JPS63145272A - 4,5-dihydro-6-(4-substituted phenyl)-3(2h)-pyridazinone derivative - Google Patents
4,5-dihydro-6-(4-substituted phenyl)-3(2h)-pyridazinone derivativeInfo
- Publication number
- JPS63145272A JPS63145272A JP29457586A JP29457586A JPS63145272A JP S63145272 A JPS63145272 A JP S63145272A JP 29457586 A JP29457586 A JP 29457586A JP 29457586 A JP29457586 A JP 29457586A JP S63145272 A JPS63145272 A JP S63145272A
- Authority
- JP
- Japan
- Prior art keywords
- group
- formula
- dihydro
- general formula
- integer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- -1 4,5-dihydro-6-(4-substituted phenyl)-3(2h)-pyridazinone Chemical class 0.000 title claims abstract description 24
- 150000001875 compounds Chemical class 0.000 claims abstract description 32
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 3
- 125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 claims abstract description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims abstract 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 5
- 206010008088 Cerebral artery embolism Diseases 0.000 abstract description 2
- 206010008132 Cerebral thrombosis Diseases 0.000 abstract description 2
- 201000001429 Intracranial Thrombosis Diseases 0.000 abstract description 2
- 206010058990 Venous occlusion Diseases 0.000 abstract description 2
- 201000010849 intracranial embolism Diseases 0.000 abstract description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 2
- 230000004520 agglutination Effects 0.000 abstract 1
- 210000001772 blood platelet Anatomy 0.000 abstract 1
- 230000001747 exhibiting effect Effects 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 230000002093 peripheral effect Effects 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000000921 elemental analysis Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 235000011181 potassium carbonates Nutrition 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- 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 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-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
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 208000007536 Thrombosis Diseases 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 229940127218 antiplatelet drug Drugs 0.000 description 2
- 229960004676 antithrombotic agent Drugs 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 229940099112 cornstarch Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-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
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- DEXFNLNNUZKHNO-UHFFFAOYSA-N 6-[3-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperidin-1-yl]-3-oxopropyl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1CCN(CC1)C(CCC1=CC2=C(NC(O2)=O)C=C1)=O DEXFNLNNUZKHNO-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 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
- 239000005995 Aluminium silicate Substances 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- RENMDAKOXSCIGH-UHFFFAOYSA-N Chloroacetonitrile Chemical compound ClCC#N RENMDAKOXSCIGH-UHFFFAOYSA-N 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 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
- MFESCIUQSIBMSM-UHFFFAOYSA-N I-BCP Chemical compound ClCCCBr MFESCIUQSIBMSM-UHFFFAOYSA-N 0.000 description 1
- 231100000111 LD50 Toxicity 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- GCKMFJBGXUYNAG-HLXURNFRSA-N Methyltestosterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)CC2 GCKMFJBGXUYNAG-HLXURNFRSA-N 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229920002472 Starch Polymers 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
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000005303 alkyl halide derivatives Chemical class 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 150000007514 bases Chemical class 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
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 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
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 238000005695 dehalogenation reaction Methods 0.000 description 1
- 238000006704 dehydrohalogenation reaction Methods 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 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
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000005764 inhibitory process 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
- 229910052740 iodine Chemical group 0.000 description 1
- 239000011630 iodine Chemical group 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は、抗血栓薬として有用な新規4.5−ジヒドロ
−6−(4−置換フェニル)−3(2H)−ピリダジノ
ン誘導体に関する。DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to novel 4,5-dihydro-6-(4-substituted phenyl)-3(2H)-pyridazinone derivatives useful as antithrombotic agents.
特開昭50−93984.特開昭58−8015及び特
開昭61−40270に本発明化合物と構造類似の4.
5ジヒドロ−3(2H)−ピリダジノン誘導体が開示さ
れている。Japanese Patent Publication No. 50-93984. 4. JP-A-58-8015 and JP-A-61-40270 have structural similarities to the compounds of the present invention.
5dihydro-3(2H)-pyridazinone derivatives are disclosed.
しかし、前記のいずれの公報にも本発明化合物ないしそ
の抗血栓作用について何ら示唆するところはない。However, none of the above-mentioned publications suggests anything about the compound of the present invention or its antithrombotic effect.
近年、高齢イし社会が進むにつれて血栓症をはじめとす
る成人病の増加がクローズアップされてきており、特に
これらの疾患を抗血小板剤を用いて予防或いは治療しよ
うとする試みが注目されている。抗血小板剤としては、
その作用機序から種々の薬剤が知られているが実際に臨
床に応用されている薬剤は数少なく、必ずしも満足でき
るものではない。In recent years, as the population ages and society progresses, the increase in adult diseases such as thrombosis has come into focus, and efforts to prevent or treat these diseases using antiplatelet agents have been attracting particular attention. . As an antiplatelet agent,
Various drugs are known based on their mechanisms of action, but only a few have actually been used clinically, and they are not always satisfactory.
