JPH01261396A - 5-substituted-2'-deoxyuridines - Google Patents
5-substituted-2'-deoxyuridinesInfo
- Publication number
- JPH01261396A JPH01261396A JP9076888A JP9076888A JPH01261396A JP H01261396 A JPH01261396 A JP H01261396A JP 9076888 A JP9076888 A JP 9076888A JP 9076888 A JP9076888 A JP 9076888A JP H01261396 A JPH01261396 A JP H01261396A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- trifluoromethyl
- formula
- group
- deoxyuridine
- 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.)
- Granted
Links
- -1 5-substituted-2'-deoxyuridines Chemical class 0.000 title claims description 9
- 125000002252 acyl group Chemical group 0.000 claims abstract description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 8
- 125000001797 benzyl group Chemical class [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 3
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 19
- 239000003443 antiviral agent Substances 0.000 abstract description 4
- 229910019142 PO4 Inorganic materials 0.000 abstract description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 abstract description 3
- 239000010452 phosphate Substances 0.000 abstract description 3
- 239000002253 acid Substances 0.000 abstract description 2
- 239000003699 antiulcer agent Substances 0.000 abstract 1
- ITVPBBDAZKBMRP-UHFFFAOYSA-N chloro-dioxido-oxo-$l^{5}-phosphane;hydron Chemical class OP(O)(Cl)=O ITVPBBDAZKBMRP-UHFFFAOYSA-N 0.000 abstract 1
- 239000011630 iodine Substances 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 abstract 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 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
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- AYJRCSIUFZENHW-UHFFFAOYSA-L barium carbonate Chemical compound [Ba+2].[O-]C([O-])=O AYJRCSIUFZENHW-UHFFFAOYSA-L 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 2
- 238000005947 deacylation reaction Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- ULWOJODHECIZAU-UHFFFAOYSA-N n,n-diethylpropan-2-amine Chemical compound CCN(CC)C(C)C ULWOJODHECIZAU-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 125000005270 trialkylamine group Chemical group 0.000 description 2
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- PMGATFZDMDTJKE-UHFFFAOYSA-N 1-chloro-4-[chloro-(4-chlorophenoxy)phosphoryl]oxybenzene Chemical compound C1=CC(Cl)=CC=C1OP(Cl)(=O)OC1=CC=C(Cl)C=C1 PMGATFZDMDTJKE-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 108010022394 Threonine synthase Proteins 0.000 description 1
- 102000005497 Thymidylate Synthase Human genes 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- AYJRCSIUFZENHW-DEQYMQKBSA-L barium(2+);oxomethanediolate Chemical compound [Ba+2].[O-][14C]([O-])=O AYJRCSIUFZENHW-DEQYMQKBSA-L 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960004716 idoxuridine Drugs 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- VSQQQLOSPVPRAZ-RRKCRQDMSA-N trifluridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C(F)(F)F)=C1 VSQQQLOSPVPRAZ-RRKCRQDMSA-N 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Landscapes
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
産業上の利用分野
本発明は、新規な物質である５−置換−２′−デオキシ
ウリジン類に関する発明であり、これらは、優れた制癌
作用、抗ウィルス作用を発揮し、抗腫瘍剤、抗ウィルス
剤として有用である。DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to novel substances, 5-substituted-2'-deoxyuridines, which exhibit excellent anticancer and antiviral effects. It is useful as an antitumor agent and an antiviral agent.
従来の技術及びその課題
５−トリフルオロメチル−２′−デオキシウリジンは、
強力なチミジル酸合成酵素の阻害能を有する事が報告さ
れている（Ｐ、Ｒｅｙｅｓ ａｎｄ Ｃ。Conventional techniques and their problems 5-trifluoromethyl-2'-deoxyuridine is
It has been reported that it has a strong ability to inhibit thymidylate synthase (P, Reyes and C.
）１ｃｉｄｅｌｂｅｒｇｅｒ、Ｍｏ１．Ｐｈａｒｍａｃ
ｏｌｏｇｙ １ １４（１９６５）及びＰ、 Ｖ、 ５
ａｎｔｉ ａｎｄ Ｔ、 Ｔ。)1cidelberger, Mo1. Pharmac
1 14 (1965) and P, V, 5
anti and T, T.
