血管紧张素II受体拮抗剂作为降压剂虽然已经被肾病患者广泛应用,但每年必须进行透析的新患者仅在日本就有超过3万人,每年还在持续增加,这一事实也表明ACE抑制剂或血管紧张素II受体拮抗剂对肾病恶化的抑制程度还不充分。
有报道指出前列腺素I衍生物アイロプロスト可降低肾小球肾炎模型Thyl诱发的肾炎模型的尿蛋白(Am J Pathol 1993Feb;142(2):441-50)。另外,前列腺素I衍生物贝雷普罗钠可降低肾小球肾炎模型大鼠(Kidney Int 1998 May;53(5):1314-20)、糖尿病性肾病患者(Nephron 2002 Dec;92(4):788-96)的尿蛋白。也有关于西卡前列素(cicaprost)抑制用链脲佐菌素(streptozotocin)诱发的糖尿病性肾病大鼠(J Hypertens Suppl 1993 Dec;11 Suppl5:S208-9)、或单个肾切除和高钠及高蛋白负荷所导致的肾功能障碍的报道(Am J Hypertens 1997 10:209-16)。
WO 00/67748中记载了包括贝雷普罗钠在内的间亚苯基PGI2衍生物对肾衰竭的治疗有效,WO99/13880中记载了包括贝雷普罗钠在内的间亚苯基PGI2衍生物对肾炎、肾小球肾炎、糖尿病性肾病的治疗有效,WO02/080929中记载了包括贝雷普罗钠在内的间亚苯基PGI2衍生物对肾间质肾炎有效。
但是这些文献中仅记载了各种前列腺素I衍生物单独对肾病恶化的效果,关于该前列腺素I衍生物与肾素-血管紧张素系统抑制剂的并用完全没有涉及。
另外有关于具有与天然结构不同的特殊结构的新前列腺烷酸(プロスタノイン酸)型化合物内-亚苯基-9-硫代-11-氧代-12-氮杂前列腺烷酸化合物与血管紧张素转化酶抑制剂的新组合物的报道。记载了这些化合物具有强的肾血管扩张作用、该组合物对高血压的治疗有效。但是,本专利文献中的化合物与前列腺素类化合物不同,并且关于该化合物是否可增强血管紧张素转化酶抑制剂的肾病恶化抑制效果未涉及(特开昭60-23324)。
有关于前列腺素I衍生物的一种西卡前列素与ACE抑制剂的一种福辛普列钠(fosinopril)并用治疗糖尿病模型大鼠,对于糖尿病性肾病的恶化评价结果的报道(Am J Hypertens.1997 10:202-8)。根据该文献的报道,两种药物单独使用的组与对照组相比,尿蛋白等肾功能参数、或肾组织的病变减轻,但即使将两种药物并用,优于两种药物单独使用时的效果未被认可,认为无并用效果。
发明内容
本发明的目的是提供肾素-血管紧张素系统抑制剂的肾病治疗或预防效果的增强剂。
本发明人仔细研究的结果发现特定的前列腺素I衍生物非常特征性地增强肾素-血管紧张素系统抑制剂的肾病恶化抑制效果,从而完成了本发明。
既,本发明是肾素-血管紧张素系统抑制剂的肾病治疗或预防效果的增强剂,其含有通式(I)表示的前列腺素I衍生物作为有效成分。
[式中,R1表示
A)COOR2,这里R2为氢或药理学上可接受的阳离子、2)碳原子数为1~12的直链烷基或碳原子数为3~14的支链烷基Z-R3,这里的Z为价键(原子価結合)或CtH2t表示的直链或支链亚烷基,t表示1~6的整数,R3为碳原子数为3~12的环烷基或被1~3个R4取代的碳原子数为3~12的取代环烷基,R4为氢或碳原子数为1~5的烷基、
-(CH2CH2O)nCH3,这里n为1~5的整数,
-Z-Ar1,这里Z与上述定义相同,Ar1为苯基、α-萘基、β-萘基、2-吡啶基、3-吡啶基、4-吡啶基、α-呋喃基、β-呋喃基、α-噻吩基、β-噻吩基或取代苯基(这里的取代基为至少一个氯、溴、氟、碘、三氟甲基、碳原子数1~4的烷基、硝基、氰基、甲氧基、苯基、苯氧基、对乙酰氨基苯甲酰氨基、-CH=N-NH-C-(=O)-NH2、-NH-C(=O)-Ph、-NH-C(=O)-CH3或-NH-C(=O)-NH2)、
-CtH2tCOOR4,这里的CtH2t、R4与上述定义相同,
-CtH2tN(R4)2,这里的CtH2t、R4与上述定义相同,
-CH(R5)-C-(=O)-R6,这里R5为氢或苯甲酰基,R6为苯基、对溴苯基、对氯苯基、对联苯基、对硝基苯基、对苯甲酰氨基苯基、2-萘基、-CpH2p-W-R7,这里W为-CH=CH-、-CH=CR7-或-C≡C-,R7为氢、碳原子数为1~30的直链或支链烷基或碳原子数为1~30的芳烷基,p为1~5的整数、或
10)-CH(CH2OR8)2,这里的R8为碳原子数为1~30的烷基或酰基、
(B)-CH2OH、
(C)-C(=O)N(R9)2,这里R9表示氢、碳原子数为1~12的直链烷基、碳原子数为3~12的支链烷基、碳原子数为3~12的环烷基、碳原子数为4~13的环烷基亚烷基、苯基、取代苯基(这里的取代基与上述(A)5)的定义相同)、碳原子数为7~12的芳烷基或-SO2R10。R10表示碳原子数为1~10的烷基、碳原子数为3~12的环烷基、苯基、取代苯基(这里的取代基与上述(A)5)的定义相同)、碳原子数为7~12的芳烷基。两个R9可以相同也可以不同,但当一个R9表示-SO2R10时,另一个R9不为-SO2R10,或
(D)-CH2OTHP(THP为四氢吡喃基)、
A为
-(CH2)m-、
-CH=CH-CH2-、
-CH2-CH=CH-、
-CH2-O-CH2-
-CH=CH-、
-O-CH2-或
7)-C≡C-,在此,m表示1至3的整数,
Y为氢、碳原子数为1~4的烷基、氯、溴、氟、甲酰基、甲氧基或硝基、
B为-X-C(R11)(R12)OR23,这里R11为氢或碳原子数为1~4的烷基,R13为氢、碳原子数为1~14的酰基、碳原子数为6~15的芳酰基、四氢吡喃基、四氢呋喃基、1-乙氧基乙基或叔丁基,
X为
-CH2-CH2-
-CH=CH-或
-C≡C-
R12为
碳原子数为1~12的直链烷基、碳原子数为3~14的支链烷基、
-Z-Ar2,这里Z与上述定义相同,Ar2为苯基、α-萘基、β-萘基或至少一个氯、溴、氟、碘、三氟甲基、碳原子数1~4的烷基、硝基、氰基、甲氧基、苯基或苯氧基取代的苯基。
-CtH2tOR14,在此CtH2t与上述定义相同,R14为碳原子数为1~6的直链烷基、碳原子数为3~6的支链烷基、苯基、至少一个氯、溴、氟、碘、三氟甲基、碳原子数1~4的烷基、硝基、氰基、甲氧基、苯基或苯氧基取代的苯基、环戊基、环己基、或被1~4个碳原子数为1~4的烷基取代的环戊基或环己基,
-Z-R3,在此R3与上述定义相同,
-CtH2t-CH=(R15)R16,CtH2t与上述定义相同,R15和R16相互独立地为氢、甲基、乙基、丙基或丁基,或
6)-CuH2u-C≡C-R17,这里u为1~7的整数,CuH2u表示直链或支链亚烷基,R17表示碳原子数为1~6的直链烷基,
E表示氢或OR18,在此R18表示碳原子数为1~12的酰基、碳原子数为7~15的芳酰基或R2(R2与上述定义相同),
通式表示d体、l体或dl体。
另外,本发明提供一种肾病的治疗或预防药,其包括上述本发明的增强剂及肾素-血管紧张素系统抑制剂作为有效成分。本发明还提供用于同时或错开时间施用上述本发明的增强剂以及肾素-血管紧张素系统抑制剂的用于治疗或预防肾病的试剂盒,其中分别含有上述增强剂、和包含肾素-血管紧张素系统抑制剂作为有效成分的药物。本发明还提供肾素-血管紧张素系统抑制剂的肾病治疗及预防效果的增强方法,其包括给施用肾素-血管紧张素系统抑制剂的肾病患者施用上述本发明的增强剂。本发明还提供肾病的治疗或预防方法,其包括给肾病患者施用上述肾病的治疗或预防剂、或肾病的治疗或预防用试剂盒中含有的药物。本发明还提供上述通式(I)所表示的前列腺素I衍生物在制备增强肾素-血管紧张素抑制剂的肾病治疗或预防效果的药物中的用途。
