JPH0333689B2 - - Google Patents
Info
- Publication number
- JPH0333689B2 JPH0333689B2 JP57221501A JP22150182A JPH0333689B2 JP H0333689 B2 JPH0333689 B2 JP H0333689B2 JP 57221501 A JP57221501 A JP 57221501A JP 22150182 A JP22150182 A JP 22150182A JP H0333689 B2 JPH0333689 B2 JP H0333689B2
- Authority
- JP
- Japan
- Prior art keywords
- fluorouracil
- platelet aggregation
- present
- higher fatty
- acyl group
- 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
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical class FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 14
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 11
- 239000000194 fatty acid Substances 0.000 claims description 11
- 229930195729 fatty acid Natural products 0.000 claims description 11
- 150000004665 fatty acids Chemical class 0.000 claims description 11
- 125000002252 acyl group Chemical group 0.000 claims description 8
- YWAKXRMUMFPDSH-UHFFFAOYSA-N pentene Chemical compound CCCC=C YWAKXRMUMFPDSH-UHFFFAOYSA-N 0.000 claims description 8
- 229940127218 antiplatelet drug Drugs 0.000 claims description 7
- 239000000106 platelet aggregation inhibitor Substances 0.000 claims description 7
- 101000783577 Dendroaspis angusticeps Thrombostatin Proteins 0.000 claims description 6
- 101000783578 Dendroaspis jamesoni kaimosae Dendroaspin Proteins 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 6
- 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 claims description 3
- HXWJFEZDFPRLBG-UHFFFAOYSA-N Timnodonic acid Natural products CCCC=CC=CCC=CCC=CCC=CCCCC(O)=O HXWJFEZDFPRLBG-UHFFFAOYSA-N 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- JAZBEHYOTPTENJ-UHFFFAOYSA-N eicosapentaenoic acid Natural products CCC=CCC=CCC=CCC=CCC=CCCCC(O)=O JAZBEHYOTPTENJ-UHFFFAOYSA-N 0.000 claims description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 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 8
- 239000000243 solution Substances 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 7
- 229960002949 fluorouracil Drugs 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 229940114079 arachidonic acid Drugs 0.000 description 4
- 235000021342 arachidonic acid Nutrition 0.000 description 4
- KWNGIKVZXFFZNN-UHFFFAOYSA-M 2-chloro-1-methylpyridin-1-ium;4-methylbenzenesulfonate Chemical compound C[N+]1=CC=CC=C1Cl.CC1=CC=C(S([O-])(=O)=O)C=C1 KWNGIKVZXFFZNN-UHFFFAOYSA-M 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 210000002381 plasma Anatomy 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- -1 1-(5,8,11, 14,17-eicosapentaenoyl)-5-fluorouracil Chemical compound 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-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
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229960005135 eicosapentaenoic acid Drugs 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
- 239000000203 mixture Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 2
- HLNJFEXZDGURGZ-UHFFFAOYSA-M 1-methylpyridin-1-ium;iodide Chemical compound [I-].C[N+]1=CC=CC=C1 HLNJFEXZDGURGZ-UHFFFAOYSA-M 0.000 description 1
- DVAZKUDTZUIOQK-UHFFFAOYSA-M 2-bromo-1-methylpyridin-1-ium;iodide Chemical compound [I-].C[N+]1=CC=CC=C1Br DVAZKUDTZUIOQK-UHFFFAOYSA-M 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 229920000084 Gum arabic Polymers 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
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 206010050661 Platelet aggregation inhibition Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000002253 acid 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