５ａｋａｉ、 Ｂｉｏｃｈｅｍｉｓｔｒｙ １０ ３５
９６ （１９７１））。又、ヨードデオキシウリジンは
現在、眼科領域での抗ウィルス剤として利用されている
。5akai, Biochemistry 10 35
96 (1971)). Furthermore, iododeoxyuridine is currently used as an antiviral agent in the ophthalmological field.
しかし、これらの薬剤はその薬理効果を発現する為に必
要な薬剤の濃度を維持することが難しい、溶解性が悪い
等の問題を有しており、抗腫瘍剤、抗ウィルス剤として
広（使用される状況に至っていない。However, these drugs have problems such as difficulty in maintaining the drug concentration required to exert their pharmacological effects and poor solubility, so they are not widely used as antitumor or antiviral agents. We have not yet reached the situation where it will be done.
課題を解決するための手段
本発明者らは、かかる状況に鑑みて、上記薬剤を臨床の
場へ提供すべく検討を加える中、本発明の５−置換−２
′−デオキシウリジン類が上記目的を達成しうろことを
・見出し、本発明を完成するに至った。Means for Solving the Problems In view of the above circumstances, the present inventors have investigated the 5-substitution-2 of the present invention in order to provide the above-mentioned drug in clinical settings.
It was discovered that '-deoxyuridines can achieve the above object, and the present invention was completed.
本発明の５−置換−２′−デオキシウリジン類は、下記
一般式（Ｉ）で表される。The 5-substituted-2'-deoxyuridines of the present invention are represented by the following general formula (I).
Ｚ
（式中、Ｘは沃素原子又はトリフルオロメチル基を、Ｒ
は低級アルキル基、フェニル基、置換基としてハロゲン
原子を有するフェニル基またはベンジル基を、Ｚは水素
原子、ベンジル基又は低級アシル基を、それぞれ示す）
上記一般式中、Ｒで示される低級アルキル基としては、
炭素数１〜６の直鎖又は分枝状のアルキル基であり、具
体的には、メチル、エチル、プロピル、イソプロピル、
ブチル、５ｅｃ−ブチル、ｔ−ブチル、ペンチル、ヘキ
シル基等であり、Ｒで示される置換基としてハロゲン原
子を有するフェニル基としては弗素、塩素、臭素、沃素
等のハロゲン原子がフェニル基のオルト、パラ、メタの
位置に１〜３個置換したもの等を意味する。又、Ｚで示
される低級アシル基としては、炭素数２〜６の直鎖又は
分枝状のアシル基であり、具体的には、アセチル、プロ
ピオニル、ブチリル、バレリル等である。Z (wherein, X is an iodine atom or a trifluoromethyl group, R
represents a lower alkyl group, a phenyl group, a phenyl group or a benzyl group having a halogen atom as a substituent, and Z represents a hydrogen atom, a benzyl group or a lower acyl group, respectively) In the above general formula, a lower alkyl group represented by R as,
A linear or branched alkyl group having 1 to 6 carbon atoms, specifically methyl, ethyl, propyl, isopropyl,
Butyl, 5ec-butyl, t-butyl, pentyl, hexyl, etc., and phenyl groups having a halogen atom as a substituent represented by R include halogen atoms such as fluorine, chlorine, bromine, and iodine, ortho to the phenyl group, It means 1 to 3 substitutions at para or meta positions. The lower acyl group represented by Z is a linear or branched acyl group having 2 to 6 carbon atoms, and specifically includes acetyl, propionyl, butyryl, valeryl, and the like.
一般式（Ｉ）で表される本発明化合物は、一般式
（式中、Ｚ′はベンジル基又は低級アシル基を示す）で
表わされる化合物に、一般式
％式％（）
（式中、Ｒは前記と同じ）で表されるジ置換１ノン酸モ
ノクロライドを脱酸剤の存在下ζこ反応させ、一般式
（式中、Ｘ、Ｒ及びＺ′は前記と同じ）で表される化合
物を得る。一般式（Ｉ）で表される化合物のうちＺが水
素原子である化合物については、更に、一般式（Ｉ′）
で表される化合物のうち２′が低級アシル基のものを脱
アシル化反応に付すことにより製造することができる。The compound of the present invention represented by the general formula (I) is a compound represented by the general formula (wherein, Z' represents a benzyl group or a lower acyl group); is the same as above) is reacted with di-substituted monononic acid monochloride in the presence of a deoxidizing agent to obtain a compound represented by the general formula (wherein X, R and Z' are the same as above) get. Among the compounds represented by general formula (I), Z is a hydrogen atom, furthermore, general formula (I')
Among the compounds represented by the above, those in which 2' is a lower acyl group can be produced by subjecting them to a deacylation reaction.
