JPH0515706B2 - - Google Patents
Info
- Publication number
- JPH0515706B2 JPH0515706B2 JP60221529A JP22152985A JPH0515706B2 JP H0515706 B2 JPH0515706 B2 JP H0515706B2 JP 60221529 A JP60221529 A JP 60221529A JP 22152985 A JP22152985 A JP 22152985A JP H0515706 B2 JPH0515706 B2 JP H0515706B2
- Authority
- JP
- Japan
- Prior art keywords
- fatty acid
- acyl group
- platelet aggregation
- group derived
- higher fatty
- 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 - Lifetime
Links
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 18
- 239000000194 fatty acid Substances 0.000 claims description 18
- 229930195729 fatty acid Natural products 0.000 claims description 18
- 150000004665 fatty acids Chemical class 0.000 claims description 18
- 235000021122 unsaturated fatty acids Nutrition 0.000 claims description 18
- 150000004670 unsaturated fatty acids Chemical class 0.000 claims description 18
- 125000002252 acyl group Chemical group 0.000 claims description 12
- 101000783577 Dendroaspis angusticeps Thrombostatin Proteins 0.000 claims description 9
- 101000783578 Dendroaspis jamesoni kaimosae Dendroaspin Proteins 0.000 claims description 9
- 229940127218 antiplatelet drug Drugs 0.000 claims description 9
- YWAKXRMUMFPDSH-UHFFFAOYSA-N pentene Chemical compound CCCC=C YWAKXRMUMFPDSH-UHFFFAOYSA-N 0.000 claims description 9
- 239000000106 platelet aggregation inhibitor Substances 0.000 claims description 9
- 150000005671 trienes Chemical class 0.000 claims description 9
- DTOSIQBPPRVQHS-PDBXOOCHSA-N alpha-linolenic acid Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCC(O)=O DTOSIQBPPRVQHS-PDBXOOCHSA-N 0.000 claims description 8
- 235000020661 alpha-linolenic acid Nutrition 0.000 claims description 4
- JAZBEHYOTPTENJ-UHFFFAOYSA-N eicosapentaenoic acid Natural products CCC=CCC=CCC=CCC=CCC=CCCCC(O)=O JAZBEHYOTPTENJ-UHFFFAOYSA-N 0.000 claims description 4
- 229960004488 linolenic acid Drugs 0.000 claims description 4
- VZCCETWTMQHEPK-UHFFFAOYSA-N gamma-Linolensaeure Natural products CCCCCC=CCC=CCC=CCCCCC(O)=O VZCCETWTMQHEPK-UHFFFAOYSA-N 0.000 claims description 3
- VZCCETWTMQHEPK-QNEBEIHSSA-N gamma-linolenic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/CCCCC(O)=O VZCCETWTMQHEPK-QNEBEIHSSA-N 0.000 claims description 3
- 235000020664 gamma-linolenic acid Nutrition 0.000 claims description 3
- 229960002733 gamolenic acid Drugs 0.000 claims description 3
- JAZBEHYOTPTENJ-JLNKQSITSA-N all-cis-5,8,11,14,17-icosapentaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O JAZBEHYOTPTENJ-JLNKQSITSA-N 0.000 claims 2
- 229960005135 eicosapentaenoic acid Drugs 0.000 claims 2
- 235000020673 eicosapentaenoic acid Nutrition 0.000 claims 2
- 239000000243 solution Substances 0.000 description 17
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 16
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- 150000001875 compounds Chemical class 0.000 description 12
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 6
