JPS63225365A - 5-fluorouracil derivative - Google Patents
5-fluorouracil derivativeInfo
- Publication number
- JPS63225365A JPS63225365A JP62110147A JP11014787A JPS63225365A JP S63225365 A JPS63225365 A JP S63225365A JP 62110147 A JP62110147 A JP 62110147A JP 11014787 A JP11014787 A JP 11014787A JP S63225365 A JPS63225365 A JP S63225365A
- Authority
- JP
- Japan
- Prior art keywords
- fluorouracil
- formula
- fluorine
- derivatives
- fluorouracil derivative
- 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
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical class FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 title claims abstract description 33
- 239000011737 fluorine Substances 0.000 claims abstract description 19
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 19
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000001931 aliphatic group Chemical group 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 abstract description 18
- 229960002949 fluorouracil Drugs 0.000 abstract description 12
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 abstract description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 abstract description 8
- 150000001412 amines Chemical class 0.000 abstract description 7
- 150000001875 compounds Chemical class 0.000 abstract description 4
- 231100000053 low toxicity Toxicity 0.000 abstract description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 abstract description 4
- 206010003840 Autonomic nervous system imbalance Diseases 0.000 abstract description 3
- 238000001816 cooling Methods 0.000 abstract description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 abstract description 3
- 231100000419 toxicity Toxicity 0.000 abstract description 3
- 230000001988 toxicity Effects 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 2
- 150000007530 organic bases Chemical class 0.000 abstract description 2
- 230000003327 cancerostatic effect Effects 0.000 abstract 2
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 208000019479 dysautonomia Diseases 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 125000000962 organic group Chemical group 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 abstract 1
- 208000018290 primary dysautonomia Diseases 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 231100001274 therapeutic index Toxicity 0.000 description 9
- 230000000694 effects Effects 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 208000012219 Autonomic Nervous System disease Diseases 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- AOCCBINRVIKJHY-UHFFFAOYSA-N Carmofur Chemical compound CCCCCCNC(=O)N1C=C(F)C(=O)NC1=O AOCCBINRVIKJHY-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000007664 blowing Methods 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- -1 lithium aluminum hydride Chemical compound 0.000 description 2
- 230000027939 micturition Effects 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- ASMQGLCHMVWBQR-UHFFFAOYSA-N Diphenyl phosphate Chemical compound C=1C=CC=CC=1OP(=O)(O)OC1=CC=CC=C1 ASMQGLCHMVWBQR-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 208000028018 Lymphocytic leukaemia Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 229960003261 carmofur Drugs 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 230000013872 defecation Effects 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000010438 heat treatment Methods 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
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 208000003747 lymphoid leukemia Diseases 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 150000003140 primary amides Chemical class 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 239000012257 stirred material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
Landscapes
- 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、抗癌剤等として利用することができる５−フ
ルオロウラシル誘導体に関する。DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to 5-fluorouracil derivatives that can be used as anticancer agents and the like.
５−フルオロウラシルは、抗腫瘍スペクトルの広い代謝
拮抗剤として、医＝床治療に用いられているが、経口投
与の場合、毒性が強く、特に消化管障害等の副作用を伴
う。5-Fluorouracil is used in medical treatment as an antimetabolite with a broad antitumor spectrum, but when administered orally, it is highly toxic and is accompanied by side effects, particularly gastrointestinal disorders.
これを和らげる為、種々の誘導化が検討され、初期のこ
ろの代表的なものとしては、１−（２〜テ］・ラヒドロ
フリル）−５−フルオロウラシルが開発された。しかし
、これは毒性は弱いが、抗１１１瘍活性も弱く、優れた
抗腫瘍剤とはいえなかった（癌と化学療法８巻１１号１
８１１頁参照）。In order to alleviate this problem, various derivatizations were investigated, and 1-(2-te]-lahydrofuryl)-5-fluorouracil was developed as a representative one in the early days. However, although this drug has low toxicity, it also has weak anti-111 tumor activity and cannot be called an excellent antitumor agent (Cancer and Chemotherapy Vol. 8, No. 11, No. 1).