基于本发明,肾素-血管紧张素系统抑制剂所具有的优异的肾病恶化抑制效果可被增强。因此,除了可彼此减少达到一定效果所必需的给药量外,还可降低彼此的副作用,提高与用药相关的顺应性。而且,以往的肾素-血管紧张素系统抑制剂的疗效不充分,本发明可安全且有效的治疗肾病。
附图说明
图1为本发明的实施例及比较例的组合物对肾炎诱发大鼠模型的药理学效果图。
图2为本发明的实施例及比较例的组合物对肾炎诱发大鼠模型的药学理效果图。
具体实施方式
作为有效成分包含在本发明增强剂中的前列腺素I衍生物如上述通式(I)所示。
在上述通式(I)所示的化合物中,优选以下化合物:
R1为COOR2,
在此,R2为氢或药理学上可接受的阳离子。
A为
1)-(CH2)m-
2)-CH2-CH=CH-
在此,m表示1至3的整数,
Y为氢,
B为-X-C(R11)(R12)OR13,
在此,R11、R13为氢,X为
1)-CH=CH-
2)-C≡C-,
R12为
1)-Z-Ar2
在此Z为价键或CtH2t表示的直链或支链亚烷基、t表示1至6的整数,Ar2表示苯基、α-萘基、β-萘基以及至少一个氯、溴、氟、碘、三氟甲基、碳原子数1~4的烷基、硝基、氰基、甲氧基、苯基或苯氧基取代的苯基,或
2)-Z-R3
在此Z与上述定义相同,R3表示碳原子数为3~12的环烷基,或
3)-CuH2u-C≡C-R17
在此u为1~7的整数,CuH2u表示直链或支链亚烷基,R17表示碳原子数为1~6的直链烷基,通式表示其d体、l体或d1体。
作为更优选的化合物,可列举上述通式(I)所表示的化合物中:
R1为COOR2,R2为氢或药理学上可接受的阳离子,
A为-(CH2)m-,在此m表示1至3的整数,
Y为氢,
B为-X-C(R11)(R12)OR13,R11与R13为氢,
X为-CH=CH-,
R12为-CuH2u-C≡C-R17,在此u为1~7的整数,CuH2u表示直链或支链亚烷基,R17表示碳原子数为1~6的直链烷基,
E为氢或-OR18,在此R18表示R2(在此R2与上述定义相同),通式表示其d体、l体或d1体。
特别是可列举下式所表示的贝雷普罗(ベラプロスト)或其盐或酯类化合物,但不限于此。
本发明中,通式(I)所表示的化合物或其盐,特别是贝雷普罗钠,除具有长期稳定性外,口服给药的生物利用度也高。因此肾病患者,特别是慢性肾病患者,因需要长期施用,可特别优选使用。
上述通式(I)所表示的4,8-内-间-亚苯基前列腺素I2衍生物为公知的化合物,可利用例如特公平1-53672号公报所记载的方法制备。
上述通式(I)所表示的4,8-内-间-亚苯基前列腺素I2衍生物可单独使用,也可2种或2种以上组合使用。
另外,作为前列腺素I衍生物,也可使用以下化合物:伊洛前列素(iroprost)、依前列醇(epoprostenol sodium)、carbacycin、西卡前列素(cicaprost)、依他前列素(eptaprost)、阿前列素(ataprost)、西前列烯(ciprostene)、他前列烯(taprostene)、克林前列素(clinprost)、尼来前列素(nileprost)、那前列烯(naxaprostene)、treprostinil、匹米前列素(pimilprost)、CS-570(明天的新药2003年4月24日)、TY-11223(明天的新药2003年4月24日)、TTC909(明天的新药2003年4月24日)、OP-2507(明天的新药2003年4月24日)。
另外,也可使用以下前列腺素I衍生物。KP-10614、CH-5084、SC-43350、RS-93427、U-68215、RO-23-6416、CH-169、TEI-9063、AFP-07、サイロプロスト、CS-570、M-19791、Hoe892、R-59274、CG-4203。
也可使用(16S)-15-脱氧-16-羟基-16-甲基-9(O)-亚甲基(methano)-Δ6(9α)-前列腺素I1、9(O)-亚甲基-Δ6(9α)-前列腺素I1甲酯、17(S),20-二甲基-9(O)-亚甲基-Δ6(9α)-前列腺素I1甲酯、特开平8-245498号公报所记载的15R-イソカルバサイクリン衍生物、
特愿平9-160320号中记载的15R-16-间-甲苯基-17,18,19,20-テトラノルイソカルバサイクリン或其甲酯。
另外,也可使用报道具有与前列腺素I2同样作用如血小板作用或血管扩张作用的化合物:沙米索格雷(samixogrel:明天的新药2003年4月24日)、BMY-42239(明天的新药2003年4月24日)、BMY-45778(明天的新药2003年4月24日)、ONO-1301(明天的新药2003年4月24日)以及EP0542203、EP0548959、EP0578847、EP0558062、EP0581187、WO9813356、特开2000-191523、WO02/088084、特许第3245864号中所记载的化合物。
本发明中作为对象肾素-血管紧张素系统抑制剂可列举:ACE抑制剂、血管紧张素II受体拮抗剂、胃促胰酶抑制药及肾素抑制药,特别优选ACE抑制剂及血管紧张素II受体拮抗剂。
特别优选在临床上被广泛使用,显示了用于肾病的安全性及有效性的药物。
作为可用于本发明的ACE抑制剂的具体例,有以下各种低分子化合物,但不限于此。
可列举依那普利(enalapril maleate)、阿拉普利(alacepril)、地拉普利(delapril)、雷米普利(ramipril)、卡托普利(captopril)、赖诺普利(lisinopril)、贝那普利(benazepril hydrochloride)、赖苯普利(libenzapril)、喹普利拉(quinaprilat)、咪唑普利(imidapril hydrochloride)、佐芬普利(zofenopril calcium)、福辛普利(fosinopril sodium)、西拉普利(cilazapril)、替莫普利(temocaprilhydrochloride)、螺普利(spiraprilhydrochloride)、哌道普利(perindopril erbumine)、莫昔普利(moexipril hydrochloride)、群哚普利(trandolapril)、omapatrilat、西罗普利(ceronapril hydrate)、伊屈普利(idrapril)、mixanpril、莫维普利(moveltipril calcium)、伦唑普利(rentiapril)、乌替普利(utibapril)、synecor、螺普利拉(spiraprilat)、扎普利(zabiciprilhydrochloride)、E-4030(DrugData Report,Vol.22,p510,2000)、セラノプリル、地拉普利、prentyl、ラマプリル、佐芬普利、山帕曲拉(sampatrilat)、喷妥普利(pentopril)、赖苯普利(libenzapril)、培哚普利拉(perindoprilat)、螺普利拉(spiraprilat)、BRL-36378(N-[4-(2,3-二氢苯并呋喃-2-基)-1-(乙氧基羰基)丁基]-L-丙氨酰基(alanyl)-L-脯氨酸)、精氨酸佐芬普利拉(Zofenoprilat arginine)、法西多曲(Fasidotril)、MDL-100240(4S,7S,12bR)-7-[2(S)-(乙酰基硫烷基(acetylsulfanyl))-3-苯丙酰氨基]-6-氧代-1,2,3,4,6,7,8,12b-八氢吡啶并[2,1-a][2]苯并氮杂-4-羧酸、S-21402(N-[2(S)-(巯甲基)-3-(R)-苯丁基]-L-丙氨酸),Gemopatrilat、AVE-7688(CAS No473289-62-2:(4S,7S,12bR)-7-[2(S)-(乙酰基硫烷基)-3-甲基丁酰氨基]-6-氧代-1,2,3,4,6,7,8,12b-八氢吡啶并[2,1-a][2]苯并氮杂-4-羧酸)。
