JPH04211666A - 4-phenylphthalazine derivative - Google Patents
4-phenylphthalazine derivativeInfo
- Publication number
- JPH04211666A JPH04211666A JP6294091A JP6294091A JPH04211666A JP H04211666 A JPH04211666 A JP H04211666A JP 6294091 A JP6294091 A JP 6294091A JP 6294091 A JP6294091 A JP 6294091A JP H04211666 A JPH04211666 A JP H04211666A
- Authority
- JP
- Japan
- Prior art keywords
- group
- carbon atoms
- compound
- formula
- alkyl
- 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
- KHIILJVSYUGMSE-UHFFFAOYSA-N 1-phenylphthalazine Chemical class C1=CC=CC=C1C1=NN=CC2=CC=CC=C12 KHIILJVSYUGMSE-UHFFFAOYSA-N 0.000 title claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 22
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims abstract description 6
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 5
- 239000002253 acid Substances 0.000 claims abstract description 4
- 230000003287 optical effect Effects 0.000 claims abstract description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 35
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 15
- 125000005843 halogen group Chemical group 0.000 claims description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 abstract description 39
- 230000002401 inhibitory effect Effects 0.000 abstract description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 7
- 208000035475 disorder Diseases 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 7
- 206010061216 Infarction Diseases 0.000 abstract description 4
- 230000007574 infarction Effects 0.000 abstract description 4
- 230000003449 preventive effect Effects 0.000 abstract description 4
- 206010008132 Cerebral thrombosis Diseases 0.000 abstract description 3
- 201000001429 Intracranial Thrombosis Diseases 0.000 abstract description 3
- 201000010849 intracranial embolism Diseases 0.000 abstract description 3
- 229940124597 therapeutic agent Drugs 0.000 abstract description 3
- 206010008088 Cerebral artery embolism Diseases 0.000 abstract description 2
- 230000004087 circulation Effects 0.000 abstract description 2
- 230000000747 cardiac effect Effects 0.000 abstract 2
- 206010059245 Angiopathy Diseases 0.000 abstract 1
- 230000004520 agglutination Effects 0.000 abstract 1
- 210000001772 blood platelet Anatomy 0.000 abstract 1
- 230000002490 cerebral effect Effects 0.000 abstract 1
- 230000008602 contraction Effects 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- 230000000302 ischemic effect Effects 0.000 abstract 1
- 230000003902 lesion Effects 0.000 abstract 1
- 230000003836 peripheral circulation Effects 0.000 abstract 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 14
- -1 te rt-butyl group Chemical group 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 235000002639 sodium chloride Nutrition 0.000 description 9
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- 239000000203 mixture Substances 0.000 description 7
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- 241000416162 Astragalus gummifer Species 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 229920001615 Tragacanth Polymers 0.000 description 6
- 239000000196 tragacanth Substances 0.000 description 6
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- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
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- 229940079593 drug Drugs 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
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- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-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
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 210000000038 chest Anatomy 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- 210000004351 coronary vessel Anatomy 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 125000001153 fluoro group Chemical group F* 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
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- 208000031225 myocardial ischemia Diseases 0.000 description 3
- WJJDLSHYLZRFDD-UHFFFAOYSA-N 1-chloro-4-phenylphthalazine Chemical compound C12=CC=CC=C2C(Cl)=NN=C1C1=CC=CC=C1 WJJDLSHYLZRFDD-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 102000008186 Collagen Human genes 0.000 description 2
- 108010035532 Collagen Proteins 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- 206010050661 Platelet aggregation inhibition Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-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
- 239000003054 catalyst Substances 0.000 description 2
- 208000026106 cerebrovascular disease Diseases 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 229920001436 collagen Polymers 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 150000004677 hydrates Chemical class 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
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 125000006606 n-butoxy group Chemical group 0.000 description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 2
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- 210000002381 plasma Anatomy 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 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
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- 235000020357 syrup Nutrition 0.000 description 2
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- RQEUFEKYXDPUSK-SSDOTTSWSA-N (1R)-1-phenylethanamine Chemical compound C[C@@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-SSDOTTSWSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 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
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- KDFDOINBXBEOLZ-UHFFFAOYSA-N 2-phenylpropan-2-amine Chemical compound CC(C)(N)C1=CC=CC=C1 KDFDOINBXBEOLZ-UHFFFAOYSA-N 0.000 description 1
- GLHCKIVVETUBAN-UHFFFAOYSA-N 4-phenylphthalazin-1-amine Chemical class C12=CC=CC=C2C(N)=NN=C1C1=CC=CC=C1 GLHCKIVVETUBAN-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical class CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
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- 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
- 239000008101 lactose Substances 0.000 description 1
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- 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
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229940039748 oxalate Drugs 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000000312 peanut oil Substances 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
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000003516 pericardium Anatomy 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 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
- 239000008363 phosphate buffer Substances 0.000 description 1
- WTYSCLHDMXBMKM-UHFFFAOYSA-N phthalazin-1-amine Chemical class C1=CC=C2C(N)=NN=CC2=C1 WTYSCLHDMXBMKM-UHFFFAOYSA-N 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 235000013772 propylene glycol Nutrition 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
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000003826 tablet Substances 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
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【0001】0001
【産業上の利用分野】本発明は血小板凝集抑制作用を有
することにより、脳血栓、脳塞栓等の脳血管障害、心筋
梗塞等の虚血性心疾患および末梢循環障害などの循環障
害に対する予防治療薬として有用なアミノフタラジン誘
導体、更に詳しくは1−α−置換ベンジルアミノ−4−
フェニルフタラジン誘導体、または薬学上許容されるそ
の酸付加塩に関する。[Industrial Application Field] The present invention has a platelet aggregation inhibiting effect, and is therefore used as a preventive treatment for cerebrovascular disorders such as cerebral thrombosis and cerebral emboli, ischemic heart diseases such as myocardial infarction, and circulatory disorders such as peripheral circulatory disorders. Useful aminophthalazine derivatives, more particularly 1-α-substituted benzylamino-4-
The present invention relates to phenyl phthalazine derivatives or pharmaceutically acceptable acid addition salts thereof.