本発明者らは1種々の血栓症の予防或いは治療剤として
安全性の高い優れた薬効を示す化合物を得ることを目的
に鋭意研究を重ねた。その結果。The present inventors have conducted extensive research with the aim of obtaining a compound that is highly safe and exhibits excellent medicinal efficacy as a prophylactic or therapeutic agent for various thromboses. the result.
4.5−ジヒドロ−6−(4−置換フェニル)−3(2
H)−ピリダジノン誘導体のなかに所期の目的を達成す
る優れた化合物を見い出し1本発明を完成した。4.5-dihydro-6-(4-substituted phenyl)-3(2
The present invention was completed by discovering an excellent compound that achieves the desired objective among H)-pyridazinone derivatives.
[問題点を解決するための手段〕
本発明の4.5−ジヒドロ−6−(4−置換フェニル)
−3(2H)−ピリダジノン誘導体は。[Means for solving the problems] 4,5-dihydro-6-(4-substituted phenyl) of the present invention
-3(2H)-pyridazinone derivatives.
一般式CI) 〔式中、Rは水素原子又は低級アルキル基を示す。General formula CI) [In the formula, R represents a hydrogen atom or a lower alkyl group.
Aは水酸基、ハロゲン原子、シアン基、アミノ基。A is a hydroxyl group, a halogen atom, a cyan group, an amino group.
ジメチルアミノ基、ジエチルアミノ基、アセチル基、ヘ
ンジイル基、P−メトキシカルボニルフェニル基、フタ
ルイシド−1−イルL 3−フェニルピリダジン−6−
イル基、3−アニリノピリダジン−6−イル基、4−フ
ェニル−1−オキソイソキノリン−2−イル基、テトラ
ゾール−5−イル基、2−オキソベンズイミダゾール−
1−イル基、2−オキソベンズチアゾール−1−イル基
。Dimethylamino group, diethylamino group, acetyl group, hendiyl group, P-methoxycarbonylphenyl group, phthalicid-1-yl L 3-phenylpyridazine-6-
yl group, 3-anilinopyridazin-6-yl group, 4-phenyl-1-oxoisoquinolin-2-yl group, tetrazol-5-yl group, 2-oxobenzimidazole-
1-yl group, 2-oxobenzthiazol-1-yl group.
2−n−オクチルチオベンズイミダゾール−1−イル基
、1−メチルヒダントイン−1−イル基又は3−オキソ
フタラジン−2−イル基を示し、nは0から12の整数
を示す。〕で表わされる。 、一般式〔I〕において、
Rの低級アルキル基としては、メチル基、エチル基等が
例示できるonは好ましくは2から6の整数があげられ
る。It represents a 2-n-octylthiobenzimidazol-1-yl group, a 1-methylhydantoin-1-yl group, or a 3-oxophthalazin-2-yl group, and n represents an integer from 0 to 12. ]. , in general formula [I],
Examples of the lower alkyl group for R include a methyl group and an ethyl group, and on is preferably an integer from 2 to 6.
本発明の化合物CI’lは、下記反応式で示す方法によ
り容易に製造できる。Compound CI'l of the present invention can be easily produced by the method shown in the reaction formula below.
すなわち、目的の化合物(1)は、アニソールと対応す
るジカルボン酸無水物とのフリーデル・クラフト反応1
次いで臭化水素酸によるエーテル結合の開裂、更にヒド
ラジンとの藺環反応によって得られる化合物(II)と
ハロゲン化アルキルキル誘導体(II[)とを反応させ
て得ることができる(A法)、。That is, the target compound (1) can be obtained by Friedel-Crafts reaction 1 between anisole and the corresponding dicarboxylic acid anhydride.
It can then be obtained by reacting the compound (II) obtained by cleavage of the ether bond with hydrobromic acid and further ring reaction with hydrazine with the alkyl halide derivative (II[) (method A).
また、一般式(1)において八が窒素原子を含む前記例
示のような複素環残基である化合物(1〕は、へ法によ
って得られる化合物CI:A=X〕と、それぞれ対応す
る複素環化合物HAとの反応によっても製造できる(B
法)。Compound (1) in which 8 in general formula (1) is a heterocyclic residue as exemplified above containing a nitrogen atom is a compound CI:A=X] obtained by the hexamethod, and the corresponding heterocyclic ring It can also be produced by reaction with compound HA (B
law).
これらの脱ハロゲン化水素反応は、塩基性化合物を脱ハ
ロゲン化剤として用いて行なわれる。例えば、水酸化ナ
トリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリ
ウム、炭酸水素ナトリウム。These dehydrohalogenation reactions are carried out using a basic compound as a dehalogenation agent. For example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate.
炭酸水素カリウムなどの無機塩基、トリエチルアミン、
ピリジン、ジメチルアニリンなどの有機塩基があげられ
る。反応に用いられる溶媒としては。Inorganic bases such as potassium bicarbonate, triethylamine,
Examples include organic bases such as pyridine and dimethylaniline. As a solvent used in the reaction.
