JPH0314316B2 - - Google Patents
Info
- Publication number
- JPH0314316B2 JPH0314316B2 JP58101691A JP10169183A JPH0314316B2 JP H0314316 B2 JPH0314316 B2 JP H0314316B2 JP 58101691 A JP58101691 A JP 58101691A JP 10169183 A JP10169183 A JP 10169183A JP H0314316 B2 JPH0314316 B2 JP H0314316B2
- Authority
- JP
- Japan
- Prior art keywords
- camptothecin
- chloroform
- mmol
- water
- formula
- 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 - Lifetime
Links
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 claims description 49
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical group C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 claims description 49
- 229940127093 camptothecin Drugs 0.000 claims description 49
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 claims description 49
- 125000004432 carbon atom Chemical group C* 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 229910052783 alkali metal Inorganic materials 0.000 claims description 5
- -1 alkali metal salt Chemical class 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 150000001340 alkali metals Chemical group 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 25
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 11
- 229960004926 chlorobutanol Drugs 0.000 description 10
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000010898 silica gel chromatography Methods 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 8
- 238000001816 cooling Methods 0.000 description 7
- SURQXAFEQWPFPV-UHFFFAOYSA-L iron(2+) sulfate heptahydrate Chemical compound O.O.O.O.O.O.O.[Fe+2].[O-]S([O-])(=O)=O SURQXAFEQWPFPV-UHFFFAOYSA-L 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000005457 ice water Substances 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- 125000003158 alcohol group Chemical group 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- 150000002978 peroxides Chemical class 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 238000007348 radical reaction Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- HPSUBMDJBRNXKK-VEIFNGETSA-M sodium;(2r)-2-hydroxy-2-[8-(hydroxymethyl)-9-oxo-11h-indolizino[1,2-b]quinolin-7-yl]butanoate Chemical compound [Na+].C1=CC=C2C=C(CN3C4=CC(=C(C3=O)CO)[C@@](O)(C([O-])=O)CC)C4=NC2=C1 HPSUBMDJBRNXKK-VEIFNGETSA-M 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- GCFHZZWXZLABBL-UHFFFAOYSA-N ethanol;hexane Chemical compound CCO.CCCCCC GCFHZZWXZLABBL-UHFFFAOYSA-N 0.000 description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 description 2
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- SZTZIXLREYEION-QHCPKHFHSA-N 11-propylcamptothecin Chemical compound C1=CC=C2C(CCC)=C(CN3C(C4=C([C@@](C(=O)OC4)(O)CC)C=C33)=O)C3=NC2=C1 SZTZIXLREYEION-QHCPKHFHSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- MYQKIWCVEPUPIL-QFIPXVFZSA-N 7-ethylcamptothecin Chemical compound C1=CC=C2C(CC)=C(CN3C(C4=C([C@@](C(=O)OC4)(O)CC)C=C33)=O)C3=NC2=C1 MYQKIWCVEPUPIL-QFIPXVFZSA-N 0.000 description 1
- XRCMSKXVQYEFOZ-NRFANRHFSA-N 7-methylcamptothecin Chemical compound C1=CC=C2C(C)=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 XRCMSKXVQYEFOZ-NRFANRHFSA-N 0.000 description 1
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical class [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- UXTMROKLAAOEQO-UHFFFAOYSA-N chloroform;ethanol Chemical compound CCO.ClC(Cl)Cl UXTMROKLAAOEQO-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229960002089 ferrous chloride Drugs 0.000 description 1
- 239000011790 ferrous sulphate Substances 0.000 description 1
- 235000003891 ferrous sulphate Nutrition 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- NMCUIPGRVMDVDB-UHFFFAOYSA-L iron dichloride Chemical compound Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 description 1
- 229910000359 iron(II) sulfate Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000013076 target substance Substances 0.000 description 1
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は、新規な7−ヒドロキシアルキルカン
プトテシン誘導体に関する。
本発明者らは、先に、ラジカル反応により、カ
ンプトテシンの7位に、アルキル基又はアラルキ
ル基を直接導入することに成功したが、さらに、
上記のラジカル反応に際して、7−ヒドロキシア
ルキルカンプトテシン誘導体が生成することを見
出した。
本発明はかかる知見に基づくものである。
本発明に係る新規な7−ヒドロキシアルキルカ
ンプトテシン誘導体は、一般式
又は
(各式中Aは、2個ないし5個の炭素原子を有す
る直鎖状または分枝鎖状のアルキレン基であり、
Mはアルカリ金属原子を表わす。ただし、A中の
水酸基の結合した炭素原子とカンプトテシンの7
位の炭素原子とは直接結合していないものとす
る)で表わされるものである。
本発明に係るこの新規な7−ヒドロキシアルキ
ルカンプトテシン誘導体はカンプトテシンを出発
物質とし、これを金層イオンの存在下に硫酸と水
と過酸化物を用い、一般式ROH(式中Rは2ない
し5個の炭素原子を有する直鎖状または分枝鎖状
のアルキル基を表わす)で表わされるアルコール
とラジカル反応させる際に7−アルキルカンプト
テシン誘導体とともに得られるものである。この
場合、上記の金属イオンとしては、金属塩を水に
溶解させることにより、その金属イオンを反応液
中に生成せしめ存在させることができる。すなわ
ち、本発明の化合物は、カンプトテシン、金属
塩、硫酸および上記の一般式ROHで表わされる
アルコールを任意の順序で水に溶解しておき、こ
れに過酸化物を加え、撹拌するという操作によつ
て製造することができる。
この操作は、通常は、金属塩を水に溶解し、こ
れにカンプトテシンを懸濁させ、次いでこれに硫
酸を加え溶解し、さらに前述の、一般式ROHで
表わされるアルコールを加えた後、氷冷撹拌下に
過酸化物を加え、室温に戻して撹拌することによ
り行うことができる。上記の金属塩の例としては
硫酸第一鉄、塩化第一鉄、などの第一鉄塩があげ
られ、過酸化物の例としては、過酸化水素、第三
級ブチルヒドロパーオキサイドなどがあげられ
る。
前記のROHで表わされるアルコールは、エタ
ノール、プロパノール、ブタノールおよびペンタ
ノールであるが、その炭化水素基部分は直鎖状で
あつても分枝鎖状であつてもよいし、また、これ
らのアルコールは第一級、第二級または第三級の
いずれであつてもよい。これらのアルコールとカ
ンプトテシンとを用いて前記の反応を行うと前記
のアルコールのアルキル基中のいずれかの炭素原
子が、カンプトテシンの7位の炭素原子と結合す
る。その結果として、1つの反応から1種もしく
はそれ以上の7−ヒドロキシアルキルカンプトテ
シン誘導体が生成する。例えば、n−プロパノー
ルの場合は、下記の2種類の誘導体が生成する。
The present invention relates to novel 7-hydroxyalkylcamptothecin derivatives. The present inventors previously succeeded in directly introducing an alkyl group or an aralkyl group into the 7-position of camptothecin by a radical reaction.
