JPS6318958B2 - - Google Patents
Info
- Publication number
- JPS6318958B2 JPS6318958B2 JP1206382A JP1206382A JPS6318958B2 JP S6318958 B2 JPS6318958 B2 JP S6318958B2 JP 1206382 A JP1206382 A JP 1206382A JP 1206382 A JP1206382 A JP 1206382A JP S6318958 B2 JPS6318958 B2 JP S6318958B2
- Authority
- JP
- Japan
- Prior art keywords
- fluoro
- formula
- carbon atoms
- cis
- acyl group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 125000002252 acyl group Chemical group 0.000 claims description 7
- 239000002246 antineoplastic agent Substances 0.000 claims description 6
- 229920006395 saturated elastomer Polymers 0.000 claims description 5
- 125000004417 unsaturated alkyl group Chemical group 0.000 claims description 4
- 125000001931 aliphatic group Chemical group 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
- 150000001875 compounds Chemical class 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- 229960000583 acetic acid Drugs 0.000 description 7
- 239000012362 glacial acetic acid Substances 0.000 description 7
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical class 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 6
- 238000004440 column chromatography Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- -1 5-fluoro-6-acetoxy-5'-O-acetyluridine Chemical compound 0.000 description 5
- ZPTBLXKRQACLCR-XVFCMESISA-N dihydrouridine Chemical class O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)CC1 ZPTBLXKRQACLCR-XVFCMESISA-N 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Chemical class 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 3
- 239000007789 gas Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Chemical class OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 3
- 229940045145 uridine Drugs 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 description 2
- 229960001674 tegafur Drugs 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- DEXFNLNNUZKHNO-UHFFFAOYSA-N 6-[3-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperidin-1-yl]-3-oxopropyl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1CCN(CC1)C(CCC1=CC2=C(NC(O2)=O)C=C1)=O DEXFNLNNUZKHNO-UHFFFAOYSA-N 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 241000725101 Clea Species 0.000 description 1
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 1
- KTMVKCZHYODLLY-PEBGCTIMSA-N [(2r,3s,4r,5r)-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl acetate Chemical compound O[C@@H]1[C@H](O)[C@@H](COC(=O)C)O[C@H]1N1C(=O)NC(=O)C=C1 KTMVKCZHYODLLY-PEBGCTIMSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 210000003567 ascitic fluid Anatomy 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
