NO311490B1 - Anvendelse av en pyridazinonforbindelse - Google Patents
Anvendelse av en pyridazinonforbindelse Download PDFInfo
- Publication number
- NO311490B1 NO311490B1 NO19963463A NO963463A NO311490B1 NO 311490 B1 NO311490 B1 NO 311490B1 NO 19963463 A NO19963463 A NO 19963463A NO 963463 A NO963463 A NO 963463A NO 311490 B1 NO311490 B1 NO 311490B1
- Authority
- NO
- Norway
- Prior art keywords
- pyridazinone
- txa2
- chlorophenyl
- compound
- bromo
- Prior art date
Links
- -1 pyridazinone compound Chemical class 0.000 title claims abstract description 32
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 7
- 238000011321 prophylaxis Methods 0.000 claims abstract description 7
- 238000011282 treatment Methods 0.000 claims abstract description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 15
- 125000005843 halogen group Chemical group 0.000 claims description 11
- 125000002947 alkylene group Chemical group 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 206010012601 diabetes mellitus Diseases 0.000 claims description 5
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 4
- 208000032131 Diabetic Neuropathies Diseases 0.000 claims description 4
- 208000033679 diabetic kidney disease Diseases 0.000 claims description 4
- 208000006575 hypertriglyceridemia Diseases 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 3
- WRTJKSNOFQWXAW-UHFFFAOYSA-N 5-bromo-3-(2,2-dimethyl-3-phenylpropoxy)-4-(pyridin-3-ylmethylamino)-1h-pyridazin-6-one Chemical compound C=1C=CC=CC=1CC(C)(C)COC1=NNC(=O)C(Br)=C1NCC1=CC=CN=C1 WRTJKSNOFQWXAW-UHFFFAOYSA-N 0.000 claims description 2
- PMLVYXZNSHKMEP-UHFFFAOYSA-N 5-chloro-3-(2,2-dimethyl-3-phenylpropoxy)-4-(pyridin-3-ylmethylamino)-1h-pyridazin-6-one Chemical compound C=1C=CC=CC=1CC(C)(C)COC1=NNC(=O)C(Cl)=C1NCC1=CC=CN=C1 PMLVYXZNSHKMEP-UHFFFAOYSA-N 0.000 claims description 2
- QQPNYUDCLZIZNS-UHFFFAOYSA-N 5-chloro-3-[3-(4-chlorophenyl)propoxy]-4-(pyridin-3-ylmethylamino)-1h-pyridazin-6-one Chemical compound C1=CC(Cl)=CC=C1CCCOC1=NNC(=O)C(Cl)=C1NCC1=CC=CN=C1 QQPNYUDCLZIZNS-UHFFFAOYSA-N 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- OQXORNGBZMWMHO-UHFFFAOYSA-N 5-bromo-3-[3-(4-chlorophenyl)-2,2-dimethylpropoxy]-4-[methyl(pyridin-3-yl)amino]-1h-pyridazin-6-one Chemical compound C=1C=C(Cl)C=CC=1CC(C)(C)COC1=NNC(=O)C(Br)=C1N(C)C1=CC=CN=C1 OQXORNGBZMWMHO-UHFFFAOYSA-N 0.000 claims 1
- COQQTKFVFMCTSU-UHFFFAOYSA-N 5-bromo-3-[3-(4-chlorophenyl)-3-hydroxypropoxy]-4-[methyl(pyridin-3-yl)amino]-1h-pyridazin-6-one Chemical compound C=1C=C(Cl)C=CC=1C(O)CCOC1=NNC(=O)C(Br)=C1N(C)C1=CC=CN=C1 COQQTKFVFMCTSU-UHFFFAOYSA-N 0.000 claims 1
- YJMYSLFFZJUXOA-UHFFFAOYSA-N 5-bromo-3-[3-(4-chlorophenyl)propoxy]-4-(pyridin-3-ylmethylamino)-1h-pyridazin-6-one Chemical compound C1=CC(Cl)=CC=C1CCCOC1=NNC(=O)C(Br)=C1NCC1=CC=CN=C1 YJMYSLFFZJUXOA-UHFFFAOYSA-N 0.000 claims 1
- 102000003960 Ligases Human genes 0.000 abstract description 13
- 108090000364 Ligases Proteins 0.000 abstract description 13
- 201000010099 disease Diseases 0.000 abstract description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 13
- 230000001404 mediated effect Effects 0.000 abstract description 11
- 239000004480 active ingredient Substances 0.000 abstract description 6
- 239000003112 inhibitor Substances 0.000 abstract description 6
- 230000002401 inhibitory effect Effects 0.000 abstract description 6
- 230000000069 prophylactic effect Effects 0.000 abstract description 6
- 230000001225 therapeutic effect Effects 0.000 abstract description 6
- DSNBHJFQCNUKMA-SCKDECHMSA-N thromboxane A2 Chemical compound OC(=O)CCC\C=C/C[C@@H]1[C@@H](/C=C/[C@@H](O)CCCCC)O[C@@H]2O[C@H]1C2 DSNBHJFQCNUKMA-SCKDECHMSA-N 0.000 abstract 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 7
- 229940126062 Compound A Drugs 0.000 description 6
- 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 6
- 241000283973 Oryctolagus cuniculus Species 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 210000001589 microsome Anatomy 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 239000013049 sediment Substances 0.000 description 5
- 239000006228 supernatant Substances 0.000 description 5
- 239000000443 aerosol Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 102000008186 Collagen Human genes 0.000 description 3
- 108010035532 Collagen Proteins 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 206010020772 Hypertension Diseases 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 229920001436 collagen Polymers 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 229930195729 fatty acid Natural products 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 2
- AAILEWXSEQLMNI-UHFFFAOYSA-N 1h-pyridazin-6-one Chemical class OC1=CC=CN=N1 AAILEWXSEQLMNI-UHFFFAOYSA-N 0.000 description 2
- 244000215068 Acacia senegal Species 0.000 description 2
- 206010002383 Angina Pectoris Diseases 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 206010007556 Cardiac failure acute Diseases 0.000 description 2
