JPS5849315A - Antitumor agent - Google Patents
Antitumor agentInfo
- Publication number
- JPS5849315A JPS5849315A JP14639381A JP14639381A JPS5849315A JP S5849315 A JPS5849315 A JP S5849315A JP 14639381 A JP14639381 A JP 14639381A JP 14639381 A JP14639381 A JP 14639381A JP S5849315 A JPS5849315 A JP S5849315A
- Authority
- JP
- Japan
- Prior art keywords
- fluoro
- deoxyuridine
- antitumor
- compound
- present
- 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.)
- Pending
Links
- 239000002246 antineoplastic agent Substances 0.000 title claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 34
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 3
- 125000001931 aliphatic group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 230000000259 anti-tumor effect Effects 0.000 abstract description 20
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 abstract description 14
- 230000000694 effects Effects 0.000 abstract description 11
- 208000007093 Leukemia L1210 Diseases 0.000 abstract description 5
- 230000001747 exhibiting effect Effects 0.000 abstract 2
- PPUUEVYUHGROKR-BEKQNFRLSA-N 5-fluoro-1-[(2r,4s,5r)-4-hexanoyl-4-hydroxy-5-(1-hydroxy-2-oxoheptyl)oxolan-2-yl]pyrimidine-2,4-dione Chemical compound C1[C@](C(=O)CCCCC)(O)[C@@H](C(O)C(=O)CCCCC)O[C@H]1N1C(=O)NC(=O)C(F)=C1 PPUUEVYUHGROKR-BEKQNFRLSA-N 0.000 abstract 1
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
- 206010028980 Neoplasm Diseases 0.000 description 9
- 239000008280 blood Substances 0.000 description 8
- 210000004369 blood Anatomy 0.000 description 8
- 210000004881 tumor cell Anatomy 0.000 description 8
- FHIDNBAQOFJWCA-UAKXSSHOSA-N 5-fluorouridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 FHIDNBAQOFJWCA-UAKXSSHOSA-N 0.000 description 7
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical group FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 230000004083 survival effect Effects 0.000 description 7
- 201000011510 cancer Diseases 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 5
- 229960002949 fluorouracil Drugs 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- MXHRCPNRJAMMIM-SHYZEUOFSA-N 2'-deoxyuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 MXHRCPNRJAMMIM-SHYZEUOFSA-N 0.000 description 3
- 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 3
- 241001465754 Metazoa Species 0.000 description 3
- 241001529936 Murinae Species 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- MXHRCPNRJAMMIM-UHFFFAOYSA-N desoxyuridine Natural products C1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 MXHRCPNRJAMMIM-UHFFFAOYSA-N 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- DNLLNUUNOCNDMT-VGBFSNKQSA-N 5-fluoro-1-[(2r,4s,5r)-4-hydroxy-5-[1-hydroxy-2-(2-methylphenyl)-2-oxoethyl]-4-(2-methylbenzoyl)oxolan-2-yl]pyrimidine-2,4-dione Chemical compound CC1=CC=CC=C1C(=O)C(O)[C@@H]1[C@@](C(=O)C=2C(=CC=CC=2)C)(O)C[C@H](N2C(NC(=O)C(F)=C2)=O)O1 DNLLNUUNOCNDMT-VGBFSNKQSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 239000001856 Ethyl cellulose Substances 0.000 description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 2
- 206010025323 Lymphomas Diseases 0.000 description 2
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 229940099112 cornstarch Drugs 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- -1 diesters Compounds Chemical class 0.000 description 2
- 238000001647 drug administration Methods 0.000 description 2
- 229920001249 ethyl cellulose Polymers 0.000 description 2
- 235000019325 ethyl cellulose Nutrition 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000007654 immersion Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- HMKVXSDEPPJDSX-GFSQRUHRSA-N 1-[(2r,4s,5r)-4-butanoyl-4-hydroxy-5-(1-hydroxy-2-oxopentyl)oxolan-2-yl]-5-fluoropyrimidine-2,4-dione Chemical compound C1[C@](C(=O)CCC)(O)[C@@H](C(O)C(=O)CCC)O[C@H]1N1C(=O)NC(=O)C(F)=C1 HMKVXSDEPPJDSX-GFSQRUHRSA-N 0.000 description 1
- TXWCDJYEKHLJSO-MYINAIGISA-N 1-[(2s,4s,5r)-2-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dione Chemical compound C1[C@H](O)[C@@H](CO)O[C@@]1(F)N1C(=O)NC(=O)C=C1 TXWCDJYEKHLJSO-MYINAIGISA-N 0.000 description 1
- 125000000242 4-chlorobenzoyl group Chemical group ClC1=CC=C(C(=O)*)C=C1 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- BKAYIFDRRZZKNF-VIFPVBQESA-N N-acetylcarnosine Chemical compound CC(=O)NCCC(=O)N[C@H](C(O)=O)CC1=CN=CN1 BKAYIFDRRZZKNF-VIFPVBQESA-N 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- GYOZYWVXFNDGLU-XLPZGREQSA-N dTMP Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)C1 GYOZYWVXFNDGLU-XLPZGREQSA-N 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000005917 in vivo anti-tumor Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 125000005425 toluyl group Chemical group 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 1
- 229940045145 uridine Drugs 0.000 description 1
Abstract
Description
【発明の詳細な説明】
本発明は抗腫瘍剤に関するものであり、本発明の目的は
、低用量で高い治療効果を発揮しかつ安全性の高い抗腫
瘍剤を提供することにある３、近年、臨床上汎用されて
いる抗腫瘍剤として、５−フルオロウラシル類があり、
その有効性に鑑みて新たに種々の５−フルオロウラシル
類が開発されつつある。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an antitumor agent, and an object of the present invention is to provide an antitumor agent that exhibits a high therapeutic effect at a low dose and is highly safe. There are 5-fluorouracils as antitumor agents that are widely used clinically.
