JPS63227588A - Methotrexate derivative - Google Patents
Methotrexate derivativeInfo
- Publication number
- JPS63227588A JPS63227588A JP5902287A JP5902287A JPS63227588A JP S63227588 A JPS63227588 A JP S63227588A JP 5902287 A JP5902287 A JP 5902287A JP 5902287 A JP5902287 A JP 5902287A JP S63227588 A JPS63227588 A JP S63227588A
- Authority
- JP
- Japan
- Prior art keywords
- methylaminobenzoyl
- methyl
- glutamate
- group
- glutamic acid
- 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
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical class C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 title claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 13
- 125000004423 acyloxy group Chemical group 0.000 claims abstract description 3
- -1 2,4-diamino-6-pteridinyl Chemical group 0.000 abstract description 18
- 229960002989 glutamic acid Drugs 0.000 abstract description 13
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 abstract description 9
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 abstract description 9
- LPNBBFKOUUSUDB-UHFFFAOYSA-N p-toluic acid Chemical compound CC1=CC=C(C(O)=O)C=C1 LPNBBFKOUUSUDB-UHFFFAOYSA-N 0.000 abstract description 4
- WBYNXAAEBPJETG-AWEZNQCLSA-N diethyl (2s)-2-[[4-(methylamino)benzoyl]amino]pentanedioate Chemical compound CCOC(=O)CC[C@@H](C(=O)OCC)NC(=O)C1=CC=C(NC)C=C1 WBYNXAAEBPJETG-AWEZNQCLSA-N 0.000 abstract description 3
- 229910052736 halogen Inorganic materials 0.000 abstract description 3
- 150000001350 alkyl halides Chemical class 0.000 abstract description 2
- 125000005843 halogen group Chemical group 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 abstract 3
- 239000003699 antiulcer agent Substances 0.000 abstract 1
- 230000003301 hydrolyzing effect Effects 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 23
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 238000001228 spectrum Methods 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 238000000034 method Methods 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- MULMBFBZGGMART-VIFPVBQESA-N dipropan-2-yl (2s)-2-aminopentanedioate Chemical compound CC(C)OC(=O)CC[C@H](N)C(=O)OC(C)C MULMBFBZGGMART-VIFPVBQESA-N 0.000 description 6
- CPNGPNLZQNNVQM-UHFFFAOYSA-N pteridine Chemical compound N1=CN=CC2=NC=CN=C21 CPNGPNLZQNNVQM-UHFFFAOYSA-N 0.000 description 6
- 239000002246 antineoplastic agent Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 230000000704 physical effect Effects 0.000 description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 description 3
- 239000011736 potassium bicarbonate Substances 0.000 description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 3
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- MNZMECMQTYGSOI-UHFFFAOYSA-N acetic acid;hydron;bromide Chemical compound Br.CC(O)=O MNZMECMQTYGSOI-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000004020 conductor Substances 0.000 description 2
- 150000005690 diesters Chemical class 0.000 description 2
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 2
- 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- NAMYKGVDVNBCFQ-UHFFFAOYSA-N 2-bromopropane Chemical compound CC(C)Br NAMYKGVDVNBCFQ-UHFFFAOYSA-N 0.000 description 1
- BIGRRCHSUAXSEE-UHFFFAOYSA-N 2-methylpteridine Chemical compound N1=CC=NC2=NC(C)=NC=C21 BIGRRCHSUAXSEE-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZNTXSIJXRMAZBL-UHFFFAOYSA-N Cl.COC(=O)C(C)(C)C Chemical compound Cl.COC(=O)C(C)(C)C ZNTXSIJXRMAZBL-UHFFFAOYSA-N 0.000 description 1
- 229930195714 L-glutamate Natural products 0.000 description 1
- 208000007093 Leukemia L1210 Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 244000309464 bull Species 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
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
[発明の目的]
(産業上の利用分野)
本発明はメントレキセート誘導体に関し、さらに詳しく
は、抗腫瘍剤として臨床ヒ広く使用されているメソトレ
キセートの新規誘導体に関する。DETAILED DESCRIPTION OF THE INVENTION [Object of the Invention] (Industrial Application Field) The present invention relates to a methotrexate derivative, and more particularly to a novel derivative of methotrexate, which is widely used clinically as an antitumor agent.
(従来の技術およびその問題点)
次式
で示される〆ソトレキセート(N−(4−[[(2,4
−ジアミノ−6−プテリジニル)−メチル]−メチルア
ミン]−ベンゾイル] −L−グルタミン酸)およびそ
の誘導体は、現在、抗腫瘍剤として臨床−L広く使用さ
れているが、そのほとんどが注射剤としてであり、経口
剤として利用されるものは少ない。(Prior art and its problems) Sotrexate (N-(4-[[(2,4
-diamino-6-pteridinyl)-methyl]-methylamine]-benzoyl]-L-glutamic acid) and its derivatives are currently widely used clinically as antitumor agents, but most of them are available as injections. However, few are used as oral preparations.
本発明者らは、メントレキセートをプロドラッグ化し、
消化管よりの吸収を高めることができれば有用な経口剤
となりうるちのと考え、経口投与可能な抗腫瘍剤として
使用できるメソトレキセート誘導体を得るべく、#l意
研究を重ねた結果、本発明を完成するに至った。The present inventors converted mentrexate into a prodrug,
We believed that if absorption from the gastrointestinal tract could be enhanced, it could become a useful oral agent, and as a result of repeated research, we completed the present invention in order to obtain a methotrexate derivative that can be used as an orally administrable antitumor agent. reached.
[発明の構成]
(問題点を解決するための手段と作用)本発明は1次式
1式中、l(1は分岐状低級アルキル基あるいはR2は
低級アルキル基を表す)で示される基のいずれかで置換
された低級アルキル基を表す]
で示されるメントレキセート誘導体を提供するものであ
る。[Structure of the Invention] (Means and Effects for Solving the Problems) The present invention provides for a group represented by l (1 represents a branched lower alkyl group or R2 represents a lower alkyl group) in the linear formula 1. represents a lower alkyl group substituted with any of the following.
