JPS6134428B2 - - Google Patents
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- Publication number
- JPS6134428B2 JPS6134428B2 JP53058470A JP5847078A JPS6134428B2 JP S6134428 B2 JPS6134428 B2 JP S6134428B2 JP 53058470 A JP53058470 A JP 53058470A JP 5847078 A JP5847078 A JP 5847078A JP S6134428 B2 JPS6134428 B2 JP S6134428B2
- Authority
- JP
- Japan
- Prior art keywords
- fluorouracil
- compound
- formula
- general formula
- chloroform
- 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
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
- C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
- C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
- C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は５−フルオロウラシルの新規誘導体及
びその製造方法ならびにこれらの化合物を有効成
分とする抗腫瘍剤に関するものである。
５−フルオロウラシルは抗腫瘍剤として一般に
用いられているが、この物質の誘導体であるフト
ラフール（１−テトラハイドロフラニル−５−フ
ルオロウラシル）がより毒性が軽減され又、経口
可能な抗腫瘍剤として最近使用されている。しか
し、これも理想とは程遠いものであり、より優れ
た抗腫瘍剤が望まれている。本発明者等は更にす
ぐれた抗腫瘍作用を有する薬剤を得る為に様々な
５−フルオロウラシル誘導体を検討した結果、５
−フルオロウラシルにフエノキシ酢酸類を導入し
た一群の新規物質が従来品に比べて、一層優れた
抗腫瘍作用を示すことを見い出し、本発明に到達
した。フエノキシ酢酸類は血中アルブミンと結合
しやすく、（Ｈ・Meinser、Biochem Biophi Res
Comm.、66、1134（1975））、又、蛋白と非可逆
的に疎水結合（Hydrophobicity）により結びつ
くことが知られている。（L.G.Butler、Chem.and
Eng.News1977、may30、23頁）。５−フルオロ
ウラシルは時間依存性であり、長時間にわたり作
用するものが望まれているが、５−フルオロウラ
シルにフエノキシ酢酸類を導入することにより得
られた本願物質は５−フルオロウラシルにくらべ
て、特に組織親和性、持続性が一段と優れてい
る。
本化合物の疎水結合（Hydrophobicity）を調
べる為に１−オクタノールと生理食塩水（PH
7.4）の分配係数を求めると対照薬の５−フルオ
ロウラシル又はフトラフールに比較していづれも
約５〜18倍に上昇した。又、本願化合物群中、特
に高い分配率を示したN1−（Ｐ−クロルフエノキ
シイソブチリル）−５−フルオロウラシルを例に
とるとその毒性（経口）は、５−フルオロウラシ
ル（246〜354mg／Kg体重）、フトラフール1125〜
1620mg／Kg体重）に比較して1215〜1683mg／Kg体
重（Ｐ＝0.05）と低い毒性である。
一方制癌作用についてエーリツヒ腹水癌、
P388リンパ球白血病、L1210リンパ球白血病、吉
田肉腫に対して制癌作用を示し、特にN1−（Ｐ−
クロルフエノキシイソブチリル）−５−フルオロ
ウラシル、N1−（フエノキシイソブチリル）−５
−フルオロウラシル、N1−（Ｐ−クロルフエノキ
シアセチル）−５−フルオロウラシルはフトラフ