- 230000015572 biosynthetic process Effects 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
- 239000000969 carrier Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 125000003074 decanoyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C(*)=O 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000005534 hematocrit Methods 0.000 description 1
- 125000000268 heptanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 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
- 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
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- 125000001402 nonanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002801 octanoyl group Chemical group C(CCCCCCC)(=O)* 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000546 pharmaceutical excipient 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
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は、ジヒドロウリジン誘導体およびその
用途に関し、更に詳しくはcis−６−アルコキシ
−５−フルオロ−５，６−ジヒドロ−5′−Ｏ−ア
シルウリジンおよび抗腫瘍剤としての用途に関す
る。
ある種のジヒドロウリジン類は、特公昭41−
18945号公報に記載されている。
本発明者らは、新規ジヒドロウリジン誘導体を
開発すべく鋭意研究を重ねた結果、該公報には開
示のない新規誘導体および公知ならびに新規ジヒ
ドロウリジン誘導体の立体異性体を製造、分離す
ることに成功し、さらにこれら新規異性体は従来
抗腫瘍剤として用いられているテガフールなどに
比較してすぐれた抗腫瘍活性を有することを見い
出し本発明を完成するに至つた。
すなわち、本発明の要旨は、式：
〔式中、R1は炭素数２〜10の脂肪族アシル基
または芳香族アシル基、R2は炭素数１〜20の飽
和または不飽和アルキル基を表わす。〕
で示されるcis−６−アルコキシ−５−フルオロ
−５，６−ジヒドロ−5′−Ｏ−アシルウリジンお
よび化合物〔〕を有効成分とする抗腫瘍剤に存
する。
式〔〕中、５および６位の結合〓は単にシス
体を表示するのみであつて、化合物〔〕はｄ−
および１−体ならびにラセミ体を包含する。
式〔〕のピリジン骨核上の６位にあるアルコ
キシ基（−OR2）のアルキル基については、炭素
数の増加に従つて化学的安定性が増加する。好ま
しい炭素数は１〜20である。飽和アルキル基の具
体例としては、メチル、エチル、プロピル、ブチ
ル、ペンチル、ヘキシル、ヘプチル、オクチル、
ノニル、デシル、ドデシル、ヘキサデシル、オク
タデシルなどが挙げられ、これらは直鎖状または
分枝状であつてよい。不飽和アルキル基の具体例
としては、これらに対応する不飽和基が挙げられ
る。
リボース上の5′位にあるアシル基（R1）は、出
発物質の選択により定まるが、好ましい炭素数は
２〜10である。具体例としては、アセチル、プロ
ピオニル、ブチリル、ペンタノイル、ヘキサノイ
ル、ヘプタノイル、オクタノイル、ノナノイル、
デカノイル、ベンゾイル、ナフトイルなどどが挙
げられる。
本発明の化合物〔〕は、たとえば式：
〔式中、R1は前記と同意義。〕
で示される化合物を出発物質として、昭和57年１
月27日出願の特許願（発明の名称：ウリジン誘導
体の製法およびウリジン誘導体）に添付の明細書
に記載された製法によつて製造し、カラムクロマ
トグラフイにより立体異性体を分離して得ること
ができる。
本発明の化合物〔〕は、各種腫瘍、特に固形
癌、たとえば消化器癌、肺癌、乳癌などに対して
すぐれた作用を有する。
本発明の化合物〔〕は、2′および3′に水酸基
を有しているため、水に溶解し易い。抗腫瘍剤に
製剤する場合、所望により既知の薬理学的に許容
される担体、賦形剤、希釈剤などと混合し、自体
既知の製剤化方法により種々の剤形に製造され
る。
投与は、経口または非経口のいずれでも安全に
行うことができる。投与量は、腫瘍の種類、患者
の状態により、医師の処方に従つて定めなければ
ならないが、通常成人患者に対して、10〜300
mg／Kg／日、好ましくは40〜200mg／Kg／日の割
合で投与する。また、１日の投与量は１回または
数回にわけて投与することができる。
さらに、本発明の化合物〔〕は、既知の抗腫
瘍剤と組み合わせて用いることもできる。
次に実施例を示し本発明を具体的に説明する。
実施例 １
撹拌器、冷却器、ガス吹込口および温度計を備
えた容量200mlのダイフロン（商標、ダイキン工
業株式会社）樹脂製フラスコ中で5′−Ｏ−アセチ
ルウリジン3.0gを氷酢酸100mlに溶解し、室温下、
これにフツ素／窒素混合ガス（フツ素20％）を流
量50ml／minで１時間吹き込んだ。薄層クロマト
グラフイ（シリカゲルプレート60F254（メルク社）
５×10cm；クロロホルム：メタノール＝５：１）
で出発物質が消費されたことを確認し、紫外吸収
の消失から５，６−飽和化合物である５−フルオ
ロ−６−アセトキシ−5′−Ｏ−アセチルウリジン
