JPH0434992B2 - - Google Patents
Info
- Publication number
- JPH0434992B2 JPH0434992B2 JP59095725A JP9572584A JPH0434992B2 JP H0434992 B2 JPH0434992 B2 JP H0434992B2 JP 59095725 A JP59095725 A JP 59095725A JP 9572584 A JP9572584 A JP 9572584A JP H0434992 B2 JPH0434992 B2 JP H0434992B2
- Authority
- JP
- Japan
- Prior art keywords
- fluorouracil
- present
- acid
- platelet aggregation
- 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 32
- MBMBGCFOFBJSGT-SFGLVEFQSA-N docosa-4,7,10,13,16,19-hexaenoic acid Chemical compound CC\C=C\C\C=C\C\C=C\C\C=C\C\C=C\C\C=C\CCC(O)=O MBMBGCFOFBJSGT-SFGLVEFQSA-N 0.000 claims description 9
- MBMBGCFOFBJSGT-KUBAVDMBSA-N docosahexaenoic acid Natural products CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCC(O)=O MBMBGCFOFBJSGT-KUBAVDMBSA-N 0.000 claims description 9
- 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 7
- HXWJFEZDFPRLBG-UHFFFAOYSA-N Timnodonic acid Natural products CCCC=CC=CCC=CCC=CCC=CCCCC(O)=O HXWJFEZDFPRLBG-UHFFFAOYSA-N 0.000 claims description 7
- 125000002252 acyl group Chemical group 0.000 claims description 7
- JAZBEHYOTPTENJ-UHFFFAOYSA-N eicosapentaenoic acid Natural products CCC=CCC=CCC=CCC=CCC=CCCCC(O)=O JAZBEHYOTPTENJ-UHFFFAOYSA-N 0.000 claims description 7
- 239000004480 active ingredient Substances 0.000 claims description 6
- 239000002246 antineoplastic agent Substances 0.000 claims description 6
- 229940127218 antiplatelet drug Drugs 0.000 claims description 6
- 239000000106 platelet aggregation inhibitor Substances 0.000 claims description 6
- 101000783577 Dendroaspis angusticeps Thrombostatin Proteins 0.000 claims description 5
- 101000783578 Dendroaspis jamesoni kaimosae Dendroaspin Proteins 0.000 claims description 5
- 229940041181 antineoplastic drug Drugs 0.000 claims description 3
- 229960005135 eicosapentaenoic acid Drugs 0.000 claims 2
- 229960002949 fluorouracil Drugs 0.000 description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 9
- 230000002401 inhibitory effect Effects 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 150000008065 acid anhydrides Chemical class 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 230000004083 survival effect Effects 0.000 description 5
- XIYUSYCTPZHVMY-UHFFFAOYSA-N (5-fluoro-2,4-dioxopyrimidin-1-yl)methyl icosa-5,8,11,14,17-pentaenoate Chemical compound CCC=CCC=CCC=CCC=CCC=CCCCC(=O)OCN1C=C(F)C(=O)NC1=O XIYUSYCTPZHVMY-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 206010027476 Metastases Diseases 0.000 description 3
- 230000001093 anti-cancer Effects 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 3
- 229930195729 fatty acid Natural products 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 150000004665 fatty acids Chemical class 0.000 description 3
- 230000009401 metastasis Effects 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- DQUUTIWXOMCKRM-UHFFFAOYSA-N (5-fluoro-2,4-dioxopyrimidin-1-yl)methyl docosa-4,7,10,13,16,19-hexaenoate Chemical compound CCC=CCC=CCC=CCC=CCC=CCC=CCCC(=O)OCN1C=C(F)C(=O)NC1=O DQUUTIWXOMCKRM-UHFFFAOYSA-N 0.000 description 2
- 102000008186 Collagen Human genes 0.000 description 2