例えばメタノール、エタノール、プロパツール。For example, methanol, ethanol, propatool.
ブタノール等のアルコール類、テトラヒドロフラン、ジ
オキサン、エチレングリコールジメチルニーfル等のエ
ーテル類、アセトン、メチルエチルケトン等のケトン類
、ベンゼン、トルエン、キンレン等の芳香族炭化水素類
、N、N−ジメチルホルムアミド、ジメチルスルフオキ
シド等の非プロトン性溶媒などがあげられる。反応温度
は、通常室温〜200℃、好ましくは50〜150℃で
行なわれ1反応時間は1〜30時間であるが、好ましく
は1−15時間である。化合物cII!とハロゲン化ア
ルキル誘導体〔■〕、及び化合物〔■:Δ=X)と複素
環化合物HAの使用割合は、特に限定されず広い範囲内
で選択されるが1通常は前者に対して後者を等モル−5
倍モル使用され、好適には等モル−2倍モル使用するの
が有利である。Alcohols such as butanol, ethers such as tetrahydrofuran, dioxane, and ethylene glycol dimethyl nitrogen, ketones such as acetone and methyl ethyl ketone, aromatic hydrocarbons such as benzene, toluene, and quinolene, N,N-dimethylformamide, and dimethyl Examples include aprotic solvents such as sulfoxide. The reaction temperature is usually room temperature to 200°C, preferably 50 to 150°C, and one reaction time is 1 to 30 hours, preferably 1 to 15 hours. Compound cII! The proportions of the halogenated alkyl derivative [■], the compound [■:Δ=X), and the heterocyclic compound HA are not particularly limited and are selected within a wide range; however, the latter is usually equal to the former. Mol-5
It is advantageous to use double moles, preferably equimolar to twice moles.
本発明化合物(T)を医薬として使用する場合。When using the compound (T) of the present invention as a medicine.
経口的にも非経口的にも投与することができる。It can be administered either orally or parenterally.
化合物CI〕の投与量は患者の年齢1体重、或いは疾患
の程度などにより異なるが1通常1日当りの投与量は5
〜2000mg、好ましくは10〜500mgである。The dosage of Compound CI] varies depending on the patient's age, body weight, degree of disease, etc., but the usual dosage per day is 5.
-2000 mg, preferably 10-500 mg.
更に本発明の化合物〔■〕は、通常の経口又は非経口投
与に適した賦形剤との混合物の形で用いることもできる
。このような賦形剤としては1例えば乳糖、シヨ糖、カ
オリン、結晶セルロース。Furthermore, the compound [■] of the present invention can also be used in the form of a mixture with excipients suitable for conventional oral or parenteral administration. Such excipients include, for example, lactose, sucrose, kaolin, and crystalline cellulose.
コーンスターチ、ステアリン酸マグネシウム、グルコー
ス、タルク、塩化ナトリウム、レシチン。Cornstarch, magnesium stearate, glucose, talc, sodium chloride, lecithin.
ゼラチン、ペクチン、植物油などをあげることができる
。また1種々の剤型をとることができ1錠剤、散剤、頚
粒剤、カプセル剤、丸刑などの固形剤とすることができ
、安定剤、湿潤化剤、乳化剤等の補助剤を含むものであ
ってもよい。Examples include gelatin, pectin, and vegetable oil. In addition, it can take a variety of dosage forms, such as solid dosage forms such as tablets, powders, granules, capsules, and pills, and may contain auxiliary agents such as stabilizers, wetting agents, and emulsifiers. It may be.
次に本発明を実施例をあげて説明する。Next, the present invention will be explained by giving examples.
〔実施例1〕
4.5−ジヒドロ−6−C4−(3−クロルプロポキシ
)フェニル)−3(2H)−ピリダジノン
4.5−ジヒドロ−6−(4−ヒドロキシフェニル)−
3(2H)−ピリダジノン(W、V、Curran。[Example 1] 4.5-dihydro-6-C4-(3-chloropropoxy)phenyl)-3(2H)-pyridazinone 4.5-dihydro-6-(4-hydroxyphenyl)-
3(2H)-pyridazinone (W, V, Curran.
^、Ross、 J、 Med、 Chemo、 1
7 D)、 273 (1974))19gと1−ブロ
ム−3−クロルプロパン19g及び水酸化カリウム12
g をインプロパツール560m1と水70m1の混
液に加え4時間還流した。減圧下に溶媒を留去して残渣
をクロロホルムに溶解し、IN水酸化す) IJウム溶
液、IN塩酸。^, Ross, J., Med, Chemo, 1
7 D), 273 (1974)), 19 g of 1-bromo-3-chloropropane, and 12 g of potassium hydroxide.
g was added to a mixed solution of 560 ml of Improper Tool and 70 ml of water, and the mixture was refluxed for 4 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in chloroform and IN hydroxide) IJum solution, IN hydrochloric acid.