这其中,优选依那普利(enalapril maleate)、阿拉普利(alacepril)、地拉普利(delapril)、雷米普利(ramipril)、卡托普利(captopril)、赖诺普利(lisinopril)、贝那普利(benazeprilhydrochloride)、赖苯普利(libenzapril)、乌替普利(utibapril)、synecor、螺普利拉(spiraprilat)、扎普利(zabiciprilhydrochloride)、喹普利拉(quinaprilat)、咪唑普利(imidapril hydrochloride)、佐芬普利(zofenopril calcium)、福辛普列钠(fosinopril sodium)、西拉普利(cilazapril)、替莫普利(temocaprilhydrochloride)、螺普利(spiraprilhydrochloride)、哌道普利(perindoprilerbumine)、西罗普利(ceronapril hydrate)、莫昔普利(moexipril hydrochloride)、群哚普利(trandolapril)、伊屈普利(idrapril)omapatrilat、喷妥普利(pentopril)、赖苯普利(Libenzapril)、培哚普利拉(perindoprilat)、螺普利拉(spiraprilat)、BRL-36378(N-[4-(2,3-二氢苯并呋喃-2-基)-1-(乙氧基羰基)丁基]-L-丙氨酰基-L-脯氨酸)、山帕曲拉(sampatrilat)、精氨酸佐芬普利拉(Zofenoprilatarginine)、法西多曲(Fasidotril)、MDL-100240(4S,7S,12bR)-7-[2(S)-(乙酰基硫烷基)-3-苯丙酰氨基]-6-氧代-1,2,3,4,6,7,8,12b-八氢吡啶并[2,1-a][2]苯并氮杂-4-羧酸、S-21402(N-[2(S)-(巯甲基)-3-(R)-苯丁基]-L-丙氨酸)、Gemopatrilat、AVE-7688((4S,7S,12bR)-7-[2(S)-(乙酰基硫烷基)-3-甲基丁酰氨基]-6-氧代-1,2,3,4,6,7,8,12b-八氢吡啶并[2,1-a][2]苯并氮杂-4-羧酸)。
其中,特别优选使用马来酸依那普利、阿拉普利、地拉普利、雷米普利、卡托普利、赖诺普利、贝那普利、赖苯普利、喹普利拉、咪唑普利、佐芬普利、福辛普利、西拉普利、替莫普利、螺普利、哌道普利、莫昔普利、群哚普利、omapatrilat、西罗普利、乌替普利以及山帕曲拉。
当然也可以使用这些化合物的药理学上允许的盐。
这些ACE抑制剂都是公知的,可通过公知的方法制备。
本发明中,可作为肾素-血管紧张素系统抑制剂使用的血管紧张素II受体拮抗剂是指具有竞争性或非竞争性地抑制血管紧张素II与细胞膜上的血管紧张素II受体特别是其亚型AT1受体的结合,从而减弱血管紧张素II所诱导的血管收缩作用或血管平滑肌增殖作用,缓和高血压症状的作用的药物。
本发明中所使用的具有血管紧张素II受体拮抗作用的化合物可以为肽性,也可以为非肽性,优选非肽性的化合物。作为具有血管紧张素II受体拮抗剂作用的化合物,列举下列化合物,但不仅限于此。例如:氯沙坦(losartan)、依普沙坦(eprosartan)、坎地沙坦酯(candesartan cilexetil)、缬沙坦(valsartan)、替米沙坦(telmisartan)、厄贝沙坦(irbesartan)、他索沙坦(tasosartan)、奥美沙坦酯(olmesartan medoxomil)、EXP-3174(Drug DataReport,Vol.14,p396,1992)、佐拉沙坦(zolasartan)、沙普立沙坦(saprisartan)、依利沙坦(elisartan potassium)、利匹沙坦(ripisartan)、(milfasartan)、福拉沙坦(forasartan)、恩布沙坦(embusartan)、BMS-184698(Drug Data Report,Vol.16,p449,1994)、3-(2’-(四唑-5-基)-1,1’-ビフエン-4-基)甲基-5,7-二甲基-2-乙基-3H-咪唑并[4,5-b]吡啶、BAY106734(Drug DataReport,Vol.18,p518,1996)、BIBR363(Drug Data Report,Vol.18,p139,1996)、CL329167(2-丁基-6-(1-甲氧基-1-甲基乙基)-3-[2’-(1H-四唑-5-基)联苯-4-基甲基]喹唑啉-4(3H)-酮:Drug DataReport,Vol.16,p728,1994)、E4177(3-(2’-羧基联苯-4-基甲基)-2-环丙基-7-甲基-3H-咪唑并[4,5-b]吡啶或4’-(2-环丙基-7-甲基-3H-咪唑并[4,5-b]吡啶-3-基甲基)联苯基-2-羧酸:Drug Data Report,Vol.14,p981,1992)、EMD73495、HN65021(Drug Data Report,Vol.16,p914,1994)、HR720(Drug Data Report,Vol.17,p147,1995)、HOE720、LRB081(Drug Data Report,Vol.16,p1002,1994)、SC52458(Drug Data Report,Vol.15,p632,1993)、SL910102、UP2696(Drug Data Report,Vol.16,p1004,1994)、YM358(2,7-二乙基-5-[2’-(1H-四唑-5-基)联苯-4-基甲基]-5H-吡唑并[1,5-b][1,2,4]三唑钾盐-水盐:Drug Data Report,Vol.15,p533,1993)、EMD66397、ME3221(3-甲氧基-2,6-二甲基-4-[2’-(1H-四唑-5-基)联苯-4-基甲氧基]吡啶:Drug Data Report,Vol.16,p636,1994)、TAK536(2-乙氧基-1-[2’-(5-氧代-2,5-二氢-1,2,4-噁二唑-3-基)联苯-4-基甲基]苯并咪唑-7-羧酸:Drug Data Report,Vol.17,p435,1995)、CGP42112A(Drug Data Report,Vol.12,p794,1990)、CGP49870、CP148130、E4188、EMD66684、EXP9954、FR1153332、GA0050、KT3579(Drug Data Report,Vol.15,p631,1993)、LF70156、LRB057(Drug Data Report,Vol.15,p922,1993)、LY266099、LY301875(Drug Data Report,Vol.16,p538,1994)、PD123177(Drug Data Report,Vol.13,p123,1994)、PD126055(Drug DataReport,Vol.16,p543,1994)、SC51757(Drug Data Report Vol.16,p453,1994)、SC54629(Drug Data