HRP20050860A2 - New medicament - Google Patents
New medicament Download PDFInfo
- Publication number
- HRP20050860A2 HRP20050860A2 HR20050860A HRP20050860A HRP20050860A2 HR P20050860 A2 HRP20050860 A2 HR P20050860A2 HR 20050860 A HR20050860 A HR 20050860A HR P20050860 A HRP20050860 A HR P20050860A HR P20050860 A2 HRP20050860 A2 HR P20050860A2
- Authority
- HR
- Croatia
- Prior art keywords
- methoxy
- compound
- formula
- zero
- inhibitor
- Prior art date
Links
- 239000003814 drug Substances 0.000 title claims description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 34
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims abstract description 19
- 208000033679 diabetic kidney disease Diseases 0.000 claims abstract description 19
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims abstract description 8
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 7
- 239000000460 chlorine Substances 0.000 claims abstract description 6
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 6
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims abstract 5
- 201000001474 proteinuria Diseases 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 12
- 229940079593 drug Drugs 0.000 claims description 7
- 239000003112 inhibitor Substances 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 229940044551 receptor antagonist Drugs 0.000 claims description 7
- 239000002464 receptor antagonist Substances 0.000 claims description 7
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 6
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 claims description 6
- 102000003979 Mineralocorticoid Receptors Human genes 0.000 claims description 6
- 108090000375 Mineralocorticoid Receptors Proteins 0.000 claims description 6
- 229960002897 heparin Drugs 0.000 claims description 6
- 229920000669 heparin Polymers 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 239000002461 renin inhibitor Substances 0.000 claims description 6
- 229940086526 renin-inhibitors Drugs 0.000 claims description 6
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 5
- 239000003288 aldose reductase inhibitor Substances 0.000 claims description 5
- 108010057863 heparin receptor Proteins 0.000 claims description 5
- 229940118148 Aldose reductase inhibitor Drugs 0.000 claims description 4
- XYDHSCZUHCZWHJ-UHFFFAOYSA-N 5-methylpyridine-2-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)N=C1 XYDHSCZUHCZWHJ-UHFFFAOYSA-N 0.000 claims description 3
- YBWLTKFZAOSWSM-UHFFFAOYSA-N n-[6-methoxy-5-(2-methoxyphenoxy)-2-pyridin-4-ylpyrimidin-4-yl]-5-methylpyridine-2-sulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=CN=CC=2)OC)=C1NS(=O)(=O)C1=CC=C(C)C=N1 YBWLTKFZAOSWSM-UHFFFAOYSA-N 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 241000124008 Mammalia Species 0.000 claims description 2
- 241001465754 Metazoa Species 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 2
- 229940123866 Protein kinase C beta inhibitor Drugs 0.000 claims 2
- 125000003342 alkenyl group Chemical group 0.000 claims 1
- 125000000335 thiazolyl group Chemical group 0.000 abstract 1
- 229940125364 angiotensin receptor blocker Drugs 0.000 description 12
- 229940126062 Compound A Drugs 0.000 description 10
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 10
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 208000017169 kidney disease Diseases 0.000 description 5
- 239000000902 placebo Substances 0.000 description 5
- 229940068196 placebo Drugs 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 5
- -1 2-thiazolyl Chemical group 0.000 description 4
- 239000007903 gelatin capsule Substances 0.000 description 4
- 229920005862 polyol Polymers 0.000 description 4
- 150000003077 polyols Chemical class 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- 239000002083 C09CA01 - Losartan Substances 0.000 description 3
- 239000002947 C09CA04 - Irbesartan Substances 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 3
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 3
- 208000020832 chronic kidney disease Diseases 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 239000008298 dragée Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 208000028208 end stage renal disease Diseases 0.000 description 3
- 201000000523 end stage renal failure Diseases 0.000 description 3
- 229960002198 irbesartan Drugs 0.000 description 3
- 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 description 3
- 239000008101 lactose Substances 0.000 description 3
- 229960004773 losartan Drugs 0.000 description 3
- 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 description 3
- 239000000203 mixture Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 230000006269 (delayed) early viral mRNA transcription Effects 0.000 description 2
- 206010001580 Albuminuria Diseases 0.000 description 2
- 239000004072 C09CA03 - Valsartan Substances 0.000 description 2
- 239000002053 C09CA06 - Candesartan Substances 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229940123924 Protein kinase C inhibitor Drugs 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 229960000932 candesartan Drugs 0.000 description 2
- SGZAIDDFHDDFJU-UHFFFAOYSA-N candesartan Chemical compound CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SGZAIDDFHDDFJU-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 239000003925 fat Substances 0.000 description 2
- 230000024924 glomerular filtration Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000003881 protein kinase C inhibitor Substances 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- NHZMQXZHNVQTQA-UHFFFAOYSA-N pyridoxamine Chemical compound CC1=NC=C(CO)C(CN)=C1O NHZMQXZHNVQTQA-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 229960004699 valsartan Drugs 0.000 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 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 239000001993 wax Substances 0.000 description 2
- KSZFSNZOGAXEGH-SCSAIBSYSA-N (2r)-5-amino-2-(methylamino)-5-oxopentanoic acid Chemical class CN[C@@H](C(O)=O)CCC(N)=O KSZFSNZOGAXEGH-SCSAIBSYSA-N 0.000 description 1
