JPH02129181A - 1-aryl-4-(1h-imidazol-1-yl)phthalazine derivative - Google Patents
1-aryl-4-(1h-imidazol-1-yl)phthalazine derivativeInfo
- Publication number
- JPH02129181A JPH02129181A JP28018188A JP28018188A JPH02129181A JP H02129181 A JPH02129181 A JP H02129181A JP 28018188 A JP28018188 A JP 28018188A JP 28018188 A JP28018188 A JP 28018188A JP H02129181 A JPH02129181 A JP H02129181A
- Authority
- JP
- Japan
- Prior art keywords
- group
- compound
- imidazol
- imidazole
- phthalazine
- 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
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical class C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 title abstract description 5
- -1 benzyloxyphenyl Chemical group 0.000 claims abstract description 29
- 125000001424 substituent group Chemical group 0.000 claims abstract description 11
- 125000001624 naphthyl group Chemical group 0.000 claims abstract description 6
- 125000001544 thienyl group Chemical group 0.000 claims abstract description 5
- 125000005036 alkoxyphenyl group Chemical group 0.000 claims abstract description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 abstract description 19
- 238000006243 chemical reaction Methods 0.000 abstract description 15
- 229940127218 antiplatelet drug Drugs 0.000 abstract description 6
- 239000000106 platelet aggregation inhibitor Substances 0.000 abstract description 6
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 abstract description 4
- 238000005695 dehalogenation reaction Methods 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 4
- 101000783577 Dendroaspis angusticeps Thrombostatin Proteins 0.000 abstract description 3
- 101000783578 Dendroaspis jamesoni kaimosae Dendroaspin Proteins 0.000 abstract description 3
- 239000003795 chemical substances by application Substances 0.000 abstract description 3
- 238000007911 parenteral administration Methods 0.000 abstract description 3
- 150000007514 bases Chemical class 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 abstract description 2
- 150000005303 alkyl halide derivatives Chemical class 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract 1
- SXPUVBFQXJHYNS-UHFFFAOYSA-N α-furil Chemical compound C=1C=COC=1C(=O)C(=O)C1=CC=CO1 SXPUVBFQXJHYNS-UHFFFAOYSA-N 0.000 abstract 1
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 239000002904 solvent Substances 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000002844 melting Methods 0.000 description 9
- 230000008018 melting Effects 0.000 description 9
- 238000000921 elemental analysis Methods 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 6
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 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
- 239000010446 mirabilite Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- RSIJVJUOQBWMIM-UHFFFAOYSA-L sodium sulfate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O RSIJVJUOQBWMIM-UHFFFAOYSA-L 0.000 description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- WWQJMQMALOQQBJ-UHFFFAOYSA-N 2-[[4-[(6-methoxypyridazin-3-yl)sulfamoyl]phenyl]carbamoyl]benzoic acid Chemical compound N1=NC(OC)=CC=C1NS(=O)(=O)C(C=C1)=CC=C1NC(=O)C1=CC=CC=C1C(O)=O WWQJMQMALOQQBJ-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 2
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-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
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 150000001350 alkyl halides Chemical class 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 description 1
- NDVLTSGHYBLBFR-UHFFFAOYSA-N 1-(furan-2-yl)-4-imidazol-1-ylphthalazine Chemical compound C1=COC(C=2C3=CC=CC=C3C(N3C=NC=C3)=NN=2)=C1 NDVLTSGHYBLBFR-UHFFFAOYSA-N 0.000 description 1
- APEHSTWDNWPSEK-UHFFFAOYSA-N 1-chloro-4-(furan-2-yl)phthalazine Chemical compound C12=CC=CC=C2C(Cl)=NN=C1C1=CC=CO1 APEHSTWDNWPSEK-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
- KHIILJVSYUGMSE-UHFFFAOYSA-N 1-phenylphthalazine Chemical class C1=CC=CC=C1C1=NN=CC2=CC=CC=C12 KHIILJVSYUGMSE-UHFFFAOYSA-N 0.000 description 1
- 125000006479 2-pyridyl methyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 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
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 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
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- 206010050661 Platelet aggregation inhibition Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- WVHBHPATSLQXGC-UHFFFAOYSA-N benzene;ethanol Chemical compound CCO.C1=CC=CC=C1 WVHBHPATSLQXGC-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 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
- 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
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- FHHZOYXKOICLGH-UHFFFAOYSA-N dichloromethane;ethanol Chemical compound CCO.ClCCl FHHZOYXKOICLGH-UHFFFAOYSA-N 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000002552 dosage form Substances 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
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 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
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000011630 iodine Chemical group 0.000 description 1
- 229910052740 iodine Chemical group 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 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
- 229940080428 lactose 200 mg Drugs 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
- 231100001231 less toxic Toxicity 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- BEATZJALKXTWKH-UHFFFAOYSA-N n,4-diphenylphthalazin-1-amine Chemical class N=1N=C(C=2C=CC=CC=2)C2=CC=CC=C2C=1NC1=CC=CC=C1 BEATZJALKXTWKH-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- JBJWASZNUJCEKT-UHFFFAOYSA-M sodium;hydroxide;hydrate Chemical compound O.[OH-].[Na+] JBJWASZNUJCEKT-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は、血小板凝集抑制剤として有用な１−アリール
−４−（ＩＨ−イミダゾール−１−イル）フタラジン誘
導体に関するものである。DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to 1-aryl-4-(IH-imidazol-1-yl)phthalazine derivatives useful as platelet aggregation inhibitors.
■−アルキルアミノー４−フェニルフタラジンが抗炎症
剤として英国特許第１３０３０６１号に、特開昭６０−
２１８３７７には循環改善剤として、また、１−アニリ
ノ−４−フェニルフタラジン誘導体が特開昭５６−５３
６５９、特開昭５６−５３６６０及び特開昭５７−４８
９７２に血小板凝集抑制剤として開示されている。■-Alkylamino-4-phenylphthalazine was published as an anti-inflammatory agent in British Patent No. 1303061, JP-A-60-
No. 218377 also contains 1-anilino-4-phenyl phthalazine derivatives as a circulation improving agent.
659, JP-A-56-53660 and JP-A-57-48
972 as a platelet aggregation inhibitor.
