JP3489009B2 - Phosphonic acid diester derivatives - Google Patents
Phosphonic acid diester derivativesInfo
- Publication number
- JP3489009B2 JP3489009B2 JP11237794A JP11237794A JP3489009B2 JP 3489009 B2 JP3489009 B2 JP 3489009B2 JP 11237794 A JP11237794 A JP 11237794A JP 11237794 A JP11237794 A JP 11237794A JP 3489009 B2 JP3489009 B2 JP 3489009B2
- Authority
- JP
- Japan
- Prior art keywords
- phosphonic acid
- acid diester
- reaction
- examples
- chloroform
- 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 - Fee Related
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】
【0001】
【産業上の利用分野】本発明は新規なホスホン酸ジエス
テル誘導体に関する。
【0002】
【従来の技術】本発明のホスホン酸ジエステル誘導体は
文献未載の新規化合物である。
【0003】
【発明が解決しようとする課題】本発明は後記するよう
に医薬品として有用な化合物の提供を目的とする。
【0004】
【課題を解決するための手段】本発明によれば下記一般
式(1)で表わされるホスホン酸ジエステル誘導体が提
供される。
【0005】
【化2】
【0006】〔式中、R1 、R2 及びR3 は同一又は異
なって水素原子、低級アルキル基、低級アルコキシ基、
フェニル低級アルコキシ基又はハロゲン原子を、R4 は
水素原子又はヒドロキシル基を、R5 は低級アルキル基
をそれぞれ示す。〕
上記一般式(1)の各基としては、具体的にはそれぞれ
次の各基を例示できる。
【0007】即ち、低級アルキル基としては、例えばメ
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、ペンチル、ヘキシル基等の
直鎖又は分枝鎖状低級アルキル基を例示できる。
【0008】低級アルコキシ基としては、例えばメトキ
シ、エトキシ、プロポキシ、ブトキシ、ペンチルオキ
シ、ヘキシルオキシ基等を例示できる。
【0009】フェニル低級アルコキシ基としては、例え
ばベンジルオキシ、2−フェニルエトキシ、3−フェニ
ルプロポキシ、4−フェニルブトキシ、5−フェニルペ
ンチルオキシ、6−フェニルヘキシルオキシ基等を例示
できる。
【0010】ハロゲン原子には、フッ素原子、塩素原
子、臭素原子、ヨウ素原子が包含される。
【0011】上記一般式(1)で表さわれる本発明のホ
スホン酸ジエステル誘導体は、優れた脂質低下作用並び
に血糖降下作用を有しており、高脂質血症治療剤や白内
障治療剤として、高コレステロール血症、高トリグリセ
リド血症、高リン脂質血症、高遊離脂肪酸血症等の各種
疾患(高脂質血症)の治療及び予防に、また糖尿病の治
療及び予防に有用である。
【0012】以下、本発明の上記一般式(1)で表され
るホスホン酸ジエステル誘導体は、各種の方法により製
造できる。その具体例を下記反応工程式に示す。
【0013】
【化3】
【0014】〔式中、R1 、R2 、R3 及びR5 は前記
に同じ。Xはハロゲン原子を示す。〕
上記反応工程式−1に示す化合物(2)と酸ハロゲン化
物(3)との反応は、ジクロロメタン、クロロホルム、
1,2−ジクロロエタン、テトラヒドロフラン(TH
F)等の不活性溶媒中、ピリジン、コリジン、ルチジ
ン、N,N−ジメチルアニリン、トリエチルアミン等の
脱酸剤の存在下に実施される。酸ハロゲン化物(3)の
使用量は、化合物(2)に対しほぼ等モル量とするのが
好ましく、脱酸剤は過剰量用いるのが一般的である。反
応は0℃〜室温の温度条件下で1〜12時間を要して行
われる。
【0015】続いて、得られるエステル体(4)を転位
反応させることにより、本発明化合物(1a)を得るこ
とができる。該転位反応は、エステル体(4)をピリジ
ン、コリジン、ルチジン等の溶媒中、1〜3当量の塩基
と処理することにより行われる。塩基としては、水酸化
ナトリウム、水酸化カリウム等のアルカリ金属水酸化物
が好ましく、反応温度は室温〜100℃の範囲を、反応
時間は0.5〜4時間程度を採用し得る。
【0016】
【化4】
【0017】〔式中、R1 、R2 、R3 、R5 及びXは
前記に同じ。R及びR′は同一又は異なって低級アルキ
ル基を示す。〕
上記反応工程式−2に示す酸ハロゲン化物(3)とアミ
ン(5)の反応は、不活性溶媒中、脱酸剤の存在下に行
われる。上記において不活性溶媒としては、例えばベン
ゼン、トルエン、キシレン、石油エーテル等の芳香族乃
至脂肪族炭化水素類、ジエチルエーテル、1,2−ジメ
トキシエタン、THF、1,4−ジオキサン等の鎖状乃
至環状エーテル類、アセトン、メチルエチルケトン、ア
セトフェノン等のケトン類、ジクロロメタン、クロロホ
ルム、四塩化炭素、1,2−ジクロロエタン等のハロゲ
ン化炭化水素類を例示できる。また脱酸剤としては、例
えばトリエチルアミン、ピリジン、4−ジメチルアミノ
ピリジン等の第3級アミン類を好ましく例示できる。上
記反応において、アミン(5)は酸ハロゲン化物(3)
に対し等モル量〜少過剰量用いるのがよく、また脱酸剤
は等モル量〜過剰量用いるのが一般的である。反応は、
通常0℃〜溶媒の還流温度範囲で約0.5〜10時間程
度で終了する。
【0018】得られるアミド(6)は、塩基の存在下
に、これをアセトフェノン誘導体(7)と反応させるこ
とにより本発明化合物(1b)に導くことができる。上
記塩基の例としては、n−ブチルリチウム、フェニルリ
チウム等の炭化水素リチウム塩類、ナトリウムメトキシ
ド、ナトリウムエトキシド等のアルカリ金属アルコキシ
ドなどを挙げることができ、これらはアセトフェノン誘
導体(7)に対し等モル量〜少過剰量用いるのがよい。
反応は、THF、ジエチルエーテル等の不活性溶媒中、
−78℃〜室温の温度条件で、5〜15時間程度を要し
て完了する。
【0019】上記それぞれの工程における目的化合物
は、通常の分離手段により容易に単離精製できる。かか
る手段としては例えば、吸着クロマトグラフィー、プレ
パラティブ薄層クロマトグラフィー、再結晶、溶媒抽出