(See page 811).
活性を強く保ち、毒性を軽減する目的で、その後も５−
フルオロウラシル誘導体に関する研究が続けられ、例え
ば、１−へキシルカルバモイル−５−フルオロウラシル
が開発された。この化合物は、活性が強く、消化管に対
して低毒性である点で、経口用としてはかなり改善され
たものであるが、他の５−フルオロウラシル誘導体に見
られない、ヘキシル基が肝臓で酸化されて生成する代謝
中間体に起因する、尿、便意の顧発、熱を等の自律神経
系失調が起こり、実用に際しては、トランキライザーの
併用を余儀無くされている（ファルマシ７１６巻、１９
８０年６号、５２４〜５２７頁参照）。In order to maintain strong activity and reduce toxicity, 5-
Research on fluorouracil derivatives continued and, for example, 1-hexylcarbamoyl-5-fluorouracil was developed. This compound is highly active and has low toxicity to the gastrointestinal tract, which is a significant improvement for oral use. However, the hexyl group is oxidized in the liver, which is not seen in other 5-fluorouracil derivatives. Autonomic nervous system disorders such as urination, involuntary defecation, and fever are caused by metabolic intermediates produced during the process, and in practical use, it is necessary to use tranquilizers in combination (Pharmacy Vol. 716, 19).
(See 1980, No. 6, pp. 524-527).
本発明者らは、１−へキシルカルバモイル−５−フルオ
ロウラシル誘導体の活性が強いことに着目し、これの類
縁体の低毒性のものを探索したところ、特定の構造を有
するフルオロアルキルカルバモイル誘導体がこの点に優
れていることを見出し、本発明に達した。The present inventors focused on the strong activity of 1-hexylcarbamoyl-5-fluorouracil derivatives, and searched for low-toxicity analogs of this derivative, and found that fluoroalkylcarbamoyl derivatives with a specific structure The inventors have discovered that the present invention is superior in these points, and have arrived at the present invention.
本発明の目的は、抗癌剤等として利用することができる
新規５−フルオロウラシル誘導体を提供することである
。An object of the present invention is to provide a novel 5-fluorouracil derivative that can be used as an anticancer agent.
本発明は、式：
（式中、１は硫黄および／または酸素を含有することが
ある炭素数１〜１０の含フッ素有ｍ基を示す。）
で表わされる５−フルオロウラシル誘導体である。The present invention is a 5-fluorouracil derivative represented by the formula: (wherein 1 represents a fluorine-containing m group having 1 to 10 carbon atoms that may contain sulfur and/or oxygen.)
治療係数（Ｔｈｅｒａｐｅｕｔｉｃ Ｉｎｄｅｘ）が大
きい点および／または前記のような自律神経系失調を惹
起しない点で、前記Ｒ＋ は、式：
％式％）
（式中、Ｒｇは水素または炭素数１〜４の脂肪族基、ｈ
は０または１〜４の整数を示す、）、式：
％式％
（式中、Ｒ”ｌよ水素またはフッ素、ｉは０または１〜
５の整数を示す、）
または
式：
％式％（）
（式中、Ｒ４は水素またはメチル基、」は１〜４の整数
を示す。）
で表わされる基であるのが好ましく、式： −Ｃ１ｈ
ＣＦ１、− （ｃｕｔ） ｔｃｐ３、− （Ｃｆｌｔ）
＊Ｃｈ、−（ＣＩｌ□）ａｃＦｉ、−（Ｃ１１２）Ｓ
ＣＦ３、−ＣＩ□Ｃｌ０（ＣＨりＣＦｓ、−ＣＩｌＩＣ
Ｉ（Ｃ，ｌｌ５）ＣＦ、、−Ｃ１１□Ｃ）１（ＣＪ？）