【0002】0002
【従来の技術】心筋梗塞、狭心症等の虚血性心疾患、脳
血栓、脳塞栓症等の脳血管障害、末梢循環障害などの循
環障害は、多くの場合血管内に血栓が形成され、血管が
閉塞されることにより引き起こされる。これは、血栓形
成の初期段階で起こる血小板凝集が重要な要因となって
いる。[Prior Art] Circulatory disorders such as myocardial infarction, ischemic heart diseases such as angina, cerebrovascular disorders such as cerebral thrombosis and cerebral embolism, and peripheral circulatory disorders are often caused by the formation of blood clots within blood vessels. is caused by blockage. Platelet aggregation, which occurs at the initial stage of thrombus formation, is an important factor in this.
【0003】従来、このような血小板凝集を抑制する作
用を有する化合物として、各種の4−フェニルフタラジ
ン誘導体が知られている。例えば特開昭56−5365
9号公報、同56−53660号公報および同57−4
897号公報には1−アニリノ−4−フェニルフタラジ
ン誘導体が、また特開昭60−218377号公報およ
び同60−243074号公報には下記の2化合物が開
示されており、in vitroで強力な血小板凝集抑
制作用を有することが開示されている。Conventionally, various 4-phenylphthalazine derivatives have been known as compounds having the effect of inhibiting platelet aggregation. For example, JP-A-56-5365
Publication No. 9, Publication No. 56-53660 and Publication No. 57-4
No. 897 discloses a 1-anilino-4-phenyl phthalazine derivative, and JP-A-60-218377 and JP-A No. 60-243074 disclose the following two compounds, which have strong in vitro properties. It is disclosed that it has a platelet aggregation inhibitory effect.
【化2】[Case 2]
【化3】[Chemical formula 3]
【0004】しかし、これらの化合物は経口投与ではほ
とんど作用を示さなかったり、実際のvivoの系にお
ける血小板凝集抑制作用は十分とは言えないものであっ
た。
一方、英国特許第1303016号、ジャーナル・オブ
・メディシナル・ケミストリー(J.Med.Chem
.), 12, 555(1969)等に下記(IV)
式で表わされる1−アミノ−4−フェニルフタラジン誘
導体が開示されている。[0004] However, these compounds show almost no effect when administered orally, and their platelet aggregation inhibiting effects in actual in vivo systems cannot be said to be sufficient. On the other hand, British Patent No. 1303016, Journal of Medicinal Chemistry (J.Med.Chem.
.. ), 12, 555 (1969), etc. (IV)
1-Amino-4-phenylphthalazine derivatives of the formula are disclosed.
【化4】
しかし、具体的に開示された同化合物は構造が限られて
おり、その薬理作用については抗炎症作用や抗リウマチ
作用が記載されているのみである。##STR00004## However, the structures of the specifically disclosed compounds are limited, and only anti-inflammatory and anti-rheumatic actions have been described regarding their pharmacological actions.
【0005】[0005]
【課題を解決するための手段】本発明者らは、4−フェ
ニルフタラジン誘導体の中で、vivoの系においても
優れた血小板凝集抑制作用を有し、更に心筋梗塞巣縮少
等の障害部位における障害性変化を直接抑制する作用を
も有する化合物について探索を行った結果、4−フェニ
ルフタラジン骨格の1位に特定のα−置換ベンジルアミ
ノ基を有する化合物がかかる要件を満足することを見出
し、本発明を完成するに至った。[Means for Solving the Problems] The present inventors have discovered that among 4-phenylphthalazine derivatives, they have an excellent platelet aggregation inhibitory effect even in vivo, and furthermore, they have been found to have an excellent platelet aggregation inhibiting effect in the in vivo system, and furthermore, they have been found to As a result of searching for compounds that also have the effect of directly suppressing the harmful changes in , we have completed the present invention.
【0006】即ち本発明の要旨は、下記式(I):That is, the gist of the present invention is the following formula (I):
【化
5】
[式中、R1は炭素数1〜5のアルキル基または炭素数
1〜5のヒドロキシアルキル基を表わし、R2は水素原
子または炭素数1〜5のアルキル基を表わすか、R1お
よびR2が互いに連結して酸素原子を有していてもよい
炭素数2〜6のアルキレン基を形成する。R3およびR
4はそれぞれ独立して水素原子、ハロゲン原子、炭素数
1〜4のアルキル基または炭素数1〜4のアルコキシ基
を表わすか、隣接するR3またはR4同志で−O−(C
H2)p−O− (pは1〜3の整数を表わす)を形成
し、R5は水素原子、ハロゲン原子、炭素数1〜4のア
ルキル基、炭素数1〜4のアルコキシ基、トリフルオロ
メチル基またはヒドロキシル基を表わすか、隣接するR
5同志で−O−(CH2)p−O−を形成する。lおよ
びmはそれぞれ独立して1または2を表わし、nは1〜
3の整数を表わす。]で示される4−フェニルフタラジ
ン誘導体、その光学対掌体または薬学上許容されるその
酸付加塩に存する。[Formula, R1 represents an alkyl group having 1 to 5 carbon atoms or a hydroxyalkyl group having 1 to 5 carbon atoms, R2 represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, or R1 and R2's are linked together to form an alkylene group having 2 to 6 carbon atoms which may have an oxygen atom. R3 and R
4 each independently represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, or -O-(C
H2) p-O- (p represents an integer of 1 to 3), R5 is a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, trifluoromethyl R representing or adjacent to a group or a hydroxyl group
5 to form -O-(CH2)p-O-. l and m each independently represent 1 or 2, and n is 1 to
Represents an integer of 3. 4-phenyl phthalazine derivatives represented by the following formulas, their optical antipodes, or pharmaceutically acceptable acid addition salts thereof.
