JPH0742230B2 - Lipid peroxide production inhibitor - Google Patents
Lipid peroxide production inhibitorInfo
- Publication number
- JPH0742230B2 JPH0742230B2 JP27736386A JP27736386A JPH0742230B2 JP H0742230 B2 JPH0742230 B2 JP H0742230B2 JP 27736386 A JP27736386 A JP 27736386A JP 27736386 A JP27736386 A JP 27736386A JP H0742230 B2 JPH0742230 B2 JP H0742230B2
- Authority
- JP
- Japan
- Prior art keywords
- pyrazolin
- pyridyl
- group
- imidazolylmethyl
- acid
- 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.)
- Expired - Fee Related
Links
- -1 Lipid peroxide Chemical class 0.000 title description 84
- 238000004519 manufacturing process Methods 0.000 title description 7
- 239000003112 inhibitor Substances 0.000 title description 6
- 150000003839 salts Chemical class 0.000 claims description 10
- 125000004076 pyridyl group Chemical group 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- JEXVQSWXXUJEMA-UHFFFAOYSA-N pyrazol-3-one Chemical class O=C1C=CN=N1 JEXVQSWXXUJEMA-UHFFFAOYSA-N 0.000 claims description 5
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 125000002883 imidazolyl group Chemical group 0.000 claims description 3
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 25
- 230000015572 biosynthetic process Effects 0.000 description 14
- 239000003814 drug Substances 0.000 description 14
- 238000003786 synthesis reaction Methods 0.000 description 14
- 210000004556 brain Anatomy 0.000 description 11
- 229940079593 drug Drugs 0.000 description 11
- 238000011160 research Methods 0.000 description 11
- 235000002639 sodium chloride Nutrition 0.000 description 11
- 239000000203 mixture Substances 0.000 description 10
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- 238000012360 testing method Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 201000006474 Brain Ischemia Diseases 0.000 description 6
- 206010008120 Cerebral ischaemia Diseases 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
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- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
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- 238000000034 method Methods 0.000 description 4
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- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
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- 238000007796 conventional method Methods 0.000 description 3
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
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- JGPMMRGNQUBGND-UHFFFAOYSA-N idebenone Chemical compound COC1=C(OC)C(=O)C(CCCCCCCCCCO)=C(C)C1=O JGPMMRGNQUBGND-UHFFFAOYSA-N 0.000 description 3
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- 125000006527 (C1-C5) alkyl group Chemical group 0.000 description 2
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- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
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- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 2
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 2
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- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 230000004872 arterial blood pressure Effects 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical group C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 1
- 150000004725 beta keto acid derivatives Chemical class 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000003925 brain function Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 125000004181 carboxyalkyl group Chemical group 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 210000001168 carotid artery common Anatomy 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 210000001638 cerebellum Anatomy 0.000 description 1
- 210000003710 cerebral cortex Anatomy 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 210000004720 cerebrum Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- QTCANKDTWWSCMR-UHFFFAOYSA-N costic aldehyde Natural products C1CCC(=C)C2CC(C(=C)C=O)CCC21C QTCANKDTWWSCMR-UHFFFAOYSA-N 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 239000003479 dental cement Substances 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- ZQGIFDMODIHKOX-UHFFFAOYSA-N ethyl 2-[4-(5-oxo-3-pyridin-3-yl-4h-pyrazol-1-yl)phenyl]acetate Chemical compound C1=CC(CC(=O)OCC)=CC=C1N1C(=O)CC(C=2C=NC=CC=2)=N1 ZQGIFDMODIHKOX-UHFFFAOYSA-N 0.000 description 1
- APQGYFNHIWMRIJ-UHFFFAOYSA-N ethyl 3-oxo-3-pyridin-3-ylpropanoate Chemical compound CCOC(=O)CC(=O)C1=CC=CN=C1 APQGYFNHIWMRIJ-UHFFFAOYSA-N 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000003191 femoral vein Anatomy 0.000 description 1
- 210000001652 frontal lobe Anatomy 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229960002598 fumaric acid Drugs 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229960004275 glycolic acid Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229940083761 high-ceiling diuretics pyrazolone derivative Drugs 0.000 description 1
- 150000002429 hydrazines Chemical class 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- ISTFUJWTQAMRGA-UHFFFAOYSA-N iso-beta-costal Natural products C1C(C(=C)C=O)CCC2(C)CCCC(C)=C21 ISTFUJWTQAMRGA-UHFFFAOYSA-N 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
- 210000005240 left ventricle Anatomy 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229940116315 oxalic acid Drugs 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000010412 perfusion Effects 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
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 239000003279 phenylacetic acid Substances 0.000 description 1
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 1
- 229940067157 phenylhydrazine Drugs 0.000 description 1
- 229920000573 polyethylene Polymers 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
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 208000024891 symptom Diseases 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
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 210000002385 vertebral artery Anatomy 0.000 description 1
- 230000001018 virulence Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】 〔産業上の利用分野〕 本発明は、過酸化脂質生成抑制剤に関し、更に詳しく
は、諸種虚血性疾患並びにそれに伴う諸種脳疾患、心疾
患及び末梢循環障害の予防・治療剤として有用な過酸化
脂質生成抑制剤に関するものである。TECHNICAL FIELD The present invention relates to a lipid peroxide production inhibitor, and more specifically, to prevent various ischemic diseases and accompanying various brain diseases, heart diseases and peripheral circulatory disorders. The present invention relates to a lipid peroxide production inhibitor useful as a therapeutic agent.
脳、心臓又は末梢における循環障害疾患において、虚血
（組織に血液が供給されない状態）により、細胞膜から
遊離されたアラキドン酸を始めとする不飽和脂肪酸に対
し、その周辺組織において生じた活性酸素種（OH′ラジ
カルスーパーオキサイド等）が作用して過酸化脂質が生
成する。このような変化は虚血中のみならず、虚血再開
通後の血液を介する再酸素化により更に加速度的に進展
し、不飽和脂肪酸に富む生体膜細胞の傷害、周辺組織の
破壊、血管内皮の破壊、血管攣縮又は浮腫等を引き起こ
し、これら一連の反応の悪循環により病態が進展するこ
とが知られている（「脳虚血と細胞傷害」浅野孝雄編集
にゆーろん社、1980;「脳虚血とフリーラジカル」浅
野孝雄編集 にゆーろん社、1983）。In circulatory disorder disease in the brain, heart, or periphery, the reactive oxygen species generated in the surrounding tissues against unsaturated fatty acids such as arachidonic acid released from the cell membrane due to ischemia (the state where blood is not supplied to the tissue). (OH 'radical superoxide etc.) acts to produce lipid peroxide. Such changes not only during ischemia but also at a further accelerated rate due to blood-mediated reoxygenation after ischemia resumption, injury of biological membrane cells rich in unsaturated fatty acids, destruction of surrounding tissues, vascular endothelium. It is known that the virulence of a series of these reactions leads to the progression of disease, vasospasm, edema, etc. (“Cerebral ischemia and cytotoxicity” edited by Takao Asano, edited by Takahiro Asano, 1980; “Brain. Ischemia and Free Radicals ”edited by Takao Asano, Niyuronsha, 1983).
従つて、活性酸素種による過酸化脂質生成を抑制すれ
ば、組織の破壊、血管内皮の破壊、血管攣縮、浮腫等を
防ぐことが可能となり、従来の血流を増加することによ
り循環改善をする薬物と全く異なり、疾患の原因に対し
て作用する新しいタイプの循環障害予防・治療剤とな
る。特に近年、梗塞部において血流を増加することの有
効性が疑問視され、急性期脳血管障害ではむしろ逆効果
とさえ言われており、このような薬剤は更に重要性を増
してきている。Therefore, by suppressing the production of lipid peroxide by reactive oxygen species, it becomes possible to prevent tissue destruction, vascular endothelium destruction, vasospasm, edema, etc., and improve circulation by increasing the conventional blood flow. It is a new type of preventive / therapeutic agent for circulatory disorders, which is different from drugs and acts on the cause of diseases. In recent years, in particular, the effectiveness of increasing blood flow in the infarct region has been questioned, and it is said that it is rather counterproductive in acute-stage cerebrovascular accidents, and such drugs have become more important.
活性酸素種による脂質過酸化を抑制する薬剤としては、
ビタミンＥ、 次式： で示されるイデベノン（バイオケミカル・アンド・バイ
オフイジカル・リサーチ・コミユニケーシヨンス（Bioc
hemical and Biophysical Research Communications）1
25,1046（1984）；武田研究所報44,30（1985））及び 次式： で示されるニゾフエノン（ジヤーナル・オブ・ニユーロ
ケミストリー（Journal of Neurochemistry）37,934（1
981））が知られている。As a drug that suppresses lipid peroxidation due to reactive oxygen species,
Vitamin E, the formula: Idebenone (Biochemical and Biophysical Research Communications (Bioc
hemical and Biophysical Research Communications) 1
25, 1046 (1984); Takeda Research Institute 44, 30 (1985)) and the following formula: In shown is Nizofuenon (journal-of-two euro Chemistry (Journal of Neurochemistry) 37, 934 (1
981)) is known.
しかしながら、ビタミンＥは作用が不充分であり、イデ
ベノン及びニゾフエノンは合成経路が長く、またイデベ
ノンは水への可溶化が困難なため注射製剤化に問題が考
えられ、ニゾフエノンは中枢神経系の抑制作用が強い
（医薬品研究16,1（1985））という欠点を有する。However, vitamin E has an insufficient action, idebenone and nizophenone have a long synthetic pathway, and idebenone is difficult to be solubilized in water, which may cause a problem in injectable preparation. Nizophenone has an inhibitory effect on the central nervous system. Is strong (Pharmaceutical Research 16 , 1 (1985)).
ピラゾロン誘導体としては、種々のものが知られてい
る。Various pyrazolone derivatives are known.
特公昭45−10148号公報、特公昭45−26736号公報には下
記式Ａ （式中R1は水素原子又はメチル基、R2は水素原子又は置
換基を表わす。） で示される３−ピリジルピラゾリン−５−オン誘導体の
鎮痛剤、鎭痙剤としての用途が、Diss.Pharm.Pharmaco
l.18（４）345−50（1966）には、下記式Ｂ で示される化合物の消炎剤としての用途が記載されてい
るが、活性酸素種による脂質過酸化を抑制する作用に関
する記載はない。The following formula A is disclosed in Japanese Patent Publication No. 45-10148 and Japanese Patent Publication No. (In the formula, R 1 represents a hydrogen atom or a methyl group, and R 2 represents a hydrogen atom or a substituent.) The use of the 3-pyridylpyrazolin-5-one derivative represented by .Pharm.Pharmaco
l. 18 (4) 345-50 (1966) has the following formula B The use of the compound represented by the formula (1) as an anti-inflammatory agent is described, but there is no description about the action of suppressing lipid peroxidation by reactive oxygen species.