- GRYSXUXXBDSYRT-WOUKDFQISA-N (2r,3r,4r,5r)-2-(hydroxymethyl)-4-methoxy-5-[6-(methylamino)purin-9-yl]oxolan-3-ol Chemical compound C1=NC=2C(NC)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1OC GRYSXUXXBDSYRT-WOUKDFQISA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 101710175516 14 kDa zinc-binding protein Proteins 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- UXOWGYHJODZGMF-QORCZRPOSA-N Aliskiren Chemical compound COCCCOC1=CC(C[C@@H](C[C@H](N)[C@@H](O)C[C@@H](C(C)C)C(=O)NCC(C)(C)C(N)=O)C(C)C)=CC=C1OC UXOWGYHJODZGMF-QORCZRPOSA-N 0.000 description 1
- 102000008873 Angiotensin II receptor Human genes 0.000 description 1
- 108050000824 Angiotensin II receptor Proteins 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 239000002080 C09CA02 - Eprosartan Substances 0.000 description 1
- 239000002081 C09CA05 - Tasosartan Substances 0.000 description 1
- 239000005537 C09CA07 - Telmisartan Substances 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 102000010180 Endothelin receptor Human genes 0.000 description 1
- 108050001739 Endothelin receptor Proteins 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 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 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 102000005741 Metalloproteases Human genes 0.000 description 1
- 108010006035 Metalloproteases Proteins 0.000 description 1
- 206010027525 Microalbuminuria Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000005480 Olmesartan Substances 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 229920000439 Sulodexide Polymers 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
- 102000012327 Urotensin II receptors Human genes 0.000 description 1
- 108050002984 Urotensin II receptors Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- MKOMESMZHZNBIZ-UHFFFAOYSA-M alagebrium Chemical compound [Cl-].CC1=C(C)SC=[N+]1CC(=O)C1=CC=CC=C1 MKOMESMZHZNBIZ-UHFFFAOYSA-M 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229940090865 aldose reductase inhibitors used in diabetes Drugs 0.000 description 1
- 229960004601 aliskiren Drugs 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 239000004004 anti-anginal agent Substances 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 description 1
- 229960004676 antithrombotic agent Drugs 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 1
- 229960000830 captopril Drugs 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 229960001208 eplerenone Drugs 0.000 description 1
- JUKPWJGBANNWMW-VWBFHTRKSA-N eplerenone Chemical compound C([C@@H]1[C@]2(C)C[C@H]3O[C@]33[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)C(=O)OC)C[C@@]21CCC(=O)O1 JUKPWJGBANNWMW-VWBFHTRKSA-N 0.000 description 1
- 229960004563 eprosartan Drugs 0.000 description 1
- 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 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 235000021472 generally recognized as safe Nutrition 0.000 description 1
- 230000001434 glomerular Effects 0.000 description 1
- 231100000853 glomerular lesion Toxicity 0.000 description 1
- 206010061989 glomerulosclerosis Diseases 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000000004 hemodynamic effect Effects 0.000 description 1
- 230000003345 hyperglycaemic effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000008011 inorganic excipient Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229960004903 invert sugar Drugs 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
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 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
- 239000011976 maleic acid Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004660 morphological change Effects 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 229960005117 olmesartan Drugs 0.000 description 1
- VTRAEEWXHOVJFV-UHFFFAOYSA-N olmesartan Chemical compound CCCC1=NC(C(C)(C)O)=C(C(O)=O)N1CC1=CC=C(C=2C(=CC=CC=2)C=2NN=NN=2)C=C1 VTRAEEWXHOVJFV-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000008012 organic excipient Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000001991 pathophysiological effect Effects 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000003909 protein kinase inhibitor Substances 0.000 description 1
- 229940076155 protein modulator Drugs 0.000 description 1
- 108010056599 proteinase C Proteins 0.000 description 1
- 235000008151 pyridoxamine Nutrition 0.000 description 1
- 239000011699 pyridoxamine Substances 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 230000008085 renal dysfunction Effects 0.000 description 1
- 230000036454 renin-angiotensin system Effects 0.000 description 1
- 230000001084 renoprotective effect Effects 0.000 description 1
- ZCBUQCWBWNUWSU-SFHVURJKSA-N ruboxistaurin Chemical compound O=C1NC(=O)C2=C1C(C1=CC=CC=C11)=CN1CCO[C@H](CN(C)C)CCN1C3=CC=CC=C3C2=C1 ZCBUQCWBWNUWSU-SFHVURJKSA-N 0.000 description 1
- 229950000261 ruboxistaurin Drugs 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229960002256 spironolactone Drugs 0.000 description 1
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 229960003491 sulodexide Drugs 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960000651 tasosartan Drugs 0.000 description 1
- 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 description 1
- 229960005187 telmisartan 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
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 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
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 230000008728 vascular permeability Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Epidemiology (AREA)
- Urology & Nephrology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Saccharide Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Description
Predmetni izum odnosi se na novi lijek/metodu koji uključuje upotrebu specifičnih piridilsulfonamido pirimidina, za liječenje dijabetske nefropatije.