Report,Vol.16,p542,1994)、U96849、UK77778、WAY126227(Drug Data Report,Vol.15,p1024,1993)、WK1260(Drug Data Report,Vol.15,p635,1993)、WK1492、YH1498以及YM31472(Drug Data Report,Vol.15,p1024,1993)、还有泊来沙坦(pomisartan)、奥美沙坦水合物(olmesartanhydrate)、KRH-594(2-[[5-乙基-3-[2’-(1H-四唑-5-基)联苯-4-基甲基]-2,3-二氢-1,3,4-噻二唑-2-イリデン]氨基羰基]-1-环戊羧酸二钾盐)、UR-7247(3-异丙基-1-丙基-5-[2’-(1H-四唑-5-基)联苯-4-基甲基]-1H-吡唑-4-羧酸)、EXP-3174(2-丁基-4-氯-1-[2’-(1H-四唑-5-基)联苯-4-基甲基]咪唑-5-羧酸)、L-159282(N-[4’-(2-乙基-5,7-二甲基-3H-咪唑并[4,5-b]吡啶-3-基甲基-)联苯基-2-磺酰基]苯甲酰胺)、CL-329167、DuP-532(4-五氟乙基-2-丙基-1-[2’-(1H-四唑-5-基)联苯-4-基甲基]咪唑-5-羧酸)、ICI-D8731(2-乙基-4-[2’[(1H-四唑-5-基)联苯-4-基甲氧基]喹啉盐酸盐)、ICI-D6888(2-乙基-4-[2’-(1H-四唑-5-基)-联苯-4-基甲氧基]-5,6,7,8-四氢喹啉盐酸盐)、CI-996(2-丙基-1-[2’-(1H-四唑-5-基)联苯-4-基甲基]-4-[2-(三氟乙酰基)吡咯-1-基]咪唑-5-羧酸),有时也可使用这些化合物的代谢活性物质(坎地沙坦等)。当然也可使用这些化合物的药理学允许的盐。
这其中优选氯沙坦(losartan)、依普沙坦(eprosartan)、坎地沙坦酯(candesartan cilexetil)、缬沙坦(valsartan)、替米沙坦(telmisartan)、厄贝沙坦(irbesartan)、他索沙坦(tasosartan)、奥美沙坦酯(olmesartan medoxomil)、EXP-3174、佐拉沙坦(zolasartan)、沙普立沙坦(saprisartan)、依利沙坦钾(elisartanpotassium)、利匹沙坦(ripisartan)、(milfasartan)、福拉沙坦(forasartan)、恩布沙坦(embusartan)、CL329167、E4177、ME3221、TAK536、泊来沙坦(pomisartan)、奥美沙坦水合物(olmesartanhydrate)、KRH-594、UR-7247、EXP-3174、L-159282、GL-329167、DuP-532、ICI-D8731、ICI-D6888、CI-996,以及有时也优选这些化合物的代谢活性物质(坎地沙坦等)。当然也可使用这些化合物的药理学允许的盐。
特别优选使用氯沙坦(losartan)、依普沙坦(eprosartan)、坎地沙坦酯(candesartan cilexetil)、缬沙坦(valsartan)、替米沙坦(telmisartan)、厄贝沙坦(irbesartan)、他索沙坦(tasosartan)、奥美沙坦酯(olmesartan medoxomil)、佐拉沙坦(zolasartan)、(milfasartan)、福拉沙坦(forasartan),有时也特别优选这些化合物的代谢活性物质(坎地沙坦等)以及这些化合物的药理学允许的盐。
非肽型血管紧张素II受体拮抗剂根据其结构可分为两大类:联苯四唑类和非联苯四唑类。前者包括氯沙坦、坎地沙坦酯、缬沙坦。后者则包括依普沙坦、佐拉沙坦、替米沙坦。在本发明中,如实施例所示,两类药物均适用。
这些血管紧张素II受体拮抗剂都为公知的,可利用公知的方法制备。
另外,作为肾素-血管紧张素系统抑制剂,列举胃促胰酶抑制药。胃促胰酶是丝氨酸蛋白酶的一种,因它与ACE一起具有将血管紧张素I转化为具有升压作用的血管紧张素II的作用,报道胃促胰酶的选择性抑制药有可能作为降压剂。作为低分子的胃促胰酶抑制剂,可列举3-(2-萘羰基-5-[2-[5-[[(1-苯基-1,2,3,4-四唑基)-5-硫]甲基]]呋喃次甲基(フリルメチリデン)]-1,3-噻唑烷-2,4-二酮、3-(4-氯苯磺酰基)-1-(4-氯苯基)咪唑烷-2,4-二酮、3-(3-烯丙氧羰甲基苯磺酰基)-1-苯基-咪唑烷-2,4-二酮、7-[6-(6-生物素基氨基己酰基)氨基己酰基]氨基-4-氯-3-(2-苯乙氧基)异香豆素等,这些药物公开在特开2000-95770、WO98/09949、WO93-25547、USP5306824、WO96-4248中。
作为肾素-血管紧张素系统抑制剂,优选使用具有肾素抑制活性的化合物。肾素是由肾脏的邻肾小球细胞分泌的蛋白质分解酶,在肾素-血管紧张素系统中将血管紧张肽原转化为血管紧张素I。在体内血管紧张素I被转化为强升压物质血管紧张素II,因此肾素抑制物质可用于高血压的治疗。因此具有肾素抑制活性的低分子化合物有做降压剂的可能性。作为有肾素抑制活性的低分子化合物的具体例子,可列举阿利克仑(aliskiren)、雷米克林(remikiren)、以及(2S,3R,4S)-2-((2R)-2-(1-(4-吗啉基羰基)甲基-N-(1-萘甲基)氨基)羰甲基-4-甲基戊硫基(メチルペンチオニル))氨基-1-环己基-3,4-二羟基-6-甲基庚烷等特开平5-32602中记载的化合物。
上述肾素-血管紧张素系统抑制剂可单独使用也可两种以上组合使用。当然也可将上述属于不同类别的2种或2种以上肾素-血管紧张素系统抑制剂组合使用。
特别是近年来,有ACE抑制剂和血管紧张素II受体拮抗剂同时使时可进一步抑制肾病恶化的报道(WO/97/02032),通过将本发明的前列腺素I衍生物、与ACE抑制剂和血管紧张素II受体拮抗剂两者并用,可更加确切地抑制肾病的恶化。
相反,对于已经在施用前列腺素I衍生物的肾病患者,施用肾素-血管紧张素系统抑制剂也非常有效。
作为通过本发明可预防或治疗的肾病,以糖尿病性肾病为首、急性肾小球肾炎以及慢性肾小球肾炎、肾病综合症、狼疮肾炎、间质性肾炎、急性肾小管间质性肾炎、慢性肾小管间质性肾炎、急性肾衰竭以及慢性肾衰竭。另外,对分类为慢性肾小球肾炎的微小肾小球变化性肾炎、局灶性/节段性肾小球肾炎(巢状/分節状糸球体腎炎)、弥漫性肾小球肾炎、系膜增生性肾小球肾炎、弥漫性毛细血管内增生性肾炎、新月体性肾炎、弥漫性硬化性肾小球肾炎、IgA肾炎也有效。
另外对于肾素-血管紧张素抑制剂的效果不充分的糖尿病性肾病的显性期、或血清肌酸酐上升的保存期肾衰竭(保存期腎不全)这类更加恶化的肾病开始给药后也表现出肾功能降低抑制作用。
以肾过滤功能的最重要指标GFR(glomerular filtration rate:肾小球滤过率)为指标时最能明确的掌握本发明的效果。GFR可通过测定肌酸酐或菊粉(イヌリン)的清除率评价。另外,为简便,也可通过换算式由血中的肌酸酐值推定。
另外,因血中肌酸酐值或BUN(血中尿素氮)的上升与肾的低分子过滤功能的下降相伴随,可通过血中肌酸酐值或BUN值明确的掌握本发明的肾病抑制效果。特别是血中肌酸酐值的倒数随着时间变化大体上呈直线下降,临床上通过这一趋势推定肾功能的下降速度,例如也可用于活性炭制剂在肾衰竭期的药效评价。(Biomater ArtifCellsImmobilization Biotechnol.1991;19(1):147-66、Am J Kidney Dis.2003 Mar;41(3 Suppl 1):S35-7.)