の生成を認めた。
氷酢酸溶液50mlを室温で減圧乾固して無定形の
５−フルオロ−６−アセトキシ−5′−Ｏ−アセチ
ルウリジン1.5gを得た。 1H−NMR（d4−Me
OH；TMSi外部標準）δ＝2.12ppm（OCOCH3）。
残りの氷酢酸溶液50mlにメタノール50mlを加
え、３日間静置した後、室温で減圧乾固して薄層
クロマトグラフイ分析（前記と同様のプレートお
よび展開液）に付し、展開後プレートを200℃で
１時間加熱し、紫外線照射してスポツト位置を測
定したところ、Rfが0.57、0.55および0.51である
異性体の存在が確認された。得られた5′−Ｏ−ア
セチル−５−フルオロ−６−メトキシ−５，６−
ジヒドロウリジンを含む反応液を濃縮し、残渣を
カラムクロマトグラフイ〔シリカゲル（メルク
社）70〜230メツシユ、30cm×9.6cm2；溶媒：塩化
メチレン／メタノール＝10／１（容量）〕に対し、
流速１ml／min.で展開し、各フラクシヨン8gを
とり、同一成分を含むフラクシヨンを合してシス
体約375mgおよびトランス体約200mgを得た。シス
異性体のRfと 19F−NMR（d4−MeOH、トリフ
ルオロ酢酸外部標準）の結果を第１表に示す。
実施例 ２
実施例１と同様の手順で調製した5′−Ｏ−アセ
チル−５−フルオロ−６−アセトキシ−５，６−
ジヒドロウリジンの氷酢酸溶液50mlにｎ−ヘキサ
ノール50mlを加え、40℃で３日間撹拌した後、減
圧下に溶媒を留去し、残渣をカラムクロマトグラ
フイで精製した。 19F−NMR分析（d4−
MeOH；トリフルオロ酢酸外部標準においてδ
＝115.2ppm、129.4ppmおよび130.4ppmの化学シ
フトを示す異性体を含む5′−Ｏ−アセチル−５−
フルオロ−６−ヘキサノキシ−５，６−ジヒドロ
ウリジン1.5gを得た。これを実施例１と同様にカ
ラムクロマトグラフイにより分離してシス異性体
を得た。この異性体のRfおよび 19F−NMRの結
果を第１表に示す。
実施例 ３
実施例１と同様のフラスコで5′−Ｏ−ヘキサノ
イルウリジン3.0gを氷酢酸100mlに溶解し、室温
下、これにフツ素／窒素混合ガス（フツ素20％）
を流量60ml／min.で１時間吹き込んだ。実施例
１と同様の手順で出発物質の消費および５，６−
飽和化合物の生成を確認した。氷酢酸溶液50mlを
室温で減圧乾固して5′−Ｏ−ヘキサノイル−５−
フルオロ−６−アセトキシ−５，６−ジヒドロウ
リジン1.6gを得た。 1H−NMR（d4−MeOH：
TMSi外部標準）δ＝2.12ppm（OCOCH3）。
残りの氷酢酸50mlにｎ−ブタノール50mlを加
え、３日間撹拌し、溶媒を留去してカラムクロマ
トグラフイ（シリカゲル（メルク社）70〜230メ
ツシユ；クロロホルム：メタノール＝10：１）に
おいてRfが0.70、0.65および0.62である異性体を
含む5′−Ｏ−ヘキサノイル−５−フルオロ−６−
ブトキシ−５，６−ジヒドロウリジン1.3gを得
た。これを実施例１と同様にカラムクロマトグラ
フイにより分離してシス異性体を得た。この異性
体のRfと 19F−NMRの結果を第１表に示す。
実施例 ４
出発物質として5′−Ｏ−イソブチリルウリジン
を用い、メタノールの代りにブタノールを用いる
以外は実施例１の手順を繰り返してcis−６−ブ
トキシ−５−フルオロ−5′−Ｏ−イソブチリル−
５，６−ジヒドロウリジンを得た。この異性体の
Rfおよび 19F−NMRの結果を第１表に示す。
実施例 ５
メタノールの代りにブタノールを用いる以外は
実施例１の手順を繰り返して5′−Ｏ−アセチル−
cis−６−ブトキシ−５−フルオロ−５，６−ジ
ヒドロウラシルを得た。この異性体のRfおよび
19F−NMRの結果を第１表に示す。
実施例 ６
Ｓ−180A実験腫瘍を移植したマウスの移植７
日目の腹水（0.05ml／匹）を実験動物（JCL−
ICR系マウス（日本クレア株式会社）、１群５匹）
の腹腔内に接種した。実施例５で得た化合物およ
び対照薬剤（テガフール）を所定濃度になる様に
1.5％CMC含有生理食塩水に懸濁した。
腫瘍細胞接種24時間後から１日１回連続４日間
上記懸濁液（0.2ml／20g）を腹腔内投与し、一
方、対照群には同量の1.5％CMC含有生理食塩水
のみを腹腔内投与した。
接種７日後に腹水量を測定し、その１部をヘマ
トクリツト管に採つて、10000rpmで遠沈し、
TPCV（Total Packed Cell Volume）を算出し
た。薬剤投与群と対照群のTPCVの比（Ｔ／Ｃ
％）を求め、Ｔ／Ｃ＝100〜66を−、65〜41を＋、
40〜11を＋＋、10〜０を＋＋＋とした。結果を第
２表に示す。
The present invention relates to dihydrouridine derivatives and their uses, and more particularly to cis-6-alkoxy-5-fluoro-5,6-dihydro-5'-O-acyluridines and their uses as antitumor agents. Certain dihydrouridines are classified as
