JP2876129B2 - 7-carboxymethoxy-4-phenylcoumarin derivatives and their preparation and use - Google Patents
7-carboxymethoxy-4-phenylcoumarin derivatives and their preparation and useInfo
- Publication number
- JP2876129B2 JP2876129B2 JP12353889A JP12353889A JP2876129B2 JP 2876129 B2 JP2876129 B2 JP 2876129B2 JP 12353889 A JP12353889 A JP 12353889A JP 12353889 A JP12353889 A JP 12353889A JP 2876129 B2 JP2876129 B2 JP 2876129B2
- Authority
- JP
- Japan
- Prior art keywords
- formula
- phenylcoumarin
- carboxymethoxy
- compound
- aldose reductase
- 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
Links
Description
【発明の詳細な説明】 〔産業上の利用分野〕 本発明は医薬品として有用を新規７−カルボキシメト
キシ−４−フェニルクマリン誘導体に関するものであ
る。Description: TECHNICAL FIELD The present invention relates to a novel 7-carboxymethoxy-4-phenylcoumarin derivative which is useful as a pharmaceutical.
食生活の欧米化に伴い近年糖尿病患者が激増し、その
治療対策は急務となっている。糖尿病治療薬としては従
来よりインシュリンや血糖降下剤が広く用いられている
が、糖尿病は単なる糖代謝異状のみならず種々の合併症
を随伴する疾患であるため、前記の薬物のみでは不十分
である。With the westernization of dietary habits, the number of diabetic patients has increased sharply in recent years, and treatment for them is urgently needed. Conventionally, insulin and hypoglycemic agents have been widely used as antidiabetic drugs, but since diabetes is a disease accompanied by various complications as well as a mere metabolic abnormality of metabolism, the above drugs alone are not sufficient. .
網膜症，白内症，神経障害，腎症等の糖尿病に於ける
各種合併症の成因として、グルコースの代謝経路である
ポリオール経路の第一段階であるアルドース・ポリオー
ル間の変換を触媒する酵素をアルドース還元酵素とい
い、この酵素がポリオール経路の律速段階と考えられて
いる。このアルドース還元酵素を阻害し、ソルビトール
の産生や蓄積を低下させることにより、前述のごとき糖
尿病合併症の予防や治療が可能である〔R.G.ジュジルミ
ッシュ等：ニューイングランド・ジャーナル・オブ・メ
ディスン（New Eng.J.Med.）,308巻,119〜125頁（198
3）:J.H.キノシタ等：メタボリズム（Metabolism）,28
巻（１）,462〜469頁（1979）〕。As a cause of various complications in diabetes such as retinopathy, cataract, neuropathy, and nephropathy, an enzyme that catalyzes the conversion between aldose-polyol, which is the first stage of the polyol pathway, which is the glucose metabolic pathway It is called aldose reductase and this enzyme is considered the rate-limiting step in the polyol pathway. By inhibiting this aldose reductase and reducing the production and accumulation of sorbitol, it is possible to prevent or treat diabetic complications as described above [RG Judylmish et al .: New England Journal of Medicine (New Eng. J. Med.), 308, 119-125 (198
3): JH Kinoshita, etc .: Metabolism, 28
Volume (1), pp. 462-469 (1979)].
本発明者らは、種々の化合物についてアルドース還元
酵素阻害作用に関する研究を行った結果、特定の７−カ
ルボキシメトキシ−４−フェニルクマリン誘導体がアル
ドース還元酵素阻害剤として有効であることを見出し本
発明に到達した。The present inventors have conducted studies on the aldose reductase inhibitory activity of various compounds, and as a result, have found that a specific 7-carboxymethoxy-4-phenylcoumarin derivative is effective as an aldose reductase inhibitor. Reached.