しかしながら、イミダゾール環を持つフェニルフタラジ
ン誘導体については、なんら示唆するところは無い。However, there is no suggestion whatsoever regarding phenyl phthalazine derivatives having an imidazole ring.
近年、高齢化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使用されているが、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０本発明者らは種々の血栓症の予防或
いは治療剤として安全性の高いまた優れた薬効を示す化
合物を得ることを目的として鋭意研究を重ねた。その結
果、１−アリール−４−（ＬＨ−イミダゾール−１−イ
ル）フタラジン誘導体の中に所期の目的を達成する優れ
た化合物を見出し本発明を完成した。In recent years, as the aging of society progresses, an increase in adult diseases such as thrombosis has been attracting attention, and attempts to prevent or treat these diseases using antiplatelet agents have been attracting particular attention. Various drugs are used as antiplatelet agents due to their mechanisms of action, but there are only a few drugs that have actually been applied clinically, and they are not necessarily satisfactory. We have conducted extensive research with the aim of obtaining compounds that are highly safe and exhibit excellent medicinal efficacy as preventive or therapeutic agents. As a result, the present invention was completed by discovering an excellent compound among 1-aryl-4-(LH-imidazol-1-yl)phthalazine derivatives that achieves the desired purpose.
本発明は、下記一般式（１）
（式中、Ｒは低級アルコキシフェニル基、アリルオキシ
フェニル基、ピリジルメチルオキシフェニル基、ベンジ
ルオキシフェニル基、置換基を有することもあるフリル
基、置換基を有することもあるチエニル基又は置換基を
有することもあるナフチル基）で表わされる１−アリー
ル−４−（１Ｈ−イミダゾール−１−イル）フタラジン
誘導体に係わる。The present invention is based on the following general formula (1) (wherein R is a lower alkoxyphenyl group, an allyloxyphenyl group, a pyridylmethyloxyphenyl group, a benzyloxyphenyl group, a furyl group which may have a substituent, or a substituent. It relates to 1-aryl-4-(1H-imidazol-1-yl)phthalazine derivatives represented by a thienyl group (which may have a thienyl group or a naphthyl group which may have a substituent).
一般式（Ｉ）においてＲに関し、具体的には４−エトキ
シフェニル基、４−プロポキシフェニル基、４−イソプ
ロポキシフェニル基、４−ブトキシフェニル基、４−イ
ソブトキシフェニル基、４−アリルオキシフェニルｉＦ
、４−（２−ピリジルメトキシ）フェニル基、４−（３
−ピリジルメトキシ）フェニル基、４−（４−ピリジル
メトキシ）フェニルＬ４−（４−メトキシベンジルオキ
シ）フェニル基、４−エトキシカルボニルメトキシフェ
ニル基、２−フリル基、２−チエニル基、５−エチル−
２−チエニル基、１−ナフチル基、２−メトキシ−１−
ナフチル基並びに６−メドキシー２−ナフチル基等を例
示できる。Regarding R in general formula (I), specific examples include 4-ethoxyphenyl group, 4-propoxyphenyl group, 4-isopropoxyphenyl group, 4-butoxyphenyl group, 4-isobutoxyphenyl group, 4-allyloxyphenyl group. iF
, 4-(2-pyridylmethoxy)phenyl group, 4-(3
-pyridylmethoxy)phenyl group, 4-(4-pyridylmethoxy)phenyl L4-(4-methoxybenzyloxy)phenyl group, 4-ethoxycarbonylmethoxyphenyl group, 2-furyl group, 2-thienyl group, 5-ethyl-
2-thienyl group, 1-naphthyl group, 2-methoxy-1-
Examples include naphthyl group and 6-medoxy-2-naphthyl group.
本発明化合物は、以下に示す〔反応式−１〕及び〔反応
式−２〕の方法により合成することができる。The compound of the present invention can be synthesized by the methods of [Reaction Formula-1] and [Reaction Formula-2] shown below.
〔反応式−１〕
〔式中、Ｒ１は低級アルキル基、アリル基、ピリジルメ
チル基並びにベンジル基を示し、更に具体的にはエチル
基、プロピル基、イソプロピル基、４−ブトキシフェニ
ル基、イソブチル基、アリル基、２−ピリジルメチル基
、３−ピリジルメチル基、４−ピリジルメチル基、４−
メトキシベンジル基及びエトキシカルボニルメチル基を
示し、またＸは塩素、臭素およびヨウ素を示す。〕本反
応の目的化合物（Ｉａ）は、（Ｉ Ｉ）と種々のハロゲ
ン化アルキル誘導体を常法により脱ハロゲン化反応に付
して得ることが出来る。この脱ハロゲン化反応は塩基性
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、炭酸カリウム等の無機塩基、トリエチルアミン、ピ
リジン、ジメチルアニリン、１．８−ジアザアビシクロ
（５，４，０）−７−ウンデセン（ＤＢＵ）の有機塩基
があげられる。溶媒としては、メタノール、エタノール
、プロパツール、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
ルエーテル等のエーテル類、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、キシレン等の
芳香族炭化水素類、Ｎ、 Ｎ−ジメチルホルムアミド、
ジメチルスルホキシド等の非プロトン性溶媒などが挙げ
られる。反応温度は、通常室温〜１００°Ｃ１好ましく
は室温〜５０’Ｃで行われ、反応時間は１時間〜２４時
間であるが、好ましくは１〜１２時間である。[Reaction formula-1] [In the formula, R1 represents a lower alkyl group, an allyl group, a pyridylmethyl group, or a benzyl group, and more specifically, an ethyl group, a propyl group, an isopropyl group, a 4-butoxyphenyl group, an isobutyl group. , allyl group, 2-pyridylmethyl group, 3-pyridylmethyl group, 4-pyridylmethyl group, 4-
It represents a methoxybenzyl group and an ethoxycarbonylmethyl group, and X represents chlorine, bromine and iodine. ] The target compound (Ia) of this reaction can be obtained by subjecting (II) and various halogenated alkyl derivatives to a dehalogenation reaction in a conventional manner. This dehalogenation reaction is carried out using a basic compound as a dehalogenation agent. For example, inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate; organic bases such as triethylamine, pyridine, dimethylaniline, and 1,8-diazabicyclo(5,4,0)-7-undecene (DBU); can give. Examples of solvents include alcohols such as methanol, ethanol, propatool, and butanol; ethers such as tetrahydrofuran, dioxane, and ethylene glycol dimethyl ether; ketones such as acetone and methyl ethyl ketone; aromatic hydrocarbons such as benzene, toluene, and xylene; N, N-dimethylformamide,
Examples include aprotic solvents such as dimethyl sulfoxide. The reaction temperature is usually room temperature to 100°C, preferably room temperature to 50°C, and the reaction time is 1 hour to 24 hours, preferably 1 to 12 hours.