It is described in Publication No. 18945. As a result of intensive research to develop new dihydrouridine derivatives, the present inventors succeeded in producing and separating a new derivative not disclosed in the publication and stereoisomers of known and new dihydrouridine derivatives. Furthermore, it was discovered that these new isomers have superior antitumor activity compared to tegafur and the like, which have been conventionally used as antitumor agents, leading to the completion of the present invention. That is, the gist of the present invention is that the formula: [In the formula, R 1 represents an aliphatic acyl group or aromatic acyl group having 2 to 10 carbon atoms, and R 2 represents a saturated or unsaturated alkyl group having 1 to 20 carbon atoms. ] An antitumor agent containing cis-6-alkoxy-5-fluoro-5,6-dihydro-5'-O-acyluridine and the compound [ ] as active ingredients. In the formula [], the bonds at the 5 and 6 positions simply represent the cis form, and the compound [] is d-
and 1- and racemic forms. The chemical stability of the alkyl group of the alkoxy group ( -OR2 ) at the 6-position on the pyridine core of formula [] increases as the number of carbon atoms increases. The preferred number of carbon atoms is 1-20. Specific examples of saturated alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl,
Examples include nonyl, decyl, dodecyl, hexadecyl, octadecyl, etc., which may be linear or branched. Specific examples of the unsaturated alkyl group include corresponding unsaturated groups. The acyl group (R 1 ) at the 5' position on the ribose is determined by the selection of the starting material, but preferably has 2 to 10 carbon atoms. Specific examples include acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl,
Examples include decanoyl, benzoyl, naphthoyl, etc. The compound [] of the present invention has the formula: [In the formula, R 1 has the same meaning as above. ] Using the compound shown as a starting material,
Produced by the production method described in the specification attached to the patent application filed on May 27th (Title of invention: Process for producing uridine derivatives and uridine derivatives), and obtained by separating stereoisomers by column chromatography. Can be done. The compound [ ] of the present invention has excellent effects on various tumors, especially solid cancers such as gastrointestinal cancer, lung cancer, and breast cancer. The compound [ ] of the present invention has 2' and 3' hydroxyl groups and is therefore easily soluble in water. When formulated into an antitumor agent, it is mixed with known pharmacologically acceptable carriers, excipients, diluents, etc., if desired, and manufactured into various dosage forms by per se known formulation methods. Administration can be safely carried out either orally or parenterally. The dosage must be determined according to the doctor's prescription depending on the type of tumor and patient's condition, but it is usually 10 to 300 mg for adult patients.