上記式(I)において、低級アルキル基とは炭素数1〜
4の直鎖状または分岐状のアルキル基をいう。かかる直
鎖状のアルキル基としては、例えばメチル基、エチル基
、プロピル基、ブチル基等が挙げられ、分岐状のアルキ
ル基としては1例えばイソプロピル基、インブチル基、
5ee−ブチル基、terL−ブチル基等が挙げら
れる。In the above formula (I), the lower alkyl group has 1 to 1 carbon atoms.
4 straight-chain or branched alkyl group. Examples of such linear alkyl groups include methyl group, ethyl group, propyl group, butyl group, etc., and examples of branched alkyl groups include isopropyl group, inbutyl group,
Examples include 5ee-butyl group and terL-butyl group.
アシルオキシ基とは、すなわち、低級アルキルカルボ二
tレオキシ基であり、この場合の低級アルキル基は前記
と同義である。このようなアシルオキジス(とじては、
例えばアセトキシ基、プロピオニルオキシ基、ブチリル
オキシ基、インブチリルオキシ基、ピバロイルオキシ基
(tart−ブチルオキシソ、0等が挙げられる。The acyloxy group is, in other words, a lower alkylcarbonitreoxy group, and the lower alkyl group in this case has the same meaning as above. This kind of acyl oxydis
Examples include acetoxy group, propionyloxy group, butyryloxy group, inbutyryloxy group, pivaloyloxy group (tart-butyloxyso, 0, etc.).
5−メチル−2−オキソ−1,3−ジオキソレン−4−
イル基、5−エチル−2−オキソ−1,3−ジオキソレ
ン−4−イル基、5−プロピル−2−オキソ−1,3−
ジオキソレン−4−イルノ^等が挙げられる。5-Methyl-2-oxo-1,3-dioxolene-4-
yl group, 5-ethyl-2-oxo-1,3-dioxolen-4-yl group, 5-propyl-2-oxo-1,3-
Examples include dioxolene-4-ylno^ and the like.
R1は、好ましくはイソプロピル基、ピバロイルオキシ
メチルハまたは5−メチル−2−オキソ−1,3−ジオ
キソレン−4−イル−メチル基である。R1 is preferably an isopropyl group, a pivaloyloxymethyl group, or a 5-methyl-2-oxo-1,3-dioxolen-4-yl-methyl group.
本発明のメントレキセート!導体は次のような方法によ
って合成することができる。Mentrexate of the present invention! The conductor can be synthesized by the following method.
まず、メントレキセート合成の際の重要な中間体である
N−(4−メチルアミノベンゾイル)−L−グルタミン
酸ジエチルを1例えばDaniel V。First, diethyl N-(4-methylaminobenzoyl)-L-glutamate, which is an important intermediate in the synthesis of mentrexate, was prepared as described by Daniel V, for example.
5anti (1)方法(J、 Heterocycl
、 Che+w、、 4 +475.1967)に従っ
て、L−グルタミン酸と4−メチル安息香酸から合成し
、これを水酸化ナトリウムを用いて、エタノール中室温
で加水分解し、N−(4−メチルアミノベンゾイル)−
L−グルタミン酸を得る。5anti (1) Method (J, Heterocycle
, Che+w,, 4 +475.1967) from L-glutamic acid and 4-methylbenzoic acid, which was hydrolyzed in ethanol at room temperature using sodium hydroxide to give N-(4-methylaminobenzoyl). −
Obtain L-glutamic acid.
次に、N−(4−メチルアミノベンゾイル)−L−グル
タミン酸と次式、
X−R五 (,
11)[式中、R1は前記と同義、Xはハロゲン原子を
表す1
で示される置換または非置換のフルキルハライドを反応
させ、N−(4−メチルアミノベンゾイル)−L−グル
タミン酸のジエステル体を得る。Next, N-(4-methylaminobenzoyl)-L-glutamic acid and the following formula, X-R5 (,
11) [In the formula, R1 has the same meaning as above and X represents a halogen atom. A substituted or unsubstituted furkyl halide represented by 1 is reacted to form a diester of N-(4-methylaminobenzoyl)-L-glutamic acid. get.
前記式(!I)におけるXは臭素または塩素であるのが
好ましく、その置換または非置換のアルキルハライドの
量は、N−(4−メチルアミノベンゾイル)−L−グル
タミン酸1モルに対して3〜6モル用いるのがよい。こ
の時、トリエチルアミン3〜6モルを存在させるのがよ
い。また、用いる溶媒としては、ジメチルホルムアミド
、ジメチルスルホキシド等がよく、反応温度は0〜50
℃、反応時間は1〜20時間である。X in the above formula (!I) is preferably bromine or chlorine, and the amount of substituted or unsubstituted alkyl halide is 3 to 3 per mole of N-(4-methylaminobenzoyl)-L-glutamic acid. It is preferable to use 6 moles. At this time, it is preferable that 3 to 6 moles of triethylamine be present. In addition, as a solvent to be used, dimethylformamide, dimethyl sulfoxide, etc. are preferable, and the reaction temperature is 0 to 50℃.
℃, reaction time is 1-20 hours.
かくして得たジエステル体を、ヨウ化カリウム存在下、
ジメチルスルホキシド中、室温で、2.4−ジアミノ−
6−バロメチルブテリジンと縮合させることにより、目
的とする本発明のメントレキセート誘導体を得ることが
できる。The diester obtained in this way was treated in the presence of potassium iodide,
2,4-diamino- in dimethyl sulfoxide at room temperature.
By condensation with 6-baromethylbuteridine, the desired mentrexate derivative of the present invention can be obtained.
2.4−ジアミノ−6−へロメチルプテリジンにおける
ハロゲンは塩素が好ましく、該プテリジンは塩酸塩とな
っているのが好ましい、該ジエステル体1モルに対して
、2,4−ジアミノ−6−バロメチルプテリジンは0.
7〜1.0モル、ヨウ化カリウムは2.5〜4.0モル
、ジメチルスルホキシドは2.0〜7 、On用いると
よい。反応時間は20〜30時間である。The halogen in 2.4-diamino-6-heromethylpteridine is preferably chlorine, and the pteridine is preferably in the form of a hydrochloride. Methylpteridine is 0.