In view of their effectiveness, various new 5-fluorouracils are being developed.
しかしながら、５−フルオロウラシル類を骨格とする化
合物を有効成分として含有する現存の抗腫瘍剤には、そ
れぞれ一長一短があり、効果が強いものの毒性及び副作
用が著しいもの、毒性及び副作用は比較的少ないが効果
が十分でないものなど様々で、さらにすぐれた５−フル
オロウラシル類の開発が待たされてる。However, existing antitumor agents containing compounds with 5-fluorouracil skeletons as active ingredients each have their own merits and demerits; some are highly effective but have significant toxicity and side effects; others have relatively little toxicity and side effects but are effective. There are various types of 5-fluorouracil that are not sufficient, and the development of even better 5-fluorouracils is awaited.
一方、５−フルオロウラシルの抗腫ｇ 作用の機序につ
いては、５−フルオロウラシルが生体内で５−フルオロ
ウリジン、さらには５−フルオロ−２′−デオキシウリ
ジン等の中間代謝物に変換され、究極的には、５−フル
オロ−２′−チオキシウリジンを介して生成される、５
−フルオＯ−２’−デオキシウリジンモノホスフェート
がチミジレートノンセターゼの強力な拮抗阻害剤として
作用するため、腫瘍細胞のデオキソリボ核酸の合成が阻
止され、効果が発現することが知られている。On the other hand, the mechanism of antitumor action of 5-fluorouracil is that 5-fluorouracil is converted in vivo to intermediate metabolites such as 5-fluorouridine and further to 5-fluoro-2'-deoxyuridine; is produced via 5-fluoro-2'-thioxyuridine, 5
-Fluo-O-2'-deoxyuridine monophosphate is known to act as a strong competitive inhibitor of thymidylate noncetase, thereby blocking the synthesis of deoxoribonucleic acid in tumor cells and exerting its effects. .
しだがって、５−フルオロウラシル類の新規な抗腫瘍剤
開発においては、上述の５−フルオロウラシルの中間代
謝物である５−フルオロウリジ／あるいは５−フルオロ
−２′−チオキシウリジンに着目し、これらの誘導体の
中から有用性を示す新規抗腫瘍剤を見い出そうとする研
究も活発に行われてきている。Therefore, in the development of new antitumor agents of the 5-fluorouracil class, we focused on 5-fluorouridine/or 5-fluoro-2'-thioxyuridine, which is an intermediate metabolite of 5-fluorouracil. Active research is being conducted to find new antitumor agents that are useful among the derivatives of .
％Ｋ、５−フルオロ−２１−デオキシウリジンに注目し
た研究では、５−フルオロ−２′−チオキシウリジンが
ｉｎ ｖｉｔｒｏ のマウス由来の樹立細胞株の増
殖阻害活性において、同一モル濃度で、５−フルオロウ
ラシルの１００倍以上の活性があること、また同様に５
−フルオロウリジンに対しても１０〜１００倍の活性を
有することが報告されている［ Ｃａｎｃｅｒ （ｐｈ
ｉｌａｄ、） 、 ３５＋１１２１（１９７５）＋
Ｐｒｏｃ、Ａｍｅｒ、 Ａｓｓ、 ＣａｎｃｅｒＲｅｓ
、、 ７１ （１９７６） 、 Ｊ、 Ｃｅ１１．Ｃ
ｏｍｐ、 ｐｈｙｓｉｏｌ。% K, a study focusing on 5-fluoro-21-deoxyuridine showed that 5-fluoro-2'-thioxyuridine had a higher growth inhibitory activity on established cell lines derived from mice in vitro than 5-fluoro-21-deoxyuridine at the same molar concentration. It has more than 100 times the activity of fluorouracil, and also has 5
- It has been reported that it has 10 to 100 times the activity against fluorouridine [Cancer (ph
ilad, ), 35+1121 (1975)+
Proc, Amer, Ass, CancerRes
,, 71 (1976), J. Ce11. C
omp, physiol.
６０ 、 Ｉ Ｏ９（］ ９６２ ） ＋ Ｃａｎｃ
ｅｒ Ｒｅ５ｅａｒｃｈ ］ ８ 。60, IO9(] 962) + Canc
er Research] 8.
７３０（１９５８））。730 (1958)).
しかしながら、担癌動物を用いた ｉｎ ｖｉｖ。However, in vivo using tumor-bearing animals.
の抗腫瘍効果に関する研究では、５−フルオロ−２１−
デオキシウリジンは ｉｎ ｖｉｔｒｏの結果とハ逆に
、５−フルオロウラツルおよび５−フルオロウリジンの
いずれに対しても投与した］［１癌動物の延命効果にお
いて明らかに劣ることが報告されている［ Ｃａｎｃｅ
ｒ Ｒｅ５ｅａｒｃｈ、 １９ 、４９４（１９５９）
＋ Ｐｒｏｃ、 Ｓｏｃ、 Ｅｘｐ、Ｂｉａｓ、
Ｎ、Ｙ。In a study on the antitumor effect of 5-fluoro-21-
Contrary to the in vitro results, deoxyuridine was administered to both 5-fluorouratur and 5-fluorouridine] [1] It has been reported that it is clearly inferior in survival effect in animals with cancer.
r Research, 19, 494 (1959)
+ Proc, Soc, Exp, Bias,
N.Y.
