JPS5862147A - Nitric acid ester derivative - Google Patents
Nitric acid ester derivativeInfo
- Publication number
- JPS5862147A JPS5862147A JP16145281A JP16145281A JPS5862147A JP S5862147 A JPS5862147 A JP S5862147A JP 16145281 A JP16145281 A JP 16145281A JP 16145281 A JP16145281 A JP 16145281A JP S5862147 A JPS5862147 A JP S5862147A
- Authority
- JP
- Japan
- Prior art keywords
- omega
- nitric acid
- compound
- acid ester
- ester derivative
- 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.)
- Granted
Links
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【発明の詳細な説明】
本発明は新＃！＠酸エステル誘導体に関するものである
。[Detailed Description of the Invention] The present invention is a new #! ＠Relates to acid ester derivatives.
本発明の化合物は一般式（１）
〔式中Ｒ１は水素原子又はニドＣ基を、２はω−にトロ
オキシ）アルキル基もしくはω−（カルボキシ）アルキ
ル基または一般式（１）す。〕で表わされ、血管拡張作
用を呈することから循ｌｌｌ器系治療剤のなかでも虚血
性心疾患治療薬として有用である。The compound of the present invention has the general formula (1) [wherein R1 is a hydrogen atom or a nido C group, and 2 is an ω-to-trooxy)alkyl group or an ω-(carboxy)alkyl group, or a general formula (1). ], and because it exhibits a vasodilatory effect, it is useful as a therapeutic agent for ischemic heart disease among therapeutic agents for the circulatory system.
本発明の化合物は２次の一般式（１）
（式中２はω−八クイドロキシアルキル基たはω−カル
ボキシアルキル基のアルカリ金属塩もシくはアルカリ土
類金属塩を示す。）で表わされるアルコール誘導体を発
煙硝酸中、低温で反応させて製造することが出来る。一
方、一般式（１）の−が一般式（１）で示される基であ
る硝酸エステルは上記の製造法で得られた一般式（ト）
（式中Ｒ１は前記に同じ。）で表わされる化合物を、テ
トラヒドロ７ラン、クロロホルム、ジクロ四メタン等の
溶媒中、トリエチルアミン存在下、クロル炭酸アルキル
と反応せしめ、混合酸無水物とし、続いてシスタミンと
反応させることにより製造することが出来る。The compound of the present invention has the following general formula (1) (In the formula, 2 represents an alkali metal salt or an alkaline earth metal salt of an ω-octaquidroxyalkyl group or an ω-carboxyalkyl group.) It can be produced by reacting the alcohol derivative represented by in fuming nitric acid at low temperature. On the other hand, the nitrate ester in which - in general formula (1) is a group represented by general formula (1) is the general formula (t) obtained by the above production method.
(In the formula, R1 is the same as above) is reacted with an alkyl chlorocarbonate in a solvent such as tetrahydro7rane, chloroform, dichlorotetramethane, etc. in the presence of triethylamine to form a mixed acid anhydride, and then cystamine It can be produced by reacting with.
かくして製された本発明化合物の代表的化合物であるパ
ンテノール三硝酸エステルの冠血管拡張作用について、
ライフサイエンス ｓ８巻１６０９頁 １９７８年（今
井昭−等）に記載の方法に準じ１モルモット摘出心臓標
本にてランゲンドル７氏法により＠０／１１９投与時の
冠自管潅流量を検討した結果、上記本発明化合物がニト
ログリセリン投与時の冠直管血流量増加作用の約７０％
の活性を呈することをｌａ認した。Regarding the coronary vasodilatory action of panthenol trinitrate, which is a representative compound of the compounds of the present invention thus prepared,
Life Science, Vol. 8, p. 1609, 1978 (Akira Imai, et al.) We examined the coronary perfusion rate during administration of @0/119 using a single guinea pig isolated heart specimen using Langendre's 7 method, and found that the above The compound of the present invention accounts for approximately 70% of the effect of increasing coronary blood flow when nitroglycerin is administered.
It was found that the enzyme exhibited the activity of 1.
以下１本発明を実施例により説明する。The present invention will be explained below with reference to examples.