【0007】以下本発明を詳細に説明するに、本発明化
合物は前記一般式(I)にて表わされる。式中、Rはメ
チル基、エチル基、n−プロピル基、i−プロピル基、
n−ブチル基、i−ブチル基、sec−ブチル基、te
rt−ブチル基、n−ペンチル基、ネオペンチル基、1
−エチルプロピル基等の炭素数1〜5のアルキル基また
はヒドロキシメチル基、2−ヒドロキシエチル基、1−
ヒドロキシエチル基、3−ヒドロキシプロピル基、1−
メチル−2−ヒドロキシエチル基、4−ヒドロキシブチ
ル基、1,1−ジメチル−2−ヒドロキシエチル基、2
−メチル−3−ヒドロキシプロピル基、5−ヒドロキシ
ペンチル基、2,2−ジメチル−3−ヒドロキシプロピ
ル基等の炭素数1〜5のヒドロキシアルキル基を表わし
、R2は水素原子またはメチル基、エチル基、n−プロ
ピル基、i−プロピル基、n−ブチル基、i−ブチル基
、sec−ブチル基、tert−ブチル基、n−ペンチ
ル基、ネオペンチル基、1−エチルプロピル基等の炭素
数1〜5のアルキル基を表わすか、R1およびR2が互
いに連結してエチレン基、トリメチレン基、テトラメチ
レン基、ペンタメチレン基、ヘキサメチレン基、−CH
2OCH2−、−CH2CH2OCH2CH2−等の酸
素原子を有していてもよい炭素数2〜6のアルキレン基
を形成する。R3およびR4はそれぞれ独立して水素原
子; フッ素原子、塩素原子、臭素原子等のハロゲン原
子; メチル基、エチル基、n−プロピル基、i−プロ
ピル基、n−ブチル基、tert−ブチル基等の炭素数
1〜4のアルキル基;またはメトキシ基、エトキシ基、
n−プロポキシ基、i−プロポキシ基、n−ブトキシ基
、i−ブトキシ基等の炭素数1〜4のアルコキシ基を表
わし、R5は水素原子; フッ素原子、塩素原子、臭素
原子等のハロゲン原子; メチル基、エチル基、n−プ
ロピル基、i−プロピル基、n−ブチル基、tert−
ブチル基等の炭素数1〜4のアルキル基; メトキシ基
、エトキシ基、n−プロポキシ基、i−プロポキシ基、
n−ブトキシ基、i−ブトキシ基等の炭素数1〜4のア
ルコキシ基; トリフルオロメチル基またはヒドロキシ
ル基を表わす。また、R3、R4もしくはR5は、隣接
するR3、R4もしくはR5同志でメチレンジオキシ基
、エチレンジオキシ基またはトリメチレンジオキシ基を
形成してもよい。lおよびmはそれぞれ独立して1ある
いは2を表わし、nは1〜3の整数を表わす。The present invention will be explained in detail below. The compound of the present invention is represented by the above general formula (I). In the formula, R is a methyl group, an ethyl group, an n-propyl group, an i-propyl group,
n-butyl group, i-butyl group, sec-butyl group, te
rt-butyl group, n-pentyl group, neopentyl group, 1
-C1-C5 alkyl group such as ethylpropyl group or hydroxymethyl group, 2-hydroxyethyl group, 1-
Hydroxyethyl group, 3-hydroxypropyl group, 1-
Methyl-2-hydroxyethyl group, 4-hydroxybutyl group, 1,1-dimethyl-2-hydroxyethyl group, 2
-Represents a hydroxyalkyl group having 1 to 5 carbon atoms such as methyl-3-hydroxypropyl group, 5-hydroxypentyl group, 2,2-dimethyl-3-hydroxypropyl group, and R2 is a hydrogen atom or a methyl group or an ethyl group. , n-propyl group, i-propyl group, n-butyl group, i-butyl group, sec-butyl group, tert-butyl group, n-pentyl group, neopentyl group, 1-ethylpropyl group, etc. having 1 to 1 carbon atoms 5 alkyl group, or R1 and R2 are connected to each other to form an ethylene group, trimethylene group, tetramethylene group, pentamethylene group, hexamethylene group, -CH
An alkylene group having 2 to 6 carbon atoms which may have an oxygen atom such as 2OCH2- and -CH2CH2OCH2CH2- is formed. R3 and R4 are each independently a hydrogen atom; a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom; a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, a tert-butyl group, etc. an alkyl group having 1 to 4 carbon atoms; or a methoxy group, an ethoxy group,
Represents an alkoxy group having 1 to 4 carbon atoms such as n-propoxy group, i-propoxy group, n-butoxy group, i-butoxy group, R5 is hydrogen atom; halogen atom such as fluorine atom, chlorine atom, bromine atom; Methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, tert-
Alkyl group having 1 to 4 carbon atoms such as butyl group; methoxy group, ethoxy group, n-propoxy group, i-propoxy group,
An alkoxy group having 1 to 4 carbon atoms such as n-butoxy group and i-butoxy group; represents a trifluoromethyl group or a hydroxyl group. Furthermore, R3, R4, or R5 may form a methylenedioxy group, an ethylenedioxy group, or a trimethylenedioxy group with adjacent R3, R4, or R5 comrades. l and m each independently represent 1 or 2, and n represents an integer of 1 to 3.