It is preferable to use 7 to 1.0 moles of potassium iodide, 2.5 to 4.0 moles of potassium iodide, and 2.0 to 7 moles of dimethyl sulfoxide. Reaction time is 20-30 hours.
また、前記式(I)において、R1がイソプロピル基の
場合には、次に述べる方法によっても合成することがで
きる。Furthermore, in the above formula (I), when R1 is an isopropyl group, it can also be synthesized by the method described below.
すなわち、L−グルタミン酸を塩酸存在下で溶媒量のイ
ンプロパツールと20〜30時間加熱し、還流させるこ
とにより、L−グルタミン酸ジイソプロピルに導き、こ
れを塩化メチレン−水混合溶媒(1: 1)中で、炭酸
水素カリウム存在下で、4−(N−メチル−N−トシル
)−アミノベンゾイルハライドと20〜30℃で20〜
30時間反応させることにより、N−(4−(N−メチ
ル−N−トシル)−7ミノベンゾイル]−L−グルタミ
ン酸ジイソプロピルを得る。このとき、4−(N−メチ
ル−N−)シル)−アミノベンゾイルハライドのハロゲ
ンとしては塩素が好ましく、その量は、L−グルタミン
酸ジイソプロピル1モルに対し、0.8〜1.0モルで
あり、炭酸水素カリウムは7〜10モルである。That is, L-glutamic acid is heated with a solvent amount of Impropatol in the presence of hydrochloric acid for 20 to 30 hours and refluxed to lead to diisopropyl L-glutamate, which is dissolved in a mixed solvent of methylene chloride and water (1:1). 4-(N-methyl-N-tosyl)-aminobenzoyl halide at 20-30°C in the presence of potassium hydrogen carbonate.
By reacting for 30 hours, diisopropyl N-(4-(N-methyl-N-tosyl)-7minobenzoyl]-L-glutamate is obtained. At this time, 4-(N-methyl-N-)yl)- The halogen of aminobenzoyl halide is preferably chlorine, and the amount thereof is 0.8 to 1.0 mol per 1 mol of diisopropyl L-glutamate, and the amount of potassium hydrogen carbonate is 7 to 10 mol.
次に、このN−[4−(N−メチル−N−トシル)−ア
ミノベンゾイル]−L−グルタミン酸ジイソプロピルを
塩化メチレンに溶解させ、臭化水素−酢酸存在下でフェ
ノールを作用させることにより、N−(4−メチルアミ
ノベンゾイル)−L−グルタミン酸ジイソプロピルを得
る。Next, this diisopropyl N-[4-(N-methyl-N-tosyl)-aminobenzoyl]-L-glutamate was dissolved in methylene chloride and treated with phenol in the presence of hydrogen bromide-acetic acid. Diisopropyl -(4-methylaminobenzoyl)-L-glutamate is obtained.
かくして得たN−(4−メチルアミノベンゾイル)−L
−グルタミン酸ジイソプロピルから目的とする本発明の
メソトレキセート誘導体を得るには先に述べた方法と同
様にして行う。The thus obtained N-(4-methylaminobenzoyl)-L
- The desired methotrexate derivative of the present invention can be obtained from diisopropyl glutamate in the same manner as described above.
上述のようにして得られたメソトレキセート誘導体の単
離は、通常の方法、例えば、抽出、溶媒除去等の方法を
用いて行なうことができ、その精製は、カラムクロマト
グラフィー、再結晶等の方法により行なうことができる
。The methotrexate derivative obtained as described above can be isolated using conventional methods such as extraction and solvent removal, and its purification can be carried out using methods such as column chromatography and recrystallization. can be done.
本発明の新規なメントレキセート誘導体は経口投与した
場合、メントレキセートと同じくらいの抗腫瘍活性を有
するので、経口可能な抗腫瘍剤として開発の可能性があ
る。The novel mentrexate derivative of the present invention has an antitumor activity comparable to that of mentrexate when administered orally, and therefore has the potential to be developed as an orally available antitumor agent.
[実施例1 以下、本発明を実施例により詳細に説明する。[Example 1 Hereinafter, the present invention will be explained in detail with reference to Examples.
実施例1
Daniel V、 5antiの方法(J、 1et
erocycl。Example 1 Daniel V, 5anti method (J, 1et
erocycle.
Chem、、4 、475 、1967)に従って合成
したN−(4−メチルアミノベンゾイル)−L−グルタ
ミン酸ジエチル2.77g (8,24mmoυをエタ
ノール50−に溶解させ、IN水酸化ナトリウム水溶液
16++Jを30分毎に2回に分けて加え、室温で1時
間攪拌した。Chem., 4, 475, 1967), 2.77 g of diethyl N-(4-methylaminobenzoyl)-L-glutamate (8.24 mmoυ) was dissolved in ethanol 50-1, and IN sodium hydroxide aqueous solution 16++J was dissolved for 30 minutes. Each mixture was added in two portions and stirred at room temperature for 1 hour.
次に、反応液をlN塩酸を用いて中和し、減圧下で濃縮
した後、残液に水1OOWJを加えて溶解させ、lN塩
酸でpH1に調整し、酢酸エチル100−を用いて7回
抽出操作を行った。Next, the reaction solution was neutralized using 1N hydrochloric acid and concentrated under reduced pressure, and then 100J of water was added to the residual solution to dissolve it, the pH was adjusted to 1 with 1N hydrochloric acid, and 100% of ethyl acetate was added 7 times. Extraction operation was performed.
得られた有機層を無水硫酸ナトリウムで乾燥後、減圧下
で濃縮することにより、N−(4−メチルアミノベンゾ
イル)−L−グルタミン酸の白色粉末2.28gを得た
。収率98.8%。The obtained organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 2.28 g of white powder of N-(4-methylaminobenzoyl)-L-glutamic acid. Yield 98.8%.