ールに比較して有意の差が認められた。
本願化合物は、経口・非経口のいずれでも投与
でき、年齢・症状等により異なるが、成人一人当
り一日量として、200〜1500mgの範囲で投与する
ことにより、治療効果が期待できる。
本願化合物は、N1−フエノキシアセチル−５
−フルオロウラシル誘導体であつて次の一般式に
よりあらわされる。
（式中、R1、R2はＨ又はCH3を、ＹはＨ又はClを
表わす。）
一般式(1)を有する化合物を下記に例示する。
(a) N1−（Ｐ−クロルフエノキシイソブチリル）
−５−フルオロウラシル
(b) N1−（フエノキシイソブチリル）−５−フル
オロウラシル
(c) N1−（Ｐ−クロルフエノキシアセチル）−５
−フルオロウラシル
(d) N1−（Ｏ−クロルフエノキシイソブチリル）
−５−フルオロウラシル
式(1)に示される化合物は５−フルオロウラシル
をシリル化して得られるたとえばビス−トリメチ
ルシリル−５−フルオロウラシルとフエノキシ酢
酸類の酸クロライドとを反応させ、次いでPH６〜
７のもとで目的物を溶媒抽出することにより得ら
れる。尚この際、炭酸カリ、ピリジン又はトリエ
チルアミンの如き脱酸剤の存在下では目的物は殆
んど得られない。又５−フルオロウラシルをシリ
ル化せず、そのまゝで酸クロライドと反応させて
も反応温度０゜〜150゜において目的物質は殆ん
ど得られない。
以下に本発明の実施例を示す。
実施例 １
化合物(a)の製造
(i) Ｐ−クロルフエノキシイソブチリル酸クロラ
イド Ｐ−クロルフエノキシイソブチル酸
64.39ｇ（0.3モル）をベンゼン360mlにとか
し、チオニルクロライド143ｇ（1.2モル）を加
えたのち塩化カルシウム管を付した還流冷却器
をつけて３時間加熱還流する。ついでベンゼン
と過剰のチオニルクロライドを共沸して除き、
残留物を減圧蒸留し115゜〜120℃／10mmHgの
留分をとる。収量61.3ｇ（87.7％）
(ii) 化合物(a)
５−フルオロウラシル13.01ｇ（0.1モル）と
ヘキサメチルジシラザラン19.37ｇ（0.12モ
ル）をモレキユラーシーブ3A管を付したフラ
スコ中で３時間加熱還流後、窒素ガス中で過剰
のヘキサメチルジシラザランを減圧留去する
（80〜100℃／10mmHg）、ついで無水トルエンを
加えて残つたヘキサメチルジシラザランを減圧
で留去する。残留物として得られたシリル−５
−フルオロウラシルをそのまゝ無水アセトニト
リル130mlに溶解後、Ｐ−クロルフエノキシイ
ソブチル酸クロライド24.24ｇ（0.104モル）を
無水アセトニトリル40mlに溶解した液を氷水で
冷却下にかくはんしながら滴下する。室温で２
時間かくはん後70℃で２時間更にかくはんを続
ける。次に30℃以下でアセトニトリルを減圧留
去してクロロホルム120mlを加え、水10ml及び
飽和炭酸水素ナトリウム液を加えPH６〜７に調
整し、１時間かくはんした後、クロロホルム層
を水洗後硫酸ナトリウムで脱水しクロロホルム
を減圧留去する。残留物（27.77ｇ収率85.0
％）をクロロホルムで再結晶し目的物質15.68
ｇ（収率48.0％）を得る。融点138〜140℃、
NVスペクトルλmax（メタノール）220、267n
ｍ、λmax（0.01N NaOH）224、270nｍ、irス
ペクトル（cm-1）3400、3100、2910、1785、
1725、1670、1170、nmrスペクトル（DMSO−
d6、PPm）1.60（Ｓ、6H、2CH3）7.20（ｇ、
ＪAB＝９、4H、芳香核）、8.01（ｄ、ＪHF＝
７、C6H）11.10（brs、1H、NH）、
元素分析値（％）
理論値 Ｃ：54.47、Ｈ：3.70、Ｎ；8.57
実測値 Ｃ：51.59、Ｈ：3.65、Ｎ；8.43
実施例 ２
化合物(b)の製造
フエノキシイソブチリル酸を用い化合物(a)の場
合と同様にして粗目的物質23.6ｇ（80.75％収
率）を得る。クロロホルムから再結晶を行い精製
品12.61ｇを得る収率43.15％、融点127〜129℃、
uvスペクトル、irスペクトル、元素分析値（C.H.
