JPS6187673A - Acylcytosine derivative - Google Patents
Acylcytosine derivativeInfo
- Publication number
- JPS6187673A JPS6187673A JP21015084A JP21015084A JPS6187673A JP S6187673 A JPS6187673 A JP S6187673A JP 21015084 A JP21015084 A JP 21015084A JP 21015084 A JP21015084 A JP 21015084A JP S6187673 A JPS6187673 A JP S6187673A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- compound shown
- compound
- dihydroxy
- agent
- 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
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は、医薬として有用な新規化合物に関する。より
詳細にはシクロペンテン環を有する新規ヌクレオシドに
関する。DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to novel compounds useful as pharmaceuticals. More specifically, the present invention relates to a novel nucleoside having a cyclopentene ring.
シクロペンテン環を有するヌクレオシド類とし′(は、
アンプラリエーラ・レギ1−1す′)、(^町l111
1ariella regularis )八110
79 (a1研菌寄第4494号)の培養液から得られ
る式
で示されるネプラノシン(Neplanocin) A
が知られている。この化合物は植物病原菌糸状菌生育阻
害作用およびL5178Y111胞に対する細胞生育阻
害作用を有するだけでな(、L1210細胞に対する生
育阻害作用を有し、制癌剤として有用性が期待されてい
る* (Current Chemotherapy
andinfectious Disease+ 15
58〜1561ページ、 1980年。Nucleosides having a cyclopentene ring′(
Amplariera Regi 1-1'), (^Town l111
1ariella regularis ) 8110
Neplanocin A expressed by the formula obtained from the culture solution of 79 (A1 Research Institute Bacteria No. 4494)
It has been known. This compound not only has an inhibitory effect on the growth of plant pathogenic mycelia and a cell growth inhibitory effect on L5178Y111 cells, but also has a growth inhibitory effect on L1210 cells, and is expected to be useful as an anticancer agent* (Current Chemotherapy
infectious Disease+ 15
Pages 58-1561, 1980.
The Am@rican 5ociety for
Microbiology発行)。The Am@rican 5ociety for
Published by Microbiology).
大野は、この骨格に着目して、シクロペンテン環がネプ
ラノシンAと同じ天然型である−礒代1代中 11 !
、14− r’ミノイミ9’ブール−!1〜カルボ+!
ノアミド、1°ノランル、ン1ンン下j:たはグアニン
の核酸塩基を示す)
で表わされる化合物を合成することに成功した(日本薬
学会第103年会)。これらの化合物は、KBIjll
胞に対し細胞毒性を示している。Ohno focused on this skeleton and discovered that the cyclopentene ring is the same natural type as neplanocin A - Isoshiro 1 of 11!
, 14-r'Minoimi9'Boole-! 1 ~ Calbo+!
We have succeeded in synthesizing a compound represented by the following formula: noamide, 1° noranru, nn1nn lower j: or guanine nucleobase) (103rd Annual Meeting of the Pharmaceutical Society of Japan). These compounds are KBIjll
It is cytotoxic to cells.
本発明者らは、これらシクロペンテン環を有するヌクレ
オノド化合物に関して、さらに新規化合物の合成研究を
続け、医薬として有用な化合物の探索を鋭意行った。The present inventors continued research on the synthesis of new compounds regarding these nucleonodide compounds having a cyclopentene ring, and earnestly searched for compounds useful as medicines.
本発明は、これらの研究結果から完成されたものである
。すなわち、本発明は一般式
(式中、R1はアキル基を、R2は水素または水酸基イ
ボ」)
で表わされン、゛l′ノルシトノン話JIF体に閏4ろ
。The present invention was completed based on the results of these studies. That is, the present invention is represented by the general formula (in the formula, R1 is an alkyl group, R2 is hydrogen or a hydroxyl group), and the compound is represented by the JIF form of norcitonone.
上記式中のアシル基とは、アセチル、プロピオニル、ブ
チリル、イソブチリル、バレリル、ピバロイル、カプロ
イル、ラウロイル、ミリストイル、バルミトイル、ステ
アロイル、ベヘノイルなどである。The acyl group in the above formula includes acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, caproyl, lauroyl, myristoyl, balmitoyl, stearoyl, behenoyl, and the like.