ＣＦ３、−ＣＩｌＩＣＨ（Ｃ４１１９）ＣＦ３、−（Ｃ
１ｈ）ｚＣ１１（Ｃ１ｌｓ）ＣＦｉ 、−ＣＩｌＩＣＨ
Ｆ２、− （ＣＬ） Ｘｔｊｌｈ −−（ＣＨｚ） ａ
ｃｌｌＦｇ 、−（Ｃ１ｈ）４ｃＩ（Ｐｇ 、−（
Ｃ１ｌｔ）ｓｃｌＩｈ 、−（ＣｔｌｚＬＣＩｌｇＦ
、 −（Ｃ１ｌ り ｔｃＨＦｃｌＩ３または−（Ｃ
１ｈ） ｔＮＨｃ（Ｊ）ＣＨｚＳＣＨＦ２で表わされる
基であるのがより好ましく、式：％式％（
ｆｉｚ）ｚｃｌｌ（Ｃ１ｈ）Ｃｈまたは＝（ＣＯり ｓ
ｃＩＩＦｇで表わされる基であるのがさらに好ましい。In terms of having a large therapeutic index and/or not causing autonomic nervous system imbalance as described above, R+ has the formula: aliphatic group, h
represents 0 or an integer from 1 to 4), Formula: %Formula% (In the formula, R"l is hydrogen or fluorine, and i is 0 or 1 to
) or the formula: %Formula%() (In the formula, R4 is hydrogen or a methyl group, "represents an integer from 1 to 4.)" is preferably a group represented by the formula: - C1h
CF1, - (cut) tcp3, - (Cflt)
*Ch, -(CIl□)acFi, -(C112)S
CF3, -CI□Cl0(CHriCFs, -CIlIC
I(C,ll5)CF,,-C11□C)1(CJ?)
CF3,-CIlICH(C4119)CF3,-(C
1h)zC11(C1ls)CFi, -CIlICH
F2, - (CL) Xtjlh -- (CHz) a
cllFg, -(C1h)4cI(Pg, -(
C1lt)scllh, -(CtlzLCIlgF
, -(C1l tcHFclI3 or -(C
1h) It is more preferable that it is a group represented by tNHc(J)CHzSCHF2, and the formula: %Formula%(fiz)zcll(C1h)Ch or =(CO s
More preferably, it is a group represented by cIIFg.
本発明の５−フルオロウラシル誘導体は、例えば、次に
示す（Ｉ）または（Ｉｔ）の方法で製造することができ
る。The 5-fluorouracil derivative of the present invention can be produced, for example, by the method (I) or (It) shown below.
（Ｉ）５−フルオロウラシルにホスゲン（ＣＯＣｈ）と
含フツ素アミン（Ｎｌｌ！Ｒ’）を順に反応させる（次
式）。(I) 5-fluorouracil is reacted with phosgene (COCh) and a fluorine-containing amine (Nll!R') in this order (the following formula).
０１１５−Ｎ−Ｒ′
（式中、Ｒ１は前記と同じ、）
前記のホスゲンを使用する反応は、通常５−フルオロウ
ラシルをピリジン、トリエチルアミン、メチルモルホリ
ン等の有機塩基に溶解し、−１０〜１０℃に冷却しなが
ら、１．２〜２当量のホスゲンを吹き込んで実施する。0115-N-R' (In the formula, R1 is the same as above.) The reaction using phosgene is usually performed by dissolving 5-fluorouracil in an organic base such as pyridine, triethylamine, or methylmorpholine, and heating at -10 to 10°C. This is carried out by blowing in 1.2 to 2 equivalents of phosgene while cooling to .
前記の含フツ素アミンを使用する反応は、５−フルオロ
ウラシルとホスゲンの反応混合物に含フツ素アミンを１
〜１．５当量添加し、−１０〜１０℃で行う。The above reaction using a fluorine-containing amine involves adding 1 fluorine-containing amine to a reaction mixture of 5-fluorouracil and phosgene.
-1.5 equivalents are added and carried out at -10 to 10°C.