N）から目的物質であることを確認する。
実施例 ３
化合物(c)の製造
Ｐ−クロルフエノキシアセチツクアシドを用い
て化合物(a)の製造の場合と同様にして、粗目的物
19.6ｇ（48.5％）、クロロホルムより再結晶を行
つて精製品10.32ｇを得る。収率34.6％、融点165
〜168℃。
実施例 ４
化合物(d)の製造
Ｏ−クロルフエノキシイソブチル酸を用いて化
合物(a)の場合と同様にして28.1ｇ（86.0％）の粗
目的物を得、これをクロロホルムより再結晶して
16.3ｇの精製品を得る、収率50.0％、融点125〜
127℃。
次に本願化合物の薬理効果検定の実験例を以下
に示す。
実験例 １
本願化合物の疎水結合力（Hydrophobicity）
をみるために１−オクタノールと生理食塩水
（0.05Mリン酸緩衝液でPH7.4に保持）との分配係
数を吸光度法で求めると表１の通りである。
The present invention relates to novel derivatives of 5-fluorouracil, methods for producing the same, and antitumor agents containing these compounds as active ingredients. 5-Fluorouracil is commonly used as an antitumor agent, but a derivative of this substance, ftorafur (1-tetrahydrofuranyl-5-fluorouracil), has less toxicity and has recently been used as an orally available antitumor agent. It is used. However, this is still far from ideal, and better antitumor agents are desired. The present inventors investigated various 5-fluorouracil derivatives in order to obtain drugs with even better antitumor effects, and found that 5-fluorouracil derivatives
-We have discovered that a group of new substances in which phenoxyacetic acids have been introduced into fluorouracil exhibit superior antitumor effects compared to conventional products, and have arrived at the present invention. Phenoxyacetic acids easily bind to blood albumin (H. Meinser, Biochem Biophi Res)
Comm., 66, 1134 (1975)), and is also known to irreversibly bind to proteins through hydrophobicity. (LGButler, Chem.and
Eng.News1977, may30, p.23). 5-Fluorouracil is time-dependent, and it is desired that it act over a long period of time. However, the present substance obtained by introducing phenoxyacetic acids into 5-fluorouracil has a particularly strong effect on tissues compared to 5-fluorouracil. Excellent affinity and durability. In order to investigate the hydrophobicity of this compound, we used 1-octanol and physiological saline (PH).
When the partition coefficients of 7.4) were determined, they were all about 5 to 18 times higher than the control drugs 5-fluorouracil or ftorafur. Taking N 1 -(P-chlorophenoxyisobutyryl)-5-fluorouracil as an example, which showed a particularly high distribution rate among the compounds of the present application, its toxicity (oral) is higher than that of 5-fluorouracil (246- 354mg/Kg body weight), Futorafur 1125~
The toxicity is lower at 1215-1683 mg/Kg body weight (P = 0.05) compared to 1620 mg/Kg body weight). On the other hand, regarding anticancer effects, Ehritzchi's ascites cancer,
It shows anticancer activity against P388 lymphocytic leukemia, L1210 lymphocytic leukemia, and Yoshida sarcoma, especially N1- (P-
Chlorphenoxyisobutyryl)-5-fluorouracil, N1- (Phenoxyisobutyryl)-5
-Fluorouracil and N1- (P-chlorophenoxyacetyl)-5-fluorouracil showed a significant difference compared to ftorafur. The compound of the present invention can be administered either orally or parenterally, and a therapeutic effect can be expected by administering the compound in a daily dose of 200 to 1500 mg per adult, although this will vary depending on age, symptoms, etc. The compound of the present invention is N 1 -phenoxyacetyl-5
- A fluorouracil derivative represented by the following general formula. (In the formula, R 1 and R 2 represent H or CH 3 and Y represents H or Cl.) Compounds having the general formula (1) are illustrated below. (a) N 1 -(P-chlorophenoxyisobutyryl)
-5-fluorouracil (b) N 1 -(phenoxyisobutyryl)-5-fluorouracil (c) N 1 -(P-chlorophenoxyacetyl)-5
-Fluorouracil (d) N 1 -(O-chlorophenoxyisobutyryl)
-5-Fluorouracil The compound represented by formula (1) is obtained by silylating 5-fluorouracil, for example, by reacting bis-trimethylsilyl-5-fluorouracil with an acid chloride of phenoxyacetic acid, and then reacting with an acid chloride of phenoxyacetic acid.
It is obtained by solvent extraction of the target product under 7. At this time, in the presence of a deoxidizing agent such as potassium carbonate, pyridine or triethylamine, the desired product is hardly obtained. Furthermore, even if 5-fluorouracil is reacted as it is with acid chloride without silylation, the target substance is hardly obtained at a reaction temperature of 0° to 150°. Examples of the present invention are shown below. Example 1 Production of compound (a) (i) P-chlorophenoxyisobutyrylic acid chloride P-chlorophenoxyisobutyric acid
Dissolve 64.39 g (0.3 mol) in 360 ml of benzene, add 143 g (1.2 mol) of thionyl chloride, and heat under reflux for 3 hours with a reflux condenser equipped with a calcium chloride tube. Benzene and excess thionyl chloride are then azeotropically removed.