化合物（Ｉ Ｉ〕とハロゲン化アルキルの使用割合は、
特に限定されず広い範囲内で選択されるが、好適には等
モル−２倍モル使用するのが有利である。The usage ratio of compound (II) and alkyl halide is:
Although it is not particularly limited and can be selected within a wide range, it is advantageous to use equimolar to twice the molar amount.
〔反応式−２〕
（式中、Ｒ２は置換基を有することもあるフリル基、置
換基を有することもあるチエニル基又は置換基を有する
こともあるナフチル基で表される。[Reaction Formula-2] (In the formula, R2 is represented by a furyl group that may have a substituent, a thienyl group that may have a substituent, or a naphthyl group that may have a substituent.
さらに具体的には２−フリル基、２−チエニル基、５−
エチル−２−チエニル基１．１−ナフチル基、２−メト
キシ−１−ナフチル基並びに６−メドキシー２−ナフチ
ル基等を例示することができる。）
一般式（ｒ Ｉ Ｉ）で示される１−了り−ルー４クロ
ロフタラジンは公知の方法［薬学雑誌、８６巻、５７６
頁、１９６６年］で合成した。次に化合物（Ｉ ｂ）は
化合物（Ｉ Ｉ Ｉ〕にイミダゾールを反応させること
により製造することができる。More specifically, 2-furyl group, 2-thienyl group, 5-
Examples include ethyl-2-thienyl group, 1-naphthyl group, 2-methoxy-1-naphthyl group, and 6-medoxy-2-naphthyl group. ) The 1-ori-ru-4chlorophthalazine represented by the general formula (r II) can be prepared by a known method [Pharmaceutical Journal, Vol. 86, 576
Page, 1966]. Next, compound (I b) can be produced by reacting compound (I II) with imidazole.
本反応に用いられる溶媒としては、例えば、ベンゼン、
トルエン、キシレン等の芳香族炭化水素類、テトラヒド
ロフラン、ジオキサン、エチレングリコールジエチルエ
ーテル、エチレングリコールジメチルエーテル等のエー
テル類、アセトン、メチルエチルケトン等のケトン類、
Ｎ、Ｎ−ジメチルホルムアミド、ジメチルスルホキシド
、アセトニトリル、ピリジン等が挙げられるが、無溶媒
でもよい。反応温度は５０°Ｃ〜２００°Ｃで、反応時
間は１時間〜２４時間で行えるが、６０〜１５０ ’Ｃ
で、１時間〜８時間で行うのが好適である。Examples of the solvent used in this reaction include benzene,
Aromatic hydrocarbons such as toluene and xylene, ethers such as tetrahydrofuran, dioxane, ethylene glycol diethyl ether and ethylene glycol dimethyl ether, ketones such as acetone and methyl ethyl ketone,
Examples include N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, pyridine, etc., but no solvent may be used. The reaction temperature is 50°C to 200°C, and the reaction time is 1 hour to 24 hours, but the reaction time is 60 to 150°C.
Therefore, it is preferable to carry out the treatment for 1 to 8 hours.
本反応に用いられる化合物（ＩＩＩ）とイミダゾールの
使用割合としては、通常前者に対して後者を２〜５倍モ
ル使用する。本反応には、炭酸ナトリウム、炭酸カリウ
ム等の無機塩基、トリエチルアミン、Ｎ、Ｎ−ジエチル
アニリン等の三級アミン類、水素化ナトリウム等の塩基
を用いることができるが、塩基としては、過剰のイミダ
ゾールを使用することもできる。The ratio of compound (III) and imidazole used in this reaction is usually 2 to 5 times the molar ratio of the former to the latter. In this reaction, inorganic bases such as sodium carbonate and potassium carbonate, tertiary amines such as triethylamine, N,N-diethylaniline, and bases such as sodium hydride can be used. You can also use
本発明化合物（Ｉ）を医薬品として使用する場合、経口
的にも非経口的にも投与できる。化合物（１）の投与量
は患者の年令、体重、或いは疾患の程度などにより異な
るが通常−日当たりの投与量は５〜２０００ｍｇ、好ま
しくは１０〜５００ｍｇである。When the compound (I) of the present invention is used as a pharmaceutical, it can be administered either orally or parenterally. The dosage of compound (1) varies depending on the patient's age, body weight, degree of disease, etc., but the usual daily dosage is 5 to 2000 mg, preferably 10 to 500 mg.
更に本発明の化合物（Ｉ）は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、例えば、乳糖、ショ糖、カオリン
、結晶セルロース、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、ゼラチン、ベプチン、植物油等をあげることがで
きる。Furthermore, the compound (I) of the present invention can also be used in the form of a mixture with excipients suitable for oral or parenteral administration. Examples of such excipients include lactose, sucrose, kaolin, crystalline cellulose, corn starch, magnesium stearate, glucose, talc, sodium chloride, lecithin, gelatin, veptin, vegetable oil, and the like.
また、種々の剤形をとることができ、錠剤、顆粒剤、散
剤、カプセル剤、丸刑などの固形製剤をとることができ
、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。更に、非経口投与の場合には注射剤として
用いる事ができる。In addition, it can take various dosage forms, including solid preparations such as tablets, granules, powders, capsules, and pills, and may contain adjuvants such as stabilizers, wetting agents, and emulsifiers. There may be. Furthermore, in the case of parenteral administration, it can be used as an injection.
次に実施例を挙げて本発明を説明する。Next, the present invention will be explained with reference to Examples.
