JPH05148293A - New capuramycin derivative and its production - Google Patents
New capuramycin derivative and its productionInfo
- Publication number
- JPH05148293A JPH05148293A JP31296391A JP31296391A JPH05148293A JP H05148293 A JPH05148293 A JP H05148293A JP 31296391 A JP31296391 A JP 31296391A JP 31296391 A JP31296391 A JP 31296391A JP H05148293 A JPH05148293 A JP H05148293A
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- Japan
- Prior art keywords
- derivative
- reacted
- capramicin
- capuramycin
- give
- Prior art date
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、新規カプラマイシン誘
導体およびその製造方法に関する。FIELD OF THE INVENTION The present invention relates to a novel couplermycin derivative and a method for producing the same.
【０００２】[0002]
【従来の技術】本発明者らは、土壌より分離した放線菌
ストレプトミセス・グリセウス・４４６−Ｓ３(Strepto
myces griseus 446-S3) から下記の構造式を有する抗生
物質４４６−Ｓ３−１を単離し、これをカプラマイシン
(Capuramycin) と命名した（特開昭６０−２５９１９０
号公報）。2. Description of the Related Art The present inventors have found that the actinomycete Streptomyces griseus 446-S3 (Strepto) isolated from soil.
The antibiotic 446-S3-1 having the following structural formula was isolated from myces griseus 446-S3)
(Capuramycin) (JP-A-60-259190)
Publication).
【０００３】[0003]
【化８】 [Chemical 8]
【０００４】上記カプラマイシンは、主として連鎖状球
菌および抗酸性菌に有効で、毒性が極めて少ないことか
ら、ヒト、動物等の感染症の治療薬としての用途が期待
されている。Since the above-mentioned capramicin is effective mainly against streptococci and acid-fast bacteria and has extremely little toxicity, it is expected to be used as a therapeutic drug for infectious diseases of humans, animals and the like.
【０００５】[0005]
【発明が解決しようとする課題】本発明者らは、上記カ
プラマイシンに種々の化学的処理を施して新規な誘導体
を合成し、それらの中に抗癌作用、抗ウィルス作用を有
するものを見出すことにより、本発明を完成させるに至
った。DISCLOSURE OF THE INVENTION The inventors of the present invention synthesize various novel chemical derivatives of the above-mentioned capramicin to synthesize novel derivatives, and find out among them those having anticancer activity and antiviral activity. As a result, the present invention has been completed.
【０００６】すなわち、本発明の目的は、新規カプラマ
イシン誘導体およびその製造方法を提供することにあ
る。That is, an object of the present invention is to provide a novel capromycin derivative and a method for producing the same.
【０００７】[0007]
【課題を解決するための手段】本発明のカプラマイシン
誘導体は、下記の一般式The capramicin derivative of the present invention has the following general formula:
【０００８】[0008]
【化９】 [Chemical 9]
【０００９】（式中、Ｒ1 およびＲ2 は同一で水素原子
を表すか、またはＲ1 およびＲ2 が一緒になって低級ア
ルキレン基を表し、Ｒ3 は水素原子またはフッ素原子を
表し、Ｒ4 は水素原子、水酸基またはフェニルチオカル
ボナート基を表す。但し、Ｒ1 およびＲ2 が水素原子の
とき、Ｒ3 が水素原子で、かつＲ4 が水酸基である場合
を除く。）で示される。(Wherein R 1 and R 2 are the same and represent a hydrogen atom, or R 1 and R 2 together represent a lower alkylene group, R 3 represents a hydrogen atom or a fluorine atom, and R 3 4 represents a hydrogen atom, a hydroxyl group or a phenylthiocarbonate group, provided that when R 1 and R 2 are hydrogen atoms, R 3 is a hydrogen atom and R 4 is a hydroxyl group). ..
【００１０】本発明のカプラマイシン誘導体は、カプラ
マイシンを原料として下記の製造工程により製造するこ
とができる。The capramycin derivative of the present invention can be produced from capramycin as a raw material by the following production steps.
【００１１】まず、酸触媒を含む有機溶媒中、カプラマ
イシンと２，２−ジメトキシプロパンとを反応させるこ
とにより、下記の式（Ｉ）First, by reacting capramicin with 2,2-dimethoxypropane in an organic solvent containing an acid catalyst, the following formula (I)
【００１２】[0012]
【化１０】 [Chemical 10]
【００１３】で示されるカプラマイシン誘導体（Ｉ）が
得られる。酸触媒としてはアンバーリストＲ−１５Ｈ+
型、パラトルエンスルホン酸などが用いられ、有機溶媒
としてはアセトン、ベンゼン、クロロホルム、塩化メチ
レンなどが用いられる。反応温度は０〜６０℃である
が、好ましくは２０〜３０℃である。また、２，２−ジ
メトキシプロパンに代えて２−メトキシプロペンなどを
用いてもよい。A couplermycin derivative (I) represented by the following formula is obtained. Amberlyst R-15H + as an acid catalyst
Methylene chloride, paratoluenesulfonic acid, etc. are used, and acetone, benzene, chloroform, methylene chloride, etc. are used as organic solvents. The reaction temperature is 0 to 60 ° C, preferably 20 to 30 ° C. Further, 2-methoxypropene or the like may be used instead of 2,2-dimethoxypropane.