Pubs.inst.quim.“Alonso Barba"（Madrid）４,310−15
（1950）（ケミカル アブストラクツ（Chemical Abstr
acts）vol.46,8082（1952））には下記式Ｃ で示される化合物の植物ホルモン作用に関する記載があ
るが、薬理作用に関する記載はない。Pubs.inst.quim. "Alonso Barba" (Madrid ) 4, 310-15
(1950) (Chemical Abstr
acts) vol.46,8082 (1952)) There is a description about the phytohormonal action of the compound represented by, but no description about the pharmacological action.
そこで、本発明者等は、活性酸素種による脂質過酸化を
抑制する作用を有する薬剤を提供することを目的として
鋭意研究を重ねた結果、 一般式（Ｉ） （式中、R1はシクロアルキル基、置換基を有していても
よいフェニル基、ピリジル基またはベンゾチアゾル基を
表わし、R2は水素原子またはアルキル基を表わし、R3は
ピリジル基、フラニル基またはイミダゾリル基を表わ
し、ｎは０または１を表わす。）で表わされるピラゾロ
ン誘導体またはその薬剤として許容される塩が強力な脂
質過酸化抑制作用を有し、実際の病態に近い脳虚血再開
通状態の動物モデルにおいて、脳波の回復等の保護作用
を有することを見出し、本発明を完成するに至つた。Therefore, the inventors of the present invention have conducted extensive studies for the purpose of providing a drug having an action of suppressing lipid peroxidation due to active oxygen species, and as a result, the compound of the general formula (I) (In the formula, R 1 represents a cycloalkyl group, a phenyl group which may have a substituent, a pyridyl group or a benzothiazole group, R 2 represents a hydrogen atom or an alkyl group, and R 3 represents a pyridyl group or a furanyl group. Alternatively, a pyrazolone derivative represented by an imidazolyl group and n represents 0 or 1) or a pharmaceutically acceptable salt thereof has a strong inhibitory effect on lipid peroxidation, and recanalization of cerebral ischemia similar to an actual pathological condition. In an animal model of the state, they found that they have a protective action such as recovery of brain waves, and completed the present invention.
本発明の過酸化脂質生成抑制剤は、下記一般式（Ｉ′）
で表わされるケト型及び／又は一般式（Ｉ″）で表わさ
れるエノール型のピラゾロン誘導体又はその薬剤として
許容される塩を有効成分とする。The lipid peroxide production inhibitor of the present invention has the following general formula (I ′):
The keto-type and / or enol-type pyrazolone derivative represented by the general formula (I ″) or a pharmaceutically acceptable salt thereof is used as an active ingredient.
式中、R1はシクロペンチル基、シクロヘキシル基、シク
ロヘプチル基等の炭素数５〜７のシクロアルキル基；置
換基を有していてもよいフェニル基；、ピリジル基；ベ
ンゾチアゾリル基を表わす。 In the formula, R 1 represents a cycloalkyl group having 5 to 7 carbon atoms such as a cyclopentyl group, a cyclohexyl group and a cycloheptyl group; a phenyl group which may have a substituent; a pyridyl group; a benzothiazolyl group.
フェニル基の置換基としては、メチル基、エチル基、プ
ロピル基、イソプロピル基、ブチル基、イソブチル基、
sec−ブチル基、tert−ブチル基、ペンチル基等の炭素
数１〜５のアルキル基；メトキシ基、エトキシ基、プロ
ポキシ基、イソプロポキシ基、プトキシ基、ペンチルオ
キシ基等の炭素数１〜５のアルコキシ基；塩素原子等の
ハロゲン原子；メトキシカルボニル基、エトキシカルボ
ニル基、プロポキシカルボニル基、ブトキシカルボニル
基等の総炭素数２〜５のアルコキシカルボニル基；カル
ボキシル基；総炭素数３〜６のアルコキシカルボニルメ
チル基等のアルコキシカルボニルアルキル基；カルボキ
シメチル基等のカルボキシアルキル基；メチルメルカプ
ト基、エチルメルカプト基、プロピルメルカプト基等の
炭素数１〜３のアルキルメルカプト基；トリフルオロメ
チル基；ヒドロキシル基等が挙げられる。As the substituent of the phenyl group, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group,
C1-C5 alkyl groups such as sec-butyl, tert-butyl, pentyl, etc .; C1-C5 alkyl groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, etc. Alkoxy group; halogen atom such as chlorine atom; methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, butoxycarbonyl group and other alkoxycarbonyl group having 2 to 5 carbon atoms; carboxyl group; alkoxycarbonyl group having 3 to 6 carbon atoms Alkoxycarbonylalkyl group such as methyl group; carboxyalkyl group such as carboxymethyl group; alkylmercapto group having 1 to 3 carbon atoms such as methylmercapto group, ethylmercapto group, propylmercapto group; trifluoromethyl group; Can be mentioned.
R2は、水素原子または炭素数１〜５のアルキル基を表わ
す。R 2 represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.
R3は、ピリジル基、フラニル基またはイミダゾリル基を
表わす。R 3 represents a pyridyl group, a furanyl group or an imidazolyl group.
ｎは０また１の数を表わす。n represents a number of 0 or 1.
本発明の化合物においては、R1としてはシクロヘキシル
基、フエニル基、４−メチルフエニル基、４−エチルフ
エニル基、４−メトキシフエニル基、４−エトキシフエ
ニル基、４−クロロフエニル基等が好ましく、R2として
は水素原子、メチル基、エチル基、プロピル基等が好ま
しく、R3としてはピリジル基、フラニル基等が好まし
い。又、特に、R1が４−メチルフエニル基又は４−クロ
ロフエニル基を表わし、R2が水素原子、メチル基、エチ
ル基、又はプロピル基を表わし、R3がピリジル基を表わ
す化合物が好ましい。In the compound of the present invention, R 1 is preferably a cyclohexyl group, a phenyl group, a 4-methylphenyl group, a 4-ethylphenyl group, a 4-methoxyphenyl group, a 4-ethoxyphenyl group, a 4-chlorophenyl group, and the like. 2 is preferably a hydrogen atom, a methyl group, an ethyl group, a propyl group or the like, and R 3 is preferably a pyridyl group, a furanyl group or the like. Further, a compound in which R 1 represents a 4-methylphenyl group or a 4-chlorophenyl group, R 2 represents a hydrogen atom, a methyl group, an ethyl group, or a propyl group, and R 3 represents a pyridyl group is particularly preferable.
かかる本発明のピラゾロン誘導体の具体例としては、例
えば、以下に示すような化合物が挙げられる。Specific examples of the pyrazolone derivative of the present invention include the compounds shown below.
１−フエニル−３−（３−ピリジル）−２−ピラゾリン
−５−オン １−（４−メチルフエニル）−３−（３−ピリジル）−
２−ピラゾリン−５−オン １−（３−メチルフエニル）−３−（３−ピリジル）−
２−ピラゾリン−５−オン １−（２−メチルフエニル）−３−（３−ピリジル）−
２−ピラゾリン−５−オン １−（４−エチルフエニル）−３−（３−ピリジル）−
２−ピラゾリン−５−オン １−（４−プロピルフエニル）−３−（３−ピリジル）
−２−ピラゾリン−５−オン １−（４−ブチルフエニル）−３−（３−ピリジル）−
２−ピラゾリン−５−オン １−（４−ペンチルフエニル）−３−（３−ピリジル）
−２−ピラゾリン−５−オン １−（3,4−ジメチルフエニル）−３−（３−ピリジ
ル）−２−ピラゾリン−５−オン １−（４−メトキシフエニル）−３−（３−ピリジル）
−２−ピラゾリン−５−オン １−（３−メトキシフエニル）−３−（３−ピリジル）
−２−ピラゾリン−５−オン １−（２−メトキシフエニル）−３−（３−ピリジル）
−２−ピラゾリン−５−オン １−（４−エトキシフエニル）−３−（３−ピリジル）
−２−ピラゾリン−５−オン １−（４−プロポキシフエニル）−３−（３−ピリジ
ル）−２−ピラゾリン−５−オン １−（４−ブトキシフエニル）−３−（３−ピリジル）
−２−ピラゾリン−５−オン １−（４−ペントキシフエニル）−３−（３−ピリジ
ル）−２−ピラゾリン−５−オン １−（3,4−ジメトキシフエニル）−３−（３−ピリジ
ル）−２−ピラゾリン−５−オン １−（４−クロロフエニル）−３−（３−ピリジル）−
２−ピラゾリン−５−オン １−（３−クロロフエニル）−３−（３−ピリジル）−
２−ピラゾリン−５−オン １−（４−ブロモフエニル）−３−（３−ピリジル）−
２−ピラゾリン−５−オン １−（４−フルオロフエニル）−３−（３−ピリジル）
−２−ピラゾリン−５−オン １−（３−クロロ−４−メチルフエニル）−３−（３−
ピリジル）−２−ピラゾリン−５−オン １−（３−トリフルオロメチルフェニル）−３−（３−
ピリジル）−２−ピラゾリン−５−オン １−（４−トリフルオロメチルフェニル）−３−（３−
ピリジル）−２−ピラゾリン−５−オン １−（４−メトキシカルボニルフエニル）−３−（３−
ピリジル）−２−ピラゾリン−５−オン １−（４−エトキシカルボニルフエニル）−３−（３−
ピリジル）−２−ピラゾリン−５−オン ４−〔３−（３−ピリジル）−５−オキソ−２−ピラゾ
リン−１−イル〕安息香酸 １−（４−エトキシカルボニルメチルフエニル）−３−
（３−ピリジル）−２−ピラゾリン−５−オン ４−〔３−（３−ピリジル）−５−オキソ−２−ピラゾ