It is administered at a rate of mg/Kg/day, preferably 40-200 mg/Kg/day. Moreover, the daily dose can be administered once or in several divided doses. Furthermore, the compound of the present invention [ ] can also be used in combination with known antitumor agents. Next, the present invention will be specifically explained with reference to Examples. Example 1 3.0 g of 5'-O-acetyluridine is dissolved in 100 ml of glacial acetic acid in a 200 ml capacity Diflon (trademark, Daikin Industries, Ltd.) resin flask equipped with a stirrer, condenser, gas inlet and thermometer. At room temperature,
A fluorine/nitrogen mixed gas (fluorine 20%) was blown into this at a flow rate of 50 ml/min for 1 hour. Thin layer chromatography (silica gel plate 60F 254 (Merck)
5×10cm; Chloroform:methanol=5:1)
It was confirmed that the starting material was consumed, and the production of 5-fluoro-6-acetoxy-5'-O-acetyluridine, a 5,6-saturated compound, was confirmed from the disappearance of ultraviolet absorption. 50 ml of the glacial acetic acid solution was dried under reduced pressure at room temperature to obtain 1.5 g of amorphous 5-fluoro-6-acetoxy-5'-O-acetyluridine. 1 H−NMR (d 4 −Me
OH; TMSi external standard) δ = 2.12 ppm (OCOCH 3 ). Add 50 ml of methanol to the remaining 50 ml of glacial acetic acid solution, let it stand for 3 days, dry it under reduced pressure at room temperature, and subject it to thin layer chromatography analysis (using the same plate and developing solution as above). After heating at 200°C for 1 hour and measuring the spot positions by irradiating with ultraviolet rays, the presence of isomers with Rf of 0.57, 0.55, and 0.51 was confirmed. The obtained 5'-O-acetyl-5-fluoro-6-methoxy-5,6-
The reaction solution containing dihydrouridine was concentrated, and the residue was subjected to column chromatography [silica gel (Merck & Co., Ltd.) 70-230 mesh, 30 cm x 9.6 cm 2 ; solvent: methylene chloride/methanol = 10/1 (volume)].
The mixture was developed at a flow rate of 1 ml/min., 8 g of each fraction was taken, and fractions containing the same components were combined to obtain about 375 mg of cis isomer and about 200 mg of trans isomer. Table 1 shows the Rf of the cis isomer and the results of 19 F-NMR (d 4 -MeOH, trifluoroacetic acid external standard). Example 2 5'-O-acetyl-5-fluoro-6-acetoxy-5,6- prepared in a similar manner to Example 1
After adding 50 ml of n-hexanol to 50 ml of a glacial acetic acid solution of dihydrouridine and stirring at 40°C for 3 days, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography. 19F -NMR analysis ( d4-
MeOH; δ in trifluoroacetic acid external standard
= 5'-O-acetyl-5- with isomers showing chemical shifts of 115.2ppm, 129.4ppm and 130.4ppm
1.5 g of fluoro-6-hexanoxy-5,6-dihydrouridine was obtained. This was separated by column chromatography in the same manner as in Example 1 to obtain the cis isomer. The Rf and 19 F-NMR results of this isomer are shown in Table 1. Example 3 In a flask similar to Example 1, 3.0 g of 5'-O-hexanoyl uridine was dissolved in 100 ml of glacial acetic acid, and a fluorine/nitrogen mixed gas (fluorine 20%) was added to this at room temperature.