〔実施例１〕
１−クロロ−４−（４−アセトキシフェニル）フタラジ
ン８．０ｇ及びイミダゾール５．５ｇをＤ Ｍ Ｆ ５
０ｄに加え、１００°Ｃで攪拌下、３時間反応した。６
後、減圧下に溶媒を留去し、更に２回水洗した。有機層
を芒硝で乾燥し、溶媒を減圧留去し、メタノールから再
結晶して、１−（１）１−イミダゾール−１−イル）−
４−（４−ヒドルキシフェニル）フタラジン（ＩＩ）
３．３ｇを得た。[Example 1] 8.0 g of 1-chloro-4-(4-acetoxyphenyl)phthalazine and 5.5 g of imidazole were mixed in DMF 5
0d and reacted at 100°C for 3 hours with stirring. 6
Thereafter, the solvent was distilled off under reduced pressure, and the mixture was further washed twice with water. The organic layer was dried with Glauber's salt, the solvent was distilled off under reduced pressure, and recrystallized from methanol to give 1-(1)1-imidazol-1-yl)-
4-(4-hydroxyphenyl)phthalazine (II)
3.3g was obtained.
化合物［１１：ｌ ３．Ｏｇと炭酸カリウム２．０ｇを
ＤＭＦ５０ｄのなかに加え、室温で３０分間攪拌した後
、臭化エチル２．５ｇを滴下し、室温で１０時間攪拌し
た。Compound [11:l 3. After adding Og and 2.0 g of potassium carbonate into DMF50d and stirring at room temperature for 30 minutes, 2.5 g of ethyl bromide was added dropwise, and the mixture was stirred at room temperature for 10 hours.
ＤＭＦを減圧留去後、残渣を塩化メチレンに溶解し、１
０χＮａＯＨ水、水で順次洗浄し、有機層を芒硝で乾燥
し、減圧留去した後、エタノール−ベンゼンから再結晶
して、１−（ＬＨ−イミダゾール−１〜イル）−４−（
４−エトキシフェニル）フタラジン２．０ｇヲ得た。After distilling off DMF under reduced pressure, the residue was dissolved in methylene chloride, and 1
The organic layer was washed successively with 0x NaOH water and water, dried over Glauber's salt, distilled off under reduced pressure, and then recrystallized from ethanol-benzene to give 1-(LH-imidazol-1-yl)-4-(
2.0 g of 4-ethoxyphenyl)phthalazine was obtained.
融点２０６〜２０７°Ｃ
元素分析： Ｃ＋Ｊ＋Ｊ４０として
理論値（χ）： Ｃ，７２，１３； Ｈ，５，０９；
Ｎ、１７．７０実測値α）： Ｃ，７１，８２； Ｈ＋
５．１６．； Ｎ、１７．７５Ｎ Ｍ Ｒ（ＤＭＳＯ−
ｄり ６ ： １．４１ （３Ｈ，ｔ Ｊ＝７Ｈ２，Ｃ
Ｈ２（Ｈ；１） 。Melting point 206-207°C Elemental analysis: Theoretical value (χ) as C+J+J40: C, 72,13; H, 5,09;
N, 17.70 actual value α): C, 71,82; H+
5.16. ; N, 17.75NMR(DMSO-
dri 6: 1.41 (3H,t J=7H2,C
H2(H;1).
４．１７（２Ｈ，ｑ Ｊ＝７）１ｘ、Ｃ１１ｚＣＨｚ）
、７．１９（２Ｈ，ｄ Ｊ＝８．５Ｈｚ、Ａｒ−Ｈ＞。4.17 (2H, q J=7) 1x, C11zCHz)
, 7.19 (2H, d J=8.5Hz, Ar-H>.
７．３０（ＩＨ，ｓ、イミダゾール−Ｈ）、７．７３（
１８，ｄ Ｊ＝８．５Ｈｚ、Ａｒ−Ｈ）。7.30 (IH, s, imidazole-H), 7.73 (
18, d J = 8.5 Hz, Ar-H).
７．９０（ＩＨ，ｓ、イミダゾール−Ｈ）、８．０１−
８．０４ （ＩＨ，ｍ、Ａｒ−Ｈ）。7.90 (IH,s, imidazole-H), 8.01-
8.04 (IH, m, Ar-H).
８．１１−８．１６（３Ｈ，ｍ、Ａｒ−Ｈ）、８．３５
（１８，ｓ、イミダゾール−Ｈ）。8.11-8.16 (3H, m, Ar-H), 8.35
(18,s, imidazole-H).
Ｍａ ｓ ｓ （ｍ／ｅ） ： ３１６ （Ｍ” ）
〔実施例２〜１０）
実施例１の方法に従い、化合物（ＩＩ）に対応するハロ
ゲン化アルキルを反応させることにり、実施例２〜１０
の化合物を合成した。得られた化合物の融点、収率を一
括して第１表に記載した。Mass (m/e): 316 (M”)
[Examples 2 to 10] Examples 2 to 10 were prepared by reacting the alkyl halide corresponding to compound (II) according to the method of Example 1.
The compound was synthesized. The melting points and yields of the obtained compounds are summarized in Table 1.
第１表
〔実施例１１）
原料化合物（ＩＩ） ２．０ｇと１．８−ジアザアビシ
クロ［５，４，０）−７−ウンデセン（ＤＢＵ） １．
６ｇを１００戚のイソプロピルアルコール加熱還流下、
ブロモ酢酸エチル１．６ｇを滴下した。滴下終了後、４
時間加熱還流し、６後、溶媒を減圧留去し、残渣を塩化
メチレンに溶解し、１０χＮａＯＨＭ水、水で順次洗浄
し、有機層を芒硝で乾燥した。溶媒を減圧留去し、残渣
をシリカゲルクロマトグラフィーに付し、塩化メチレン
−エタノールで展開すると、１− （ＩＨ−イミダゾー
ル−１−イル）−４〜（４−エトキシカルボニルメトキ
シフェニル）フタラジン０．３ｇを得た。Table 1 [Example 11] 2.0 g of starting compound (II) and 1.8-diazabicyclo[5,4,0)-7-undecene (DBU) 1.