Distill the residue under reduced pressure and take a fraction of 115° to 120°C/10 mmHg. Yield: 61.3 g (87.7%) (ii) Compound (a) 13.01 g (0.1 mol) of 5-fluorouracil and 19.37 g (0.12 mol) of hexamethyldisilazalane were heated in a flask fitted with a 3A molecular sieve for 3 hours. After heating to reflux, excess hexamethyldisilazalane is distilled off under reduced pressure in nitrogen gas (80-100°C/10 mmHg), then anhydrous toluene is added and the remaining hexamethyldisilazalane is distilled off under reduced pressure. Silyl-5 obtained as residue
- After dissolving fluorouracil as it is in 130 ml of anhydrous acetonitrile, a solution obtained by dissolving 24.24 g (0.104 mol) of P-chlorophenoxyisobutylic acid chloride in 40 ml of anhydrous acetonitrile is added dropwise while stirring while cooling with ice water. 2 at room temperature
After stirring for an hour, continue stirring at 70°C for 2 hours. Next, acetonitrile was distilled off under reduced pressure at 30°C or below, 120 ml of chloroform was added, 10 ml of water and saturated sodium bicarbonate solution were added, and the pH was adjusted to 6-7. After stirring for 1 hour, the chloroform layer was washed with water and then dehydrated with sodium sulfate. Then chloroform is distilled off under reduced pressure. Residue (27.77g yield 85.0
%) was recrystallized with chloroform to obtain the target substance 15.68
g (yield 48.0%). Melting point 138-140℃,
NV spectrum λmax (methanol) 220, 267n
m, λmax (0.01N NaOH) 224, 270nm, IR spectrum (cm -1 ) 3400, 3100, 2910, 1785,
1725, 1670, 1170, nmr spectrum (DMSO−
d 6 , PPm) 1.60 (S, 6H, 2CH 3 ) 7.20 (g,
J AB = 9, 4H, aromatic nucleus), 8.01 (d, J HF =
7, C 6 H) 11.10 (brs, 1H, NH), Elemental analysis value (%) Theoretical value C: 54.47, H: 3.70, N; 8.57 Actual value C: 51.59, H: 3.65, N; 8.43 Example 2 Production of Compound (b) Using phenoxyisobutyric acid, 23.6 g (80.75% yield) of the crude target substance was obtained in the same manner as in the case of Compound (a). Recrystallize from chloroform to obtain 12.61 g of purified product, yield 43.15%, melting point 127-129°C,
UV spectrum, IR spectrum, elemental analysis value (CH
N) to confirm that it is the target substance. Example 3 Production of compound (c) The crude target product was produced in the same manner as in the production of compound (a) using P-chlorophenoxyacetic acid.
19.6g (48.5%) was recrystallized from chloroform to obtain 10.32g of purified product. Yield 34.6%, melting point 165
~168℃. Example 4 Production of compound (d) 28.1 g (86.0%) of the crude target product was obtained in the same manner as in the case of compound (a) using O-chlorophenoxyisobutyric acid, and this was recrystallized from chloroform. hand
Obtain 16.3g of purified product, yield 50.0%, melting point 125~
127℃. Next, an experimental example for assaying the pharmacological effects of the compound of the present invention is shown below. Experimental example 1 Hydrophobicity of the compound of the present application
In order to see this, the partition coefficient between 1-octanol and physiological saline (maintained at pH 7.4 with 0.05M phosphate buffer) was determined by absorbance method and is shown in Table 1.
【表】
を示す。
これによれば本願化合物の分配係数は５−フル
オロウラシルよりいづれも大であり、特に化合物
(a)が最大である。
実験例 ２
急性毒性を検定のためLD50（経口）をマウス
を用い２週間の生存数より求める。[Table] is shown below.
According to this, the distribution coefficients of the present compound are all larger than those of 5-fluorouracil, and especially the compound
(a) is the maximum. Experimental Example 2 To test acute toxicity, LD 50 (oral) is determined from the number of mice that survive for 2 weeks.
【表】【table】
【表】
表２によれば５−フルオロウラシル化合物(a)及
び化合物(c)は毒性が弱いことが明らかである。
実験例 ３
本願化合物の制癌作用の検定のため、下記(イ)、
(ロ)、(ハ)、(ニ)をマウスあるいはラツトに移植して、
化合物(a)、(b)、(c)、(d)を夫々投与し延命効果を調
べる。投与量は腹腔内投与の場合、50mg／体重１
Kg／day、経口投与の場合100mg／体重１Kg／day
で、夫々５日間連続投与後村の生存日数を調べ
る。
(イ) 吉田肉腫
（雄性ラツト（Donryu）に１×106cell/mlを
腹腔内接種）[Table] According to Table 2, it is clear that 5-fluorouracil compound (a) and compound (c) have low toxicity. Experimental Example 3 To test the anticancer effect of the claimed compound, the following (a):
Transplant (b), (c), and (d) into mice or rats,
Compounds (a), (b), (c), and (d) are administered individually to examine their survival effects. The dose is 50 mg/body weight for intraperitoneal administration.