なお、含フツ素アミンは、例えば、ヒドロキシル基と塩
素を有する化合物のヒドロキシル基と塩素をそれぞれフ
ッ素とアミノ基に変換する〔例えばプルチン・ケミカル
・ソサエティー・シアパン５１巻（１９７８年＞ １２
６７頁およびアンゲバンテ・ヘミ−・インターナショナ
ルエディシラン７＠（１９６８年）９１９頁参照〕、あ
るいは含フッ素第一アミドを水素化硼素ナトリウム、水
素化リチウムアルミニウム等の還元剤で還元して合成す
ることができる（例えばテトラヘドロン・レターズ、１
９６９年、４５５５頁参照）。Note that fluorine-containing amines can be used, for example, to convert the hydroxyl group and chlorine of a compound having a hydroxyl group and chlorine into fluorine and amino groups, respectively [for example, Plutin Chemical Society Xiapan Vol. 51 (1978> 12
67 and Angewante Hemi-International Edicilane 7 @ (1968) p. 919], or it can be synthesized by reducing a fluorine-containing primary amide with a reducing agent such as sodium borohydride or lithium aluminum hydride. Yes (e.g. Tetrahedron Letters, 1
969, p. 4555).
（ＩＩ）式：
％式％
（式中、Ｒ１は前記と同じ。）
で表わされる含フツ素カルボン酸とジフェニルリン酸ア
ジドを反応させ式：
％式％
（式中、Ｒ１は前記と同じ、）
で表わされるイソシアネートを合成し、次いでこのイソ
シアネートと５−フルオロウラシルを反応させて製造す
る。(II) A fluorine-containing carboxylic acid represented by the formula: %Formula% (wherein R1 is the same as above) is reacted with diphenylphosphoric acid azide to obtain the formula: %Formula% (wherein R1 is the same as above, ) is synthesized, and then this isocyanate is reacted with 5-fluorouracil to produce it.
前記含フツ素カルボン酸は、ジャーナル・オブ・ジ・ア
メリカン・ケミカル・ソサエティー７６＠（１９５４年
） ３７２２頁記載の方法で合成することができる。The fluorine-containing carboxylic acid can be synthesized by the method described in Journal of the American Chemical Society 76 @ (1954) p. 3722.
含フツ素カルボン酸、ジフェニルリン酸アジドおよび５
−フルオロウラシルの混合物を有機溶媒中で加熱すると
、前記の両反応が順に進行するので、通常は前記の両反
応を分けて行わない。Fluorine-containing carboxylic acid, diphenylphosphoric azide and 5
- When a mixture of fluorouracil is heated in an organic solvent, both of the above-mentioned reactions proceed in sequence, so the above-mentioned reactions are usually not carried out separately.
有機溶媒としては、例えば、ピリジン、トリエチルアミ
ン、ジメチルアセトアミド、ジメチルホルムアミド等を
挙げることができる。これらの混合物も使用することか
で５る０反応温度は、通索ｌＯ〜１１０℃、反応時間は
、通常１〜１０時間である。Examples of the organic solvent include pyridine, triethylamine, dimethylacetamide, dimethylformamide, and the like. When a mixture of these is used, the reaction temperature is usually 10 to 110°C, and the reaction time is usually 1 to 10 hours.
通常、含フツ素カルボン酸は、５−フルオロウラシル１
モルに対し１〜１．５モル、ジフェニルリン酸アジドは
、５−フルオロウラシル１モルに対し１〜１．５モル使
用する。Usually, the fluorine-containing carboxylic acid is 5-fluorouracil 1
1 to 1.5 mol per mole, and 1 to 1.5 mol of diphenyl phosphoric acid azide is used per 1 mol of 5-fluorouracil.