実施例Ｉ
Ｄ−パンテノール８．０２を米酢＠４−に溶かした溶液
を、氷水浴中、ｏ−ｓ”ｃに冷却した発煙硝酸（比重１
．５１ＳＳｄ中に滴下する。滴加した後、更に８．５時
間、０〜５℃にて攪拌した後、氷水１００−中に注加す
る。得られた水溶液をりｐロホルムにて抽出する。抽出
液を水洗し、無水硫酸ナトリウムで乾燥後、減圧下に濃
縮する。得られた油状物の残液をシリカゲル５０りを用
いてカラムクロマトを行ない、クロロホルムにて溶出し
、シリカゲル薄層クロマト（ｌｌｌ１［：りｐロホルム
ーイソプロビルエーテル（１：１）の混合物〕にてＲｆ
値約０．７のスポットを認めるフラクションを集め、減
圧下に濃縮すれば無色プリズム基のパンテノール玉硝酸
エステルＬ４８１１を得る。Example I A solution of 8.02 D-panthenol in rice vinegar
．． 51SSd. After the dropwise addition, the mixture was further stirred for 8.5 hours at 0 to 5°C, and then poured into 100 ml of ice water. The resulting aqueous solution is extracted with chloroform. The extract is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting oily residue was subjected to column chromatography using 50ml of silica gel, eluted with chloroform, and silica gel thin layer chromatography (111 [: mixture of chloroform-isopropyl ether (1:1)]). At Rf
Fractions in which a spot with a value of about 0.7 is observed are collected and concentrated under reduced pressure to obtain colorless prismatic panthenol nitrate L4811.
融点 ５４．５〜６６℃
ＮＭＲ（ＯＤＣｊｓ、 ９０ＭＨｚ ） ’ｐｐＨ：１
．１９． ＩＪ ｌ （各＊ ８ Ｈ，１１，−０ｊｌ
）ＬＯｌ （ＢＨ，ＩＩ、 ０ＨｓＯｊｊ；１０に
勺８．４６ （！Ｈ，ｑ、 −ＮＨＣｉＣＨ２−３４，
４ｋ （！Ｈ，ａ、 −＋Ｃ，１ｉｌＯＮＯｉ ）４．
６８ （ｗＨ，ｔ、 −ＣＨ５Ｃ！ｌ０ＮＯ２）５．１
８ （ｌ Ｈ，ｓ、 −ｃｏ６ｍｏａＯり６Ｊ ８ （
ｌ Ｈ，ｂｒ、 −ＣＯＮｉｌ−）元素分析（４） ０
ｓＨｕ＋Ｎｉ０１・として計算値 Ｃ１１１，７？、
Ｈ４Ｌ７も Ｎ １６．４７実測値 ０ ８１．５
６． Ｈ表８８． Ｎ １６．４４上記シリカゲ
ルカラムクロマトをさらにりｐｐホルムτアセトン（１
：ｌ）の混合溶媒で溶出し、シリカゲル薄層クロマトに
てＲｆ値約０４を示す７ラクシ、ンを合わせ、減圧下に
濃縮シテ無色油状物としてＮ−（４−ニトロオキシ−８
，ｓ−ジメチル−２−ハイド田キシブチル）−６−アミ
ツブ鴛ビルナイトレート◎、ｓｙを得る。Melting point 54.5-66℃ NMR (ODCjs, 90MHz) 'ppH: 1
．． 19. IJ l (each * 8 H, 11, -0jl
) LOl (BH, II, 0HsOjj; 10 to 8.46 (!H, q, -NHCiCH2-34,
4k (!H,a, -+C,1ilONOi)4.
68 (wH,t, -CH5C!l0NO2)5.1
8 (l H,s, -co6moaOri6J 8 (
l H, br, -CONil-) elemental analysis (4) 0
Calculated value as sHu+Ni01・C111,7? ,
H4L7 also N 16.47 Actual value 0 81.5
6. H table 88. N 16.44 The above silica gel column chromatography was further carried out with pp form τ acetone (1
N-(4-nitrooxy-8
, s-dimethyl-2-hyde (xybutyl)-6-amitsubu-obivir nitrate ◎, sy is obtained.