Dijabetska nefropatija je prouzročena zadnjim stadijem renalnog oboljenja u zapadnom svijetu. To je najčešći uzrok oboljenja i smrtnosti kod dijabetesa Tipa-I, ali u porastu je i problem s dijabetesom Tipa-II i budući da je pojavljivanje ovoga pet puta veće nego dijabetesa Tipa-I, to pridonosi porastu broja dijabetičara sa zadnjim stadijem renalnog oboljenja barem 50%.
Početni stadij promjena morfologije u renalnim glomerulima praćen je mikroalbuminuriom. To je popraćeno umjerenim porastom krvnog tlaka i češćim pojavljivanjem kardiovaskularnih oboljenja. Slijedi kontinuirani porast izlučivanja proteina u urin i opada udio glomularne filtracije. Dijabetska nefropatija može imati više patofizioloških uzroka uključujući metaboličke, glikozilaciju proteina, hemodinamiku, promjenu toka/tlaka u glomeruli, razvoj hipertenzije i proizvodnje cikotina; sve ovo je povezano sa razvojem posebnog staničnog matriksa i povećanjem vaskularnog permeabiliteta koji vodi do glomerularnog oštećenja i proteinurie.
Brojne publikacije osiguravaju dokaze za predvidive vrijednosti proteinurie kao jednog najvažnijeg faktora za predviđanje napredovanja renalne disfunkcije i posebno dijabetske nefropatije; W.F. Keane et al., Proteinuria, Albuminuria, Risk, Assessment, Detection, Elimination (PARADE) :A Position paper of the National Kidney Foundation, American J. of Kidney Diseases, Vol.33, May 1999, pp 1004-1010. K tomu pokazalo se da perzistentna proteinuria ili albuminuria indiciraju porast rizika za akutne koronarne promjene i za moždani udar. Studijska istraživanja losartana i irbesartana (pripadaju razredu blokera receptora angiotenzina) pokazuju opadanje u korelaciji proteinurie sa redukcijom u početku zadnjeg stadija renalnog oboljenja ali bez promjene u smrtnosti; M. Brenner et al. Effects of losartan on renal end cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J med 2002; 345:861-869 and E.J. Lewis et al. Renoprotective effect of the angiotensin-receptor irbesartan in patients with nephropathy due to type 2 diabetes. N Engl. J. Med 2001; 345; 851-860. Tako, ovdje se priznaje da se još nije potpuno udovoljilo medicinskim potrebama za kontrolu ili snižavanje proteinurie, i smanjenje omjera smrtnosti i učestalosti zadnjeg stadija renalnog oboljenja, i posebno k tome postojanja liječenja.
Predmetni izum odnosi se na spojeve formule (I)
[image]
gdje R� je piridil ili tiazol, bilo koji po izboru može biti supstituiran sa C1-8alkilom ili C2-8alkenilom; i
a) R2 je metoksi i n je nula ili jedan; ili
b) R 2 je klor i n je nula
i njihove farmaceutski prihvatljive soli,
koji iznenađujuće pokazuje značajno smanjenje efekta proteinurie, posebno kod davanja bolesniku sa dijabetesom Tipa-II.
Predmetni izum odnosi se na upotrebu spoja formule (I) za proizvodnju lijeka za snižavanje ili kontroliranje proteinurie, posebno za liječenje dijabetske nefropatije, bio oboljeli od Tipa-I ili Tipa-II dijabetesa.
Nadalje, predmetni izum odnosi se na postupak liječenja dijabetske nefropatije, koja uključuje za liječenje dijabetske nefropatije davanje djelotvorne količine spoja formule (I) ljudskom biću ili životinjskom sisavcu.
Izraz «postupak liječenja« kao što je korišten u opisu izuma podrazumjeva također uključivanje «prevencije«i« odgađanja napredovanja«. Posebno izraz «postupak liječenja« uključuje snižavanje stope smrtnosti.
Sulfonamidi iz predmetnog izuma poznati su kao inhibitori receptora endotelina a postupak pripravljanja razotkriven je u WO 00/52007.
Posebno, predmetni izum odnosi se na slijedeće spojeve formule (I):
R� je poželjno, po izboru supstituiran sa C1-8 alkilom ili C2-8 alkenilom, 2-piridilom, ili 2-tiazolilom i najbolje, po izboru supstituiran sa C1-8 alkilom ili C2-8 alkenilom, 2-piridilom.