【0008】本発明においては、1)R1は炭素数1〜
5のアルキル基または炭素数1〜3のヒドロキシアルキ
ル基を表わし、R2は水素原子または炭素数1〜5のア
ルキル基を表わすか、R1およびR2が互いに連結して
炭素数4〜6のアルキレン基を形成する化合物、2)R
3およびR4はそれぞれ独立して水素原子、ハロゲン原
子、炭素数1〜4のアルキル基または炭素数1〜4のア
ルコキシ基を表わす化合物、および/または3)R5は
水素原子、ハロゲン原子、炭素数1〜4のアルキル基、
炭素数1〜4のアルコキシ基またはトリフルオロメチル
基を表わすか、隣接するR5同志で−O−(CH2)p
−O−を形成する化合物が好ましい。In the present invention, 1) R1 has 1 to 1 carbon atoms;
5 alkyl group or a hydroxyalkyl group having 1 to 3 carbon atoms, R2 represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, or R1 and R2 are connected to each other to form an alkylene group having 4 to 6 carbon atoms. 2) a compound forming R
3 and R4 each independently represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms; and/or 3) R5 is a hydrogen atom, a halogen atom, a compound having a carbon number of 1 to 4; 1 to 4 alkyl groups,
Represents an alkoxy group or trifluoromethyl group having 1 to 4 carbon atoms, or -O-(CH2)p with adjacent R5 comrades
Compounds that form -O- are preferred.
【0009】さらに本発明においては、4)R1は炭素
数1〜5のアルキル基を表わし、R2は水素原子または
炭素数1〜5のアルキル基を表わすか、R1およびR2
が互いに連結して炭素数4〜6のアルキレン基を形成す
る化合物、5)R3およびR4はそれぞれ独立して水素
原子、フッ素原子、塩素原子、炭素数1〜3のアルキル
基または炭素数1〜3のアルコキシ基を表わす化合物、
および/または6)R5は水素原子、ハロゲン原子、炭
素数1〜4のアルキル基または炭素数1〜4のアルコキ
シ基を表わす化合物が好ましい。特に好ましくは、l、
mおよびnが1である化合物である。Furthermore, in the present invention, 4) R1 represents an alkyl group having 1 to 5 carbon atoms, R2 represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, or R1 and R2
5) R3 and R4 are each independently a hydrogen atom, a fluorine atom, a chlorine atom, an alkyl group having 1 to 3 carbon atoms, or a C 1 to 3 alkyl group. A compound representing an alkoxy group of 3,
and/or 6) R5 is preferably a compound representing a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms. Particularly preferably l,
A compound where m and n are 1.
【0010】以下の表−I(表1〜表9)に、本発明化
合物の具体例を示すが、これらは個々の異性体のみなら
ず、それらの混合物をも包含するものである。
表−ISpecific examples of the compounds of the present invention are shown in Table I below (Tables 1 to 9), which include not only individual isomers but also mixtures thereof. Table-I
【表1】[Table 1]
【表2】[Table 2]
【表3】[Table 3]
【表4】[Table 4]
【表5】[Table 5]
【表6】[Table 6]
【表7】[Table 7]
【表8】[Table 8]
【表9】
注)構造式に付した位置番号は、置換基の位置を示すた
めに便宜上つけたものであり、化合物の正式な位置番号
とは必ずしも一致しない。[Table 9] Note) The position numbers attached to the structural formula are added for convenience to indicate the positions of substituents, and do not necessarily correspond to the official position numbers of the compound.
【0011】次に本発明化合物の製造法について説明す
る。本発明化合物は合目的な任意の方法で製造すること
ができ、例えば以下の合成法が挙げられる。Next, the method for producing the compound of the present invention will be explained. The compound of the present invention can be produced by any suitable method, including the following synthetic method.
【化6】
(式中、R1、R2、R3、R4、R5、l、m、nは
前記と同意義である)[Formula 6] (wherein, R1, R2, R3, R4, R5, l, m, and n have the same meanings as above)
【0012】この製造法は、溶媒の存在下あるいは無溶
媒で、塩基触媒の存在下あるいは触媒非存在下、出発物
質(V)を化合物(VI)と反応させることからなる。
出発物質(V)は薬学雑誌、86 576(1966)
に記載されている方法に従って合成することができる。This production method consists of reacting the starting material (V) with the compound (VI) in the presence or absence of a solvent and in the presence or absence of a basic catalyst. Starting material (V) is Pharmaceutical Journal, 86 576 (1966)
It can be synthesized according to the method described in .