９７ ＋４７０（１９５Ｂ）、 Ｐｒｏｃ、 Ｓｏｃ、
Ｅｘｐ、Ｂｉｏｌ。97 +470 (195B), Proc, Soc,
Exp, Biol.
Ｎ、Ｙ、、 １’０４，１２７（１９６０）、 、Ａ
ｎｎ、 Ｎ、Ｙ、 Ａｃａｄ。N, Y, 1'04, 127 (1960), ,A
nn, N, Y, Acad.
Ｓｃｉ、、７６．５７５（１９５８）］。Sci., 76.575 (1958)].
また、上述の ｉｌ ｖｉｖｏ の抗腫瘍効果を一部
裏付ける知見として、５−フルオロ−２′−チオキシウ
リジンは、ヒトおよびマウスに投与した場合、血中濃度
の半減期が著しく短いこともよく知られているＣ Ｂｕ
ｌｌ、Ｃａｎｃｅｒ （Ｐａｒｉｓ ） 。Additionally, it is well known that 5-fluoro-2'-thioxyuridine has an extremely short half-life in the blood when administered to humans and mice, which partially supports the above-mentioned il vivo antitumor effect. C Bu
ll, Cancer (Paris).
６６．６７（１９７９）＋ Ｃａｎｃｅｒ Ｒｅ５ｅａ
ｒｃｈ、 ３２ｅ１０４５（１９７２） 、 Ｃ１ｊｎ
、 Ｐｈａｒｍａｃｏ】、Ｔｈｅｒ、。66.67 (1979) + Cancer Re5ea
rch, 32e1045 (1972), C1jn
, Pharmaco], Ther.
５．５８１（１９６４）、 Ｂｕｌｌ Ｃａｎｃｅｒ（
Ｐａｒｉｓ ）ｐ６６ 、７５（１９７９） ＋ Ｃａ
ｎｃｅｒ Ｒｅ５ｅａｒｃｈ、 ３８ 。5.581 (1964), Bull Cancer (
Paris) p66, 75 (1979) + Ca
ncer Research, 38.
３４７９（１９７８）：］。3479 (1978): ].
ところで、本発明者らは最近、５−フルオロ−２′−デ
オキシウリジンの腫瘍細胞に対する作用態度を明らかに
するため、マウスリンパ腫細胞を用いて５−フルオロウ
リジンと比較する形で詳細な検討を行った。By the way, the present inventors have recently conducted a detailed study comparing 5-fluoro-2'-deoxyuridine with 5-fluorouridine using mouse lymphoma cells in order to clarify the action of 5-fluoro-2'-deoxyuridine on tumor cells. Ta.
その結果、ｉｎ ｖｉｔｒｏ において５−フルオロ
−２′−チオキシウリジンで長時間にわたって持続浸漬
処理（１５時間以上）された腫瘍細胞は５−フルオロウ
リジンの％という低濃度で増殖が阻止されるが、短時間
の浸漬処理（１時間）では逆に５−フルオロ−２′−デ
オキシウリジンは細胞増殖を阻止するために５−フルオ
ロウリジンより１６倍高い濃度を要す、るという事実を
見い出し、５−フルオロ−２′−チオキシウリジンの抗
腫瘍効果は腫瘍細胞への５−フルオロ−２′−デオキシ
ウリジンの浸漬処理時間に大きく依存すること、またそ
れ故５−フルオロー２′−デオキシウリジンに担癌生体
における体内貯留時間が長くなるような性質を飼与する
ことが出来れば ｉｎ ｖｉｖｏ の抗腫瘍効果が著
しく増大する可能性が示唆された（ Ｅｕｒｏｐ、Ｊ、
Ｃａｎｃｅｒ１６．１０８７（１９８０）：］。As a result, tumor cells treated with 5-fluoro-2'-thioxyuridine for a long period of time (more than 15 hours) in vitro were inhibited from growing at a low concentration of 5-fluorouridine of %. We discovered that in short-time immersion treatment (1 hour), 5-fluoro-2'-deoxyuridine requires a concentration 16 times higher than that of 5-fluorouridine to inhibit cell proliferation. The antitumor effect of fluoro-2'-thioxyuridine is highly dependent on the immersion treatment time of 5-fluoro-2'-deoxyuridine into tumor cells, and therefore, the antitumor effect of 5-fluoro-2'-deoxyuridine on 5-fluoro-2'-deoxyuridine is highly dependent on the treatment time. It has been suggested that in vivo antitumor effects may be significantly increased if the animal is given a property that increases its retention time in the body (Europ, J.
Cancer 16.1087 (1980): ].
］
上こで、本発明者らは上述の知見に基づいて、体内貯留
性にすぐれ、かつ高い抗腫瘍活性と安全性を有する５−
フルオロ−２７−チオキシウリジンの誘導体を得るべく
、５−フルオロ−２７−チオキシウリジンの３′および
５′部位をエステル化したマスク型化合物について鋭意
検索した結果、本発明の化合物が著しく低用量で高水準
の抗腫瘍効果を示し、かつ安全係数が犬で、抗腫瘍効果
を裏付ける血中濃度め持続性も良好であることを見い出
し、本発明を完成するに至った。] Based on the above-mentioned findings, the present inventors have found that 5-5 has excellent retention in the body, high antitumor activity, and safety.