6g was heated under reflux with 100% isopropyl alcohol,
1.6 g of ethyl bromoacetate was added dropwise. After completion of dripping, 4
The mixture was heated under reflux for 6 hours, and after 6 hours, the solvent was distilled off under reduced pressure, and the residue was dissolved in methylene chloride, washed successively with 10×NaOHM water and water, and the organic layer was dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography and developed with methylene chloride-ethanol to obtain 0.3 g of 1-(IH-imidazol-1-yl)-4-(4-ethoxycarbonylmethoxyphenyl)phthalazine. I got it.
融点１２５〜１２８°Ｃ
元素分析： Ｃ□Ｈ＋ｅＮａＯ３・０．２）１！Ｏとし
て理論値α’）： Ｃ，６６，７２、Ｈ，４，９０、Ｎ
、１４．８２実測値α’）： Ｃ，６６，７２、Ｈ，４
，９８，； Ｎ、１４．６ＯＮ Ｍ Ｒ（ＤＭＳＯ−ｃ
ｌｈ）δ： １．２５（３Ｈ，ｔ Ｊ＝７Ｈ２，ＣＨ２
Ｃｌ）。Melting point 125-128°C Elemental analysis: C□H+eNaO3・0.2)1! Theoretical value α' for O: C, 66, 72, H, 4, 90, N
, 14.82 actual measurement value α'): C, 66, 72, H, 4
,98,; N, 14.6ON MR(DMSO-c
lh) δ: 1.25 (3H, t J=7H2, CH2
Cl).
４．２２（２Ｈ，ｑ Ｊ＝７Ｈｚ、ＣＨｚＣＨ３）、
４．９ （２Ｈ，Ｓ、−ＣＨ２０−）。4.22 (2H, q J=7Hz, CHzCH3),
4.9 (2H,S, -CH20-).
７．２１ （２Ｈ，ｄ Ｊ＝８．５Ｈｚ、Ａｒ−Ｈ）
、７．３１ （ＩＨ，ｓ、イミダゾール−Ｈ）。7.21 (2H, dJ=8.5Hz, Ar-H)
, 7.31 (IH,s, imidazole-H).
７．７４（２Ｈ，ｄ Ｊ＝８．５Ｈｚ、Ａｒ−Ｈ）、
７．９１（ＩＨ，ｓ、イミダゾール−Ｈ）。7.74 (2H, dJ=8.5Hz, Ar-H),
7.91 (IH,s, imidazole-H).
８．０１−８．１７（４８，ｎ＋、Ａｒ−Ｈ）、８．３
６（ＩＨ，ｓ、イミダゾール−Ｈ）。8.01-8.17 (48, n+, Ar-H), 8.3
6 (IH,s, imidazole-H).
Ｍａ ｓ ｓ （ｍ／ｅ） ： ３７４ （Ｍ’
）〔実施例１２〕
１−クロロ−４−（２−フリル）フタラジン２．０ｇ及
びイミダゾール１．８ｇをＤＭＦ５０ｉＦ！に加え、１
００ ”Ｃで攪拌下、５時間反応した。６後、減圧下に
溶媒を留去し、得られた残渣にをクロロホルムに溶解し
水洗した。を機層を芒硝で乾燥し、減圧留去し、エタノ
ール−エーテルから再結晶して、１−（ＩＨ−イミダゾ
ール−１−イル）−４−（２−フリル）フタラジン１．
０ｇを得た。Ma s s (m/e): 374 (M'
) [Example 12] 2.0 g of 1-chloro-4-(2-furyl)phthalazine and 1.8 g of imidazole were mixed in DMF50iF! In addition to 1
The reaction was carried out for 5 hours with stirring at 0.00"C. After 6 hours, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in chloroform and washed with water. The organic layer was dried with sodium sulfate and evaporated under reduced pressure. , recrystallized from ethanol-ether to give 1-(IH-imidazol-1-yl)-4-(2-furyl)phthalazine 1.
Obtained 0g.
融点１４８〜１４９°Ｃ
元素分析： Ｃ＋ｓＨｒ。Ｎ、Ｏとして理論値（χ）：
Ｃ，６Ｂ、６９ ； Ｈ，３，８４； Ｎ、２１．３
７実測値α）： Ｃ，６Ｂ、８１ ； Ｈ，３，９５，
； Ｎ、２１．４２Ｎ Ｍ Ｒ（ＤＭＳＯ−ｄ、）
δ ： ６．８〜７．０（ＩＨ，ｍ、フラン−Ｈ）Ｉ７
．３６（ＬＨ，ｓ、イミダゾール−Ｈ）、７．４４〜７
．６０（ＬＨ，ｍ、万：ｚ−１）。Melting point 148-149°C Elemental analysis: C+sHr. Theoretical value (χ) for N and O:
C, 6B, 69; H, 3,84; N, 21.3
7 Actual measurement value α): C, 6B, 81; H, 3, 95,
; N, 21.42NMR (DMSO-d,)
δ: 6.8-7.0 (IH, m, furan-H) I7
．． 36 (LH,s, imidazole-H), 7.44-7
．． 60 (LH, m, 10,000:z-1).
７．８６（ＬＨ，ｓ、イミダゾール−Ｈ）、８．０−８
．４０（３）１．ｎ、Ａｒ−Ｈ）、８．４０（ＬＨ，ｓ
、便ダシールーＨ）、８．８−９．０（３Ｈ，ｔｏ、Ａ
ｒ−Ｈ）。7.86 (LH,s, imidazole-H), 8.0-8
．． 40(3)1. n, Ar-H), 8.40 (LH, s
, stool Dashiru H), 8.8-9.0 (3H, to, A
r-H).
Ｍａ ｓ ｓ （ｍ／ａ） ： ２６２ （Ｍ”
）〔実施例１３〕
１−クロロ−４−（２−チエニル）フタラジン４．０ｇ
及びイミダゾール３．３８をＤＭＦ５０戚に加え、１４
０°Ｃで攪拌下、３時間反応した。６後、減圧下に溶媒
を留去し、得られた残渣をクロロホルムに溶解し水洗し
た。有機層を芒硝で乾燥し、減圧留去し、メタノール−
エーテルから再結晶して、１−（ＩＨ−イミダゾール−
１−イル）−４−（２−チエニル）フタラジン１．０ｇ
を得た。Mass (m/a): 262 (M”
) [Example 13] 4.0 g of 1-chloro-4-(2-thienyl)phthalazine
and imidazole 3.38 to DMF50 relative, 14
The reaction was carried out at 0°C for 3 hours with stirring. After 6 days, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in chloroform and washed with water. The organic layer was dried with mirabilite, evaporated under reduced pressure, and diluted with methanol.