実施例2
N−4−メチルアミノベンゾ ル −L−グN−(4−
メチルアミノベンゾイル)−L−グルタミン酸2 、5
0g (8、93+mmol)を乾燥ジメチルホルムア
ミド13mgに溶解させ、トリエチルアミン3 、 l
ag (22、3mmol)と臭化イソプロピル2 、
5mg (26、8mmol)を加えた後、室温で20
時間攪拌した。Example 2 N-4-methylaminobenzole -L-gN-(4-
methylaminobenzoyl)-L-glutamic acid 2,5
0 g (8,93+ mmol) was dissolved in 13 mg of dry dimethylformamide and 3,1 ml of triethylamine
ag (22.3 mmol) and isopropyl bromide 2,
After adding 5 mg (26, 8 mmol), 20
Stir for hours.
反応終了後、反応液に酢酸エチル250Talを加え、
これを飽和炭酸水素ナトリウム水溶液125−で2回、
水125wJで2回洗浄した。有機層を、無水硫酸ナト
リウムで乾燥し、減圧下で濃縮することにより、N−(
4−メチルアミノベンゾイル)−L−グルタミン酸ジイ
ソプロピル3.09gを得た。収率95.2%。After the reaction was completed, 250 Tal of ethyl acetate was added to the reaction solution.
This was treated twice with saturated aqueous sodium hydrogen carbonate solution 125-
Washed twice with 125 wJ of water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give N-(
3.09 g of diisopropyl (4-methylaminobenzoyl)-L-glutamate was obtained. Yield 95.2%.
IHNMRスペクトル(CDCfL3)の結果を以下に
示す、δ(ppm) : 1 、24 (m、 12H
。The results of the IHNMR spectrum (CDCfL3) are shown below, δ (ppm): 1, 24 (m, 12H
.
−CH(CI(3)2X2)、1.9〜2.6 (m。-CH (CI(3)2X2), 1.9-2.6 (m.
4H、−CH2C旦2−)、2.84 (S 、3H。4H, -CH2Cdan2-), 2.84 (S, 3H.
N CH3)、4.70 (m、1)1.NHCH1
″″
CH2)、5.00 (m、2H,0−CH(CH3
) 2 X 2) 、 6 、52および7.64(d
、各2H、C6Ha ) 、 6 、80 (m。N CH3), 4.70 (m, 1)1. NHCH1
″″CH2), 5.00 (m, 2H,0-CH(CH3
) 2 X 2) , 6 , 52 and 7.64 (d
, 2H, C6Ha), 6, 80 (m.
2H、−N旦−CH3および−N旦−CH)実施例3か
ら実施例5において、N−(4−メチルアミノベンゾイ
ル)−L−グルタミン酸ジイソプロピルの別の方法によ
る合成例を示す。(2H, -Ndan-CH3 and -Ndan-CH) Examples 3 to 5 show examples of the synthesis of diisopropyl N-(4-methylaminobenzoyl)-L-glutamate by another method.
実施例3
L−グルタミン ジイソプロピルの
L−グルタミン酸7 、0OK (48、3maol)
を2−プロパツール350−に懸濁し、35%塩酸30
++Jを加えて24時間還流した。Example 3 L-glutamine diisopropyl L-glutamic acid 7,0OK (48,3maol)
was suspended in 2-propatool 350-, and 35% hydrochloric acid 30-
++J was added and the mixture was refluxed for 24 hours.
反応終了後、反応液を2N水酸化ナトリウム水溶液を用
いて中和し、減圧下で濃縮した。得られた残渣を塩化メ
チレン300−に溶解させ、飽和炭酸水素ナトリウム水
溶液250−で2回、水250−で1回洗浄した後、無
水硫酸ナトリウムで乾燥し、減圧下で濃縮することによ
り、シロップ状のL−グルタミン酸ジイソプロピル7.
43gを得た。収率66.6%。After the reaction was completed, the reaction solution was neutralized using a 2N aqueous sodium hydroxide solution and concentrated under reduced pressure. The resulting residue was dissolved in 300° of methylene chloride, washed twice with 250° of a saturated aqueous sodium bicarbonate solution and once with 250° of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a syrup. Diisopropyl L-glutamate7.
43g was obtained. Yield 66.6%.
実施例4
Daniel V、 5anti (7)方法(J、
Heterocycl。Example 4 Daniel V, 5anti (7) Method (J,
Heterocycle.
Che+w、、4,475.1967)に従ッテ合成し
た4−(N−メチル−N−トシル)−アミノベンゾイル
クロライド5.30g (16,4+smol)を塩化
メチレン80+eJに溶解させ、L−グルタミン酸ジイ
ソプロピル4.16g (18,0+mol)を加えた
。さらに、炭酸水素カリウム13.1g(0、l 3e
+a+ol)を水80−に溶解させた溶液を加えて、室
温で23時間激しく撹拌した。5.30 g (16,4+ smol) of 4-(N-methyl-N-tosyl)-aminobenzoyl chloride synthesized according to Che+w, 4,475.1967) was dissolved in 80+ eJ of methylene chloride, and diisopropyl L-glutamate was dissolved. 4.16g (18.0+mol) was added. Furthermore, 13.1 g of potassium hydrogen carbonate (0, l 3e
A solution of +a+ol) dissolved in 80- of water was added, and the mixture was vigorously stirred at room temperature for 23 hours.
反応終了後、反応液の有機層を分液し、IN塩酸80−
で2回、水80+IJで1回洗浄した。無水硫酸ナトリ
ウムで乾燥した後、減圧下で濃縮することにより、N−
[4−(N−メチル−N−1シル)−アミノベンゾイル
]−L−グルタミン酸ジイソプロピル8.27gを得た
。収率97.4%。After the reaction is completed, the organic layer of the reaction solution is separated and added with IN hydrochloric acid 80-
and once with 80+IJ of water. After drying with anhydrous sodium sulfate, N-
8.27 g of diisopropyl [4-(N-methyl-N-1 sil)-aminobenzoyl]-L-glutamate was obtained. Yield 97.4%.