- 206010008132 Cerebral thrombosis Diseases 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- 201000001429 Intracranial Thrombosis Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 208000006011 Stroke Diseases 0.000 description 2
- 229920001615 Tragacanth Polymers 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 239000000205 acacia gum Substances 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 210000001715 carotid artery Anatomy 0.000 description 2
- 206010008118 cerebral infarction Diseases 0.000 description 2
- 208000026106 cerebrovascular disease Diseases 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 229960000905 indomethacin Drugs 0.000 description 2
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 231100000053 low toxicity Toxicity 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
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 208000010125 myocardial infarction Diseases 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 210000004623 platelet-rich plasma Anatomy 0.000 description 2
- YIBNHAJFJUQSRA-YNNPMVKQSA-N prostaglandin H2 Chemical compound C1[C@@H]2OO[C@H]1[C@H](/C=C/[C@@H](O)CCCCC)[C@H]2C\C=C/CCCC(O)=O YIBNHAJFJUQSRA-YNNPMVKQSA-N 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- XNRNNGPBEPRNAR-JQBLCGNGSA-N thromboxane B2 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1OC(O)C[C@H](O)[C@@H]1C\C=C/CCCC(O)=O XNRNNGPBEPRNAR-JQBLCGNGSA-N 0.000 description 2
- 235000010487 tragacanth Nutrition 0.000 description 2
- 239000000196 tragacanth Substances 0.000 description 2
- 229940116362 tragacanth Drugs 0.000 description 2
- DDMOUSALMHHKOS-UHFFFAOYSA-N 1,2-dichloro-1,1,2,2-tetrafluoroethane Chemical compound FC(F)(Cl)C(F)(F)Cl DDMOUSALMHHKOS-UHFFFAOYSA-N 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- RFCAUADVODFSLZ-UHFFFAOYSA-N 1-Chloro-1,1,2,2,2-pentafluoroethane Chemical compound FC(F)(F)C(F)(F)Cl RFCAUADVODFSLZ-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- IQHSSYROJYPFDV-UHFFFAOYSA-N 2-bromo-1,3-dichloro-5-(trifluoromethyl)benzene Chemical group FC(F)(F)C1=CC(Cl)=C(Br)C(Cl)=C1 IQHSSYROJYPFDV-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 description 1
- HJYXVAZPXSDJAC-XFULWGLBSA-N 5-bromo-3-[(3r)-3-(4-chlorophenyl)-3-hydroxypropoxy]-4-(pyridin-3-ylmethylamino)-1h-pyridazin-6-one;hydrochloride Chemical compound Cl.C([C@@H](O)C=1C=CC(Cl)=CC=1)COC1=NNC(=O)C(Br)=C1NCC1=CC=CN=C1 HJYXVAZPXSDJAC-XFULWGLBSA-N 0.000 description 1
- HJYXVAZPXSDJAC-RSAXXLAASA-N 5-bromo-3-[(3s)-3-(4-chlorophenyl)-3-hydroxypropoxy]-4-(pyridin-3-ylmethylamino)-1h-pyridazin-6-one;hydrochloride Chemical compound Cl.C([C@H](O)C=1C=CC(Cl)=CC=1)COC1=NNC(=O)C(Br)=C1NCC1=CC=CN=C1 HJYXVAZPXSDJAC-RSAXXLAASA-N 0.000 description 1
- CSHCYQVKCLCXTK-UHFFFAOYSA-N 5-bromo-3-[3-(4-chlorophenyl)-2,2-dimethylpropoxy]-4-(pyridin-3-ylmethylamino)-1h-pyridazin-6-one Chemical compound C=1C=C(Cl)C=CC=1CC(C)(C)COC1=NNC(=O)C(Br)=C1NCC1=CC=CN=C1 CSHCYQVKCLCXTK-UHFFFAOYSA-N 0.000 description 1
- HZVJNIUTIWSMAC-UHFFFAOYSA-N 5-bromo-3-[3-(4-chlorophenyl)-3-hydroxypropoxy]-4-(pyridin-3-ylmethylamino)-1h-pyridazin-6-one Chemical compound C=1C=C(Cl)C=CC=1C(O)CCOC1=NNC(=O)C(Br)=C1NCC1=CC=CN=C1 HZVJNIUTIWSMAC-UHFFFAOYSA-N 0.000 description 1
- QWGUGDYWUADMGB-UHFFFAOYSA-N 5-bromo-3-[3-(4-chlorophenyl)propoxy]-4-(pyridin-3-ylmethylamino)-1h-pyridazin-6-one;hydrochloride Chemical compound Cl.C1=CC(Cl)=CC=C1CCCOC1=NNC(=O)C(Br)=C1NCC1=CC=CN=C1 QWGUGDYWUADMGB-UHFFFAOYSA-N 0.000 description 1
- AVGCJKOSOVAHOX-UHFFFAOYSA-N 5-chloro-3-(3-phenylpropoxy)-4-(pyridin-3-ylmethylamino)-1h-pyridazin-6-one Chemical compound C=1C=CC=CC=1CCCOC1=NNC(=O)C(Cl)=C1NCC1=CC=CN=C1 AVGCJKOSOVAHOX-UHFFFAOYSA-N 0.000 description 1
- ADAGMNCCEJMUMC-UHFFFAOYSA-N 5-chloro-3-[3-(4-chlorophenyl)-2-hydroxypropoxy]-4-(pyridin-3-ylmethylamino)-1h-pyridazin-6-one Chemical compound C=1C=C(Cl)C=CC=1CC(O)COC1=NNC(=O)C(Cl)=C1NCC1=CC=CN=C1 ADAGMNCCEJMUMC-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000022309 Alcoholic Liver disease Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 208000000575 Arteriosclerosis Obliterans Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 208000033386 Buerger disease Diseases 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 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
- 241000283073 Equus caballus Species 0.000 description 1
- IMROMDMJAWUWLK-UHFFFAOYSA-N Ethenol Chemical group OC=C IMROMDMJAWUWLK-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 108010010803 Gelatin 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
- 239000007995 HEPES buffer Substances 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 208000011200 Kawasaki disease Diseases 0.000 description 1
- 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 1
- 239000004166 Lanolin Substances 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 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
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 206010043540 Thromboangiitis obliterans Diseases 0.000 description 1