was blown for 1 hour at a flow rate of 60 ml/min. Consumption of starting material and 5,6-
The formation of saturated compounds was confirmed. Dry 50ml of glacial acetic acid solution under reduced pressure at room temperature to obtain 5'-O-hexanoyl-5-
1.6 g of fluoro-6-acetoxy-5,6-dihydrouridine was obtained. 1H -NMR ( d4 -MeOH:
TMSi external standard) δ = 2.12 ppm (OCOCH 3 ). Add 50 ml of n-butanol to the remaining 50 ml of glacial acetic acid, stir for 3 days, distill off the solvent, and perform column chromatography (silica gel (Merck) 70-230 mesh; chloroform:methanol = 10:1) to 5'-O-hexanoyl-5-fluoro-6- with isomers that are 0.70, 0.65 and 0.62
1.3 g of butoxy-5,6-dihydrouridine was obtained. This was separated by column chromatography in the same manner as in Example 1 to obtain the cis isomer. Table 1 shows the Rf and 19 F-NMR results of this isomer. Example 4 The procedure of Example 1 was repeated using 5'-O-isobutyryl uridine as the starting material and butanol instead of methanol to prepare cis-6-butoxy-5-fluoro-5'-O- Isobutyryl
5,6-dihydrouridine was obtained. of this isomer
The Rf and 19 F-NMR results are shown in Table 1. Example 5 The procedure of Example 1 was repeated except that butanol was used instead of methanol to prepare 5'-O-acetyl-
Cis-6-butoxy-5-fluoro-5,6-dihydrouracil was obtained. Rf of this isomer and
The results of 19 F-NMR are shown in Table 1. Example 6 Transplantation 7 of mice transplanted with S-180A experimental tumor
Ascites (0.05ml/animal) was collected from experimental animals (JCL-
ICR mouse (Clea Japan Co., Ltd., 5 mice per group)
was inoculated intraperitoneally. The compound obtained in Example 5 and the control drug (tegafur) were added to a predetermined concentration.
It was suspended in physiological saline containing 1.5% CMC. The above suspension (0.2 ml/20 g) was intraperitoneally administered once a day for 4 consecutive days starting 24 hours after tumor cell inoculation, while the same amount of physiological saline containing 1.5% CMC was intraperitoneally administered to the control group. administered. Seven days after inoculation, the amount of ascitic fluid was measured, and a portion of it was taken into a hematocrit tube and centrifuged at 10,000 rpm.
TPCV (Total Packed Cell Volume) was calculated. Ratio of TPCV between drug administration group and control group (T/C
%), T/C=100~66 -, 65~41 +,
40-11 was set as ++, and 10-0 was set as +++. The results are shown in Table 2.
【表】【table】
Claims (1)
または芳香族アシル基、R2は炭素数１〜20の飽
和または不飽和アルキル基を表わす。〕 で示されるcis−６−アルコキシ−５−フルオロ
−５，６−ジヒドロ−5′−Ｏ−アシルウリジン。 ２ 式： 〔式中、R1は炭素数２〜10の脂肪族アシル基
または芳香族アシル基、R2は炭素数１〜20の飽
和または不飽和アルキル基を表わす。〕 で示されるcis−６−アルコキシ−５−フルオロ
−５，６−ジヒドロ−5′−Ｏ−アシルウリジンを
有効成分とする抗腫瘍剤。[Claims] 1 Formula: [In the formula, R 1 represents an aliphatic acyl group or aromatic acyl group having 2 to 10 carbon atoms, and R 2 represents a saturated or unsaturated alkyl group having 1 to 20 carbon atoms. ] cis-6-alkoxy-5-fluoro-5,6-dihydro-5'-O-acyluridine. 2 formula: [In the formula, R 1 represents an aliphatic acyl group or aromatic acyl group having 2 to 10 carbon atoms, and R 2 represents a saturated or unsaturated alkyl group having 1 to 20 carbon atoms. ] An antitumor agent containing cis-6-alkoxy-5-fluoro-5,6-dihydro-5'-O-acyluridine as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1206382A JPS58128398A (en) | 1982-01-28 | 1982-01-28 | Dihydrouridine derivative and its use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1206382A JPS58128398A (en) | 1982-01-28 | 1982-01-28 | Dihydrouridine derivative and its use |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS58128398A JPS58128398A (en) | 1983-07-30 |
| JPS6318958B2 true JPS6318958B2 (en) | 1988-04-20 |
Family
ID=11795137
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1206382A Granted JPS58128398A (en) | 1982-01-28 | 1982-01-28 | Dihydrouridine derivative and its use |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS58128398A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6352558U (en) * | 1986-09-26 | 1988-04-08 |
-
1982
- 1982-01-28 JP JP1206382A patent/JPS58128398A/en active Granted
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6352558U (en) * | 1986-09-26 | 1988-04-08 |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS58128398A (en) | 1983-07-30 |
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