It has been found that 7-hydroxyalkylcamptothecin derivatives are produced during the above radical reaction. The present invention is based on this knowledge. The novel 7-hydroxyalkylcamptothecin derivative according to the present invention has the general formula or (In each formula, A is a linear or branched alkylene group having 2 to 5 carbon atoms,
M represents an alkali metal atom. However, the carbon atom bonded to the hydroxyl group in A and the 7 of camptothecin
(assuming that it is not directly bonded to the carbon atom in the position). This novel 7-hydroxyalkylcamptothecin derivative according to the present invention is produced using camptothecin as a starting material, which is prepared using sulfuric acid, water, and peroxide in the presence of gold ion, and is prepared using the general formula ROH (wherein R is 2 to 5). It is obtained together with a 7-alkylcamptothecin derivative when it is subjected to a radical reaction with an alcohol represented by a linear or branched alkyl group having 7 carbon atoms. In this case, the above-mentioned metal ions can be generated and present in the reaction solution by dissolving a metal salt in water. That is, the compound of the present invention can be prepared by dissolving camptothecin, a metal salt, sulfuric acid, and the alcohol represented by the above general formula ROH in water in any order, adding peroxide thereto, and stirring. It can be manufactured by This operation usually involves dissolving the metal salt in water, suspending camptothecin therein, adding sulfuric acid to dissolve it, then adding the aforementioned alcohol represented by the general formula ROH, and cooling it on ice. This can be carried out by adding peroxide while stirring, returning the temperature to room temperature, and stirring. Examples of the above metal salts include ferrous salts such as ferrous sulfate and ferrous chloride, and examples of peroxides include hydrogen peroxide and tertiary butyl hydroperoxide. It will be done. The alcohols represented by ROH above are ethanol, propanol, butanol, and pentanol, but the hydrocarbon group portion thereof may be linear or branched, and these alcohols may be primary, secondary or tertiary. When the above reaction is carried out using these alcohols and camptothecin, any carbon atom in the alkyl group of the alcohol bonds with the carbon atom at the 7-position of camptothecin. As a result, one or more 7-hydroxyalkylcamptothecin derivatives are produced from one reaction. For example, in the case of n-propanol, the following two types of derivatives are produced.
【式】 7−(1−ヒド ロキシメチルエチル)カンプトテシン[Formula] 7-(1-hydro (roxymethylethyl)camptothecin
【式】 7−(3−ヒ
ドロキシプロピル)カンプトテシン
しかしながら、用いたアルコールのα位の炭素
原子(水酸基の結合した炭素原子)はカンプトテ
シンの7位の炭素原子に対し直接は結合しない。
結局、前記の反応に際し、得られる本発明の化
合物は、前記式()における7位の基−A−
OHとして列挙すると次のとおりとなる。[Formula] 7-(3-hydroxypropyl)camptothecin However, the α-position carbon atom (the carbon atom to which the hydroxyl group is bonded) of the alcohol used does not directly bond to the 7-position carbon atom of camptothecin. In the end, the compound of the present invention obtained in the above reaction has a group -A-
When enumerated as OH, it becomes as follows.
【表】【table】
【表】【table】
【表】
なお、前記反応においては、本発明の新規化合
物の他に、用いたアルコールにおける炭化水素基
より炭素原子数の1つ少いアルキル基がカンプト
テシンの7位に結合した形の7−アルキルカンプ
トテシンが生成する。
前記の反応液からの目的物質の分離、精製は、
例えば、反応混合物をクロロホルム抽出し、溶媒
を留去させて得られる残留分をシリカゲルカラム
クロマトグラフイーにかけることにより行われ
る。
前掲の式で表わされる7−ヒドロキシアルキル
カンプトテシンは、これをアルカリ金属水酸化物
とともに水に溶解すると前記式のE環が開裂して
カルボン酸基を生じ、カルボン酸のアルカリ金属
塩が得られる(前記式及び後記実施例7、8、
9参照)。
したがつて、本発明は、前記の7−ヒドロキシ
アルキルカンプトテシン誘導体とともに、そのア
ルカリ金属塩を提供するものである。
本発明に係る新規な7−ヒドロキシアルキルカ
ンプトテシン誘導体は、その7位の置換基にある
ヒドロキシ基の反応性により、それが容易に他の
置換基に変わり得るので、そのため、この物質を
用いて多くの有用な置換体を製造することができ
るので、医薬特に制ガン剤、およびその製造中間
体として有用な物質である。例えば、後記参考例
1、2に示されているように、この7−ヒドロキ
シアルキルカンプトテシン誘導体は、定量的に7
−クロロアルキルカンプトテシン誘導体に変換す
ることができ、さらにそれから、7−アミノアル
キルカンプトテシン誘導体に変換することができ
る。この7−アミノアルキルカンプトテシン誘導
体は水溶性の塩酸塩に変換することができる。
次に本発明の実施例および参考例を掲げる。
実施例 1
7−(2−ヒドロキシエチル)カンプトテシン
(式中、A=−CH2CH2−)
硫酸第1鉄・7水和物(FeSO4・7H2O;200
mg、0.72mmol)を水(10ml)に溶解し、これに
カンプトテシン(500mg、1.43mmol)を懸濁し、
濃硫酸(5ml)を加え、溶解する。これに、エタ
ノール(5ml)を加えた後、氷冷下30%過酸化水
素水(1ml)をゆつくり滴下し、その後、室温で
1時間撹拌する。反応混合物を氷水(100ml)に
注ぎ、クロロホルムで抽出(100ml×10回)する。
このクロロホルム層を無水硫酸マグネシウムで乾
燥した後、溶媒を減圧下に留去し、残留物をシリ
カゲルカラムクロマトグラフイー(クロロホル
ム)で分離精製すると標記化合物(185mg、32.8
%)が得られる。この際、7−メチルカンプトテ
シン(210mg、40.8%)がともに得られ、原料
(82mg、16.4%)が回収される。
mp.264−266℃(dec.)(エタノールより)TLC.