- 108010069102 Thromboxane-A synthase Proteins 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical group OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000000702 anti-platelet effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940124572 antihypotensive agent Drugs 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 230000003177 cardiotonic effect Effects 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 125000004857 imidazopyridinyl group Chemical class N1C(=NC2=C1C=CC=N2)* 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229940079865 intestinal antiinfectives imidazole derivative Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 230000003228 microsomal effect Effects 0.000 description 1
- 208000001725 mucocutaneous lymph node syndrome Diseases 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 230000001991 pathophysiological effect Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229940051841 polyoxyethylene ether Drugs 0.000 description 1
- 229920000056 polyoxyethylene ether Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- BTURAGWYSMTVOW-UHFFFAOYSA-M sodium dodecanoate Chemical compound [Na+].CCCCCCCCCCCC([O-])=O BTURAGWYSMTVOW-UHFFFAOYSA-M 0.000 description 1
- 229940082004 sodium laurate Drugs 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- WSWCOQWTEOXDQX-MQQKCMAXSA-N sorbic acid group Chemical class C(\C=C\C=C\C)(=O)O WSWCOQWTEOXDQX-MQQKCMAXSA-N 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- RZWIIPASKMUIAC-VQTJNVASSA-N thromboxane Chemical compound CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC RZWIIPASKMUIAC-VQTJNVASSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
-
- 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
- A61K31/50—Pyridazines; Hydrogenated pyridazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- 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
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- 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
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Urology & Nephrology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Neurology (AREA)
- Vascular Medicine (AREA)
- Biomedical Technology (AREA)
- Diabetes (AREA)
- Neurosurgery (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Hematology (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
- Plural Heterocyclic Compounds (AREA)
- Confectionery (AREA)
- Medicines Containing Plant Substances (AREA)
- Pyridine Compounds (AREA)
Description
Foreliggende oppfinnelse angår anvendelse av en pyridazinonforbindelse eller et farmakologisk akseptabelt salt derav som en aktiv ingrediens, særlig en tromboksan A2 syntetasehemmer.
Tromboksan Å£ (TXA2) blir hovedsakelig produsert og frigjort fra blodplater, og viser sterk blodplateaggregeringsvirkning og vasopresserende virkning. Det foreligger mange rapporter med hensyn på patofysiologisk rolle. Produksjon av TXÅ£ har blitt funnet å øke i sykdommene slik som arteriosklerose, diabetes, ischemiske hjertesykdommer, pulmonære sykdommer, hypertensjon, sjokk, Kawasaki-sykdom og alkoholisk leversyk-dom, og indikerer således en høy sannsynlighet for at TXAg er involvert ved igangsetting og forverring av disse sykommene. Til forbedring av disse sykdommene er TXA2 syntetasehemmere og TXA2 antagonister slik som imidazolderivater, pyridinderi-vater og imidazopyridinderivater blitt utviklet. Et middel for profylakse og behandling av TXA2~medierte sykdommer med sterkt bedrede effekter har vært ønskelig.
Det er allerede kjent at pyridazinonforbindelser har blodplateaggregeringshemmende virkning, kardiotonvirkning, vasodilaterende virkning og anti-SRS-A (Slow Reacting Substances of Anaphylaxis) virkning (W091/16314, US-patent nr. 5202323, EP-A-482208).
Det har nå blitt funnet at disse pyridazinonforbindelsene og farmakologisk aksepterbare saltene derav har en virkning som til nå ikke har vært kjent, nemlig profylaktisk og terapeutiske aktiviteter mot TXA2-medierte sykdommer, særlig TXA2-syntetasehemmende virkning.
Det er derfor et mål med foreliggende oppfinnelse å skaffe til veie et middel for profylakse og behandling av TXA2-medierte sykdommer, ved å anvendeen pyridazinonforbindelse, særlig en TXA2-syntetasehemmer.
Foreliggende oppfinnelse angår således anvendelse av en pyridazinonforbindelse med formel (I)
der R<1>, R<2> og R<3> hver uavhengig av hverandre er et hydrogenatom eller en laverealkyl, X er et halogenatom, cyano eller et hydrogenatom, Y er et halogenatom, trifluormetyl eller et hydrogenatom og A er en C^-Cg alkylen eventuelt substituert med hydroksyl, eller et farmakologisk aksepterbart salt derav for fremstilling av et middel for profylakse eller behandling av arteriosklerotisk obliterans, diabetisk nefropati, diabetisk neuropati og hypertriglyseridemi forårsaket av diabetes.
Symbolene som blir anvendt i foreliggende beskrivelse blir forklart i det følgende.
Laverealkyl med hensyn på R<*>, R<2> og R<3> kan være lineær eller forgrenet og ha 1 til 6 karbonatomer, slik som metyl, etyl, n-propyl, isopropyl, n-butyl, isobutyl, sek-butyl, t-butyl, pentyl og heksyl.