水で順次洗浄後、無水硫酸ナトリウムで乾燥、溶媒留去
し、残渣をエタノール−エーテルから再結晶して融点1
20℃の黄色針状晶15.5g(収率58.1%)を得
た。After successively washing with water, drying over anhydrous sodium sulfate, evaporating the solvent, and recrystallizing the residue from ethanol-ether to give a melting point of 1.
15.5 g (yield 58.1%) of yellow needle crystals at 20° C. were obtained.
元素分析 Cl 3 HO4N a O2Clとして
理論値(%) : C,58,54; H,5,63
; ’I、 10.51゜実測値(%) : C,5
8,36: H,5,54: N、 10.63゜IR
νman cm 、 1680 (cmo)N
MR(DMSOd+、)δ:2.18(2H。Elemental analysis Cl3HO4Na Theoretical value (%) as O2Cl: C, 58,54; H, 5,63
'I, 10.51゜Actual value (%): C, 5
8,36: H, 5,54: N, 10.63°IR
νman cm, 1680 (cmo)N
MR (DMSOd+,) δ: 2.18 (2H.
g、J=6Hz 、−CH,CH2CH,−)、2゜4
2 (2H,t、 J=7Hz 、 C−H) 、 2
.90 (2H,t、 J=7H,、C,−H) 、
3.78(2H,t、J=6Hz、−CH2C1)、4
.12(2H,t、J=68.、−0CH2−)、6.
95(2日、 a、 J=88.、A、 −H) 、
7.65 (2H,d、J=8z、Ar H)、10.
74 (IH。g, J=6Hz, -CH,CH2CH,-), 2゜4
2 (2H, t, J=7Hz, C-H), 2
.. 90 (2H, t, J=7H,,C,-H),
3.78 (2H, t, J=6Hz, -CH2C1), 4
.. 12 (2H, t, J=68., -0CH2-), 6.
95 (2 days, a, J=88., A, -H),
7.65 (2H, d, J=8z, Ar H), 10.
74 (IH.
S、 NH> 、 Mass (m/Z) : 26
6 (M+) 。S, NH>, Mass (m/Z): 26
6 (M+).
〔実施例2〕
4.5−ジヒドロ−6−(4−シアノメトキシフェニル
)−3(2H)−ピリダジノン4.5−ジヒドロ−6(
4−ヒドロキシフェニル)−3(2H)−ピリダジノン
3.8 g 、クロルアセトニトリル1.5 g 、炭
酸カリウム3gをジメチルホルムアミド59m1に加え
、100℃、4時間加熱攪拌した。以後実施例1と同様
にして融点174〜176℃の淡黄色針状晶1.2g(
収率26.2%)を得た。[Example 2] 4.5-dihydro-6-(4-cyanomethoxyphenyl)-3(2H)-pyridazinone 4.5-dihydro-6(
3.8 g of 4-hydroxyphenyl)-3(2H)-pyridazinone, 1.5 g of chloroacetonitrile, and 3 g of potassium carbonate were added to 59 ml of dimethylformamide, and the mixture was heated and stirred at 100° C. for 4 hours. Thereafter, in the same manner as in Example 1, 1.2 g of pale yellow needle crystals with a melting point of 174 to 176°C (
A yield of 26.2%) was obtained.
元素分析 CI 28 + 、N s O2理論値(
%) ’: C,62,88、H,4,80、N、
18.34実測値(%) : C,62,69; H
,4,95、N、 18.66+’ u J # L
1 11Rνv、ax C1−−1665(
C・0)N M R(D M S O−d s )δ:
2.44(2H。Elemental analysis CI 28 +, N s O2 theoretical value (
%) ': C, 62, 88, H, 4, 80, N,
18.34 Actual value (%): C, 62, 69; H
,4,95,N, 18.66+' u J # L
1 11Rνv, ax C1--1665(
C・0)NMR(DMSO-ds)δ:
2.44 (2H.
t、J=8Hz 、C,−H)、2.94 (2H,t
。t, J=8Hz, C, -H), 2.94 (2H, t
.
J=8H2、Cs −H) 、 5.17 (2H,S
、−CH2) 、 7.08 (2H,d、 J=8H
z、Ar−H)、7.74 (2H,d、J=8Hz、
Ar−H)、10.83 (LH,S、NH)。J=8H2, Cs-H), 5.17 (2H,S
, -CH2) , 7.08 (2H,d, J=8H
z, Ar-H), 7.74 (2H, d, J=8Hz,
Ar-H), 10.83 (LH, S, NH).
実施例2に従い、実施例3〜19の化合物を合成した。According to Example 2, the compounds of Examples 3 to 19 were synthesized.
得られた化合物及びその分析データを一括して第1表に
記載する。なお、第1表中の実施例20,21.22.
23.24のノヒ合物は、実施例15,16.17.1
8.19の化合物を。The obtained compounds and their analytical data are listed in Table 1. In addition, Examples 20, 21, 22. in Table 1.
Nohi compound of 23.24 is Example 15, 16.17.1
8.19 compounds.