Rf値0.05(30%アセトン−クロロホルム)ms.m/
e 392〔M+〕(C22H20N2O5=392.13)1H−NMR
(CDCl3−DMSO−d6中)δppm;1.00(3H,t,
J=6.9Hz),1.92(2H,q,J=6.9Hz),3.42
(2H,t,J=6.3Hz),3.99(2H,m),4.72(1H,
t,J=4.0Hz),5.35(2H,s),5.45(2H,
ABq),6.01(1H,s),7.58(1H,s),7.5−7.9
(2H,m),8.1−8.2(2H,m)。
実施例 2
7−(1−ヒドロキシメチルエチル)カンプト
テシン(式中、[Table] In addition to the novel compound of the present invention, in the above reaction, a 7-alkyl group in which an alkyl group having one carbon atom less than the hydrocarbon group in the alcohol used is bonded to the 7-position of camptothecin is used. Produced by camptothecin. Separation and purification of the target substance from the reaction solution are as follows:
For example, the reaction mixture is extracted with chloroform, the solvent is distilled off, and the resulting residue is subjected to silica gel column chromatography. When 7-hydroxyalkylcamptothecin represented by the above formula is dissolved in water together with an alkali metal hydroxide, the E ring of the above formula is cleaved to produce a carboxylic acid group, and an alkali metal salt of the carboxylic acid is obtained. The above formula and Examples 7 and 8 below,
9). Therefore, the present invention provides the above-mentioned 7-hydroxyalkylcamptothecin derivatives as well as their alkali metal salts. The novel 7-hydroxyalkylcamptothecin derivatives of the present invention can be easily converted into other substituents due to the reactivity of the hydroxy group in the 7-position substituent. Since it is possible to produce a useful substituted product of , it is a substance useful as a medicine, especially an anticancer drug, and an intermediate for its production. For example, as shown in Reference Examples 1 and 2 below, this 7-hydroxyalkylcamptothecin derivative quantitatively
-chloroalkylcamptothecin derivatives, which can be further converted into 7-aminoalkylcamptothecin derivatives. This 7-aminoalkylcamptothecin derivative can be converted into a water-soluble hydrochloride salt. Next, examples and reference examples of the present invention are listed. Example 1 7-(2-hydroxyethyl)camptothecin (wherein A=-CH 2 CH 2 -) Ferrous sulfate heptahydrate (FeSO 4 7H 2 O; 200
mg, 0.72 mmol) was dissolved in water (10 ml), camptothecin (500 mg, 1.43 mmol) was suspended in this,
Add concentrated sulfuric acid (5 ml) and dissolve. After adding ethanol (5 ml) to this, 30% hydrogen peroxide solution (1 ml) was slowly added dropwise under ice cooling, and the mixture was stirred at room temperature for 1 hour. Pour the reaction mixture into ice water (100 ml) and extract with chloroform (100 ml x 10 times).
After drying this chloroform layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform) to obtain the title compound (185 mg, 32.8
%) is obtained. At this time, 7-methylcamptothecin (210 mg, 40.8%) was obtained, and the raw material (82 mg, 16.4%) was recovered. mp.264−266℃ (dec.) (from ethanol) TLC.
Rf value 0.05 (30% acetone-chloroform) ms.m/
e 392 [M + ] (C 22 H 20 N 2 O 5 = 392.13) 1 H−NMR
(in CDCl 3 -DMSO-d 6 ) δppm; 1.00 (3H, t,
J = 6.9Hz), 1.92 (2H, q, J = 6.9Hz), 3.42
(2H, t, J=6.3Hz), 3.99 (2H, m), 4.72 (1H,
t, J = 4.0Hz), 5.35 (2H, s), 5.45 (2H,
ABq), 6.01 (1H, s), 7.58 (1H, s), 7.5-7.9
(2H, m), 8.1−8.2 (2H, m). Example 2 7-(1-hydroxymethylethyl)camptothecin (wherein
【式】)および7
−(3−ヒドロキシプロピル)カンプトテシン
(式中、A=−CH2CH2CH2−)
硫酸第1鉄・7水和物(FeSO4・7H2O;200
mg、0.72mmol)を水(10ml)に溶解し、これに
カンプトテシン(500mg、1.43mmol)を懸濁し、
濃硫酸(4ml)を加え溶解する。これにプロパノ
ール(4ml)を加えた後、氷冷下30%過酸化水素
水(1ml)をゆつくり滴下し、その後室温で0.5
時間撹拌する。反応混合物を氷水(100ml)に注
ぎ、クロロホルムで抽出(100ml×5回)する。
このクロロホルム層を無水硫酸マグネシウムで乾
燥した後、溶媒を減圧下で留去し、残留物をシリ
カゲルカラムクロマトグラフイー(クロロホル
ム)で分離精製すると、標記の7−(1−ヒドロ
キシメチルエチル)カンプトテシン(178mg、
30.5%)および7−(3−ヒドロキシプロピル)
カンプトテシン(68mg、11.6%)が得られる。こ
の際、7−エチルカンプトテシン(215mg、39.8
%)がともに得られる。
7−(1−ヒドロキシメチルエチル)カンプトテ
シン
mp.257−259℃(dec.)(エタノールより)TLC.