Det er foretrukket at R^ og R<2> hver er hydrogenatom, og fortrinnsvis er R<3> hydrogenatom eller C1-C4 alkyl.
<;> ci_c4 alkyl for R<3> kan eksemplifiseres med metyl, etyl, n-propyl, isopropyl, n-butyl, isobutyl, sek-butyl og t-butyl.
Halogenatomet for X og Y er for eksempel et fluoratom, kloratom, bromatom eller jodatom, med preferanse gitt til halogenatom for X og halogenatom eller hydrogenatomet for Y.
Cj,-Cg alkylen for A, som eventuelt er substituert med hydroksyl, kan være linær eller forgrenet og kan eksemplifiseres med metylen, etylen, propylen, butylen, pentylen, heksylen, heptylen, oktylen, 2,2-dimetyletylen, 2,2-dietyl-etylen, 2,2-di-n-propyletylen, hydroksymetylen, 1-hydroksyetylen, 2-hydroksyetylen og 3-hydroksypropylen. Foretrukket er C^-Cg alkylen eventuelt substituert med hydroksyl.
I formel (I) er bindingsstedet mellom metylen og pyridinringen ikke spesielt begrenset. Foretrukket sted er 3-posisjonen relativt til nitrogenatomet på pyridinringen.
Y kan være substituert i en hvilken som helst posisjon på benzenringen, med preferanse for 4-posisj onen.
Særlig er det foretrukket en pyridazinonforbindelse hvori formelen (I), R<1> og R<2> er hydrogenatomer, R<3> er et hydrogenatom eller en C1-C4 alkyl, X er et halogenatom, Y er et halogenatom eller hydrogenatom og A er en C^-Cg alkylen eventuelt substituert med hydroksyl.
Eksempler på mer foretrukket pyridazinonforbindelse (I) innbefatter 4-brom-6-(3-fenylpropoksy )-5-(2-pyridylmetyl-amino)-3(2H)-pyridazinon, 4-klor-6-(3-fenylpropoksy)-5-(3-pyridylmetylamino )-3(2H)-pyridazinon, 4-klor-6-[3-(4-klorfenyl )propoksy] -5-( 3-pyridylmetylamino)-3(2H)-pyridazinon, 4-brom-6-[3-(4-klorfenyl)propoksy]-5-(3-pyridylmetyl-amino ) -3 ( 2H ) -pyr i dazinon , 4-brom-6-(2,2-dimetyl-3-fenylprop-oksy ) -5-(3-pyridylmetylamino)-3(2H)-pyridazinon, 4-klor-6-(2 ,2-dimetyl-3-fenylpropoksy)-5-(3-pyridylmetylamino )-3(2H)-pyridazinon, 4-brom-6-[3-(4-klorfenyl)-2,2-dimetylpropoksy]-5-(3-pyridylmetylamino)-3(2H)-pyridazinon, 4-klor-6-[3-(4-klorf enyl)-2,2-dimetylpropoksy]-5-(3-pyridyImetylamino)-3(2H)-pyridazinon, 4-brom-6-[3-( 4-klorfenyl)-3-hydroksy-propoksy]-5-(3-pyridylmetylamino)-3(2H)-pyridazinon, 4-klor-6-[3-(4-klorfenyl)-3-hydroksypropoksy]-5-(3-pyridy Ime tyl-amino)-3(2H)-pyridazinon, 4-brom-6-[3-(4-klorfenyl)-2-hydroksypropoksy] - 5- ( 3-pyridylmetylamino )-3 (2H)-pyr i dazinon og 4-klor-6-[3-(4-klorfenyl)-2-hydroksypropoksy]-5-(3-pyridylmetylamino)-3(2H)-pyridazinon.
Pyridazinonforbindelsen (I) som blir anvendt i foreliggende oppfinnelse innbefatter stereo og optiske isomerer.
Pyridazinonforbindelsen (I) er en kjent forbindelse og kan bli fremstilt ved en fremgangsmåte som for eksempel er beskrevet i W091/16314, US-patent nr. 5202323, EP-A-482208 og internasjonal patentsøknad nr. PCT/JP95/69.
De farmakologisk aksepterbare saltene av pyridazinonforbindelsen (I) er, for eksempel, salter med uorganisk syre (for eksempel hydroklorid, hydrobromid, fosfat og sulfat) og salter med organisk syre (acetat, succinat, maleat, fumarat, maleat og tartrat).
Pyridazinonforbindelsen (I) kan bli omdannet til de foran-nevnte saltene ved en kjent fremgangsmåte.
Fremgangsmåten for å bekrefte virkningen av forbindelsen (I) er ikke gjenstand for noen spesiell begrensning og virkningen kan bekreftes ved en kjent fremgangsmåte.
Pyridazinonforbindelsen (I) og farmakologisk akseptable salter derav, som er aktive ingredienser i foreliggende oppfinnelse, er ekstremt lavtoksiske og har profylaktisk og terapeutiske aktiviteter mot TXAg-medierte sykdommer, særlig en TXA2-syntetasehemmende virkning, i pattedyr slik som menneskter, hund, ku, hest, kanin, mus og rotte. Dvs. at de har profylaktiske og terapeutiske effekter mot TXA2~medierte sykdommer, slik som cerebralt infarkt, cerebral trombose, bronkial astma, cerebralt slag, myokardialt infarkt, akutt hjertesvikt, angina pectoris, hypertensjon, arteriosklerotisk oblitterans, trombongiitis oblitterans, diabetisk nefropati, diabetisk neuropati og hypertriglyceridemi forårsaket av diabetes.
Doseringsformen av pyridazinonforbindelsen (I) og farmakologisk akseptable salter derav kan eksemplifiseres ved ikke-oral administrering av for eksempel injeksjon (subkutan, intravenøs, intramuskulær, intraperitoneale injeksjoner), salver, suppositorier eller aersol, og oral administrering av for eksempel tablett, kapsel, granul, pille, sirup, væske, emulsjon eller suspensjon.