本発明の化合物(1)は、一般式
(式中、R2は前記と同義である)
で表わされるシトシン誘導体と一触式
%式%()
(式中、R1は前記と同義である)
で表わされるカルボン酸化合物またはその反応性誘導体
とを反応させることにより製造される。The compound (1) of the present invention is a cytosine derivative represented by the general formula (wherein R2 has the same meaning as above) and a monocatalytic formula %() (wherein R1 has the same meaning as above). It is produced by reacting the represented carboxylic acid compound or its reactive derivative.
−M式(Ill)の化合物の反応性誘導体としては、/
l!II t、 Oケア 化’l”I 、 fl”J−
/ト物、tf9 i”+ 1’+67jjj水1力、反
応r1エステル化合物などがJ、ぼられる。-M Reactive derivatives of the compound of formula (Ill) include /
l! II t, O care 'l"I, fl"J-
/ material, tf9 i''+ 1'+67jjj water 1 force, reaction r1 ester compound, etc. are extracted.
反応は通常不活性な溶媒(水、アルコール、ジオキサン
、ジエチルエーテル、アセトン、ジメチルホルムアミド
、ジメチルスルホキシド、アセトニトリルなど、または
それらの混合溶媒)中、0℃から用いた溶媒の環流温度
までの温度で、数時間から数十時間で進行する。場合に
よっては、縮合剤を用いてもよい。The reaction is usually carried out in an inert solvent (water, alcohol, dioxane, diethyl ether, acetone, dimethylformamide, dimethyl sulfoxide, acetonitrile, etc., or a mixed solvent thereof) at a temperature from 0°C to the reflux temperature of the solvent used. It progresses over a period of several hours to several tens of hours. In some cases, a condensing agent may be used.
本発明の化合物(+)は抗腫瘍作用、抗ウィルス作用、
分化誘導能を有し、たとえば抗腫瘍剤、抗ウィルス剤と
して有用である。The compound (+) of the present invention has antitumor activity, antiviral activity,
It has the ability to induce differentiation and is useful as, for example, an antitumor agent or an antiviral agent.
本発明の化合物を医薬として用いる場合、医薬上許容で
きる担体、賦形剤、希釈剤などと混合して散剤、錠剤、
カプセル剤、注射剤などの形態で投与できる。投与量は
症状、投与法などにより異なるが、通常成人1日当り、
経口投与で5〜100呵/ kg体重が適当である。When the compound of the present invention is used as a medicine, it can be mixed with pharmaceutically acceptable carriers, excipients, diluents, etc. to form powders, tablets, etc.
It can be administered in the form of capsules, injections, etc. Dosage varies depending on symptoms, administration method, etc., but is usually given per day for adults.
The appropriate dose for oral administration is 5 to 100 m/kg body weight.
本発明の出発物質である一般式(11)の化合物のうり
、R′が水酸’+j ’(lシ、る化1′1物は )、
: 、J′、、<番まIF11頭昭58111i 15
1号に記載の/Jl大に、Iす、またR”が水素である
化合物は、たとえば同[1付特許出願(発明の名称ニジ
クロペンテン環を有する新規ヌクレオシド)に記載の方
法により製造される。In the compound of the general formula (11) which is the starting material of the present invention, R' is hydroxyl '+j' (1, and the compound 1'1 is),
: ,J',,<Banma IF11 Showa 58111i 15
The compound described in No. 1, in which I, I, and R'' are hydrogen, can be produced, for example, by the method described in Patent Application No. 1 (Invention Title: Novel Nucleoside Having a Nidiclopentene Ring).
(実施例〕
以下、実施例により本発明を説明するが、本発明はこれ
らに限定されるものではない。(Examples) The present invention will be described below with reference to Examples, but the present invention is not limited thereto.