Rf値0.09(30%アセトン−クロロホルム)ms.m/
e 406〔M+〕(C23H22N2O5=406.15)1H=NMR
(DMSO−d6中)δppm;0.89(3H,t,J=7.3
Hz),1.48(3H,d,J=6.3Hz),1.88(2H,q,
J=7.3Hz),3.8−4.0(3H,m),4.90(1H,t,
J=4.9Hz),5.43(4H,s),6.50(1H,s),7.34
(1H,s),7.6−7.9(2H,m),8.16(1H,dd,
J=1.4および8.3Hz),8.37(1H,d,J=7.3Hz)。
7−(3−ヒドロキシプロピル)カンプトテシン
mp.210−212℃(dec.)(エタノール−n−ヘキ
サンより)
TLC.Rf値0.06(30%アセトン−クロロホルム)
ms.m/e 406〔M+〕(C23H22N2O5=406.15)1H
−NMR(DMSO−d6中)δppm;0.89(3H,t,
J=7.3Hz),1.87(4H,m),3.30(2H,m),3.51
(2H,t,J=5.8Hz),4.68(1H,br.s),5.37
(2H,s),5.43(2H,s),6.49(1H,s),7.33
(1H,s),7.5−7.9(2H,m),8.1−8.3(2H,
m)。
実施例 3
7−(1−ヒドロキシメチルプロピル)カンプ
トテシン(式中、[Formula]) and 7-(3-hydroxypropyl)camptothecin (wherein A=-CH 2 CH 2 CH 2 -) ferrous sulfate heptahydrate (FeSO 4 7H 2 O; 200
mg, 0.72 mmol) was dissolved in water (10 ml), camptothecin (500 mg, 1.43 mmol) was suspended in this,
Add concentrated sulfuric acid (4 ml) to dissolve. After adding propanol (4 ml) to this, 30% hydrogen peroxide solution (1 ml) was slowly added dropwise under ice cooling, and then 0.5 ml of hydrogen peroxide solution was added at room temperature.
Stir for an hour. The reaction mixture was poured into ice water (100 ml) and extracted with chloroform (100 ml x 5).
After drying this chloroform layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography (chloroform). 178mg,
30.5%) and 7-(3-hydroxypropyl)
Camptothecin (68 mg, 11.6%) is obtained. At this time, 7-ethylcamptothecin (215 mg, 39.8
%) are both obtained. 7-(1-Hydroxymethylethyl)camptothecin mp.257-259℃ (dec.) (from ethanol) TLC.
Rf value 0.09 (30% acetone-chloroform) ms.m/
e 406 [M + ] (C 23 H 22 N 2 O 5 = 406.15) 1 H = NMR
(in DMSO-d 6 ) δppm; 0.89 (3H, t, J = 7.3
Hz), 1.48 (3H, d, J = 6.3Hz), 1.88 (2H, q,
J=7.3Hz), 3.8-4.0 (3H, m), 4.90 (1H, t,
J=4.9Hz), 5.43 (4H, s), 6.50 (1H, s), 7.34
(1H, s), 7.6−7.9 (2H, m), 8.16 (1H, dd,
J = 1.4 and 8.3Hz), 8.37 (1H, d, J = 7.3Hz). 7-(3-hydroxypropyl)camptothecin mp.210-212℃ (dec.) (from ethanol-n-hexane) TLC.Rf value 0.06 (30% acetone-chloroform)
ms.m/e 406 [M + ] (C 23 H 22 N 2 O 5 = 406.15) 1 H
-NMR (in DMSO-d 6 ) δppm; 0.89 (3H, t,
J=7.3Hz), 1.87 (4H, m), 3.30 (2H, m), 3.51
(2H, t, J=5.8Hz), 4.68 (1H, br.s), 5.37
(2H, s), 5.43 (2H, s), 6.49 (1H, s), 7.33
(1H, s), 7.5-7.9 (2H, m), 8.1-8.3 (2H,
m). Example 3 7-(1-hydroxymethylpropyl)camptothecin (wherein
【式】)および
7−(3−ヒドロキシ−1−メチルプロピル)カ
ンプトテシン(式中、
[Formula]) and 7-(3-hydroxy-1-methylpropyl)camptothecin (wherein,
【式】)および7−(4−
ヒドロキシブチル)カンプトテシン(式中、A=
−(CH2)4)
硫酸第1鉄・7水和物(200mg、0.72mmol)を
水(10ml)に溶解し、これにカンプトテシン
(500mg、1.43mmol)を懸濁し濃硫酸(4ml)を
加え溶解する。これにブタノール(4ml)を加え
た後、氷冷下30%過酸化水素水(1ml)をゆつく
り滴下し、その後室温で0.5時間撹拌する。反応
混合物を氷水(100ml)に注ぎ、クロロホルムで
抽出(100ml×5回)を行い、このクロロホルム
層を無水硫酸マグネシウムで乾燥した後、溶媒を
減圧下で留去し、残留物をシリカゲルカラムクロ
マトグラフイー(クロロホルム)で分離精製する
と標記の7−(1−ヒドロキシメチルプロピル)
カンプトテシン(121mg、20%)および7−(3−
ヒドロキシ−1−メチルプロピル)カンプトテシ
ン(91mg、15%)および7−(4−ヒドロキシブ
チル)カンプトテシン(30mg、5%)が得られ
る。この際、7−プロピルカンプトテシン(196
mg、35%)がともに得られる。
7−(1−ヒドロキシメチルプロピル)カンプト
テシン
mp.228−229℃(dec.)(エタノールより)TLC.