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 229910052786 argon Inorganic materials 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
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002148 esters Chemical class 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
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000008101 lactose Substances 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
- 238000005259 measurement Methods 0.000 description 1
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 description 1
- 239000010446 mirabilite Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N oxalic acid Substances OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 210000004623 platelet-rich plasma Anatomy 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000011160 research Methods 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
- 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
- RSIJVJUOQBWMIM-UHFFFAOYSA-L sodium sulfate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O RSIJVJUOQBWMIM-UHFFFAOYSA-L 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 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
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 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
- 210000003462 vein Anatomy 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
Description
【発明の詳細な説明】
発明の背景
技術分野
本発明は、５−フルオロウラシル誘導体を有効
成分とする血小板凝集抑制剤に関するものであ
る。
先行技術
５−フルオロウラシルは優れた制ガン作用を有
することが知られている。他方、５，８，11，
14，17−エイコサペンタエン酸は、魚油中に多く
含まれていることが報告されている。
本発明者等は５−フルオロウラシルの不飽和高
級脂肪酸アミドを種々合成し、それらの薬理活性
を鋭意研究した結果、ある種のアミドが優れた血
小板凝集抑制作用を有することを知つた。
発明の目的
本発明は血小板凝集阻止剤として有用な５−フ
ルオロウラシル誘導体を提供することを目的とす
る。
発明の具体的説明
本発明の目的は以下の各項の示す構成によつて
達成される。
すなわち、本発明は一般式
（式中Ｒはペンタエン高級脂肪酸から誘導され
るアシル基である）で示される５−フルオロウラ
シル誘導体を有効成分とする血小板凝集抑制剤で
ある。
また、上記Ｒが18ないし24個の炭素原子を有す
るペンタエン高級脂肪酸から誘導されるアシル基
であることが望ましい。
また、上記Ｒが５，８，11，14，17−エイコサ
ペンタエン酸から誘導されるアシル基であること
が望ましい。
本発明によつて提供される前記一般式で示され
る５−フルオロウラシル誘導体において、Ｒの定
義としてのペンタエン高級脂肪酸から誘導される
アシル基とは、炭素鎖中に５個の二重結合を有す
る高級脂肪酸のカルボキシル基から水酸基を除い
た基を意味する。高級脂肪酸としては18ないし24
個の炭素原子を有するものが好適である。
前記式で示される５−フルオロウラシル誘導体
として最も好ましい化合物は、１−（５，８，11，
14，17−エイコサペンタエノイル）−５−フルオ
ロウラシルであるが、他の例として１−（７，10，
13，16，19−ドコサペンタエノイル）−５−フル
オロウラシルを挙げることができる。
本発明の前記式で示される化合物は、ペンタエ
ン高級脂肪酸と５−フルオロウラシルとを縮合剤
の存在下で反応させるか、あるいはペンタエン高
級脂肪酸の反応性誘導体と５−フルオロウラシル
とを反応させることによつて得られる。縮合剤の
例としては、２−クロロ−１−メチルピリジニウ
ムｐ−トルエンスルホン酸塩、２−ブロモ−１−
メチルピリジニウムアイオダイド等が挙げられ
る。２−クロロ−１−メチルピリジニウムｐ−ト
ルエンスルホン酸塩及び２−ブロモ−１−メチル
ピリジニウムアイオダイドは通常トリエチルアミ
ン，トリブチルアミンのような第三級アミンの存
在下で使用できる。これらの縮合剤を使用する場
合は、塩化メチレン、１，２−ジクロルエタン、
テトラヒドロフラン、ベンゼン等の非プロトン性
溶媒が用いられる。
ペンタエン高級脂肪酸の反応性誘導体としては
酸塩化物が挙げられる。該反応性誘導体を使用す
る場合は溶媒に特に制限はなく、塩化メチレン，
クロロホルム，ジメチルホルムアミド，ジメチル
スルホキシド，テトラヒドロフラン，ベンゼン，
トルエン等の有機溶媒が広く使用される。
反応は通常−20℃ないし120℃で約0.5〜10時間
行われる。反応終了後所望の生成物は常法に従つ
て反応混合物中から採取される。例えば、反応混
合物を濾過し、濾液を減圧濃縮し、残留物をカラ
ムクロマトグラフイー処理すると所望のエステル
が純品として得られる。
本発明の５−フルオロウラシル誘導体を有効成
分とする血小板凝集抑制剤の投与量は活性成分と
しては成人１日量約0.1〜10ｇであり、必要によ
り数回に分けて投与する。
投与方法は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
としては炭酸カルシウム，リン酸カルシウム，と
うもろこしでんぷん、馬鈴薯でんぷん，砂糖，ラ
クトース，タルク，ステアリン酸マグネシウム，
アラビアゴム等が挙げられる。錠剤は常法に従つ
てコーテイングしてもよい。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。
本発明の化合物は、その分子中に５個の二重結
合を有するので、安定化させる目的で製剤中にα
−トコフエロール，２，６−ジ第三ブチル−ｐ−
クレゾール（BHT）等を配合させることもでき
る。あるいは本発明の化合物をサイクロデキスト
リン等で包接して安定化させることもできる。
次に実施例及び試験例を示して本発明をさらに
具体的に説明する。
製造例
アルゴン気流中、無水１，２−ジクロロエタン
（５ml）に５，８，11，14，17−エイコサペンタ
エン酸（278mg）を溶解し、２−クロロ−１−メ
チルピリジニウムｐ−トルエンスルホン酸塩
（303mg），５−フルオロウラシル（120mg），トリ
エチルアミン（204mg）を順番に加え、室温で24
時間撹拌する。反応液を減圧濃縮して得られた残
渣にｎ−ペンタン（10ml），水（５ml）を加えて
撹拌する。ついで、0.5N−蓚酸でPHを約４とし、
ｎ−ペンタンで抽出する。
ｎ−ペンタン層を水洗し、芒硝により乾燥す
る。抽出液を減圧乾固して得られる残渣をセフア
デツクス（Sephadex）LH−20（30ｇ）を用いた
カラムクロマトグラフイーに付し、塩化メチレン
溶出部から溶媒を留去して１−（５，８，11，14，
17−エイコサペンタエノイル）−５−フルオロウ
ラシル（196mg，収率51％）が得られた。このも