- 206010027476 Metastases Diseases 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 230000009401 metastasis Effects 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 208000007536 Thrombosis Diseases 0.000 description 4
- 238000004220 aggregation Methods 0.000 description 4
- 230000002776 aggregation Effects 0.000 description 4
- -1 imidazole alkylamine Chemical class 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 102000008186 Collagen Human genes 0.000 description 3
- 108010035532 Collagen Proteins 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 235000021342 arachidonic acid Nutrition 0.000 description 3
- 229940114079 arachidonic acid Drugs 0.000 description 3
- 239000012300 argon atmosphere Substances 0.000 description 3
- 150000001793 charged compounds Chemical class 0.000 description 3
- 229920001436 collagen Polymers 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- SBHCLVQMTBWHCD-METXMMQOSA-N (2e,4e,6e,8e,10e)-icosa-2,4,6,8,10-pentaenoic acid Chemical compound CCCCCCCCC\C=C\C=C\C=C\C=C\C=C\C(O)=O SBHCLVQMTBWHCD-METXMMQOSA-N 0.000 description 2
- QKVHAKICMNABGB-UHFFFAOYSA-N 2-(5-bromopentyl)isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(CCCCCBr)C(=O)C2=C1 QKVHAKICMNABGB-UHFFFAOYSA-N 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 102000007330 LDL Lipoproteins Human genes 0.000 description 2
- 108010007622 LDL Lipoproteins Proteins 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- HXWJFEZDFPRLBG-UHFFFAOYSA-N Timnodonic acid Natural products CCCC=CC=CCC=CCC=CCC=CCCCC(O)=O HXWJFEZDFPRLBG-UHFFFAOYSA-N 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000000702 anti-platelet effect Effects 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 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
- 208000010125 myocardial infarction Diseases 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 2
- 230000003449 preventive effect Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- HOBAELRKJCKHQD-UHFFFAOYSA-N (8Z,11Z,14Z)-8,11,14-eicosatrienoic acid Natural products CCCCCC=CCC=CCC=CCCCCCCC(O)=O HOBAELRKJCKHQD-UHFFFAOYSA-N 0.000 description 1
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 1
- WGJCBBASTRWVJL-UHFFFAOYSA-N 1,3-thiazolidine-2-thione Chemical compound SC1=NCCS1 WGJCBBASTRWVJL-UHFFFAOYSA-N 0.000 description 1
- IBODDUNKEPPBKW-UHFFFAOYSA-N 1,5-dibromopentane Chemical compound BrCCCCCBr IBODDUNKEPPBKW-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010008111 Cerebral haemorrhage Diseases 0.000 description 1
- 206010008132 Cerebral thrombosis Diseases 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 235000021298 Dihomo-γ-linolenic acid Nutrition 0.000 description 1
