JP2619042B2 - Bisdioxopiperazine derivatives - Google Patents
Bisdioxopiperazine derivativesInfo
- Publication number
- JP2619042B2 JP2619042B2 JP1706189A JP1706189A JP2619042B2 JP 2619042 B2 JP2619042 B2 JP 2619042B2 JP 1706189 A JP1706189 A JP 1706189A JP 1706189 A JP1706189 A JP 1706189A JP 2619042 B2 JP2619042 B2 JP 2619042B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- hydrogen atom
- formula
- lower alkyl
- compound
- 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
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Description
【発明の詳細な説明】 本発明は、優れた制癌作用を有する化合物（１）に関
する。The present invention relates to a compound (1) having an excellent anticancer effect.
特開昭60−97963および特開昭62−281870号公報には
ビスジオキソピペラジン誘導体が記載されているが、発
明者等は関連化合物について研究し、制癌剤として改良
された性質を有する化合物（１）を見出した。Japanese Patent Application Laid-Open Nos. 60-97963 and 62-281870 describe bisdioxopiperazine derivatives. The present inventors have studied related compounds and found that compounds having improved properties as anticancer agents (1) ) Was found.
式中、R3は水素原子またはArCH（OR1）COOCH2−基を
示し、Arはヒドロキシ、低級アルキル、低級ハロアルキ
ル、低級アルコキシ、低級アルカノイルオキシまたはハ
ロゲン原子から選ばれた１〜３個の置換基を有してもよ
いフエニル基を示し、R1は水素原子、低級アルカノイル
基、置換されていてもよいベンゾイル基または置換され
ていてもよいフエニルアセチル基を示し、これらの置換
基は同一または異なる１〜３個のヒドロキシ、低級アル
キル、低級アルコキシ、ハロゲン原子またはニトロを示
し、R2は水素原子または低級アルキル基を示す。ただし
R1およびR2がともに水素原子である場合を除く。 In the formula, R 3 represents a hydrogen atom or an ArCH (OR 1 ) COOCH 2 — group, and Ar represents 1 to 3 substituents selected from hydroxy, lower alkyl, lower haloalkyl, lower alkoxy, lower alkanoyloxy and halogen atoms. A phenyl group which may have a group; R 1 represents a hydrogen atom, a lower alkanoyl group, an optionally substituted benzoyl group or an optionally substituted phenylacetyl group, and these substituents are the same; Or 1 to 3 different hydroxy, lower alkyl, lower alkoxy, halogen atom or nitro, and R 2 represents a hydrogen atom or a lower alkyl group. However
Except when both R 1 and R 2 are hydrogen atoms.
Arにおける置換基の低級アルカノイルオキシ基および
R1の低級アルカノイル基は、たとえばアセチル、プロピ
オニル、ブチリル、ペンタノイルがあげられる。A lower alkanoyloxy group for a substituent on Ar and
Examples of the lower alkanoyl group for R 1 include acetyl, propionyl, butyryl, and pentanoyl.
ArおよびR1における置換基ならびにR2の低級アルキル
は、たとえばメチル、エチル、プロピル、イソプロピ
ル、ブチル、イソブチル、tert−ブチルがあげられる。Substituents for Ar and R 1 and lower alkyl for R 2 include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl.
ArおよびR1における置換基の低級アルコキシは、たと
えばメトキシ、エトキシ、プロポキシ、イソプロポキシ
があげられる。Lower alkoxy as a substituent for Ar and R 1 includes, for example, methoxy, ethoxy, propoxy, isopropoxy.
ArおよびR1における置換基のハロゲン原子は、たとえ
ば弗素、塩素、臭素があげられる。Examples of the halogen atom for the substituent in Ar and R 1 include fluorine, chlorine and bromine.
Arにおける置換基の低級ハロアルキル基は、たとえば
トリフルオロメチル、ジクロロエチルまたはジクロロブ
チルがあげられる。Examples of the lower haloalkyl group for the substituent in Ar include trifluoromethyl, dichloroethyl and dichlorobutyl.