それぞれガブリエル法に従ってヒドラジンヒトラード処
理して得た。Each was obtained by treatment with hydrazine hydride according to the Gabriel method.
第1表 A−(CH2)、つ()吾)す〔実施例2
5〕
4.5−ジヒドロ−6−C4−(3−(2−オキ゛ソベ
ンズオキサゾールー1−イル)プロポキシ)フェニル)
−3(2H)−ピリダジノン4.5−ジヒドロ−6−C
4−(3−(3−クロルブロホキシ)フェニルE−3(
2H)−ピリダジノン2.7g、2−ベンズオキサシリ
ノン1.5g、炭酸カリウム1.7gをDMF50ml
l:加え。Table 1 A-(CH2), Tsu()go) [Example 2
5] 4.5-dihydro-6-C4-(3-(2-oxobenzobenzoxazol-1-yl)propoxy)phenyl)
-3(2H)-pyridazinone 4,5-dihydro-6-C
4-(3-(3-chlorobrofoxy)phenyl E-3(
2.7 g of 2H)-pyridazinone, 1.5 g of 2-benzoxacylinone, and 1.7 g of potassium carbonate in 50 ml of DMF.
l: Add.
3時間加熱攪拌した。冷後、不溶物を炉去、溶媒を留去
し、残渣をクロロホルムに溶解、IN水酸化ナトリウム
溶液、IN塩酸、水で順次洗浄した後、無水硫酸す)
IJウムで乾燥した。溶媒を留去し残渣をエタノールよ
り再結晶して融点178〜180℃の無色針状晶1.8
g(収率50%)を得た。The mixture was heated and stirred for 3 hours. After cooling, insoluble matter was removed from the oven, the solvent was distilled off, the residue was dissolved in chloroform, and washed with IN sodium hydroxide solution, IN hydrochloric acid, and water in sequence, and then dissolved in anhydrous sulfuric acid.
It was dried with IJum. The solvent was distilled off and the residue was recrystallized from ethanol to give colorless needle crystals with a melting point of 178-180°C.
g (yield 50%) was obtained.
元素分析 C20H1s N s O−として理論値
(%) : C,65,75; it、 5.21 :
N、11.51゜実測値(%) : C,65,91
; H,5,16; N、11.34゜r Rシ二謬
@L Cm−’ : 1780 (Cm0)、
1680 (Cm0)NMR(DMSO−’ds )
δ:2.20(2H。Elemental analysis Theoretical value (%) as C20H1sNsO-: C, 65,75; it, 5.21:
N, 11.51° Actual value (%): C, 65,91
; H, 5, 16; N, 11.34゜r R error @L Cm-': 1780 (Cm0),
1680 (Cm0) NMR (DMSO-'ds)
δ: 2.20 (2H.
q、J=6H2,−CH2CH2CH2−)、2゜44
(2H,t、J=7Hz、C< H) 、2.8
8(2H,t、J=7Hz、C5H)、4.00 (2
H,t、J=6Hz、−CH,O−)、4.04 (2
H,t、 J=6H2,CH2N ) 、6.80
(2H,d、J=88.、 Ar−H)、7.0〜7
.3(4H,m、A、−H)、7.56 (2H,d、
J=8Hz、Ar−H)、10.72 (IH,S、N
H)
Mass (m/z);365 (M゛ )実施例25
に従い、実施例26〜38の化合物を合成した。得られ
た化合物及びその分析データを一括して第2表に記載す
る。q, J=6H2, -CH2CH2CH2-), 2゜44
(2H, t, J=7Hz, C<H), 2.8
8 (2H, t, J=7Hz, C5H), 4.00 (2
H, t, J=6Hz, -CH,O-), 4.04 (2
H, t, J=6H2,CH2N), 6.80
(2H, d, J=88., Ar-H), 7.0-7
.. 3 (4H, m, A, -H), 7.56 (2H, d,
J=8Hz, Ar-H), 10.72 (IH, S, N
H) Mass (m/z); 365 (M゛) Example 25
Compounds of Examples 26 to 38 were synthesized according to the following. The obtained compounds and their analytical data are listed in Table 2.
〔製剤例1〕
有効物質 50mg結晶セルロー
ス 40mgコーンスターチ
40mg乳糖 1
50mgステアリン酸マグネシウム 2.5 m
g上記混合物を通常の方法により打錠し、1錠中主薬
50mgを含有する錠剤を作製する。[Formulation Example 1] Active substance 50mg crystalline cellulose 40mg cornstarch
40mg lactose 1
50mg magnesium stearate 2.5 m
g The above mixture is compressed into tablets by a conventional method to prepare tablets containing 50 mg of the active ingredient per tablet.
〔製剤例2〕
有効物jlij 50mg乳@
100mgバレーショデン
プン 50mgタルク
20mgステアリン酸マグネシウム 5m
g上記混合物を常法に従って造粒し、顆粒剤とする。[Formulation Example 2] Active substance jlij 50mg milk @
100mg Vallecho starch 50mg Talc
20mg magnesium stearate 5m
g The above mixture is granulated according to a conventional method to obtain granules.