【００１４】次に、上記カプラマイシン誘導体（Ｉ）と
４−ジメチルアミノピリジンとフェノキシチオカルボニ
ルクロリドとを有機溶媒中で反応させることにより、下
記の式（II）Next, by reacting the above-mentioned capramicin derivative (I), 4-dimethylaminopyridine and phenoxythiocarbonyl chloride in an organic solvent, the following formula (II)
【００１５】[0015]
【化１１】 [Chemical 11]
【００１６】で示されるカプラマイシン誘導体（II) が
得られる。有機溶媒としては乾燥塩化メチレン、クロロ
ホルム、ベンゼン、トルエンなどが用いられる。反応温
度は−２０〜３０℃であるが、好ましくは２０〜３０℃
である。A capramicin derivative (II) represented by is obtained. As the organic solvent, dry methylene chloride, chloroform, benzene, toluene and the like are used. The reaction temperature is -20 to 30 ° C, preferably 20 to 30 ° C
Is.
【００１７】次に、上記カプラマイシン誘導体（II) と
アゾイソブチロニトリルとｎ−Ｂｕ3 ＳｎＨとを有機溶
媒中、アルゴンなどの不活性ガス気流下で加熱還流する
ことにより、下記の式(III）Then, the above-mentioned couplermycin derivative (II), azoisobutyronitrile and n-Bu 3 SnH are heated to reflux in an organic solvent under a stream of an inert gas such as argon to give the following formula ( III)
【００１８】[0018]
【化１２】 [Chemical 12]
【００１９】で示されるカプラマイシン誘導体(III）が
得られる。有機溶媒としてはトルエン、ベンゼンなどが
用いられる。A capramicin derivative (III) represented by is obtained. Toluene, benzene or the like is used as the organic solvent.
【００２０】次に、酸触媒を含む有機溶媒中、上記カプ
ラマイシン誘導体(III）とメタノールとを反応させるこ
とにより、下記の式（IV）Next, by reacting the above-mentioned capramicin derivative (III) with methanol in an organic solvent containing an acid catalyst, the following formula (IV)
【００２１】[0021]
【化１３】 [Chemical 13]
【００２２】で示されるカプラマイシン誘導体（IV）が
得られる。酸触媒としてはアンバーリストＲ−１５Ｈ+
型、パラトルエンスルホン酸、希塩酸などが用いられ
る。反応温度は０〜４０℃であるが、好ましくは２０〜
３０℃である。A couplermycin derivative (IV) represented by is obtained. Amberlyst R-15H + as an acid catalyst
Mold, paratoluenesulfonic acid, dilute hydrochloric acid, etc. are used. The reaction temperature is 0 to 40 ° C, preferably 20 to
It is 30 ° C.
【００２３】また、前記カプラマイシン誘導体（Ｉ）と
ジエチルアミノ三フッ化硫黄とを冷却した有機溶媒中、
アルゴンなどの不活性ガス気流下で反応させることによ
り、下記の式（Ｖ）Further, in the organic solvent obtained by cooling the capramicin derivative (I) and diethylaminosulfur trifluoride,
By reacting under an inert gas stream such as argon, the following formula (V)
【００２４】[0024]
【化１４】 [Chemical 14]
【００２５】で示されるカプラマイシン誘導体（Ｖ）が
得られる。有機溶媒としては乾燥塩化メチレン、エチル
エーテルなどが用いられる。反応温度は−７８〜２５℃
であるが、好ましくは−７８〜０℃である。A couplermycin derivative (V) represented by is obtained. As the organic solvent, dry methylene chloride, ethyl ether or the like is used. Reaction temperature is -78 to 25 ° C
However, it is preferably −78 to 0 ° C.
【００２６】次に、酸触媒を含む有機溶媒中、上記カプ
ラマイシン誘導体（Ｖ）とメタノールとを反応させるこ
とにより、下記の式（VI）Next, by reacting the above-mentioned capromycin derivative (V) with methanol in an organic solvent containing an acid catalyst, the following formula (VI) is obtained.