化合物（ＩＩ）と（ｍ）の反応において使用される溶媒
としては、反応に悪影響を与えないものである限り特に
限定されなく、公知のものを広（使用でき、具体的には
ベンゼン、トルエン、キシレン等の芳香族炭化水素類、
ジエチルエーテル、ジオキサン、テトラヒドロフラン等
の非環状及び環状エーテル類、ジクロルメタン、クロロ
ホルム、四塩化炭素、トリクロルエタン、ジクロルエタ
ン等のハロゲン化炭化水素類、及びアセトニトリル、ピ
リジン、ニトロメタン、ジメチルホルムアミド、ジメチ
ルスルホキサイド等の非プロトン性極性溶媒が使用でき
る。脱酸剤としては、有機、無機の種々のものが使用で
きるが、具体的には、炭酸カリウム、炭酸ナトリウム、
炭酸バリウム等の炭酸金属塩及び炭酸水素ナトリウム、
トリエチルアミン及びジエチルイソプロピルアミンを代
表とするトリアルキルアミン類、ピリジン、ジアルキル
アミノピリジン、ピコリン、ルチジン等の芳香族アミン
類が例示できる。脱酸剤の反応割合は、一般式（ＩＩ）
で表される化合物１モルに対し、各々等モル〜１０倍モ
ル程度であり、反応温度は、反応基質により異なるが、
通常−８０℃〜５０℃程度である。反応時間も反応条件
により異なるが、−般に、１〜２０時間程度である。The solvent used in the reaction of compound (II) and (m) is not particularly limited as long as it does not adversely affect the reaction, and a wide variety of known solvents can be used, including benzene, toluene, Aromatic hydrocarbons such as xylene,
Acyclic and cyclic ethers such as diethyl ether, dioxane, and tetrahydrofuran; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, trichloroethane, and dichloroethane; and acetonitrile, pyridine, nitromethane, dimethylformamide, dimethyl sulfoxide, etc. Aprotic polar solvents can be used. Various organic and inorganic deoxidizing agents can be used, but specifically, potassium carbonate, sodium carbonate,
Metal carbonates such as barium carbonate and sodium hydrogen carbonate,
Examples include trialkylamines such as triethylamine and diethylisopropylamine, and aromatic amines such as pyridine, dialkylaminopyridine, picoline, and lutidine. The reaction rate of the deoxidizing agent is expressed by the general formula (II)
For 1 mole of the compound represented by, the amount is approximately equal to 10 times the mole of each, and the reaction temperature varies depending on the reaction substrate, but
It is usually about -80°C to 50°C. The reaction time also varies depending on the reaction conditions, but is generally about 1 to 20 hours.
また、脱アシル化反応において使用される溶媒としては
、反応に悪影響を与えないものである限り特に限定され
なく、公知のものを広く使用でき、具体的にはメタノー
ル、エタノール等のアルコール類、アセトン、メチルエ
チルケトン等の脂肪族ケトン類、ジオキサン、テトラヒ
ドロフラン等のエーテル類を単独で、又は、これらと水
の混合系をあげることができる。脱アシル化剤としては
有機、無機の種々のものが使用できるが、具体的には炭
酸カリウム、炭酸ナトリウム、炭酸バリウム等の炭酸金
属塩、及び炭酸水素ナトリウム、ジエチルアミン、ブチ
ルアミン、トリエチルアミン及びジエチルイソプロピル
アミンを代表とするモノ、ジあるいはトリアルキルアミ
ン類等が使用できる。In addition, the solvent used in the deacylation reaction is not particularly limited as long as it does not adversely affect the reaction, and a wide variety of known solvents can be used. Specifically, alcohols such as methanol and ethanol, acetone, etc. , aliphatic ketones such as methyl ethyl ketone, ethers such as dioxane and tetrahydrofuran alone, or a mixture of these and water. Various organic and inorganic deacylating agents can be used, but specific examples include metal carbonates such as potassium carbonate, sodium carbonate, and barium carbonate, as well as sodium bicarbonate, diethylamine, butylamine, triethylamine, and diethylisopropylamine. Mono-, di-, or trialkylamines such as those typified by can be used.
