JPS6312476B2 - - Google Patents
Info
- Publication number
- JPS6312476B2 JPS6312476B2 JP5596682A JP5596682A JPS6312476B2 JP S6312476 B2 JPS6312476 B2 JP S6312476B2 JP 5596682 A JP5596682 A JP 5596682A JP 5596682 A JP5596682 A JP 5596682A JP S6312476 B2 JPS6312476 B2 JP S6312476B2
- Authority
- JP
- Japan
- Prior art keywords
- mice
- compound
- test
- altropyranoside
- deoxy
- 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
- 150000008191 D-altropyranosides Chemical class 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000002246 antineoplastic agent Substances 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 description 15
- 241000699670 Mus sp. Species 0.000 description 14
- 241000699666 Mus <mouse, genus> Species 0.000 description 7
- 230000000259 anti-tumor effect Effects 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- 201000005202 lung cancer Diseases 0.000 description 4
- 208000020816 lung neoplasm Diseases 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- BCMYXYHEMGPZJN-UHFFFAOYSA-N 1-chloro-2-isocyanatoethane Chemical compound ClCCN=C=O BCMYXYHEMGPZJN-UHFFFAOYSA-N 0.000 description 2
- 230000000719 anti-leukaemic effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- LZDSILRDTDCIQT-UHFFFAOYSA-N dinitrogen trioxide Inorganic materials [O-][N+](=O)N=O LZDSILRDTDCIQT-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 1
- -1 D-allose nitrosourea derivatives Chemical class 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VSOAQEOCSA-N L-altropyranose Chemical compound OC[C@@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-VSOAQEOCSA-N 0.000 description 1
- 208000007093 Leukemia L1210 Diseases 0.000 description 1
- FUSGACRLAFQQRL-UHFFFAOYSA-N N-Ethyl-N-nitrosourea Chemical compound CCN(N=O)C(N)=O FUSGACRLAFQQRL-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- OSTGTTZJOCZWJG-UHFFFAOYSA-N nitrosourea Chemical class NC(=O)N=NO OSTGTTZJOCZWJG-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
Landscapes
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は式〔〕で示されるD―アルトロピラ
ノシド誘導体即ち、メチル―4,6―O―ベンジ
リデン―3―〔3―(2―クロロエチル)―3―
ニトロソウレイド〕―3―デオキシ―α―D―ア
ルトロピラノシド及びこれを有効成分とする抗腫
瘍剤に関する。
従来より抗腫瘍作用及び抗白血病作用を有する
糖ニトロソ尿素誘導体は数多く知られているが、
化合物自体不安定で製剤化困難なものや、効果に
比し、毒性や副作用の大きいものが多く、医薬品
として問題が多く、かならずしも満足出来るもの
は無い。
本発明者等はこれらの問題を解決するため多数
の化合物を合成し鋭意研究の結果、先に優れた抗
腫瘍作用を示すD―アロースニトロソ尿素誘導
体、3―〔3―(2―クロロエチル)―3―ニト
ロソウレイド〕―3―デオキシ―D―アロースを
発明し特許出願(特願昭55―36200号)した。
本発明者等はさらに研究を進め、著しく高い抗
腫瘍活性を有し且つ低毒性の化合物を創製し本発
明を完成した。
本発明の化合物は式〔〕の化合物、メチル―
4,6―O―ベンジリデン―3―〔3―(2―ク
ロロエチル)ウレイド〕―3―デオキシ―α―D
―アルトロピラノシドをクロロホルム、アセト
ン,エーテル等の有機溶媒中で三二酸化窒素でニ
トロソ化することにより製造出来る。
式〔〕の化合物は、メチル―3―アミノ―
4,6―O―ベンジリデン―3―デオキシ―α―
D―アルトロピラノシド〔J.Chem.Soc.5288
(1963).〕をアセトン,アルコール等の有機溶媒
中で2―クロロエチルイソシアネートと反応させ
ることにより容易に製造出来る。
以下、本発明化合物の製造法及び抗腫瘍作用に
ついて詳細に説明する。
実施例
メチル4,6―O―ベンジリデン―3―〔3―
(2―クロロエチル)ウレイド〕―3―デオキシ
―α―D―アルトロピラノシド1.0gをクロロホ
ルム20mlに溶解し、0〜5℃に冷却し、ついで三
二酸化窒素のエーテル溶液を反応液が緑色になる
まで加え、30分間撹拌した後、室温で減圧濃縮す
る。濃縮残査に2―プロパノール10mlを加え、析
出した粉末をろ取する。このものを減圧乾燥して
淡黄色のメチル4,6―O―ベンジリデン―3―
〔3―(2―クロロエチル)―3―ニトロソウレ
イド〕―3―デオキシ―α―D―アルトロピラノ
シド0.8gを得た。
収 率 74%
融 点 130−131℃
比旋光度 〔α〕22 D84.6(C=1,CHCl3)
元素分析値 C17H22N3O7Cl
C% H% N%
計算値 49.09 5.33 10.11