In order to obtain derivatives of fluoro-27-thioxyuridine, we conducted extensive searches for mask-type compounds in which the 3' and 5' sites of 5-fluoro-27-thioxyuridine were esterified. The present inventors have completed the present invention by discovering that it shows a high level of antitumor effect in dogs, has a safety factor, and has good persistence in blood concentration that supports the antitumor effect.
すなりち、本発明は一般式
Ｏ
（但し、式中Ｒ１、Ｒ２は同一または異なってよい、Ｒ
は炭素数６個以上からなる脂肪族アシル基又は芳香族ア
シル基を表わす。）
で示される化合物を有効成分として含有することを特徴
とする抗腫瘍剤にかかわる。Therefore, the present invention relates to the general formula O (wherein R1 and R2 may be the same or different, R
represents an aliphatic acyl group or an aromatic acyl group having 6 or more carbon atoms. ) It relates to an antitumor agent characterized by containing the compound shown in the following as an active ingredient.
さらには、上述の一般式Ｃ１） で示され、かつマウ
ス白血病Ｌ−１２１０に対して５−フルオロ−２１−デ
オキシウリジンの１０倍乃至１００倍以上の抗腫瘍効果
を有する５−フルオロ−２′−デオキシウリジンの３／
、５／−ジエステル類から選ばれた化合物を有効成分と
して含有するととを特徴とする抗腫瘍剤に関する１゜
本発明の化合物は著しく低用量で高水準のｊγ１゜腫瘍
作用を示す有用な医薬化合物であり、−１二述の一般式
（１） で示される化合物であって、例工ば一般式Ｃ
１３においてＲがヘキサノイル基、バルミトイル基、ベ
ンゾイル基、トルオイル基およびパラクロロベンゾイル
基等である化合物があげられる。Furthermore, 5-fluoro-2'- is represented by the general formula C1) and has an antitumor effect 10 to 100 times more than 5-fluoro-21-deoxyuridine against murine leukemia L-1210. Deoxyuridine 3/
The compound of the present invention is a useful pharmaceutical compound that exhibits a high level of jγ1° tumor activity at a significantly low dose. -1 is a compound represented by the general formula (1) described above, and for example, the general formula C
Examples include compounds in which R in 13 is a hexanoyl group, a valmitoyl group, a benzoyl group, a toluoyl group, a parachlorobenzoyl group, or the like.
本発明化合物の具体例としては ３／、５７−ジヘキサ
ノイルー５−フルオロ−２′−デオキシウリジン、３′
、５′−ジパルミトイル−５−フルオロ−２′−チオキ
シウリジン ３′、５Ｉ−ジベンゾイル−５−フルオロ
−２′−チオキシウリジンおヨヒ３′、５′−ジクロロ
ベンゾイル−５−フルオロ−２′−チオキシウリジンな
どがある。。Specific examples of the compounds of the present invention include 3/, 57-dihexanoyl-5-fluoro-2'-deoxyuridine, 3'
, 5'-dipalmitoyl-5-fluoro-2'-thioxyuridine 3', 5I-dibenzoyl-5-fluoro-2'-thioxyuridine and 3', 5'-dichlorobenzoyl-5-fluoro-2 '-thioxyuridine, etc. .
本発明によれば、一般式〔１〕 で示される化合物は、
抗腫瘍効果をマウス白血病Ｌ−１２１０を移植した担癌
マウスの延命効果で調べると、５−フルオロ−２′−チ
オキシウリジンあるい（・１−炭素数６個未満の脂肪族
アシル基３′および５′部を
位に導入した５−フルオロ−２′−デオキシウリジンの
３／、５／−ジエステル類が抗腫瘍効果を示す用量の１
／１ｏ〜１／１００ という極めて低用量で、強い延
命効果を示すばかりでなく、安全係数も高く、かつ投与
時の体内持続性も顕著にすぐれていることが示される。According to the present invention, the compound represented by the general formula [1] is
When the antitumor effect was examined by the survival effect of tumor-bearing mice transplanted with murine leukemia L-1210, it was found that 5-fluoro-2'-thioxyuridine or and 1 of the dose at which 3/, 5/-diesters of 5-fluoro-2'-deoxyuridine introduced at the 5' position exhibit antitumor effects.
It has been shown that at an extremely low dose of 1/1 to 1/100, it not only shows a strong survival effect, but also has a high safety factor and is extremely durable in the body upon administration.
例えば、３′、５′−ジパルミトイル−５−フルオロ−
２／−デオキシウリジンおよヒ３′、５′−ジトルオイ
ルー５−フルオロ−２′−デオキシウリジンは、マウス
白血病Ｌ−１２１０を移植した担癌マウスの延命日数を
３０％増加させるに要する投与量（ｉｔ’５ｓｏ）が同
じ延命効果を示す５−フルオロ−２／−デオキシウリジ
ンの１／１００ 以下（それぞれ０．４５．０．３７
ｑ／に９／ 日） ト極めて低用量でよく、また最大
延命効果を示すのに要する投与量（ＩＬＳｍａｘ）が５
−フルオロ−２′−デオキシウリジンの１／３ｏ以下の
量と少ない。For example, 3',5'-dipalmitoyl-5-fluoro-
2/-deoxyuridine and 3',5'-ditoluoyl-5-fluoro-2'-deoxyuridine were administered at a dose ( it'5so) is less than 1/100 of 5-fluoro-2/-deoxyuridine (0.45 and 0.37, respectively), which has the same life-prolonging effect.
q/9/day) can be administered at extremely low doses, and the dose required to show the maximum survival effect (ILSmax) is 5
-The amount is small, less than 1/3 of that of fluoro-2'-deoxyuridine.