【００２７】[0027]
【化１５】 [Chemical 15]
【００２８】で示されるカプラマイシン誘導体（Ｖ）が
得られる。酸触媒としてはアンバーリストＲ−１５Ｈ+
型、パラトルエンスルホン酸などが用いられる。反応温
度は０〜６０℃であるが、好ましくは２０〜３０℃であ
る。A couplermycin derivative (V) represented by is obtained. Amberlyst R-15H + as an acid catalyst
Mold, paratoluene sulfonic acid and the like are used. The reaction temperature is 0 to 60 ° C, preferably 20 to 30 ° C.
【００２９】[0029]
【発明の効果】動物実験の結果、本発明のカプラマイシ
ン誘導体は、抗癌作用、抗ウィルス作用を有し、抗癌
剤、抗ウィルス剤としての用途が期待される。As a result of animal experiments, the capramicin derivative of the present invention has anticancer activity and antiviral activity, and is expected to be used as an anticancer agent and an antiviral agent.
【００３０】以下、実施例を用いて、本発明のカプラマ
イシン誘導体およびその製造方法を詳述する。Hereinafter, the couplermycin derivative of the present invention and the method for producing the same will be described in detail with reference to Examples.
【００３１】[0031]
【実施例１】カプラマイシン２９mg（0.０５１mmol）を
アセトン5.０mlに溶かし、２，２−ジメトキシプロパン
0.２ml（1.６３mmol）、アンバーリストＲ−１５Ｈ+ 型
５ｍｇを加え、室温で一晩攪拌した。反応終了後、樹脂
を濾過し、溶媒を減圧下で留去した後、クロロホルム−
ヘキサンで結晶化し、カプラマイシン誘導体（Ｉ）２８
ｍｇを得た（収率８８％）。Example 1 Capramycin 29 mg (0.051 mmol) was dissolved in acetone 5.0 ml to give 2,2-dimethoxypropane.
0.2 ml (1.63 mmol) and Amberlyst R-15H + type 5 mg were added, and the mixture was stirred at room temperature overnight. After the reaction was completed, the resin was filtered, the solvent was distilled off under reduced pressure, and then chloroform-
Crystallized with hexane to give capramicin derivative (I) 28
mg was obtained (88% yield).
【００３２】[0032]
【化１６】 [Chemical 16]
【００３３】融点：１８５〜１８８℃ 1 Ｈ−ＮＭＲ（ＣＤＣｌ3) δ： 1.43(C-CH3, s), 1.48(C-CH3, s),1.69-2.12( CH2×3,
m),3.27(6'''-H, m), 3.44(3'-OCH3, s), 3.92(3'-H,
m),4.19(2''-H, t, J=6.0Hz), 4.30(2'-H, t, J=6.4H
z), 4.55(2'''-H, m),4.63(4',5'-H, m), 4.74(3''-H,
dd, J=4.5, 6.0Hz),4.91(1''-H, d, J=6.6Hz), 5.73(5-
H, d, J=8.5Hz),5.90(1'-H, d, J=5.3Hz), 6.30(4''-H,
d, J=4.3Hz), 7.37(NH, br),7.77(6-H, d, J=8.3Hz),
7.93(2'''-NH, d, J=6.1Hz), 10.3(3-NH, br)．Melting point: 185-188 ° C. 1 H-NMR (CDCl 3 ) δ: 1.43 (C-CH 3 , s), 1.48 (C-CH 3 , s), 1.69-2.12 (CH 2 × 3,
m), 3.27 (6 '''-H, m), 3.44 (3'-OCH 3 , s), 3.92 (3'-H,
m), 4.19 (2``-H, t, J = 6.0Hz), 4.30 (2'-H, t, J = 6.4H
z), 4.55 (2 '''-H, m), 4.63 (4', 5'-H, m), 4.74 (3 ''-H,
dd, J = 4.5, 6.0Hz), 4.91 (1``-H, d, J = 6.6Hz), 5.73 (5-
H, d, J = 8.5Hz), 5.90 (1'-H, d, J = 5.3Hz), 6.30 (4``-H,
d, J = 4.3Hz), 7.37 (NH, br), 7.77 (6-H, d, J = 8.3Hz),
7.93 (2 '''-NH, d, J = 6.1Hz), 10.3 (3-NH, br).
【００３４】[0034]
【実施例２】実施例１で得たカプラマイシン誘導体
（Ｉ）２２mg（0.０３５mmol）を乾燥塩化メチレン1.０
mlに溶かし、４−ジメチルアミノピリジン１2.６mg（0.
１０３mmol）、フェノキシチオカルボニルクロリド１０
μl(0.０７２mmol）を加え、室温で１０分間攪拌した。
反応液を酢酸エチルで希釈し、希塩酸、飽和炭酸ナトリ
ウム水溶液、飽和食塩水で順次洗浄し、無水硫酸ナトリ
ウムで乾燥した後、溶媒を留去し、カプラマイシン誘導
体（II）３０mg（油状物）を定量的に得た。Example 2 22 mg (0.035 mmol) of the couplermycin derivative (I) obtained in Example 1 was dried with methylene chloride 1.0.