- 108010035532 Collagen Proteins 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 230000007059 acute toxicity Effects 0.000 description 2
- 231100000403 acute toxicity Toxicity 0.000 description 2
- 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 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 150000001793 charged compounds Chemical class 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229920001436 collagen Polymers 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- WBKFWQBXFREOFH-UHFFFAOYSA-N dichloromethane;ethyl acetate Chemical compound ClCCl.CCOC(C)=O WBKFWQBXFREOFH-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000005227 gel permeation chromatography Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- LIKMAJRDDDTEIG-UHFFFAOYSA-N 1-hexene Chemical compound CCCCC=C LIKMAJRDDDTEIG-UHFFFAOYSA-N 0.000 description 1
- -1 1-hydroxymethyl form Chemical group 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- DDKMFOUTRRODRE-UHFFFAOYSA-N chloromethanone Chemical compound Cl[C]=O DDKMFOUTRRODRE-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 235000004626 essential fatty acids Nutrition 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 235000021323 fish oil Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000010446 mirabilite Substances 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- YWAKXRMUMFPDSH-UHFFFAOYSA-N pentene Chemical compound CCCC=C YWAKXRMUMFPDSH-UHFFFAOYSA-N 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 210000004623 platelet-rich plasma Anatomy 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000007761 synergistic anti-cancer Effects 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
- 150000003512 tertiary amines Chemical class 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
１ 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および
これを有効成分として含有する医薬製剤に関する
ものである。
本発明によつて提供される５−フルオロウラシ
ル誘導体は新規化合物であつて、強力な制癌作用
を有する。また本発明の５−フルオロウラシル誘
導体は強力な血小板凝集抑制作用も有する。
先行技術
５，８，11，14，17−エイコサペンタエン酸あ
るいは４，７，10，13，16，19−ドコサヘキサエ
ン酸は魚油に含まれる必須脂肪酸であることが知
られている。
５−フルオロウラシルは制癌剤として臨床で使
用されているが、毒性が高く有効血中濃度の幅が
狭いという問題点がある。
本発明者等は５−フルオロウラシルの１−ヒド
ロキシメチル体のペンタエン高級脂肪酸またはヘ
キサエン高級脂肪酸のエステルを合成し、それら
の薬理活性を鋭意研究した結果、それらが優れた
制癌作用および血小板凝集抑制作用を有すること
を見い出し、本発明を完成するに至つた。
発明の目的
本発明は新規な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。さらに、該誘導体を
有効成分として含有する制癌剤ならびに血小板凝
集抑制剤を提供することを目的とする。
発明の具体的説明
本願の目的は以下に示す構成によつて達成され
る。すたわち、本発明は一般式
（式中Ｒは５，８，11，14，17−エイコサペン
タエン酸または４，７，10，13，16，19−ドコサ
ヘキサエン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である。
また、本発明は一般式
（式中Ｒは５，８，11，14，17−エイコサペン
タエン酸または４，７，10，13，16，19−ドコサ
ヘキサエン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
として含有する制癌剤である。
また、本発明は一般式
（式中Ｒは５，８，11，14，17−エイコサペン
タエン酸または４，７，10，13，16，19−ドコサ
ヘキサエン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
として含有する血小板凝集抑制剤である。
本発明の前記式で示される５−フルオロウラシ
ル誘導体は、前記高級脂肪酸とクロルギ酸エチル
（ClCO2C2H5）とを塩基存在下に反応して得られ
る混合酸無水物の溶液に、５−フルオロウラシル
（５−FU）をホルマリンと反応して得られる反応
混合物を塩基存在下に反応させることによつて得
られる。
塩基としては、トリエチルアミン、トリブチル
アミン、ジメチルアミノピリジン等の三級アミン
が好ましく用いられる。
本発明の５−フルオロウラシル誘導体は臨床に
用いられている５−フルオロウラシルと動物試験
において同等以上の抗腫瘍作用を示し、且つ、５
−フルオロウラシルに比べて低毒性である。また
本発明の５−フルオロウラシル誘導体は５−FU
には見られない強力な血小板凝集抑制作用を有す
るという特徴も持つている。
本発明の５−フルオロウラシル誘導体は制癌剤
として、また、血小板凝集抑制剤として有用に使
用される。投与量は成人１日量約0.1〜3gが好ま
しい。