実施例1
1− ((I R,2S、3R)−2,3−ジヒドロキ
シ−4−ヒドロキシメチル−4−シクロペンテン−1−
イル)シトシン10(Igを水1.1mlに1容カし、
さらにジオキサン10m1および無水へヘン酸550■
を加え、70℃で7時間加熱撹拌した後、反応液を40
℃で減圧濃縮する。得られたあめ状物質を水洗し、さら
にベンセン、酢酸エチル、エーテルで順次洗浄し、副生
成物のベヘン酸を除去する。残渣をクロロホルム−メタ
ノール(9i 1)混液を展開溶媒としてシリカゲルカ
ラムクロマトC′r↑11製’I口、i:、 l−’
+8’+カj+1’i色シハシlZJ、170でで分解
するN4−ヘヘノイル−1−((I R。Example 1 1-((IR,2S,3R)-2,3-dihydroxy-4-hydroxymethyl-4-cyclopentene-1-
1 volume of cytosine 10 (Ig) in 1.1 ml of water,
Additionally, 10ml of dioxane and 550ml of anhydrous hehenic acid
After heating and stirring at 70°C for 7 hours, the reaction solution was heated to 40°C.
Concentrate under reduced pressure at °C. The resulting candy-like substance is washed with water, and then sequentially with benzene, ethyl acetate, and ether to remove the byproduct behenic acid. The residue was subjected to silica gel column chromatography using a chloroform-methanol (9i 1) mixture as a developing solvent.
N4-Hehenoyl-1-((I R.
2S、3R)−2,3−ジヒドロキシ−4−ヒドロキン
メチル−4−シクロペンテン−1−イル〕シトンン12
0■が得られる。2S,3R)-2,3-dihydroxy-4-hydroquinemethyl-4-cyclopenten-1-yl]sitonone 12
0 ■ is obtained.
紫外線吸収スペクトル〔クロロホルム−メタノール(9
:1)混液〕λmax (n+n) : 302赤外
線吸収スペクトル(vnaw、 elm−’) :
2915゜2852、2850 (アルキル’) 、
1710.1645 (ウレイドアミド)
プロトン核磁気共鳴スペクトル(DMSOd、 −DS
S)δ <pp閤 ) ニ
ア、81 (d、 1. L6. Js、h□T、3N
Z )7.22 (d、 1.H−5,Js、i=7.
3+1z )5.56 (bs、 1゜ト5゛)
5.42 (br、 1. H−1’ )4.80 (
br、 511 )
4.40 (br、 l、 H−3’ )4.10 (
bs、 2. H−6’ )3.95 (br、 1.
H−2’ )2.22 (1+r、 i、 f
’、lll;1M:llz 11.51 (hs、
2. C0CIhCIIffi )1.23
(bs、 36. Cl1i x 18 )
0.84 (L、 3. C1h )実施例2
1− [(IR,2S、3R)−2,3−ジヒドロキシ
−4−ヒドロキシメチル−4−ンクロペンテン=1−イ
ル〕シトシン12■を水0.51及びジオキサン2ml
中に懸lWさせ、無水酢酸9.5μρを加え、50℃で
一晩加熱攪拌する0反応液を減圧上濃縮し、水−メタノ
ール混液に溶かして、分取薄層クロマト〔展開溶媒;ク
ロロホルム−メタノール(3:1))に付し、クロロホ
ルム−エタノール(1: 1)混液で抽出すると、融点
188〜189℃(分解)のN4−アセチル〜1− (
(I R,23゜3R)−2,3−ジヒドロキシ−4−
ヒドロキシメチル−4−シクロペンテン−■−イル〕シ
トンン7111rが得られる。Ultraviolet absorption spectrum [chloroform-methanol (9
:1) Mixed liquid] λmax (n+n) : 302 Infrared absorption spectrum (vnaw, elm-') :
2915°2852, 2850 (alkyl'),
1710.1645 (Ureidoamide) Proton nuclear magnetic resonance spectrum (DMSOd, -DS
S) δ < pp 閤 ) Near, 81 (d, 1. L6. Js, h□T, 3N
Z ) 7.22 (d, 1.H-5, Js, i=7.
3+1z) 5.56 (bs, 1° to 5°) 5.42 (br, 1. H-1') 4.80 (
br, 511) 4.40 (br, l, H-3') 4.10 (
bs, 2. H-6') 3.95 (br, 1.