ＮＭＲ（ＣＤ０７ｇ、 ９０ＭＨｃ ） ａｐｐ、 ：
１．０５，１．０？ （各々８Ｍ、 ｓ、−Ｃ胸）２．
００ （！■ｅ ｍｅ ＣｌｈＯＨｌｏ％ ）８．
４ Ｓ （ｓｕ、 ｑ、 −ｍｎｃ！！！ｃｂ −）４
．０１ （ＩＨ，ｓ、−００δ旦ＯＮＯ！−）４．４６
（ＢＨ，ａ、−※０ＨｘＯＨ）４．５５ （ｆｉ Ｉ
Ｉ、 ｔ、 −Ｃｏｏ）４１０１０３ ）７．１８ （
ＩＨ，ｂｒ、−ｃｏ町ヒ）実施例２
Ｄ−パントテン酸ナトリウム８．０ｇを１〜８℃に冷却
した発煙硝酸（比重１．１１）２１１−中に少量づつ加
える。加え終った後、更に２〜５℃にて３時間攪拌する
。その後１反応液を氷水１６０−中に注加し、酢酸エチ
ルにて抽出する。NMR (CD07g, 90MHc) app:
1.05, 1.0? (8M, s, -C chest each)2.
00 (!■e me ClhOHlo%)8.
4 S (su, q, -mnc!!!cb -)4
．． 01 (IH,s, -00δdanONO!-)4.46
(BH,a,-*0HxOH)4.55 (fi I
I, t, -Coo) 410103 ) 7.18 (
IH, br, -co town Hi) Example 2 8.0 g of sodium D-pantothenate is added little by little into fuming nitric acid (specific gravity 1.11) 211- cooled to 1-8°C. After the addition is complete, the mixture is further stirred at 2 to 5°C for 3 hours. Thereafter, one reaction solution was poured into 160 ml of ice water and extracted with ethyl acetate.
酢酸エチル層を水洗し、無水硫酸ナトリウムで乾燥後、
減圧下に濃縮する。残留する油状物をシリカゲル８５１
を用いてカラムクロマトを行なう。りｏａホルム５ＱＱ
＠ｌを流した後＊ｐ＊ロホルムーメタノール（ｔｏ ：
ｌ ）のｍ台湾ｍにて溶出し、得られた７ラクシ、ン
を減圧下に濃縮して無色油状物のパントテン酸二硝酸エ
ステル８．６９を得る。After washing the ethyl acetate layer with water and drying with anhydrous sodium sulfate,
Concentrate under reduced pressure. Remove the remaining oil with silica gel 851
Perform column chromatography using Rioa form 5QQ
After flowing @l *p* loform-methanol (to :
1) was eluted with m Taiwan, and the obtained 7-lactic acid was concentrated under reduced pressure to obtain 8.69 g of pantothenic acid dinitrate as a colorless oil.
ＮＭＩＩ （ＧＤＯＩｓ、 ９０ＭＨｚ ）δｐｐｍ
”１．１ ａ、 １．１８ （各々８ＨＩ ｓｅ −ｃ
Ｈｉ ）２．６４ （ｚＨ，ｔ、 −Ｃ％０！！１ＣＯ
ＯＨ）８−６０ （ｆＡ Ｈｅ ｑ＊ ＮＨＯ！ｋＣ
ｋ ）４．４１ （ＢＨ，ａ、−※ＯＭＯＭ−）５．
１０ （ＩＨ，ｔｓ、−ｃｏ６ＨｏＮｏり７．００ （
ｌ Ｈ，ｂｒ、 −ＣＯＮｆｉ−）１０．１ （ＬＨ，
ｂｒ、 −０００Ｈ）実施例魯
実施例８で得られたパントテン酸二硝酸エステルＬ６Ｆ
をトリエチルアミン１．ｌＦとテトラヒドリ７ランｓＯ
−の混液中に溶かし、氷水浴中で冷却する。これにクロ
ル炭酸エチル０．８８２とテトラヒドロ７ラン８−の混
液を滴加した後、ｓ−５℃にて１．６時間攪拌する。こ
の溶液にシスタミン・二塩酸塩Ｏ１・ｌり、トリメチル
アミン１．ＩＦ、テトラヒドロ７ランｚＯ−の混合液を
滴加した後、８〜５℃にてＳ時間攪拌する。反応溶液を
減圧下に濃縮し、残渣にクロロホルム１００−を加え攪
拌する。この溶液を２Ｎ−水酸化す） ＩＪウム水溶液
、希塩酸、水にて順次洗浄した後、無水硫酸ナトリウム
で乾燥し、減圧下に濃縮して得られる油状物をシリカゲ
ル４０ｇを用いてカラムクルマドを行なう。NMII (GDOIs, 90MHz) δppm
”1.1 a, 1.18 (each 8HI se -c
Hi )2.64 (zH,t, -C%0!!1CO
OH) 8-60 (fA He q* NHO!kC
k)4.41 (BH,a,-*OMOM-)5.