这些通过肌酸酐值的评价方法适于肾病发展至肌酸酐上升的阶段,即肾衰竭特别是保存期肾衰竭的评价。
对于血中肌酸酐值或BUN未上升的更早期的肾病患者的药效评价,可用被广泛使用的尿中的蛋白量,特别是对于糖尿病性肾病的评价,也可通过可更早期掌握病情的尿中微量白蛋白判断本发明的效果。
本发明中作为肾素-血管紧张素抑制剂的用量,优选设定对于不同的患者可得到降压效果的用量。另一方面,作为前列腺素I衍生物的用量,优选使用副作用允许范围的近可能高的用量。如本发明所示,两者并用时,前列腺素I衍生物与肾素-血管紧张素抑制剂两者显示了协同地抑制肾病恶化的效果,因此可以期待以更低用量抑制肾病恶化。
特别是本发明中前列腺素I衍生物的用量加大时,除有脸面潮红、发热、头重感、悸动等与血管扩张相伴随的副作用外,还发现呕吐、腹泻等消化系统症状、下颌疼痛等副作用,其高用量的使用被限制时,通过本发明的效果可减少前列腺素I衍生物的用量。
作为肾素-血管紧张素抑制剂的用量,优选显示血压下降作用的用量,即使是更低的用量,通过本发明的相协同效果,也可设定更低的用量。
因此,可以期待减轻ACE抑制剂的副作用,即,以干咳为首、过度的血压下降、眩晕或起立眩晕、高钙血症、血管浮肿、脸面或咽喉肿、肝损伤等副作用。另外,对于肾衰竭患者在服药初始时可见的肾机能暂时恶化、特别是高钙血症的减轻也有效。另外对于作为血管紧张素II受体拮抗剂的副作用而被知晓的、过度的血压降低引起的起立眩晕、高钙血症、血管浮肿、脸面或咽喉肿、肝损伤、肾机能的暂时恶化的减轻也有效。
本发明中,作为肾素-血管紧张素抑制剂的用量,成人(体重50kg)口服时,含有效成分的化合物,通常优选以1次量(组合物1个单位)为0.01~1000mg,优选0.1~100mg的用量每日给药1~3次其前药或其盐。
作为前列腺素I衍生物特别是4,8-内-间-亚苯基前列腺素I2的用药量,通常1次量(组合物1个单位)对于成人为0.01~5000μg左右,优选0.1~500μg,优选以该用量每日给与1~3次左右。特别是贝雷普罗钠,人肾衰竭患者的每日用量为0.02~500μg,1日给药2至4次是适宜的。
作为本发明的前列腺素I衍生物的制剂,可添加赋形剂,例如淀粉类、乳糖、蔗糖、葡萄糖、甘露糖醇、碳酸钙、硫酸钙等,粘合剂,例如淀粉类、糊精、阿拉伯胶、西黄蓍胶、甲基纤维素、明胶、聚乙烯吡咯烷酮、聚乙烯醇等,崩解剂,例如淀粉类、聚乙烯吡咯烷酮、结晶纤维素等,润滑剂,例如硬脂酸镁、滑石粉等,着色剂、香料等制成。
本发明中前列腺素I衍生物和血管紧张素抑制剂可以作为不同的制剂同时、分别或错开时间施用。为了提高便利性,也可使用含这两种制剂的试剂盒、或两种制剂和单剂组合的试剂盒制剂。特别是因前列腺素I衍生物制剂和血管紧张素抑制剂制剂的用法常常不同,施用方法繁杂,可特别优选这种试剂盒制品。另外,也可以包含这些药物各自的颗粒的胶囊剂形式给药。
当然也可根据各药物的特性,分别采取缓释、延迟释放等控制其释放的方法。特别是将前列腺素I衍生物做成缓释制剂,因可更安全地提高前列腺素I衍生物的用量而得到好的结果。
作为本发明的给药形式,可使用各种剂型,具体地,口服时,可列举片剂、散剂、细粒剂、颗粒剂、片剂、液体制剂、糖浆剂、胶囊剂、丸剂、喷雾剂等以往被使用的剂型,优选片剂、散剂、细粒剂、颗粒剂、片剂、液体制剂、糖浆剂、胶囊剂。
本发明制剂也可以灭菌溶液等形式经非口服途径给药,另外也可使用其他溶质,例如足以使溶液等张的氯化钠或葡萄糖等。本发明的治疗或预防药除有上述口服制剂外,也可以应用各种注射剂、栓剂等各种非口服制剂等广泛的给药途径。口服与非口服制剂可按照医疗领域广泛采取的常法来使用。
本发明的药物不仅适用于人,也可以适用于作为宠物饲养的以哺乳类为首的各种动物。
以下通过实施例具体说明本发明。
实施例1给来源于日本チヤ—ルズリバ—的9周龄WKY大鼠施用兔抗大鼠肾小球基底膜抗血清(NTS,稀释10倍,3ml/kg),诱发肾小球肾炎。2周后进行采尿、采血,根据尿蛋白量、血清肌酸酐值将试验动物分成6组,开始给药。这时血清肌酸酐值已经上升,判断已可分类为肾衰竭期。根据血清肌酸酐值评价肾机能。
1)对照组:只给与溶剂,n=6
2)BPS100组(比较例):贝雷普罗钠100μg/kg(BID:本用量每日给与2次),n=6
3)BPS300组(比较例):贝雷普罗钠300μg/kg(BID),n=6
4)坎地沙坦10组(比较例):坎地沙坦酯10mg/kg(OAD:本用量每日给与1次),n=6
5)坎地沙坦30组(比较例):坎地沙坦酯30mg/kg(OAD),n=6
6)BPS100+坎地沙坦10组(本发明):
贝雷普罗钠100μg/kg(BID)+坎地沙坦酯10mg/kg(OAD),n=7
给药后每隔一周进行采血测定血清肌酸酐值。结果如图1所示。
如图1所示BPS100组、坎地沙坦10组的肾炎恶化抑制效果与对照组相比几乎没有差别。另一方面,将两药配合使用的BPS100+坎地沙坦10组在给药后的血清肌酸酐上升大体上完全被抑制。而即使将两药的用量增加(坎地沙坦30组、以及BPS300组),它们的肾病恶化抑制效果与BPS100+坎地沙坦10组相比也弱。
这样,通过将单剂使用时完全不抑制肾病恶化的低用量的BPS与坎地沙坦酯配合,与这两种单剂高剂量使用时相比更好地改善了肾衰竭恶化抑制作用。该结果显示了2种药物的配合剂对于本疾病的优异疗效。
此时,尿中的PGF1α的产生并未因坎地沙坦的给药而变化,因此确认本现象中没有内源性前列腺素I2的产生增加起作用的可能性。另外测定了血浆中的纤维蛋白原浓度,各组之间无显著性差异。
实施例2给9周龄WKY大鼠施用兔抗大鼠肾小球基底膜抗血清,诱发肾炎。施用抗血清2周后将试验动物分成以下4组,开始给药。
1)对照组:0.5%CMC(OAD)+蒸馏水(BID),n=6
2)替米沙坦组(比较例):替米沙坦40mg/kg(OAD)+蒸馏水(BID),n=5
3)BPS组(比较例):0.5%CMC(OAD)+贝雷普罗钠100μg/kg(BID),n=5
4)替米沙坦+BPS组(本发明):替米沙坦40mg/kg(OAD)+贝雷普罗钠100μg/kg(BID),n=6。
如表1所示BPS组的肾衰竭恶化抑制效果与对照组相比几乎没有差别。替米沙坦组与替米沙坦+BPS组均可抑制肾衰竭恶化,替米沙坦+BPS组的抑制作用较强。给药结束一周后再次测定血清肌酸酐值,发现与替米沙坦组的肾衰竭恶化了相比,替米沙坦+BPS组的血清肌酸酐值大体上被抑制至正常动物程度。如此,并用组在给药结束后血清肌酸酐值不上升反而下降,说明了并用有极高的疗效。
表1
组 | 诱发7周后的血清肌酸酐值(mg/dL) | 诱发8周后(给药结束1周后)的血清肌酸酐值(mg/dL) |