（課題を解決するための手段） 本発明はすなわち式（Ｉ） （但し、式中Ｒ1,R2,R3及びＲ1′,R2′,R3′,R4′,R5′
は水素原子，ハロゲン原子，低級アルキル基，低級アル
コキシ基，ジ低級アルキルアミノ基，パーフルオロ低級
アルキル基を表わす） で示される７−カルボキシメトキシ−４−フェニルクマ
リン誘導体及び該誘導体を有効成分として含有するアル
ドース還元酵素阻害剤であり次のようにして製造するこ
とができる。(Means for Solving the Problems) The present invention provides a compound of the formula (I) (Where R 1 , R 2 , R 3 and R 1 ′, R 2 ′, R 3 ′, R 4 ′, R 5 ′
Represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a di-lower alkylamino group, or a perfluoro-lower alkyl group), and contains the derivative as an active ingredient. Aldose reductase inhibitor and can be produced as follows.
すちわち式（II） （但し、式中Ｒ1,R2,R3及びＲ1′,R2′,R3′,R4′,R5′
は上記式（Ｉ）と同様の意味を表わす） で示される７−ヒドロキシ−４−フェニルクマリン誘導
体をグリコール酸エーテル化することによって得られ
る。なお本明細書において「低級」なる語は、この語が
付された基の炭素原子数が６個以下，好ましくは４個以
下であることを意味する。Smooth expression (II) (Where R 1 , R 2 , R 3 and R 1 ′, R 2 ′, R 3 ′, R 4 ′, R 5 ′
Represents the same meaning as in the above formula (I).) 7-hydroxy-4-phenylcoumarin derivative represented by the following formula: In this specification, the term "lower" means that the group to which this term is attached has 6 or less, preferably 4 or less carbon atoms.
本発明化合物の原料となる式（II）化合物は天然成分
として存在することもある。例えば７−ヒドロキシ−４
−フェニルクマリンはバシラスチホサス（Bacillus typ
hosus）やスタフィロコカスオーレウス（Staphylococus
aureus）等の植物に含有する。またペッヒマン縮合反
応（Pechmann Condensation Reaction）により、置換ベ
ンゾイル酢酸エステルと、置換レゾルジン等から合成す
ることができる（例えば、Mukerjee,et.al.,Indian.J.C
hem.,7,671.（1969））。The compound of the formula (II) as a raw material of the compound of the present invention may exist as a natural component. For example, 7-hydroxy-4
-Phenylcoumarin is Bacillus typus
hosus) and Staphylococus aureus (Staphylococus)
aureus). Further, it can be synthesized from a substituted benzoyl acetate and a substituted resorudin by a Pechmann Condensation Reaction (for example, Mukerjee, et.al., Indian. JC
hem., 7,671. (1969)).
式（II）化合物をグリコール酸エーテル化して式
（Ｉ）化合物を合成するには、通常の方法で行われる。
例えばアセトン中、炭酸カリウムとブロム酢酸エチルを
用いて反応すると式（Ｉ）化合物のエステルが得られ
る。Synthesis of the compound of the formula (I) by etherifying the compound of the formula (II) with glycolic acid is carried out in a usual manner.
For example, reaction with potassium carbonate and ethyl bromoacetate in acetone gives an ester of the compound of formula (I).
得られた式（Ｉ）化合物のエステルを塩基性で加水分
解し、鉱酸でPH4付近に調整することにより、遊離酸す
なわち式（Ｉ）化合物となり、これを無機塩基でPH9付
近に調整することにより、式（Ｉ）化合物の無機塩とな
る。The resulting ester of the compound of formula (I) is hydrolyzed with basicity and adjusted to around PH4 with a mineral acid to give a free acid, that is, the compound of formula (I), which is adjusted to around PH9 with an inorganic base. As a result, an inorganic salt of the compound of the formula (I) is obtained.