本発明の５−フルオロウラシル誘導体は通常の
方法でカプセル剤、錠剤、顆粒剤、シロツプ剤等
の形態で経口投与するとか、注射剤、坐剤等とし
て非経口投与することが可能である。
次に実施例および試験例を挙げて本発明をさら
に詳細に説明するが本発明はこれらに限定される
ものではない。
実施例 １
アルゴン気流中、５，８，11，14，17−エイコ
サペンタエン酸3.024gを無水テトラヒドロフラン
200mlに溶解し、氷冷下クロルギ酸エチル1.085g
を加え、15分後トリエチルアミン1.012gを滴下し
た。更に１時間攪拌して混合酸無水物の溶液を調
製する。該混合酸無水物の溶液に、５−フルオロ
ウラシル1.3gと37％ホルマリン1.3mlを50℃で５
時間加温したのちベンゼンで水を共沸させて得ら
れる残渣を無水ジメチルホルムアミド20mlに溶か
した溶液を氷冷下に加え、つづいてこれにトリエ
チルアミン2.024gを加える。室温にて24時間攪拌
した。生じる沈殿を濾去して得られる濾液を濃縮
した。残渣を水50mlに溶解し、1N−修酸でpH4
とした後、エーテル抽出し、水洗、芒硝乾燥後、
減圧濃縮し、残渣3.88gを得た。これをシリカゲ
ルクロマトの付し、塩化メチレン−酢酸エチル
（４：１）溶出部を更にゲルクロマトに付し、塩
化メチレン溶出部より目的の１−（５，８，11，
14，17−エイコサペンタエノイルオキシメチル）
−５−フルオロウラシル1.72gを得た。このもの
の物理化学的データは下記の通りである。
IR（CHCl3）cm−１max：1715，1675，1260，
1120NMR（CDCl3）δ（ppm）：0.97（3H，ｔ，Ｊ
＝7.5Hz）、
2.40（2H，ｔ，Ｊ＝7.6Hz）、5.64（2H，ｓ）、
7.62（1H，ｄ，Ｊ＝5.4Hz）
MASS（ｍ／ｚ）：444（分子イオンピーク）
実施例 ２
アルゴン気流中、４，７，10，13，16，19−ド
コサヘキサエン酸1.971gを無水テトラヒドロフラ
ン100mlに溶解し、氷冷下にクロルギ酸エチル651
mgを加え、15分後トリエチルアミン607mgを滴下
した。更に１時間攪拌して混合酸無水物の溶液を
調製する。該混合酸無水物の溶液に、５−フルオ
ロウラシル780mgと37％ホルマリン1.1mlを50℃で
５時間加温したのちベンゼンで水を共沸させて得
られる残渣を無水ジメチルホルムアミド15mlに溶
かした溶液を氷冷下に加え、つづいてトリエチル
アミン1.214gを加える。室温にて24時間攪拌し
た。生じた白色沈殿を濾去し、沈殿をテトラヒド
ロフランで洗浄して得られた濾液を減圧濃縮し
た。残渣を水50mlに溶解し、1N−修酸でpH4と
した後、エーテル抽出し、水洗、芒硝乾燥後、減
圧濃縮して残渣2.84gを得た。これをシリカゲル
クロマトに付し、塩化メチレン−酢酸エチル
（４：１）溶出部を更にゲルクロマトに付し、塩
化メチレン溶出部より目的の１−（４，７，10，
13，16，19−ドコサヘキセノイルオキシメチル）
−５−フルオロウラシル1.215gを得た。このもの
の物理化学的データは下記の通りである。
IR（CHCl3）cm−１max：1715，1670，1265，
1125NMR（CDCl3）δ（ppm）：0.97（3H，ｔ，Ｊ
＝7.6Hz），
2.07（2H，ｍ），5.65（2H，ｓ），7.61（1H，ｄ，
Ｊ＝5.4Hz）
MASS（ｍ／ｚ）：470（分子イオンピーク）
〔試験例〕
１ 抗腫瘍作用
CDF1、マウス（雄性、５週令）にP388細胞１
×106個／マウスを腹腔内移植する。実施例１で
得られた１−（５，８，11，14，17−エイコサペ
ンタエノイルオキシメチル）−５−フルオロウラ
シル、あるいは実施例２で得られた１−（４，７，
10，13，16，19−ドコサヘキセノイルオキシメチ
ル）−５−フルオロウラシルの0.5％カルボキシメ
チルセルロース懸濁液を翌日より１日１回５日間
連続して腹腔内投与し延命率を測定する。延命率
（ILS％）＝処置群の生存日数の中央値／コントロール
群の生存日数の中央値
×100−100として５−フルオロウラシル（５−
FU）と比較した結果を表に示す。
1. BACKGROUND OF THE INVENTION Technical Field The present invention relates to a 5-fluorouracil derivative and a pharmaceutical preparation containing the same as an active ingredient. The 5-fluorouracil derivative provided by the present invention is a new compound and has a strong anticancer effect. The 5-fluorouracil derivative of the present invention also has a strong platelet aggregation inhibiting effect. Prior Art 5,8,11,14,17-eicosapentaenoic acid or 4,7,10,13,16,19-docosahexaenoic acid is known to be an essential fatty acid contained in fish oil. Although 5-fluorouracil is used clinically as an anticancer agent, it has the problems of high toxicity and a narrow range of effective blood concentrations. The present inventors synthesized esters of pentaene higher fatty acids or hexaene higher fatty acids of the 1-hydroxymethyl form of 5-fluorouracil, and as a result of intensive research on their pharmacological activities, they found that they have excellent anticancer and platelet aggregation inhibitory effects. The present invention was completed based on the discovery that the present invention has the following properties. OBJECTS OF THE INVENTION The purpose of the present invention is to provide novel 5-fluorouracil derivatives. Furthermore, it is an object of the present invention to provide an anticancer agent and a platelet