- 201000001429 Intracranial Thrombosis Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- HOBAELRKJCKHQD-QNEBEIHSSA-N dihomo-γ-linolenic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/CCCCCCC(O)=O HOBAELRKJCKHQD-QNEBEIHSSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 235000004626 essential fatty acids Nutrition 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000021323 fish oil Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- KQQKGWQCNNTQJW-UHFFFAOYSA-N linolenic acid Natural products CC=CCCC=CCC=CCCCCCCCC(O)=O KQQKGWQCNNTQJW-UHFFFAOYSA-N 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- OWAUOGGPRMBHPQ-UHFFFAOYSA-N n,n-dimethylformamide;isoindole-1,3-dione;potassium Chemical compound [K].CN(C)C=O.C1=CC=C2C(=O)NC(=O)C2=C1 OWAUOGGPRMBHPQ-UHFFFAOYSA-N 0.000 description 1
- XVEIGUQEXNENQF-HPFCUAHCSA-N octadeca-6,9,12-trienoic acid;(6z,9z,12z)-octadeca-6,9,12-trienoic acid Chemical compound CCCCCC=CCC=CCC=CCCCCC(O)=O.CCCCC\C=C/C\C=C/C\C=C/CCCCC(O)=O XVEIGUQEXNENQF-HPFCUAHCSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 210000004623 platelet-rich plasma Anatomy 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- GMVPRGQOIOIIMI-DWKJAMRDSA-N prostaglandin E1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(O)=O GMVPRGQOIOIIMI-DWKJAMRDSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 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
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 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
- 239000007787 solid Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 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
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 238000004879 turbidimetry Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- DTOSIQBPPRVQHS-UHFFFAOYSA-N α-Linolenic acid Chemical compound CCC=CCC=CCC=CCCCCCCCC(O)=O DTOSIQBPPRVQHS-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】
発明の背景
技術分野
本発明は新規な不飽和脂肪酸アミド誘導体およ
びこれを含有する血小板凝集抑制剤に関するもの
である。本発明によつて提供される不飽和脂肪酸
アミド誘導体は新規化合物であつて、強力な血小
板凝集抑制作用を有する。従つて血小板凝集に起
因する疾患即ち血栓症等の予防に有効である。ま
た、血小板の凝集がガンの転移にも関与している
ことが知られており、本発明の化合物はガン転移
の予防効果も有する。
先行技術
トリエン高級脂肪酸であるα−リノレン酸は必
須脂肪酸であり、またγ−リノレン酸はプロスタ
グランジンE1の前駆体であるジホモγ−リノレ
ン酸へ生体内で変換されることが知られており、
各々重要な化合物である。ペンタエン高級脂肪酸
については、５，８，11，14，17−エイコサペン
タエン酸が魚油中に多く含まれており低密度リポ
プロテイン（LDL）を低下させる作用のあるこ
とが報告されている。心筋梗塞や脳血栓といつた
血栓症は、近年成人病の中で大きな割合を占める
に至つており、これを有効に予防する薬剤の出現
が強く望まれている。
発明の目的
本発明者等は不飽和脂肪酸アミド誘導体を種種
合成し、それらの薬理活性を鋭意研究した結果、
本発明に係る不飽和脂肪酸アミド誘導体が優れた
血小板凝集抑制作用を有することを見い出し本発
明を完成させるに至つた。
本発明は新規な不飽和脂肪酸アミド誘導体およ
びこれを含有する血小板凝集抑制剤を提供するこ
とを目的とする。本発明に係る不飽和脂肪酸アミ
ド誘導体は強力な血小板凝集抑制作用を有し、血
小板凝集に起因する疾患即ち血栓症やガン転移等
の予防剤として有用である。
本発明の目的は以下に示す構成によつて達成さ
れる。すなわち本発明は一般式（）
（式中Ｒはトリエン高級脂肪酸およびペンタエ
ン高級脂肪酸のいずれかから誘導されるアシル基
を示し、ｎは５〜10の整数を示す）で表わされる
不飽和脂肪酸アミド誘導体である。また本発明は
一般式（）
（式中Ｒはトリエン高級脂肪酸およびペンタエ
ン高級脂肪酸のいずれかから誘導されるアシル基
を示し、ｎは５〜10の整数を示す）で表わされる
不飽和脂肪酸アミド誘導体を含有する血小板凝集
抑制剤である。
前記トリエン高級脂肪酸としては９，12，15−
オクタデカトリエン酸（α−リノレン酸）あるい
は、６，９，12−オクタデカトリエン酸（γ−リ
ノレン酸）が望ましく、前記ペンタエン高級脂肪
酸としては５，８，11，14，17−エイコサペンタ
エン酸が望ましい。尚、本発明において血小板凝
集抑制剤とは血小板の凝集を抑制する作用を有す
る製剤を意味する。
発明の具体的説明
本発明の不飽和脂肪酸アミド誘導体は、トリエ
ン高級脂肪酸またはペンタエン高級脂肪酸あるい
はこれらの反応性誘導体と下記式（）で示すイ
ミダゾールアルキルアミンとを縮合させることに
より得られる。
（式中ｎは５〜10の整数を示す）
縮合させるとき用いられる縮合剤としては、例
えばジシクロヘキシルカルボジイミドが好適に用
いられる。前記反応性誘導体としてはカルボン酸
のチアゾリジンチオンアミド誘導体を挙げること
ができる。
本発明の不飽和脂肪酸アミド誘導体は血小板凝
集抑制剤の有効成分若しくは有効成分の１つとし
て使用可能で、血小板凝集に起因する疾患であれ
ば有効に作用するが、特に抗血栓症剤、狭心症ま
たはガン転移予防剤として使用され、投与量は一
般に成人１日量約50〜1500mgであり、必要により