Recrystallized from ether to give 1-(IH-imidazole-
1-yl)-4-(2-thienyl)phthalazine 1.0g
I got it.
融点１６０〜１６３°Ｃ０
元素分析： Ｃ＋ｓＨ＋。Ｎ、Ｓとして理論値ＣＺ”）
： Ｃ，６４，７２； Ｈ，３，６２、Ｎ、２０．１３
実測値α）： Ｃ，６４，５１； Ｈ，３，８８； Ｎ
、２０．０５Ｎ Ｍ Ｒ（ＤＭＳＯ−ｄａ） δ ：
７．２８−７．４８（２Ｈ，ｓ、イミダゾール−Ｈ
，Ａｒ−Ｈ）、７．８−８．３２（６８，ｍ、イミダゾ
ール−Ｈ，Ａｒ−Ｈ）、８．４０（ＩＨ，ｓ、イミダゾ
ール−Ｈ）、８．６０−８．７６（ＬＨ，ｍ、Ａｒ−Ｈ
）。Melting point 160-163°C0 Elemental analysis: C+sH+. Theoretical value CZ” for N and S)
: C, 64,72; H, 3,62, N, 20.13
Actual measurement value α): C, 64,51; H, 3,88; N
, 20.05N M R (DMSO-da) δ:
7.28-7.48 (2H,s, imidazole-H
, Ar-H), 7.8-8.32 (68, m, imidazole-H, Ar-H), 8.40 (IH, s, imidazole-H), 8.60-8.76 (LH, m, Ar-H
).
Ｍａ ｓ ｓ （ｍ／ｅ） ： ２７８ （Ｍ”
）〔実施例１４〕
１−り四ロー４−（５−エチル−２−チエニル）フタラ
ジン３．５ｇ及びイミダゾール４．３ｇをＤＭＦ７０ｄ
に加え、１００°Ｃで攪拌下、４時間反応した。６後、
減圧下に溶媒を留去し、得られた残渣にをクロロフォル
ムに溶解し水洗した。有機層を芒硝で乾燥し、減圧留去
し、エタノールから再結晶して、１− （ＬＨ−イミダ
ゾール−１−イル）−４−（５−エチル−２−チエニル
）フタジン１．４ｇを得た。Mass (m/e): 278 (M”
) [Example 14] 3.5 g of 1-ri-4-(5-ethyl-2-thienyl)phthalazine and 4.3 g of imidazole were dissolved in DMF70d.
In addition, the mixture was reacted at 100°C for 4 hours with stirring. After 6,
The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in chloroform and washed with water. The organic layer was dried with Glauber's salt, evaporated under reduced pressure, and recrystallized from ethanol to obtain 1.4 g of 1-(LH-imidazol-1-yl)-4-(5-ethyl-2-thienyl)phthadine. .
融点１５４〜１５６°Ｃ０
元素分析’ ＣＩＨＩ４Ｎ４Ｓとして理論値α＞：
Ｃ，６６，６４； ）１，４．６１ ； Ｎ、１８．２
９実測値α）： Ｃ，６６，３７； Ｈ，４，Ｓ４ 、
Ｎ、１８．３９Ｎ Ｍ Ｒ（ＤＭＳＯ−ｄ＆） δ
： １．３５（３Ｈ，ｔ Ｊ＝７．５Ｈｚ。Melting point 154-156°C0 Elemental analysis' Theoretical value α as CIHI4N4S>:
C, 66, 64; ) 1, 4.61; N, 18.2
9 actual measurement value α): C, 66, 37; H, 4, S4,
N, 18.39N M R (DMSO-d&) δ
: 1.35 (3H, tJ=7.5Hz.
ＣＨｚＣＨｉ）、２．９６（２）１．ｑ Ｊ＝７．５Ｈ
ｚ、Ｃ）ｌｚｃＨｚ）、 ７．１０−７．１２（１）１
．ｍ、チオ７ｚ：ｚ−Ｈ）、７．３０（ＩＨ，ｓ、化ダ
シールー）１）、７．７７（ＬＨ，ｄＪ＝３．７Ｈｚ、
チオ）ｚン−Ｈ）、７．８７（１８，ｓ、イミダゾール
−Ｈ）、７．９８−８．１９（３Ｈ，ｍ、Ａｒ−Ｈ）、
８．３２（ＬＨ，ｓ、イミダゾール−Ｈ）、８．６５（
ＬＨ。CHzCHi), 2.96 (2) 1. q J=7.5H
z, C)lzcHz), 7.10-7.12(1)1
．． m, thio7z:z-H), 7.30 (IH, s, chloride) 1), 7.77 (LH, dJ = 3.7Hz,
thio)zn-H), 7.87 (18,s, imidazole-H), 7.98-8.19 (3H,m, Ar-H),
8.32 (LH,s, imidazole-H), 8.65 (
LH.
ｄ Ｊ＝８Ｈｚ、 Ａｒ−Ｈ）。d J=8Hz, Ar-H).
Ｍａ ｓ ｓ （ｍ／ｅ） ： ３０６ （Ｍ”
）〔実施例１５］
１−クロロ−４−（１−ナフチル）フタラジン１５ｇ及
びイミダゾール１７．６ｇをＤＭＦ２００ｄに加え、１
００°Ｃで攪拌下、３時間反応した。６後、減圧下に溶
媒を留去し、得られた残渣にを塩化メチレンに熔解し水
洗した＝有機層を芒硝で乾燥し、減圧留去し、ベンゼン
−エタノールから再結晶して、１−（ＩＨ−イミダゾー
ル−１−イル）−４−（１−ナフチル）フタジン５．８
ｇを得た。Mass (m/e): 306 (M”
) [Example 15] 15 g of 1-chloro-4-(1-naphthyl)phthalazine and 17.6 g of imidazole were added to 200 d of DMF, and 1
The reaction was carried out at 00°C for 3 hours with stirring. After 6, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in methylene chloride and washed with water. (IH-imidazol-1-yl)-4-(1-naphthyl)phthazine 5.8
I got g.