実施例5
N−[4−(N−メチル−N−トシル)−アミノベンゾ
イル]−L−グルタミン酸ジイソプロピル8 、27g
(16,0mmol)を塩化メチレン30−に溶解さ
せ、30重量%臭化水素酢酸溶液33−とフェノ−jt
z3. OOg (32、0mmol)を加えた後、室
温で4時間攪拌した。Example 5 Diisopropyl N-[4-(N-methyl-N-tosyl)-aminobenzoyl]-L-glutamate 8, 27 g
(16.0 mmol) was dissolved in methylene chloride 30-, and a 30% by weight hydrogen bromide acetic acid solution 33- and pheno-jt
z3. After adding OOg (32,0 mmol), the mixture was stirred at room temperature for 4 hours.
反応終了後、反応液に塩化メチレン130−を加え、1
0%のアンモニア水で中和した。有機層を減圧下で濃縮
し、得られた残渣をエチルエーテル150m/に溶解さ
せた後、IN塩酸100−で5回抽出操作を行った。After the reaction, 130-methylene chloride was added to the reaction solution, and 130-methylene chloride was added to the reaction solution.
Neutralized with 0% aqueous ammonia. The organic layer was concentrated under reduced pressure, and the resulting residue was dissolved in 150ml of ethyl ether, followed by extraction five times with 100ml of IN hydrochloric acid.
水層を合わせて、3N水酸化ナトリウム水溶液でpH8
に調整し、塩化メチレン300mJで3回抽出操作を行
った。Combine the aqueous layers and adjust to pH 8 with 3N aqueous sodium hydroxide solution.
The mixture was extracted with 300 mJ of methylene chloride three times.
有機層を無水硫酸ナトリウムで乾燥後、減圧下で濃縮す
ることにより、N−(4−メチルアミノベンゾイル)−
L−グルタミン酸ジイソプロピル4.71gを得た。収
率81.0%。The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give N-(4-methylaminobenzoyl)-
4.71 g of diisopropyl L-glutamate was obtained. Yield 81.0%.
実施例6
2.4−ジアミノ−6−クロロメチルプテリジン塩酸塩
2.33g (’9.44a+mol)を乾燥ジメチル
スルホキシド25−に懸濁させ、これにN−(4−メチ
ルアミノベンゾイル)−L−グルタミン酸ジイソプロピ
ル4.81g (13,2mmol)およびヨウ化カリ
ウム6 、26g (37、7mmol)を加え、室温
で30時間攪拌した。Example 6 2.33 g ('9.44a+mol) of 2.4-diamino-6-chloromethylpteridine hydrochloride was suspended in dry dimethyl sulfoxide 25-, and N-(4-methylaminobenzoyl)-L- 4.81 g (13.2 mmol) of diisopropyl glutamate and 6.26 g (37.7 mmol) of potassium iodide were added, and the mixture was stirred at room temperature for 30 hours.
反応終了後、反応液を減圧下で濃縮し、得られた残渣を
クロロホルム2.0mlに溶解させた後、5重量%チオ
硫酸ナトリウム水、溶液125−で洗油し、無水硫酸ナ
トリウムで乾燥した。有機層を減圧下で濃縮した。After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in 2.0 ml of chloroform, washed with 5% by weight aqueous sodium thiosulfate, solution 125, and dried over anhydrous sodium sulfate. . The organic layer was concentrated under reduced pressure.
次にこれをシリカゲルカラムクロマトグラフィー(JJ
C開港6M、クロロホルム:メタノール=10:1)に
より精製した。さらに、エタノールから再結晶させ、N
−[4−[[(2,4−ジアミノ−6−プテリジニル)
−メチル]−メチルアミノ]−ベンゾイル]−L−グル
タミン酸ジイソプロピル(I−1)の黄色結晶1.09
gを得た。収率21.4%。This was then subjected to silica gel column chromatography (JJ
Purification was performed using 6M chloroform:methanol (10:1). Furthermore, it was recrystallized from ethanol and N
-[4-[[(2,4-diamino-6-pteridinyl)
-Methyl]-methylamino]-benzoyl]-L-glutamate diisopropyl (I-1) yellow crystals 1.09
I got g. Yield 21.4%.
得られた黄色結晶の物性を以下に示す。The physical properties of the obtained yellow crystals are shown below.
融 点:156〜160℃(分解)
旋光度: [α]D +9.4゜
(CO,5、DMSO)
MSスペクトル(S IMS) : m/z 53
9(MH”)
IHNMRスペクトル(DMSOda )、δ(pp+
i) :1.1B(m、12H,−CH(CH3)2X
2)、2.00 (m、2H,−CI(CH2CH2)
、2.32 (m、2H、CHCH2CH2)、3.2
2 (、s、3H。Melting point: 156-160°C (decomposed) Optical rotation: [α]D +9.4° (CO, 5, DMSO) MS spectrum (SIMS): m/z 53
9(MH”) IHNMR spectrum (DMSOda), δ(pp+
i): 1.1B(m, 12H, -CH(CH3)2X
2), 2.00 (m, 2H, -CI(CH2CH2)
, 2.32 (m, 2H, CHCH2CH2), 3.2
2 (, s, 3H.
N−CH5)、4.32 (m、IH,−CHCH2C
H2)、4.80 (s、2H。N-CH5), 4.32 (m, IH, -CHCH2C
H2), 4.80 (s, 2H.
CH2N)、4.84 (m、2H,−CH(CH3)
2X2)、6.80および7.70(d、各2H,−c
6旦4−)。CH2N), 4.84 (m, 2H, -CH(CH3)
2X2), 6.80 and 7.70 (d, each 2H, -c
6dan 4-).
7、16 (broad s、2H,プテリジン環2位
(7)−NH2) 、 8 、20 (m、 3H。7, 16 (broad s, 2H, pteridine ring 2-position (7)-NH2), 8, 20 (m, 3H.