【0013】反応温度は通常0〜250℃、好ましくは
20〜200℃であり、反応時間は10分〜24時間で
ある。溶媒を使用する場合はテトラヒドロフラン、ジオ
キサン等のエーテル類、クロロホルム、メチレンクロリ
ド等のハロゲン化炭化水素類、ベンゼン、トルエン、キ
シレン、クロルベンゼン等の芳香族炭化水素類、ジメチ
ルホルムアミド、ジメチルアセトアミド、N−メチルピ
ロリドン等のアミド類、またはジメチルスルホキシド等
を化合物(V)に対し重量比で0.1〜100使用する
。触媒を使用する場合は、トリエチルアミン、ジイソプ
ロピルエチルアミン、N,N−ジメチルアニリン、ピリ
ジン等の有機塩基、あるいは、NaHCO3、Na2C
O3、K2CO3、NaOH、KOH等の無機塩基を化
合物(V)に対し、モル比で通常0.5〜5、好ましく
は1〜3使用する。化合物(VI)の使用量は、化合物
(V)に対し、モル比で通常0.5〜30、好ましくは
1〜10である。The reaction temperature is usually 0 to 250°C, preferably 20 to 200°C, and the reaction time is 10 minutes to 24 hours. When using a solvent, ethers such as tetrahydrofuran and dioxane, halogenated hydrocarbons such as chloroform and methylene chloride, aromatic hydrocarbons such as benzene, toluene, xylene and chlorobenzene, dimethylformamide, dimethylacetamide, N- Amides such as methylpyrrolidone or dimethyl sulfoxide are used in a weight ratio of 0.1 to 100 relative to compound (V). When using a catalyst, an organic base such as triethylamine, diisopropylethylamine, N,N-dimethylaniline, pyridine, or NaHCO3, Na2C
The molar ratio of an inorganic base such as O3, K2CO3, NaOH, KOH, etc. to compound (V) is usually 0.5 to 5, preferably 1 to 3. The amount of compound (VI) to be used is usually 0.5 to 30, preferably 1 to 10 in molar ratio to compound (V).
【0014】反応終了後、必要であれば溶媒を留去し、
大過剰の水にあけるか、またはそのままジクロルメタン
等の溶媒に溶解した後、アルカリ水溶液で中和し、再結
晶またはクロマトグラフィー等通常の方法で精製する。After the reaction is completed, if necessary, the solvent is distilled off,
After pouring into a large excess of water or directly dissolving in a solvent such as dichloromethane, it is neutralized with an aqueous alkaline solution and purified by a conventional method such as recrystallization or chromatography.
【0015】前記式(I)で表わされる化合物の塩類と
しては、生理学的に許容される塩類が好ましく、例えば
塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、硫酸塩、リン
酸塩等の無機酸の塩、またはメタンスルホン酸塩、p−
トルエンスルホン酸塩、ベンゼンスルホン酸塩、カンフ
ァースルホン酸塩、酢酸塩、安息香酸塩、リンゴ酸塩、
乳酸塩、グリコール酸塩、グルクロン酸塩、マレイン酸
塩、フマル酸塩、シュウ酸塩、アスコルビン酸塩、クエ
ン酸塩、サリチル酸塩、ニコチン酸塩、酒石酸塩等の有
機酸の塩が挙げられる。式(I)の化合物およびその塩
は水和物または溶媒和物の形で存在することもあるので
これらの水和物、溶媒和物も本発明の化合物に含まれる
。The salts of the compound represented by formula (I) are preferably physiologically acceptable salts, such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc. salts of inorganic acids, or methanesulfonates, p-
Toluene sulfonate, benzene sulfonate, camphor sulfonate, acetate, benzoate, malate,
Examples include salts of organic acids such as lactate, glycolate, glucuronate, maleate, fumarate, oxalate, ascorbate, citrate, salicylate, nicotinate, tartrate and the like. Since the compound of formula (I) and its salts may exist in the form of hydrates or solvates, these hydrates and solvates are also included in the compounds of the present invention.
【0016】本発明の化合物を循環改善剤として臨床に
応用するに際し、経口的に用いる場合は、成人に対し1
回1〜100mgを1日1〜3回投与するのが好ましく
、静脈注射の場合は、成人に対し1回0.01〜10m
gを1日2〜5回投与するのが好ましく、また、直腸内
投与の場合は、1回1〜100mgを1日1〜3回投与
するのが好ましい。また、以上の投与量は、年齢、病態
、症状により適宜増減することが更に好ましい。When the compound of the present invention is clinically applied as a circulation improving agent, when used orally, it is recommended to
It is preferable to administer 1 to 100 mg once to 3 times a day, and in the case of intravenous injection, 0.01 to 10 mg per dose for adults.
It is preferable to administer 2 to 5 times a day, and in the case of rectal administration, it is preferable to administer 1 to 100 mg at a time, 1 to 3 times a day. Further, it is more preferable that the above dosage is adjusted as appropriate depending on the age, pathological condition, and symptoms.
【0017】製剤化に際しては、化合物(I)あるいは
その薬学的に許容される塩の1種または2種以上を、通
常用いられる製薬用担体、賦形剤その他の添加物と混合
する。担体は固体でも液体でもよく、固体担体の例とし
ては乳糖、白陶土(カオリン)、ショ糖、結晶セルロー
ス、コーンスターチ、タルク、寒天、ペクチン、アカシ
ア、ステアリン酸、ステアリン酸マグネシウム、レシチ
ン、塩化ナトリウムなどが挙げられる。[0017] For formulation, compound (I) or one or more pharmaceutically acceptable salts thereof are mixed with commonly used pharmaceutical carriers, excipients, and other additives. The carrier may be solid or liquid; examples of solid carriers include lactose, kaolin, sucrose, crystalline cellulose, corn starch, talc, agar, pectin, acacia, stearic acid, magnesium stearate, lecithin, and sodium chloride. can be mentioned.
【0018】液状の担体の例としては、シロップ、グリ
セリン、落花生油、ポリビニルピロリドン、オリーブ油
、エタノール、ベンジルアルコール、プロピレングリコ
ール、水などが挙げられる。Examples of liquid carriers include syrup, glycerin, peanut oil, polyvinylpyrrolidone, olive oil, ethanol, benzyl alcohol, propylene glycol, water, and the like.