リン−１−イル〕フエニル酢酸 １−（４−メチルチオフエニル）−３−（３−ピリジ
ル）−２−ピラゾリン−５−オン １−（３−メチルチオフエニル）−３−（３−ピリジ
ル）−２−ピラゾリン−５−オン １−（４−ヒドロキシフエニル）−３−（３−ピリジ
ル）−２−ピラゾリン−５−オン １−（３−ヒドロキシフエニル）−３−（３−ピリジ
ル）−２−ピラゾリン−５−オン １−（3,4−ジヒドロキシフエニル）−３−（３−ピリ
ジル）−２−ピラゾリン−５−オン １−（3,4,5−トリメチルフエニル）−３−（３−ピリ
ジル）−２−ピラゾリン−５−オン １−シクロヘキシル−３−（３−ピリジル）−２−ピラ
ゾリン−５−オン １−シクロペンチル−３−（３−ピリジル）−２−ピラ
ゾリン−５−オン １−シクロヘプチル−３−（３−ピリジル）−２−ピラ
ゾリン−５−オン １−（２−ピリジル）−３−（３−ピリジル）−２−ピ
ラゾリン−５−オン １−（４−ピリジル）−３−（３−ピリジル）−２−ピ
ラゾリン−５−オン １−フエニル−３−（２−ピリジル）−２−ピラゾリン
−５−オン １−フエニル−３−（４−ピリジル）−２−ピラゾリン
−５−オン ４−メチル−１−フエニル−３−（３−ピリジル）−２
−ピラゾリン−５−オン ４−メチル−１−（４−メチルフエニル）−３−（３−
ピリジル）−２−ピラゾリン−５−オン ４−メチル−１−（３−メチルフエニル）−３−（３−
ピリジル）−２−ピラゾリン−５−オン １−（４−エチルフエニル）−４−メチル−３−（３−
ピリジル）−２−ピラゾリン−５−オン ４−メチル−１−（４−プロピルフエニル）−３−（３
−ピリジル）−２−ピラゾリン−５−オン １−（４−ブチルフエニル）−４−メチル−３−（３−
ピリジル）−２−ピラゾリン−５−オン １−（3,4−ジメチルフエニル）−４−メチル−３−
（３−ピリジル）−２−ピラゾリン−５−オン １−（４−メトキシフエニル）−４−メチル−３−（３
−ピリジル）−２−ピラゾリン−５−オン １−（３−メトキシフエニル）−４−メチル−３−（３
−ピリジル）−２−ピラゾリン−５−オン １−（４−エトキシフエニル）−４−メチル−３−（３
−ピリジル）−２−ピラゾリン−５−オン １−（４−ブトキシフエニル）−４−メチル−３−（３
−ピリジル）−２−ピラゾリン−５−オン １−（3,4−ジメトキシフエニル）−４−メチル−３−
（３−ピリジル）−２−ピラゾリン−５−オン １−（４−クロロフエニル）−４−メチル−３−（３−
ピリジル）−２−ピラゾリン−５−オン １−（４−フルオロフエニル）−４−メチル−３−（３
−ピリジル）−２−ピラゾリン−５−オン ４−メチル−１−（４−メチルチオフエニル）−３−
（３−ピリジル）−２−ピラゾリン−５−オン １−（４−トリフルオロメチルフエニル）−４−メチル
−３−（３−ピリジル）−２−ピラゾリン−５−オン １−（４−ヒドロキシフエニル）−４−メチル−３−
（３−ピリジル）−２−ピラゾリン−５−オン １−シクロヘキシル−４−メチル−３−（３−ピリジ
ル）−２−ピラゾリン−５−オン ４−メチル−１−（２−ピリジル）−３−（３−ピリジ
ル）−２−ピラゾリン−５−オン ４−エチル−１−フエニル−３−（３−ピリジル）−２
−ピラゾリン−５−オン ４−エチル−１−（４−メチルフエニル）−３−（３−
ピリジル）−２−ピラゾリン−５−オン ４−エチル−１−（４−エチルフエニル）−３−（３−
ピリジル）−２−ピラゾリン−５−オン １−（４−ブチルフエニル）−４−エチル−３−（３−
ピリジル）−２−ピラゾリン−５−オン ４−エチル−１−（3,4−ジメチルフエニル）−３−
（３−ピリジル）−２−ピラゾリン−５−オン ４−エチル−１−（４−メトキシフエニル）−３−（３
−ピリジル）−２−ピラゾリン−５−オン １−（４−エトキシフエニル）−４−エチル−３−（３
−ピリジル）−２−ピラゾリン−５−オン １−（４−クロロフエニル）−４−エチル−３−（３−
ピリジル）−２−ピラゾリン−５−オン １−シクロヘキシル−４−エチル−３−（３−ピリジ
ル）−２−ピラゾリン−５−オン ４−エチル−１−（２−ピリジル）−３−（３−ピリジ
ル）−２−ピラゾリン−５−オン １−フエニル−４−プロピル−３−（３−ピリジル）−
２−ピラゾリン−５−オン １−（４−メチルフエニル）−４−プロピル−３−（３
−ピリジル）−２−ピラゾリン−５−オン １−（４−エチルフエニル）−４−プロピル−３−（３
−ピリジル）−２−ピラゾリン−５−オン １−（４−メトキシフエニル）−４−プロピル−３−
（３−ピリジル）−２−ピラゾリン−５−オン １−（４−エトキシフエニル）−４−プロピル−３−
（３−ピリジル）−２−ピラゾリン−５−オン １−（４−クロルフエニル）−４−プロピル−３−（３
−ピリジル）−２−ピラゾリン−５−オン １−シクロヘキシル−４−プロピル−３−（３−ピリジ
ル）−２−ピラゾリン−５−オン ４−ブチル−１−フエニル−３−（３−ピリジル）−２
−ピラゾリン−５−オン １−フエニル−３−（３−ピリジルメチル）−２−ピラ
ゾリン−５−オン １−（４−メチルフエニル）−３−（３−ピリジルメチ
ル）−２−ピラゾリン−５−オン １−（３−メチルフエニル）−３−（３−ピリジルメチ
ル）−２−ピラゾリン−５−オン １−（２−メチルフエニル）−３−（３−ピリジルメチ
ル）−２−ピラゾリン−５−オン １−（４−エチルフエニル）−３−（３−ピリジルメチ
ル）−２−ピラゾリン−５−オン １−（４−プロピルフエニル）−３−（３−ピリジルメ
チル）−２−ピラゾリン−５−オン １−（４−ブチルフエニル）−３−（３−ピリジルメチ
ル）−２−ピラゾリン−５−オン １−（3,4−ジメチルフエニル）−３−（３−ピリジル
メチル）−２−ピラゾリン−５−オン １−（４−メトキシフエニル）−３−（３−ピリジルメ
チル）−２−ピラゾリン−５−オン １−（３−メトキシフエニル）−３−（３−ピリジルメ
チル）−２−ピラゾリン−５−オン １−（４−エトキシフエニル）−３−（３−ピリジルメ
チル）−２−ピラゾリン−５−オン １−（４−ブトキシフエニル）−３−（３−ピリジルメ
チル）−２−ピラゾリン−５−オン １−（3,4−ジメトキシフエニル）−３−（３−ピリジ
ルメチル）−２−ピラゾリン−５−オン １−（４−クロロフエニル）−３−（３−ピリジルメチ
ル）−２−ピラゾリン−５−オン １−（４−フルオロフエニル）−３−（３−ピリジルメ
チル）−２−ピラゾリン−５−オン １−（４−トリフルオロメチルフエニル）−３−（３−
ピリジルメチル）−２−ピラゾリン−５−オン １−（４−メチルチオフエニル）−３−（３−ピリジル
メチル）−２−ピラゾリン−５−オン ４−〔３−（３−ピリジルメチル）−５−オキソ−２−
ピラゾリン−１−イル〕安息香酸 １−（４−ヒドロキシフエニル）−３−（３−ピリジル
メチル）−２−ピラゾリン−５−オン １−シクロヘキシル−３−（３−ピリジルメチル）−２
−ピラゾリン−５−オン １−（２−ピリジル）−３−（３−ピリジルメチル）−
２−ピラゾリン−５−オン １−フエニル−３−（２−ピリジルメチル）−２−ピラ
ゾリン−５−オン １−（４−メチルフエニル）−３−（２−ピリジルメチ
ル）−２−ピラゾリン−５−オン １−フエニル−３−（４−ピリジルメチル）−２−ピラ
ゾリン−５−オン ３−（２−フラニル）−１−フエニル−２−ピラゾリン
−５−オン ３−（２−フラニル）−１−（４−メチルフエニル）−
２−ピラゾリン−５−オン ３−（２−フラニル）−１−（３−メチルフエニル）−
２−ピラゾリン−５−オン ３−（２−フラニル）−１−（２−メチルフエニル）−
２−ピラゾリン−５−オン １−（４−エチルフエニル）−３−（２−フラニル）−
２−ピラゾリン−５−オン １−（４−ブチルフエニル）−３−（２−フラニル）−
２−ピラゾリン−５−オン ３−（２−フラニル）−１−（3,4−ジメチルフエニ
ル）−２−ピラゾリン−５−オン ３−（２−フラニル）−１−（４−メトキシフエニル）
−２−ピラゾリン−５−オン ３−（２−フラニル）−１−（３−メトキシフエニル）
−２−ピラゾリン−５−オン １−（４−エトキシフエニル）−３−（２−フラニル）
−２−ピラゾリン−５−オン １−（４−ブトキシフエニル）−３−（２−フラニル）
−２−ピラゾリン−５−オン ３−（２−フラニル）−１−（3,4−ジメトキシフエニ
ル）−２−ピラゾリン−５−オン １−（４−クロロフエニル）−３−（２−フラニル）−
２−ピラゾリン−５−オン １−（４−フルオロフエニル）−３−（２−フラニル）
−２−ピラゾリン−５−オン ３−（２−フラニル）−１−（４−メチルチオフエニ
ル）−２−ピラゾリン−５−オン １−（４−トリフルオロメチルフェニル）−３−（２−
フラニル）−２−ピラゾリン−５−オン ３−（２−フラニル）−１−（４−ヒドロキシフエニ
ル）−２−ピラゾリン−５−オン １−シクロヘキシル−３−（２−フラニル）−２−ピラ
ゾリン−５−オン ３−（２−フラニル）−１−（２−ピリジル）−２−ピ
ラゾリン−５−オン ３−（１−イミダゾリルメチル）−１−フェニル−２−
ピラゾリン−５−オン ３−（１−イミダゾリルメチル）−１−（４−メチルフ
ェニル）−２−ピラゾリン−５−オン ３−（１−イミダゾリルメチル）−１−（３−メチルフ
ェニル）−２−ピラゾリン−５−オン １−（４−エチルフェニル）−３−（１−イミダゾリル
メチル）−２−ピラゾリン−５−オン １−（４−ブチルフェニル）−３−（１−イミダゾリル
メチル）−２−ピラゾリン−５−オン ３−（１−イミダゾリルメチル）−１−（3,4−ジメチ
ルフェニル）−２−ピラゾリン−５−オン ３−（１−イミダゾリルメチル）−１−（４−メトキシ
フェニル）−２−ピラゾリン−５−オン ３−（１−イミダゾリルメチル）−１−（３−メトキシ
フェニル）−２−ピラゾリン−５−オン １−（４−エトキシフェニル）−３−（１−イミダゾリ
ルメチル）−２−ピラゾリン−５−オン １−（４−ブトキシフェニル）−３−（１−イミダゾリ
ルメチル）−２−ピラゾリン−５−オン １−（４−クロロフェニル）−３−（１−イミダゾリル
メチル）−２−ピラゾリン−５−オン １−（４−フルオロフェニル）−３−（１−イミダゾリ
ルメチル）−２−ピラゾリン−５−オン １−（４−ヒドロキシフェニル）−３−（１−イミダゾ
リルメチル）−２−ピラゾリン−５−オン ３−（１−イミダゾリルメチル）−１−（α−ナフチ
ル）−２−ピラゾリン−５−オン １−シクロヘキシル−３−（１−イミダゾリルメチル）
−２−ピラゾリン−５−オン ３−（１−イミダゾリルメチル）−１−（２−ピリジ
ル）−２−ピラゾリン−５−オン ３−（１−イミダゾリルメチル）−４−メチル−１−フ
ェニル−２−ピラゾリン−５−オン ３−（１−イミダゾリルメチル）−４−メチル−１−
（４−メチルフェニル）−２−ピラゾリン−５−オン １−（４−エチルフェニル）−３−（１−イミダゾリル
メチル）−４−メチル−２−ピラゾリン−５−オン １−（４−ブチルフェニル）−３−（１−イミダゾリル
メチル）−４−メチル−２−ピラゾリン−５−オン １−（４−クロロフェニル）−３−（１−イミダゾリル
メチル）−４−メチル−２−ピラゾリン−５−オン ３−（１−イミダゾリルメチル）−１−（４−メトキシ
フェニル）−４−メチル−２−ピラゾリン−５−オン １−シクロヘキシル−３−（１−イミダゾリルメチル）
−４−メチル−２−ピラゾリン−５−オン ３−（１−イミダゾリルメチル）−４−メチル−１−
（２−ピリジル）−２−ピラゾリン−５−オン ４−エチル−３−（１−イミダゾリルメチル）−１−フ
ェニル−２−ピラゾリン−５−オン ４−エチル−３−（１−イミダゾリルメチル）−１−
（４−メチルフェニル）−２−ピラゾリン−５−オン １−（４−ブチルフェニル）−４−エチル−３−（１−
イミダゾリルメチル）−２−ピラゾリン−５−オン １−（４−クロロフェニル）−４−エチル−３−（１−
イミダゾリルメチル）−２−ピラゾリン−５−オン １−（3,4−ジクロロフェニル）−４−エチル−３−
（１−イミダゾリルメチル）−２−ピラゾリン−５−オ
ン ４−エチル−３−（１−イミダゾリルメチル）−１−
（４−メトキシフェニル）−２−ピラゾリン−５−オン １−シクロヘキシル−３−（１−イミダゾリルメチル）
−２−ピラゾリン−５−オン ３−（１−イミダゾリルメチル）−４−イソプロピル−
１−フェニル−２−ピラゾリン−５−オン １−（４−クロロフェニル）−３−（１−イミダゾリル
メチル）−４−イソプロピル−２−ピラゾリン−５−オ
ン ３−（１−イミダゾリルメチル）−４−イソプロピル−
１−（４−メチルフェニル）−２−ピラゾリン−５−オ
ン ４−ブチル−３−（１−イミダゾリルメチル）−１−フ
ェニル−２−ピラゾリン−５−オン ４−ブチル−３−（１−イミダゾリルメチル）−１−
（４−メチルフェニル）−２−ピラゾリン−５−オン ４−ブチル−３−（１−イミダゾリルメチル）−１−
（３−メチルフェニル）−２−ピラゾリン−５−オン ４−ブチル−１−（４−ブチルフェニル）−３−（１−
イミダゾリルメチル）−２−ピラゾリン−５−オン ４−ブチル−１−（４−クロロフェニル）−３−（１−
イミダゾリルメチル）−２−ピラゾリン−５−オン ４−ブチル−１−（3,4−ジクロロフェニル）−３−
（１−イミダゾリルメチル）−２−ピラゾリン−５−オ
ン ４−ブチル−３−（１−イミダゾリルメチル）−１−
（４−メトキシフェニル）−２−ピラゾリン−５−オン ４−ブチル−１−シクロヘキシル−３−（１−イミダゾ