等を例示できる。
【0020】
【実施例】以下、本発明を更に詳しく説明するため、本
発明化合物の製造例を実施例として挙げる。
【0021】
【実施例1】
ジエチル 4−〔3−(5−フルオロ−2−ヒドロキシ
フェニル)−1,3−ジオキソプロピル〕ベンジルホス
ホナートの製造
4−〔(ジエトキシホスホリル)メチル〕ベンゾイル
クロリド19.0gを乾燥ジクロロメタン65mlに溶
かし、氷冷攪拌下、この溶液中に5′−フルオロ−2′
−ヒドロキシアセトフェノン10gのピリジン(65m
l)溶液をゆっくりと滴下した。室温で10時間攪拌し
た後、水100mlを注入し、クロロホルムで抽出し
た。クロロホルム層を10%塩酸100ml、水100
mlで順次洗浄した後、無水硫酸ナトリウムで乾燥し、
減圧濃縮した。次に、残渣をピリジン65mlに溶か
し、水酸化カリウム5.4gを加え、50℃で2時間攪
拌した。反応終了後、10%塩酸200mlを注入して
酸性とし、クロロホルムで抽出した。クロロホルム層を
水100mlで洗浄し、無水硫酸ナトリウムで乾燥した
後、減圧濃縮した。残渣をジエチルエーテル−n−ヘキ
サンより再結晶して、目的化合物の黄色結晶15.7g
を得た。得られた化合物の構造及び物性を表1に示す。
【0022】
【実施例2〜11】実施例1と同様にして、表1に示す
各化合物を合成した。得られた化合物の構造及び物性を
表1に併記する。
【0023】
【実施例12】
ジエチル 4−〔3−(4−クロロフェニル)−1.3
−ジオキソプロピル〕ベンジルホスホナートの製造
4−〔(ジエトキシホスホリル)メチル〕ベンゾイル
クロリド74.4gを乾燥ジクロロメタン250mlに
溶解し、氷冷攪拌下、この溶液中にN,O−ジメチルヒ
ドロキシルアミン・塩酸塩25gのピリジン500ml
溶液をゆっくり滴下した。室温で2時間攪拌した後、反
応混合物中に水200mlを加え、クロロホルムで抽出
した。クロロホルム層を飽和炭酸水素ナトリウム水溶液
200ml、10%塩酸200ml、飽和食塩水200
mlで順次洗浄を行い、無水硫酸ナトリウムで乾燥した
後、減圧濃縮して、油状のジエチル 4−〔(N−メト
キシ−N−メチル)カルバモイル〕ベンジルホスホナー
トの粗生成物48gを得た。
【0024】1H−NMR〔δ:ppm(CDC
l3 )〕
1.24(t,J=7.1,6H)、3.19(d,J
=21.9,2H)、3.36(s,3H)、3.54
(s,3H)、4.0−4.1(m,4H)、7.35
(dd,J=7.9,2.1,2H)、7.65(d,
J=7.9,2H)。
【0025】次に、4′−クロロアセトフェノン3.9
gを無水THF25mlに溶解させ、−78℃に冷却攪
拌下、この溶液中に1.55Mn−ブチルリチウムヘキ
サン溶液19mlをゆっくりと滴下した。−78℃で1
時間攪拌した後、続いて上記で得られた化合物7.9g
の無水THF20ml溶液を−78℃でゆっくりと滴下
した後、混合液を徐々に室温まで戻し、室温で12時間
攪拌した。反応混合液中に10%塩酸50mlを加え、
クロロホルムで抽出した。クロロホルム層を飽和食塩水
100mlで洗浄し、無水硫酸ナトリウムで乾燥した
後、減圧濃縮した。残渣をシリカゲルカラムクロマトグ
ラフィー(溶出液…クロロホルム:酢酸エチル=1:
1)で精製し、更にジエチルエーテルより再結晶して、
目的化合物の無色結晶500mgを得た。得られた化合
物の構造及び物性を表1に併記する。
【0026】
【表1】 Description: BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel phosphonic acid diester derivative. [0002] The phosphonic acid diester derivative of the present invention is a novel compound which has not been described in any literature. [0003] The object of the present invention is to provide compounds useful as pharmaceuticals as described below. According to the present invention, there is provided a phosphonic acid diester derivative represented by the following general formula (1). [0005] [Wherein R 1 , R 2 and R 3 are the same or different and are each a hydrogen atom, a lower alkyl group, a lower alkoxy group,
R 4 represents a hydrogen atom or a hydroxyl group; R 5 represents a lower alkyl group; Specific examples of the respective groups of the general formula (1) include the following groups. That is, examples of the lower alkyl group include linear or branched lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl. Examples of the lower alkoxy group include methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy and the like. Examples of the phenyl lower alkoxy group include benzyloxy, 2-phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy, 5-phenylpentyloxy, and 6-phenylhexyloxy. The halogen atom includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. The phosphonic acid diester derivative of the present invention represented by the general