〔製剤例3〕
有効物質 5mgメタンスルホ
ン酸 2mg塩化ナトリウム
3mg注射用蒸留水 1m
lml上記音常法に従って混合して1mlアンプルを調
整する。[Formulation Example 3] Active substance 5mg methanesulfonic acid 2mg sodium chloride
3mg distilled water for injection 1m
Prepare a 1 ml ampoule by mixing according to the standard method above.
薬理実験
〔I〕血小板凝集抑制作用
本発明化合物の血小板凝集抑制作用をポーンの方法CG
、V、R,Born、Nature、927−929頁
(1962年)〕により測定した。Pharmacological experiment [I] Platelet aggregation inhibitory effect Method CG to demonstrate the platelet aggregation inhibitory effect of the compound of the present invention
, V.R., Born, Nature, pp. 927-929 (1962)].
すなわち、クエン酸加ウサギ血液を採取し、遠心分離操
作により血小板濃度の高い血漿(PPP)および血小板
濃度の低い血漿(PPP)を得た。That is, citrated rabbit blood was collected and centrifuged to obtain plasma with a high platelet concentration (PPP) and plasma with a low platelet concentration (PPP).
ついで、ジメチルスルフオキシドに溶解した被検化合物
1.5μlをPRP270μmに加え37℃で1分間イ
ンキュベーションした後、コラ−ケン又はΔDPを加え
凝集を若起した。血小板凝集はNKKヘマトレーサーで
測定し、被検化合物の50%抑制濃度(IC,。μM〉
は濃度抑制率曲線から求めた。なお、対照薬としてアス
ピリンを用いた。代表例の結果を第3表に示す。Next, 1.5 .mu.l of the test compound dissolved in dimethyl sulfoxide was added to 270 .mu.m of PRP and incubated at 37.degree. C. for 1 minute, followed by addition of Kolaken or .DELTA.DP to induce aggregation. Platelet aggregation was measured with NKK hematotracer, and the 50% inhibitory concentration (IC, μM) of the test compound was measured.
was determined from the concentration inhibition rate curve. Note that aspirin was used as a control drug. Table 3 shows the results of representative examples.
第3表
〔2〕急性毒性実験
被検薬を0.5%カルボキシメチルセルロース溶液に懸
濁し1体重20〜25gのDDY系雄性マウス(1群l
O匹)に経口投与して、投与後7日間の累積死亡率から
50%致死量(LD、。)を算出した。代表例の結果を
第4表に示す。対照薬として用いたアスピリンの結果に
ついても併記する。Table 3 [2] Acute toxicity test drug was suspended in 0.5% carboxymethyl cellulose solution and DDY male mice weighing 20-25 g (1 group)
The 50% lethal dose (LD, ) was calculated from the cumulative mortality rate for 7 days after administration. Table 4 shows the results of representative examples. The results of aspirin, which was used as a control drug, are also listed.
第4表
〔発明の効果〕
本発明化合物[1)はマウスを用いた毒性実験において
極めて毒性が低く、またその薬理作用は。Table 4 [Effects of the Invention] The compound [1] of the present invention has extremely low toxicity in toxicity experiments using mice, and its pharmacological effects are as follows.
in VitrOにおいて優れた血小板凝集抑制作用
を示し、抗血栓薬として1例えば脳血栓症。Shows excellent platelet aggregation inhibitory effect in VitrO, and is used as an antithrombotic agent, for example, for cerebral thrombosis.
脳塞栓症、末梢勤・静脈閉塞症等の予防及び治療に優れ
た効果を特徴するCharacterized by excellent effects on the prevention and treatment of cerebral embolism, peripheral occlusion and venous occlusion, etc.
Claims (6)
チルアミノ基、ジエチルアミノ基、アセチル基、ベンゾ
イル基、p−メトキシカルボニルフェニル基、フタルイ
ミド−1−イル基、3−フェニルピリダジン−6−イル
基、3−アニリノピリダジン−6−イル基、4−フェニ
ル−1−オキソイソキノリン−2−イル基、テトラゾー
ル−5−イル基、2−オキソベンズイミダゾール−1−
イル基、2−オキソベンズオキサゾール−1−イル基2
−オキソベンズチアゾール−1−イル基、2−n−オク
チルチオベンズイミダゾール−1−イル基、1−メチル
ヒダントイン−1−イル基又は3−オキソフタラジン−
2−イル基を示し、nは0から12の整数を示す。〕で
表わされる4,5−ジヒドロ−6−(4−置換フェニル
)−3(2H)−ピリダジノン誘導体。(1) General formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [I] [In the formula, R represents a hydrogen atom or a lower alkyl group. A is a hydroxyl group, a halogen atom, a cyano group, an amino group, a dimethylamino group, a diethylamino group, an acetyl group, a benzoyl group, a p-methoxycarbonylphenyl group, a phthalimid-1-yl group, a 3-phenylpyridazin-6-yl group, 3-anilinopyridazin-6-yl group, 4-phenyl-1-oxoisoquinolin-2-yl group, tetrazol-5-yl group, 2-oxobenzimidazole-1-
yl group, 2-oxobenzoxazol-1-yl group 2
-Oxobenzthiazol-1-yl group, 2-n-octylthiobenzimidazol-1-yl group, 1-methylhydantoin-1-yl group or 3-oxophthalazine-
It represents a 2-yl group, and n represents an integer from 0 to 12. ] A 4,5-dihydro-6-(4-substituted phenyl)-3(2H)-pyridazinone derivative.