10 (IH, ts, -co6HoNori7.00 (
l H,br, -CONfi-)10.1 (LH,
br, -000H) Pantothenic acid dinitrate L6F obtained in Example 8
triethylamine 1. IF and Tetrahydri 7 run sO
- and cooled in an ice-water bath. A mixed solution of 0.882% of ethyl chlorocarbonate and 8% of tetrahydro-7rane was added dropwise thereto, followed by stirring at s-5°C for 1.6 hours. To this solution was added 1 liter of cystamine dihydrochloride and 1 liter of trimethylamine. After adding dropwise a mixed solution of IF and tetrahydro 7ranzO-, the mixture was stirred at 8 to 5°C for S hours. The reaction solution was concentrated under reduced pressure, and 100% of chloroform was added to the residue and stirred. This solution was washed sequentially with an aqueous IJ solution, diluted hydrochloric acid, and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Let's do it.
クロロホルム−メタノール（２０：ｌ）の混合溶媒にて
溶出し、目的物を含有する７ラクシ。Eluted with a mixed solvent of chloroform-methanol (20:l), 7 lacs containing the target product.
ンを合わせ減圧濃縮して得られる残渣をクロロホルム−
エーテル混液より再結晶して無色粉末のパンテチン西硝
酸エステル１．（１ｇを得る。The mixture was combined and concentrated under reduced pressure, and the resulting residue was diluted with chloroform.
Recrystallize pantethine nitric acid ester as a colorless powder from an ether mixture 1. (You get 1g.
融点 １０４〜１０８℃Melting point: 104-108℃
Claims (1)
トワオキ、シ）アルキル基若しくはω−（カルボキシ）
アルキル基又は一般式 す。〕で表わされる硝酸エステル誘導体。[Claims] General formula [In the formula, R1 is a hydrogen atom or a nitro group, and R2 is an ω-(nitrooxy, cy)alkyl group or ω-(carboxy)
Alkyl group or general formula. ] A nitrate ester derivative represented by
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP16145281A JPS5862147A (en) | 1981-10-09 | 1981-10-09 | Nitric acid ester derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP16145281A JPS5862147A (en) | 1981-10-09 | 1981-10-09 | Nitric acid ester derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5862147A true JPS5862147A (en) | 1983-04-13 |
| JPH027942B2 JPH027942B2 (en) | 1990-02-21 |
Family
ID=15735366
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP16145281A Granted JPS5862147A (en) | 1981-10-09 | 1981-10-09 | Nitric acid ester derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5862147A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5284872A (en) * | 1989-09-12 | 1994-02-08 | Schwarz Pharma Ag | Nitrato alkanoic acid derivatives, methods for their production, pharmaceutical compositions containing the derivatives and medicinal uses thereof |
| JP2001520670A (en) * | 1997-03-26 | 2001-10-30 | イッサム・リサーチ・アンド・ディベロープメント・カンパニー・リミテッド・オブ・ザ・ヘブルー・ユニヴァーシティ・オブ・エルサレム | Aromatic and heterocyclic nitric acid derivatives |
-
1981
- 1981-10-09 JP JP16145281A patent/JPS5862147A/en active Granted
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5284872A (en) * | 1989-09-12 | 1994-02-08 | Schwarz Pharma Ag | Nitrato alkanoic acid derivatives, methods for their production, pharmaceutical compositions containing the derivatives and medicinal uses thereof |
| JP2001520670A (en) * | 1997-03-26 | 2001-10-30 | イッサム・リサーチ・アンド・ディベロープメント・カンパニー・リミテッド・オブ・ザ・ヘブルー・ユニヴァーシティ・オブ・エルサレム | Aromatic and heterocyclic nitric acid derivatives |
| EP0984928A4 (en) * | 1997-03-26 | 2004-08-18 | Yissum Res Dev Co | Aromatic and heterocyclic nitrato derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH027942B2 (en) | 1990-02-21 |
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