aggregation inhibitor containing the derivative as an active ingredient. DETAILED DESCRIPTION OF THE INVENTION The object of the present application is achieved by the configuration shown below. Therefore, the present invention is based on the general formula (wherein R is an acyl group derived from 5,8,11,14,17-eicosapentaenoic acid or 4,7,10,13,16,19-docosahexaenoic acid) be. Furthermore, the present invention also relates to the general formula (wherein R is an acyl group derived from 5,8,11,14,17-eicosapentaenoic acid or 4,7,10,13,16,19-docosahexaenoic acid) It is an anticancer drug containing as an active ingredient. Furthermore, the present invention also relates to the general formula (wherein R is an acyl group derived from 5,8,11,14,17-eicosapentaenoic acid or 4,7,10,13,16,19-docosahexaenoic acid) It is a platelet aggregation inhibitor contained as an active ingredient. The 5-fluorouracil derivative represented by the above formula of the present invention is obtained by adding 5-fluorouracil to a solution of a mixed acid anhydride obtained by reacting the higher fatty acid with ethyl chloroformate (ClCO 2 C 2 H 5 ) in the presence of a base. It is obtained by reacting a reaction mixture obtained by reacting fluorouracil (5-FU) with formalin in the presence of a base. As the base, tertiary amines such as triethylamine, tributylamine, and dimethylaminopyridine are preferably used. The 5-fluorouracil derivative of the present invention exhibits an antitumor effect equivalent to or superior to that of clinically used 5-fluorouracil in animal tests, and
-Low toxicity compared to fluorouracil. Furthermore, the 5-fluorouracil derivative of the present invention is 5-FU
It also has the characteristic of having a strong platelet aggregation inhibitory effect that is not found in other drugs. The 5-fluorouracil derivatives of the present invention are useful as anticancer agents and platelet aggregation inhibitors. The dosage is preferably about 0.1 to 3 g per day for adults. The 5-fluorouracil derivatives of the present invention can be administered orally in the form of capsules, tablets, granules, syrups, etc., or parenterally in the form of injections, suppositories, etc., in a conventional manner. 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 3.024 g of 5,8,11,14,17-eicosapentaenoic acid was dissolved in anhydrous tetrahydrofuran in an argon stream.
1.085g of ethyl chloroformate dissolved in 200ml and cooled on ice
was added, and 1.012 g of triethylamine was added dropwise after 15 minutes. Stir for an additional hour to prepare a mixed acid anhydride solution. Add 1.3 g of 5-fluorouracil and 1.3 ml of 37% formalin to the mixed acid anhydride solution at 50°C.
After heating for an hour, a solution of the residue obtained by azeotropically distilling water with benzene in 20 ml of anhydrous dimethylformamide is added under ice cooling, and then 2.024 g of triethylamine is added thereto. The mixture was stirred at room temperature for 24 hours. The resulting precipitate was filtered off and the resulting filtrate was concentrated. Dissolve the residue in 50 ml of water and adjust to pH 4 with 1N oxalic acid.