H-2')2.22 (1+r, i, f
', lll; 1M:llz 11.51 (hs,
2. C0CIhCIIffi ) 1.23
(bs, 36.Cl1i x 18)
0.84 (L, 3.C1h) Example 2 1-[(IR,2S,3R)-2,3-dihydroxy-4-hydroxymethyl-4-enclopenten=1-yl]cytosine was dissolved in 0.84 g of water. 51 and dioxane 2ml
Add 9.5μρ of acetic anhydride and stir overnight at 50°C. The reaction solution was concentrated under reduced pressure, dissolved in a water-methanol mixture, and subjected to preparative thin layer chromatography [developing solvent: chloroform- When extracted with a mixture of chloroform and ethanol (1:1), N4-acetyl~1-(
(I R, 23°3R)-2,3-dihydroxy-4-
Hydroxymethyl-4-cyclopenten-■-yl]sitonne 7111r is obtained.
紫外線吸収スペクトル(メタノール) λWaX(n−
) : 303. 247. 217プOトンll
’ Chi 気j’、lj’l’S7. ヘク(Jl’
(IIMS(ldthIlz+1)δ (ρρ柵);
1.1G (d、 1. ll−6,Ja、a4.
382 )7.13 (d、 1. H−5)
5.54 (d、 1. 11−5’ )5.4
1 (翔、 1. ll−1″)4.43 (d、 1
. If−3’ )4.09 (bs、 2.
L6° )3.96 (br、 1. H−2’
)2.09 (s、 3. Co臘)
質量スペクトル(F A B)(m/a): 282
(Ml+” )実施例3
1−C(I R,2S、3R)−2,3−ジヒドロキシ
−4−ヒドロキシメチル−4−シクロペンテン−1−イ
ルコントシン12■および無水ラウリンM38■を水0
.5ml及びジオキサン1,51中に加え、65℃で2
4時間加?、t1.環流する0反応液を残圧乾固し、つ
いで実施例2と同様に分取薄層クロマトに付すと、N′
−ラウロイル−1−((IR。Ultraviolet absorption spectrum (methanol) λWaX(n-
): 303. 247. 217 puotonll
'Chi kij',lj'l'S7. Heku (Jl'
(IIMS(ldthIlz+1)δ (ρρ fence); 1.1G (d, 1. ll-6, Ja, a4.
382) 7.13 (d, 1. H-5) 5.54 (d, 1. 11-5') 5.4
1 (Sho, 1.ll-1″)4.43 (d, 1
.. If-3') 4.09 (bs, 2.
L6°)3.96 (br, 1.H-2'
)2.09 (s, 3.Co臘) Mass spectrum (F A B) (m/a): 282
(Ml+”) Example 3 1-C(IR,2S,3R)-2,3-dihydroxy-4-hydroxymethyl-4-cyclopenten-1-ylcontosine 12■ and anhydrous laurin M38■ were dissolved in water 0
.. 5 ml and dioxane 1,51 mL and heated at 65°C for 2 hours.
4 hours plus? , t1. When the refluxing 0 reaction solution was dried under residual pressure and then subjected to preparative thin layer chromatography in the same manner as in Example 2, N'
-Lauroyl-1-((IR.
2S、3R)−2,3〜ジヒドロキシ−4−とドロ1ツ
ノ−トルー4−ンクaペンテンー1−イル(シトノン1
2■が得られる。2S,3R)-2,3-dihydroxy-4-and dolo-1-to-4-k-a-penten-1-yl (cytonone-1
2■ is obtained.