融点２３１〜２３４°Ｃ０
元素分析： Ｃｚ＋Ｈ＋４Ｎ４として
理論値Ｃ％）： Ｃ，７８，２４； Ｈ，４，３７；
Ｎ、１７．３７実測値（χ）： Ｃ，７８，３０、Ｈ，
４，２９； Ｎ、１７．４４Ｎ Ｍ Ｒ（ＤＭＳＯ−ｄ
６） δ ： ７．３３（ＩＨ，ｓ、化ダシ−＋に−
Ｈ）。Melting point 231-234°C0 Elemental analysis: Theoretical value C% as Cz+H+4N4): C, 78,24; H, 4,37;
N, 17.37 Actual value (χ): C, 78,30, H,
4,29; N, 17.44NMR(DMSO-d
6) δ: 7.33 (IH, s, conversion to + to -
H).
７．６５−７．７０（２Ｈ，ｍ、Ａｒ−Ｈ）、７．９０
−７．９５（２１（、ｍ、Ａｒ−Ｈ＋イミダゾール−Ｈ
）、８．０８−８．２１ （７Ｈ，ｍ、Ａｒ−Ｈ）、８
．３７（ＩＨ，ｓ、イミダゾール−Ｈ）、８．４０（１
）１．ｓ、Ａｒ−Ｈ） 。7.65-7.70 (2H, m, Ar-H), 7.90
-7.95(21(, m, Ar-H+imidazole-H
), 8.08-8.21 (7H, m, Ar-H), 8
．． 37 (IH,s, imidazole-H), 8.40 (1
)1. s, Ar-H).
Ｍａ ｓ ｓ （ｍ／ｅ） ： ３２２ （Ｍ″″）
［実施例１６］
１−クロロ−４−（２−メトキシ−１−ナフチル）フタ
ラジン２．８ｇ及びイミダゾール２．８ｇをＤＭＦ５０
戚に加え、１００°Ｃで攪拌下、５時間反応した。６後
、減圧下に溶媒を留去し、得られた残渣にを塩化メチレ
ンに溶解し水洗した。有機層を芒硝で乾燥し、減圧留去
した後、エタノールから再結晶して、１（ＩＨ−イミダ
ゾール−１−イル）−４−（２−メトキシ−１＝ナフチ
ル）フタジン２．０ｇを得た。Mass (m/e): 322 (M″″)
[Example 16] 2.8 g of 1-chloro-4-(2-methoxy-1-naphthyl)phthalazine and 2.8 g of imidazole were dissolved in DMF50
The mixture was added to the mixture and reacted at 100°C for 5 hours with stirring. After 6 days, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in methylene chloride and washed with water. The organic layer was dried with Glauber's salt, evaporated under reduced pressure, and then recrystallized from ethanol to obtain 2.0 g of 1(IH-imidazol-1-yl)-4-(2-methoxy-1=naphthyl)phthazine. .
融点１９８〜２００’Ｃ。Melting point 198-200'C.
元素分析二０２□ＨＩ６８４０として
理論値（χ）： Ｃ，７４，９８； Ｈ，４，５７；
Ｎ、１５．８９実測値（χ）： Ｃ，７４，６９； Ｈ
，４，７０； Ｎ、１５．９ＯＮＭＲ（聞５Ｏ−ｄ６）
δ： ３．８０（３Ｈ，ｓ、Ｏｃ！Ｕｉ）、７．０
５（ＩＨ，ｄ Ｊ＝８Ｈｚ、Ａｒ−１（）、７．３１
（１８，ｓ、イミダゾール−〇）、７．３３−７．４４
（２Ｈ，ｍ、Ａｒ−Ｈ）、７．５１（ＩＨ，ｄ Ｊ＝８
Ｈｚ、Ａｒ−Ｈ）、７．７３（ＬＨ，ｄ Ｊ＝９Ｈｚ
、Ａｒ−Ｈ）、７．９４−８．１３（５Ｈ，ｍ、Ａｒ−
Ｈ＋イミタゾール−Ｈ）、８．２６（ＩＨ，ｄ Ｊ＝
９）！ｚ、Ａｒ−Ｈ）、８．４７（ＩＨ，ｓ、イミダゾ
ールーＨ） 。Elemental analysis 202□Theoretical value (χ) as HI6840: C, 74,98; H, 4,57;
N, 15.89 Actual value (χ): C, 74,69; H
,4,70; N, 15.9ONMR (min.5O-d6)
δ: 3.80 (3H,s, Oc!Ui), 7.0
5 (IH, d J = 8 Hz, Ar-1 (), 7.31
(18,s, imidazole-〇), 7.33-7.44
(2H, m, Ar-H), 7.51 (IH, d J=8
Hz, Ar-H), 7.73 (LH, d J=9Hz
, Ar-H), 7.94-8.13 (5H, m, Ar-
H + imitazole-H), 8.26 (IH, d J=
9)! z, Ar-H), 8.47 (IH, s, imidazole-H).
Ｍａ ｓ ｓ （ｍ／ｅ） ： ３５２ （Ｍ” ）
〔実施例１７〕
１−クロロ−４−（６−メドキシー２−ナフチル）フタ
ラジン７．５ｇ及びイミダゾール８．０ｇをＤＭＦｌｏ
ｏｄに加え、１００°Ｃで攪拌下、５時間反応した。６
後、減圧下に溶媒を留去し、得られた残渣にを塩化メチ
レンに溶解し水洗した。を機層を芒硝で乾燥し、減圧留
去した後、エタノールから再結晶して、１−（ＩＨ−イ
ミダゾール−１−イル）−４−（６−メドキシー２−ナ
フチル）フタジン３．０ｇを得た。Mass (m/e): 352 (M")
[Example 17] 7.5 g of 1-chloro-4-(6-medoxy-2-naphthyl)phthalazine and 8.0 g of imidazole were added to DMFlo.
od and reacted at 100°C for 5 hours with stirring. 6
Thereafter, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in methylene chloride and washed with water. The organic layer was dried with Glauber's salt, evaporated under reduced pressure, and then recrystallized from ethanol to obtain 3.0 g of 1-(IH-imidazol-1-yl)-4-(6-medoxy-2-naphthyl)phthazine. Ta.