Pyridazinonforbindelsen (I) og farmakologisk akseptable salter derav blir formulert til preparater ved en fremgangsmåte som konvensjonelt blir anvendt for fremstilling av farmasøytiske midler.
Tabletten, kapselen, granulen og pillen for oral administrering blir for eksempel fremstilt ved å anvende eksipient (for eksempel sukrose, laktose, glukose, stivelse og mannit), bindemiddel (for eksempel sirup, gummi arabicumn, gelatin, sorbit, tragakant, metylcellulose og polyvinylpyrrolidon), disintegrator (for eksempel stivelse, karboksymetylcellulose eller kalsiumsaltet derav, mikrokrystallinsk cellulose og polyetylenglykol) og smøremiddel (for eksempel talk, magnesiumstearat, kalsiumstearat, silika, natriumlaurat og glycerol).
Injeksjonen, aerosol, sirup, væske, emulsjon og suspensjon blir fremstilt ved å anvende oppløsningsmidler for den aktive bestanddelen (for eksempel vann, etylalkohol, isopropylalko-hol, propylenglykol, 1,3-butylenglykol og polyetylenglykol), overflateaktivt middel (for eksempel sorbitanfettsyreester, polyoksyetylensorbitanfettsyreester, polyoksyetylenfett-syreester, polyoksyetyleneter av hydrogenert kastorolje og lecitin), suspenderingsmiddel (for eksempel cellulosederlvat slik som metylcellulose og natriumsalt av karboksymetylcellulose, og naturgummi slik som tragakant og gummi arabicum), preservativ (for eksempel p-hydroksybenzoat, benzalkoniumklo-rid og sorbinsyresalt) og lignende. Suppositorier blir anvendt ved for eksempel å anvende polyetylenglykol, lanolin og kokosnøttolje.
Dosen av pyridazinonforbindelsen (I) og farmakologisk akseptable salter derav blir hensiktsmessig bestemt i henhold til alder, kroppsvekt, alvorlighet av symptomer og lignende hos pasienten, og de blir generelt administrert ved 0,001-500 mg/dag, fortrinnsvis 0,005-100 mg/dag i en enkeltdose til flere ganger oppdelte doser til en voksent menneske.
Følgende eksperimenter ble gjennomført ved å anvende følgende medikamenter og lignende.
Forbindelse A, 4-brom-6-[3-(4-klorfenyl)propoksy]-5-(3-pyridylmetylamino)-3(2H )-pyridazinonhydroklorid, forbindelse B, 4-brom-6-[(3S)-(4-klorfenyl)-3-hydroksypropoksy]-5-(3-pyridylmetylamino)-3(2H)-pyridazinonhydroklorid, og forbindelse C, 4-brom-6-[(3R )-(4-klorfenyl)-3-hydroksypropoksy]-5-(3-pyridylmetylamino )-3(2H)-pyridazinonhydroklorid, som blir fremstilt ved konvensjonelle metoder, ble oppløst i 10096 dimetylsulfoksid (DMSO) og anvendt som reagenser i fortynning med DMSO når de er i bruk.
Indometacin (fremstilt av Sigma Chemical Co.) ble suspendert i fysiologisk saltvann og en en 2,5$ natriumkarbonatoppløs-ning (pH ca. 8,0) ble dråpvis tilsatt for å oppløse den. Kollagen (Collagen Reagent Horm; fremstilt av Niko Bio-science) ble fortynnet med et enkelt fortynningsmiddel når det var i bruk. Med hensyn på prostaglandin H2 (PGHg; fremstilt av Funakoshi) ble den på nytt oppløst i etanol når den var i bruk etter fjerning av aceton under en N2 gassat-mosfaere.
Eksperiment eksempel 1; TXA2 frigjort fra kaninblodplater
Blod ble tatt fra karotidarterien i normal kanin ved å anvende etylendiamintetraeddiksyre (EDTA; 77 mM EDTA, 1/10 vol). Blodet ble sentrifugert ved 1800 opm i 8 minutter og blodplaterikt plasma i supernatanten ble utvunnet, og dette ble sentrifugert ved 3200 opm i 8 minutter. Sedimentet (blodplaten) ble vasket med Tyrode-HEPES-EDTA buffer og sentrifugert ved 3200 opm i 8 minutter. Sedimentet ble suspendert i Tyrode-HEPES buffer for å fremstille vaskede blodplater (5 x 10<8> blodplater/ml).
100% DMSO eller et reagens (forbindelse A, 1,5 ul) ble tilsatt de vaskede blodplatene (270 ul) og blandingen ble oppvarmet ved 37°C i 2 minutter. Deretter ble kollagen (10 ug/ml) og 1 mM Ca<2+> (eller 1 mM Ca<2+> alene når man undersøker frigjøring fra ustimulerte blodplater) ble tilsatt og eksperimentet ble startet. Etter oppvarming ved 37°C i 8 minutter ble IO-<3> M indometacin tilsatt og kuvetten ble anbrakt i is for å stoppe reaksjonen. Etter sentrifugering ved 10000 opm i 10 minutter ble supernatanten tatt og lagret ved -20°C inntil den ble benyttet for TXA2 bestemmelse.