（以下余白、次頁に続く）
〔実施例〕
実施例１〜１３
５−フルオロウラシル２．６ｇ （０，０２モル）をピ
リジン５０ ｍｌに溶解し、−３〜２℃に冷却した。こ
の液中に、同温度を保ちながら、トリクロロメチルクロ
ルフオルメー） ４ ｇ （０，０２モル）を活性炭に
滴下して発生させたホスゲンを導入した。窒素ガスを吹
き込んで未反応ホスゲンを除いた後、−５℃に冷却し、
第１衷に示す含フツ素アミン（０，０２モル）を添加し
、同温度で１時間攪拌後さらに室温で３０分攪拌した。(The following margins are continued on the next page) [Examples] Examples 1 to 13 2.6 g (0.02 mol) of 5-fluorouracil was dissolved in 50 ml of pyridine and cooled to -3 to 2°C. Phosgene, which was generated by dropping 4 g (0.02 mol) of trichloromethylchloroforme) onto activated carbon, was introduced into this liquid while maintaining the same temperature. After blowing nitrogen gas to remove unreacted phosgene, it was cooled to -5°C.
The fluorine-containing amine (0.02 mol) shown in the first section was added, and the mixture was stirred at the same temperature for 1 hour and then further stirred at room temperature for 30 minutes.
反応混合物を減圧上濃縮し、酢酸エチル２０ｈｌとＩＮ
の塩酸５０■１を加え、撹拌後不溶物を濾別した。濾液
の酢酸エチル層を分増し、脱水後減圧上乾固し、シリカ
ゲルカラムクロマトグラフィーで精製した。第１表に使
用した含フツ素アミン、目的物に含有されるｌｉｔ基、
目的物の収率、目的物の’Ｉ＋および１ｌｐ−核磁気共
鳴分析（ＮＭＲ）結果、生存日数延長率（ＩＬＳＩ）な
らびに治療係数（ＴＩ）を示す。The reaction mixture was concentrated under reduced pressure and mixed with 20 hl of ethyl acetate and IN
of hydrochloric acid was added, and after stirring, insoluble matter was filtered off. The ethyl acetate layer of the filtrate was separated, dehydrated, dried under reduced pressure, and purified by silica gel column chromatography. The fluorine-containing amines used in Table 1, the lit group contained in the target product,
The yield of the target product, the 'I+ and 1lp- nuclear magnetic resonance analysis (NMR) results of the target product, the survival index (ILSI) and the therapeutic index (TI) are shown.
なお、前記生存日数延長率（ＩＬＳＩ）および治療係数
（ＴＩ）は、本技術分野における通常の意味で用いられ
、その測定方法は、ケミカル・ファーマシューティカル
・ブレタン（Ｃｈｅｍ、Ｐｈａｒｍ、Ｂｕｌｌ） ２Ｇ
−＠（１９７８年）１号１６１〜１６５頁に記載の方法
に従った（但し、
として、一群五匹のＢＤＩＩ系マウス（メス）にリンパ
性白血病Ｉｌ！ｌｒ！に細胞Ｌ−１２１０（Ｎａｔ４ｏ
ｎａｌ Ｃａｎｃｅｒ Ｉｎ５ｔＨｕｔｅ系）をＬＸＩ
Ｏ’個腹腔内に移植したものを用いた。マウスの体重は
１６±２ｇ、投与経路は経口投与である。）
実施例１４〜１７
ジメチルホルムアミド１５鋼１．５−フルオロウラシル
Ｉｇ（７，７ミリモル）、ジフェニルリン酸アジド２．
２ｇ（８ミリモル）およびトリエチルアミン５．１ｇ（
５０ミリモル）からなる混合物中に第２表に示す含フツ
素カルボン酸（８ミリモル）を添加し、８０℃で２時間
反応を行った。The above-mentioned survival-day extension rate (ILSI) and therapeutic index (TI) are used in the usual sense in this technical field, and the measurement method is Chemical Pharmaceutical Bulletin (Chem, Pharm, Bull) 2G.
-@ (1978) No. 1, pp. 161-165 (However, one group of five BDII mice (female) was infected with lymphocytic leukemia Il!lr! cells L-1210 (Nat4o
nal Cancer In5tHute series) to LXI
O' cells implanted intraperitoneally were used. The weight of the mouse was 16±2 g, and the administration route was oral. ) Examples 14-17 Dimethylformamide 15 steel 1.5-fluorouracil Ig (7.7 mmol), diphenyl phosphoric azide 2.