【0019】医薬製剤は、種々の剤形をとることができ
、固体担体を用いる場合は、錠剤、散剤、顆粒剤、硬ゼ
ラチンカプセル剤、坐剤またはトローチ剤とすることが
できる。固体担体の量は広範に変えることができるが、
好ましくは約1mg〜約1gとする。Pharmaceutical formulations can take a variety of dosage forms, including tablets, powders, granules, hard gelatin capsules, suppositories, or troches when solid carriers are used. The amount of solid carrier can vary widely, but
Preferably it is about 1 mg to about 1 g.
【0020】液状の担体を用いる場合は、シロップ、乳
液、軟ゼラチンカプセル、更にアンプル入りのような滅
菌注射液または水性もしくは非水性の懸濁液とすること
ができる。When a liquid carrier is used, it can be a syrup, emulsion, soft gelatin capsule, sterile injectable solution such as an ampoule, or an aqueous or non-aqueous suspension.
【0021】以下、実施例により本発明をさらに具体的
に説明するが、本発明は以下の実施例に限定されるもの
ではない。[0021] The present invention will be explained in more detail with reference to examples below, but the present invention is not limited to the following examples.
【0022】[0022]
【実施例】実施例1
D−1−α−メチルベンジルアミノ−4−フェニル
フタラジン(表−Iの化合物No.1のD体)の合成N
−メチルピロリドン5mlに1−クロロ−4−フェニル
フタラジン(化合物V)5.0g、D−α−メチルベン
ジルアミン5.0gを添加した後、混合物を130〜1
40℃にて3時間加熱撹拌した。反応終了後冷却し、5
%NaOH水溶液20mlを添加後、クロロホルムにて
抽出した。有機層をMgSO4にて乾燥後濃縮し、シリ
カゲルカラムクロマトにて精製し(溶離液:酢酸エチル
−n−ヘキサン−クロロホルム)、酢酸エチル−n−ヘ
キサンより再結晶し、無色結晶としてD−1−α−メチ
ルベンジルアミノ−4−フェニルフタラジン3.31g
を得た。融点184〜185.5℃。[Example] Example 1 Synthesis of D-1-α-methylbenzylamino-4-phenylphthalazine (D form of compound No. 1 in Table I) N
- After adding 5.0 g of 1-chloro-4-phenylphthalazine (compound V) and 5.0 g of D-α-methylbenzylamine to 5 ml of methylpyrrolidone, the mixture was
The mixture was heated and stirred at 40°C for 3 hours. After the reaction is completed, cool and
After adding 20 ml of % NaOH aqueous solution, the mixture was extracted with chloroform. The organic layer was dried over MgSO4, concentrated, purified using silica gel column chromatography (eluent: ethyl acetate-n-hexane-chloroform), and recrystallized from ethyl acetate-n-hexane to give D-1- as colorless crystals. α-methylbenzylamino-4-phenylphthalazine 3.31g
I got it. Melting point: 184-185.5°C.
【0023】実施例2〜38
下記表−II(表10〜表11)に示す化合物を実
施例1と同様にして合成した。Examples 2 to 38 The compounds shown in Table II below (Tables 10 to 11) were synthesized in the same manner as in Example 1.
【0024】実施例39
1−α,α−ジメチルベンジルアミノ−4−フェニ
ルフタラジン(表−Iの化合物No.119)の合成N
−メチルピロリドン4mlに1−クロロ−4−フェニル
フタラジン1.5g、α,α−ジメチルベンジルアミン
2.1gを添加した後、混合物を160℃にて6時間加
熱撹拌した。反応終了後冷却し、5%NaOH水溶液2
0mlを添加後、クロロホルムにて抽出した。有機層を
MgSO4にて乾燥後濃縮し、シリカゲルカラムクロマ
トグラフィーにて精製し、クロロホルム−エーテルより
再結晶し、無色結晶として1−α,α−ジメチルベンジ
ルアミノ−4−フェニルフタラジン0.79gを得た。
融点234−235℃。Example 39 Synthesis of 1-α,α-dimethylbenzylamino-4-phenylphthalazine (Compound No. 119 in Table I) N
- After adding 1.5 g of 1-chloro-4-phenylphthalazine and 2.1 g of α,α-dimethylbenzylamine to 4 ml of methylpyrrolidone, the mixture was heated and stirred at 160° C. for 6 hours. After the reaction is completed, cool and add 5% NaOH aqueous solution 2.
After adding 0 ml, extraction was performed with chloroform. The organic layer was dried over MgSO4, concentrated, purified by silica gel column chromatography, and recrystallized from chloroform-ether to give 0.79 g of 1-α,α-dimethylbenzylamino-4-phenylphthalazine as colorless crystals. Obtained. Melting point 234-235°C.
【0025】実施例40〜42
下記表−IIに示す化合物を実施例39と同様の方
法で合成した。
表−IIExamples 40 to 42 The compounds shown in Table II below were synthesized in the same manner as in Example 39. Table-II
【表10】[Table 10]
【表11】[Table 11]
【0026】試験例1 in vitro 血小
板凝集抑制作用
ラット動脈血を遠心分離して血小板多血漿(Plate
let richplasma)を得、その250μl
に薬物溶液5μlを加えて2分間インキュベートした後
、血小板凝集誘発剤としてコラーゲン(Hormon−
Chemie社)3μgを加え、血小板凝集の変化を2
チャンネル血小板凝集計(Sienco社DP247E
型)で10分間観察記録した。
血小板凝集抑制率は次式にて算出した。
抑制率=(Tc−Ts)/Tc×100Tc: 溶剤だ
けを添加した時の凝集度Ts: 薬物溶液を添加した時
の凝集度化合物の各モル濃度における抑制率を表−II
I(表12〜表15)に示す。Test Example 1 In vitro platelet aggregation inhibitory effect Rat arterial blood was centrifuged to produce platelet-rich plasma (Platelet-rich plasma).
let rich plasma) and 250 μl of it.