実測値 49.21 5.39 10.02
IRスペクトル(KBr)
3480cm-1(νOH),3370cm-1(νNH)
1710cm-1(νC=O),1490cm-1(νNO)
NMRスペクトル(CDCl3―TMS)
δ 3.50(3H,s,CH3)
δ 4.80(1H,s,H―1)
δ 5.73(1H,s,CHPh)
δ 7.50(5H,s,CHPh)
δ 8.30(1H,d,NH,JNH,3=9Hz)
次に、本発明化合物の製造に使用する、原料化
合物〔〕の製法を参考例により具体的に説明す
る。
参考例
メチル3―アミノ―4,6―O―ベンジリデン
―3―デオキシ―α―D―アルトロピラノシド
2.0gを無水メタノール30mlに溶解し、0〜5℃
に冷却した後、撹拌しながら、2―クロロエチル
イソシアネート1.0mlを加え、30分間撹拌した後、
減圧濃縮する。得られた油状物質をシリカゲルカ
ラムクロマトグラフイー(Wako,c300,50g;
流出溶媒クロロホルム―メタノール95:5v/v)
で精製し、メチル4,6―O―ベンジリデン―3
―〔3―(2―クロロエチル)ウレイド〕―3―
デオキシ―α―D―アルトロピラノシド1.8gを
得る。
収 率 65%
比旋光度 〔α〕22 D48.8(C=1,CHCl3)
元素分析値 C17H23N2O6Cl
C% H% N%
計算値 52.78 5.99 7.25
実測値 52.57 5.91 7.05
IRスペクトル
3350cm-1(νOH,NH),1640cm-1(νC=0)
NMRスペクトル(CDCl3―TMS)
δ 3.40(3H,s,CH3)
δ 3.45(4H,bs,CH2CH2)
δ 4.70(1H,s,H―1)
δ 5.10(1H,bs,OH)
δ 5.60(1H,s,CHPh)
δ 6.05(2H,m,NH)
δ 7.50(5H,s,Ph)
次に本発明化合物の抗腫瘍作用を説明するため
試験例を示す。
試験例1 (抗白血病効果試験)
供試動物としてCDF1マウス、オス6週令、体
重22±1gを使用した。腹腔内投与試験では1群
7匹とし、経口投与試験では1群5匹とした。ロ
イケミヤL―1210結胞1×105細胞/マウスをマ
ウス腹腔内に移植し、その24時間後に化合物
〔〕を0.5%CMC水溶液に懸濁してマウスに腹
腔内投与又は経口投与した。
マウスの中間生存日数(1群7匹のときは4匹
目,1群5匹のときは3匹目が死亡するまでに要
した日数、以下MSDと略称する)及び60日間生
存した数を調査し、薬剤を投与しない群を対照と
して延命率(以下ILSと略称する)を算出した。
ILS(%)
=薬剤投与群のMSD―対照のMSD/対照のMSD×100
本試験結果は第1表に示す。
The present invention relates to D-altropyranoside derivatives represented by the formula [], namely methyl-4,6-O-benzylidene-3-[3-(2-chloroethyl)-3-
This invention relates to [nitrosourade]-3-deoxy-α-D-altropyranoside and an antitumor agent containing the same as an active ingredient. Many sugar nitrosourea derivatives have been known to have antitumor and antileukemia effects, but
Many of the compounds themselves are unstable and difficult to formulate, and many have toxicity and side effects that are greater than their effectiveness, causing many problems as pharmaceuticals, and none of them are necessarily satisfactory. In order to solve these problems, the present inventors synthesized a large number of compounds and, as a result of intensive research, found that D-allose nitrosourea derivatives, 3-[3-(2-chloroethyl)- He invented 3-nitrosouride]-3-deoxy-D-allose and filed a patent application (Japanese Patent Application No. 36,200/1983). The present inventors further advanced their research and completed the present invention by creating a compound with extremely high antitumor activity and low toxicity. The compound of the present invention is a compound of formula [], methyl-
4,6-O-benzylidene-3-[3-(2-chloroethyl)ureido]-3-deoxy-α-D
-It can be produced by nitrosating altropyranoside with nitrogen sesquioxide in an organic solvent such as chloroform, acetone, or ether. The compound of formula [] is methyl-3-amino-
4,6-O-benzylidene-3-deoxy-α-
D-Altropyranoside [J.Chem.Soc.5288
(1963). ] can be easily produced by reacting it with 2-chloroethyl isocyanate in an organic solvent such as acetone or alcohol. Hereinafter, the manufacturing method and antitumor effect of the compound of the present invention will be explained in detail. Example Methyl 4,6-O-benzylidene-3-[3-