さらに、Ｉ ＬＳ ｍａｘ／ Ｉ ＬＳ８０で示される
治験係数が親化合物である５−フルオロ−２′−チオキ
シウリジンのそれぞれ３．３倍、４倍と安全性も高い０
また、５−フルオロ−２′−デオキシウリジンが５分程
度の血中半減期をもって、著しく早期に血中より清適す
るのに対して、両化合物は投与後の血中濃度においても
、腫瘍細胞の増殖を阻止するに足る５−フルオロ−２７
−ジオキシウリジン活性濃度を４８時間以上持続すると
いう特徴が見い出されておシ、両化合物の高い抗腫瘍効
果を裏付けている。Furthermore, the clinical trial index indicated by I LS max / I LS 80 is 3.3 times and 4 times that of the parent compound, 5-fluoro-2'-thioxyuridine, respectively, making it highly safe. '-Deoxyuridine has a blood half-life of about 5 minutes and is cleared from the blood extremely quickly, whereas both compounds have a blood concentration of 5 minutes that is sufficient to inhibit tumor cell proliferation even after administration. -Fluoro-27
- It has been found that the active concentration of dioxyuridine is sustained for more than 48 hours, supporting the high antitumor effects of both compounds.
なお、本発明の化合物には公知化合物が含１れている。Note that the compounds of the present invention include one known compound.
例えば ３／、５７−ジヘキサノイルー５−フルオロ−
２１−デオキシウリジン ３１ 、５′−ジパルミトイ
ル−５−フルオロ−２′−デオキシウリジン ａ／、Ｓ
／−ジベンゾイル−５−フルオロ−２′−デオキシウリ
ジンは、バイオケミカル、ファーマコロジー、第１４巻
、１６０５頁。For example, 3/, 57-dihexanoyl-5-fluoro-
21-deoxyuridine 31, 5'-dipalmitoyl-5-fluoro-2'-deoxyuridine a/, S
/-dibenzoyl-5-fluoro-2'-deoxyuridine, Biochemical, Pharmacology, Vol. 14, p. 1605.
１９６５年 に抗腫瘍活性を有することが示されている
が、上述の報告によればこれらの化合物はいずれも親化
合物の５−フルオロ−２′−テオキノウリジンが抗腫瘍
効果を示す１０〜４０■／に９ ／日の投与量の範囲で
活性測定を試みているた・′すで、５−フルオロ−２１
−チオキシウリジンに比べて有意に高水準の抗腫瘍効果
を有する有用性の高いものであることを見い出すには至
っていない。In 1965, it was shown to have antitumor activity; however, according to the above-mentioned report, all of these compounds have 10 to 40 5-Fluoro-21
- It has not yet been found that it is highly useful and has a significantly higher level of antitumor effect than thioxyuridine.
本発明の化合物はいずれも本発明者らによってはじめて
上述の如く低用量で高度の有用性を示すことが見い出さ
れ、医薬としての適用価値があることがわかった。It was discovered for the first time by the present inventors that all of the compounds of the present invention exhibit a high degree of usefulness at low doses as described above, and have been found to be valuable as medicines.
本発明の化合物は、例えば、バイオケミ力ルファーマコ
ロジー、第１４巻＃ １６０５頁。The compounds of the present invention can be used, for example, in Biochemistry Pharmacology, Vol. 14, page #1605.
１９６５年に示されている如く、いずれも公知の方法で
容易に合成することが出来る。かぐして得られる本発明
の化合物は医薬として適用する場合には経口もしくは非
経口的に投与することが出来る。経口投与の場合には、
例えば、錠剤、散剤、カプセル、顆粒剤等とすることが
出来、また非経口的に投与する場合には、例えば、注射
用製剤もしくは坐剤として適用することが出来る。また
、製剤化にあたっては本発明の化合物を２種以上配合さ
せることも可能であり、投与にあたって、本発明の化合
物を１種のみ単用あるいは２種以上を適宜選んで併用投
与することも出来る。As shown in 1965, all of them can be easily synthesized by known methods. When the compound of the present invention obtained by sniffing is used as a medicine, it can be administered orally or parenterally. For oral administration,
For example, it can be made into tablets, powders, capsules, granules, etc., and when administered parenterally, it can be applied, for example, as an injection preparation or a suppository. Furthermore, in formulating a formulation, it is possible to combine two or more compounds of the present invention, and in administering, one compound of the present invention can be used alone, or two or more compounds can be appropriately selected and administered in combination.
か＼る種類の投与剤型の中に配合させる本発明の化合物
の量は ３／、５７部位のエステルの種類に応じて特性
が異なるので、特に限定することが出来ないが、臨床用
量は１人１日当り０ 、３〜５００■の範囲が望ましい
。The amount of the compound of the present invention to be incorporated into these types of dosage forms cannot be particularly limited since the properties differ depending on the type of ester at the 3/57 site, but the clinical dose is 1. A range of 0.3 to 500 cm per person per day is desirable.