After adding 5 μl of the drug solution and incubating for 2 minutes, collagen (Hormon-
Chemie) was added to 3 μg, and the change in platelet aggregation was
Channel platelet aggregometer (Sienco DP247E
Observations and records were made for 10 minutes using a mold). The platelet aggregation inhibition rate was calculated using the following formula. Inhibition rate = (Tc - Ts) / Tc x 100 Tc: Aggregation degree when only solvent is added Ts: Aggregation degree when drug solution is added The inhibition rate at each molar concentration of the compound is shown in Table II
I (Tables 12 to 15).
【0027】
試験例2 ex vivo 血小板凝集抑制作用(経
口)体重約250gの雄性ウィスター(Wistar)
−ST系ラットを1群8匹用いた。1%トラガカント水
溶液にてそれぞれの化合物を懸濁した溶液4ml/kg
を経口投与し、1時間後に総頸動脈よりカニューレを用
いて採血した。血液を3.8%クエン酸ナトリウム(1
/10容)の入ったプラスチック試験管に採取し、転倒
撹拌後、200×gで15分間遠心分離し、上清を血小
板多血漿(PRP)とし、残渣を、更に2000×gで
15分間遠心分離して上清を乏血小板血漿(PPP)と
し、血小板凝集能の測定に用いた。血小板凝集能の測定
には、2チャンネル血小板凝集計(Sienco社DP
247E型)を用いて、2ペン式記録計上に記録した。
凝集誘発剤としては、7〜10μg/mlの濃度のコラ
ーゲン(Hormon−Chemie社)を用いた。
血小板凝集の抑制率は次式によって算出した。
抑制率=(A−B)/A×100(%)A: 1%トラ
ガカント溶液単独投与群(対照群)の凝集率B: 化合
物含有トラガカント溶液投与群の凝集率その結果を表−
IIIに示す。Test Example 2 Ex Vivo Platelet Aggregation Inhibition Effect (Oral) Male Wistar weighing approximately 250 g
-Eight ST rats were used per group. 4ml/kg of a suspension of each compound in 1% tragacanth aqueous solution
was orally administered, and 1 hour later, blood was collected from the common carotid artery using a cannula. Blood was diluted with 3.8% sodium citrate (1
/10 volumes), stirred by inversion, and centrifuged at 200 x g for 15 minutes. The supernatant was used as platelet-rich plasma (PRP), and the residue was further centrifuged at 2000 x g for 15 minutes. The supernatant was separated and used as platelet-poor plasma (PPP), which was used to measure platelet aggregation ability. To measure platelet aggregation ability, a two-channel platelet aggregometer (Sienco DP) was used.
247E) on a two-pen recorder. Collagen (Hormon-Chemie) at a concentration of 7 to 10 μg/ml was used as the aggregation inducing agent. The inhibition rate of platelet aggregation was calculated using the following formula. Inhibition rate = (A-B)/A x 100 (%) A: Aggregation rate of the group administered with 1% tragacanth solution alone (control group) B: Aggregation rate of the group administered with compound-containing tragacanth solution The results are shown in Table-
It is shown in III.
【0028】表−IIITable III
【表12】[Table 12]
【表13】[Table 13]
【表14】[Table 14]
【表15】[Table 15]
【0029】試験例3 ラット左冠動脈結紮誘発心筋
梗塞に対する作用
体重200〜250gのSD系雄性ラットを1群8匹用
いた。エーテル軽麻酔下に背位固定しSelyeらの方
法に従い、胸骨左線に沿って約1.5cmの縦切開を加
え開胸し心膜を破り心臓を露出させ左主冠動脈を起始部
から1〜2mmのところで黒ブレードシルク縫合糸(浜
医科工業、4−O)にて結紮した後、心臓をもとの位置
に戻し速やかに閉胸した。両側胸部を圧迫し、胸腔内の
空気を排出し、呼吸運動を再開後、心電計(日本光電・
ECG−6601)にてII誘導のST上昇を確認した
。結紮24時間後に腹部大静脈から採血後、脱血致死さ
せ心臓を取り出し中央部の横断輪状切片(約2mm)を
0.09Mリン酸緩衝液(pH8.6)にて溶解した1
%TTC(tryphenyl tetrazoliu
m chloride 和光純薬)20ml中に遮光下
37℃で20分間インキュベートした。その後、実体顕
微鏡下にて切片を写真に撮りカラースライドを作成した
。壁面にスライドを映写し、切断面および梗塞部(TT
C、非染色部)、非梗塞部(TTC染色部)をトレース
し、全断面積中の梗塞部面積を算出した。薬物は冠動脈
結紮60分前に1%トラガカント水溶液に懸濁して経口
投与した。
心筋梗塞の抑制率は次式によって算出した。
抑制率=(A−B)/A×100(%)A: 1%トラ
ガカント溶液単独投与群(対照群)の梗塞率B: 薬物
含有トラガカント溶液投与群の梗塞率その結果を表−I
V(表16)に示す。
表−IVTest Example 3 Effect on myocardial infarction induced by ligation of the rat left coronary artery One group of 8 SD male rats weighing 200 to 250 g were used. The patient was fixed in the dorsal position under light ether anesthesia, and according to the method of Selye et al., a vertical incision of approximately 1.5 cm was made along the left sternal line, the chest was opened, the pericardium was broken, the heart was exposed, and the left main coronary artery was opened from its origin. After ligating with black braided silk suture (Hama Medical Industries, 4-O) at ~2 mm, the heart was returned to its original position and the chest was immediately closed. After compressing the chest on both sides, expelling the air in the chest cavity, and restarting breathing exercises, an electrocardiograph (Nihon Kohden,
ST elevation in induction II was confirmed using ECG-6601). 24 hours after ligation, blood was collected from the abdominal vena cava, the heart was sacrificed by exsanguination, and the central transverse circular section (approximately 2 mm) was dissolved in 0.09 M phosphate buffer (pH 8.6).