１〜３回に分けて投与するのがよい。投与方法は
投与に適した任意の形態をとることができ、特に
経口投与が望ましいが、静注も可能である。
本発明の化合物は単独または通常の方法で製剤
担体あるいは賦形剤と混合され、錠剤、散剤、カ
プセル剤、顆粒剤に製剤化される。担体あるいは
賦形剤の例として炭酸カルシウム、リン酸カルシ
ウム、でんぷん、しよ糖、乳糖、タルク、ステア
リン酸マグネシウム等があげられる。本発明の化
合物は、上記の固形剤の他に油性懸濁剤、シロツ
プのような液剤とすることもできる。
本発明の化合物をサイクロデキストリンで包接
し安定化することもできる。
次に実施例および試験例を示して本発明をさら
に具体的に説明するが、本発明はこれらに何ら限
定されるものではない。
実施例 １
アルゴン雰囲気下、１，５−ジブロムペンタン
18.3mlを、乾燥Ｎ，Ｎ−ジメチルホルムアミド
100mlに溶解した溶液に、フタルイミドカリウム
5.00ｇを室温にて加えた。室温で１時間20分反応
させた後、反応混液を水200mlで希釈しこれより
塩化メチレンで３回抽出した。抽出有機層を水洗
し無水硫酸ナトリウムで乾燥後、溶媒を減圧留去
し、抽出残渣14.80ｇを得た。該残渣をシリカゲ
ルカラムクロマトグラフイーに付しベンゼン溶出
画分よりＮ−（５−ブロモペンチル）フタルイミ
6.41ｇを得た。続いてアルゴン雰囲気下、該化合
物5.90ｇの乾燥キシレン（80ml）溶液にイミダゾ
ール2.64ｇを加え、３時間加熱還流させた。反応
液をクロロホルムにて希釈し、飽和炭酸水素ナト
リウム水溶液、続いて水にて洗浄後、無水硫酸ナ
トリウムにて乾燥し、溶媒を減圧留去後、得られ
た残渣5.927ｇをシリカゲルカラムクロマトグラ
フイーに付し、クロロホルム乃至メタノール対ク
ロロホルム（１対99）溶出画分より、Ｎ−〔５−
（イミダゾール−１−イル）ペンチル〕フタルイ
ミド4.301ｇを得た。アルゴン雰囲気下、該フタ
ルイミド体500mgのエタノール（10ml）溶液に80
％ヒドラジン・ヒドレート107mgを加え、２時間
加熱還流させた。反応液を放冷後、自然濾過し、
濾液を減圧留去し、得られた残渣に乾燥Ｎ，Ｎ−
ジメチルホルムアミド（５ml）を加えた。この溶
液にＮ−（５，８，11，14，17−エイコサペンタ
エノイル）チアゾリジン−２−チオン626mgの乾
燥Ｎ，Ｎ−ジメチルホルムアミド（10ml）溶液を
加え室温にて15時間反応させた。反応液を減圧濃
縮後、得られた残渣をクロロホルムにて希釈し、
１規定水酸化リチウム水溶液、続いて水にて洗浄
した。有機層を無水硫酸ナトリウムにて乾燥後、
溶媒を減圧留去し、得られた残渣986Kgをシリカ
ゲルカラムクロマトグラフイーに付し、メタノー
ル対クロロホルム（１対99乃至２対98）溶出画分
より、５−（Ｎ−５，８，11，14，17−エイコサ
ペンタエノイル）アミノペンチル−１−イミダゾ
ール442mgを得た。このものの物理化学的データ
は下記式（）の構造を支持する。
IRνCHCl3 naxcm-1：3450，1665
MS（ｍ／ｅ）：437（分子イオンピーク）
1H−NMR（重クロロホルム）δppm：0.94
（3H，ｔ，Ｊ＝７Hz）、3.87（2H，ｔ，Ｊ＝6.5
Hz）、6.83（1H，br.s）、6.95（1H，br.s）、7.37
（1H，br.s）
実施例 ２
先にＮ−（５−ブロモペンチル）フタルイミド
を得た製法に従い、Ｎ−（７−ブロモヘプチル）
フタルイミドを製し、該化合物とＮ−（９，12，
15−オクタデカトリエノイル）チアゾリジン−２
−チオンより実施例−１と同様の反応操作によつ
て７−（Ｎ−９，12，15−オクタデカトリエノイ
ル）アミノヘプチル−１−イミダゾールを製し
た。このものの物理化学的データは下記式（）
の構造を支持する。
IRνCHCl3 naxcm-1：3450，1665
MS（ｍ／ｅ）：441（分子イオンピーク）
実施例 ３
先にＮ−（５−ブロモペンチル）フタルイミド
を得た製法に従い、Ｎ−（10−ブロモデシル）フ
タルイミドを製し、該化合物とＮ−（５，８，11，
24，17−エイコサペンタエノイル）チアゾリジン
−２−チオンより実施例−１と同様の反応操作に
よつて、10−（Ｎ−５，８，11，24，17−エイコ
サペンタエノイル）アミノデシル−１−イミダゾ
ールを製した。このものの物理化学的データは下
記式（）の構造を支持する。
IRνCHCl3 naxcm-1：3450，1665
MS（ｍ／ｅ）：507（分子イオンピーク）
試験例
血小板凝集抑制作用
3.8％クエン酸ナトリウム溶液（１容）を入れ
た注射器を用いてウサギ頸動脈より９容の血液を
採取する。該血液を遠心分離し、血小板に富む血
漿（PRP：4.7×105個／μl）を得る。
該PRP250μlをキユベツトに入れ、37℃恒温槽
で２分間加温し、試験する不飽和脂肪酸アミド誘
導体の溶液〔1.4×10-2Ｍエタノール溶液をトリ
ス緩衝等張食塩水溶液−生理食塩水（１：３）で
希釈〕20μlを加え３分間インキユベートした後、
凝集惹起剤であるアラキドン酸溶液あるいはコラ
ーゲン溶液10μlを加え血小板凝集をボーン
（Born）の比濁法〔たとえばジヤーナル・オブ・
フイジオロジー（J.Physiol.第168巻、第178頁、
1968年発行）に記載されている〕で測定した。ア
ラキドン酸（60μM）、コラーゲン（10μｇ／ml）
によつて誘起される血小板凝集に対する50％抑制
濃度をアスピリンを比較例として表１に示す。
試験の結果、代表例として下記の表１に示す如
く著明な抗血小板凝集活性を見出した。また、表
１に示さない本発明に係る不飽和脂肪酸アミド誘
導体についても同様な抗血小板凝集活性を有する
ことが確認された。尚、表中50％阻害濃度とは本
発明に係る不飽和脂肪酸アミド誘導体を導入しな
い場合の血小板の凝集能を100％とした場合、該
不飽和脂肪酸アミド誘導体の導入により前記血小
板の凝集能を50％まで抑制する為に要した不飽和