Rf値0.10(30%アセトン−クロロホルム)ms.m/
e 420〔M+〕(C24H24N2O5=420.16)1H−NMR
(DMSO−d6中)δppm;0.88(6H,t,J=7.1
Hz),1.88(2H,q,J=7.1Hz),1.17−2.25(2H,
m),3.90(2H,br.s),4.33(1H,br.s),4.83
(1H,br,s),5.39(2H,s),5.44(2H,s),
6.52(1H,s),7.35(1H,s),7.61−7.94(2H,
m),8.18(1H,d,J=7.3Hz),8.41(1H,d,
J=7.8Hz)。
7−(3−ヒドロキシ−1−メチルプロピル)カ
ンプトテシン
mp.214−216℃(dec.)(エタノールより)
TLC.Rf値0.09(30%アセトン−クロロホルム)
ms.m/e 420〔M+〕(C24H24N2O5=420.16)1H
−NMR(DMSO−d6中)δppm;0.90(3H,t,
J=7.1Hz),1.51(3H,t,J=7.3Hz)1.89(2H,
q,J=7.1Hz),1.92−2.20(2H,m),3.30−
3.50(2H,m),3.98(1H,br,s),4.59(1H,
t,J=5.1Hz),5.39(2H,s),5.44(2H,s),
6.53(1H,s),7.35(1H,s),7.63−7.94(2H,
m),8.19(1H,dd,J=1.2および8.0Hz),8.42
(1H,d,J=7.8Hz)
7−(4−ヒドロキシブチル)カンプトテシン
mp.197−199℃(dec.)(エタノール−n−ヘキ
サンより)
TLC.Rf値0.07(30%アセトン−クロロホルム)
ms.m/e 420〔M+〕(C24H24N2O5=420.16)1H
−NMR(DMSO−d6中)δppm;0.90(3H,t,
J=7.0Hz),1.60−1.70(4H,m),1.88(2H,q,
J=7.3Hz),3.20(2H,br,s),3.47(2H,q,
J=6.4Hz),4.42(1H,t,J=5.1Hz),5.26
(2H,s),5.43(2H,s),6.51(1H,s),7.32
(1H,s),7.63−7.91(2H,m),8.10−8.30
(2H,m)。
実施例 4
7−(2−ヒドロキシプロピル)カンプトテシ
ン(式中、[Formula]) and 7-(4-hydroxybutyl)camptothecin (wherein A=
-( CH2 ) 4 ) Dissolve ferrous sulfate heptahydrate (200 mg, 0.72 mmol) in water (10 ml), suspend camptothecin (500 mg, 1.43 mmol), and add concentrated sulfuric acid (4 ml). dissolve. After adding butanol (4 ml) to this, 30% hydrogen peroxide solution (1 ml) was slowly added dropwise under ice cooling, and the mixture was stirred at room temperature for 0.5 hour. The reaction mixture was poured into ice water (100 ml), extracted with chloroform (100 ml x 5 times), the chloroform layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. When separated and purified with E (chloroform), the title 7-(1-hydroxymethylpropyl) is obtained.
Camptothecin (121 mg, 20%) and 7-(3-
Hydroxy-1-methylpropyl)camptothecin (91 mg, 15%) and 7-(4-hydroxybutyl)camptothecin (30 mg, 5%) are obtained. At this time, 7-propylcamptothecin (196
mg, 35%). 7-(1-Hydroxymethylpropyl)camptothecin mp.228-229℃ (dec.) (from ethanol) TLC.
Rf value 0.10 (30% acetone-chloroform) ms.m/
e 420 [M + ] (C 24 H 24 N 2 O 5 = 420.16) 1 H−NMR
(in DMSO-d 6 ) δppm; 0.88 (6H, t, J = 7.1
Hz), 1.88 (2H, q, J = 7.1Hz), 1.17−2.25 (2H,
m), 3.90 (2H, br.s), 4.33 (1H, br.s), 4.83
(1H, br, s), 5.39 (2H, s), 5.44 (2H, s),
6.52 (1H, s), 7.35 (1H, s), 7.61−7.94 (2H,
m), 8.18 (1H, d, J = 7.3Hz), 8.41 (1H, d,
J = 7.8Hz). 7-(3-Hydroxy-1-methylpropyl)camptothecin mp.214-216℃ (dec.) (from ethanol) TLC.Rf value 0.09 (30% acetone-chloroform)
ms.m/e 420 [M + ] (C 24 H 24 N 2 O 5 = 420.16) 1 H
-NMR (in DMSO-d 6 ) δppm; 0.90 (3H, t,
J = 7.1Hz), 1.51 (3H, t, J = 7.3Hz) 1.89 (2H,
q, J=7.1Hz), 1.92−2.20 (2H, m), 3.30−
3.50 (2H, m), 3.98 (1H, br, s), 4.59 (1H,
t, J=5.1Hz), 5.39 (2H, s), 5.44 (2H, s),
6.53 (1H, s), 7.35 (1H, s), 7.63−7.94 (2H,
m), 8.19 (1H, dd, J = 1.2 and 8.0Hz), 8.42
(1H, d, J=7.8Hz) 7-(4-hydroxybutyl)camptothecin
mp.197-199℃ (dec.) (from ethanol-n-hexane) TLC.Rf value 0.07 (30% acetone-chloroform)
ms.m/e 420 [M + ] (C 24 H 24 N 2 O 5 = 420.16) 1 H
-NMR (in DMSO-d 6 ) δppm; 0.90 (3H, t,
J=7.0Hz), 1.60−1.70 (4H, m), 1.88 (2H, q,
J=7.3Hz), 3.20 (2H, br, s), 3.47 (2H, q,
J = 6.4Hz), 4.42 (1H, t, J = 5.1Hz), 5.26
(2H, s), 5.43 (2H, s), 6.51 (1H, s), 7.32
(1H, s), 7.63-7.91 (2H, m), 8.10-8.30
(2H, m). Example 4 7-(2-hydroxypropyl)camptothecin (wherein
【式】)
硫酸第1鉄・7水和物(200mg、0.72mmol)を
水(10ml)に溶解し、これにカンプトテシン
(500mg、1.40mmol)を懸濁し、濃硫酸(4ml)
を加え溶解する。これにイソプロパノール(4
ml)を加えた後、氷冷下30%過酸化水素水(1
ml)をゆつくり滴下し、その後室温で4時間撹拌
する。反応混合物を氷水(100ml)に注ぎ、クロ
ロホルム抽出(100ml×5回)を行う。このクロ
ロホルム層を無水硫酸マグネシウムで乾燥した
後、溶媒を減圧下で留去し、残留物をシリカゲル
カラムクロマトグラフイー(クロロホルム)で分
離精製すると標記化合物(108mg,11.0%)が得
られる。原料回収(185mg,37.0%)。
mp.237−239℃(エタノール−クロロホルムよ
り)TLC.Rf値0.09(30%アセトン−クロロホル
ム)ms.m/e 406〔M+〕(C23H22N2O5=
406.15)1H−NMR(DMSO−d6中)δppm;0.89
(3H,t,J=7.0Hz),1.28(3H,d,J=5.9
Hz),1.88(2H,q,J=7.0Hz),3.04−3.47(2H,
m),4.00−4.10(1H,m),4.85(1H,d,J=
7.0Hz),5.34(2H,s),5.43(2H,s),6.51
(1H,s),7.34(1H,s),7.63−7.93(2H,m),
8.12−8.34(2H,m)。
実施例 5
7−(2−ヒドロキシメチルプロピル)カンプ
トテシン(式中、[Formula]) Dissolve ferrous sulfate heptahydrate (200 mg, 0.72 mmol) in water (10 ml), suspend camptothecin (500 mg, 1.40 mmol), and add concentrated sulfuric acid (4 ml).