リルメチル）−２−ピラゾリン−５−オン ４−ブチル−３−（１−イミダゾリルメチル）−１−
（２−ピリジル）−２−ピラゾリン−５−オン １−（3,4−ジクロロフェニル）−３−（１−イミダゾ
リルメチル）−２−ピラゾリン−５−オン ４−〔３−（１−イミダゾリルメチル）−５−オキソ−
２−ピラゾリン−１−イル〕フェニル酢酸 ４−〔３−（１−イミダゾリルメチル）−５−オキソ−
２−ピラゾリン−１−イル〕安息香酸 １−（４−エトキシカルボニルメチルフェニル）−３−
（１−イミダゾリルメチル）−２−ピラゾリン−５−オ
ン １−（４−エトキシカルボニルフェニル）−３−（１−
インダゾリルメチル）−２−ピラゾリン−５−オン 等 本発明に用いられる化合物（Ｉ）の塩のうち、薬剤とし
て許容される塩としては、塩酸、硫酸、臭化水素酸、リ
ン酸等の鉱酸との塩；メタンスルホン酸、ｐ−トルエン
スルホン酸、ベンゼンスルホン酸、酢酸、グリコール
酸、グルクロン酸、マレイン酸、フマル酸、シユウ酸、
アスコルビン酸、クエン酸、サリチル酸、ニコチン酸、
酒石酸等の有機酸との塩；ナトリウム、カリウム等のア
ルカリ金属との塩；マグネシウム、カルシウム等のアル
カリ土類金属との塩；アンモニア、トリス（ヒドロキシ
メチル）アミノメタン、N,N−ビス（ヒドロキシエチ
ル）ピペラジン、２−アミノ−２−メチル−１−プロパ
ノール、エタノールアミン、Ｎ−メチルグルカミン、Ｌ
−グルカミン等のアミンとの塩が挙げられる。1-phenyl-3- (3-pyridyl) -2-pyrazolin-5-one 1- (4-methylphenyl) -3- (3-pyridyl)-
2-Pyrazolin-5-one 1- (3-methylphenyl) -3- (3-pyridyl)-
2-Pyrazolin-5-one 1- (2-methylphenyl) -3- (3-pyridyl)-
2-Pyrazolin-5-one 1- (4-ethylphenyl) -3- (3-pyridyl)-
2-Pyrazolin-5-one 1- (4-propylphenyl) -3- (3-pyridyl)
-2-Pyrazolin-5-one 1- (4-butylphenyl) -3- (3-pyridyl)-
2-pyrazolin-5-one 1- (4-pentylphenyl) -3- (3-pyridyl)
-2-Pyrazolin-5-one 1- (3,4-dimethylphenyl) -3- (3-pyridyl) -2-pyrazolin-5-one 1- (4-methoxyphenyl) -3- (3- Pyridyl)
-2-Pyrazolin-5-one 1- (3-methoxyphenyl) -3- (3-pyridyl)
-2-Pyrazolin-5-one 1- (2-methoxyphenyl) -3- (3-pyridyl)
-2-Pyrazolin-5-one 1- (4-ethoxyphenyl) -3- (3-pyridyl)
-2-Pyrazolin-5-one 1- (4-propoxyphenyl) -3- (3-pyridyl) -2-pyrazolin-5-one 1- (4-butoxyphenyl) -3- (3-pyridyl)
2-Pyrazolin-5-one 1- (4-pentoxyphenyl) -3- (3-pyridyl) -2-pyrazolin-5-one 1- (3,4-dimethoxyphenyl) -3- (3 -Pyridyl) -2-pyrazolin-5-one 1- (4-chlorophenyl) -3- (3-pyridyl)-
2-Pyrazolin-5-one 1- (3-chlorophenyl) -3- (3-pyridyl)-
2-pyrazolin-5-one 1- (4-bromophenyl) -3- (3-pyridyl)-
2-Pyrazolin-5-one 1- (4-fluorophenyl) -3- (3-pyridyl)
-2-Pyrazolin-5-one 1- (3-chloro-4-methylphenyl) -3- (3-
Pyridyl) -2-pyrazolin-5-one 1- (3-trifluoromethylphenyl) -3- (3-
Pyridyl) -2-pyrazolin-5-one 1- (4-trifluoromethylphenyl) -3- (3-
Pyridyl) -2-pyrazolin-5-one 1- (4-methoxycarbonylphenyl) -3- (3-
Pyridyl) -2-pyrazolin-5-one 1- (4-ethoxycarbonylphenyl) -3- (3-
Pyridyl) -2-pyrazolin-5-one 4- [3- (3-pyridyl) -5-oxo-2-pyrazolin-1-yl] benzoic acid 1- (4-ethoxycarbonylmethylphenyl) -3-
(3-Pyridyl) -2-pyrazolin-5-one 4- [3- (3-pyridyl) -5-oxo-2-pyrazolin-1-yl] phenylacetic acid 1- (4-methylthiophenyl) -3- (3-Pyridyl) -2-pyrazolin-5-one 1- (3-methylthiophenyl) -3- (3-pyridyl) -2-pyrazolin-5-one 1- (4-hydroxyphenyl) -3- (3-Pyridyl) -2-pyrazolin-5-one 1- (3-hydroxyphenyl) -3- (3-pyridyl) -2-pyrazolin-5-one 1- (3,4-dihydroxyphenyl)- 3- (3-Pyridyl) -2-pyrazolin-5-one 1- (3,4,5-trimethylphenyl) -3- (3-pyridyl) -2-pyrazolin-5-one 1-cyclohexyl-3- (3-Pyridyl) -2-pyrazolin-5-one 1 Cyclopentyl-3- (3-pyridyl) -2-pyrazolin-5-one 1-cycloheptyl-3- (3-pyridyl) -2-pyrazolin-5-one 1- (2-pyridyl) -3- (3- Pyridyl) -2-pyrazolin-5-one 1- (4-pyridyl) -3- (3-pyridyl) -2-pyrazolin-5-one 1-phenyl-3- (2-pyridyl) -2-pyrazolin-5 -One 1-phenyl-3- (4-pyridyl) -2-pyrazolin-5-one 4-methyl-1-phenyl-3- (3-pyridyl) -2
-Pyrazolin-5-one 4-methyl-1- (4-methylphenyl) -3- (3-
Pyridyl) -2-pyrazolin-5-one 4-methyl-1- (3-methylphenyl) -3- (3-
Pyridyl) -2-pyrazolin-5-one 1- (4-ethylphenyl) -4-methyl-3- (3-
Pyridyl) -2-pyrazolin-5-one 4-methyl-1- (4-propylphenyl) -3- (3
-Pyridyl) -2-pyrazolin-5-one 1- (4-butylphenyl) -4-methyl-3- (3-
Pyridyl) -2-pyrazolin-5-one 1- (3,4-dimethylphenyl) -4-methyl-3-
(3-Pyridyl) -2-pyrazolin-5-one 1- (4-methoxyphenyl) -4-methyl-3- (3
-Pyridyl) -2-pyrazolin-5-one 1- (3-methoxyphenyl) -4-methyl-3- (3
-Pyridyl) -2-pyrazolin-5-one 1- (4-ethoxyphenyl) -4-methyl-3- (3
-Pyridyl) -2-pyrazolin-5-one 1- (4-butoxyphenyl) -4-methyl-3- (3
-Pyridyl) -2-pyrazolin-5-one 1- (3,4-dimethoxyphenyl) -4-methyl-3-
(3-Pyridyl) -2-pyrazolin-5-one 1- (4-chlorophenyl) -4-methyl-3- (3-
Pyridyl) -2-pyrazolin-5-one 1- (4-fluorophenyl) -4-methyl-3- (3
-Pyridyl) -2-pyrazolin-5-one 4-methyl-1- (4-methylthiophenyl) -3-
(3-Pyridyl) -2-pyrazolin-5-one 1- (4-trifluoromethylphenyl) -4-methyl-3- (3-pyridyl) -2-pyrazolin-5-one 1- (4-hydroxy (Phenyl) -4-methyl-3-
(3-Pyridyl) -2-pyrazolin-5-one 1-cyclohexyl-4-methyl-3- (3-pyridyl) -2-pyrazolin-5-one 4-methyl-1- (2-pyridyl) -3- (3-Pyridyl) -2-pyrazolin-5-one 4-ethyl-1-phenyl-3- (3-pyridyl) -2
-Pyrazolin-5-one 4-ethyl-1- (4-methylphenyl) -3- (3-
Pyridyl) -2-pyrazolin-5-one 4-ethyl-1- (4-ethylphenyl) -3- (3-
Pyridyl) -2-pyrazolin-5-one 1- (4-butylphenyl) -4-ethyl-3- (3-
Pyridyl) -2-pyrazolin-5-one 4-ethyl-1- (3,4-dimethylphenyl) -3-
(3-Pyridyl) -2-pyrazolin-5-one 4-ethyl-1- (4-methoxyphenyl) -3- (3
-Pyridyl) -2-pyrazolin-5-one 1- (4-ethoxyphenyl) -4-ethyl-3- (3
-Pyridyl) -2-pyrazolin-5-one 1- (4-chlorophenyl) -4-ethyl-3- (3-
Pyridyl) -2-pyrazolin-5-one 1-cyclohexyl-4-ethyl-3- (3-pyridyl) -2-pyrazolin-5-one 4-ethyl-1- (2-pyridyl) -3- (3- Pyridyl) -2-pyrazolin-5-one 1-phenyl-4-propyl-3- (3-pyridyl)-
2-Pyrazolin-5-one 1- (4-methylphenyl) -4-propyl-3- (3
-Pyridyl) -2-pyrazolin-5-one 1- (4-ethylphenyl) -4-propyl-3- (3
-Pyridyl) -2-pyrazolin-5-one 1- (4-methoxyphenyl) -4-propyl-3-
(3-Pyridyl) -2-pyrazolin-5-one 1- (4-ethoxyphenyl) -4-propyl-3-
(3-Pyridyl) -2-pyrazolin-5-one 1- (4-chlorophenyl) -4-propyl-3- (3
-Pyridyl) -2-pyrazolin-5-one 1-cyclohexyl-4-propyl-3- (3-pyridyl) -2-pyrazolin-5-one 4-butyl-1-phenyl-3- (3-pyridyl)- Two
-Pyrazolin-5-one 1-phenyl-3- (3-pyridylmethyl) -2-pyrazolin-5-one 1- (4-methylphenyl) -3- (3-pyridylmethyl) -2-pyrazolin-5-one 1- (3-methylphenyl) -3- (3-pyridylmethyl) -2-pyrazolin-5-one 1- (2-methylphenyl) -3- (3-pyridylmethyl) -2-pyrazolin-5-one 1- (4-Ethylphenyl) -3- (3-pyridylmethyl) -2-pyrazolin-5-one 1- (4-propylphenyl) -3- (3-pyridylmethyl) -2-pyrazolin-5-one 1- (4-Butylphenyl) -3- (3-pyridylmethyl) -2-pyrazolin-5-one 1- (3,4-dimethylphenyl) -3- (3-pyridylmethyl) -2-pyrazolin-5-one 1- (4 Methoxyphenyl) -3- (3-pyridylmethyl) -2-pyrazolin-5-one 1- (3-methoxyphenyl) -3- (3-pyridylmethyl) -2-pyrazolin-5-one 1- ( 4-Ethoxyphenyl) -3- (3-pyridylmethyl) -2-pyrazolin-5-one 1- (4-butoxyphenyl) -3- (3-pyridylmethyl) -2-pyrazolin-5-one 1- ( 3,4-Dimethoxyphenyl) -3- (3-pyridylmethyl) -2-pyrazolin-5-one 1- (4-chlorophenyl) -3- (3-pyridylmethyl) -2-pyrazolin-5-one 1 -(4-Fluorophenyl) -3- (3-pyridylmethyl) -2-pyrazolin-5-one 1- (4-trifluoromethylphenyl) -3- (3-