脂肪酸アミド誘導体溶液濃度を意味する。BACKGROUND OF THE INVENTION Technical Field The present invention relates to a novel unsaturated fatty acid amide derivative and a platelet aggregation inhibitor containing the same. The unsaturated fatty acid amide derivative provided by the present invention is a new compound and has a strong platelet aggregation inhibiting effect. Therefore, it is effective in preventing diseases caused by platelet aggregation, such as thrombosis. Furthermore, platelet aggregation is known to be involved in cancer metastasis, and the compounds of the present invention also have a preventive effect on cancer metastasis. Prior Art α-linolenic acid, which is a triene higher fatty acid, is an essential fatty acid, and it is known that γ-linolenic acid is converted in vivo to dihomo-γ-linolenic acid, which is a precursor of prostaglandin E 1 . Ori,
Each is an important compound. Regarding pentaene higher fatty acids, it has been reported that 5,8,11,14,17-eicosapentaenoic acid is contained in large amounts in fish oil and has the effect of lowering low-density lipoprotein (LDL). Thrombosis, such as myocardial infarction and cerebral thrombosis, has recently come to account for a large proportion of adult diseases, and there is a strong desire for the emergence of a drug that can effectively prevent this. Purpose of the Invention The present inventors synthesized various unsaturated fatty acid amide derivatives and as a result of intensive research on their pharmacological activities,
It was discovered that the unsaturated fatty acid amide derivative according to the present invention has an excellent platelet aggregation inhibiting effect, and the present invention was completed. An object of the present invention is to provide a novel unsaturated fatty acid amide derivative and a platelet aggregation inhibitor containing the same. The unsaturated fatty acid amide derivative according to the present invention has a strong platelet aggregation inhibiting effect and is useful as a preventive agent for diseases caused by platelet aggregation, such as thrombosis and cancer metastasis. The object of the present invention is achieved by the configuration shown below. That is, the present invention is based on the general formula () (In the formula, R represents an acyl group derived from either a triene higher fatty acid or a pentaene higher fatty acid, and n represents an integer of 5 to 10.) The present invention also relates to the general formula () A platelet aggregation inhibitor containing an unsaturated fatty acid amide derivative represented by (wherein R represents an acyl group derived from either triene higher fatty acid or pentaene higher fatty acid, and n represents an integer of 5 to 10). be. The triene higher fatty acid is 9,12,15-
Octadecatrienoic acid (α-linolenic acid) or 6,9,12-octadecatrienoic acid (γ-linolenic acid) is preferable, and the pentaene higher fatty acid is 5,8,11,14,17-eicosapentaenoic acid. is desirable. In the present invention, the term "platelet aggregation inhibitor" means a preparation that has the effect of inhibiting platelet aggregation. DETAILED DESCRIPTION OF THE INVENTION The unsaturated fatty acid amide derivative of the present invention is obtained by condensing a triene higher fatty acid, a pentaene higher fatty acid, or a reactive derivative thereof with an imidazole alkylamine represented by the following formula (). (In the