formula (1) has an excellent lipid-lowering effect and hypoglycemic effect, and is useful as a therapeutic agent for hyperlipidemia or cataract. It is useful for the treatment and prevention of various diseases (hyperlipidemia) such as cholesterolemia, hypertriglyceridemia, hyperphospholipidemia, and high free fatty acidemia, and for the treatment and prevention of diabetes. Hereinafter, the phosphonic acid diester derivative represented by the above general formula (1) of the present invention can be produced by various methods. Specific examples thereof are shown in the following reaction scheme. [0013] Wherein R 1 , R 2 , R 3 and R 5 are as defined above. X represents a halogen atom. The reaction between the compound (2) and the acid halide (3) shown in the above reaction scheme 1 is carried out by using dichloromethane, chloroform,
1,2-dichloroethane, tetrahydrofuran (TH
It is carried out in an inert solvent such as F) in the presence of a deoxidizing agent such as pyridine, collidine, lutidine, N, N-dimethylaniline, triethylamine and the like. The amount of the acid halide (3) to be used is preferably approximately equimolar to the compound (2), and an excess of the deoxidizing agent is generally used. The reaction is carried out at a temperature of 0 ° C. to room temperature for 1 to 12 hours. Subsequently, the compound (1a) of the present invention can be obtained by subjecting the resulting ester (4) to a rearrangement reaction. The rearrangement reaction is carried out by treating the ester (4) with 1 to 3 equivalents of a base in a solvent such as pyridine, collidine or lutidine. The base is preferably an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide. The reaction temperature may be in the range of room temperature to 100 ° C., and the reaction time may be about 0.5 to 4 hours. Embedded image Wherein R 1 , R 2 , R 3 , R 5 and X are as defined above. R and R 'are the same or different and represent a lower alkyl group. The reaction between the acid halide (3) and the amine (5) shown in the above reaction process formula-2 is carried out in an inert solvent in the presence of a deoxidizing agent. In the above, as the inert solvent, for example, aromatic or aliphatic hydrocarbons such as benzene, toluene, xylene, petroleum ether and the like, and linear or aliphatic hydrocarbons such as diethyl ether, 1,2-dimethoxyethane, THF, and 1,4-dioxane Examples thereof include cyclic ethers, ketones such as acetone, methyl ethyl ketone, and acetophenone, and halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane. Preferred examples of the deoxidizing agent include tertiary amines such as triethylamine, pyridine and 4-dimethylaminopyridine. In the above reaction, the amine (5) is replaced with an acid halide (3)
It is preferable to use an equimolar amount to a small excess amount, and the deoxidizing agent is generally used in an equimolar amount to an excess amount. The reaction is