C1-8 alkil ili C2-8 alkenil su razgranati ili ravnolančani radikali, na primjer metil, etil, n-propil, izopropil, n-butil, izobutil, t-butil, vinil, 1-propenil, alkil, izopropenil, 1-butenil, 2-butenil, 3-butenil i slično. Poželjni su rečeni ostaci koji imaju do (i uključivo) četiri atoma ugljika. Najpoželjniji je metil.
Posebno poželjni su spojevi formule (I) gdje
R� je 2-piridil po izboru supstituiran sa C1-4 alkilom; i
R2 je metoksi i n je nula
I njihove farmaceutski prihvatljive soli.
Najpoželjniji je 5-metil-piridin-2-sulfonska kiselina [6-metoksi-5-(2-metoksi-fenoksi)-2-piridin-4-il-pirimidin-4-il]-amid.
Izraz farmaceutski prihvatljive soli « sadrži soli spojeva formule (I) sa anorganskim ili organskim kiselinama kao što je hidrokloridna kiselina, hidrobromidna kiselina, dušična kiselina, sumporna kiselina, fosforna kiselina, limunska kiselina, mravlja kiselina, maleinska kiselina, octena kiselina, octena kiselina, sukcinska kiselina, tartarna kiselina, metansulfonska kiselina, p-toluenska kiselina i slične, koje nisu otrovne za žive organizme. To također uključuje soli sa anorganskim i organskim bazama kao što su alkalne soli poput natrijevih i kalijevih soli, soli zemnoalkalnih metala poput kalcijevih i magnezijevih soli, N-metil-D-glutamin soli i soli sa amino kiselinama poput arginina, lizina i sličnih.
Smatrat će se vrijednim to što spojevi formule (I) iz ovog izuma reakcijom na funkcionalnim skupinama osiguravaju derivate prolijekova koji su sposobni konvertirati natrag u izvorne spojeve in vivo. Dodatno, bilo koji fiziološki prihvatljiv ekvivalent spojeva opće formule (I), koji je sposoban proizvesti početne spojeve opće formule (I) in vivo, je unutar opsega ovog izuma.
Kao što je ranije spomenuto, upotreba spoja formule (I) za proizvodnju lijeka za liječenje dijabetske nefropatije je cilj ovog izuma, proizvodnja koja uključuje dovođenje jednog ili više spojeva formule (I) i ako je poželjno jedne ili više drugih farmaceutski vrijednih supstanci u oblik za farmaceutsko davanje.
Farmaceutski pripravci mogu se davati oralno, na primjer u obliku tableta, presvučenih tableta, dražeja, tvrdih ili mekih želatinskih kapsula, otopina, emulzija ili suspenzija. Davanje također može biti rektalno, na primjer korištenjem mekanih preparata, krema, gelova ili otopina ili parenteralno, na pr. intravenozno, intramuskularno, subkutano, intratekalno ili transdermalno, koristeći na primjer injektibilne otopine. Nadalje, davanje se može izvoditi sublingvalno ili kao oftalmološki preparat ili kao aerosol, na primjer u obliku spreja.
Za pripremu tableta, presvučenih tableta, dražeja ili tvrdih želatinskih kapsula, spojevi iz predmetnog izuma mogu se miješati sa farmaceutski inertnim, anorganskim ili organskim ekscipijensima. Primjeri prikladnih ekscipijensa za tablete, dražeje ili tvrde želatinske kapsule uključuju laktoze, kukuruzni škrob ili njihove derivate, talk ili stearinsku kiselinu ili soli istih.
Prikladni ekscipijensi za upotrebu u mekim želatinskim kapsulama mogu uključivati na primjer biljna ulja, voskove, masti, polukrute ili tekuće poliole itd.
Za pripremu otopina i sirupa, ekscipijensi koji mogu biti upotrebljeni uklučuju na primjer vodu, poliole, saharozu invertni šećer i glukozu.
Ekscipijensi koji se mogu koristiti za injektibilne otopine, uključuju na primjer vodu, alkohole, poliole, glicerin i biljna ulja.
Ekscipijensi koji se mogu koristiti za čepiće i lokalnu ili perkutanu primjenu, uključuju na primjer prirodna ulja, voskove, masti i polutvrde ili tekuće poliole.
Slijedeći primjeri ilustriraju moguće oblike za davanje:
Tablete koje sadrže slijedeće sastojke mogu se proizvesti na konvencioalan način:
Sastav mg po tableti
Spoj formule (I) 10.0-100.0
Laktoza 125.0
Kukuruzni škrob 75.0
Talk 4.0
Magnezij stearat 1.0
Kapsule koje sadrže slijedeće sastojke mogu se proizvesti na konvencioalan način:
Sastav mg po kapsuli
Spoj formule (I) 25.0
Laktoza 150.0
Kukuruzni škrob 20.0
Talk 5.0
Otopine za injekcije imaju slijedeći sastav:
Spoj formule (I) 1.0 mg
Natrijev klorid 8.5 mg
Tri (hidroksimetil) aminometan 0.5 mg
0.1N HCl ad pH 8
Voda za injekciju ad 1.0 ml
Farmaceutski pripravci također mogu sadržavati tvari za konzerviranje, za otapanje, stabilizatore, tvari za kvašenje, emulgatore, zaslađivače, boje, mirise, soli za mijenjanje osmotskog tlaka, pufere, tvari za prevlačenje ili antioksidanse.