Add and dissolve. Add isopropanol (4
ml), then add 30% hydrogen peroxide solution (1 ml) under ice-cooling.
ml) slowly dropwise and then stirred at room temperature for 4 hours. The reaction mixture was poured into ice water (100 ml) and extracted with chloroform (100 ml x 5 times). After drying this chloroform layer over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is separated and purified by silica gel column chromatography (chloroform) to obtain the title compound (108 mg, 11.0%). Raw material recovery (185 mg, 37.0%). mp.237-239℃ (from ethanol-chloroform) TLC.Rf value 0.09 (30% acetone-chloroform) ms.m/e 406 [M + ] (C 23 H 22 N 2 O 5 =
406.15) 1 H-NMR (in DMSO- d6 ) δppm; 0.89
(3H, t, J=7.0Hz), 1.28 (3H, d, J=5.9
Hz), 1.88 (2H, q, J = 7.0Hz), 3.04-3.47 (2H,
m), 4.00−4.10 (1H, m), 4.85 (1H, d, J=
7.0Hz), 5.34 (2H, s), 5.43 (2H, s), 6.51
(1H, s), 7.34 (1H, s), 7.63−7.93 (2H, m),
8.12−8.34 (2H, m). Example 5 7-(2-hydroxymethylpropyl)camptothecin (wherein
【式】)
硫酸第1鉄・7水和物(200mg、0.72mmol)を
水(10ml)に溶解し、これにカンプトテシン
(500mg、1.43mmol)を懸濁し、濃硫酸(4ml)
を加え、溶解する。これにイソブタパノール(4
ml)を加えた後氷冷下30%過酸化水素水(1ml)
をゆつくり滴下し、その後室温で4時間撹拌す
る。反応混合物を氷水(100ml)に注ぎ、クロロ
ホルムで抽出(100ml×5回)する。このクロロ
ホルム層を無水硫酸マグネシウムで乾燥した後、
溶媒を減圧下で留去し、残留物をシリカゲルカラ
ムクロマトグラフイー(クロロホルム)で分離精
製すると標記化合物(72mg,12%)が得られた。
この際、7−イソプロピルカンプトテシン(270
mg,48%)がともに得られる。
mp.211−213℃(エタノールより)TLC.Rf値
0.09(30%アセトン−クロロホルム)ms.m/e
420〔M+〕(C24H24N2O5=420.17)1H−NMR
(CDCl3中)δppm;1.03(3H,d,J=6.8Hz),
1.04(3H,t,J=7.3Hz),1.90(2H,q,J=
7.3Hz),2.83−3.04(1H,m),3.42−3.80(4H,
m),5.20−5.83(4H,m),7.66(1H,s),7.57
−7.88(2H,m),8.12−8.27(2H,m)。
実施例 6
7−(1−ヒドロキシメチル−2−メチルプロ
ピル)カンプトテシン(式中、
[Formula]) Dissolve ferrous sulfate heptahydrate (200 mg, 0.72 mmol) in water (10 ml), suspend camptothecin (500 mg, 1.43 mmol), and add concentrated sulfuric acid (4 ml).
Add and dissolve. Add to this isobutapanol (4
ml) and then 30% hydrogen peroxide solution (1 ml) under ice cooling.
was slowly added dropwise, and then stirred at room temperature for 4 hours. The reaction mixture was poured into ice water (100 ml) and extracted with chloroform (100 ml x 5). After drying this chloroform layer with anhydrous magnesium sulfate,
The solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography (chloroform) to obtain the title compound (72 mg, 12%).