After that, extract with ether, wash with water, dry with mirabilite,
It was concentrated under reduced pressure to obtain 3.88 g of residue. This was subjected to silica gel chromatography, and the methylene chloride-ethyl acetate (4:1) eluate was further subjected to gel chromatography, and the target 1-(5,8,11,
14,17-eicosapentaenoyloxymethyl)
1.72 g of -5-fluorouracil was obtained. The physicochemical data of this product are as follows. IR (CHCl 3 ) cm−1max: 1715, 1675, 1260,
1120NMR (CDCl 3 ) δ (ppm): 0.97 (3H, t, J
= 7.5Hz), 2.40 (2H, t, J = 7.6Hz), 5.64 (2H, s),
7.62 (1H, d, J = 5.4Hz) MASS (m/z): 444 (molecular ion peak) Example 2 In an argon stream, 1.971 g of 4,7,10,13,16,19-docosahexaenoic acid was dissolved in anhydrous tetrahydrofuran. Dissolve ethyl chloroformate 651 in 100ml and cool on ice.
15 minutes later, 607 mg of triethylamine was added dropwise. Stir for an additional hour to prepare a mixed acid anhydride solution. Into the solution of the mixed acid anhydride, 780 mg of 5-fluorouracil and 1.1 ml of 37% formalin were heated at 50°C for 5 hours, and then a solution of the residue obtained by azeotropically distilling water with benzene in 15 ml of anhydrous dimethylformamide was added. Add under ice cooling, and then add 1.214 g of triethylamine. The mixture was stirred at room temperature for 24 hours. The resulting white precipitate was filtered off, the precipitate was washed with tetrahydrofuran, and the resulting filtrate was concentrated under reduced pressure. The residue was dissolved in 50 ml of water, adjusted to pH 4 with 1N oxalic acid, extracted with ether, washed with water, dried with sodium sulfate, and concentrated under reduced pressure to obtain 2.84 g of a residue. This was subjected to silica gel chromatography, and the methylene chloride-ethyl acetate (4:1) eluate was further subjected to gel chromatography, and the target 1-(4,7,10,
13,16,19-docosahexenoyloxymethyl)
1.215 g of -5-fluorouracil was obtained. The physicochemical data of this product are as follows. IR (CHCl 3 ) cm−1max: 1715, 1670, 1265,
1125NMR (CDCl 3 ) δ (ppm): 0.97 (3H, t, J
=7.6Hz), 2.07 (2H, m), 5.65 (2H, s), 7.61 (1H, d,
J=5.4Hz) MASS (m/z): 470 (molecular ion peak) [Test example] 1 Antitumor effect CDF 1 , P388 cells 1 in mice (male, 5 weeks old)
x106 mice/mouse are implanted intraperitoneally. 1-(5,8,11,14,17-eicosapentaenoyloxymethyl)-5-fluorouracil obtained in Example 1, or 1-(4,7,
Starting from the next day, a 0.5% suspension of carboxymethylcellulose (10,13,16,19-docosahexenoyloxymethyl)-5-fluorouracil is administered intraperitoneally once a day for 5 consecutive days, and the survival rate is measured. Survival prolongation rate (ILS%) = Median survival days in the treatment group / Median survival days in the control group x 100-100
The results of comparison with FU) are shown in the table.
【表】
表から明らかな通り、本発明に係る１−（５，
８，11，14，17−エイコサペンタエノイルオキシ
メチル）−５−フルオロウラシルおよび１−（４，
７，10，13，16，19−ドコサヘキセノイルオキシ
メチル）−５−フルオロウラシルは５−FUにくら
べて同等以上の抗腫瘍活性を示している。また、
５−FUは30mg／Kg／日では毒性によりマウスの
生存日数が上記制癌剤を投与しないコントロール
より短かくなつてしまうのに反し、本発明に係る
１−（５，８，11，14，17−エイコサペンタエノ
イルオキシメチル）−５−フルオロウラシルおよ
び１−（４，７，10，13，16，19−ドコサヘキセ
ノイルオキシメチル）−５−フルオロウラシルは
70mg／Kg／日でもILS％がそれぞれ36，30であ
り、毒性が５−FUより低いことが明らかとなつ
た。
２ 血小板凝集抑制作用
3.8％クエン酸ナトリウム（１溶）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。該血液より遠心分離し血小板に富む血漿
（PRP：40万個／μl）を得る。該PRPを用い、凝
集惹起剤としてアラキドン酸あるいはコラーゲン
を用いて本発明化合物の血小板凝集抑制作用を測
定した。アラキドン酸（80μM）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オキシメチル）−５