紫外線吸収スペクトル(メタノール)λ−aX(nm)
; 303.248.217プロトン核磁気共鳴スペ
クトル(DMSOdi DtO)δ (ppta)
ニ
ア、81 (d、 1. ll−6,Js、a・7.3
H2)7.21 (d、 1. H−5)
5.55 (bs、 1. L5’ )5.45 (b
r、 1. H−1°)4.38 (d、 1. H−
3°)
4.10 (bs、 2. ll−6’ )3.94
(dd、 1. ll−2’ )2.32 (t+ 2
. Co更1iCIIx )2.53 (br、 21
COC1hCIIg )1.24 (C11t x 8
)
0.85 (L、 3. CI+3 )’T[スペクト
ル(FAB)(m/e): 422 (Mll’ )実
施例4
1− ((l R,3R) −3−ヒドロキシ−4−ヒ
トリ4ジメチル−4−ツクロー<7デシ′〜1〜fル]
ントシン55■をジオキサン5.51及び水0.61に
溶かし、ついで無水酢酸55■を加え、65〜70℃に
て7時間加n Rl’l’する0反応液を冷却後、溶媒
を留去し、インプロパツールを加えて固化物を濾去する
。メタノール−エタノール(1: l)混液から再結晶
すると、融点198〜200℃(分解)のN4−アセチ
ル−1−((IR,3R)−3−ヒドロキソ−4−ヒド
ロキシメチル−4−シクロペンテン−1−イル〕シトシ
ン24■が得られる。Ultraviolet absorption spectrum (methanol) λ-aX (nm)
; 303.248.217 Proton nuclear magnetic resonance spectrum (DMSOdi DtO) δ (ppta)
Near, 81 (d, 1.ll-6, Js, a.7.3
H2) 7.21 (d, 1. H-5) 5.55 (bs, 1. L5') 5.45 (b
r, 1. H-1°) 4.38 (d, 1. H-
3°) 4.10 (bs, 2.ll-6') 3.94
(dd, 1.ll-2')2.32 (t+2
.. Co change 1iCIIx ) 2.53 (br, 21
COC1hCIIg ) 1.24 (C11t x 8
) 0.85 (L, 3. CI+3)'T[Spectrum (FAB) (m/e): 422 (Mll') Example 4 1-((lR,3R)-3-hydroxy-4-hytri4 Dimethyl-4-tucrow <7 d'~1~f]
Dissolve 55 μ of totocin in 5.51 μ of dioxane and 0.61 μ of water, then add 55 μ of acetic anhydride, and heat at 65 to 70°C for 7 hours. After cooling the reaction solution, the solvent is distilled off. Then, add Improper Tool and filter off the solidified material. Recrystallization from a methanol-ethanol (1:l) mixture yields N4-acetyl-1-((IR,3R)-3-hydroxo-4-hydroxymethyl-4-cyclopentene-1 with a melting point of 198-200°C (decomposed)). -yl]cytosine 24■ is obtained.
プロトン核磁気共鳴スペクトル(DMSOd& −D!
0゜TMS ) δ (ppm) ニ
ア、85 (d、 1. H−6)
7.25 (d、 1.11−.5 )5.70 (d
s、 2.1l−1’、 H−5’ )4.19 (s
、 2. ll−6°)2.40〜1.80 (br、
2.8−2’ )2.12 (sI3. COCl1
3)li!スペクトル(m/e): 24B (M’
−OH) 、206.188.187Proton nuclear magnetic resonance spectrum (DMSOd&-D!
0゜TMS) δ (ppm) Near, 85 (d, 1. H-6) 7.25 (d, 1.11-.5) 5.70 (d
s, 2.1l-1', H-5')4.19 (s
, 2. ll-6°)2.40~1.80 (br,
2.8-2')2.12 (sI3. COCl1
3) li! Spectrum (m/e): 24B (M'
-OH), 206.188.187
Claims (1)
基を示す) で表わされるアシルシトシン誘導体。[Claims] An acylcytosine derivative represented by the general formula ▲There are numerical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 represents an acyl group, and R^2 represents a hydrogen or hydroxyl group).
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP21015084A JPS6187673A (en) | 1984-10-06 | 1984-10-06 | Acylcytosine derivative |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP21015084A JPS6187673A (en) | 1984-10-06 | 1984-10-06 | Acylcytosine derivative |
Publications (1)
Publication Number | Publication Date |
---|---|
JPS6187673A true JPS6187673A (en) | 1986-05-06 |
Family
ID=16584589
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP21015084A Pending JPS6187673A (en) | 1984-10-06 | 1984-10-06 | Acylcytosine derivative |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS6187673A (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2009161541A (en) * | 2000-10-18 | 2009-07-23 | Pharmasset Inc | Modified nucleoside for treating viral infection and abnormal cellular proliferation |
-
1984
- 1984-10-06 JP JP21015084A patent/JPS6187673A/en active Pending
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2009161541A (en) * | 2000-10-18 | 2009-07-23 | Pharmasset Inc | Modified nucleoside for treating viral infection and abnormal cellular proliferation |
JP2013079250A (en) * | 2000-10-18 | 2013-05-02 | Gilead Pharmasset Llc | Modified nucleoside for treatment of viral infection and abnormal cellular proliferation |
US10100076B2 (en) | 2000-10-18 | 2018-10-16 | Gilead Pharmasset Llc | Modified nucleosides for the treatment of viral infections and abnormal cellular proliferation |
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