脱アシル化剤の反応割合は、一般式（Ｉ′）で表される
化合物１モルに対し、各々等モル〜１０倍モル程度であ
り、反応温度は、使用する脱アシル化剤の塩基強度によ
り異なるが、通常、０℃〜使用する溶媒の沸点程度であ
る。反応時間も反応条件により異なるが、一般に、１〜
１０時間程度である。The reaction ratio of the deacylating agent is approximately equal to 10 times the mole of each deacylating agent per mole of the compound represented by the general formula (I'), and the reaction temperature varies depending on the base strength of the deacylating agent used. Although it varies, it is usually about 0°C to the boiling point of the solvent used. The reaction time also varies depending on the reaction conditions, but generally 1 to
It takes about 10 hours.
上記方法で製造された本発明化合物は、通常公知の分離
精製手段、具体的には再結晶、カラムクロマトグラフィ
ー等により、単離精製することができる。The compound of the present invention produced by the above method can be isolated and purified by commonly known separation and purification means, specifically recrystallization, column chromatography, etc.
実施例 次に、本発明の実施例を示す。Example Next, examples of the present invention will be shown.
実施例１
３′−アセチル−５−トリフルオロメチル−２′−デオ
キシウリジン３３８Ｉｌ１ｇをピリジン５ｍＱに溶解し
水冷した。ビス（パラクロルフェノキシ）リン酸クロラ
イド３３３■を加え終夜撹拌した。Example 1 338Il1g of 3'-acetyl-5-trifluoromethyl-2'-deoxyuridine was dissolved in 5mQ of pyridine and cooled with water. 333 μl of bis(parachlorophenoxy)phosphoryl chloride was added and stirred overnight.
少ｎのメタノールを加え未反応のリン酸クロライドを分
解した後減圧下に濃縮した。シリカゲルカラムクロマト
グラフィー（留出液、クロロホルム）にて精製し、３′
−アセチル−５−トリフルオロメチル−２′−デオキシ
ウリジン−５′−ビス（パラクロルフェニル）ホスフェ
ート（本発明化合物Ａ）５４０■（収率８５％）を得た
。白色アモルファス。A small amount of methanol was added to decompose unreacted phosphoric acid chloride, and the mixture was concentrated under reduced pressure. Purified by silica gel column chromatography (distillate, chloroform) and
-Acetyl-5-trifluoromethyl-2'-deoxyuridine-5'-bis(parachlorophenyl)phosphate (compound A of the present invention) 540 μm (yield: 85%) was obtained. White amorphous.
実施例２
実施例１と同様の操作を行ない、３′−アセチル−５−
トリフルオロメチル−２′−デオキシウリジン−５′−
ジエチルホスフェート（本発明化合物Ｂ１収率７３％）
、３′−アセチル−５−トリフルオロメチル−２′−デ
オキシウリジン−５′−ジフェニルホスフェート（本発
明化合物Ｃ１収率８２％）、３′−ベンジル−５−ヨウ
ビー２′−デオキシウリジン−５′−ジベンジルホスフ
ェート（本発明化合物Ｄ１収率３６％）、３′−ベンジ
ル−５−トリフルオロメチル−２′ −デオキシウリジ
ン−５′−ジベンジルホスフェート（本発明化合物Ｅ１
収率３２％）を得た。Example 2 The same operation as in Example 1 was carried out to obtain 3'-acetyl-5-
Trifluoromethyl-2'-deoxyuridine-5'-
Diethyl phosphate (yield of the present compound B1: 73%)
, 3'-acetyl-5-trifluoromethyl-2'-deoxyuridine-5'-diphenylphosphate (yield of the present compound C1 82%), 3'-benzyl-5-iobi-2'-deoxyuridine-5' -dibenzyl phosphate (yield of the present compound D1: 36%), 3'-benzyl-5-trifluoromethyl-2'-deoxyuridine-5'-dibenzyl phosphate (the present compound E1)
A yield of 32%) was obtained.