Kg/day, 100mg/body weight 1Kg/day for oral administration
Then, the number of days the villagers survived after 5 consecutive days of administration was determined. (b) Yoshida sarcoma (intraperitoneal inoculation of 1×10 6 cells/ml to male rats (Donryu))
【表】
化合物(a)〜(d)はいづれもフトラフールより有
効である。
(ロ) エーリツヒ膜水癌
（雄性マウス（I.C.R）に５×106cell／0.2ml
を腹腔内接種）[Table] Compounds (a) to (d) are all more effective than ftorafur. (b) Ehritzch membrane carcinoma (5×10 6 cells/0.2ml in male mice (ICR)
(intraperitoneal inoculation)
【表】【table】
【表】
(ハ) L1210 リンパ球白血病
（雄性マウス（C.D.F1）に１×105cell/mlを
腹腔内接種）[Table] (c) L1210 Lymphocytic leukemia (intraperitoneal inoculation of 1×10 5 cells/ml into male mice (CDF 1 ))
【表】
(ニ) P388 リンパ球白血病
（雌性マウス（B.D.F1）に１×106cell／0.1ml
を腹腔内接種）[Table] (d) P388 Lymphocytic leukemia (1×10 6 cells/0.1ml in female mice (BDF 1 )
(intraperitoneal inoculation)
【表】【table】
Claims (1)
わす。］ で示される５−フルオロウラシル誘導体。 ２ 一般式： ［式中、R1、R2はＨ又はCH3、ＹはＨ又はClを表
わす。］ で示される５−フルオロウラシル誘導体を有効成
分として含有する抗腫瘍剤。 ３ ５−フルオロウラシルをシリル化したのち、
一般式： ［式中、R1、R2はＨ又はCH3、ＹはＨ又はClを
夫々表わす。］ で示される化合物を反応させることを特徴とする
一般式： ［式中、R1、R2、Ｙは前記に同じ。］ で示される５−フルオロウラシル誘導体の製造方
法。[Claims] 1. General formula: [In the formula, R 1 and R 2 represent H or CH 3 , and Y represents H or Cl. ] A 5-fluorouracil derivative represented by the following. 2 General formula: [In the formula, R 1 and R 2 represent H or CH 3 , and Y represents H or Cl. ] An antitumor agent containing a 5-fluorouracil derivative shown as an active ingredient. 3 After silylating 5-fluorouracil,
General formula: [In the formula, R 1 and R 2 represent H or CH 3 , and Y represents H or Cl, respectively. ] A general formula characterized by reacting a compound represented by: [In the formula, R 1 , R 2 and Y are the same as above. ] A method for producing a 5-fluorouracil derivative shown in the following.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5847078A JPS54151988A (en) | 1978-05-17 | 1978-05-17 | 55fluorouracil derivative*its manufacture and antiitumor drug containing it |
| BE78190883A BE870982A (en) | 1978-05-17 | 1978-10-03 | 5-FLUOROURACIL DERIVATIVES, THEIR PREPARATION AND THEIR USE |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5847078A JPS54151988A (en) | 1978-05-17 | 1978-05-17 | 55fluorouracil derivative*its manufacture and antiitumor drug containing it |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS54151988A JPS54151988A (en) | 1979-11-29 |
| JPS6134428B2 true JPS6134428B2 (en) | 1986-08-07 |
Family
ID=13085309
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP5847078A Granted JPS54151988A (en) | 1978-05-17 | 1978-05-17 | 55fluorouracil derivative*its manufacture and antiitumor drug containing it |
Country Status (2)
| Country | Link |
|---|---|
| JP (1) | JPS54151988A (en) |
| BE (1) | BE870982A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5719132A (en) * | 1996-06-27 | 1998-02-17 | Bristol-Myers Squibb Company | Compositions and methods of treating HIV with d4T, 5-fluorouracil/tegafur, and uracil |
-
1978
- 1978-05-17 JP JP5847078A patent/JPS54151988A/en active Granted
- 1978-10-03 BE BE78190883A patent/BE870982A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| JPS54151988A (en) | 1979-11-29 |
| BE870982A (en) | 1979-02-01 |
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