Kao što je ranije spomenuto, oni mogu sadržavati i druge terapeurski vrijedne tvari.
Preduvjet je da svi adjuvanti korišteni u proizvodnji pripravaka su općenito priznati kao sigurni.
Poželjni oblici za davanje su intravenozni, intramuskularni ili oralni, a najpoželjnije je oralno davanje. Doze u kojima se daju učinkovite količine spoja formule (I) ovise o prirodi specifičnog aktivnog sastojka, dobi i zahtjevima pacijenta i obliku primjene. Općenito, u razmatranje ulaze doze od oko 0.01-10 mg/kg tjelesne težine na dan.
Također se spojevi formule (I) smiju davati u kombinaciji sa lijekovima za visoki tlak, antiaritmiju, anti anginalnim lijekovima, inhibitorima proteinkinaza i/ili modulatorima, antagonistima receptora urotensina II, lijekovima koji djeluju na proteine kao fibrinogen i matriks metaloproteaza, antitromboticima, tvarima za snižavanj lipida, antioksidansima i poželjno, s bilo kojim lijekovima koji djeluju renin-angiotenzin sustav kao što su inhibitori konverzije angiotenzin enzima (ACEIs; kakav je kaptopril i benzaperil), renin inhibitore (kakav je aliskiren), inhibitore reduktaze aldoze (kakav je AS-3201), inhibitore beta-proteinkinaze C (kakav je ruboksistaurin), AGE crosslink breakers/inhibitori (kao što je piridoksamin ili ALT-711) molekulski tip heparina (kao što je sulodeksid), antagonisti receptora aldosterona (kao što je eplerenon ili spironolakton) i, posebno poželjni receptor blokeri angiotenzina (ARBs). Primjeri ARBs-a su, među ostalima, eprosartan, olmesartan, tasosartan, telmisartan, irbesartan, valsartan, candesartan i losartanb. Rečeni ARBs mogu se upotrijebiti u visokim dozama u slučajevima u kojima visoke doze odgovaraju do 300 mg od irbesartina, 160 mg od valsartina, 32 mg od kandesartana ili 50 mg bid losartana.
Za gornje spojeve koji se mogu davati u kombinaciji sa spojem formule (I), prednost se daje komercijalno dostupnim spojevima koji su odobreni prema zakonu o zdravlju.
Prema tome, drugi cilj ovog izuma je postupak liječenja dijabetske nefropatije, koji se sastoji u davanju, pri liječenju dijabetske nefropatije, djelotvornekoličine spoja formule (I) čovjeku ili sisavcu životinje u kombinaciji sa ARB, ACEI, renin inhibitorom, inhibitorom reduktaze aldoze, beta-inhibitorom proteinkinaze C, AGE crosslink breaker/inhibitorom, heparinom molekulskog tipa ili antagonistom receptora aldosterona. Poželjno, kombinacija se može davati istodobno ili sekvencijalno bilo kojim redom, odvojeno ili u fiksnoj kombinaciji.
Nadalje, cilj ovog izuma je farmaceutski pripravak koji sadrži spoj formule (I), ARB, ACEI, inhibitor renina, inhibitor reduktaze aldoze, beta-inhibitor proteinaze C, AGE crosslinking breaker/inhibitor, molekulski tip heparina ili antagonist receptora aldosterona i neki ekscipijens.
Daljnji cilj izuma je kit za liječenje dijabetske nefropatije koji sadrži :
a) količinu spoja formule (I) u obliku jedinične doze:
b) količinu barem jedne terapeutske tvari odabrane iz skupine koja se sastoji od ARBs, ACEIs, inhibitora renina, molekulskog tipa heparina i antagonista receptora aldosterona u drugom etc. obliku jedinične doze; i
c) kontejnera koji sadrži rečene prvi, drugi etc. oblike jediničnih doza.
Učinkovitost spojeva formule (I) na smanjenje ili kontroliranje proteinurie i naročito na dijabetsku nefropatiju može se pokazati korištenjem životinjskih modela, poznatim stručnjacima u području, ili postupkom opisanim iza ovoga u primjeru izvođenja.
Tako, na primjer, kratko i dugo trajanje učinka spojeva formule (I) na razvoj glomeluralnih lezija, može se odrediti poslije davanja pokusnog spoja miševima sa hiperglikemijskim dijabetesomm. Korišteni postupak analogan je postupku pokusa opisanom u J: Am. Nephrol. 1993, 4 : 40-49. Terapeutski učinak je prisutan, na primjer, kada je spriječen porast glomerularne filtracije kod takvih dijabetičnih štakora, i onemogućeni proteinuria i glomeruloskleroza.