以下に実験例、実施例をもって、本発明の内容を具体的
に説明する。The content of the present invention will be specifically explained below using experimental examples and examples.
実験例１
５−フルオロ−２′−デオキシウリジンの３′、５′−
ジエステル類の抗腫瘍活性
本発明の化合物３’、、５’−ヘキサノイル−５−フル
オロ−２′−デオキシウリジン ３／、５′−ジパルミ
トイル−５−フルオロ−２′−チオキシウリジン ３１
，５／−ジベンゾイル−５−フルオロ−２１−デオキシ
ウリジン ３／、 ５／ −シト及オイル−５−フルオ
ロ−２′−デオキシウリジンおよび３’、 ５’−ジク
ロロベンゾイル−５−フルオロ−２′ニデオキシウリジ
ンについて、マウス白血病Ｌ−１２１０に対する抗腫瘍
効果を鋭化合物の５−フルオロ−２／−デオキシウリジ
ンおよび炭素数６個未満の脂肪族アシル基を配した３′
、５′−ジアセチル−５−フルオロ−２ノーデオキシウ
リジン ３／、 ５７−ジプロビニルー５−フルオロ−
２′−デオキシウリジン、３’、５’−ジブチリル−５
−フルオロ−２′−デオキシウリジンと比較した。Experimental Example 1 3', 5'- of 5-fluoro-2'-deoxyuridine
Antitumor activity of diesters Compounds of the present invention 3', 5'-hexanoyl-5-fluoro-2'-deoxyuridine 3/, 5'-dipalmitoyl-5-fluoro-2'-thioxyuridine 31
, 5/-dibenzoyl-5-fluoro-21-deoxyuridine 3/, 5/-cyto-5-fluoro-2'-deoxyuridine and 3', 5'-dichlorobenzoyl-5-fluoro-2'-di Regarding deoxyuridine, the antitumor effect against murine leukemia L-1210 was demonstrated using the acute compound 5-fluoro-2/-deoxyuridine and the 3'
, 5'-diacetyl-5-fluoro-2-nodeoxyuridine 3/, 57-diprovinyl-5-fluoro-
2'-deoxyuridine, 3',5'-dibutyryl-5
-fluoro-2'-deoxyuridine.
移植７１目のマウス白血病Ｌ−１２１０腹水腫瘍細胞１
０５個をＢＤＦ、マウ・ス（♂１９〜２２Ｉ、１群：６
匹）の腹腔内に移植し、実験に供した。Mouse leukemia L-1210 ascites tumor cells 1 at 71st transplantation
05 to BDF, mouse (♂19-22I, group 1: 6
It was transplanted into the abdominal cavity of a mouse and used for experiments.
腫瘍細胞移植２４時間後より、１日１回５日間薬剤を連
続膜腔内投与した。Starting 24 hours after tumor cell implantation, the drug was continuously administered intramembraneally once a day for 5 days.
薬剤の抗腫瘍効果は、薬剤投与群の生存期間を対照群（
薬剤無投与）のそれに対する増加割合で示した。The antitumor effect of a drug is determined by comparing the survival period of the drug administration group with that of the control group (
It is expressed as an increase percentage compared to that of (no drug administration).
すなわち、対照群に比し３０％生存期間を延長させるに
要する薬剤投与量をＩＬＳｓｏとし、最大延命率（Ｍａ
ｘ、 ＩＬＳ（％） ）を示すに要する投与量をＩＬＳ
ｍａｘ、とじて表わした。またＩ Ｌ Ｓ ｍａｘ、／
Ｉ Ｌ ８Ｂｇ を治療係数としてその薬剤の安全性
を示す指標とした。In other words, the drug dose required to extend the survival period by 30% compared to the control group is defined as ILSso, and the maximum survival rate (Ma
x, ILS (%))
It is expressed as max. Also, I L S max, /
I L 8Bg was used as a therapeutic index and an index indicating the safety of the drug.
結果は表１の通りである。The results are shown in Table 1.
本発明の化合物はいずれも、５−フルオロ−２′−デオ
キシウリジンの１／１ｏ乃至’／１００という極めて低
用量で高い抗腫瘍効果を示し、また安全性もすぐれてい
た。All of the compounds of the present invention exhibited high antitumor effects at extremely low doses of 1/1 to 1/100 of 5-fluoro-2'-deoxyuridine, and were also highly safe.
実験例２
５−フルオロ−２′−デオキシウリジンの３′、５′−
ジエステル類の血中濃度動態
本発明の化合物３′、５／−ジヘキザノイルー５−フル
オロ−２′−デオキシウリジン、３′。Experimental Example 2 3', 5'- of 5-fluoro-2'-deoxyuridine
Blood concentration dynamics of diesters Compound 3', 5/-dihexanoyl-5-fluoro-2'-deoxyuridine, 3' of the present invention.
５′−ジパルミトイル−５−フルオロ−２７−デオキシ
ウリジンおよび３’、 ５’−ジトルオイルー５−フル
オロ−２′−デオキシウリジンについて、マウスにおけ
る血中濃度動態を５−フルオロ−２′−デオキシウリジ
ンおよび３１．５１−ジアセチル−５−フルオロ−２′
−テオキ／つ、リジンと比較した。Blood concentration dynamics in mice for 5'-dipalmitoyl-5-fluoro-27-deoxyuridine and 3',5'-ditoluoyl-5-fluoro-2'-deoxyuridine were investigated. 31.51-Diacetyl-5-fluoro-2'
- Teoki/tsu, compared with lysine.