Dissolve in 1 ml, 4-dimethylaminopyridine 12.6 mg (0.
103 mmol), phenoxythiocarbonyl chloride 10
μl (0.072 mmol) was added, and the mixture was stirred at room temperature for 10 minutes.
The reaction solution was diluted with ethyl acetate, washed successively with diluted hydrochloric acid, saturated aqueous sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off to obtain 30 mg of capramicin derivative (II) (oil). Obtained quantitatively.
【００３５】[0035]
【化１７】 [Chemical 17]
【００３６】 1Ｈ−ＮＭＲ（ＣＤＣｌ3) δ： 1.33(C-CH3, s), 1.40(C-CH3, s),1.66-2.20( CH2×3,
m),3.26(6'''-H, m), 3.47(3'-OCH3, s), 4.13(2''-H,
dd, J=4.1, 4.8Hz),4.25(3'-H, m), 4.44(2'''-H, m),
4.60(4',5',3''-H, m),4.78(1''-H, d, J=4.5Hz), 5.83
(5-H, dd, J=1.4, 5.6Hz),5.88(2'-H, t, J=4.1Hz), 6.
23(4''-H, d, J=3.0Hz),6.26(1'-H, d, J=4.7Hz), 6.41
(NH, m), 6.85-7.22(aromatic, m),7.32(NH, br), 7.53
(6-H, d, J=5.7Hz), 7.56(2'''-NH,d, J=4.2Hz). 1 H-NMR (CDCl 3 ) δ: 1.33 (C-CH 3 , s), 1.40 (C-CH 3 , s), 1.66-2.20 (CH 2 × 3,
m), 3.26 (6 '''-H, m), 3.47 (3'-OCH 3 , s), 4.13 (2''-H,
dd, J = 4.1, 4.8Hz), 4.25 (3'-H, m), 4.44 (2 '''-H, m),
4.60 (4 ', 5', 3``-H, m), 4.78 (1 ''-H, d, J = 4.5Hz), 5.83
(5-H, dd, J = 1.4, 5.6Hz), 5.88 (2'-H, t, J = 4.1Hz), 6.
23 (4``-H, d, J = 3.0Hz), 6.26 (1'-H, d, J = 4.7Hz), 6.41
(NH, m), 6.85-7.22 (aromatic, m), 7.32 (NH, br), 7.53
(6-H, d, J = 5.7Hz), 7.56 (2 '''-NH, d, J = 4.2Hz).
【００３７】[0037]
【実施例３】実施例２で得たカプラマイシン誘導体（I
I）１４１mg（0.１８９mmol）をトルエン6.０mlに溶か
し、アゾイソブチロニトリル6.５mg（0.０４０mmol）、
ｎ−Ｂｕ3 ＳｎＨ１５０μl(0.５５８mmol）を加え、ア
ルゴン気流下で加熱還流した。Example 3 The capramicin derivative (I obtained in Example 2
I) 141 mg (0.189 mmol) was dissolved in 6.0 ml of toluene, and 6.5 mg (0.040 mmol) of azoisobutyronitrile was added,
150 μl (0.558 mmol) of n-Bu 3 SnH was added, and the mixture was heated under reflux under an argon stream.
【００３８】８時間後、減圧下で溶媒を留去し、クロロ
ホルム−ヘキサンで結晶化し、粗生成物を得た。これを
シリカゲルカラムクロマトグラフィー（ベンゼン−メタ
ノール＝５：１）で精製し、カプラマイシン誘導体（II
I)４６mgを得た（収率４１％）。After 8 hours, the solvent was distilled off under reduced pressure and the residue was crystallized from chloroform-hexane to obtain a crude product. This was purified by silica gel column chromatography (benzene-methanol = 5: 1) to give a capramicin derivative (II
I) 46 mg was obtained (41% yield).
【００３９】[0039]
【化１８】 [Chemical 18]
【００４０】融点：１６０〜１６３℃ 1 Ｈ−ＮＭＲ（ＣＤＣｌ3) δ： 1.44(C-CH3, s), 1.50(C-CH3, s),2.08(2'-H, m),2.48
(2'-H, ddd, J=0.6,5.8, 13.6Hz), 3.28(6'''-H, m),3.
38(3'-OCH3, s), 4.08(2''-H, dd, J=6.8,7.2Hz),4.19
(3'-H, d, J=5.9Hz), 4.55(2'''-H, m), 4.60(5'-H, d,
J=2.9Hz),4.63(4'-H, dd, J=2.3, 4.1Hz), 4.72(3''-
H, dd, J=4.2, 6.3Hz),4.78(1''-H, d, J=7.4Hz), 5.72
(5-H, d, J=8.6Hz),6.26(1'-H, dd, J=5.5, 9.0Hz), 6.