Smatrat će se vrijednim ako reduciranje proteinuria, posebno u slučaju gdje je proteinuria već reducirana zbog postojećeg davanja lijekova, bi rezultiralo smanjenjem učestalosti zadnjeg stadija renalnog oboljenja i smanjenjem mortaliteta u štakora. Primjer ilustrira predmetni izum i ni na koji način ga ne ograničava specifičnim načinom ostvarivanja.
Primjer:
Istpitivanje uključuje 23 pacijenta sa dijabetskom nefropatijom. Ispitivanje je vođeno prema kliničkom postupku (double-blind) koji uključuje pacijente koji su dobivali lijek i placebo kontrolom. Svi pacijenti su bili tretirani sa visokom dozom blokera receptora angiotenzina (ARBs) u periodu od 4 tjedna prije početka tretiranj sa 5-metil-piridin-2-sulfonska kiselina[6-metoksi-5-(2-metoksi-fenoksi)-2-piridin-4-il-pirimidin-il]-amida (spoj A). Pacijenti su uključeni, ako je na kraju 4-ero tjednog tretmana sa visokom dozom ARBs, njihova 24-satna proteinuria bila veća od 300 mg/24 h. Oni koji su dobivali lijek razdvojeni su u tri skupine: 20 mg spoja A, 50 mg spoja A ili placebo jednom dnevno na najvišu dozu ARB. Tretman je trajao 4 tjedna. Primarna varijabla bila je 24-satna proteinuria.
Od 23 pacijenta koja su sudjelovala u ispitivanju, 7 je dobivalo 20 mg spoja A, 8 je dobivalo 50 mg spoja A i 8 je dobivalo placebo. Prosječna dob (± SD) je bila slična za sve tri skupine. HbA1c razina na početku je također bila slična za sve tri skupine.
Djelotvornost
Podaci o 24-satnoj proteinurii pokazuju da je za individualne skupine opadanje u proteinurii bilo -1.0 ± 1.96 g/24 h sa 20 mg spoja A i -1.3 ± 1.3 g /24 h sa 50 mg spoja A. Kod placebo skupine se pokazao porast u proteinurii od 0.5 ± 1.78 g/24 h. Premda je bilo razlike u 24-satnoj proteinurii na početku tretmana spojem A između tri skupine, za razliku od placebo skupine, 2 skupine tretirane spojem A pokazale su opadanje u 24-satnoj proteinurii od oko 1 g/24 h što je klinički svrsishodno.
Spoj A korišten u gornjem primjeru odgovara 5-metil-piridin-2-sulfonska kiselina[6-metoksi-5-(2-metoksi-fenoksi )-2-piridin-4-il-pirimidin-il]-amidu.
Claims (7)
1. Upotreba spoja formule (I)
[image]
gdje R� je piridil ili tiazol, od kojih bilo koji može biti supstituiran sa C1-8 alkilom ili C2-8 alkenilom; i
a) R2 je metoksi i n je nula ili jedan; ili
b) R2 je klor i n je nula
i njihovih farmaceutskih soli, naznačena time, da je za proizvodnju lijeka za snižavanje ili kontroliranje proteinurie, posebno za liječenje dijabetske nefropatije.
2. Upotreba prema zahtjevu 1, naznačena time, spoj formule (I) je 5-metil-piridin-2-sulfonska kiselina[6-metoksi-5-(2-metoksi-fenoksi)-2-piridin-4-il-pirimidin-il]-amid.
3. Metoda liječenja dijabetske nefropatije, naznačena time, da se sastoji od davanja kod tretiranja dijabetske nefropatije učinkovite količine spoja formule (I)
[image]
gdje R1 je piridil ili tiazol, od kojih bilo koji može biti supstituiran sa C1-8 alkilom ili C2-8 alkenilom; i
a) R2 je metoksi i n je nula ili jedan; ili
b) R2 je klor i n je nula
i njihovih farmaceutskih soli ljudskom biću ili sisavcu životinja.
4. Metoda liječenja dijabetske nefropatije, naznačena time, da se sastoji od davanja kod tretiranja dijabetske nefropatije učinkovite količine spoja formule (I)
[image]
gdje R� je piridil ili tiazol, od kojih bilo koji može biti supstituiran sa C1-8 alkilom ili C2-8 alkenilom; i
c) R2 je metoksi i n je nula ili jedan; ili
d) R2 je klor i n je nula
i njihovih farmaceutskih soli ljudskom biću ili sisavcu životinja u kombinaciji sa ARB, ACEI, inhibitorom renina, inhibitorom reduktaze aldoze, beta-inhibitorom proteinkinaze C, AGE crosslink breaker/inhibitorom, heparinom molekulskog tipa ili antagonistom receptora aldosterona.
5. Metoda liječenja prema zahtjevu 3 ili 4, naznačena time, da spoj formule (I) je 5-metil-piridin-2-sulfonska kiselina[6-metoksi-5-(2-metoksi-fenoksi)-2-piridin-4-il-pirimidin-il]-amid.