のの物理化学的データは下記の通りである。
IR（CHCl3）νnaxcm-1：1740，1725，1680，
1320，1255
NMR（CDCl3）δ（ppm）：0.97（3H，ｔ，Ｊ＝7.3
Hz，−CH2 −CH3 ），5.37（10H，ｍ，−CH＝
CH−），8.29（1H，ｄ，Ｊ＝6.8Hz，
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耳介静脈より９容の血液
を採取する。
該血液を900rpmで10分間遠心分離し、上清部
分から血小板に富む血漿（Platelet Rich
Plasma，以下PRPと言う）を得る。該上清の3/
４を採取し、3000rpmで15分間遠心分離し、上清
部分に乏血小板血漿（Platelet Poor Plasma，
以下PPPと言う）を得る。
血小板凝集能の測定には、PRPをPPPで希釈
し、血小板数を約50万個／μに調整したものを
用いた。
250μの該調整PRPをキユベツトに入れ37℃
恒温槽で３分間加温し、１−（５，８，11，14，
17−エイコサペンタエノイル）−５−フルオロウ
ラシルの溶液（1.2×10-2Mエタノール溶液を
0.05Mトリス緩衝液で希釈）25μを加えて５分
間インキユベートした後、凝集誘起剤であるアラ
キドン酸の溶液（3.2×10-1Mエタノール溶液を
トリス緩衝等張食塩水溶液で希釈）25μを加
え、血小板凝集の抑制率を測定した。アラキドン
酸（３×10-4M）によつて誘起される血小板凝集
に対する１−（５，８，11，14，17−エイコサペ
ンタエノイル−５−フルオロウラシルの抑制率
は、7.5×10-5M用量で40.2％，１×10-4M用量で
100％であつた。これに対して５，８，11，14，
17−エイコサペンタエン酸の抑制率は１×10-4M
用量で70.9％であつた。
急性毒性
ICR系雄性マウス（７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800mg／Kg以上であり、高い安全性が
確認された。
発明の作用効果
本発明によれば、アラキドン酸によつて誘起さ
れる血小板凝集作用を顕著に抑制する。 BACKGROUND OF THE INVENTION Technical Field The present invention relates to a platelet aggregation inhibitor containing a 5-fluorouracil derivative as an active ingredient. Prior Art 5-fluorouracil is known to have excellent anticancer effects. On the other hand, 5, 8, 11,
It has been reported that 14,17-eicosapentaenoic acid is contained in large amounts in fish oil. The present inventors have synthesized various unsaturated higher fatty acid amides of 5-fluorouracil, and as a result of intensive research into their pharmacological activities, have found that certain amides have excellent platelet aggregation inhibiting effects. OBJECTS OF THE INVENTION An object of the present invention is to provide 5-fluorouracil derivatives useful as platelet aggregation inhibitors. DETAILED DESCRIPTION OF THE INVENTION The objects of the present invention are achieved by the configurations shown in the following sections. That is, the present invention is based on the general formula This is a platelet aggregation inhibitor containing a 5-fluorouracil derivative represented by the formula (wherein R is an acyl group derived from a pentaene higher fatty acid) as an active ingredient. Further, it is preferable that the above R is an acyl group derived from a pentaene higher fatty acid having 18 to 24 carbon atoms. Further, it is desirable that the above R is an acyl group derived from 5,8,11,14,17-eicosapentaenoic acid. In the 5-fluorouracil derivative represented by the above general formula provided by the present invention, an acyl group derived from a pentaene higher fatty acid as defined by R means a higher acyl group having five double bonds in the carbon chain. It means a group obtained by removing the hydroxyl group from the carboxyl group of a fatty acid. 18 to 24 as higher fatty acids
carbon atoms are preferred. The most preferred compound as the 5-fluorouracil derivative represented by the above formula is 1-(5,8,11,
14,17-eicosapentaenoyl)-5-fluorouracil, but other examples include 1-(7,10,
Mention may be made of 13,16,19-docosapentaenoyl)-5-fluorouracil. The compound represented by the above formula of the present invention can be prepared by reacting a pentaene higher fatty acid with 5-fluorouracil in the presence of a condensing agent, or by reacting a reactive derivative of a pentaene higher fatty acid with 5-fluorouracil. can get. Examples of condensing agents include 2-chloro-1-methylpyridinium p-toluenesulfonate, 2-bromo-1-
Examples include methylpyridinium iodide. 2-chloro-1-methylpyridinium p-toluenesulfonate and 2-bromo-1-methylpyridinium iodide can usually be used in the presence of a tertiary amine such as triethylamine or tributylamine. When using these condensing agents, methylene chloride, 1,2-dichloroethane,