nが2から6の整数で表わされる特許請求の範囲第1項
記載の化合物。(2) In the general formula [I], R is a hydrogen atom,
The compound according to claim 1, wherein n is an integer from 2 to 6.
ミノ基であり、nが3から6の整数で表わされる特許請
求の範囲第1項記載の化合物。(3) The compound according to claim 1, wherein in the general formula [I], R is a hydrogen atom, A is an amino group, and n is an integer from 3 to 6.
ミノ基であり、nが4の整数で表わされる特許請求の範
囲第3項記載の化合物。(4) The compound according to claim 3, wherein in the general formula [I], R is a hydrogen atom, A is an amino group, and n is an integer of 4.
−オキソベンズオキサゾール−1−イル基を示し、nが
2又は3の整数で表わされる特許請求の範囲第1項記載
の化合物。(5) In the general formula [I], R is a hydrogen atom, and A is 2
-oxobenzoxazol-1-yl group, and n is an integer of 2 or 3.
の範囲第4項記載の化合物。(6) The compound according to claim 4, which is in the form of a pharmacologically acceptable salt.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP29457586A JPS63145272A (en) | 1986-12-09 | 1986-12-09 | 4,5-dihydro-6-(4-substituted phenyl)-3(2h)-pyridazinone derivative |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP29457586A JPS63145272A (en) | 1986-12-09 | 1986-12-09 | 4,5-dihydro-6-(4-substituted phenyl)-3(2h)-pyridazinone derivative |
Publications (1)
Publication Number | Publication Date |
---|---|
JPS63145272A true JPS63145272A (en) | 1988-06-17 |
Family
ID=17809554
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP29457586A Pending JPS63145272A (en) | 1986-12-09 | 1986-12-09 | 4,5-dihydro-6-(4-substituted phenyl)-3(2h)-pyridazinone derivative |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS63145272A (en) |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5698554A (en) * | 1995-06-27 | 1997-12-16 | Tanabe Seiyaku Co., Ltd. | Pyridazinone derivatives and processes for preparing the same |
WO2001019818A1 (en) * | 1999-09-14 | 2001-03-22 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Phthalazinone derivatives as pd3/4 inhibitors |
US6410536B1 (en) | 1998-03-31 | 2002-06-25 | Warner-Lambert Company | Quinoxalinones as serine protease inhibitors such as factor XA and thrombin |
US7652009B2 (en) | 2004-11-30 | 2010-01-26 | Amgem Inc. | Substituted heterocycles and methods of use |
US7858623B2 (en) | 2005-04-27 | 2010-12-28 | Amgen Inc. | Substituted amide derivatives and methods of use |
US8207168B2 (en) | 2006-07-25 | 2012-06-26 | Cephalon, Inc. | Pyridazinone derivatives |
US20160200711A1 (en) * | 2014-04-25 | 2016-07-14 | Pfizer Inc. | Heteroaromatic compounds and their use as dopamine d1 ligands |
KR20180118717A (en) * | 2016-03-04 | 2018-10-31 | 오츠카 세이야쿠 가부시키가이샤 | 5-methyl-6-phenyl-4,5-dihydro-2H-pyridazin-3- |
-
1986
- 1986-12-09 JP JP29457586A patent/JPS63145272A/en active Pending
Cited By (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5698554A (en) * | 1995-06-27 | 1997-12-16 | Tanabe Seiyaku Co., Ltd. | Pyridazinone derivatives and processes for preparing the same |
US5808065A (en) * | 1995-06-27 | 1998-09-15 | Tanabe Seiyaku Co., Ltd. | Pyridazinone derivatives and processes for preparing the same |
US6410536B1 (en) | 1998-03-31 | 2002-06-25 | Warner-Lambert Company | Quinoxalinones as serine protease inhibitors such as factor XA and thrombin |
US6916805B2 (en) | 1998-03-31 | 2005-07-12 | Warner-Lambert Company Llc | Quinoxalinones as serine protease inhibitors |
WO2001019818A1 (en) * | 1999-09-14 | 2001-03-22 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Phthalazinone derivatives as pd3/4 inhibitors |
US7652009B2 (en) | 2004-11-30 | 2010-01-26 | Amgem Inc. | Substituted heterocycles and methods of use |
US8685983B2 (en) | 2005-04-27 | 2014-04-01 | Amgen Inc. | Method of treating cancer with substituted amide derivatives |
US8088794B2 (en) | 2005-04-27 | 2012-01-03 | Amgen Inc. | Substituted amide derivatives and methods of use |
US7858623B2 (en) | 2005-04-27 | 2010-12-28 | Amgen Inc. | Substituted amide derivatives and methods of use |