对照 | 1.79±0.37 | |
替米沙坦 | 0.93±0.43 | 1.18±0.80 |
BPS | 1.56±0.76 | |
替米沙坦+BPS | 0.61±0.09 | 0.29±0.01 |
平均值±标准偏差
实施例3
给9周龄WKY大鼠施用兔抗大鼠肾小球基底膜抗血清,诱发肾炎。施用抗血清2周后将试验动物分成以下4组,开始给药。
1)对照组:0.5%CMC(BID)+蒸馏水(BID),n=6
2)氯沙坦组(比较例):氯沙坦30mg/kg(BID)+蒸馏水(BID),n=5
3)BPS组(比较例):0.5%CMC(BID)+贝雷普罗钠100μg/kg(BID),n=6
4)氯沙坦+BPS组(本发明):氯沙坦30mg/kg(BID)+贝雷普罗钠100μg/kg(BID),n=5
肾炎诱发6周后测定血清肌酸酐值,评价肾衰竭的恶化程度。如表2所示,该用量的氯沙坦组、BPS组对于肾衰竭的恶化抑制效果与对照组相比无差异。另一方面,将两药配合使用的氯沙坦+BPS组与对照组相比显著肾衰竭的恶化(p<0.05)。这样,通过将单种药物使用无效的量的BPS与ARB的氯沙坦并用,得到了显著的肾衰竭恶化抑制效果。
表2
组 | 诱发6周后的血清肌酸酐值(mg/dL) |
对照 | 1.83±0.47 |
氯沙坦 | 1.94±0.61 |
BPS | 0.93±0.18 |
氯沙坦+BPS | 0.65±0.13* |
平均值±标准偏差
*:p<0.05与对照组比较(t检验)
实施例4
给9周龄WKY大鼠施用兔抗大鼠肾小球基底膜抗血清,诱发肾炎。施用抗血清2周后将试验动物分成以下4组,开始给药。
1)对照组:0.5%CMC(OAD)+蒸馏水(BID),n=6
2)依那普利组(比较例):马来酸依那普利10mg/kg(OAD)+蒸馏水(BID),n=5
3)BPS组(比较例):0.5%CMC(OAD)+贝雷普罗钠100μg/kg(BID),n=6
4)依那普利+BPS组(本发明):马来酸依那普利10mg/kg(OAD)+贝雷普罗钠100μg/kg(BID),n=6
开始给药后每隔1周进行采血,测定血清肌酸酐值。以开始给药至给药5周的血清肌酸酐值的倒数为纵轴,时间为横轴作图,以渐近线的斜率作为每个个体肾衰竭的恶化速度。结果如表3所示。
如表3所示,该用量的依那普利组、BPS组对于肾衰竭的恶化抑制效果与对照组相比无差异。另一方面,将两药配合使用的依那普利+BPS组与对照组相比显著抑制肾衰竭的恶化(p<0.05)。这样,通过将单种药物使用无效的量的BPS与ACE抑制剂的依那普利并用,得到了显著的肾衰竭恶化抑制效果。
表3
组 | 肾衰竭的恶化速度(dL/mg×周) | 诱发6周后的血清肌酸酐值(mg/dL) |
对照 | 0.41±0.04 | 1.83±0.47 |
依那普利 | 0.41±0.04 | 1.83±0.44 |
BPS | 0.32±0.04 | 0.93±0.18 |
依那普利+BPS | 0.24±0.05* | 0.60±0.08 |
平均值±标准偏差
*:p<0.05与对照组比较(t检验)
实施例5
给9周龄WKY大鼠施用兔抗大鼠肾小球基底膜抗血清,诱发肾炎。投与抗血清2周后将试验动物分成以下4组,开始给药。
1)对照组:0.5%CMC(OAD)+蒸馏水(BID),n=6
2)赖诺普利组(比较例):赖诺普利10mg/kg(OAD)+蒸馏水(BID),n=5
3)BPS组(比较例):0.5%CMC(OAD)+贝雷普罗钠100μg/kg(BID),n=5
4)赖诺普利+BPS组(本发明):赖诺普利10mg/kg(OAD)+贝雷普罗钠100μg/kg(BID),n=6
开始给药后每隔1周进行采血,测定血清肌酸酐值。以开始给药至给药5周的血清肌酸酐值的倒数为纵轴,时间为横轴作图,以渐近线的斜率作为每个个体肾衰竭的恶化速度。结果如表4所示。
如表4所示,赖诺普利组、BPS组对于肾衰竭的恶化抑制效果与对照组相比几乎无差异。另一方面,将两药配合使用的赖诺普利+BPS组与对照组相比显著抑制肾衰竭的恶化(p<0.05)。
表4
组 | 肾衰竭恶化速度(dL/mg×周) | 诱发6周后的血清肌酸酐值(mg/dL) |
对照 | 0.43±0.02 | 1.49±0.41 |
赖诺普利 | 0.39±0.08 | 1.20±0.34 |
BPS | 0.37±0.07 | 1.49±0.59 |
赖诺普利+BPS | 0.27±0.05* | 0.81±0.32 |
平均值±标准偏差
*:p<0.05与对照组比较(Wilcoxon检验)
实施例6
给9周龄WKY大鼠施用兔抗大鼠肾小球基底膜抗血清,诱发肾炎。给与抗血清2周后将试验动物分成以下4组,开始给药。
1)对照组:0.5%CMC(OAD)+蒸馏水(BID),n=6
2)哌道普利组(比较例):哌道普利10mg/kg(OAD)+蒸馏水(BID),n=6
3)BPS组(比较例):0.5%CMC(OAD)+贝雷普罗钠100μg/kg(BID),n=6
4)哌道普利+BPS组(本发明):哌道普利10mg/kg(OAD)+贝雷普罗钠100μg/kg(BID),n=6
开始给药后每隔1周进行采血,测定血清肌酸酐值。以开始给药至给药6周的血清肌酸酐值的倒数为纵轴,时间为横轴作图,以渐近线的斜率作为每个个体肾衰竭的恶化速度。结果如表5所示。
如表5所示,哌道普利组、BPS组对于肾衰竭的恶化抑制效果与对照组相比无抑制倾向。另一方面,将两药配合使用的哌道普利+BPS组对于肾衰竭的恶化抑制效果与对照组相比有强的抑制倾向。
表5
组 | 肾衰竭恶化速度(dL/mg×周) | 诱发6周后的血清肌酸酐值(mg/dL) |
对照 | 0.35±0.04 | 1.45±0.32 |
哌道普利 | 0.30±0.05 | 1.09±0.42 |
BPS | 0.29±0.03 | 0.93±0.18 |
哌道普利+BPS | 0.21±0.07* | 0.75±0.16 |
实施例7
给9周龄WKY大鼠施用兔抗大鼠肾小球基底膜抗血清,诱发肾炎。投与抗血清2周后将试验动物分成以下4组,开始给药。
1)对照组:0.5%CMC(OAD)+蒸馏水(BID),n=11
2)坎地沙坦组(比较例):坎地沙坦酯10mg/kg(OAD)+蒸馏水(BID),n=11
3)BPS组(比较例):0.5%CMC(OAD)+贝雷普罗钠100μg/kg(BID),n=11
4)坎地沙坦+BPS组(本发明):坎地沙坦酯10mg/kg(OAD)+贝雷普罗钠100μg/kg(BID),n=12