−フルオロウラシルの50％抑制濃度（IC50）は
1.2×10-4Ｍであり、１−（４，７，10，13，16，
19−ドコサヘキセノイルオキシメチル）−５−フ
ルオロウラシルのIC50は5.4×10-5Ｍであるのに対
し５−FUは１×10-3Ｍ以上投与しても50％抑制
することができなかつた。
また、コラーゲン（25μg／ml）による血小板
凝集に対する１−（５，８，11，14，17−エイコ
サペンタエノイルオキシメチル）−５−フルオロ
ウラシルのIC50は7.1×10-4Ｍであり、１−（４，
７，10，13，16，19−ドコサヘキセノイルオキシ
メチル）−５−フルオロウラシルのIC50は9.0×
10-5Ｍであるのに対し、５−FUのIC50は１×
10-3Ｍ以上であり、本発明化合物が強力な血小板
凝集抑制作用を有していることが明らかとなつ
た。
３ 急性毒性
１−（５，８，11，14，17−エイコサペンタエ
ノイルオキシメチル）−５−フルオロウラシルお
よび１−（４，７，10，13，16，19−ドコサヘキ
セノイルオキシメチル）−５−フルオロウラシル
の腹腔内投与による急性毒性についてICRマウス
（雄、７週令）を用じて調べた結果、５−フルオ
ロウラシルのLD50値は235mg／Kgであるのに対
し、前記本発明に係る化合物のLD50値はいずれ
も500mg／Kgよりも大きく、本発明に係る化合物
の高い安全性が確認された。
発明の効果
本発明によれば、一般式
（式中Ｒは５，８，11，14，17−エイコサペン
タエン酸または４，７，10，13，16，19−ドコサ
ヘキサエン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が提供され
る。
本発明に係る前記誘導体は強力な制癌作用およ
び血小板凝集抑制作用を有する。
また、近年、血小板の凝集が、ガンの転移に関
与していることを示唆する結果が得られてきてい
る。従つて本発明の５−フルオロウラシル誘導体
を用いた血小板凝集抑制剤はガン転移予防剤とし
ても使用できる。よつて本発明の５−フルオロウ
ラシル誘導体は制癌作用とガン転移予防作用が相
乗的に働き、かつ低毒性であるため癌治療に有効
に使用することもできる。
さらに、本発明の５−フルオロウラシル誘導体
を用いた血小板凝集抑制剤は採取された血液の血
液凝固防止用としても有効に使用することができ
る。[Table] As is clear from the table, 1-(5,
8,11,14,17-eicosapentaenoyloxymethyl)-5-fluorouracil and 1-(4,
7,10,13,16,19-docosahexenoyloxymethyl)-5-fluorouracil has shown an antitumor activity equal to or higher than that of 5-FU. Also,
At 30 mg/Kg/day of 5-FU, the survival period of mice is shorter than that of the control without administering the above anticancer drug due to toxicity. Eicosapentaenoyloxymethyl)-5-fluorouracil and 1-(4,7,10,13,16,19-docosahexenoyloxymethyl)-5-fluorouracil are
Even at 70 mg/Kg/day, the ILS% was 36 and 30, respectively, indicating that the toxicity was lower than that of 5-FU. 2 Platelet aggregation inhibitory effect Collect 9 volumes of blood from the rabbit carotid artery using a syringe containing 3.8% sodium citrate (1 solution). The blood is centrifuged to obtain platelet-rich plasma (PRP: 400,000 cells/μl). Using the PRP and arachidonic acid or collagen as an aggregation-inducing agent, the platelet aggregation inhibitory effect of the compound of the present invention was measured. 1-(5,8,11,14,
17-eicosapentaenoyloxymethyl)-5
-The 50% inhibitory concentration (IC 50 ) of fluorouracil is
1.2×10 -4 M, 1-(4,7,10,13,16,
The IC 50 of 19-docosahexenoyloxymethyl)-5-fluorouracil is 5.4×10 -5 M, whereas 5-FU can be inhibited by 50% even when administered at 1×10 -3 M or more. Nakatsuta. Furthermore, the IC 50 of 1-(5,8,11,14,17-eicosapentaenoyloxymethyl)-5-fluorouracil against platelet aggregation induced by collagen (25 μg/ml) is 7.1×10 −4 M; 1-(4,
The IC 50 of 7,10,13,16,19-docosahexenoyloxymethyl)-5-fluorouracil is 9.0×
10 -5 M, whereas the IC 50 of 5-FU is 1×
10 -3 M or more, demonstrating that the compound of the present invention has a strong platelet aggregation inhibitory effect. 3 Acute toxicity 1-(5,8,11,14,17-eicosapentaenoyloxymethyl)-5-fluorouracil and 1-(4,7,10,13,16,19-docosahexenoyloxymethyl) ) - As a result of investigating the acute toxicity of 5-fluorouracil by intraperitoneal administration using ICR mice (male, 7 weeks old), the LD 50 value of 5-fluorouracil was 235 mg/Kg, whereas the present invention The LD 50 values of the compounds according to the present invention were all greater than 500 mg/Kg, confirming the high safety of the compounds according to the present invention. Effects of the Invention According to the present invention, the general formula (wherein R is an acyl group derived from 5,8,11,14,17-eicosapentaenoic acid or 