Dissolve 1.0 g of (2-chloroethyl)ureido]-3-deoxy-α-D-altropyranoside in 20 ml of chloroform, cool it to 0-5°C, and then add an ether solution of nitrogen sesquioxide until the reaction mixture turns green. After stirring for 30 minutes, concentrate under reduced pressure at room temperature. Add 10 ml of 2-propanol to the concentrated residue and filter the precipitated powder. This product was dried under reduced pressure to produce a pale yellow methyl 4,6-O-benzylidene-3-
0.8 g of [3-(2-chloroethyl)-3-nitrosouride]-3-deoxy-α-D-altropyranoside was obtained. Yield 74% Melting point 130-131℃ Specific optical rotation [α] 22 D 84.6 (C=1, CHCl 3 ) Elemental analysis value C 17 H 22 N 3 O 7 Cl C% H% N% Calculated value 49.09 5.33 10.11 Actual value 49.21 5.39 10.02 IR spectrum (KBr) 3480cm -1 (ν OH ), 3370cm -1 (ν NH ) 1710cm -1 (ν C=O ), 1490cm -1 (ν NO ) NMR spectrum (CDCl 3 -TMS) δ 3.50 (3H, s, CH 3 ) δ 4.80 (1H, s, H-1) δ 5.73 (1H, s, CH Ph) δ 7.50 (5H, s, CH Ph ) δ 8.30 (1H, d, NH, J NH,3 =9 Hz) Next, the method for producing the raw material compound [] used for producing the compound of the present invention will be specifically explained using reference examples. Reference example Methyl 3-amino-4,6-O-benzylidene-3-deoxy-α-D-altropyranoside
Dissolve 2.0g in 30ml of anhydrous methanol and heat to 0-5℃.
After cooling to , 1.0 ml of 2-chloroethyl isocyanate was added while stirring, and after stirring for 30 minutes,
Concentrate under reduced pressure. The obtained oily substance was subjected to silica gel column chromatography (Wako, c300, 50g;
Effluent solvent chloroform-methanol 95:5v/v)
methyl 4,6-O-benzylidene-3
―[3-(2-chloroethyl)ureido]-3-
1.8 g of deoxy-α-D-altropyranoside is obtained. Yield 65% Specific rotation [α] 22 D 48.8 (C=1, CHCl 3 ) Elemental analysis value C 17 H 23 N 2 O 6 Cl C% H% N% Calculated value 52.78 5.99 7.25 Actual value 52.57 5.91 7.05 IR Spectrum 3350cm -1 (ν OH,NH ), 1640cm -1 (ν C=0 ) NMR spectrum (CDCl 3 -TMS) δ 3.40 (3H, s, CH 3 ) δ 3.45 (4H, bs, CH 2 CH 2 ) δ 4.70 (1H, s, H-1) δ 5.10 (1H, bs, OH) δ 5.60 (1H, s, CH Ph) δ 6.05 (2H, m, NH) δ 7.50 (5H, s, Ph) Next A test example is shown below to explain the antitumor effect of the compound of the present invention. Test Example 1 (Anti-leukemia effect test) A CDF 1 mouse, male, 6 weeks old, weighing 22±1 g was used as a test animal. In the intraperitoneal administration test, there were 7 mice per group, and in the oral administration test, there were 5 mice per group. Leukemia L-1210 nodules (1×10 5 cells/mouse) were intraperitoneally transplanted into mice, and 24 hours later, the compound [] was suspended in a 0.5% CMC aqueous solution and administered intraperitoneally or orally to mice. We investigated the median survival days of mice (the number of days required for the fourth mouse to die when there are 7 mice in a group, and the number of days required for the third mouse to die when there are 5 mice in a group, hereinafter abbreviated as MSD) and the number of mice that survived for 60 days. The survival rate (hereinafter abbreviated as ILS) was calculated using the group to which no drug was administered as a control. ILS (%) = MSD of drug administration group - MSD of control/MSD of control x 100 The results of this test are shown in Table 1.