Pyridylmethyl) -2-pyrazolin-5-one 1- (4-methylthiophenyl) -3- (3-pyridylmethyl) -2-pyrazolin-5-one 4- [3- (3-pyridylmethyl) -5 -Oxo-2-
Pyrazolin-1-yl] benzoic acid 1- (4-hydroxyphenyl) -3- (3-pyridylmethyl) -2-pyrazolin-5-one 1-cyclohexyl-3- (3-pyridylmethyl) -2
-Pyrazolin-5-one 1- (2-pyridyl) -3- (3-pyridylmethyl)-
2-Pyrazolin-5-one 1-phenyl-3- (2-pyridylmethyl) -2-pyrazolin-5-one 1- (4-methylphenyl) -3- (2-pyridylmethyl) -2-pyrazolin-5- On 1-phenyl-3- (4-pyridylmethyl) -2-pyrazolin-5-one 3- (2-furanyl) -1-phenyl-2-pyrazolin-5-one 3- (2-furanyl) -1- (4-methylphenyl)-
2-Pyrazolin-5-one 3- (2-furanyl) -1- (3-methylphenyl)-
2-Pyrazolin-5-one 3- (2-furanyl) -1- (2-methylphenyl)-
2-Pyrazolin-5-one 1- (4-ethylphenyl) -3- (2-furanyl)-
2-Pyrazolin-5-one 1- (4-butylphenyl) -3- (2-furanyl)-
2-Pyrazolin-5-one 3- (2-furanyl) -1- (3,4-dimethylphenyl) -2-pyrazolin-5-one 3- (2-furanyl) -1- (4-methoxyphenyl) )
-2-Pyrazolin-5-one 3- (2-furanyl) -1- (3-methoxyphenyl)
-2-Pyrazolin-5-one 1- (4-ethoxyphenyl) -3- (2-furanyl)
-2-Pyrazolin-5-one 1- (4-butoxyphenyl) -3- (2-furanyl)
-2-Pyrazolin-5-one 3- (2-furanyl) -1- (3,4-dimethoxyphenyl) -2-pyrazolin-5-one 1- (4-chlorophenyl) -3- (2-furanyl) −
2-Pyrazolin-5-one 1- (4-fluorophenyl) -3- (2-furanyl)
-2-Pyrazolin-5-one 3- (2-furanyl) -1- (4-methylthiophenyl) -2-pyrazolin-5-one 1- (4-trifluoromethylphenyl) -3- (2-
Furanyl) -2-pyrazolin-5-one 3- (2-furanyl) -1- (4-hydroxyphenyl) -2-pyrazolin-5-one 1-cyclohexyl-3- (2-furanyl) -2-pyrazolin -5-one 3- (2-furanyl) -1- (2-pyridyl) -2-pyrazolin-5-one 3- (1-imidazolylmethyl) -1-phenyl-2-
Pyrazolin-5-one 3- (1-imidazolylmethyl) -1- (4-methylphenyl) -2-pyrazolin-5-one 3- (1-imidazolylmethyl) -1- (3-methylphenyl) -2- Pyrazolin-5-one 1- (4-ethylphenyl) -3- (1-imidazolylmethyl) -2-pyrazolin-5-one 1- (4-butylphenyl) -3- (1-imidazolylmethyl) -2- Pyrazolin-5-one 3- (1-imidazolylmethyl) -1- (3,4-dimethylphenyl) -2-pyrazolin-5-one 3- (1-imidazolylmethyl) -1- (4-methoxyphenyl)- 2-Pyrazolin-5-one 3- (1-imidazolylmethyl) -1- (3-methoxyphenyl) -2-pyrazolin-5-one 1- (4-ethoxyphenyl) -3- (1-imidazole Rylmethyl) -2-pyrazolin-5-one 1- (4-butoxyphenyl) -3- (1-imidazolylmethyl) -2-pyrazolin-5-one 1- (4-chlorophenyl) -3- (1-imidazolylmethyl ) -2-Pyrazolin-5-one 1- (4-fluorophenyl) -3- (1-imidazolylmethyl) -2-pyrazolin-5-one 1- (4-hydroxyphenyl) -3- (1-imidazolylmethyl) ) -2-Pyrazolin-5-one 3- (1-imidazolylmethyl) -1- (α-naphthyl) -2-pyrazolin-5-one 1-cyclohexyl-3- (1-imidazolylmethyl)
2-Pyrazolin-5-one 3- (1-imidazolylmethyl) -1- (2-pyridyl) -2-pyrazolin-5-one 3- (1-imidazolylmethyl) -4-methyl-1-phenyl-2 -Pyrazolin-5-one 3- (1-imidazolylmethyl) -4-methyl-1-
(4-Methylphenyl) -2-pyrazolin-5-one 1- (4-ethylphenyl) -3- (1-imidazolylmethyl) -4-methyl-2-pyrazolin-5-one 1- (4-butylphenyl ) -3- (1-Imidazolylmethyl) -4-methyl-2-pyrazolin-5-one 1- (4-chlorophenyl) -3- (1-imidazolylmethyl) -4-methyl-2-pyrazolin-5-one 3- (1-Imidazolylmethyl) -1- (4-methoxyphenyl) -4-methyl-2-pyrazolin-5-one 1-cyclohexyl-3- (1-imidazolylmethyl)
-4-Methyl-2-pyrazolin-5-one 3- (1-imidazolylmethyl) -4-methyl-1-
(2-Pyridyl) -2-pyrazolin-5-one 4-ethyl-3- (1-imidazolylmethyl) -1-phenyl-2-pyrazolin-5-one 4-ethyl-3- (1-imidazolylmethyl)- 1-
(4-Methylphenyl) -2-pyrazolin-5-one 1- (4-butylphenyl) -4-ethyl-3- (1-
Imidazolylmethyl) -2-pyrazolin-5-one 1- (4-chlorophenyl) -4-ethyl-3- (1-
Imidazolylmethyl) -2-pyrazolin-5-one 1- (3,4-dichlorophenyl) -4-ethyl-3-
(1-Imidazolylmethyl) -2-pyrazolin-5-one 4-ethyl-3- (1-imidazolylmethyl) -1-
(4-Methoxyphenyl) -2-pyrazolin-5-one 1-cyclohexyl-3- (1-imidazolylmethyl)
-2-Pyrazolin-5-one 3- (1-imidazolylmethyl) -4-isopropyl-
1-Phenyl-2-pyrazolin-5-one 1- (4-chlorophenyl) -3- (1-imidazolylmethyl) -4-isopropyl-2-pyrazolin-5-one 3- (1-imidazolylmethyl) -4- Isopropyl-
1- (4-methylphenyl) -2-pyrazolin-5-one 4-butyl-3- (1-imidazolylmethyl) -1-phenyl-2-pyrazolin-5-one 4-butyl-3- (1-imidazolyl Methyl) -1-
(4-Methylphenyl) -2-pyrazolin-5-one 4-butyl-3- (1-imidazolylmethyl) -1-
(3-Methylphenyl) -2-pyrazolin-5-one 4-butyl-1- (4-butylphenyl) -3- (1-
Imidazolylmethyl) -2-pyrazolin-5-one 4-butyl-1- (4-chlorophenyl) -3- (1-
Imidazolylmethyl) -2-pyrazolin-5-one 4-butyl-1- (3,4-dichlorophenyl) -3-
(1-Imidazolylmethyl) -2-pyrazolin-5-one 4-butyl-3- (1-imidazolylmethyl) -1-
(4-Methoxyphenyl) -2-pyrazolin-5-one 4-butyl-1-cyclohexyl-3- (1-imidazolylmethyl) -2-pyrazolin-5-one 4-butyl-3- (1-imidazolylmethyl) -1-
(2-Pyridyl) -2-pyrazolin-5-one 1- (3,4-dichlorophenyl) -3- (1-imidazolylmethyl) -2-pyrazolin-5-one 4- [3- (1-imidazolylmethyl) -5-oxo-
2-Pyrazolin-1-yl] phenylacetic acid 4- [3- (1-imidazolylmethyl) -5-oxo-
2-Pyrazolin-1-yl] benzoic acid 1- (4-ethoxycarbonylmethylphenyl) -3-
(1-Imidazolylmethyl) -2-pyrazolin-5-one 1- (4-ethoxycarbonylphenyl) -3- (1-
Indazolylmethyl) -2-pyrazolin-5-one, etc. Among the salts of compound (I) used in the present invention, pharmaceutically acceptable salts include hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid and the like. Salts with mineral acids; methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, acetic acid, glycolic acid, glucuronic acid, maleic acid, fumaric acid, oxalic acid,
Ascorbic acid, citric acid, salicylic acid, nicotinic acid,
Salts with organic acids such as tartaric acid; salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as magnesium and calcium; ammonia, tris (hydroxymethyl) aminomethane, N, N-bis (hydroxy) Ethyl) piperazine, 2-amino-2-methyl-1-propanol, ethanolamine, N-methylglucamine, L
-Salts with amines such as glucamine.