4,7,10,13,16,19-docosahexaenoic acid) provided. The derivative according to the present invention has a strong anticancer effect and an inhibitory effect on platelet aggregation. Furthermore, in recent years, results have been obtained suggesting that platelet aggregation is involved in cancer metastasis. Therefore, the platelet aggregation inhibitor using the 5-fluorouracil derivative of the present invention can also be used as an agent for preventing cancer metastasis. Therefore, the 5-fluorouracil derivative of the present invention has a synergistic anticancer effect and a preventive effect against cancer metastasis, and has low toxicity, so that it can be effectively used for cancer treatment. Furthermore, the platelet aggregation inhibitor using the 5-fluorouracil derivative of the present invention can also be effectively used for preventing blood coagulation of collected blood.
Claims (1)
ンタエン酸または４，７，10，13，16，19−ドコ
サヘキサエン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。 ２ 一般式 （式中Ｒは５，８，11，14，17−エイコサペン
タエン酸または４，７，10，13，16，19−ドコサ
ヘキサエン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
として含有する制癌剤。 ３ 一般式 （式中Ｒは５，８，11，14，17，−エイコサペ
ンタエン酸または４，７，10，13，16，19−ドコ
サヘキサエン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
分として含有する血小板凝集抑制剤。[Claims] 1. General formula (In the formula, R is an acyl group derived from 5,8,11,14,17,-eicosapentaenoic acid or 4,7,10,13,16,19-docosahexaenoic acid)
A 5-fluorouracil derivative represented by 2 General formula (wherein R is an acyl group derived from 5,8,11,14,17-eicosapentaenoic acid or 4,7,10,13,16,19-docosahexaenoic acid) An anticancer drug containing as an active ingredient. 3 General formula (In the formula, R is an acyl group derived from 5,8,11,14,17,-eicosapentaenoic acid or 4,7,10,13,16,19-docosahexaenoic acid)
A platelet aggregation inhibitor containing a 5-fluorouracil derivative as an active ingredient.
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP59095725A JPS60239472A (en) | 1984-05-15 | 1984-05-15 | 5-fluorouracil derivative and medicinal pharmaceutical containing same as active constituent |
| EP84903816A EP0162924B1 (en) | 1983-10-20 | 1984-10-19 | 5-fluorouracil derivatives and medicinal preparation containing same |
| PCT/JP1984/000499 WO1985001729A1 (en) | 1983-10-20 | 1984-10-19 | 5-fluorouracil derivatives and medicinal preparation containing same |
| DE8484903816T DE3480706D1 (en) | 1983-10-20 | 1984-10-19 | 5-FLUORURACILABRED COMBINATIONS AND MEDICAL COMPOSITIONS CONTAINING THEM. |
| US06/749,626 US4704393A (en) | 1983-10-20 | 1984-10-19 | 1-substituted 5-fluorouracil useful for inhibiting the aggregation of platelets |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP59095725A JPS60239472A (en) | 1984-05-15 | 1984-05-15 | 5-fluorouracil derivative and medicinal pharmaceutical containing same as active constituent |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS60239472A JPS60239472A (en) | 1985-11-28 |
| JPH0434992B2 true JPH0434992B2 (en) | 1992-06-09 |
Family
ID=14145446
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP59095725A Granted JPS60239472A (en) | 1983-10-20 | 1984-05-15 | 5-fluorouracil derivative and medicinal pharmaceutical containing same as active constituent |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS60239472A (en) |
-
1984
- 1984-05-15 JP JP59095725A patent/JPS60239472A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS60239472A (en) | 1985-11-28 |
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