実施例３
３′−アセチル−５−トリフルオロメチル−２′−デオ
キシウリジン−５′−ジフェニルホスフェート５０ｍｇ
をメタノール３ｍＱに溶解し、炭酸水素ナトリウム２０
ｍｇを水０．５ｍＱに溶かしたものを室温下に加えた。Example 3 3'-acetyl-5-trifluoromethyl-2'-deoxyuridine-5'-diphenylphosphate 50 mg
was dissolved in 3 mQ of methanol, and 20 mQ of sodium hydrogen carbonate was added.
mg dissolved in 0.5 mQ of water was added at room temperature.
３時間撹拌後、２％塩酸にて弱酸性とした後減圧濃縮し
た。シリカゲルカラムクロマトグラフィー（留出液、ク
ロロホルム：エタノール−２０：１）にて精製し、５−
トリフルオロメチル−２′−デオキシウリジン−５′−
ジフェニルホスフェート（本発明化合物Ｆ）２６■（収
率５６％）を得た。オイル。After stirring for 3 hours, the mixture was made weakly acidic with 2% hydrochloric acid and concentrated under reduced pressure. Purified by silica gel column chromatography (distillate, chloroform:ethanol-20:1), 5-
Trifluoromethyl-2'-deoxyuridine-5'-
Diphenyl phosphate (compound F of the present invention) 26 cm (yield 56%) was obtained. oil.
実施例４
実施例３と同様の操作を行ない、５−トリフルオロメチ
ル−２′ −デオキシウリジン−５′−ジエチルホスフ
ェート（本発明化合物Ｇ１収率６２％）、５−トリフル
オロメチル−２′−デオキシウリジン−５′−ビス（パ
ラクロルフェニル）ホスフェート（本発明化合物Ｈ１収
率４８％）を得た。Example 4 The same operation as in Example 3 was carried out, and 5-trifluoromethyl-2'-deoxyuridine-5'-diethyl phosphate (yield of the present compound G1 62%), 5-trifluoromethyl-2'- Deoxyuridine-5'-bis(parachlorophenyl)phosphate (compound of the present invention H1 yield: 48%) was obtained.
各実施例で得られた本発明化合物Ａ−ＨのＮＭＲデータ
ーを、第１表に示す。Table 1 shows the NMR data of compounds A-H of the present invention obtained in each example.
Claims (1)
は低級アルキル基、フェニル基、置換基としてハロゲン
原子を有するフェニル基またはベンジル基を、Ｚは水素
原子、ベンジル基又は低級アシル基を、それぞれ示す）
で表わされる５−置換−２′−デオキシウリジン類。[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, X is an iodine atom or a trifluoromethyl group, R
represents a lower alkyl group, a phenyl group, a phenyl group or a benzyl group having a halogen atom as a substituent, and Z represents a hydrogen atom, a benzyl group or a lower acyl group, respectively)
5-substituted-2'-deoxyuridines represented by:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63090768A JP2631223B2 (en) | 1988-04-12 | 1988-04-12 | 5-substituted-2'-deoxyuridines |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63090768A JP2631223B2 (en) | 1988-04-12 | 1988-04-12 | 5-substituted-2'-deoxyuridines |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH01261396A true JPH01261396A (en) | 1989-10-18 |
| JP2631223B2 JP2631223B2 (en) | 1997-07-16 |
Family
ID=14007785
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63090768A Expired - Lifetime JP2631223B2 (en) | 1988-04-12 | 1988-04-12 | 5-substituted-2'-deoxyuridines |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2631223B2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0601520A1 (en) * | 1992-12-07 | 1994-06-15 | MITSUI TOATSU CHEMICALS, Inc. | Trifluorothymidine derivatives, process for producing the same and anti-cancer agent containing the same |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH01308295A (en) * | 1988-02-29 | 1989-12-12 | Kuraray Co Ltd | 2'-deoxy-5-fluorouridine derivative, production thereof and antitumor agent containing said derivative as active ingredient |
-
1988
- 1988-04-12 JP JP63090768A patent/JP2631223B2/en not_active Expired - Lifetime
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH01308295A (en) * | 1988-02-29 | 1989-12-12 | Kuraray Co Ltd | 2'-deoxy-5-fluorouridine derivative, production thereof and antitumor agent containing said derivative as active ingredient |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0601520A1 (en) * | 1992-12-07 | 1994-06-15 | MITSUI TOATSU CHEMICALS, Inc. | Trifluorothymidine derivatives, process for producing the same and anti-cancer agent containing the same |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2631223B2 (en) | 1997-07-16 |
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