34(4''-H, d, J=4.4Hz),6.67(NH, m), 7.87(6-H, d, J=
8.5Hz), 7.93(2'''-NH, d, J=6.3Hz),9.20(3-NH, br).Melting point: 160-163 ° C. 1 H-NMR (CDCl 3 ) δ: 1.44 (C-CH 3 , s), 1.50 (C-CH 3 , s), 2.08 (2'-H, m), 2.48
(2'-H, ddd, J = 0.6,5.8, 13.6Hz), 3.28 (6 '''-H, m), 3.
38 (3'-OCH 3 , s), 4.08 (2``-H, dd, J = 6.8,7.2Hz), 4.19
(3'-H, d, J = 5.9Hz), 4.55 (2 '''-H, m), 4.60 (5'-H, d,
J = 2.9Hz), 4.63 (4'-H, dd, J = 2.3, 4.1Hz), 4.72 (3``-
H, dd, J = 4.2, 6.3Hz), 4.78 (1``-H, d, J = 7.4Hz), 5.72
(5-H, d, J = 8.6Hz), 6.26 (1'-H, dd, J = 5.5, 9.0Hz), 6.
34 (4``-H, d, J = 4.4Hz), 6.67 (NH, m), 7.87 (6-H, d, J =
8.5Hz), 7.93 (2 '''-NH, d, J = 6.3Hz), 9.20 (3-NH, br).
【００４１】[0041]
【実施例４】実施例３で得たカプラマイシン誘導体（II
I)４６mg（0.０７７mmol）をメタノール2.０mlに溶か
し、アンバーリストＲ−１５Ｈ+ 型１０mgを加え、室温
で４６時間攪拌した。反応終了後、樹脂を濾過し、溶媒
を減圧下で留去した後、エタノール−ヘキサンで結晶化
し、粗生成物を得た。これをシリカゲルカラムクロマト
グラフィー（クロロホルム−メタノール＝１０：１）で
精製し、カプラマイシン誘導体(IV)３８mgを得た（収率
８９％）。Example 4 The capramicin derivative obtained in Example 3 (II
46 mg (0.077 mmol) of I) was dissolved in 2.0 ml of methanol, 10 mg of Amberlyst R-15H + type was added, and the mixture was stirred at room temperature for 46 hours. After completion of the reaction, the resin was filtered, the solvent was distilled off under reduced pressure, and the residue was crystallized from ethanol-hexane to obtain a crude product. This was purified by silica gel column chromatography (chloroform-methanol = 10: 1) to obtain 38 mg of capramicin derivative (IV) (yield 89%).
【００４２】[0042]
【化１９】 [Chemical 19]
【００４３】融点：１４６〜１４９℃ 1 Ｈ−ＮＭＲ（ＣＤ3 ＯＤ） δ： 1.03-1.96(2',3''',4''',5'''-H, m),2.36(2'-H, ddd,
J=1.5, 5.8, 14.0Hz), 3.20(6'''-H, m),3.30(3'-OCH3,
s), 3.88(2''-H, dd, J=4.9, 5.8Hz),4.03(3'-H, dd,
J=1.6, 4.2Hz), 4.27(3''-H, t, J=4.4Hz),4.50(4'-H,
dd, J=1.9, 2.1Hz), 4.54(2'''-H, br),4.65(5'-H, d,
J=2.1Hz), 5.15(1''-H, d, J=6.0Hz),5.69(5-H, d, J=
8.1Hz), 5.95(4''-H, d, J=3.9Hz),6.13(1'-H, dd, J=
5.7, 8.6Hz), 7.95(6-H, d, J=8.3Hz).Melting point: 146-149 ° C. 1 H-NMR (CD 3 OD) δ: 1.03-1.96 (2 ′, 3 ″ ′, 4 ″ ′, 5 ″ ′-H, m), 2.36 (2 '-H, ddd,
J = 1.5, 5.8, 14.0Hz), 3.20 (6 '''-H, m), 3.30 (3'-OCH 3 ,
s), 3.88 (2``-H, dd, J = 4.9, 5.8Hz), 4.03 (3'-H, dd,
J = 1.6, 4.2Hz), 4.27 (3``-H, t, J = 4.4Hz), 4.50 (4'-H,
dd, J = 1.9, 2.1Hz), 4.54 (2 '''-H, br), 4.65 (5'-H, d,
J = 2.1Hz), 5.15 (1``-H, d, J = 6.0Hz), 5.69 (5-H, d, J =
8.1Hz), 5.95 (4``-H, d, J = 3.9Hz), 6.13 (1'-H, dd, J =
5.7, 8.6Hz), 7.95 (6-H, d, J = 8.3Hz).