formula, n represents an integer of 5 to 10.) As the condensing agent used in the condensation, for example, dicyclohexylcarbodiimide is preferably used. Examples of the reactive derivatives include thiazolidine thionamide derivatives of carboxylic acids. The unsaturated fatty acid amide derivative of the present invention can be used as an active ingredient or one of the active ingredients of a platelet aggregation inhibitor, and is effective in treating diseases caused by platelet aggregation. The dosage is generally about 50 to 1,500 mg per day for adults, and it is preferably administered in 1 to 3 divided doses if necessary. The method of administration can take any form suitable for administration, with oral administration being particularly preferred, although intravenous injection is also possible. The compound of the present invention may be formulated into tablets, powders, capsules, or granules either alone or mixed with pharmaceutical carriers or excipients in a conventional manner. Examples of carriers or excipients include calcium carbonate, calcium phosphate, starch, sucrose, lactose, talc, magnesium stearate, and the like. In addition to the solid formulations mentioned above, the compounds of the present invention can also be formulated into liquid formulations such as oily suspensions and syrups. The compound of the present invention can also be stabilized by inclusion with cyclodextrin. EXAMPLES Next, the present invention will be explained in more detail with reference to Examples and Test Examples, but the present invention is not limited thereto. Example 1 1,5-dibromopentane under argon atmosphere
18.3 ml of dry N,N-dimethylformamide
Potassium phthalimide in a solution dissolved in 100ml
5.00g was added at room temperature. After reacting for 1 hour and 20 minutes at room temperature, the reaction mixture was diluted with 200 ml of water and extracted three times with methylene chloride. The extracted organic layer was washed with water and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 14.80 g of an extracted residue. The residue was subjected to silica gel column chromatography, and N-(5-bromopentyl)phthalimide was extracted from the benzene elution fraction.
6.41g was obtained. Subsequently, under an argon atmosphere, 2.64 g of imidazole was added to a solution of 5.90 g of the compound in dry xylene (80 ml), and the mixture was heated under reflux for 3 hours. The reaction solution was diluted with chloroform, washed with a saturated aqueous sodium bicarbonate solution and then with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. 5.927 g of the resulting residue was subjected to silica gel column chromatography. N-[5-
4.301 g of (imidazol-1-yl)pentyl]phthalimide was obtained. Under an argon atmosphere, add 80% to a solution of 500mg of the phthalimide compound in ethanol (10ml).
% hydrazine hydrate was added thereto, and the mixture was heated under reflux for 2 hours. After cooling the reaction solution, it was naturally filtered.