Eksperimentelt eksempel 2; Hemming av TXA2 syntetase ved å anvende kaninblodplatemikrosom
Blod ble tatt fra karotidarterien i normal kanin ved å anvende EDTA (77 mM EDTA, 1/10 vol). Blodet ble sentrifugert ved 1300 opm i 10 minutter og blodplaterikt plasma i supernatanten ble utvunnet, og dette ble sentrifugert ved 3400 opm i 15 minutter. Sedimentet ble vasket med fysiologisk saltvann (opprinnelig volum) og sentrifugert ved 3400 opm i 15 minutter. Deretter ble 0,05 M Tris-HCl buffer (1 mM EDTA, pH 7,5, 3 ganger vekt av vekten av blodplatene) tilsatt sedimentet og blandingen ble homogenisert (2 minutter, full hastighet) ved å anvende polytron. Homogenatet ble sentrifugert ble 8300 opm i 15 minutter (Tomy RD-20III, nr. 3N) og supernatanten ble sentrifugert ved 1.000.000 opm i 1 time (Beckman TL-100, TLA100.3). Sedimentet ble suspendert i 0,05 M Tris-HCl buffer (1 mM EDTA, pH 7,5, en tredjedel vekt av vekten av blodplatene) for å fremstille en mikrosomal fraksjon. Fraksjonen ble lagret ved -80°C inntil den ble anvendt for eksperimentet.
0,05 M Tris-HCl buffer (pH 7,5, 890 ul), 100 ul av ovenfornevnte mikrosom (85 ug protein) og 100$ DMSO eller reagens (forbindelse A, 5 pl) ble tilsatt og blandingen forinkubert ved 22° C i 3 minutter. Deretter ble PGH2 (5 nmol, 5 ul) tilsatt for å starte reaksjonen. Etter inkubering ved 22°C i 3 minutter ble IN saltsyre tilsatt (50 ul) for å avslutte reaksjonen. IM Tris base (55 ul) ble tilsatt for å nøytrali-sere reaksjonsblandingen og blandingen ble sentrifugert ved 10.000 opm i 5 minutter. Supernatanten ble utvunnet og lagret ved -20°C inntil den ble anvendt for TXA2 måling.
TXA2 mengden i ovenfornevnte eksemperimentelle eksempler ble målt som TXB2 (stabil forbindelse derav) mengden ved EIA metoden ble anvendt TXB2 analysesett (fremstilt av Amersham).
Resultatene fra eksperimentelle eksempler 1 og 2 er vist i tabell 1.
Eksperimentelt eksempel 3: Hemming av TXAg syntetase ved anvendelse av humant blodplatemikrosome
På samme måte som i eksperimentelt eksempel 2 med unntagelse av at humant blodplatemikrosom ble anvendt i stedet for kaninblodplatemikrosom, ble eksperimentet gjennomført. Forbindelse A, forbindelse B og forbindelse C ble anvendt som reagenser.
Som et resultat av IC5Q (mengde som er nødvendig til å hemme 50% TXA2 syntese) av TXA2 syntetasehemmende virkning, når det ble anvendt humant blodplatemikrosom, var henholdsvis 0,010 jjM for forbindelse A og 0,020 uM og 0,030 uM for forbindelse B og forbindelse C som optiske isomerer.
Eksperimentelt eksempel 4: akutt toksisitet
Forbindelse A ble administrert oralt til rotter og hunder, og LD5Q ble funnet å være mindre enn 2 g/kg, og viser således ekstremt lav toksisitet av forbindelse (I) som ble anvendt i foreliggende oppfinnelse.
Fra de eksperimentelle resultatene over er det åpenbart at pyridazinonforbindelsen (I) og et salt derav har ypperlig TXA2 frigjørende suppressiv virkning og TXA2 syntetasehemmende virkning, og har markert lav toksisitet.
Eksempel 1 Tablett
Følgende ingredienser ble blandet ved en konvensjonell fremgangsmåte og fremstilt til en sukkerbelagt tablett inneholdende 50 mg av den aktive ingrediensen pr. tablett.
Eksempel 2 Kapsel
Følgende ingredienser ble blandet ved en konvensjonell metode og pakket i en gelat inkapsel for å fremstille en kapsel inneholdende 50 mg av den aktive ingrediensen pr. kapsel.
Eksempel 3 Salve
Følgende ingredienser ble blandet ved en konvensjonell metode for å fremstille en 1% salve.
Eksempel 4 Aerosolsuspensjon
Følgende ingredienser (A) ble blandet og den oppnådde blandingen ble fylt i en beholder utstyrt med en ventil. Et drivmiddel (B) ble presset inn ved 20° C fra ventildysen til ca. 2,46-2,81 mg/cm<2> trykk for å fremstille en aerosolsuspensjon.
(B) En 60-40 vekt-56 blanding av 1,2-diklortetrafluoretan og 1-klorpentafluoretan 73,25 vekt-#
Pyridazinonforbindelsen (I) og farmakologisk akseptable salter derav har profylaktiske og terapeutiske aktiviteter mot TXA2-medierte sykdommer, særlig en TXA2 syntetasehemmende virkning, og er nyttige som midler for profylakse og behandling av TXA2-medierte sykdommer, særlig som TXA2 syntetasehemmere. De har profylaktiske og terapeutiske effekter mot TXA2-medierte sykdommer, slik som cerebralt infarkt, cerebral trombose, bronkial astma, cerebralt slag, myokardialt infarkt, akutt hjertesvikt, angina pectoris, hypertensjon, arteriosklerose obliteranser, trombioangitt obliteraner, diabetisk nefropati, diabetisk neuropati og hypertriglyceridemi forårsaket av diabetes.
Claims (3)
1.
Anvendelse av en pyridazinonforbindelse med formel (I)
der R<1>, R<2> og R<3> hver uavhengig av hverandre er et hydrogenatom eller en laverealkyl, X er et halogenatom, cyano eller et hydrogenatom, Y er et halogenatom, trifluormetyl eller et hydrogenatom og A er en C^-Cg alkylen eventuelt substituert med hydroksyl, eller et farmakologisk aksepterbart salt derav for fremstilling av et middel for profylakse eller behandling av arteriosklerotisk obliterans, diabetisk nefropati, diabetisk neuropati og hypertriglyseridemi forårsaket av diabetes.