%TTC(tryphenyl tetrazoliu)
The mixture was incubated in 20 ml of m chloride (Wako Pure Chemical Industries) at 37° C. for 20 minutes in the dark. Thereafter, the sections were photographed under a stereomicroscope and color slides were created. Project the slide on the wall and examine the cut plane and the infarcted area (TT
C, non-stained area) and non-infarcted area (TTC-stained area) were traced, and the area of the infarcted area in the total cross-sectional area was calculated. The drug was suspended in a 1% aqueous tragacanth solution and orally administered 60 minutes before coronary artery ligation. The suppression rate of myocardial infarction was calculated using the following formula. Suppression rate = (A-B) / A × 100 (%) A: Infarction rate of the group administered with 1% tragacanth solution alone (control group) B: Infarction rate of the group administered with drug-containing tragacanth solution The results are shown in Table-I
V (Table 16). Table-IV
【表16】[Table 16]
【0030】[0030]
【発明の効果】本発明化合物はin vitroだけで
なく、経口投与でも強力に血小板凝集を抑制する作用を
有するので、各種循環障害の予防治療薬として有用であ
る。また、虚血性心疾患に関しては、血小板凝集抑制作
用に基づかず、直接、心筋梗塞巣を縮少する作用を併せ
有することから、特に有用性が高いと考えられる。EFFECTS OF THE INVENTION The compounds of the present invention have a strong effect of inhibiting platelet aggregation not only in vitro but also when administered orally, and therefore are useful as preventive and therapeutic agents for various circulatory disorders. Furthermore, with regard to ischemic heart disease, it is considered to be particularly useful because it also has the effect of directly reducing myocardial infarction focus, not based on the platelet aggregation inhibitory effect.
Claims (1)
1〜5のヒドロキシアルキル基を表わし、R2は水素原
子または炭素数1〜5のアルキル基を表わすか、R1お
よびR2が互いに連結して酸素原子を有していてもよい
炭素数2〜6のアルキレン基を形成する。R3およびR
4はそれぞれ独立して水素原子、ハロゲン原子、炭素数
1〜4のアルキル基または炭素数1〜4のアルコキシ基
を表わすか、隣接するR3またはR4同志で−O−(C
H2)p−O− (pは1〜3の整数を表わす)を形成
し、R5は水素原子、ハロゲン原子、炭素数1〜4のア
ルキル基、炭素数1〜4のアルコキシ基、トリフルオロ
メチル基またはヒドロキシル基を表わすか、隣接するR
5同志で−O−(CH2)p−O−を形成する。lおよ
びmはそれぞれ独立して1または2を表わし、nは1〜
3の整数を表わす。]で示される4−フェニルフタラジ
ン誘導体、その光学対掌体または薬学上許容されるその
酸付加塩。Claim 1: Formula (I): [Formula, R1 represents an alkyl group having 1 to 5 carbon atoms or a hydroxyalkyl group having 1 to 5 carbon atoms, and R2 represents a hydrogen atom or a hydroxyalkyl group having 1 to 5 carbon atoms] -5 alkyl group, or R1 and R2 are linked to each other to form an alkylene group having 2 to 6 carbon atoms which may have an oxygen atom. R3 and R
4 each independently represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, or -O-(C
H2) p-O- (p represents an integer of 1 to 3), R5 is a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, trifluoromethyl R representing or adjacent to a group or a hydroxyl group
5 to form -O-(CH2)p-O-. l and m each independently represent 1 or 2, and n is 1 to
Represents an integer of 3. ] A 4-phenylphthalazine derivative, its optical antipode, or a pharmaceutically acceptable acid addition salt thereof.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP6294091A JPH04211666A (en) | 1990-03-30 | 1991-03-27 | 4-phenylphthalazine derivative |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2-85447 | 1990-03-30 | ||
JP8544790 | 1990-03-30 | ||
JP6294091A JPH04211666A (en) | 1990-03-30 | 1991-03-27 | 4-phenylphthalazine derivative |
Publications (1)
Publication Number | Publication Date |
---|---|
JPH04211666A true JPH04211666A (en) | 1992-08-03 |
Family
ID=26404004
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP6294091A Pending JPH04211666A (en) | 1990-03-30 | 1991-03-27 | 4-phenylphthalazine derivative |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH04211666A (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0682947A1 (en) | 1994-05-19 | 1995-11-22 | Mitsubishi Chemical Corporation | Medicament for therapeutic and prophylactic treatment of diseases caused by smooth muscle cell hyperplasia |
WO2004089412A1 (en) * | 2003-04-08 | 2004-10-21 | Mitsubishi Pharma Corporation | Specific nad(p)h oxidase inhibitor |
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 |
-
1991
- 1991-03-27 JP JP6294091A patent/JPH04211666A/en active Pending
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0682947A1 (en) | 1994-05-19 | 1995-11-22 | Mitsubishi Chemical Corporation | Medicament for therapeutic and prophylactic treatment of diseases caused by smooth muscle cell hyperplasia |
WO2004089412A1 (en) * | 2003-04-08 | 2004-10-21 | Mitsubishi Pharma Corporation | Specific nad(p)h oxidase inhibitor |
JPWO2004089412A1 (en) * | 2003-04-08 | 2006-07-06 | 三菱ウェルファーマ株式会社 | Specific NAD (P) H oxidase inhibitor |
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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