プテリジン環4位の−NH,および−NH−CH−)、
8.60(S、IH,プテリジン環7位のH)
実施例7
N−(4−メチルアミノベンゾイル)−L−グルタミン
酸2 、68g (9、57mmol)を乾燥ジメチル
ホルムアミド14−に溶解させ、トリエチルアミン3
、30d (23、9m+*ol)と塩化メチルピバレ
ート4 、1+J (28、7mmol)を加えた後、
室温で20時間攪拌した。-NH at the 4-position of the pteridine ring, and -NH-CH-),
8.60 (S, IH, H at position 7 of pteridine ring) Example 7 N-(4-methylaminobenzoyl)-L-glutamic acid 2, 68 g (9, 57 mmol) was dissolved in dry dimethylformamide 14- and triethylamine 3
, 30d (23,9 m+*ol) and methyl pivalate chloride 4,1+J (28,7 mmol),
Stirred at room temperature for 20 hours.
反応終了後、反応液に酢酸エチル200wJを加え、こ
れを飽和炭酸水素ナトリウム水溶液20〇−および水2
00Walで洗浄した。有機層を無水硫酸ナトリウムで
乾燥し、減圧下で濃縮することにより、N−(4−メチ
ルアミノベンゾイル)−L−グルタミン酸ジピバロイル
オキシメチル4.76gを得た。収率97.9%。After the reaction was completed, 200 wJ of ethyl acetate was added to the reaction solution, and this was mixed with 200 wJ of saturated aqueous sodium hydrogen carbonate solution and 200 wJ of water.
Washed with 00Wal. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 4.76 g of dipivaloyloxymethyl N-(4-methylaminobenzoyl)-L-glutamate. Yield 97.9%.
IHNMRスペクトル(C00文、)の結果を以下に示
す、δ(PPOI) : 1 、20 (s 、9H。The results of the IHNMR spectrum (C00 text) are shown below, δ (PPOI): 1, 20 (s, 9H.
−c (cH3)3)、1.22 (s、9H。-c (cH3)3), 1.22 (s, 9H.
C(CH3)a)、2.1〜2.6 (m、4H。C(CH3)a), 2.1-2.6 (m, 4H.
−CHCH2C月2−)、2.87 (s、、3H。-CHCH2C month 2-), 2.87 (s,, 3H.
CH2)、5.70 (s 、4H、Coo−CH2−
X2)、、5.78 (m、IH、NH−C,H3)
、 6.、33および7.62.(d、各2)(、C
M H4)、6.74 (d、IH。CH2), 5.70 (s, 4H, Coo-CH2-
X2), 5.78 (m, IH, NH-C, H3)
, 6. , 33 and 7.62. (d, each 2) (,C
M H4), 6.74 (d, IH.
−NH−CH)
実施例8
2.4−ジアミノ−6−クロロメチルプテリジン塩酸塩
1 、70g (6、75mmol)を乾燥ジメチルス
ルホキシド26−に懸濁させ、これにN−(4−メチル
アミノベンゾイル)−L−グルタミン酸ジピバロイルオ
キシメチル4.80g(9、45smol)およびヨウ
化カリウム4.50g (27、0+i+5ol)を加
え、室温で30時間攪拌した。-NH-CH) Example 8 2.4-Diamino-6-chloromethylpteridine hydrochloride 1.70 g (6.75 mmol) was suspended in dry dimethyl sulfoxide 26- and N-(4-methylaminobenzoyl )-4.80 g (9,45 smol) of dipivaloyloxymethyl L-glutamate and 4.50 g (27,0+i+5 mol) of potassium iodide were added, and the mixture was stirred at room temperature for 30 hours.
反応終了後、反応液を減圧下で濃縮し、得られた残液を
酢酸エチル170wJに溶解させた後、水100−で洗
浄した。水層を酢酸子チル200dで2回抽出し、有機
層に合わせた。有機層を5重量%チオ硫酸ナトリウム水
溶液300WJで洗浄した後、無水硫酸ナトリウムで乾
燥し、減圧下で濃縮した。After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the resulting residual solution was dissolved in 170 wJ of ethyl acetate, and then washed with 100 wJ of water. The aqueous layer was extracted twice with 200 d of chilled acetate and combined with the organic layer. The organic layer was washed with 300 WJ of a 5% by weight aqueous sodium thiosulfate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
次にこれをシリカゲルカラムクロマトグラフィー(展開
溶媒、クロロホルム:メタノール−20:1)により精
製した。さらにエタノールから再結晶させ、N−[4−
[[(2,4−ジアミノ−6−プテリジニル)−メチル
1−メチルアミノコ−ベンゾイル]−L−グルタミン酸
ジピバロイルオキシメチル(I−2)の黄色結晶1.1
5gを得た。収率24.6%。Next, this was purified by silica gel column chromatography (developing solvent: chloroform:methanol-20:1). Furthermore, it was recrystallized from ethanol and N-[4-
Yellow crystals of [[(2,4-diamino-6-pteridinyl)-methyl 1-methylaminoco-benzoyl]-L-glutamate dipivaloyloxymethyl (I-2) 1.1
5g was obtained. Yield 24.6%.
得られた黄色結晶の物性を以下に示す。The physical properties of the obtained yellow crystals are shown below.
融 点=135〜139℃(分解)
旋光度: [α]。 −8,00
(C1,0,CHC皇3)
MSスペクトル(SIMS):m/z 683(MH
”)
IHNMRスペクトル(DMSO−ds )、δ(pp
m):1.18 (s、9H,−C(CH3)り。Melting point = 135-139°C (decomposed) Optical rotation: [α]. -8,00 (C1,0, CHC Emperor 3) MS spectrum (SIMS): m/z 683 (MH
”) IHNMR spectrum (DMSO-ds), δ(pp
m): 1.18 (s, 9H, -C(CH3)).
1.20(s、9B、−C(CH3)3)。1.20(s, 9B, -C(CH3)3).
2.1〜2.7 (m、4H,CH2CH2)。2.1-2.7 (m, 4H, CH2CH2).
3.12 (s、3m、N−CH3)、4.5〜4.9
(m 、3H、−NHCH−および−CH2N(CH
3) )、5.68 (s。3.12 (s, 3m, N-CH3), 4.5-4.9
(m, 3H, -NHCH- and -CH2N(CH
3) ), 5.68 (s.