薬剤は生理食塩水に溶解し、ＢＤＦ、マウスに４０μＭ
／Ｋｐ（５−フルオロ−２′−デオギ／ウリジン当量換
算）の投与量で腹腔内投与し、投与後１５分、３０分、
６０分および２、：３．１２．４．８時間に採血した。The drug was dissolved in physiological saline, BDF, 40 μM in mice.
/Kp (5-fluoro-2'-deogy/uridine equivalent) was administered intraperitoneally, 15 minutes, 30 minutes after administration,
Blood was drawn at 60 minutes and 2:3.12.4.8 hours.
、得られた血漿中の５−フルオロ−２′−デオキンウリ
ジノ活１／１濃度は ｉｎ ｖｉｔｒｏのマウスリンパ
腫Ｌ −５１７８Ｙ細胞の増殖阻害割合によりバイオア
ッセイした１゜
結果は表２に示す通シである。The 1/1 concentration of 5-fluoro-2'-deoquinuridino activity in the obtained plasma was bioassayed by the growth inhibition rate of mouse lymphoma L-5178Y cells in vitro.The results are shown in Table 2. .
本発明の化合物はいずれも腫瘍細胞に対しテ増殖阻害を
示すに足る５−フルオロ−２′−デオキシウリジン活性
濃度を著しく長時間維持した。All of the compounds of the present invention maintained a concentration of 5-fluoro-2'-deoxyuridine activity sufficient to inhibit the growth of tumor cells for an extremely long time.
つぎに本発明の抗腫瘍剤の処方を実施例で示す０
実施例１ 錠 剤
本発明の化合物 ５０
■乳 糖
５０ｑｌコーンスターチ
３０■エチルセルロース
１０■力ルボキシメチルセルロース力ルンウム
５７〜ステアリン酸マグネンウム
３■計 ２０
０■本錠剤は通常行われるフィルムコーティングを行っ
ても差支えなく、さらに糖衣を行うこともできる。Next, the formulation of the antitumor agent of the present invention will be shown in Examples 0 Example 1 Tablet Compound of the present invention 50
■Lactose
50ql cornstarch
30 ■ Ethyl cellulose
10 ■ Ruboxymethyl cellulose
57 ~ Magnenium stearate
3■Total 20
0■ This tablet can be subjected to the usual film coating, and can also be sugar-coated.
実施例２ カプセル剤
本発明の化合物 １０（
Ｉ＋７乳 糖
９７ｍｇ結晶セルロース
５０ｍｇステアリン酸マグネシウム
３〜実施例３ 顆粒剤
本発明の化合物 ５０
ｍｆ／乳 糖
５８７〜エチルセルロース
１０ｍ９コーンスターチ
２５（］ｍｇカルホキンメチルセルロース力ル／ウム
１００ｍｇ００ｍｇステアリン酸マグネシウム
３ｑ計
１．００（１１ｇ実施例４ 注射剤
本発明の化合物の水溶液（ｐＨ６，０〜７．５）で１ｍ
７！に本発明の化合物０．３〜゛〜１００■を含む。Example 2 Capsule Compound of the Invention 10 (
I+7 lactose
97mg crystalline cellulose
50mg magnesium stearate
3 to Example 3 Granule Compound of the Invention 50
mf/lactose
587 ~ Ethylcellulose
10m9 cornstarch
25(]mg Calfoquine Methylcellulose 1/Um 100mg00mg Magnesium Stearate 3q Total
1.00 (11 g Example 4 Injection) 1 m with an aqueous solution (pH 6.0 to 7.5) of the compound of the present invention
7! contains 0.3 to 100 μ of the compound of the present invention.
特許出願人 三井製薬工業株式会社patent applicant Mitsui Pharmaceutical Industries, Ltd.
Claims (1)
炭素数６個以上からなる脂肪族アシル基又は芳香族アシ
ル基を表わす。） で示すれる５−フルオロ−２７−デオキシウリジンの３
′、５′−ジエステル類から選ばれる化合物を有効成分
として含有することを特徴とする抗腫瘍剤。[Claims] General formula % formula % (wherein R1% and R2 may be the same or different,
Represents an aliphatic acyl group or an aromatic acyl group having 6 or more carbon atoms. ) 3 of 5-fluoro-27-deoxyuridine represented by
An antitumor agent characterized by containing a compound selected from ',5'-diesters as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP14639381A JPS5849315A (en) | 1981-09-18 | 1981-09-18 | Antitumor agent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP14639381A JPS5849315A (en) | 1981-09-18 | 1981-09-18 | Antitumor agent |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS5849315A true JPS5849315A (en) | 1983-03-23 |
Family
ID=15406679
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP14639381A Pending JPS5849315A (en) | 1981-09-18 | 1981-09-18 | Antitumor agent |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5849315A (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1985000608A1 (en) * | 1983-07-20 | 1985-02-14 | Teijin Limited | Antineoplastic agent |
| JPS61189215A (en) * | 1985-02-18 | 1986-08-22 | Teijin Ltd | Oily pharmaceutical composition of 5-fluoro-2'-deoxyuridine ester |
| JPS63196519A (en) * | 1987-02-12 | 1988-08-15 | Mitsui Toatsu Chem Inc | Carcinostatic agent |
| US5013828A (en) * | 1988-04-21 | 1991-05-07 | Central Glass Company, Limited | Preparation of diacyl derivatives of 2'-deoxy-5-fluorouridine via novel intermediate compound |
| US5470838A (en) * | 1987-10-28 | 1995-11-28 | Pro-Neuron, Inc. | Method of delivering exogenous uridine or cytidine using acylated uridine or cytidine |
| US5583117A (en) * | 1987-10-28 | 1996-12-10 | Pro-Neuron, Inc. | Acylated uridine and cytidine for elevating tissue uridine and cytidine |
| US6020320A (en) * | 1987-10-28 | 2000-02-01 | Pro-Neuron, Inc. | Acyl deoxyribonucleoside derivatives and uses thereof |