US8207168B2 (en) | 2006-07-25 | 2012-06-26 | Cephalon, Inc. | Pyridazinone derivatives |
US8247414B2 (en) | 2006-07-25 | 2012-08-21 | Cephalon, Inc. | Pyridizinone derivatives and the use thereof as H3 inhibitors |
US8586588B2 (en) | 2006-07-25 | 2013-11-19 | Cephalon, Inc. | Aryl pyridazinone derivatives and their use as H3 receptor ligands |
US8673916B2 (en) | 2006-07-25 | 2014-03-18 | Cephalon, Inc. | Methods of treating disorders mediated by histamine H3 receptors using pyridazinone derivatives |
US20160200711A1 (en) * | 2014-04-25 | 2016-07-14 | Pfizer Inc. | Heteroaromatic compounds and their use as dopamine d1 ligands |
US9850232B2 (en) * | 2014-04-25 | 2017-12-26 | Pfizer Inc. | Heteroaromatic compounds and their use as dopamine D1 ligands |
KR20180118717A (en) * | 2016-03-04 | 2018-10-31 | 오츠카 세이야쿠 가부시키가이샤 | 5-methyl-6-phenyl-4,5-dihydro-2H-pyridazin-3- |
JP2019506432A (en) * | 2016-03-04 | 2019-03-07 | 大塚製薬株式会社 | 5-Methyl-6-phenyl-4,5-dihydro-2H-pyridazin-3-one derivative |
US10611731B2 (en) | 2016-03-04 | 2020-04-07 | Otsuka Pharmaceutical Co., Ltd. | 5-methyl-6-phenyl-4,5-dihydro-2H-pyridazin-3-one derivative |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JPH054983A (en) | Isoquinolinone derivative, its production and 5-ht3 receptor antagonist containing the derivative as active component | |
JPH0912560A (en) | Improved antiviral compound | |
JPH0224821B2 (en) | ||
JP2009542642A (en) | New pyridine analogues | |
JPS63145272A (en) | 4,5-dihydro-6-(4-substituted phenyl)-3(2h)-pyridazinone derivative | |
JPS6322082A (en) | 1-(hydroxystiryl)-5h-2, 3-benzodiazepine derivative and its production, drug containing said derivative and its production | |
DK151803B (en) | METHOD OF ANALOGUE FOR THE PREPARATION OF N-PYRROLYLPYRIDAZINAMINE DERIVATIVES OR PHARMACEUTICAL ACCEPTABLE SALTS THEREOF | |
WO1997026242A1 (en) | 3-(bis-substituted-phenylmethylene)oxindole derivatives | |
JPH02223570A (en) | 2-imino-6-polyfluoroalkoxybenzothiazole derivative, preparation thereof, and pharmaceutical composition containing same | |
JPH03106875A (en) | 1-(3-pyridylmethyl)phthalazine derivative | |
JPS58128384A (en) | Benzodioxine compound, manufacture and medicinal composition for psychotic trouble treatment | |
CZ325196A3 (en) | Derivatives of hydroximic acid, pharmaceutical compositions containing thereof, process of their preparation and intermediates used in the preparation process | |
HU181608B (en) | Process for producing imidazo-thieno-pyrimidine derivatives | |
US4929616A (en) | Novel basic-substituted 5-halo-thienoisothiazol-3(2H)-one 1,1-dioxides, a process for the preparation thereof, and pharmaceutical preparations containing these compounds | |
HU197003B (en) | Process for producing new isoxazole derivatives and pharmaceuticals comprising same | |
CA2584918A1 (en) | Cyanothiophenes, the production thereof and their use as medicaments | |
JPH02129180A (en) | 1-(1h-imidazol-1-yl)phthalazine derivative | |
JPS63139172A (en) | 4,5-dihydro-6-(6-substituted-2-naphthyl)-3(2h)-pyridazinone derivative | |
JPH02129183A (en) | 1-anilino-4-(1h-imidazol-1-yl)phthalazine derivative and platelet agglutination inhibitor containing the same as active ingredient | |
JP2757353B2 (en) | Indane derivative, its production method and its synthetic intermediate | |
JPS63141970A (en) | 4,5-dihydro-6-(4-substituted phenyl)-3(2h)-pyridazinone derivative | |
JPH03106873A (en) | 1-pyridylphthalazine derivative and inhibitor of blood platelet agglutination containing same derivative | |
JPH05148250A (en) | Antithrombotic agent containing oxadiazine derivative as active ingredient | |
JPS59141565A (en) | Psychotropic pyridazine derivative, manufacture and drug | |
JPH02129181A (en) | 1-aryl-4-(1h-imidazol-1-yl)phthalazine derivative |