4H,−COOCH2−x2)、6.68および7.6
4(d、各2H,−C6H4) 。4H, -COOCH2-x2), 6.68 and 7.6
4(d, each 2H, -C6H4).
8.50(5,IH,プテリジン環7位のH)
実施例9
N−4−メチルアミノベンゾイル −し一グ在虞
N−(4−メチルアミノベンゾイル)−L−グルタミン
酸10 、0g (35、7mmol)を乾燥ジメチル
ホルムアミド56−に溶解させ、トリエチルアミン19
.8+5J(143腸+mo l)を加え、0℃に冷却
した。これに、Chew、 Phar+w、 Bull
、。8.50 (5, IH, H at the 7th position of the pteridine ring) Example 9 N-4-methylaminobenzoyl -1g N-(4-methylaminobenzoyl)-L-glutamic acid 10,0 g (35, 7 mmol) was dissolved in dry dimethylformamide 56- and triethylamine 19-
.. 8+5J (143 intestines+mol) was added and cooled to 0°C. In addition to this, Chew, Phar+w, Bull
,.
1ヱ、2241 (19B4)の方法に従って合成した
4−臭化メチル−5−メチル−2−オキソ−1,3−ジ
オキソレン20.8g (110mmol)を30分間
で滴下し、0℃を維持して2時間攪拌した。さらに4−
臭化メチル−5−メチル−2−オキソ−1,3−ジオキ
ソレン8.80g(35、0s+5ol)を10分間で
滴下した後、0℃で1時間攪拌した。1, 2241 (19B4) 20.8 g (110 mmol) of 4-methyl bromide-5-methyl-2-oxo-1,3-dioxolene was added dropwise over 30 minutes, maintaining the temperature at 0°C. Stirred for 2 hours. Furthermore 4-
After 8.80 g (35,0s+5ol) of methyl bromide-5-methyl-2-oxo-1,3-dioxolene was added dropwise over 10 minutes, the mixture was stirred at 0°C for 1 hour.
反応終了後、反応液を減圧下で濃縮し、得られた残渣を
クロロホルム300aJに溶解させ、水300−で洗浄
した。有機層を無水硫酸ナトリウムで乾燥後、減圧下で
濃縮した。After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in 300 aJ of chloroform and washed with 300 J of water. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure.
次にこれをシリカゲルカラムクロマトグラフィー(i開
港fi、クロロホルム:メタノール=100:l)によ
り精製して、シロップ状のN−(4−メチルアミノベン
ゾイル)−L−グルタミン酸−ジ[(5−メチル−2−
オキソ−1,3−ジオキソレン−4−イル)−メチル3
6.12gを得た。収率34.1%。Next, this was purified by silica gel column chromatography (i-open port fi, chloroform:methanol=100:l) to give a syrupy N-(4-methylaminobenzoyl)-L-glutamic acid-di[(5-methyl- 2-
Oxo-1,3-dioxolen-4-yl)-methyl 3
6.12g was obtained. Yield 34.1%.
IHNMRスペクトル(CDC立3)の結果を以下に示
す。δ(ppm):2 、1〜2 、7 (m、 4B
。The results of the IHNMR spectrum (CDC standing 3) are shown below. δ (ppm): 2, 1~2, 7 (m, 4B
.
−〇旦、CB、−)、2.13 (5,3H。-〇dan, CB, -), 2.13 (5,3H.
2.83 (s、3H,N−CH5)、4.7〜4.8
(m、l)(、−NCH−)、4.78(s 、2
H、−COOCH2−)、4.85(S 、2H、−C
OOC)(2−)、6.48および7.61(d、各2
H,−C,旦4)。2.83 (s, 3H, N-CH5), 4.7-4.8
(m, l) (, -NCH-), 4.78 (s, 2
H, -COOCH2-), 4.85(S, 2H, -C
OOC) (2-), 6.48 and 7.61 (d, 2 each
H, -C, Dan4).
6 、86 (d 、 IH、−NH−CH)実施例1
O
N−4−24−ジアミノ−6−プテ
2.4−ジアミノ−6−クロロメチルプテリジン塩酸塩
2.70g (10,4+wmol)を乾燥ジメチルス
ルホキシド70wJに懸濁させ、N−(4−メチルアミ
ノベンゾイル)−L−グルタミン酸−ジー[(5−メチ
ル−2−オキソ−1,3−ジオキソレン−4−イル)−
メチル]5.25g(10、4mmol)とヨウ化カリ
ウムe 、 91 g(41、4m園of)を加えた後
、室温で30時間攪拌した。6,86 (d, IH, -NH-CH) Example 1
O 2.70 g (10,4+wmol) of N-4-24-diamino-6-pute2,4-diamino-6-chloromethylpteridine hydrochloride was suspended in 70 wJ of dry dimethyl sulfoxide, and N-(4-methylamino benzoyl)-L-glutamic acid-di[(5-methyl-2-oxo-1,3-dioxolen-4-yl)-
After adding 5.25 g (10.4 mmol) of potassium iodide and 91 g (41.4 mmol) of potassium iodide, the mixture was stirred at room temperature for 30 hours.
O′Cに冷却した2交の飽和食塩水を攪拌させた中に、
上述の反応液を少しずつ添加することにより、黄褐色の
沈殿を析出させた。添加終了後、0℃で1時間攪拌した
。In two stirred saturated saline solutions cooled to O'C,
By adding the above reaction solution little by little, a yellowish brown precipitate was precipitated. After the addition was complete, the mixture was stirred at 0°C for 1 hour.
沈殿を枦取し、これをシリカゲルクロマトグラフィー(
展開溶媒、クロロホルム:メタノール=30:1)によ
り精製した。さらに、メタノールから再結晶させ、N−
[4−[[(2,4−ジアミノ−6−プテリジン環)−
メチル]−メチルアミノ]−ベンゾイル]−L−グルタ
ミン酸−ジー[(5−メチル−2−オキソ−1,3−ジ
オキソレン−4−イル)−メチル]の黄色結晶1 、2
2gを得た。収率17.4%。Collect the precipitate and subject it to silica gel chromatography (
Purification was performed using a developing solvent (chloroform:methanol=30:1). Furthermore, it was recrystallized from methanol and N-
[4-[[(2,4-diamino-6-pteridine ring)-
Yellow crystals of methyl]-methylamino]-benzoyl]-L-glutamic acid-di[(5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl] 1, 2
2g was obtained. Yield 17.4%.