これらはいずれも公知の方法，例えば濃縮乾固その他
の方法で単離し、再結晶等で精製することができる。こ
こで用いる鉱酸としては、塩酸，硫酸，リン酸等があ
り、無機塩基としては水酸化ナトリウム，水酸化カリウ
ム，水酸化リチウム，水酸化アンモニウム等の水酸化ア
ルカリ，（重）炭酸ナトリウム，（重）炭酸カリウム，
（重）炭酸アンモニウム等の（重）炭酸アルカリがあ
る。All of these can be isolated by a known method, for example, concentration to dryness or other methods, and purified by recrystallization or the like. The mineral acids used here include hydrochloric acid, sulfuric acid, phosphoric acid and the like, and the inorganic bases include alkali hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and ammonium hydroxide, sodium (bi) carbonate, ( Bi) potassium carbonate,
There are (bi) alkali carbonates such as (bi) ammonium carbonate.
式（Ｉ）化合物は酸性又はアルカリ性溶液中いずれで
もかなり安定である。The compounds of formula (I) are fairly stable in either acidic or alkaline solutions.
式（Ｉ）で示される化合物を有効成分とするアルドー
ス還元酵素阻害剤は、通常用いられるキャリアーを用
い、常法にしたがって錠剤，カプセル剤，注射剤，散
剤，丸剤，顆粒剤，坐剤，点眼剤等に使用してもよい。The aldose reductase inhibitor containing the compound represented by the formula (I) as an active ingredient can be used in the form of tablets, capsules, injections, powders, pills, granules, suppositories, and the like, using a commonly used carrier according to a conventional method. It may be used in eye drops and the like.
次に実施例を挙げて本発明の化合物，その製造法及び
アルドース還元阻害作用を詳しく説明するが、本発明は
下記実施例に限定されるものではない。なお各実施例中
における生成物の融点はいずれも未補正である。Next, the compound of the present invention, its production method and aldose reduction inhibitory action will be described in detail with reference to examples, but the present invention is not limited to the following examples. Note that the melting points of the products in each of the examples are uncorrected.
参考例 式（II）化合物の製造…ペッヒマン縮合 置換レゾルジンと当モルの置換ベンゾイル酢酸エチル
をエタノール中に溶解し、氷冷下、塩化水素ガスを飽和
させる。室温で１夜放置後、氷水中に流入し、析出する
沈澱を集，水洗する。乾燥後、溶媒で再結晶する。Reference example Production of compound of formula (II): Pechmann condensation Substituted resorudine and an equimolar amount of substituted benzoyl acetate are dissolved in ethanol, and hydrogen chloride gas is saturated under ice-cooling. After left overnight at room temperature, the precipitate flows into ice water, and the precipitated precipitate is collected and washed with water. After drying, it is recrystallized with a solvent.
このようにして得られた式（II）化合物の物性値を第
１表に示す。Table 1 shows the physical property values of the compound of formula (II) thus obtained.
実施例 式（Ｉ）化合物の製造 ６−エチル−７−ヒドロキシ−４−（３−イソプロピ
ルオキシフェニル）クマリン〔第１表式（II−42）〕4.
7g（0.0145モル），ブロモ酢酸エチル2.6g（0.0145モ
ル），ヨウ化カリウム0.2g及び無水炭酸カリウム2.0gを
アセトン200ml中に加え、撹拌下、４時間加熱還流す
る。冷却後、不溶物を別し、溶媒を留去して得られる
残渣をエーテルに溶解する。このエーテル溶液を水,5％
NaOH水溶液，水の順に洗浄し、エーテル層を無水硫酸ナ
トリウムで乾燥する。溶媒を留去し、得られる残渣をシ
リカゲルカラムで処理する。クロロフォルム分画によ
り、６−エチル−４−（３−イソプロピルオキシフェニ
ル）クマリン−７−イルオキシ酢酸エチル4.5gを得る。 Examples Production of compound of formula (I) 6-ethyl-7-hydroxy-4- (3-isopropyloxyphenyl) coumarin [Table 1 (II-42)] 4.