2 g (8 mmol) and triethylamine 5.1 g (
The fluorine-containing carboxylic acid shown in Table 2 (8 mmol) was added to a mixture consisting of 50 mmol), and the reaction was carried out at 80° C. for 2 hours.
冷却後、減圧で濃縮し、酢酸エチル１００ｍ１と１規定
の塩酸５０ ｍｌを加え撹拌し、不溶物を濾別した。濾
液の酢酸エチル層を分瑠し、脱水後減圧上乾固しシリカ
ゲルクロマトグラフィー〔溶媒：クロロホルム／エタノ
ール−１０／１ （容り ）で精製した。第２表に使
用した含フツ素カルボン酸、目的物に含有される１１１
５、目的物の収率、目的物のＩＨおよび’ ”Ｆ−ＮＭ
Ｉ？分析結果、生存日数延長率（ＩＬＳＩ）ならびに治
療係数（ＴＩ）を示す。After cooling, the mixture was concentrated under reduced pressure, 100 ml of ethyl acetate and 50 ml of 1N hydrochloric acid were added, stirred, and insoluble materials were filtered off. The ethyl acetate layer of the filtrate was separated, dehydrated, dried under reduced pressure, and purified by silica gel chromatography [solvent: chloroform/ethanol-10/1 (volume)]. Fluorine-containing carboxylic acids used in Table 2, 111 contained in the target product
5. Yield of target product, IH and 'F-NM of target product
I? The results of the analysis show the survival rate (ILSI) and therapeutic index (TI).
（註） Ｎ？ｌＲ測定において、溶媒として実施例６．
８．１０．１１．１３．１６および１７ではＣＤＣ１，
を使用し、その他の実施例では（ＣＤ＋）ｇｓｏを使用
した。 ”Ｆ−ＮＭＲではｌ・リフルオロ酢酸を標準物
質とした。(Note) N? In the IR measurement, Example 6.
CDC1 on 8.10.11.13.16 and 17,
was used, and (CD+)gso was used in other examples. ``In F-NMR, 1-lifluoroacetic acid was used as a standard substance.
なお、副作用の自律神経系失調に関し、臨床薬理１１巻
（１９８０） １号１７頁および２７頁記載の方法に従
い、本発明の誘導体の■ラットの体温調節中枢である視
束前野と視束前野以外のニューロンに対する作用（熱感
の発生程度）および■猫の膀胱運動に対する作用（尿意
頻数）を調べたところ、前記Ｒ１が−（Ｃｔｈ）ｇｃＦ
ｉ、−（ＣＨｚ） ｚｃｈ、−ＣＨｔＣＩｌ （ＣＨ３
）ＣＦ３、−（ＣＴｏ） ｚｃｌＩ（ＣＨｓ）ＣＦｉお
よび−ｉｃ＋ｔｔ）ｍｃｔｌｈのものが優れていた。Regarding autonomic nervous system imbalance as a side effect, according to the method described in Clinical Pharmacology, Vol. 11 (1980), No. 1, pages 17 and 27, the derivatives of the present invention were treated with When examining the effect on neurons (degree of generation of heat sensation) and the effect on bladder movement (frequency of urination) in cats, it was found that the R1 is -(Cth)gcF
i, -(CHz) zch, -CHtCIl (CH3
)CF3, -(CTo)zclI(CHs)CFi and -ic+tt)mctlh were superior.
比較例１〜２
前記Ｒ１が−（ＣＴｏ）ｓｅｔｌｉ （比較例１）およ
び−ＣＩ＋。Comparative Examples 1 and 2 R1 is -(CTo)setli (Comparative Example 1) and -CI+.