【００４４】[0044]
【実施例５】実施例１で得たカプラマイシン誘導体
（Ｉ）４３mg（0.０７mmol）を乾燥塩化メチレン1.０ml
に溶かし、−７８℃に冷却した後、アルゴン気流下でＤ
ＡＳＴ(diethylaminosulfur trifluoride)３７μl(0.２
８mmol）を滴下した。−７８℃で４時間、０℃で２時間
攪拌し、飽和炭酸ナトリウム水溶液を加えた。反応液を
酢酸エチルで抽出し、有機層を飽和食塩水で洗浄し、無
水硫酸ナトリウムで乾燥した後、溶媒を留去した。残渣
をシリカゲルカラムクロマトグラフィー（ベンゼン−メ
タノール＝１０：１）で精製し、カプラマイシン誘導体
（Ｖ）２１mg（油状物）を得た（収率４９％）。Example 5 43 mg (0.07 mmol) of the capramicin derivative (I) obtained in Example 1 was dried in methylene chloride (1.0 ml).
Dissolved in water and cooled to -78 ° C.
AST (diethylaminosulfur trifluoride) 37μl (0.2
8 mmol) was added dropwise. The mixture was stirred at -78 ° C for 4 hours and at 0 ° C for 2 hours, and a saturated aqueous sodium carbonate solution was added. The reaction solution was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (benzene-methanol = 10: 1) to obtain 21 mg (oil) of capromycin derivative (V) (yield 49%).
【００４５】[0045]
【化２０】 [Chemical 20]
【００４６】 1Ｈ−ＮＭＲ（ＣＤＣｌ3) δ： 1.35(C-CH3, s), 1.42(C-CH3, s),1.60-2.25( CH2×3,
m),3.24(6'''-H, m), 3.56(3'-OCH3, s), 4.13(2''-H,
dd, J=4.0, 5.0Hz),4.42(2'''-H, m), 4.55-4.72(4',
5',3''-H, m),4.73(1''-H, d, J=4.4Hz), 5.33(3'-H,
m),5.83(5-H, dd, J=1.4, 5.6Hz), 6.01(2'-H, ddd, J=
53, 3.6, 2.5Hz),6.26(4''-H, d, J=3.0Hz), 6.92(1'-
H, dd, J=3.6, 7.0Hz),6.41(NH, m), 7.32(NH, br), 7.
52(6-H, d, J=5.7Hz),7.58(2'''-NH, d, J=4.2Hz). 1 H-NMR (CDCl 3 ) δ: 1.35 (C-CH 3 , s), 1.42 (C-CH 3 , s), 1.60-2.25 (CH 2 × 3,
m), 3.24 (6 '''-H, m), 3.56 (3'-OCH 3 , s), 4.13 (2''-H,
dd, J = 4.0, 5.0Hz), 4.42 (2``'-H, m), 4.55-4.72 (4 ',
5 ', 3''-H, m), 4.73 (1''-H, d, J = 4.4Hz), 5.33 (3'-H,
m), 5.83 (5-H, dd, J = 1.4, 5.6Hz), 6.01 (2'-H, ddd, J =
53, 3.6, 2.5Hz), 6.26 (4``-H, d, J = 3.0Hz), 6.92 (1'-
H, dd, J = 3.6, 7.0Hz), 6.41 (NH, m), 7.32 (NH, br), 7.
52 (6-H, d, J = 5.7Hz), 7.58 (2 '''-NH, d, J = 4.2Hz).
【００４７】[0047]
【実施例６】実施例５で得たカプラマイシン誘導体
（Ｖ）７３mg（0.１２mmol）をメタノール2.０mlに溶か
し、アンバーリストＲ−１５Ｈ+ 型１０mgを加え、室温
で３０時間攪拌した。反応終了後、樹脂を濾過し、溶媒
を減圧下で留去した後、残渣をシリカゲルカラムクロマ
トグラフィー（クロロホルム−メタノール＝１５：１）
で精製し、カプラマイシン誘導体（VI) ５１mg（シロッ
プ状）を得た（収率７５％）。Example 6 73 mg (0.12 mmol) of the capramicin derivative (V) obtained in Example 5 was dissolved in 2.0 ml of methanol, 10 mg of Amberlyst R-15H + type was added, and the mixture was stirred at room temperature for 30 hours. After the reaction was completed, the resin was filtered, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform-methanol = 15: 1).
Purification was performed to obtain 51 mg (syrupy form) of capramicin derivative (VI) (yield 75%).