At this time, 7-isopropylcamptothecin (270
mg, 48%). mp.211−213℃ (from ethanol) TLC.Rf value
0.09 (30% acetone-chloroform) ms.m/e
420 [M + ] (C 24 H 24 N 2 O 5 = 420.17) 1 H−NMR
(in CDCl 3 ) δppm; 1.03 (3H, d, J = 6.8Hz),
1.04 (3H, t, J = 7.3Hz), 1.90 (2H, q, J =
7.3Hz), 2.83-3.04 (1H, m), 3.42-3.80 (4H,
m), 5.20-5.83 (4H, m), 7.66 (1H, s), 7.57
-7.88 (2H, m), 8.12 - 8.27 (2H, m). Example 6 7-(1-hydroxymethyl-2-methylpropyl)camptothecin (wherein
【式】および7−(4−ヒドロキ
シ−2−メチルブチル)カンプトテシン(式中、
[Formula] and 7-(4-hydroxy-2-methylbutyl)camptothecin (wherein,
【式】)
硫酸第1鉄・7水和物(200mg;0.72mmol)を
水(10ml)に溶解し、これにカンプトテシン
(500mg、1.43mmol)を懸濁し、濃硫酸(4ml)
を加え溶解する。これにイソアミルアルコール
(2ml)を加えた後、氷冷下30%過酸化水素水
(1ml)をゆつくり滴下し、その後室温で6時間
撹拌する。反応混合物を氷水(100ml)に注ぎ、
クロロホルムで抽出(100ml×5回)する。この
クロロホルム層を無水硫酸マグネシウムで乾燥し
た後溶媒を減圧下に留去し残留物をシリカゲルカ
ラムクロマトグラフイー(クロロホルム)で分離
精製すると標記の7−(1−ヒドロキシメチル−
2−メチルプロピル)カンプトテシン(118mg、
19%)と7−(4−ヒドロキシ−2−メチルブチ
ル)カンプトテシン(137mg、22%)が得られた。
この際、7−イソブチルカンプトテシン(46mg、
8%)がともに得られる。原料回収(170mg,34
%)。
7−(1−ヒドロキシメチル−2−メチルプロピ
ル)カンプトテシン
mp.171−173℃(エタノールより)TLC.Rf値
0.14(30%アセトン−クロロホルム)ms.m/e
434〔M+〕(C25H26N2O5=434.18)1H−NMR
(CDCl3中)δppm;0.94−1.30(9H,m),1.88
(2H,q,J=7.0Hz),3.85(2H,br,s),4.20
−4.46(2H,m),5.10−5.79(4H,m),7.61
(1H,s),7.30−7.82(2H,m),8.10−8,33
(2H,m)。
7−(4−ヒドロキシ−2−メチルブチル)カン
プトテシン
mp.222−224℃(エタノールより)
TLC.Rf値0.09(30%アセトン−クロロホルム)
ms.m/e 434〔M+〕(C25H26N2O5=434.18)1H
−NMR(CDCl3中)δppm;1.01(3H,d,J=
6.3Hz),1.02(3H,t,J=7.3Hz),2.94−3.39
(2H,m),3.68−4.14(2H,m),5.24(2H,s),
5.48(2H,ABq,J=16.6および45.4Hz),7.50−
7.80(3H,m),8.03−8.17(2H,m)。
実施例 7
7−(2−ヒドロキシエチル)カンプトテシン
ナトリウム塩
7−(2−ヒドロキシエチル)カンプトテシン
(60mg、0.147mmol)を精製水(5ml)に懸濁し、
これに0.1N NaOH水溶液(1.8ml)を加え室温で
1時間撹拌する。この溶液を過した後、凍結乾
燥すると、標記化合物が淡黄色粉末として得られ
る。
IRνKBr naxcm-1;3400,2950,1636,1580,1370,
1134,1040,1000,764。
実施例 8
7−(3−ヒドロキシ−1−メチルプロピル)
カンプトテシンナトリウム塩
7−(3−ヒドロキシ−1−メチルプロピル)
カンプトテシン(50mg、0.119mmol)を精製水
(5ml)に懸濁し、これに、0.1N NaOH水溶液
(1.5ml)を加え室温で1時間撹拌する。この溶液
を過した後、凍結乾燥するとことにより標記化
合物が淡黄色粉末として得られる。
IRνKBr naxcm-1;3370,2950,1635,1576,1440,
1370,1135,990,760。
実施例 9
7−(1−ヒドロキシメチル−2−メチルプロ
ピル)カンプトテシンナトリウム塩
7−(1−ヒドロキシメチル−2−メチルプロ
ピル)カンプトテシン(50mg、0.115mmol)を精
製水(5ml)に懸濁し、これに0.1N NaOH水溶
液(1.5ml)を加え、室温で1時間撹拌する。こ
の溶液を過した後、凍結乾燥すると標記化合物
が淡黄色粉末として得られる。
IRνKBr naxcm-1;3350,2950,1638,1580,1443,
1380,1135,1000,758。
参考例 1
7−(2−クロル−1−メチルエチル)カンプ
トテシン
7−(1−ヒドロキシメチルエチル)カンプト
テシン(100mg、0.25mmol)をDMF(2ml)に溶
解し、ピリジン(0.2ml)とp−トルエンスルホ
ニルクロリド(200mg、1.00mmol)を加え室温で
0.5時間撹拌する。その後、溶媒を減圧下に留去
し、残留物をシリカゲルカラムクロマトグラフイ
ー(クロロホルム)で分離精製すると標記化合物
(98mg、93.7%)が得られる。
m.p.228−230℃(dec)(エタノール.エーテル)
参考例 2
7−(2−ジエチルアミノ−1−メチルエチル)
カンプトテシン
7−(2−クロル−1−メチルエチル)カンプ
トテシン(50mg、0.11mmol)をアセトン(2ml)
に溶解し、これにジエチルアミン(1ml)を加え
室温で2時間撹拌する。その後溶媒を減圧下に留
去し、残留物をシリカゲルカラムクロマトグラフ
イー(クロロホルム)で分離精製すると、標記化
合物(38mg、70%)が得られる。m.p.256−258℃
(dec)。[Formula]) Dissolve ferrous sulfate heptahydrate (200 mg; 0.72 mmol) in water (10 ml), suspend camptothecin (500 mg, 1.43 mmol), and add concentrated sulfuric acid (4 ml).
Add and dissolve. After adding isoamyl alcohol (2 ml) to this, 30% hydrogen peroxide solution (1 ml) was slowly added dropwise under ice cooling, and the mixture was stirred at room temperature for 6 hours. Pour the reaction mixture into ice water (100ml) and
Extract with chloroform (100ml x 5 times). After drying this chloroform layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography (chloroform) to obtain the title 7-(1-hydroxymethyl-
2-methylpropyl) camptothecin (118mg,
19%) and 7-(4-hydroxy-2-methylbutyl)camptothecin (137 mg, 22%) were obtained.