The filtrate was distilled off under reduced pressure, and the resulting residue was dried with N,N-
Dimethylformamide (5ml) was added. A solution of 626 mg of N-(5,8,11,14,17-eicosapentaenoyl)thiazolidine-2-thione in dry N,N-dimethylformamide (10 ml) was added to this solution and reacted at room temperature for 15 hours. . After concentrating the reaction solution under reduced pressure, the resulting residue was diluted with chloroform,
It was washed with a 1N aqueous lithium hydroxide solution and then with water. After drying the organic layer with anhydrous sodium sulfate,
The solvent was distilled off under reduced pressure, and the resulting residue (986 kg) was subjected to silica gel column chromatography, and from the fraction eluted with methanol and chloroform (1:99 to 2:98), 5-(N-5, 8, 11, 442 mg of 14,17-eicosapentaenoyl)aminopentyl-1-imidazole was obtained. The physicochemical data of this product support the structure of the following formula (). IRν CHCl3 nax cm -1 : 3450, 1665 MS (m/e): 437 (molecular ion peak) 1 H-NMR (heavy chloroform) δppm: 0.94
(3H, t, J = 7Hz), 3.87 (2H, t, J = 6.5
Hz), 6.83 (1H, br.s), 6.95 (1H, br.s), 7.37
(1H, br.s) Example 2 N-(7-bromoheptyl) was prepared according to the method previously used to obtain N-(5-bromopentyl)phthalimide
Phthalimide is prepared, and the compound and N-(9,12,
15-octadecatrienoyl)thiazolidine-2
7-(N-9,12,15-octadecatrienoyl)aminoheptyl-1-imidazole was produced from -thione by the same reaction procedure as in Example-1. The physicochemical data of this is the following formula ()
supports the structure of IRν CHCl3 nax cm -1 : 3450, 1665 MS (m/e): 441 (molecular ion peak) Example 3 N-(10-bromodecyl) was prepared according to the manufacturing method previously used to obtain N-(5-bromopentyl)phthalimide. Phthalimide is prepared, and the compound and N-(5,8,11,
10-(N-5,8,11,24,17-eicosapentaenoyl) was obtained from 24,17-eicosapentaenoyl)thiazolidine-2-thione by the same reaction procedure as in Example-1. Aminodecyl-1-imidazole was produced. The physicochemical data of this product support the structure of the following formula (). IRν CHCl3 nax cm -1 : 3450, 1665 MS (m/e): 507 (molecular ion peak) Test example Platelet aggregation inhibitory effect From rabbit carotid artery using a syringe containing 3.8% sodium citrate solution (1 volume) Collect 9 volumes of blood. The blood is centrifuged to obtain platelet-rich plasma (PRP: 4.7×10 5 cells/μl). 250 μl of the PRP was placed in a cuvette, heated for 2 minutes in a constant temperature bath at 37°C, and a solution of the unsaturated fatty acid amide derivative to be tested [1.4×10 -2 M ethanol solution] was added to a Tris-buffered isotonic saline solution-physiological saline solution (1: After adding 20 μl of diluted solution in 3) and incubating for 3 minutes,
Platelet aggregation was determined by adding 10 µl of arachidonic acid solution or collagen solution, which is an aggregation-inducing agent, using Born's turbidimetry [for example, Journal of
Physiology (J. Physiol. Vol. 168, p. 178,
(published in 1968)]. Arachidonic acid (60μM), collagen (10μg/ml)
Table 1 shows the 50% inhibitory concentration for platelet aggregation induced by aspirin, using aspirin as a comparative example. As a result of the test, significant anti-platelet aggregation activity was found as shown in Table 1 below as a representative example. Furthermore, it was confirmed that unsaturated fatty acid amide derivatives according to the present invention not shown in Table 1 also have similar antiplatelet aggregation activity. In addition, the 50% inhibitory concentration in the table refers to the aggregation ability of platelets when the unsaturated fatty acid amide derivative according to the present invention is not introduced, assuming that the aggregation ability of platelets is 100%. It means the concentration of unsaturated fatty acid amide derivative solution required to suppress the concentration to 50%.
【表】
急性毒性
ICR系雄性マウス（５週令）を用いて、経口投
与による急性毒性試験を行つた。本発明の化合物
のLD50値はいずれも１ｇ／Kg以上であり、高い
安全性が確認された。
発明の効果
本発明によれば新規な不飽和脂肪酸アミド誘導
体およびこれを含有する血小板凝集抑制剤が提供
される。
本発明の上記化合物はアラキドン酸あるいはコ
ラーゲンによつて誘起される血小板凝集作用を顕
著に抑制するので、血小板凝集に起因する疾患、
特に心筋梗塞、脳出血後の虚血性発作、脳梗塞等
血小板凝集の関与する血栓症の予防剤として使用
することができる。また、ガン転移には血小板凝
集が関与しているので、本発明の上記化合物はガ
ン転移予防剤としても使用することができる。[Table] Acute toxicity An acute toxicity test was conducted by oral administration using ICR male mice (5 weeks old). The LD 50 values of the compounds of the present invention were all 1 g/Kg or more, confirming their high safety. Effects of the Invention According to the present invention, a novel unsaturated fatty acid amide derivative and a platelet aggregation inhibitor containing the same are provided. The above-mentioned compounds of the present invention significantly inhibit platelet aggregation induced by arachidonic acid or collagen, thereby preventing diseases caused by platelet aggregation.