本発明に用いる化合物は、合目的な任意の方法で合成す
ることができるが、好ましい方法の一例を次に示す。The compound used in the present invention can be synthesized by any purposeful method, but an example of a preferable method is shown below.
（式中、R1、R2、R3及びｎは前記と同義であり、R4は炭
素数１〜５のアルキル基を表わす。） 即ち、式（II）で示されるβ−ケト酸誘導体と式（II
I）で示されるヒドラジン誘導体を、例えばメタノー
ル、エタノール等のアルコール類若しくはベンゼン、ト
ルエン等芳香族炭化水素溶媒の存在下、又は無溶媒で、
必要に応じて、炭酸カリウム、ナトリウムエトキシド、
カリウム−ｔ−ブトキシド、水酸化ナトリウム、水酸化
カリウム、酢酸ナトリウム等の塩基；塩酸、硫酸、臭化
水素酸等の鉱酸；酢酸、パラトルエンスルホン酸等の有
機酸等の触媒の存在下、10〜200℃の温度で反応させる
ことにより、化合物（Ｉ）が得られる。 (In the formula, R 1 , R 2 , R 3 and n have the same meanings as described above, and R 4 represents an alkyl group having 1 to 5 carbon atoms.) That is, the β-keto acid derivative represented by the formula (II) And the expression (II
The hydrazine derivative represented by I) is, for example, in the presence of an alcohol such as methanol or ethanol or an aromatic hydrocarbon solvent such as benzene or toluene, or in the absence of a solvent,
If necessary, potassium carbonate, sodium ethoxide,
In the presence of a catalyst such as a base such as potassium t-butoxide, sodium hydroxide, potassium hydroxide or sodium acetate; a mineral acid such as hydrochloric acid, sulfuric acid or hydrobromic acid; an organic acid such as acetic acid or paratoluenesulfonic acid. Compound (I) is obtained by reacting at a temperature of 10 to 200 ° C.
また、R1のフエニル基の置換基によつては次に示す様に
して目的化合物（Ｉ）を合成できる。The target compound (I) can be synthesized as follows depending on the substituent of the phenyl group of R 1 .
（式中、R1、R2、R3及びｎは前記と同義であり、R5及び
R6はそれぞれ炭素数１〜５のアルキル基を表わし、ｍは
０又は１の数を表わす。） 又、該置換基が水酸基である目的化合物（Ｉ）は、例え
ば適当なアルコキシ基を臭化水素酸又はルイス酸等で分
解して得られる。更に、該置換基がカルボキシル基ある
いはカルボキシメチル基の場合には、例えばアルコキシ
カルボニル基、アルコキシカルボニルメチル基を酸ある
いはアルカリ等通常の条件により加水分解することによ
り目的化合物（Ｉ）を得ることが出来る。 (In the formula, R 1 , R 2 , R 3 and n are as defined above, and R 5 and
R 6 represents an alkyl group having 1 to 5 carbon atoms, and m represents a number of 0 or 1. The target compound (I) in which the substituent is a hydroxyl group can be obtained, for example, by decomposing an appropriate alkoxy group with hydrobromic acid, Lewis acid or the like. Further, when the substituent is a carboxyl group or a carboxymethyl group, the target compound (I) can be obtained by hydrolyzing an alkoxycarbonyl group or an alkoxycarbonylmethyl group under ordinary conditions such as acid or alkali. .
化合物（Ｉ）を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回化合物（Ｉ）として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回化合物（Ｉ）として0.01〜10mgを１
日２〜５回投与又はこれらの用量を点滴持続注入するの
が好ましく、また、直腸内投与の場合は、１回化合物
（Ｉ）として、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 clinically applying Compound (I), when used orally, 1 to 100 mg of Compound (I) once for an adult
It is preferable to administer 1 to 3 times a day. In the case of intravenous injection, 0.01 to 10 mg of Compound (I) is administered once to an adult.
It is preferable to administer 2 to 5 times a day or continuous infusion of these doses. In the case of rectal administration, 1 to 100 mg of Compound (I) is administered 1 to 3 times a day. preferable. Further, it is more preferable that the above dose is appropriately increased or decreased depending on age, disease state, and symptom.
また、経口又は直腸内投与の場合は、徐放化製剤として
用いてもよい。In the case of oral or rectal administration, it may be used as a sustained release preparation.
製剤化に際しては、化合物（Ｉ）又はその薬学的に許容
される塩の一種又は二種以上を、通常用いられる製剤用
担体、賦形剤その他の添加物を含む組成物として使用す
るのふつうである。医薬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）、シヨ
糖、結晶セルロース、コーンスターチ、タルク、寒天、
ベクチン、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、塩化ナトリウム等が挙げられる。Upon formulation, one or more compounds (I) or pharmaceutically acceptable salts thereof are usually used as a composition containing a commonly used pharmaceutical carrier, excipient or other additive. is there. The pharmaceutical carrier may be solid or liquid,
Examples of solid carriers are lactose, white clay (kaolin), sucrose, crystalline cellulose, corn starch, talc, agar,
Bectin, acacia, stearic acid, magnesium stearate, lecithin, sodium chloride and the like can be mentioned.
液状の担体の例としては、シロツプ、グリセリン、落花
生油、ポリビニルピロリドン、オリーブ湯、エタノー
ル、ベンジルアルコール、プロピレングリコール、水等
が挙げられる。Examples of liquid carriers include syrup, glycerin, peanut oil, polyvinylpyrrolidone, olive water, ethanol, benzyl alcohol, propylene glycol, water and the like.
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
又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。It can take various dosage forms, and when a solid carrier is used, it can be tablets, powders, granules, hard gelatin capsules, suppositories or troches. The amount of solid carrier may vary widely but preferably will be from about 1 mg to about 1 g.
液状の担体を用いる場合は、シロツプ、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又は
水性若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 ampoules, or aqueous or non-aqueous suspension.
また、化合物（Ｉ）をシクロデキストリン包接体又はリ
ポソーム中に入れる等の操作をして、用いることもでき
る。In addition, the compound (I) can also be used by performing an operation such as putting it in a cyclodextrin inclusion complex or a liposome.
本発明の過酸化脂質生成抑制剤は、優れた作用を有し、
諸種虚血性疾患若しくはそれに基づく諸種疾患、即ち、
脳梗塞、脳卒中等の脳血管障害、又はそれらに起因する
脳機能低下、血管性痴呆、加齢に伴う脳血管組織病変等
の諸種脳疾患、心筋梗塞、心不全等心筋虚血に基づく諸
種心疾患及び諸種末梢循環障害等の予防・治療剤として
有用である。The lipid peroxide production inhibitor of the present invention has an excellent action,
Various ischemic diseases or various diseases based on them, that is,
Cerebral infarctions such as cerebral infarction and stroke, or various cerebral diseases such as cerebral dysfunction caused by them, vascular dementia, cerebral vascular tissue lesions with aging, myocardial infarction, various heart diseases based on myocardial ischemia such as heart failure It is also useful as a prophylactic / therapeutic agent for various peripheral circulatory disorders.
以下、合成例及び実施例を挙げて本発明を更に具体的に
説明するが、本発明はその要旨を越えない限り以下の実
施例によつて限定されるものではない。Hereinafter, the present invention will be described in more detail with reference to Synthesis Examples and Examples, but the present invention is not limited to the following Examples unless the gist thereof is exceeded.
合成例１ （１−フエニル−３−（３−ピリジル）−２−ピラゾリ
ン−５−オン（化合物No.1）の合成）エタノール（15m
l）中に、３−オキソ−３−（３−ピリジル）プロピオ
ン酸エチル3.86g及びフエニルヒドラジン2.16gを加え、
50〜60℃で２時間撹拌した。放冷後、析出した結晶を
取し、エタノールより再結晶して１−フエニル−３−
（３−ピリジル）−２−ピラゾリン−５−オン（化合物
No.1）2.83gを無色結晶として得た。Synthesis Example 1 (Synthesis of 1-phenyl-3- (3-pyridyl) -2-pyrazolin-5-one (Compound No. 1)) Ethanol (15 m
In l), 3.86 g of ethyl 3-oxo-3- (3-pyridyl) propionate and 2.16 g of phenylhydrazine were added,
The mixture was stirred at 50-60 ° C for 2 hours. After cooling, the precipitated crystals were collected and recrystallized from ethanol to give 1-phenyl-3-
(3-pyridyl) -2-pyrazolin-5-one (compound
No. 1) 2.83 g was obtained as colorless crystals.