【００４８】[0048]
【化２１】 [Chemical 21]
【００４９】 1Ｈ−ＮＭＲ（ＣＤ3 ＯＤ） δ： １．１２−１．８７（３’’’，４’’’，５’’’−
Ｈ， ｍ）， ３．１８（６’’’−Ｈ， ｍ），３．
４２（３’−ＯＣＨ３， ｓ）， ３．８５（２’’−
Ｈ， ｔ， Ｊ＝５．５Ｈｚ）， ４．５６（３’−
Ｈ， ｍ），４．２５（３’’−Ｈ， ｔ， Ｊ＝４．
４Ｈｚ）， ４．４４（４’−Ｈ， ｔ， Ｊ＝２．０
Ｈｚ），４．５０（２’’’−Ｈ， ｂｒ）， ４．６
８（５’−Ｈ， ｄ， Ｊ＝２．２Ｈｚ）， ５．１５
（１’’−Ｈ， ｄ， Ｊ＝６．０Ｈｚ），５．６９
（５−Ｈ， ｄ， Ｊ＝８．１Ｈｚ）， ５．９５
（４’’−Ｈ， ｄ， Ｊ＝３．９Ｈｚ），６．０１
（２’−Ｈ， ｄｄｄ， Ｊ＝５８， ３．６， ２．
５Ｈｚ）， ６．８８（１’−Ｈ， ｄｄ， Ｊ＝３．
６， ７．０Ｈｚ），７．９２（６−Ｈ， ｄ， Ｊ＝
８．３Ｈｚ）． 1 H-NMR (CD 3 OD) δ: 1.12-1.87 (3 ′ ″, 4 ′ ″, 5 ″ ′-
H, m), 3.18 (6 '''-H, m), 3.
42 (3′-OCH 3 , s), 3.85 (2 ″-
H, t, J = 5.5 Hz), 4.56 (3'-
H, m), 4.25 (3 ''-H, t, J = 4.
4 Hz), 4.44 (4'-H, t, J = 2.0)
Hz), 4.50 (2 '''-H, br), 4.6
8 (5'-H, d, J = 2.2 Hz), 5.15
(1 ''-H, d, J = 6.0 Hz), 5.69
(5-H, d, J = 8.1 Hz), 5.95
(4 ″ -H, d, J = 3.9 Hz), 6.01
(2'-H, ddd, J = 58, 3.6, 2.
5 Hz), 6.88 (1'-H, dd, J = 3.
6, 7.0 Hz), 7.92 (6-H, d, J =
8.3 Hz).
Claims (3)
たはＲ1 およびＲ2 が一緒になって低級アルキレン基を
表し、Ｒ3 は水素原子またはフッ素原子を表し、Ｒ4 は
水素原子、水酸基またはフェニルチオカルボナート基を
表す。但し、Ｒ1 およびＲ2 が水素原子のとき、Ｒ3 が
水素原子で、かつＲ4 が水酸基である場合を除く。）で
示される新規カプラマイシン誘導体。1. A general formula: (In the formula, R 1 and R 2 are the same and represent a hydrogen atom, or R 1 and R 2 together represent a lower alkylene group, R 3 represents a hydrogen atom or a fluorine atom, and R 4 represents hydrogen. Represents a hydrogen atom, a hydroxyl group or a phenylthiocarbonate group, provided that R 1 and R 2 are hydrogen atoms, and R 3 is a hydrogen atom and R 4 is a hydroxyl group.). Derivative.
ンと２，２−ジメトキシプロパンとを室温で反応させ
て、下記の式（Ｉ） 【化２】 で示されるカプラマイシン誘導体（Ｉ）を製造し、次い
で、有機溶媒中、前記カプラマイシン誘導体（Ｉ）と４
−ジメチルアミノピリジンとフェノキシチオカルボニル
クロリドとを室温で反応させて、下記の式（II) 【化３】 で示されるカプラマイシン誘導体（II) を製造し、次い
で、有機溶媒中、前記カプラマイシン誘導体（II) とア
ゾイソブチロニトリルとｎ−Ｂｕ3 ＳｎＨとを不活性ガ
ス気流下で加熱還流して、下記の式(III） 【化４】 で示されるカプラマイシン誘導体(III）を製造し、次い
で、酸触媒の存在下、前記カプラマイシン誘導体(III）
とメタノールとを室温で反応させて、下記の式（IV） 【化５】 で示されるカプラマイシン誘導体（IV）を得ることを特
徴とする新規カプラマイシン誘導体の製造方法。2. Capramycin is reacted with 2,2-dimethoxypropane at room temperature in an organic solvent containing an acid catalyst to give a compound represented by the following formula (I): To produce a couplermycin derivative (I), which is then added to the above-mentioned couplermycin derivative (I) in an organic solvent.