【表】
試験例2 (抗ルイス肺癌効果試験)
供試動物としてBDF1マウス、オス6週令、体
重22±1gを1群5匹使用した。
ルイス肺癌細胞5×105/マウスを皮下に移植
し、24時間後に化合物〔〕を0.5%CMC水溶液
に懸濁して経口投与した。
マウスの中間生存日数及び60日間生存した数を
調査し、試験例1と同様な方法で本発明薬剤の効
果を評価した。
本試験の結果は第2表に示す。[Table] Test Example 2 (Anti-Lewis Lung Cancer Effect Test) As test animals, 5 BDF 1 mice, male, 6 weeks old, weighing 22±1 g, were used in each group. Lewis lung cancer cells (5×10 5 /mouse) were subcutaneously transplanted, and 24 hours later, the compound [] was suspended in a 0.5% CMC aqueous solution and orally administered. The median survival number of mice and the number of mice that survived for 60 days were investigated, and the effect of the drug of the present invention was evaluated in the same manner as in Test Example 1. The results of this test are shown in Table 2.
【表】
試験例3 (抗肺自家腫瘍効果試験)
妊娠後15〜16日目のddy系マウスにエチルニト
ロソウレア100mg/Kgを腹腔内投与し、その後出
産した仔が5週令に達した時より1群7匹(オ
ス)に対し、週2回,3週にわたつて化合物
〔〕を経口投与した。
9週目に解剖し、立体顕微鏡下で肺表面を観察
し、腫瘍数及び腫瘍面積を測定した。
本試験の結果は第3表に示す。[Table] Test Example 3 (Anti-lung autotumor efficacy test) Ethylnitrosourea 100mg/Kg was intraperitoneally administered to DDY mice on the 15th to 16th day after pregnancy, and when the offspring reached 5 weeks of age. The compound [ ] was orally administered to 7 male rats in each group twice a week for 3 weeks. The mice were dissected at 9 weeks, the lung surface was observed under a stereoscopic microscope, and the number of tumors and tumor area were measured. The results of this test are shown in Table 3.
【表】
以上の試験結果から明らかなように、本発明に
係る化合物〔〕は白血病、ルイス肺癌及びマウ
ス肺自家腫瘍に対して強力な抗腫瘍作用を発揮
し、これらの腫瘍に羅患した温血動物の生存期間
を延長し、腫瘍細胞の増殖を抑制した。
なお、本発明に係る化合物〔〕の急性毒性
LD50は腹腔内投与で192mg/Kg、経口投与で500
mg/Kg(いづれもDDY系オスマウス、体重20〜
22.5gを使用)であつた。[Table] As is clear from the above test results, the compound according to the present invention [] exerts strong antitumor effects against leukemia, Lewis lung cancer, and mouse lung autologous tumors, and has a strong antitumor effect on leukemia, Lewis lung cancer, and mouse lung autologous tumors. It extended the survival period of blood animals and suppressed the proliferation of tumor cells. In addition, the acute toxicity of the compound [] according to the present invention
LD 50 is 192mg/Kg for intraperitoneal administration and 500 for oral administration.
mg/Kg (all DDY male mice, weight 20~
22.5g was used).
Claims (1)
誘導体。 2 式〔〕で示されるD―アルトロピラノシド
誘導体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] 1. A D-altropyranoside derivative represented by the formula []. 2. An antitumor agent comprising a D-altropyranoside derivative represented by the formula [] as an active ingredient.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP5596682A JPS58174326A (en) | 1982-04-06 | 1982-04-06 | Novel arthropyranoside derivative and antineoplastic agnet containing said derivative as active component |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP5596682A JPS58174326A (en) | 1982-04-06 | 1982-04-06 | Novel arthropyranoside derivative and antineoplastic agnet containing said derivative as active component |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS58174326A JPS58174326A (en) | 1983-10-13 |
JPS6312476B2 true JPS6312476B2 (en) | 1988-03-18 |
Family
ID=13013811
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP5596682A Granted JPS58174326A (en) | 1982-04-06 | 1982-04-06 | Novel arthropyranoside derivative and antineoplastic agnet containing said derivative as active component |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS58174326A (en) |
-
1982
- 1982-04-06 JP JP5596682A patent/JPS58174326A/en active Granted
Also Published As
Publication number | Publication date |
---|---|
JPS58174326A (en) | 1983-10-13 |
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