得られた黄色結晶の物性を以下に示す。The physical properties of the obtained yellow crystals are shown below.
融 点:171−175℃(分解)
旋光度: [α]D +2.5゜
(CO,2,DMSO)
MSスペクトル(SIMS):m/z 679(MH
”)
IHNMRスペクトル(DMSO−d6)、δ(ppm
) :CH3
(s 、 3H、)=/ )、3 、22 (s
。Melting point: 171-175°C (decomposed) Optical rotation: [α]D +2.5° (CO, 2, DMSO) MS spectrum (SIMS): m/z 679 (MH
”) IHNMR spectrum (DMSO-d6), δ (ppm
): CH3 (s, 3H,)=/ ), 3, 22 (s
.
3H,N CH3)、4.76 (s、2H。3H, N CH3), 4.76 (s, 2H.
CH2N) 、 4 、91 (s 、 2H。CH2N), 4, 91 (s, 2H.
Coo CH2)、4.97 C3。Coo CH2), 4.97 C3.
2H、−COOCH2)、6.79および7.68(d
、各シ、H,−C6旦4)。2H, -COOCH2), 6.79 and 7.68 (d
, each shi, H, -C6dan4).
8.55(s、IH,プテリジン環7位のH)
試験例
実施例6,8.10において合成したメントレキセート
誘導体I−1、I−2、I−3を経口投与した時の抗腫
瘍活性を測定した。8.55 (s, IH, H at position 7 of pteridine ring) Antitumor effect when mentrexate derivatives I-1, I-2, and I-3 synthesized in Test Examples 6 and 8.10 were orally administered Activity was measured.
体重20〜22gの雄性BDF、マウス(一群6匹)に
マウス白血病L−1210細胞l×105個を腹腔内に
移植した。移植後24時間後より、1日1回、メソトレ
キセート誘導体I−1、I−2,I−3のそれぞれの投
与星を、胃ゾンデにより強制的に経口投与した(治療群
)。1×10 5 murine leukemia L-1210 cells were intraperitoneally transplanted into male BDF mice (6 mice per group) weighing 20 to 22 g. Starting 24 hours after transplantation, methotrexate derivatives I-1, I-2, and I-3 were forcibly administered orally once a day using a gastric probe (treatment group).
5日間連日投与後、動物の生死を観察し1次式に従って
延命率(ILS(%))を計算した。After daily administration for 5 days, the animals were observed for survival and survival rate (ILS (%)) was calculated according to the linear equation.
なお、メントレキセー14導体の代わりに生理食塩液の
みを投与したこと以外は上記と同様に処理したものを対
照群とした。A control group was treated in the same manner as above except that only physiological saline was administered instead of Mentrexe 14 conductor.
結果を表工に示す。Show the results to the table worker.
表Iかられかるように、メントレキセート誘導体(I−
2)および(1−3)は経口投与において、メントレキ
セートとほぼ同程度の抗腫瘍活性を有することがわかっ
た。As seen from Table I, the mentrexate derivative (I-
It was found that 2) and (1-3) had almost the same antitumor activity as mentrexate upon oral administration.
[発明の効果]
本発明によれば、経口投与可能な抗腫瘍剤となりうる新
規なメントレキセート誘導体を提供することができる。[Effects of the Invention] According to the present invention, a novel mentrexate derivative that can be used as an orally administrable antitumor agent can be provided.
Claims (1)
オキシ基または▲数式、化学式、表等があります▼(式
中、 R^2は低級アルキル基を表す)で示される基のいずれ
かで置換された低級アルキル基を表す] で示されるメソトレキセート誘導体。[Claims] General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 is a branched lower alkyl group or acyloxy group, or ▲ There are numerical formulas, chemical formulas, tables, etc. ▼ (In the formula, R ^2 represents a lower alkyl group) A methotrexate derivative represented by the following.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP5902287A JPS63227588A (en) | 1987-03-16 | 1987-03-16 | Methotrexate derivative |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP5902287A JPS63227588A (en) | 1987-03-16 | 1987-03-16 | Methotrexate derivative |
Publications (1)
Publication Number | Publication Date |
---|---|
JPS63227588A true JPS63227588A (en) | 1988-09-21 |
Family
ID=13101248
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP5902287A Pending JPS63227588A (en) | 1987-03-16 | 1987-03-16 | Methotrexate derivative |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS63227588A (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105367575A (en) * | 2015-12-03 | 2016-03-02 | 何黎琴 | Folic acid compound, and preparation method and pharmaceutical application thereof |
CN105646493A (en) * | 2014-12-08 | 2016-06-08 | 李玉明 | Compound for preventing and treating organ damage, preparation method and applications thereof |
WO2018096853A1 (en) * | 2016-11-25 | 2018-05-31 | 学校法人近畿大学 | Novel medoxomil and hemiacetal esters of pemetrexed, production method therefor, and pharmaceutical composition containing ester prodrug |
-
1987
- 1987-03-16 JP JP5902287A patent/JPS63227588A/en active Pending
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105646493A (en) * | 2014-12-08 | 2016-06-08 | 李玉明 | Compound for preventing and treating organ damage, preparation method and applications thereof |
CN105646493B (en) * | 2014-12-08 | 2018-02-02 | 李玉明 | It is a kind of to be used to prevent and treat compound of organ damage and its production and use |
CN105367575A (en) * | 2015-12-03 | 2016-03-02 | 何黎琴 | Folic acid compound, and preparation method and pharmaceutical application thereof |
WO2018096853A1 (en) * | 2016-11-25 | 2018-05-31 | 学校法人近畿大学 | Novel medoxomil and hemiacetal esters of pemetrexed, production method therefor, and pharmaceutical composition containing ester prodrug |
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