Aprotic solvents such as tetrahydrofuran and benzene are used. Reactive derivatives of pentaene higher fatty acids include acid chlorides. When using this reactive derivative, there are no particular restrictions on the solvent, and methylene chloride,
Chloroform, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, benzene,
Organic solvents such as toluene are widely used. The reaction is usually carried out at -20°C to 120°C for about 0.5 to 10 hours. After the reaction is complete, the desired product is collected from the reaction mixture in a conventional manner. For example, the reaction mixture is filtered, the filtrate is concentrated under reduced pressure, and the residue is subjected to column chromatography to obtain the desired ester as a pure product. The dose of the platelet aggregation inhibitor containing the 5-fluorouracil derivative of the present invention as an active ingredient is approximately 0.1 to 10 g per day for an adult, and the dose may be divided into several doses if necessary. Oral administration is preferable, but intravenous injection is also possible. The compounds of the present invention can be mixed with pharmaceutical carriers or excipients in a conventional manner to form tablets, powders, capsules, etc.
Formulated into granules. Examples of carriers or excipients include calcium carbonate, calcium phosphate, corn starch, potato starch, sugar, lactose, talc, magnesium stearate,
Examples include gum arabic. The tablets may be coated according to conventional methods. The compound of the present invention is
In addition to the above-mentioned solid formulations, liquid formulations such as oily suspensions and syrups can also be used. Since the compound of the present invention has five double bonds in its molecule, α
-tocopherol, 2,6-di-tert-butyl-p-
Cresol (BHT) etc. can also be blended. Alternatively, the compound of the present invention can be stabilized by inclusion with cyclodextrin or the like. Next, the present invention will be explained in more detail with reference to Examples and Test Examples. Production example In an argon stream, 5,8,11,14,17-eicosapentaenoic acid (278 mg) was dissolved in anhydrous 1,2-dichloroethane (5 ml), and 2-chloro-1-methylpyridinium p-toluenesulfonate was dissolved. (303 mg), 5-fluorouracil (120 mg), and triethylamine (204 mg) were added in order, and
Stir for an hour. The reaction solution was concentrated under reduced pressure, and to the resulting residue were added n-pentane (10 ml) and water (5 ml), and the mixture was stirred. Then, adjust the pH to about 4 with 0.5N-oxalic acid,
Extract with n-pentane. The n-pentane layer is washed with water and dried with Glauber's salt. The residue obtained by drying the extract under reduced pressure was subjected to column chromatography using Sephadex LH-20 (30 g), and the solvent was distilled off from the methylene chloride eluate to obtain 1-(5,8 ,11,14,
17-eicosapentaenoyl)-5-fluorouracil (196 mg, yield 51%) was obtained. The physicochemical data of this product are as follows. IR (CHCl 3 ) ν nax cm -1 : 1740, 1725, 1680,
1320, 1255 NMR (CDCl 3 ) δ (ppm): 0.97 (3H, t, J = 7.3
Hz, −CH 2 −CH 3 ), 5.37 (10H, m, −CH =
CH−), 8.29 (1H, d, J=6.8Hz, Test Example Platelet Aggregation Inhibition Effect Nine volumes of blood are collected from the rabbit auricular vein using a syringe containing 3.8% sodium citrate solution (1 volume). The blood was centrifuged at 900 rpm for 10 minutes, and the supernatant was extracted with platelet rich plasma.