At this time, 7-isobutylcamptothecin (46 mg,
8%) are obtained in both cases. Raw material recovery (170 mg, 34
%). 7-(1-Hydroxymethyl-2-methylpropyl)camptothecin mp.171-173℃ (from ethanol) TLC.Rf value
0.14 (30% acetone-chloroform) ms.m/e
434 [M + ] (C 25 H 26 N 2 O 5 = 434.18) 1 H−NMR
(in CDCl 3 ) δppm; 0.94−1.30 (9H, m), 1.88
(2H, q, J=7.0Hz), 3.85 (2H, br, s), 4.20
−4.46 (2H, m), 5.10 −5.79 (4H, m), 7.61
(1H, s), 7.30-7.82 (2H, m), 8.10-8, 33
(2H, m). 7-(4-Hydroxy-2-methylbutyl)camptothecin mp.222-224℃ (from ethanol) TLC.Rf value 0.09 (30% acetone-chloroform)
ms.m/e 434 [M + ] (C 25 H 26 N 2 O 5 = 434.18) 1 H
−NMR (in CDCl 3 ) δppm; 1.01 (3H, d, J=
6.3Hz), 1.02 (3H, t, J = 7.3Hz), 2.94−3.39
(2H, m), 3.68−4.14 (2H, m), 5.24 (2H, s),
5.48 (2H, ABq, J=16.6 and 45.4Hz), 7.50−
7.80 (3H, m), 8.03-8.17 (2H, m). Example 7 7-(2-hydroxyethyl)camptothecin sodium salt 7-(2-hydroxyethyl)camptothecin (60 mg, 0.147 mmol) was suspended in purified water (5 ml),
Add 0.1N NaOH aqueous solution (1.8ml) to this and stir at room temperature for 1 hour. The solution is filtered and then lyophilized to yield the title compound as a pale yellow powder. IRν KBr nax cm -1 ; 3400, 2950, 1636, 1580, 1370,
1134, 1040, 1000, 764. Example 8 7-(3-hydroxy-1-methylpropyl)
Camptothecin sodium salt 7-(3-hydroxy-1-methylpropyl)
Camptothecin (50 mg, 0.119 mmol) was suspended in purified water (5 ml), 0.1N NaOH aqueous solution (1.5 ml) was added thereto, and the mixture was stirred at room temperature for 1 hour. The solution is filtered and lyophilized to give the title compound as a pale yellow powder. IRν KBr nax cm -1 ; 3370, 2950, 1635, 1576, 1440,
1370, 1135, 990, 760. Example 9 7-(1-hydroxymethyl-2-methylpropyl)camptothecin sodium salt 7-(1-hydroxymethyl-2-methylpropyl)camptothecin (50 mg, 0.115 mmol) was suspended in purified water (5 ml). Add 0.1N NaOH aqueous solution (1.5ml) to the mixture and stir at room temperature for 1 hour. This solution is filtered and then lyophilized to yield the title compound as a pale yellow powder. IRν KBr nax cm -1 ; 3350, 2950, 1638, 1580, 1443,
1380, 1135, 1000, 758. Reference example 1 7-(2-chloro-1-methylethyl)camptothecin 7-(1-hydroxymethylethyl)camptothecin (100 mg, 0.25 mmol) was dissolved in DMF (2 ml), and pyridine (0.2 ml) and p-toluene were dissolved. Add sulfonyl chloride (200 mg, 1.00 mmol) and stir at room temperature.
Stir for 0.5 hours. Thereafter, the solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography (chloroform) to obtain the title compound (98 mg, 93.7%). mp228-230℃ (dec) (ethanol.ether) Reference example 2 7-(2-diethylamino-1-methylethyl)
Camptothecin 7-(2-chloro-1-methylethyl)camptothecin (50 mg, 0.11 mmol) was dissolved in acetone (2 ml).
To this was added diethylamine (1 ml) and stirred at room temperature for 2 hours. Thereafter, the solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography (chloroform) to obtain the title compound (38 mg, 70%). mp256−258℃
(dec).
Claims (1)
する直鎖状または分枝鎖状のアルキレン基であ
り、Mは、アルカリ金属原子を表わす。ただし、
A中の水酸基の結合した炭素原子とカンプトテシ
ンの7位の炭素原子とは直接結合していないもの
とする)で表わされる新規な7−ヒドロキシアル
キルカンプトテシン誘導体又はそのアルカリ金属
塩。[Claims] 1. General formula or (In each formula, A is a linear or branched alkylene group having 2 to 5 carbon atoms, and M represents an alkali metal atom. However,
A novel 7-hydroxyalkylcamptothecin derivative or an alkali metal salt thereof, represented by (assuming that the carbon atom to which the hydroxyl group in A is bonded and the carbon atom at the 7-position of camptothecin are not directly bonded).
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP10169183A JPS59227884A (en) | 1983-06-09 | 1983-06-09 | Novel 7-hydroxyalkylcamptothecin derivative |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP10169183A JPS59227884A (en) | 1983-06-09 | 1983-06-09 | Novel 7-hydroxyalkylcamptothecin derivative |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS59227884A JPS59227884A (en) | 1984-12-21 |
JPH0314316B2 true JPH0314316B2 (en) | 1991-02-26 |
Family
ID=14307359
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP10169183A Granted JPS59227884A (en) | 1983-06-09 | 1983-06-09 | Novel 7-hydroxyalkylcamptothecin derivative |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS59227884A (en) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5004758A (en) * | 1987-12-01 | 1991-04-02 | Smithkline Beecham Corporation | Water soluble camptothecin analogs useful for inhibiting the growth of animal tumor cells |
US5447936A (en) * | 1993-12-22 | 1995-09-05 | Bionumerik Pharmaceuticals, Inc. | Lactone stable formulation of 10-hydroxy 7-ethyl camptothecin and methods for uses thereof |
US5468754A (en) * | 1994-04-19 | 1995-11-21 | Bionumerik Pharmaceuticals, Inc. | 11,7 substituted camptothecin derivatives and formulations of 11,7 substituted camptothecin derivatives and methods for uses thereof |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5612391A (en) * | 1979-07-10 | 1981-02-06 | Yakult Honsha Co Ltd | Novel camptothecin derivative and its preparaion |
-
1983
- 1983-06-09 JP JP10169183A patent/JPS59227884A/en active Granted
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5612391A (en) * | 1979-07-10 | 1981-02-06 | Yakult Honsha Co Ltd | Novel camptothecin derivative and its preparaion |
Also Published As
Publication number | Publication date |
---|---|
JPS59227884A (en) | 1984-12-21 |
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