式（１）を有する好適化合物は、 Arが、フエニル、４−ヒドロキシフエニル、３−ヒド
ロキシ−４−メトキシフエニルまたは、４−ヒドロキシ
−３−メトキシフエニルであり、 R1が、アセチル、ベンゾイルまたはフエニルアセチル
であり、 R2が、水素原子、メチル、エチル、プロピル、イソプ
ロピル、ブチルまたはイソブチルである。Preferred compounds having the formula (1) are: wherein Ar is phenyl, 4-hydroxyphenyl, 3-hydroxy-4-methoxyphenyl or 4-hydroxy-3-methoxyphenyl, wherein R 1 is acetyl, Benzoyl or phenylacetyl, and R 2 is a hydrogen atom, methyl, ethyl, propyl, isopropyl, butyl or isobutyl.
式（１）を有する化合物には不斉炭素原子を有するた
め種々の異性体が存在する。本発明は、これらの異性体
の１種またはこれらの異性体の混合物を含む。Since the compound having the formula (1) has an asymmetric carbon atom, various isomers exist. The invention includes one of these isomers or a mixture of these isomers.
一般式（１）を有する化合物は、以下のようにして合
成される。The compound having the general formula (1) is synthesized as follows.
式 〔式中、R2は前述したものと同意義を示す〕 を有する化合物に一般式（３） 〔式中、ArおよびR1は前記したものと同意義を示す〕を
有する化合物の反応制誘導体たとえば酸クロリド、酸無
水物などを特開昭60−97963号および特開昭62−281870
号に開示されている方法で、縮合剤の存在下反応させる
と、一般式 式中、Ar,R1,R2およびR3は前述したものと同意義を有す
る〕を有する化合物が得られる。化合物（１）を腹腔内
投与したマウスは、無処理対照群のマウスの生存日数に
比べ約３倍（R.L.Geran等の評価方法（Cancer Chamothe
r.Rept.,3,part3,1〜52（1972））生存した。また化合
物（１）は経口投与によってP388白血球細胞に対して抗
腫瘍活性を示した。formula [Wherein R 2 has the same meaning as described above]. [Wherein Ar and R 1 have the same meanings as described above], such as acid chloride, acid anhydride and the like, as disclosed in JP-A-60-97963 and JP-A-62-281870.
Reacting in the presence of a condensing agent by the method disclosed in In the formula, Ar, R 1 , R 2 and R 3 have the same meanings as described above]. Mice to which compound (1) was intraperitoneally administered were approximately three times as long as the days of survival of the mice in the untreated control group (the evaluation method by RL Geran et al. (Cancer Chamothe
r. Rept., 3, part3 , 1-52 (1972)) survived. Compound (1) showed antitumor activity against P388 leukocytes by oral administration.
本発明の化合物（１）は経口的に投与可能であり、経
口投与の剤型としては錠剤、コーティング剤、散剤、顆
粒剤、カプセル剤、シロップ剤などができる。The compound (1) of the present invention can be administered orally, and the dosage form for oral administration includes tablets, coatings, powders, granules, capsules, syrups and the like.
投与量は患者の症状、年令、体重などに応じて異なる
が、成人に対する１日量とし50〜3000mg、好ましくは50
0〜1000mgを１〜３回に分けて投与することができる。The dose varies depending on the patient's condition, age, weight, etc., but the daily dose for an adult is 50 to 3000 mg, preferably 50 to 3000 mg.
0 to 1000 mg can be administered in 1 to 3 divided doses.
次に実施例を示して、本発明を説明するが、本発明の
範囲はその実施例に限定されるものではない。Next, the present invention will be described with reference to examples, but the scope of the present invention is not limited to the examples.
実施例１ 1,2−ビス〔４−（α−アセトキシ−α−フエニルアセ
トキシメチル）−3,5−ジオキソピペラジン−１−イ
ル〕プロパン 1,2−ビス〔（４−ヒドロキシメチル）−3,5−ジオキ
ソピペラジン−１−イル）プロパン5.00gを乾燥ジオキ
サン100mlに溶かし、10℃下で０−アセチルアンデル酸
クロリド7.92gとピリジン7.52gを滴下して10〜15℃下で
30分間、続いて室温下で２時間攪拌後、酢酸エチルエス
テル400mlを加え、反応溶液を0.2N−HCl400mlで洗浄後
さらに10％NaCl400mlで洗浄し、有機層を無水硫酸マグ
ネシウム上で乾燥する。乾燥剤去後、液の溶剤を減
圧下留去して得られる残渣をシリカゲルクロマトグラフ
（Merck Art.1040;展開剤：シクロヘキサン／酢酸エチ
ルエステル＝1/2）により精製するとアメ状の油状物が
得られ、このものをベンゼンに溶かし凍結乾燥すると標
記化合物3.16gを得た。Example 1 1,2-bis [4- (α-acetoxy-α-phenylacetoxymethyl) -3,5-dioxopiperazin-1-yl] propane 1,2-bis [(4-hydroxymethyl)- 5.00 g of 3,5-dioxopiperazin-1-yl) propane was dissolved in 100 ml of dry dioxane, and 7.92 g of 0-acetylandelic acid chloride and 7.52 g of pyridine were added dropwise at 10 ° C, and the mixture was added at 10 to 15 ° C.