Plasma (hereinafter referred to as PRP) is obtained. 3/3 of the supernatant
4 was collected, centrifuged at 3000 rpm for 15 minutes, and the supernatant was mixed with platelet poor plasma (Platelet Poor Plasma,
(hereinafter referred to as PPP). For the measurement of platelet aggregation ability, PRP was diluted with PPP and the platelet count was adjusted to approximately 500,000/μ. Place 250μ of the adjusted PRP in a cuvette at 37°C.
Heat it for 3 minutes in a constant temperature bath, and add 1-(5, 8, 11, 14,
A solution of 17-eicosapentaenoyl)-5-fluorouracil (1.2 x 10 -2 M ethanol solution)
After adding 25μ of a solution of arachidonic acid, an aggregation inducer (diluted with 0.05M Tris buffer) and incubating for 5 minutes, 25μ of a solution of arachidonic acid (3.2 × 10 -1 M ethanol solution diluted with Tris-buffered isotonic saline solution) was added. The inhibition rate of platelet aggregation was measured. The inhibition rate of 1-(5,8,11,14,17-eicosapentaenoyl-5-fluorouracil) against platelet aggregation induced by arachidonic acid (3×10 -4 M) was 7.5×10 - 40.2% at 5 M dose, 40.2% at 1×10 -4 M dose
It was 100%. On the other hand, 5, 8, 11, 14,
The inhibition rate of 17-eicosapentaenoic acid is 1×10 -4 M
The dose was 70.9%. Acute toxicity An acute toxicity test was conducted by oral administration using ICR male mice (7 weeks old). The LD 50 value of the compound of the present invention was 800 mg/Kg or more, confirming its high safety. Effects of the Invention According to the present invention, platelet aggregation induced by arachidonic acid is significantly suppressed.
Claims (1)
るアシル基である）で示される５−フルオロウラ
シル誘導体を有効成分とする血小板凝集抑制剤。 ２ 前記一般式中Ｒが18ないし24個の炭素原子を
有するペンタエン高級脂肪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５−フル
オロウラシル誘導体を有効成分とする血小板凝集
抑制剤。 ３ 前記一般式中Ｒが５，８，11，14，17−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５−フルオロウラシ
ル誘導体を有効成分とする血小板凝集抑制剤。[Claims] 1. General formula A platelet aggregation inhibitor containing a 5-fluorouracil derivative represented by the formula (wherein R is an acyl group derived from a pentaene higher fatty acid) as an active ingredient. 2. A platelet aggregation inhibitor comprising a 5-fluorouracil derivative as an active ingredient according to claim 1, wherein R in the general formula is an acyl group derived from a pentaene higher fatty acid having 18 to 24 carbon atoms. 3. A platelet aggregation inhibitor containing a 5-fluorouracil derivative as an active ingredient according to claim 1, wherein R in the general formula is an acyl group derived from 5,8,11,14,17-eicosapentaenoic acid. .
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP57221501A JPS59110682A (en) | 1982-12-17 | 1982-12-17 | 5-fluorouracil derivative and its preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP57221501A JPS59110682A (en) | 1982-12-17 | 1982-12-17 | 5-fluorouracil derivative and its preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS59110682A JPS59110682A (en) | 1984-06-26 |
| JPH0333689B2 true JPH0333689B2 (en) | 1991-05-20 |
Family
ID=16767694
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP57221501A Granted JPS59110682A (en) | 1982-12-17 | 1982-12-17 | 5-fluorouracil derivative and its preparation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS59110682A (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5186480A (en) * | 1975-01-22 | 1976-07-29 | Asahi Chemical Ind | 55 furuororashirujudotainoseiho |
-
1982
- 1982-12-17 JP JP57221501A patent/JPS59110682A/en active Granted
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5186480A (en) * | 1975-01-22 | 1976-07-29 | Asahi Chemical Ind | 55 furuororashirujudotainoseiho |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS59110682A (en) | 1984-06-26 |
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