如图2所示,本给药量的坎地沙坦组、BPS组的死亡率与对照组相比无差异。另一方面,将两药配合使用的坎地沙坦+BPS组的存活率与对照组相比有显著改善(p<0.05)。这样,通过将单种药物使用无效的量的ARB的坎地沙坦与BPS并用,对肾衰竭的死亡有显著的改善效果。
Claims (20)
1.肾素-血管紧张素系统抑制剂的肾病治疗或预防效果增强剂,其含有通式(I)表示的前列腺素I衍生物作为有效成分,
通式(I)
[式中,R1表示
(A)COOR2,这里R2为
氢或药理学上可接受的阳离子、
2)碳原子数为1~12的直链烷基或碳原子数为3~14的支链烷基Z-R3,这里的Z为价键、或CtH2t表示的直链或支链亚烷基,t表示1~6的整数,R3为碳原子数为3~12的环烷基或被1~3个R4取代的碳原子数为3~12的取代环烷基,R4为氢或碳原子数为1~5的烷基、-(CH2CH2O)nCH3,这里n为1~5的整数,
-Z-Ar1,这里Z与上述定义相同,Ar1为苯基、α-萘基、β-萘基、2-吡啶基、3-吡啶基、4-吡啶基、α-呋喃基、β-呋喃基、α-噻吩基、β-噻吩基或取代苯基(这里的取代基为至少一个氯、溴、氟、碘、三氟甲基、碳原子数1~4的烷基、硝基、氰基、甲氧基、苯基、苯氧基、对乙酰氨基苯甲酰氨基、-CH=N-NH-C-(=O)-NH2、-NH-C(=O)-Ph、-NH-C(=O)-CH3或-NH-C(=O)-NH2)、
-CtH2tCOOR4,这里的CtH2t、R4与上述定义相同,
-CtH2tN(R4)2,这里的CtH2t、R4与上述定义相同,
-CH(R5)-C-(=O)-R6,在此R5为氢或苯甲酰基,R6为苯基、对溴苯基、对氯苯基、对联苯基、对硝基苯基、对苯甲酰氨基苯基、2-萘基、-CpH2p-W-R7,这里W为-CH=CH-、-CH=CR7-或-C≡C-,R7为氢、碳原子数为1~30的直链或支链烷基或碳原子数为1~30的芳烷基,p为1~5的整数,或
10)-CH(CH2OR8)2,这里的R8为碳原子数为1~30的烷基或酰基、
(B)-CH2OH、
(C)-C(=O)N(R9)2,
这里R9表示氢、碳原子数为1~12的直链烷基、碳原子数为3~12的支链烷基、碳原子数为3~12的环烷基、碳原子数为4~13的环烷基亚烷基、苯基、取代苯基(这里的取代基与上述(A)5)中的定义相同)、碳原子数为7~12的芳烷基或-SO2R10,R10表示碳原子数为1~10的烷基、碳原子数为3~12的环烷基、苯基、取代苯基(这里的取代基与上述(A)5)的定义相同)、碳原子数为7~12的芳烷基,两个R9可以相同也可以不同,但当一个R9表示-SO2R10时,另一个R9不为-SO2R10,或
(D)-CH2OTHP(THP为四氢吡喃基),
A为
-(CH2)m-、
-CH=CH-CH2-、
-CH2-CH=CH-、
-CH2-O-CH2-
-CH=CH-、
-O-CH2-或
7)-C≡C-,在此,m表示1至3的整数,
Y为氢、碳原子数为1~4的烷基、氯、溴、氟、甲酰基、甲氧基或硝基,
B为-X-C(R11)(R12)OR13,这里R11为氢或碳原子数为1~4的烷基,R13为氢、碳原子数为1~14的酰基、碳原子数为6~15的芳酰基、四氢吡喃基、四氢呋喃基、1-乙氧基乙基或叔丁基,
X为
-CH2-CH2-
-CH=CH-、或
-C≡C-
R12为
碳原子数为1~12的直链烷基、碳原子数为3~14的支链烷基、-Z-Ar2,这里Z与上述定义相同,Ar2为苯基、α-萘基、β-萘基或至少一个氯、溴、氟、碘、三氟甲基、碳原子数1~4的烷基、硝基、氰基、甲氧基、苯基或苯氧基取代的苯基,
-CtH2tOR14,在此CtH2t与上述定义相同,R14为碳原子数为1~6的直链烷基、碳原子数为3~6的支链烷基、苯基、至少一个氯、溴、氟、碘、三氟甲基、碳原子数1~4的烷基、硝基、氰基、甲氧基、苯基或苯氧基取代的苯基、环戊基、环己基、或被1~4个碳原子数为1~4的烷基取代的环戊基或环己基,
-Z-R3、在此R3与上述定义相同,
-CtH2t-CH=(R15)R16,CtH2t与上述定义相同,R15和R16相互独立地为氢、甲基、乙基、丙基或丁基,或
6)-CuH2u-C≡C-R17,这里u为1~7的整数,CuH2u表示直链或支链亚烷基,R17表示碳原子数为1~6的直链烷基,
E为氢或-OR18,在此R18表示碳原子数为1~12的酰基、碳原子数为7~15的芳酰基或R2(在此R2与上述定义相同),
通式表示d体、1体或d1体。
2.权利要求1中所述的增强剂,
上述通式(I)中,
R1为COOR2,
这里R2为氢或药理学上可接受的阳离子、
A为
1)-(CH2)m-
2)-CH2-CH=CH-
在此,m表示1至3的整数,
Y为氢,
B为-X-C(R11)(R12)OR13,
这里R11、R13为氢、X为
1)-CH=CH-
2)-C≡C-
R12为
1)-Z-Ar2,
这里Z为价键,或CtH2t表示的直链或支链亚烷基、t表示1~6的整数,Ar2表示苯基、α-萘基、β-萘基、或至少一个氯、溴、氟、碘、三氟甲基、碳原子数1~4的烷基、硝基、氰基、甲氧基、苯基或苯氧基取代的苯基,或
2)-Z-R3、
在此Z与上述定义相同,R3表示碳原子数3~12的环烷基,或
3)-CuH2u-C≡C-R17
在此u为1~7的整数,CuH2u表示直链或支链亚烷基,R17表示碳原子数为1~6的直链烷基,
通式表示d体、1体或d1体。
3.权利要求1所述的增强剂,
上述通式(I)中,
R1为COOR2,这里R2为氢或药理学上可接受的阳离子、
A为-(CH2)m-,在此,m表示1至3的整数,
Y为氢,
B为-X-C(R11)(R12)OR13,这里R11、R13为氢,
X为-CH=CH-,
R12为-CuH2u-C≡C-R17,在此u为1~7的整数,CuH2u表示直链或支链亚烷基,R17表示碳原子数为1~6的直链烷基,
E为氢或-OR18,在此R18表示R2(R2与上述定义相同),
通式表示d体、1体或d1体。
4.权利要求1所述的增强剂,上述前列腺素I衍生物为贝雷普罗或药理学允许的盐或酯。
5.权利要求1至4中任意一项记载的增强剂,上述肾素-血管紧张素系统抑制物质为ACE抑制剂。
6.权利要求5记载的增强剂,上述ACE抑制剂选自依那普利、阿拉普利、地拉普利、雷米普利、卡托普利、赖诺普利、贝那普利、赖苯普利、喹普利拉、咪唑普利、佐芬普利、福辛普列钠、西拉普利、替莫普利、螺普利、哌道普利、莫昔普利、群哚普利、西罗普利、乌替普利、omapatrilat、山帕曲拉以及各化合物的药理学上允许的盐。
7.权利要求1至4中任意一项记载的增强剂,上述肾素-血管紧张素系统抑制物质为具有血管紧张素II受体拮抗作用的化合物。