Usually, the reaction is completed in about 0.5 to 10 hours in the range of 0 ° C. to the reflux temperature of the solvent. The resulting amide (6) can be converted to the compound (1b) of the present invention by reacting the amide (6) with an acetophenone derivative (7) in the presence of a base. Examples of the base include hydrocarbon lithium salts such as n-butyllithium and phenyllithium, and alkali metal alkoxides such as sodium methoxide and sodium ethoxide. These are based on the acetophenone derivative (7). It is preferable to use a molar amount to a small excess amount.
The reaction is carried out in an inert solvent such as THF and diethyl ether.
The process is completed under a temperature condition of −78 ° C. to room temperature in about 5 to 15 hours. The target compound in each of the above steps can be easily isolated and purified by ordinary separation means. Examples of such means include adsorption chromatography, preparative thin-layer chromatography, recrystallization, and solvent extraction. EXAMPLES In order to explain the present invention in more detail, examples of the production of the compounds of the present invention will be given below as examples. Example 1 Preparation of diethyl 4- [3- (5-fluoro-2-hydroxyphenyl) -1,3-dioxopropyl] benzylphosphonate 4-[(diethoxyphosphoryl) methyl] benzoyl
Dissolve 19.0 g of chloride in 65 ml of dry dichloromethane, and add 5′-fluoro-2 ′
-Hydroxyacetophenone 10 g pyridine (65 m
l) The solution was slowly added dropwise. After stirring at room temperature for 10 hours, 100 ml of water was injected and extracted with chloroform. The chloroform layer was washed with 100% 10% hydrochloric acid and 100 ml of water.
After successively washing with water, dried over anhydrous sodium sulfate,
It was concentrated under reduced pressure. Next, the residue was dissolved in 65 ml of pyridine, 5.4 g of potassium hydroxide was added, and the mixture was stirred at 50 ° C. for 2 hours. After completion of the reaction, 200 ml of 10% hydrochloric acid was injected to make the mixture acidic, and extracted with chloroform. The chloroform layer was washed with 100 ml of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from diethyl ether-n-hexane to give 15.7 g of the target compound as yellow crystals.
Got. Table 1 shows the structure and physical properties of the obtained compound. Examples 2 to 11 In the same manner as in Example 1, the compounds shown in Table 1 were synthesized. Table 1 also shows the structure and physical properties of the obtained compound. Example 12 Diethyl 4- [3- (4-chlorophenyl) -1.3
Preparation of -dioxopropyl] benzylphosphonate 4-[(diethoxyphosphoryl) methyl] benzoyl
74.4 g of chloride are dissolved in 250 ml of dry dichloromethane, and under ice-cooling and stirring, 500 ml of pyridine of 25 g of N, O-dimethylhydroxylamine hydrochloride is added to this solution.