In particular, it can be used as a prophylactic agent for thrombosis involving platelet aggregation, such as myocardial infarction, ischemic attack after cerebral hemorrhage, and cerebral infarction. Furthermore, since platelet aggregation is involved in cancer metastasis, the above compounds of the present invention can also be used as agents for preventing cancer metastasis.
Claims (1)
ン高級脂肪酸のいずれかから誘導されるアシル基
を示し、ｎは５〜10の整数を示す）で表わされる
不飽和脂肪酸アミド誘導体。 ２ トリエン高級脂肪酸から誘導されるアシル基
がα−リノレン酸あるいはγ−リノレン酸から誘
導されるアシル基である特許請求の範囲第１項記
載の不飽和脂肪酸アミド誘導体。 ３ ペンタエン高級脂肪酸から誘導されるアシル
基がエイコサペンタエン酸から誘導されるアシル
基である特許請求の範囲第１項記載の不飽和脂肪
酸アミド誘導体。 ４ 一般式（） （式中Ｒはトリエン高級脂肪酸およびペンタエ
ン高級脂肪酸のいずれかから誘導されるアシル基
を示し、ｎは５〜10の整数を示す）で表わされる
不飽和脂肪酸アミド誘導体を含有する血小板凝集
抑制剤。 ５ トリエン高級脂肪酸から誘導されるアシル基
がα−リノレン酸あるいはγ−リノレン酸から誘
導されるアシル基である特許請求の範囲第４項記
載の血小板凝集抑制剤。 ６ ペンタエン高級脂肪酸から誘導されるアシル
基がエイコサペンタエン酸から誘導されるアシル
基である特許請求の範囲第４項記載の血小板凝集
抑制剤。[Claims] 1 General formula () An unsaturated fatty acid amide derivative represented by the formula (wherein R represents an acyl group derived from either a triene higher fatty acid or a pentaene higher fatty acid, and n represents an integer of 5 to 10). 2. The unsaturated fatty acid amide derivative according to claim 1, wherein the acyl group derived from the triene higher fatty acid is an acyl group derived from α-linolenic acid or γ-linolenic acid. 3. The unsaturated fatty acid amide derivative according to claim 1, wherein the acyl group derived from pentaene higher fatty acid is an acyl group derived from eicosapentaenoic acid. 4 General formula () A platelet aggregation inhibitor containing an unsaturated fatty acid amide derivative represented by the formula (wherein R represents an acyl group derived from either a triene higher fatty acid or a pentaene higher fatty acid, and n represents an integer of 5 to 10). 5. The platelet aggregation inhibitor according to claim 4, wherein the acyl group derived from the triene higher fatty acid is an acyl group derived from α-linolenic acid or γ-linolenic acid. 6. The platelet aggregation inhibitor according to claim 4, wherein the acyl group derived from pentaene higher fatty acid is an acyl group derived from eicosapentaenoic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60221529A JPS6281372A (en) | 1985-10-04 | 1985-10-04 | Unsaturated fatty acid amide derivative and blood platelet agglutination inhibitor containing said derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60221529A JPS6281372A (en) | 1985-10-04 | 1985-10-04 | Unsaturated fatty acid amide derivative and blood platelet agglutination inhibitor containing said derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6281372A JPS6281372A (en) | 1987-04-14 |
| JPH0515706B2 true JPH0515706B2 (en) | 1993-03-02 |
Family
ID=16768143
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP60221529A Granted JPS6281372A (en) | 1985-10-04 | 1985-10-04 | Unsaturated fatty acid amide derivative and blood platelet agglutination inhibitor containing said derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS6281372A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107582430B (en) * | 2017-10-31 | 2020-10-27 | 西华大学 | Preparation and application method of highland barley beta-glucan-polyaspartic acid compound |
-
1985
- 1985-10-04 JP JP60221529A patent/JPS6281372A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6281372A (en) | 1987-04-14 |
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