8.权利要求7中记载的增强剂,上述具有血管紧张素II受体拮抗作用的化合物选自氯沙坦、依普沙坦、坎地沙坦酯、缬沙坦、替米沙坦、厄贝沙坦、他索沙坦、奥美沙坦酯、EXP-3174、佐拉沙坦、沙普立沙坦、依利沙坦钾、利匹沙坦、milfasartan、福拉沙坦、恩布沙坦、フオンサルタン、E4177、YM358、ICI-D8731、TAK536、CL329167、泊来沙坦、坎地沙坦以及各化合物的药理学允许的盐。
9.权利要求8中记载的增强剂,上述具有血管紧张素II受体拮抗作用的化合物为选自氯沙坦、依普沙坦、坎地沙坦酯、缬沙坦、替米沙坦、厄贝沙坦、他索沙坦、奥美沙坦酯、EXP-3174、佐拉沙坦、沙普立沙坦、恩布沙坦、坎地沙坦以及各化合物的药理学上允许的盐。
10.权利要求1至9中任意一项记载的增强剂,肾病为糖尿病性肾病、肾小球肾炎、间质性肾炎、急性肾衰竭、慢性肾衰竭。
11.权利要求9中记载的增强剂,肾病为慢性肾衰竭。
12.权利要求1至11中任意一项记载的增强剂,其增强患肾病时通过施用肾素-血管紧张素系统抑制剂而产生的血清肌酸酐的经时上升抑制效果。
13.权利要求1至11中任意一项记载的增强剂,其增强通过施用肾素-血管紧张系统抑制剂产生的血清肌酸酐的倒数的经时下降抑制效果。
14.权利要求1至11中任意一项记载的增强剂,其增强患肾病时通过施用肾素-血管紧张素系统抑制剂产生的肾小球滤过率的经时下降抑制效果。
15.肾病治疗或预防剂,其含有权利要求1至14中任意一项记载的增强剂,和肾素-血管紧张素系统抑制剂作为有效成分。
16.肾病治疗或预防用试剂盒,其分别含有权利要求1至14中任意一项记载的增强剂,和包含肾素-血管紧张素系统抑制剂作为有效成分的药物,用于同时或错开时间施用上述增强剂与肾素-血管紧张素系统抑制剂。
17.肾素-血管紧张素系统抑制剂的肾病治疗或预防效果增强方法,包括给施用肾素-血管紧张素系统抑制剂的患者施用权利要求1至14中任意一项记载的增强剂。
18.肾病的治疗或预防方法,包括施用权利要求15或16中记载的肾病治疗或预防剂、或肾病治疗或预防用试剂盒中含有的药物。
19.权利要求1至4中任意一项记载的前列腺素I衍生物在制备肾素-血管紧张素系统抑制剂的肾病治疗或预防效果增强剂中的用途。
20.权利要求19中记载的用途,上述增强剂为权利要求5至14中任意一项记载的增强剂。
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CN (2) | CN100477995C (zh) |
CA (1) | CA2529351C (zh) |
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WO2007007668A1 (ja) * | 2005-07-08 | 2007-01-18 | Toray Industries, Inc. | 尿毒症改善のための治療剤および処置方法 |
BR112012011237A2 (pt) * | 2009-11-13 | 2019-09-24 | Univ Tokyo | agente terapêutico e profilático para diabetes |
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US4472384A (en) | 1983-06-15 | 1984-09-18 | Merck & Co., Inc. | Antihypertensive composition |
JPH04334358A (ja) | 1991-05-02 | 1992-11-20 | Ono Pharmaceut Co Ltd | 縮合ベンゼンオキシ酢酸誘導体 |
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CA2137832C (en) | 1992-06-12 | 2000-09-26 | Dennis J. Hoover | Inhibitors of angiotensin i chymase(s) including human heart chymase |
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TW282456B (zh) * | 1994-03-10 | 1996-08-01 | Fujisawa Yakusin Kogyo Kk | |
WO1996004248A1 (fr) | 1994-07-29 | 1996-02-15 | Suntory Limited | Derives d'imidazolidine et son utilisation |
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Publication number | Publication date |
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CN101439039B (zh) | 2012-06-13 |
WO2004098611A1 (ja) | 2004-11-18 |
KR101187693B1 (ko) | 2012-10-05 |
US20170080089A1 (en) | 2017-03-23 |
JP4702054B2 (ja) | 2011-06-15 |
CA2529351C (en) | 2012-04-17 |
CN101439039A (zh) | 2009-05-27 |
CA2529351A1 (en) | 2004-11-18 |
EP1627638A1 (en) | 2006-02-22 |
JPWO2004098611A1 (ja) | 2006-07-13 |
US10149909B2 (en) | 2018-12-11 |
KR20060003083A (ko) | 2006-01-09 |
EP1627638A4 (en) | 2011-08-24 |
US20060217421A1 (en) | 2006-09-28 |
US20090176848A1 (en) | 2009-07-09 |
CN100477995C (zh) | 2009-04-15 |
US9546145B2 (en) | 2017-01-17 |
EP1627638B1 (en) | 2017-07-12 |
ES2636943T3 (es) | 2017-10-10 |
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