After stirring for 30 minutes and then at room temperature for 2 hours, 400 ml of ethyl acetate is added, and the reaction solution is washed with 400 ml of 0.2N HCl and then with 400 ml of 10% NaCl, and the organic layer is dried over anhydrous magnesium sulfate. After removing the desiccant, the residue obtained by distilling off the solvent of the liquid under reduced pressure is purified by silica gel chromatography (Merck Art. 1040; developing agent: cyclohexane / ethyl acetate = 1/2) to give a candy-like oily substance. This was dissolved in benzene and lyophilized to give 3.16 g of the title compound.
IR（KBr）cm-1:1751,1703（Ｃ＝０） NMR（CDCl3）δ:0.96（3H×2,d,J＝60.Hz）、1.90〜3.0
6（2H＋1H,m）、2.14（3H×2,s）、3.43（2H×2,s）、
3.46（2H×2,s）、5.83（2H×2,s）、5.88（1H,s）、5.
90（1H,s）、7.20〜7.60（5H×2,m） 実施例１と同様にして表１の化合物が得られた。IR (KBr) cm -1 : 1751, 1703 (C = 0) NMR (CDCl 3 ) δ: 0.96 (3H × 2, d, J = 60.Hz), 1.90 to 3.0
6 (2H + 1H, m), 2.14 (3H × 2, s), 3.43 (2H × 2, s),
3.46 (2H × 2, s), 5.83 (2H × 2, s), 5.88 (1H, s), 5.
90 (1H, s), 7.20 to 7.60 (5H × 2, m) The compounds in Table 1 were obtained in the same manner as in Example 1.
実施例11 １−〔（Ｒ）−４−（２−アセトキシ−２−フエニル）
アセトキシメチル−3,5−ジオキソピペラジン−１−イ
ル〕−２−（3,5−ジオキソピペラジン−１−イル）エ
タンの合成 1,2−ビス（４−ヒドロキシメチル−3,5−ジオキソピ
ペラジン−１−イル）エタン1.57gのピリジン30ml溶液
を５℃に冷却下、（Ｒ）−α−アセトキシフエニルアセ
チルクロライド1.06gを滴下し３〜５℃にて30分間、さ
らに室温にて２時間攪拌する。反応液を減圧下濃縮して
得られる残渣を酢酸エチル（100ml）に溶解し、冷５％K
HSO4（100mlで洗浄後、有機層を無水硫酸マグネシウム
上にて乾燥し、乾燥剤を去後、溶剤を減圧下留去して
得られる残渣をシリカゲルカラムクロマトグラフ（展開
剤；酢酸エチル）により精製すると融点59〜62℃の無色
粉末体として目的物0.56gを得た。 Example 11 1-[(R) -4- (2-acetoxy-2-phenyl)
Synthesis of Acetoxymethyl-3,5-dioxopiperazin-1-yl] -2- (3,5-dioxopiperazin-1-yl) ethane A solution of 1.57 g of 1,2-bis (4-hydroxymethyl-3,5-dioxopiperazin-1-yl) ethane in 30 ml of pyridine was cooled to 5 ° C. and 1.06 g of (R) -α-acetoxyphenylacetyl chloride was cooled. And the mixture is stirred at 3 to 5 ° C. for 30 minutes and further at room temperature for 2 hours. The residue obtained by concentrating the reaction solution under reduced pressure was dissolved in ethyl acetate (100 ml),
After washing with HSO 4 (100 ml, the organic layer was dried over anhydrous magnesium sulfate, the desiccant was removed, the solvent was distilled off under reduced pressure, and the residue obtained was subjected to silica gel column chromatography (developing agent; ethyl acetate). Purification gave 0.56 g of the desired product as a colorless powder having a melting point of 59-62 ° C.