融点２６４〜２６５°Ｃゆ
元素分析： ＣｚＪ＋６Ｎ４０・０．１８２０として理
論値（χ）： Ｃ，７４，６０； ｉ（，４，６１；
Ｎ、１５．８１実測値（χ）： Ｃ，７４，７４； Ｈ
，４，５３； Ｎ、１５．８２Ｎ Ｍ Ｒ（ＤＭＳＯ−
ｄ＆） δ： ３．９６（３Ｈ，ｓ、０Ｃｈ）、７．２
８−７．３３（２８，ｍ、ｚ、Ａｒ−Ｈ＋イミダシート
Ｈ）、７．５１（１８，ｓ、Ａｒ−Ｈ）。Melting point 264-265°C Elemental analysis: Theoretical value (χ) as CzJ+6N40・0.1820: C, 74,60; i(,4,61;
N, 15.81 Actual value (χ): C, 74, 74; H
, 4,53; N, 15.82NMR(DMSO-
d&) δ: 3.96 (3H, s, 0Ch), 7.2
8-7.33 (28, m, z, Ar-H + imida sheet H), 7.51 (18, s, Ar-H).
７．８５−８．３０（９Ｈ，ｍ、Ａｒ−Ｈ＋イミダゾー
ル−Ｈ）、８．３９（ＩＨ，ｓ、イミダゾルーＨ）。7.85-8.30 (9H, m, Ar-H+imidazole-H), 8.39 (IH, s, imidazole-H).
Ｍａ ｓ ｓ （ｍ／ｅ） ： ３５２ （Ｍ”
）〔製剤例１〕
有効物質 ５０ｍｇ
乳糖 ２００ｍｇ
結晶セルロース ４Ｑｍｇステアリン酸マ
グネシウム ５ｍｇ
上記混合物を常法に従って混合し、打錠することにより
生薬５０■を含有する錠剤を得た。Mass (m/e): 352 (M”
) [Formulation Example 1] Active substance 50mg Lactose 200mg Crystalline cellulose 4Qmg Magnesium stearate 5mg The above mixture was mixed in a conventional manner and tableted to obtain a tablet containing 50 ml of crude drug.
〔製剤例２〕
有効物質 ５０ｍｇ
乳糖 ９０ｍｇ
とうもろこし澱粉 ６０ｍｇタルク
３０ｍｇステアリン酸マグネシウム １
０ｍｇ
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 50mg Lactose 90mg Corn starch 60mg Talc
30mg magnesium stearate 1
0 mg The above mixture is granulated according to a conventional method to obtain granules.
〔製剤例３］
有効物質 １０ｍｇ溶解補助剤
（所望により使用） 適量塩化ナトリウム（所望によ
り使用）適量注射用蒸留水 １ｄ上
上記骨を常法に従って混合し、アンプル充填後滅菌する
ことにより、注射用アンプルを作製する。[Formulation Example 3] Active substance: 10 mg Solubilizing agent (used as desired) Appropriate amount of sodium chloride (used as desired) Appropriate amount of distilled water for injection Prepare an ampoule.
［発明の効果］
本発明化合物は、Ｉｎ Ｖｉｔｒｏにおける血小板凝集
抑制試験においてアスピリンよりも強い活性を示すと共
に動物実験においても毒性が低い事が確認された。[Effects of the Invention] It was confirmed that the compound of the present invention exhibits stronger activity than aspirin in an in vitro platelet aggregation inhibition test, and is also less toxic in animal experiments.
本発明化合物は、血小板凝集抑制剤として優れた効果を
特徴するThe compound of the present invention is characterized by excellent effects as a platelet aggregation inhibitor.
Claims (1)
フェニル基、ピリジルメチルオキシフェニル基、ベンジ
ルオキシフェニル基、置換基を有することもあるフリル
基、置換基を有することもあるチエニル基又は置換基を
有することもあるナフチル基）で示される１−アリール
−４−（１Ｈ−イミダゾール−１−イル）フタラジン誘
導体。(1) General formula [I] ▲Mathematical formulas, chemical formulas, tables, etc.▼[I] (In the formula, R is a lower alkoxyphenyl group, allyloxyphenyl group, pyridylmethyloxyphenyl group, benzyloxyphenyl group, substituent 1-aryl-4-(1H-imidazol-1-yl)phthalazine derivatives represented by a furyl group, which may have a substituent, a thienyl group, which may have a substituent, or a naphthyl group, which may have a substituent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP28018188A JPH02129181A (en) | 1988-11-04 | 1988-11-04 | 1-aryl-4-(1h-imidazol-1-yl)phthalazine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP28018188A JPH02129181A (en) | 1988-11-04 | 1988-11-04 | 1-aryl-4-(1h-imidazol-1-yl)phthalazine derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH02129181A true JPH02129181A (en) | 1990-05-17 |
Family
ID=17621427
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP28018188A Pending JPH02129181A (en) | 1988-11-04 | 1988-11-04 | 1-aryl-4-(1h-imidazol-1-yl)phthalazine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH02129181A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5324727A (en) * | 1991-09-26 | 1994-06-28 | Mitsubishi Chem Ind | 3,6-disubstituted pyridazine derivatives |
| JP2007536276A (en) * | 2004-05-08 | 2007-12-13 | ニューロジェン・コーポレーション | 3-Aryl-5,6-disubstituted pyridazines |
-
1988
- 1988-11-04 JP JP28018188A patent/JPH02129181A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5324727A (en) * | 1991-09-26 | 1994-06-28 | Mitsubishi Chem Ind | 3,6-disubstituted pyridazine derivatives |
| US5462941A (en) * | 1991-09-26 | 1995-10-31 | Mitsubishi Chemical Corporation | 3,6-disubstituted pyradazine derivatives |
| JP2007536276A (en) * | 2004-05-08 | 2007-12-13 | ニューロジェン・コーポレーション | 3-Aryl-5,6-disubstituted pyridazines |
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