6. Farmaceutski pripravak, naznačen time, da sadrži
A) Spoj formule (I)
[image]
gdje R� je piridil ili tiazol, od kojih bilo koji može biti supstituiran sa C1-8 alkilom ili C2-8 alkenilom; i
a) R2je metoksi i n je nula ili jedan; ili
e) R2 je klor i n je nula
i njihovih farmaceutskih soli
B) ARB, ACEI, inhibitor renina, inhibitor reduktaze aldoze, beta-inhibitor proteinkinaze C, AGE cross breaker/inhibitor, molekulski tip heparina ili antagonist receptora aldosterona i
C) ekscipijens.
7. Farmaceutski sastav prema zahtjevu 6, naznačen time, da spoj formule (I) je 5-metil-piridin-2-sulfonska kiselina[6-metoksi-5-( 2-metoksi-fenoksi )-2-piridin-4-il-pirimidin-il ]-amid.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP03100549A EP1454625A1 (en) | 2003-03-06 | 2003-03-06 | Pyridylsulfonamidyl-pyrimidines for the treatment of diabetic nephropathies |
| PCT/EP2004/050242 WO2004078104A2 (en) | 2003-03-06 | 2004-03-03 | Pyridylsulfonamido pyrimidines for treating diabetic nephropathy |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP20050860A2 true HRP20050860A2 (en) | 2005-10-31 |
Family
ID=32799012
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HR20050860A HRP20050860A2 (en) | 2003-03-06 | 2005-09-28 | New medicament |
Country Status (27)
| Country | Link |
|---|---|
| US (2) | US20060094731A1 (hr) |
| EP (2) | EP1454625A1 (hr) |
| JP (1) | JP4737686B2 (hr) |
| KR (1) | KR101099189B1 (hr) |
| CN (1) | CN100453081C (hr) |
| AT (1) | ATE395063T1 (hr) |
| AU (2) | AU2004216858B2 (hr) |
| BR (1) | BRPI0408082A (hr) |
| CA (1) | CA2517930C (hr) |
| CY (1) | CY1108241T1 (hr) |
| DE (1) | DE602004013734D1 (hr) |
| DK (1) | DK1601361T3 (hr) |
| EC (1) | ECSP056060A (hr) |
| ES (1) | ES2305737T3 (hr) |
| HK (1) | HK1083761A1 (hr) |
| HR (1) | HRP20050860A2 (hr) |
| IL (1) | IL170626A (hr) |
| MX (1) | MXPA05009478A (hr) |
| NO (1) | NO20054148L (hr) |
| NZ (1) | NZ542155A (hr) |
| PL (1) | PL1601361T3 (hr) |
| PT (1) | PT1601361E (hr) |
| RS (1) | RS20050683A (hr) |
| SI (1) | SI1601361T1 (hr) |
| UA (1) | UA82087C2 (hr) |
| WO (1) | WO2004078104A2 (hr) |
| ZA (1) | ZA200507122B (hr) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1595880A1 (en) * | 2004-05-13 | 2005-11-16 | Speedel Pharma AG | Crystalline forms of a pyridinyl-sulfonamide and their use as endothelin receptor antagonists |
| BRPI0615794A2 (pt) * | 2005-09-12 | 2011-05-24 | Speedel Pharma Ag | piridilsulfonamidil-pirimidinas para a prevenção de falha de enxerto de vaso sangüìneo |
| JP2012020995A (ja) | 2010-06-17 | 2012-02-02 | Nitto Denko Corp | 腎線維症処置剤 |
| CN109260164A (zh) * | 2018-10-07 | 2019-01-25 | 威海贯标信息科技有限公司 | 一种阿伏生坦片剂组合物 |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH09510225A (ja) * | 1994-03-17 | 1997-10-14 | チバ−ガイギー アクチェンゲゼルシャフト | バルサルタンを用いる糖尿病性ネフロパシーの治療 |
| CA2162630C (en) * | 1994-11-25 | 2007-05-01 | Volker Breu | Sulfonamides |
| DE69626986T2 (de) * | 1995-08-02 | 2004-02-05 | Smithkline Beecham Corp. | Endothelinrezeptorantagonist |
| US6417360B1 (en) * | 1999-03-03 | 2002-07-09 | Hoffmann-La Roche Inc. | Heterocyclic sulfonamides |
| WO2001081335A1 (en) * | 2000-04-20 | 2001-11-01 | Actelion Pharmaceuticals Ltd | Pyrimidine-sulfonamides having endothelin-antagonist activity |
-
2003
- 2003-03-06 EP EP03100549A patent/EP1454625A1/en not_active Withdrawn
-
2004
- 2004-03-03 DE DE602004013734T patent/DE602004013734D1/de not_active Expired - Lifetime
- 2004-03-03 WO PCT/EP2004/050242 patent/WO2004078104A2/en active IP Right Grant
- 2004-03-03 UA UAA200509348A patent/UA82087C2/uk unknown
- 2004-03-03 CN CNB2004800058469A patent/CN100453081C/zh not_active Expired - Fee Related
- 2004-03-03 SI SI200430798T patent/SI1601361T1/sl unknown
- 2004-03-03 KR KR1020057016511A patent/KR101099189B1/ko not_active IP Right Cessation