（Ｃｈ） ｔｃＦｚ （比較例２）の５−フルオロウラ
シル誘導体について生存日数延長率（ｒＬｓχ）および
治療係数（ＴＩ）を測定した。結果を第３表に示す。(Ch) The survival day extension rate (rLsχ) and therapeutic index (TI) were measured for the 5-fluorouracil derivative of tcFz (Comparative Example 2). The results are shown in Table 3.
本発明の５−フルオロウラシル誘導体は、優れた抗癌効
果を存し、かつ従来公知の５−フルオロウラシル誘導体
のような消化管に対する強い毒性や自律神経系障害がな
い。The 5-fluorouracil derivatives of the present invention have excellent anticancer effects and are free from strong toxicity to the gastrointestinal tract and autonomic nervous system disorders unlike conventionally known 5-fluorouracil derivatives.
以上that's all
Claims (1)
とがある炭素数１〜１０の含フッ素有機基を示す。） で表わされる５−フルオロウラシル誘導体。 ２、前記Ｒ＾１が式： −（ＣＨ＿２）＿ｈ−ＣＨ（Ｒ＾２）−ＣＦ＿３（式中
、Ｒ＾２は水素または炭素数１〜４の脂肪族基、ｈは０
または１〜４の整数を示す。）で表わされる基である特
許請求の範囲第１項記載の５−フルオロウラシル誘導体
。 ３、前記Ｒ＾１が式： −ＣＨ＿２−（ＣＲ＾３＿２）＿ｉ−ＣＨＦ＿２（式中
、Ｒ＾３は水素またはフッ素、ｉは０または１〜５の整
数を示す。） で表わされる基である特許請求の範囲第１項記載の５−
フルオロウラシル誘導体。 ４、前記Ｒ＾１が式： −（ＣＨ＿２）＿ｊ−ＣＨＦ（Ｒ＾４） （式中、Ｒ＾４は水素またはメチル基、ｊは１〜４の整
数を示す。） で表わされる基である特許請求の範囲第１項記載の５−
フルオロウラシル誘導体。 ５、前記Ｒ＾１が−ＣＨ＿２ＣＦ＿３、−（ＣＨ＿２）
＿２ＣＦ＿３、−（ＣＨ＿２）＿３ＣＦ＿３、−（ＣＨ
＿２）＿４ＣＦ＿３、−（ＣＨ＿２）＿５ＣＦ＿３、−
ＣＨ＿２ＣＨ（ＣＨ＿３）ＣＦ＿３、−ＣＨ＿２ＣＨ（
Ｃ＿２Ｈ＿５）ＣＦ＿３、−ＣＨ＿２ＣＨ（Ｃ＿３Ｈ＿
７）ＣＦ＿３、−ＣＨ＿２ＣＨ（Ｃ＿４Ｈ＿９）ＣＦ＿
３または−（ＣＨ＿２）＿２ＣＨ（ＣＨ＿３）ＣＦ＿３
である特許請求の範囲第１項または第２項記載の５−フ
ルオロウラシル誘導体。 ６、前記Ｒ＾１が−（ＣＨ＿２）＿２ＣＦ＿３、−（Ｃ
Ｈ＿２）＿３ＣＦ＿３、−ＣＨ＿２ＣＨ（ＣＨ＿３）Ｃ
Ｆ＿３または−（ＣＨ＿２）＿２ＣＨ（ＣＨ＿３）ＣＦ
＿３である特許請求の範囲第１項、第２項または第５項
記載の５−フルオロウラシル誘導体。 ７、前記Ｒ＾１が−ＣＨ＿２ＣＨＦ＿２、−（ＣＨ＿２
）＿２ＣＨＦ＿２、−（ＣＨ＿２）＿３ＣＨＦ＿２、−
（ＣＨ＿２）＿４ＣＨＦ＿２または−（ＣＨ＿２）＿５
ＣＨＦ＿２である特許請求の範囲第１項または第３項記
載の５−フルオロウラシル誘導体。 ８、前記Ｒ＾１が−（ＣＨ＿２）＿５ＣＨＦ＿２である
特許請求の範囲第１項、第３項または第７項記載の５−
フルオロウラシル誘導体。 ９、前記Ｒ＾１が−（ＣＨ＿２）＿４ＣＨ＿２Ｆまたは
−（ＣＨ＿２）＿４ＣＨＦＣＨ＿３である特許請求の範
囲第１項または第４項記載の５−フルオロウラシル誘導
体。 １０、前記Ｒ＾１が−（ＣＨ＿２）＿２ＮＨＣ（＝０）
ＣＨ＿２ＳＣＨＦ＿２である特許請求の範囲第１項記載
の５−フルオロウラシル誘導体。[Claims] 1. Formulas: ▲ Numerical formulas, chemical formulas, tables, etc. A 5-fluorouracil derivative represented by: 2. The above R^1 has the formula: -(CH_2)_h-CH(R^2)-CF_3 (wherein R^2 is hydrogen or an aliphatic group having 1 to 4 carbon atoms, h is 0
Or indicates an integer from 1 to 4. ) The 5-fluorouracil derivative according to claim 1, which is a group represented by: 3. The above R^1 is a group represented by the formula: -CH_2-(CR^3_2)_i-CHF_2 (wherein R^3 is hydrogen or fluorine, and i represents 0 or an integer from 1 to 5) 5- of Claim 1