| US7169765B1 (en) | 1988-10-27 | 2007-01-30 | Wellstat Therapeutics Corporation | Acyl deoxyribonucleoside derivatives and uses thereof |
-
1981
- 1981-09-18 JP JP14639381A patent/JPS5849315A/en active Pending
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1985000608A1 (en) * | 1983-07-20 | 1985-02-14 | Teijin Limited | Antineoplastic agent |
| JPH0434964B2 (en) * | 1985-02-18 | 1992-06-09 | Teijin Ltd | |
| JPS61189215A (en) * | 1985-02-18 | 1986-08-22 | Teijin Ltd | Oily pharmaceutical composition of 5-fluoro-2'-deoxyuridine ester |
| EP0214299A1 (en) * | 1985-02-18 | 1987-03-18 | Teijin Limited | Preparation of 5-fluoro-2'-deoxyuridine esters for intraarterial administration |
| US4943564A (en) * | 1985-02-18 | 1990-07-24 | Teijin Limited | Intraarterial injection pharmaceuticals of 5-fluoro-2'-deoxyuridine esters |
| JPS63196519A (en) * | 1987-02-12 | 1988-08-15 | Mitsui Toatsu Chem Inc | Carcinostatic agent |
| US5470838A (en) * | 1987-10-28 | 1995-11-28 | Pro-Neuron, Inc. | Method of delivering exogenous uridine or cytidine using acylated uridine or cytidine |
| US5583117A (en) * | 1987-10-28 | 1996-12-10 | Pro-Neuron, Inc. | Acylated uridine and cytidine for elevating tissue uridine and cytidine |
| US6020320A (en) * | 1987-10-28 | 2000-02-01 | Pro-Neuron, Inc. | Acyl deoxyribonucleoside derivatives and uses thereof |
| US6258795B1 (en) | 1987-10-28 | 2001-07-10 | Pro-Neuron, Inc. | Acylated uridine and cytidine and uses thereof |
| US6274563B1 (en) | 1987-10-28 | 2001-08-14 | Pro-Neuron, Inc. | Acylated uridine and cytidine and uses thereof |
| US6316426B1 (en) | 1987-10-28 | 2001-11-13 | Pro-Neuron, Inc. | Acylated uridine and cytidine and uses thereof |
| US5013828A (en) * | 1988-04-21 | 1991-05-07 | Central Glass Company, Limited | Preparation of diacyl derivatives of 2'-deoxy-5-fluorouridine via novel intermediate compound |
| US7169765B1 (en) | 1988-10-27 | 2007-01-30 | Wellstat Therapeutics Corporation | Acyl deoxyribonucleoside derivatives and uses thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU618997B2 (en) | Pharmaceutical compositions with anti-cancer activity and method for the treatment of cancer | |
| EP0491018A1 (en) | Use of taurolidine and/or taurultam for the treatment of tumours | |
| US4328229A (en) | Anti-cancer composition for delivering 5-fluorouracil to cancer tissues | |
| JPS5849315A (en) | Antitumor agent | |
| JPH07505380A (en) | Melamine derivatives for use in cancer treatment | |
| US4914105A (en) | Anti-cancer compositions for delivering 5-fluorouracil | |
| Lynch et al. | Treatment of mouse neoplasms with high doses of tubercidin | |
| US6071888A (en) | Composition for treating cancer | |
| AU732120B2 (en) | Pyrimidine nucleotide precursors for treatment of systemic inflammation and inflammatory hepatitis | |
| US4652570A (en) | Anti-cancer composition for delivering 5-fluorouracil | |
| JP2002515892A (en) | Treatment of cytokine-related diseases | |
| KR20050106119A (en) | Antitumor effect potentiator and antitumor agent | |
| NL194430C (en) | Non-injectable pharmaceutical preparation with anti-cancer effect. | |
| JPH02218689A (en) | Adenosine derivative,and its manufacture and use | |
| NZ266359A (en) | Use of tiazofurin and ribavirin to prepare medicament for treatment of neoplastic disease | |
| US3169091A (en) | Process for inhibiting tumors with substituted pyrazoles | |
| JPS6337767B2 (en) | ||
| JPH06503084A (en) | Aromatic aldehydes and their derivatives and their pharmaceutical compositions useful in the treatment of skin diseases and arthritis | |
| JPH0120128B2 (en) | ||
| EP1421942A1 (en) | Use of glycyrrhizin and its derivatives as RANTES inducers | |
| JP2836797B2 (en) | Thrombocytopenia and / or leukopenia treatment agent | |
| JP2848634B2 (en) | Drugs with immunosuppressive action | |
| JPS61129124A (en) | Antitumor agent | |
| KR20030055878A (en) | Radiosensitizer containing ceramides or derivatives thereof and dimethylsphingosine as the active ingredient | |
| JP3845307B2 (en) | Myocardial infarction treatment |