-Dimethylaminopyridine is reacted with phenoxythiocarbonyl chloride at room temperature to give the following formula (II): To produce a couplermycin derivative (II), and then heating and refluxing the couplermycin derivative (II), azoisobutyronitrile and n-Bu 3 SnH in an organic solvent under an inert gas stream. , The following formula (III): A capramicin derivative (III) represented by
And methanol are reacted at room temperature to give the following formula (IV): A method for producing a novel capramicin derivative, which comprises obtaining the capramicin derivative (IV) represented by:
プラマイシン誘導体（Ｉ）とジエチルアミノ三フッ化硫
黄とを不活性ガス気流下で反応させて、下記の式（Ｖ） 【化６】 で示されるカプラマイシン誘導体（Ｖ）を製造し、次い
で、酸触媒の存在下、前記カプラマイシン誘導体（Ｖ）
とメタノールとを室温で反応させて、下記の式（VI） 【化７】 で示されるカプラマイシン誘導体（VI）を得ることを特
徴とする新規カプラマイシン誘導体の製造方法。3. A couplermycin derivative (I) according to claim 2 and diethylaminosulfur trifluoride are reacted in a cooled organic solvent under an inert gas stream to give the following formula (V): To produce a capramicin derivative (V), which is then prepared in the presence of an acid catalyst.
And methanol are reacted at room temperature to give the following formula (VI): A method for producing a novel capramicin derivative, which comprises obtaining the capramicin derivative (VI) represented by:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP31296391A JPH05148293A (en) | 1991-11-28 | 1991-11-28 | New capuramycin derivative and its production |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP31296391A JPH05148293A (en) | 1991-11-28 | 1991-11-28 | New capuramycin derivative and its production |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH05148293A true JPH05148293A (en) | 1993-06-15 |
Family
ID=18035595
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP31296391A Pending JPH05148293A (en) | 1991-11-28 | 1991-11-28 | New capuramycin derivative and its production |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH05148293A (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000002892A1 (en) * | 1998-07-09 | 2000-01-20 | Sankyo Company, Limited | Novel antibacterial compounds |
| JP2000159765A (en) * | 1998-09-24 | 2000-06-13 | Sankyo Co Ltd | New antibacterial compound |
| WO2001014399A1 (en) * | 1999-08-20 | 2001-03-01 | Sankyo Company, Limited | Novel a-500359 derivatives |
| JP2009256380A (en) * | 1998-07-09 | 2009-11-05 | Sequella Inc | Antibiotic a-500359 and derivative |
| WO2019088179A1 (en) * | 2017-10-31 | 2019-05-09 | ヤマサ醤油株式会社 | Nucleoside derivative and use thereof |
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-
1991
- 1991-11-28 JP JP31296391A patent/JPH05148293A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000002892A1 (en) * | 1998-07-09 | 2000-01-20 | Sankyo Company, Limited | Novel antibacterial compounds |
| US6472384B1 (en) | 1998-07-09 | 2002-10-29 | Sankyo Company, Limited | Antimicrobial compounds |
| EP1319406A1 (en) * | 1998-07-09 | 2003-06-18 | Sankyo Company, Limited | Novel antibacterial compounds |
| US6844173B2 (en) | 1998-07-09 | 2005-01-18 | Sankyo Company, Limited | Strain of Streptomyces griseus |
| KR100622889B1 (en) * | 1998-07-09 | 2006-09-12 | 상꾜 가부시키가이샤 | Novel antibacterial compounds |
| JP2009256380A (en) * | 1998-07-09 | 2009-11-05 | Sequella Inc | Antibiotic a-500359 and derivative |
| JP2000159765A (en) * | 1998-09-24 | 2000-06-13 | Sankyo Co Ltd | New antibacterial compound |
| JP4531167B2 (en) * | 1998-09-24 | 2010-08-25 | セケラ インコーポレイテッド | New antibacterial compounds |
| KR100787849B1 (en) * | 1999-08-20 | 2007-12-27 | 다이이찌 산쿄 가부시키가이샤 | Novel a-500359 derivatives |
| US7157442B2 (en) | 1999-08-20 | 2007-01-02 | Sankyo Company, Limited | Antibacterial compound |
| WO2001014399A1 (en) * | 1999-08-20 | 2001-03-01 | Sankyo Company, Limited | Novel a-500359 derivatives |
| US11643432B2 (en) | 2016-12-16 | 2023-05-09 | National University Corporation Tokai National Higher Education And Research System | Nucleoside derivative and use thereof |
| WO2019088179A1 (en) * | 2017-10-31 | 2019-05-09 | ヤマサ醤油株式会社 | Nucleoside derivative and use thereof |
| CN111868067A (en) * | 2017-10-31 | 2020-10-30 | 山佐酱油株式会社 | Nucleoside derivatives and use thereof |
| JPWO2019088179A1 (en) * | 2017-10-31 | 2020-11-12 | ヤマサ醤油株式会社 | Nucleoside derivatives and their use |
| US11780874B2 (en) | 2017-10-31 | 2023-10-10 | Yamasa Corporation | Nucleoside derivative and use thereof |
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