2.
Anvendelse av et middel ifølge krav 1, der R<1> og R<2> hver er et hydrogenatom, R<3> er et hydrogenatom eller en C-^- C^ alkyl,
X er et halogenatom, Y er et halogenatom eller et hydrogenatom og A er et C^-Cg alkylen eventuelt substituert med hydroksyl.
3.
Anvendelse av et middel ifølge krav 1, der pyridazinonforbindelsen med formel (I) er et medlem valgt fra gruppen bestående av;
4-brom-6-(3-fenylpropoksy)-5-(3-pyr idyImetylamino)-3( 2H )-pyridazinon, 4-klor-6-(3-fenylpropoksy)-5-(3-pyridylmetylamino)-3(2H)-pyridazinon, 4-klor-6-[3-(4 -klor f enyl )propoksy] -5-(3-pyridylmetylamino)-3(2H)-pyridazinon, 4-brom-6-[3-( 4-klorfenyl )propoksy] - 5-(3-pyridylmetylamino )-3(2H)-pyridazinon, 4-brom-6-(2,2-dimetyl-3-fenylpropoksy)-5-(3-pyridylmetyl-amino )-3(2H)-pyridazinon, 4-klor-6-(2,2-dimetyl-3-fenylpropoksy)-5-(3-pyridylmetyl amino)-3(2H)-pyridazinon, 4-brom-6- [3-(4-klorfenyl)-2,2-dimetylpropoksy]-5-(3-pyridyl-metylamino )-3(2H)-pyridazinon, 4-klor-6- [3-(4-klorfenyl)-2,2-dimetylpropoksy]-5-(3-pyridyl-metylamino )-3( 2H )-pyridazinon og 4-brom-6-[3-(4 -kl or f enyl )-3-hydroksypropoksy] - 5- (3-pyridyl-metylamino )-3(2H)-pyridazinon, 4-klor-6-[3-( 4-klorfenyl )-3-hydroksypropoksy]-5-(3-pyridyl-metylamino )-3(2H)-pyridazinon, 4-brom-6-[3-( 4-klorfenyl )-2-hydroksypropoksy] - 5-(3-pyridyl-metylamino )-3( 2H )-pyridazinon og 4-klor-6-[3-( 4-klorfenyl )-2-hydroksypropoksy]- 5-(3-pyridyl-metylamino )-3(2H)-pyridazinon.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2455694 | 1994-02-22 | ||
| PCT/JP1995/000244 WO1995022329A1 (en) | 1994-02-22 | 1995-02-20 | Agent for prophylaxis and treatment of thromboxane a2-mediated diseases |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NO963463L NO963463L (no) | 1996-08-20 |
| NO311490B1 true NO311490B1 (no) | 2001-12-03 |
Family
ID=12141437
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO19963463A NO311490B1 (no) | 1994-02-22 | 1996-08-20 | Anvendelse av en pyridazinonforbindelse |
Country Status (16)
| Country | Link |
|---|---|
| US (1) | US5798357A (no) |
| EP (1) | EP0744950B1 (no) |
| JP (1) | JP3858279B2 (no) |
| KR (1) | KR100345187B1 (no) |
| CN (1) | CN1084620C (no) |
| AT (1) | ATE273708T1 (no) |
| AU (1) | AU1718395A (no) |
| CA (1) | CA2183234C (no) |
| DE (1) | DE69533392T2 (no) |
| DK (1) | DK0744950T3 (no) |
| ES (1) | ES2222464T3 (no) |
| FI (1) | FI116882B (no) |
| IL (1) | IL112695A (no) |
| NO (1) | NO311490B1 (no) |
| WO (1) | WO1995022329A1 (no) |
| ZA (1) | ZA951470B (no) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW482675B (en) * | 1997-01-31 | 2002-04-11 | Green Cross Corp | Compositions for oral administration containing pyridazinone compounds technical field of the invention |
| AU8886298A (en) * | 1997-08-28 | 1999-03-22 | Nissan Chemical Industries Ltd. | Neovascularization promoters and neovascularization potentiators |
| US6143113A (en) | 1998-03-02 | 2000-11-07 | Le Groupe Recherche I.D. Inc. | Repulpable corrugated boxboard |
| DE69919191T2 (de) | 1998-09-01 | 2005-07-28 | Nissan Chemical Industries, Ltd. | Heilmittel für die stenose des rückenmarkkanals |
| AU768825B2 (en) * | 1998-12-07 | 2004-01-08 | Nissan Chemical Industries Ltd. | Remedial agent for erectile dysfunction |
| US20070117806A1 (en) * | 2003-12-26 | 2007-05-24 | Nissan Chemical Industries, Ltd. | Neutrophilia inhibitor |
| AU2009209152A1 (en) * | 2008-01-29 | 2009-08-06 | Indigo Pharmaceuticals | A method of administering a PDE3 inhibitor via titration for the treatment of peripheral arterial disease |
| CN113546049B (zh) * | 2021-04-30 | 2023-03-17 | 贵州汉方药业有限公司 | 一种柔性丸剂药物黏合剂及使用该黏合剂制成的柔性丸剂 |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4599336A (en) * | 1983-08-08 | 1986-07-08 | Hoffmann-La Roche Inc. | Derivatives of (E)-3-(4-oxo-4H-quinazolin-3-yl)-2-propenamide |
| EP0142057A3 (en) * | 1983-11-04 | 1988-03-30 | F. Hoffmann-La Roche Ag | Thiazoloquinazoline derivatives, their preparation and pharmaceutical compositions containing same |
| US4978665A (en) * | 1987-01-20 | 1990-12-18 | Nissan Chemical Industries Ltd. | 3(2H)pyridazinone, and antagonistic agent against SRS-A containing it |