収率:60％ 融点:200〜204℃ 合成例２〜54 （化合物No.2〜８及び11〜47、51〜59の合成） 合成例１と同様にして表１に化合物No.2〜８、11〜47、
51〜59として示す化合物を合成した。Yield: 60% Melting point: 200 to 204 ° C. Synthesis Examples 2 to 54 (Synthesis of Compound Nos. 2 to 8 and 11 to 47, 51 to 59) In the same manner as in Synthesis Example 1, Table 1 shows compound Nos. 2 to 8. , 11 to 47,
The compounds shown as 51-59 were synthesized.
合成例55 （４−〔３−（３−ピリジル）−５−オキソ−２−ピラ
ゾリン−１−イル〕フエニル酢酸（化合物No.9の合成） ５％水酸化ナトリウム水溶液1.6mlに１−（４−エトキ
シカルボニルメチルフエニル）−３−（３−ピリジル）
−２−ピラゾリン−５−オン323mgを加え、室温で１時
間撹拌した。反応液を２％塩酸にてpH3に調節し、析出
した結晶を取し、（４−〔３−（３−ピリジル）−５
−オキソ−２−ピラゾリン−１−イル〕フエニル酢酸
（化合物No.9）182mgを無色結晶として得た。Synthesis Example 55 (4- [3- (3-pyridyl) -5-oxo-2-pyrazolin-1-yl] phenylacetic acid (synthesis of compound No. 9) 1- (4 -Ethoxycarbonylmethylphenyl) -3- (3-pyridyl)
2-Pyrazolin-5-one (323 mg) was added, and the mixture was stirred at room temperature for 1 hr. The reaction solution was adjusted to pH 3 with 2% hydrochloric acid, and the precipitated crystals were collected, and the crystals (4- [3- (3-pyridyl) -5] were collected.
182 mg of -oxo-2-pyrazolin-1-yl] phenylacetic acid (Compound No. 9) was obtained as colorless crystals.
収率:62％ 融点：＞250℃ 合成例56、57 合成例55と同様にして、化合物No.48、49を合成した。Yield: 62% Melting point:> 250 ° C Synthesis Examples 56 and 57 In the same manner as in Synthesis Example 55, compound Nos. 48 and 49 were synthesized.
合成例58 （１−（４−ヒドロキシフエニル）−３−（３−ピリジ
ル）−２−ピラゾリン−５−オン（化合物No.10）の合
成） （１−（４−メトキシフエニル）−３−（３−ピリジ
ル）−２−ピラゾリン−５−オン267mgを47％臭化水素
酸1ml及び酢酸1mlの混合液中に加え、６時間還流撹拌し
た。溶媒留去後、水及びNaHCO3水溶液を加えてpH4とし
た後、酢酸エチルにより抽出した。有機層を乾燥し、濃
縮後、残渣をエタノールから再結晶して、１−（４−ヒ
ドロキシフエニル）−３−（３−ピリジル）−２−ピラ
ゾリン−５−オン（化合物No.10）162mgを無色結晶とし
て得た。Synthesis Example 58 (Synthesis of 1- (4-hydroxyphenyl) -3- (3-pyridyl) -2-pyrazolin-5-one (Compound No. 10)) (1- (4-Methoxyphenyl) -3 -. (3-pyridyl) -2-pyrazolin-5-one 267mg was added into a mixture of 47% hydrobromic acid 1ml and acetic 1ml, was stirred at reflux for 6 hours and then the solvent was distilled off, water and aqueous NaHCO 3 After the pH was adjusted to pH 4, the mixture was extracted with ethyl acetate, the organic layer was dried and concentrated, and the residue was recrystallized from ethanol to give 1- (4-hydroxyphenyl) -3- (3-pyridyl) -2. 162 mg of -pyrazolin-5-one (Compound No. 10) was obtained as colorless crystals.
収率:64％ 融点：＞250℃ 合成例59 合成例58と同様にして、化合物No.50を合成した。Yield: 64% Melting point:> 250 ° C Synthesis Example 59 In the same manner as in Synthesis Example 58, compound No. 50 was synthesized.
実施例１ （１） 脂質過酸化抑制作用 （ａ） 脳ホモジエネートの作製 ウイスター（Wistar）系雄性ラツトを用い、以下の操作
手順に従つて脳ホモジエネートを作製した。ペントバル
ビタールナトリウム45mg/kgの腹腔内投与で麻酔下に開
胸し、左心室からポリエチレンチユーブを大動脈内に挿
入し固定した。次いで、このチユーブを介して氷冷した
50mMリン酸塩緩衝生理食塩水（pH7.4）（以下「PBS」と
いう。）で脳潅流を行い、全脳を摘出した。小脳を除去
後、大脳の湿重量を測定し、その９倍量のPBSを加え、
氷水中においてテフロンホモジエナイザーで破砕し均質
化した。この脳ホモジエネートを４℃において2200rpm
で10分間遠心分離後、上清部0.3mlを共栓付遮光試験管
に分取し、薬物評価用脳ホロジエネートとした。Example 1 (1) Lipid peroxidation inhibitory action (a) Preparation of brain homogenate Using a Wistar male rat, a brain homogenate was prepared according to the following procedure. The chest was opened under anesthesia by intraperitoneal administration of sodium pentobarbital 45 mg / kg, and polyethylene tube was inserted into the aorta from the left ventricle and fixed. It was then ice-cooled through this tube
Brain perfusion was performed with 50 mM phosphate buffered saline (pH 7.4) (hereinafter referred to as "PBS"), and the whole brain was extracted. After removing the cerebellum, measure the wet weight of the cerebrum, add 9 times the amount of PBS,
It was homogenized by crushing with a Teflon homogenizer in ice water. This brain homogenate is 2200 rpm at 4 ° C.
After centrifuging for 10 minutes, 0.3 ml of the supernatant was collected in a light-shielding test tube with a stopper to give a brain holodienate for drug evaluation.
（ｂ） 被験薬の評価 （ａ）で調製した脳ホモジエネートにPBS0.6ml及び被験
薬のエタノール溶液10μ0.3〜100μＭの公比３での濃
度）を添加し、37℃の温浴中で30分間加温した。次い
で、35％過塩素酸水溶液200μを添加後、４℃におい
て2600rpmで10分間遠心分離し、上清を得た。また、ブ
ランク測定用として被験薬のエタノール溶液10μの代
りにエタノール10μを添加し（ブランク）、同様に操
作した。(B) Evaluation of test drug To the brain homogenate prepared in (a), 0.6 ml of PBS and an ethanol solution of the test drug of 10 μ0.3 to 100 μM in a common ratio of 3) were added, and the mixture was kept in a hot bath at 37 ° C. for 30 minutes. Heated. Then, 200 μ of 35% perchloric acid aqueous solution was added, followed by centrifugation at 2600 rpm for 10 minutes at 4 ° C. to obtain a supernatant. For blank measurement, 10 μl of ethanol was added instead of 10 μl of the ethanol solution of the test drug (blank), and the same operation was performed.
（ｃ） 過酸化脂質の定量 （ｂ）で得た上清部0.1mlに8.1％ドデシル硫酸ナトリウ
ム水溶液0.2ml、20％酢酸緩衝液（pH3.5）1.5ml、0.67
％２−チオバルビツール酸水溶液1.5ml及び蒸溜水0.7ml
を加えて混和した。次いで、この混液を沸騰水浴中で60
分間加熱後、氷水で急速に冷却し、蒸留水1.0ml及びピ
リジン−ブタノール混液（1:15）5.0mlを加え、約30秒
間振盪後、3000rpmで10分間遠心分離し、その上清部を
過酸化脂質測定用試料とした。なお、リポパーオキシド
−テスト試薬（Lipoperoxide−test）（和光純薬（株）
製;1,1,3,3−テトラエトキシプロパン5nmol/ml含有）0.
1mlを（ｂ）で得た脳ホモジエネートの代りに添加し、
標準液とした。(C) Quantification of lipid peroxide In 0.1 ml of the supernatant obtained in (b), 0.2 ml of 8.1% sodium dodecyl sulfate aqueous solution, 1.5 ml of 20% acetate buffer (pH 3.5), 0.67
% 2-thiobarbituric acid aqueous solution 1.5 ml and distilled water 0.7 ml
And mixed. This mixture is then placed in a boiling water bath at 60
After heating for 10 minutes, rapidly cool with ice water, add 1.0 ml of distilled water and 5.0 ml of pyridine-butanol mixed solution (1:15), shake for about 30 seconds, centrifuge at 3000 rpm for 10 minutes, and discard the supernatant. The sample was used for measurement of oxidized lipid. In addition, Lipoperoxide-test reagent (Lipoperoxide-test) (Wako Pure Chemical Industries, Ltd.)
Made; containing 1,1,3,3-tetraethoxypropane 5 nmol / ml)
1 ml was added instead of the brain homogenate obtained in (b),
The standard solution was used.
過酸化脂質は螢光分光光度計（（株）日立製作所204
型）を用い、励起波長515nm、螢光波長550nmで測定し、
次式に従つて過酸化脂質量（TBA値）を求めた。Lipid peroxide is measured by a fluorescence spectrophotometer (Hitachi, Ltd. 204
Type), the excitation wavelength is 515 nm, and the fluorescence wavelength is 550 nm.
The amount of lipid peroxide (TBA value) was calculated according to the following formula.
F;標準液の螢光強度 f;被験薬の螢光強度 次いで、（ｂ）のブリンクのTBA値に対する被験薬各濃
度の抑制率を求め、最小二乗法に従つてIC50値を算出し
た。結果を表１に示す。 F: Fluorescence intensity of standard solution f: Fluorescence intensity of test drug Then, the inhibition rate of each concentration of the test drug against the TBA value of the blink in (b) was determined, and the IC 50 value was calculated according to the least squares method. The results are shown in Table 1.
（２） 脳虚血再開通モデルにおける保護作用 体重役400gのウイスター（Wistar）系雄性ラツトにｄ−
ツボクラリン0.6mgを筋肉内投与して不動化し、気管カ
ニユーレ装着後、人工呼吸下に頭部を脳定位固定装置に
保定した。頭比を切開し、頭蓋骨を穿孔後、硬膜下左大
脳皮質前頭葉表面上に脳波導出用の電極を存置した。電
極を歯科用セメントを用いて頭蓋骨に固定後、動物を背
位に保持した。次いで、全身圧測定用のカニユーレを左
大腿動脈内に、ｄ−ツボクラリン追加投与用のカニユー
レを左大腿静脈内にそれぞれ留置した。心拍数は動脈波
によつて心拍数計を駆動し測定記録した。(2) Protective effect in cerebral ischemia recanalization model d-on Wistar male rats weighing 400 g
After immobilizing 0.6 mg of tubocurarine im and immobilizing it, the head was held on a stereotaxic apparatus under artificial respiration after wearing a tracheal cannula. After incising the head ratio and perforating the skull, an electrode for electroencephalography was placed on the surface of the frontal lobe of the subdural left cerebral cortex. After fixing the electrodes to the skull using dental cement, the animals were held in the dorsal position. Then, a cannula for measuring whole body pressure was placed in the left femoral artery, and a cannula for additional administration of d-tubocurarine was placed in the left femoral vein. The heart rate was measured and recorded by driving the heart rate meter by the arterial wave.