NMR（CDCl3）δ（Ｊ＝Hz）90MHz:2.16（3H,s）,2.63（2
H×2,s）,3.43（2H×2,s）,3.50（2H×2,s）,5.85（2H,
s）,5.90（1H,s）,7.30〜7.60（5H,m）,8.41（1H,s） 実施例12 実施例11と同様にして下記の混合物が得られた。NMR (CDCl 3 ) δ (J = Hz) 90 MHz: 2.16 (3H, s), 2.63 (2
H × 2, s), 3.43 (2H × 2, s), 3.50 (2H × 2, s), 5.85 (2H,
s), 5.90 (1H, s), 7.30 to 7.60 (5H, m), 8.41 (1H, s) Example 12 The following mixture was obtained in the same manner as in Example 11.
NMR（CDCl3）δ（Ｊ＝Hz）90MHz:0.98（1.5H,d,J＝6.
0）,1.01（1.5H,d,J＝6.0）,2.16（3H,s）,2.00〜3.20
（2H＋1H,m）,3.40（2H,s）,3.43（2H,s）,3.46（2H,
s）,3.50（2H,s）,5.83（2H,s）,5.90（0.5H,s）,5.91
（0.5H,s）,7.36（2.5H,s）,7.30〜7.60（5H,m） NMR (CDCl 3 ) δ (J = Hz) 90 MHz: 0.98 (1.5H, d, J = 6.
0), 1.01 (1.5H, d, J = 6.0), 2.16 (3H, s), 2.00 ~ 3.20
(2H + 1H, m), 3.40 (2H, s), 3.43 (2H, s), 3.46 (2H,
s), 3.50 (2H, s), 5.83 (2H, s), 5.90 (0.5H, s), 5.91
(0.5H, s), 7.36 (2.5H, s), 7.30 to 7.60 (5H, m)
Claims (1)
し、Arはヒドロキシ、低級アルキル、低級ハロアルキ
ル、低級アルコキシ、低級アルカノイルオキシまたはハ
ロゲン原子から選ばれた１〜３個の置換基を有してもよ
いフエニル基を示し、R1は水素原子、低級アルカノイル
基、置換されていてもよいベンゾイル基または置換され
ていてもよいフエニルアセチル基を示し、これらの置換
基は同一または異なる１〜３個のシドロキシ、低級アル
キル、低級アルコキシ、ハロゲン原子またはニトロを示
し、R2は水素原子または低級アルキル基を示す。ただし
R1およびR2がともに水素原子である場合を除く。(1) Expression A compound having the formula: In the formula, R 3 represents a hydrogen atom or an ArCH (OR 1 ) COOCH 2 — group, and Ar represents 1 to 3 substituents selected from hydroxy, lower alkyl, lower haloalkyl, lower alkoxy, lower alkanoyloxy and halogen atoms. A phenyl group which may have a group; R 1 represents a hydrogen atom, a lower alkanoyl group, an optionally substituted benzoyl group or an optionally substituted phenylacetyl group, and these substituents are the same; Or 1 to 3 different hydroxy, lower alkyl, lower alkoxy, halogen atom or nitro, and R 2 represents a hydrogen atom or a lower alkyl group. However
Except when both R 1 and R 2 are hydrogen atoms.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1614188 | 1988-01-27 | ||
| JP63-16141 | 1988-01-27 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH01279875A JPH01279875A (en) | 1989-11-10 |
| JP2619042B2 true JP2619042B2 (en) | 1997-06-11 |
Family
ID=11908222
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1706189A Expired - Lifetime JP2619042B2 (en) | 1988-01-27 | 1989-01-26 | Bisdioxopiperazine derivatives |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2619042B2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992000971A1 (en) * | 1990-07-04 | 1992-01-23 | Zenyaku Kogyo Kabushiki Kaisha | Water-soluble bis-dioxopiperazine derivative |
-
1989
- 1989-01-26 JP JP1706189A patent/JP2619042B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPH01279875A (en) | 1989-11-10 |
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