| JPH02256668A (ja) * | 1988-12-20 | 1990-10-17 | Nissan Chem Ind Ltd | ピリダジノン誘導体 |
| CA2053863C (en) * | 1990-04-25 | 1996-10-29 | Keizo Tanikawa | Pyridazinone derivatives |
-
1995
- 1995-02-19 IL IL11269595A patent/IL112695A/xx not_active IP Right Cessation
- 1995-02-20 KR KR1019960704529A patent/KR100345187B1/ko not_active IP Right Cessation
- 1995-02-20 DE DE69533392T patent/DE69533392T2/de not_active Expired - Lifetime
- 1995-02-20 US US08/687,604 patent/US5798357A/en not_active Expired - Lifetime
- 1995-02-20 EP EP95909122A patent/EP0744950B1/en not_active Expired - Lifetime
- 1995-02-20 ES ES95909122T patent/ES2222464T3/es not_active Expired - Lifetime
- 1995-02-20 CN CN95191744A patent/CN1084620C/zh not_active Expired - Lifetime
- 1995-02-20 WO PCT/JP1995/000244 patent/WO1995022329A1/en active IP Right Grant
- 1995-02-20 CA CA002183234A patent/CA2183234C/en not_active Expired - Lifetime
- 1995-02-20 AT AT95909122T patent/ATE273708T1/de active
- 1995-02-20 AU AU17183/95A patent/AU1718395A/en not_active Abandoned
- 1995-02-20 DK DK95909122T patent/DK0744950T3/da active
- 1995-02-21 JP JP03230095A patent/JP3858279B2/ja not_active Expired - Fee Related
- 1995-02-22 ZA ZA951470A patent/ZA951470B/xx unknown
-
1996
- 1996-08-20 NO NO19963463A patent/NO311490B1/no not_active IP Right Cessation
- 1996-08-21 FI FI963264A patent/FI116882B/fi not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| FI963264A0 (fi) | 1996-08-21 |
| CN1141590A (zh) | 1997-01-29 |
| JP3858279B2 (ja) | 2006-12-13 |
| KR970701048A (ko) | 1997-03-17 |
| US5798357A (en) | 1998-08-25 |
| ZA951470B (en) | 1995-12-07 |
| DE69533392T2 (de) | 2005-09-01 |
| ATE273708T1 (de) | 2004-09-15 |
| WO1995022329A1 (en) | 1995-08-24 |
| IL112695A0 (en) | 1995-05-26 |
| EP0744950B1 (en) | 2004-08-18 |
| DE69533392D1 (de) | 2004-09-23 |
| ES2222464T3 (es) | 2005-02-01 |
| DK0744950T3 (da) | 2004-10-25 |
| NO963463L (no) | 1996-08-20 |
| CN1084620C (zh) | 2002-05-15 |
| AU1718395A (en) | 1995-09-04 |
| KR100345187B1 (ko) | 2002-12-05 |
| IL112695A (en) | 1999-04-11 |
| JPH07285869A (ja) | 1995-10-31 |
| CA2183234A1 (en) | 1995-08-24 |
| EP0744950A1 (en) | 1996-12-04 |
| FI116882B (fi) | 2006-03-31 |
| CA2183234C (en) | 2004-05-04 |
| FI963264A (fi) | 1996-08-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4661499A (en) | 2-[(substituted)-phenoxymethyl]quinolines | |
| JP5872552B2 (ja) | 化学化合物 | |
| JP2009514848A (ja) | 医薬組成物 | |
| MX2008001020A (es) | Un monohidrato de pirrolo[1-2-b]pirazol piridin quinolin substituido como inhibidor de factor de crecimiento de transformacion-beta (tgf-beta). | |
| TW200822924A (en) | Pyrazoline compounds | |
| TW200831089A (en) | Substituted bicyclocarboxyamide compounds | |
| WO2004067003A1 (ja) | 動脈硬化及び高血圧症の予防及び治療のための医薬 | |
| AU2017244777A1 (en) | Griseofulvin compound | |
| NO311490B1 (no) | Anvendelse av en pyridazinonforbindelse | |
| RU2339381C2 (ru) | Ингибитор гиперплазии интимы сосудов | |
| CN109843283B (zh) | 脲衍生物 | |
| CA3091642A1 (en) | Agents and methods for treating dysproliferative diseases | |
| JP6275517B2 (ja) | Ｉｌ−２産生抑制 | |
| TW201031659A (en) | Novel compound having 3-(5-alkoxypyrimidin-2-yl) pyrimidin-4(3H)-on structure and medicine containg same | |
| AU768825B2 (en) | Remedial agent for erectile dysfunction | |
| CN101102775A (zh) | 采用pdev抑制剂治疗充血性心衰的方法 | |
| EP3091001B1 (en) | Diphenylmethyl piperazine derivative and pharmaceutical composition using same | |
| KR101293350B1 (ko) | 호중구증다 억제제 | |
| EP1171133B1 (en) | R-hydroxynefazodone | |
| WO1997046515A1 (fr) | Benzenes substitues ne presentant pas d'effets inhibiteurs | |
| JP2024504982A (ja) | マラリアを治療するための化合物および方法 | |
| CA2369225A1 (en) | S-hydroxynefazodone | |
| JPH111479A (ja) | アミド結合を有するイソオキサゾール誘導体、並びにこれらを含有するキマーゼ阻害剤及びアンジオテンシンｉｉ産生抑制剤 | |
| CA2714160A1 (en) | A method of administering a pde3 inhibitor via titration for the treatment of peripheral arterial disease | |
| JP2012158535A (ja) | ピラゾール誘導体及びその医薬用途 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MK1K | Patent expired |