血圧、心拍数及び脳波の諸パラメーターの安定後に、１
％トラガカントゴム溶液で1ml/kgとなるように懸濁調製
した本発明の有効成分10mg/kgを脳虚血負荷30分前に十
二指腸内に直接投与した。対照群には、同容量の１％ト
ラガカントゴム溶液のみを同様に投与した。After stabilization of blood pressure, heart rate, and EEG parameters, 1
10 mg / kg of the active ingredient of the present invention, which was prepared by suspension in a 1% tragacanth gum solution so as to be 1 ml / kg, was directly administered into the duodenum 30 minutes before the cerebral ischemia. The control group was similarly administered with the same volume of 1% tragacanth gum solution alone.
薬物投与10〜20分後に脳波、血圧及び心拍数を多用途監
視記録装置（日本光電（株）製、RM−85型）上で監視し
ながら、脳虚血負荷のために以下の術式に従つて操作を
行つた。While monitoring EEG, blood pressure, and heart rate on a versatile monitoring and recording device (Nihon Kohden Co., Ltd., RM-85 type) 10 to 20 minutes after drug administration, the following surgical procedure was performed for cerebral ischemic load. Therefore, the operation was performed.
先ず、左肋軟骨端部で肋骨を遊離し、開胸した。次い
で、大動脈起始部で露出した左総頚動脈と左椎骨動脈を
同時に、続いて腕頭動脈を、動脈クリツプを用いて薬物
投与30分後に閉塞することによつて、10分間の頭部血流
の遮断を行つた。First, the ribs were released at the end of the left costal cartilage, and the chest was opened. Then, the left common carotid artery and the left vertebral artery exposed at the origin of the aorta were simultaneously blocked, and then the brachiocephalic artery was occluded 30 minutes after drug administration using an arterial clip to obtain 10 minutes of head blood flow. Cut off.
頭部血流の再開通は、前記各部位に装着した２本の動脈
クリツプを同時に解除することによつて行つた。Recanalization of head blood flow was performed by simultaneously releasing the two arterial clips attached to the respective sites.
薬物の脳虚血負荷要開通後の障害に対する保護作用は、
脳波の回復の有無によつて検討した。The protective effect of the drug against damage after cerebral ischemic load is required,
It was examined whether or not the EEG was recovered.
なお、実験中は保温マツトを用い、動物の直腸温を37〜
38℃に保持した。また、直腸温は脳波、大腿動脈圧及び
心拍数と共にレコーダー上に連続描記した。During the experiment, use a heat-retaining mat to keep the rectal temperature of the animal at 37-
Hold at 38 ° C. The rectal temperature was continuously plotted on the recorder along with the electroencephalogram, femoral artery pressure and heart rate.
脳虚血を10分間負荷したところ、虚血直後から脳波の電
圧は低下し、約15秒も経過すると脳波は消失、平坦化し
た。このような虚血負荷中の脳波の平坦化は対照群及び
本発明の有効成分投与群の双方に共通して認められた。When cerebral ischemia was applied for 10 minutes, the electroencephalogram voltage decreased immediately after ischemia, and after about 15 seconds, the electroencephalogram disappeared and flattened. The flattening of the electroencephalogram during ischemic load was commonly observed in both the control group and the active ingredient administration group of the present invention.
10分間の脳虚血を解除し、再開通しても、対照群では全
例脳波の出現は全く認められず、虚血負荷中と同様に平
坦化されたままに推移した。このような平坦脳波の持続
によつて、動物は再開通後平均75分には死亡した。Even if cerebral ischemia was released for 10 minutes and recanalization was resumed, no electroencephalogram was observed in all cases in the control group, and the level remained flat as in ischemia. Due to this sustained flat EEG, the animals died an average of 75 minutes after recanalization.
しかしながら、本発明の有効成分化合物No.1又はNo.24
投与群では、再開通中に脳波が回復出現し、いわゆる脳
機能の回復と共に心脈管系の機能が賦活、正常化され
た。これらの総合的な結果として、動物の生存時間は明
らかに延長された。However, the active ingredient compound No. 1 or No. 24 of the present invention
In the administration group, EEG recovered and appeared during recanalization, and the function of the cardiovascular system was activated and normalized along with the recovery of so-called brain function. As a result of these overall results, the survival time of the animals was clearly extended.
実施例２ 本発明の過酸化脂質生成抑制剤の製剤化 （１） 錠 剤 下記成分を常法に従つて混合し、慣用の装置により打錠
した。Example 2 Formulation of Lipid Peroxide Production Inhibitor of the Present Invention (1) Tablets The following ingredients were mixed according to a conventional method and tableted by a conventional device.
化合物No.1 10 mg 結晶セルロース 21 mg コーンスターチ 33 mg 乳 糖 65 mg ステアリン酸マグネシウム 1.3mg （２） 軟カプセル剤 下記成分を常法に従つて混合し、軟カプセルに充填し
た。Compound No. 1 10 mg Crystalline cellulose 21 mg Corn starch 33 mg Lactose 65 mg Magnesium stearate 1.3 mg (2) Soft capsules The following ingredients were mixed according to a conventional method and filled into soft capsules.
化合物No.1 10 mg オリーブ油 105 mg レシチン 6.5mg （３） 注射用製剤 下記成分を常法に従つて混合して1mlアンプルを調製し
た。Compound No. 1 10 mg Olive oil 105 mg Lecithin 6.5 mg (3) Formulation for injection 1 ml ampoule was prepared by mixing the following components according to a conventional method.
化合物No.1 0.7mg 塩化ナトリウム 3.5mg 注射用蒸留水 1.0ml Compound No. 1 0.7 mg Sodium chloride 3.5 mg Distilled water for injection 1.0 ml
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.6 識別記号 庁内整理番号 ＦＩ 技術表示箇所 Ｃ０７Ｄ 401/14 ２３１ 403/04 ２３１ 403/06 ２３１ 405/04 ２１３ 405/06 ２１３ 405/14 ２１３ 417/04 ２３１ 417/14 ２１３ ２３１ (72)発明者 渡辺 俊明 茨城県稲敷郡阿見町中央８丁目５番１号 三菱化成工業株式会社総合研究所筑波医薬 研究所内 (72)発明者 幸 敏志 茨城県稲敷郡阿見町中央８丁目５番１号 三菱化成工業株式会社総合研究所筑波医薬 研究所内 (72)発明者 櫻井 洋子 茨城県稲敷郡阿見町中央８丁目５番１号 三菱化成工業株式会社総合研究所筑波医薬 研究所内 (72)発明者 林 良夫 茨城県稲敷郡阿見町中央８丁目５番１号 三菱化成工業株式会社総合研究所筑波医薬 研究所内 (72)発明者 福島 信子 茨城県稲敷郡阿見町中央８丁目５番１号 三菱化成工業株式会社総合研究所筑波医薬 研究所内─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. 6 Identification code Internal reference number FI Technical display location C07D 401/14 231 403/04 231 403/06 231 405/04 213 405/06 213 405/14 213 417/04 231 417/14 213 231 (72) Inventor Toshiaki Watanabe 8-5-1 Chuo, Ami-cho, Inashiki-gun, Ibaraki Prefecture Mitsubishi Kasei Co., Ltd. General Research Institute Tsukuba Pharmaceutical Research Institute (72) Inventor Toshishi Ko Ibaraki 8-5-1 Chuo, Ami-cho, Inashiki-gun Mitsubishi Kasei Co., Ltd. Research Institute, Tsukuba Pharmaceutical Research Institute (72) Inventor Yoko Sakurai 8-5-1 Chuo, Ami-cho, Inashiki-gun, Ibaraki Mitsubishi Kasei Kogyo Co., Ltd. Tsukuba Pharmaceutical Research Laboratory (72) Inventor Yoshio Hayashi 8-5-1 Chuo, Ami-cho, Inashiki-gun, Ibaraki Mitsubishi Kasei Co., Ltd. Tokoro Tsukuba pharmaceutical research laboratories (72) inventor Fukushima Nobuko Inashiki-gun, Ibaraki Ami-cho, central 8-chome fifth No. 1 Mitsubishi Chemical Industry Co., Ltd. Research Institute, Tsukuba pharmaceutical the laboratory
Claims (1)
よいフェニル基、ピリジル基またはベンゾチアゾリル基
を表わし、R2は水素原子またはアルキル基を表わし、R3
はピリジル基、フラニル基またはイミダゾリル基を表わ
し、ｎは０または１を表わす。）で表わされるピラゾロ
ン誘導体またはその薬剤として許容される塩を有効成分
とすることを特徴とする過酸化脂質生成抑制剤。1. A general formula (I) (In the formula, R 1 represents a cycloalkyl group, an optionally substituted phenyl group, a pyridyl group or a benzothiazolyl group, R 2 represents a hydrogen atom or an alkyl group, and R 3
Represents a pyridyl group, a furanyl group or an imidazolyl group, and n represents 0 or 1. ) A pyrazolone derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP27736386A JPH0742230B2 (en) | 1986-11-20 | 1986-11-20 | Lipid peroxide production inhibitor |
| DE3789754T DE3789754T2 (en) | 1986-11-20 | 1987-11-20 | The formation of lipid-peroxide-inhibiting composition and suitable compounds. |
| EP87117175A EP0269030B1 (en) | 1986-11-20 | 1987-11-20 | Lipid-peroxide formation inhibiting composition and novel compounds useful therefor |
| US07/123,237 US4906644A (en) | 1986-11-20 | 1987-11-20 | Lipid-peroxide formation inhibiting composition and novel compounds useful therefor |
| US07/451,526 US4990619A (en) | 1986-11-20 | 1989-12-18 | Pyrazoline derivatives |
| US07/606,829 US5089515A (en) | 1986-11-20 | 1990-10-31 | Lipid-peroxide formation inhibiting composition and novel compounds useful therefor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP27736386A JPH0742230B2 (en) | 1986-11-20 | 1986-11-20 | Lipid peroxide production inhibitor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS63130592A JPS63130592A (en) | 1988-06-02 |
| JPH0742230B2 true JPH0742230B2 (en) | 1995-05-10 |
Family
ID=17582480
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP27736386A Expired - Fee Related JPH0742230B2 (en) | 1986-11-20 | 1986-11-20 | Lipid peroxide production inhibitor |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0742230B2 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE102006050513A1 (en) * | 2006-10-26 | 2008-04-30 | Bayer Healthcare Ag | New substituted dihydropyrazolone derivatives are hypoxia-inducible transcription factor-prolyl-4-hydroxylase inhibitors useful to treat/prevent e.g. cardiovascular diseases, heart-circulation diseases, heart failure and anemia |
| US8877766B2 (en) * | 2013-02-15 | 2014-11-04 | Peter F. Kador | Neuroprotective multifunctional antioxidants and their monofunctional analogs |
-
1986
- 1986-11-20 JP JP27736386A patent/JPH0742230B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPS63130592A (en) | 1988-06-02 |
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