The solution was slowly added dropwise. After stirring at room temperature for 2 hours, 200 ml of water was added to the reaction mixture, and extracted with chloroform. The chloroform layer was washed with 200 ml of a saturated aqueous solution of sodium hydrogen carbonate, 200 ml of 10% hydrochloric acid, and 200 ml of saturated saline.
The mixture was washed successively with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 48 g of a crude oily diethyl 4-[(N-methoxy-N-methyl) carbamoyl] benzylphosphonate. 1 H-NMR [δ: ppm (CDC
l 3 )] 1.24 (t, J = 7.1, 6H), 3.19 (d, J
= 21.9, 2H), 3.36 (s, 3H), 3.54
(S, 3H), 4.0-4.1 (m, 4H), 7.35
(Dd, J = 7.9, 2.1, 2H), 7.65 (d,
J = 7.9, 2H). Next, 4'-chloroacetophenone 3.9
g was dissolved in 25 ml of anhydrous THF, and 19 ml of a 1.55 Mn-butyllithium hexane solution was slowly dropped into this solution with cooling and stirring at -78 ° C. 1 at -78 ° C
After stirring for hours, subsequently 7.9 g of the compound obtained above
Was slowly added dropwise at −78 ° C., and the mixture was gradually returned to room temperature and stirred at room temperature for 12 hours. 50 ml of 10% hydrochloric acid was added to the reaction mixture,
Extracted with chloroform. The chloroform layer was washed with 100 ml of saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: chloroform: ethyl acetate = 1:
Purified in 1) and recrystallized from diethyl ether,
500 mg of colorless crystals of the target compound were obtained. Table 1 also shows the structure and physical properties of the obtained compound. [Table 1]
───────────────────────────────────────────────────── フロントページの続き (72)発明者 奈波 智恵子 徳島県鳴門市撫養町南浜字蛭子前東4の 4 (56)参考文献 特開 平4−244090(JP,A) (58)調査した分野(Int.Cl.7,DB名) C07F 9/40 A61K 31/66 CA(STN) REGISTRY(STN)──────────────────────────────────────────────────続 き Continuation of the front page (72) Inventor Chieko Nawa 4-4, Higashimae, Higashi, Minamihama, Naruto-shi, Tokushima Pref. (Int.Cl. 7 , DB name) C07F 9/40 A61K 31/66 CA (STN) REGISTRY (STN)
Claims (1)
子、低級アルキル基、低級アルコキシ基、フェニル低級
アルコキシ基又はハロゲン原子を、R4 は水素原子又は
ヒドロキシル基を、R5 は低級アルキル基をそれぞれ示
す。〕で表わされるホスホン酸ジエステル誘導体。(57) [Claims] [Claim 1] The general formula: Wherein R 1 , R 2 and R 3 are the same or different and are a hydrogen atom, a lower alkyl group, a lower alkoxy group, a phenyl lower alkoxy group or a halogen atom, R 4 is a hydrogen atom or a hydroxyl group, and R 5 is Each represents a lower alkyl group. A phosphonic acid diester derivative represented by the formula:
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP11237794A JP3489009B2 (en) | 1993-07-15 | 1994-05-26 | Phosphonic acid diester derivatives |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP5-175525 | 1993-07-15 | ||
JP17552593 | 1993-07-15 | ||
JP11237794A JP3489009B2 (en) | 1993-07-15 | 1994-05-26 | Phosphonic acid diester derivatives |
Publications (2)
Publication Number | Publication Date |
---|---|
JPH0776591A JPH0776591A (en) | 1995-03-20 |
JP3489009B2 true JP3489009B2 (en) | 2004-01-19 |
Family
ID=26451554
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP11237794A Expired - Fee Related JP3489009B2 (en) | 1993-07-15 | 1994-05-26 | Phosphonic acid diester derivatives |
Country Status (1)
Country | Link |
---|---|
JP (1) | JP3489009B2 (en) |
-
1994
- 1994-05-26 JP JP11237794A patent/JP3489009B2/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
JPH0776591A (en) | 1995-03-20 |
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