Fluorouracil derivatives. 4. The above R^1 is a group represented by the formula: -(CH_2)_j-CHF(R^4) (wherein R^4 is hydrogen or a methyl group, and j is an integer from 1 to 4) 5- of Claim 1
Fluorouracil derivatives. 5. The above R^1 is -CH_2CF_3, -(CH_2)
_2CF_3, -(CH_2)_3CF_3, -(CH
_2)_4CF_3, -(CH_2)_5CF_3, -
CH_2CH(CH_3)CF_3, -CH_2CH(
C_2H_5) CF_3, -CH_2CH(C_3H_
7) CF_3, -CH_2CH(C_4H_9)CF_
3 or -(CH_2)_2CH(CH_3)CF_3
The 5-fluorouracil derivative according to claim 1 or 2, which is 6. The above R^1 is -(CH_2)_2CF_3, -(C
H_2)_3CF_3, -CH_2CH(CH_3)C
F_3 or -(CH_2)_2CH(CH_3)CF
The 5-fluorouracil derivative according to claim 1, 2 or 5, which is _3. 7. The above R^1 is -CH_2CHF_2, -(CH_2
)_2CHF_2, -(CH_2)_3CHF_2, -
(CH_2)_4CHF_2 or -(CH_2)_5
The 5-fluorouracil derivative according to claim 1 or 3, which is CHF_2. 8. 5- according to claim 1, 3 or 7, wherein the R^1 is -(CH_2)_5CHF_2
Fluorouracil derivatives. 9. The 5-fluorouracil derivative according to claim 1 or 4, wherein the R^1 is -(CH_2)_4CH_2F or -(CH_2)_4CHFCH_3. 10. The above R^1 is -(CH_2)_2NHC (=0)
5-fluorouracil derivative according to claim 1, which is CH_2SCHF_2.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP87114796A EP0264080B1 (en) | 1986-10-09 | 1987-10-09 | 5-fluorouracil derivatives, pharmaceutical composition and use |
| US07/106,423 US4810790A (en) | 1986-10-09 | 1987-10-09 | 5-fluorouracil derivatives useful as carcinostatic substances |
| DE8787114796T DE3781357T2 (en) | 1986-10-09 | 1987-10-09 | 5-FLUOROURACIL DERIVATIVES, PHARMACEUTICAL PREPARATION AND USE. |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP61-241118 | 1986-10-09 | ||
| JP24111886 | 1986-10-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS63225365A true JPS63225365A (en) | 1988-09-20 |
Family
ID=17069551
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP62110147A Pending JPS63225365A (en) | 1986-10-09 | 1987-05-06 | 5-fluorouracil derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS63225365A (en) |
-
1987
- 1987-05-06 JP JP62110147A patent/JPS63225365A/en active Pending
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