- 2004-03-03 NZ NZ542155A patent/NZ542155A/en not_active IP Right Cessation
- 2004-03-03 PL PL04716605T patent/PL1601361T3/pl unknown
- 2004-03-03 PT PT04716605T patent/PT1601361E/pt unknown
- 2004-03-03 RS YUP-2005/0683A patent/RS20050683A/sr unknown
- 2004-03-03 US US10/548,080 patent/US20060094731A1/en not_active Abandoned
- 2004-03-03 JP JP2006505443A patent/JP4737686B2/ja not_active Expired - Fee Related
- 2004-03-03 BR BRPI0408082-3A patent/BRPI0408082A/pt not_active IP Right Cessation
- 2004-03-03 ES ES04716605T patent/ES2305737T3/es not_active Expired - Lifetime
- 2004-03-03 CA CA2517930A patent/CA2517930C/en not_active Expired - Fee Related
- 2004-03-03 AT AT04716605T patent/ATE395063T1/de active
- 2004-03-03 MX MXPA05009478A patent/MXPA05009478A/es active IP Right Grant
- 2004-03-03 AU AU2004216858A patent/AU2004216858B2/en not_active Ceased
- 2004-03-03 DK DK04716605T patent/DK1601361T3/da active
- 2004-03-03 EP EP04716605A patent/EP1601361B1/en not_active Expired - Lifetime
-
2005
- 2005-09-01 IL IL170626A patent/IL170626A/en not_active IP Right Cessation
- 2005-09-05 ZA ZA200507122A patent/ZA200507122B/en unknown
- 2005-09-06 NO NO20054148A patent/NO20054148L/no not_active Application Discontinuation
- 2005-09-28 HR HR20050860A patent/HRP20050860A2/hr not_active Application Discontinuation
- 2005-09-29 EC EC2005006060A patent/ECSP056060A/es unknown
-
2006
- 2006-03-30 HK HK06103985A patent/HK1083761A1/xx not_active IP Right Cessation
-
2008
- 2008-07-28 US US12/219,751 patent/US20090005404A1/en not_active Abandoned
- 2008-08-06 CY CY20081100825T patent/CY1108241T1/el unknown
-
2009
- 2009-10-14 AU AU2009225323A patent/AU2009225323B2/en not_active Expired - Fee Related
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Gottlieb | Therapeutic options in the treatment of psoriasis and atopic dermatitis | |
| CN101616673A (zh) | 2-[6-(3-氨基-哌啶-1-基)-3-甲基-2,4-二氧代-3,4-二氢-2h-嘧啶-1-基甲基]-4-氟-苄腈的用途 | |
| TW200932249A (en) | Combination therapy comprising SGLT inhibitors and DPP4 inhibitors | |
| AU2024227697A1 (en) | Use of neutrophil elastase inhibitors in liver disease | |
| MX2011000511A (es) | Uso de derivados de pirimidil-amino-benzamida para el tratamiento de fibrosis. | |
| AU751053B2 (en) | Method for combating obesity | |
| Schaier et al. | Isotretinoin alleviates renal damage in rat chronic glomerulonephritis | |
| AU2009225323B2 (en) | Pyridylsulfonamido pyrimidines for treating diabetic nephropathy | |
| Xu et al. | Aprocitentan, a dual endothelin-1 (ET-1) antagonist for treating resistant hypertension: mechanism of action and therapeutic potential | |
| KR20050008773A (ko) | 안사마이신계 항생물질의 신규용도 및 신규혈관신생억제물질의 스크리닝 방법 | |
| Bernardelli et al. | To market, to market-2001 | |
| Calado | Dapagliflozin, an oral sodium glucose cotransporter type 2 inhibitor for the treatment of type 2 diabetes mellitus | |
| AU2020408067B2 (en) | Combination treatment of liver diseases using integrin inhibitors | |
| MX2015005004A (es) | Uso de un compuesto de pirazolo[4,3-d]pirimidina tetrasubstituida para tratar la nefropatia diabetica. | |
| Cole et al. | Dapagliflozin | |
| WO2013016718A1 (en) | Compositions, process of preparation of said compositions and method of treating inflammatory diseases | |
| CZ292946B6 (cs) | Farmaceutický prostředek pro snížení krevního tlaku a léčení městnavého srdečního selhání a použití | |
| JP2011026255A (ja) | 肝炎の治療剤もしくは予防剤 | |
| MXPA96002577A (en) | Treatment of arterioesclerosis and xant |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A1OB | Publication of a patent application | ||
| AIPI | Request for the grant of a patent on the basis of a substantive examination of a patent application | ||
| ODRP | Renewal fee for the maintenance of a patent |
Payment date: 20120229 Year of fee payment: 9 |
|
| OBST | Application withdrawn |