7 g (0.0145 mol), 2.6 g (0.0145 mol) of ethyl bromoacetate, 0.2 g of potassium iodide and 2.0 g of anhydrous potassium carbonate are added to 200 ml of acetone, and the mixture is heated under reflux with stirring for 4 hours. After cooling, the insolubles are separated, and the residue obtained by evaporating the solvent is dissolved in ether. This ether solution is water, 5%
Wash with NaOH aqueous solution and water in this order, and dry the ether layer with anhydrous sodium sulfate. The solvent is distilled off and the residue obtained is treated on a silica gel column. 4.5 g of ethyl 6-ethyl-4- (3-isopropyloxyphenyl) coumarin-7-yloxyacetate is obtained by chloroform fractionation.
上記エステル4.5gをエタノール60mlと５％NaOH水溶液
20mlの混液中に加え、30分間加熱還流する。放冷後、不
溶物を別し、液を塩酸酸性にする。析出する沈澱を
アセトン−ベンゼンで再結晶すると６−エチル−４−
（３−イソプロピルオキシフェニル）クマリン−７−イ
ルオキシ酢酸〔第２表式（Ｉ−42）〕4.0gが得られる。4.5 g of the above ester is added to 60 ml of ethanol and 5% NaOH aqueous solution
Add to 20 ml of the mixture and heat to reflux for 30 minutes. After cooling, the insolubles are separated and the solution is acidified with hydrochloric acid. The precipitated precipitate was recrystallized from acetone-benzene to give 6-ethyl-4-.
4.0 g of (3-isopropyloxyphenyl) coumarin-7-yloxyacetic acid [Table 2 (I-42)] is obtained.
また上記と同様の手法で第１表に示される式（II）化
合物より第２表に示される式（Ｉ）化合物を得た。それ
らの物性値及びアルドース還元酵素阻害活性を第２表に
併記する。Further, a compound of the formula (I) shown in Table 2 was obtained from the compound of the formula (II) shown in Table 1 in the same manner as described above. Their physical properties and aldose reductase inhibitory activity are also shown in Table 2.
アルドース還元酵素阻害作用 ７週齢のウィスター（Wistar）系雄性ラットをエーテ
ル麻酔下に犠殺し、直ちに水晶体を摘出した。水晶体は
1.0mM2−メルカプトエタノール及び1.0mM NADP（酸化型
nicotinamide adenine dinucleotide phosphate）を含
む100mMナトリウム−カリウム−リン酸緩衝液（pH6.8）
にてホモジナイズした。ついで12,000rpmで15分間遠心
分離し、その上清をアルドース還元酵素活性測定の検体
とした。また以上の操作はすべて４℃で行い検体は−80
℃で保存した。Aldose reductase inhibitory action A 7-week-old male Wistar strain rat was sacrificed under ether anesthesia, and the lens was immediately removed. Lens
1.0 mM 2-mercaptoethanol and 1.0 mM NADP (oxidized form
100 mM sodium-potassium-phosphate buffer containing nicotinamide adenine dinucleotide phosphate (pH6.8)
Was homogenized. Then, the mixture was centrifuged at 12,000 rpm for 15 minutes, and the supernatant was used as a sample for measuring aldose reductase activity. All the above procedures were performed at 4 ° C and the sample was -80.
Stored at ° C.
アルドース還元酵素の活性の測定はカドア（KADOA）
らの方法〔Biophysical Chemistry8（1978）81−85参
照）に準じて行った。すなわち補酵素として0.1mM NADP
H（還元型nicotinamide adenine dinucleotide phosph
ate）及び基質として2.0mM DL−グリセルアルデヒドを
含む100mMナトリウム−カリウム−リン酸緩衝液（pH6.
2）970μｌに、本発明化合物の各種濃度液を10μｌ添加
し、ついで上記検体20μｌを加え、25℃で反応を行っ
た。対照として基質のみを欠いたものを用い、340nmに
おいて吸光度の減少を200秒間測定した。また、試料溶
液を加える代りに溶媒のみを加えて、上記と同様に反応
させ測定したものをコントロール値とした。吸光度の測
定はUV−260（株式会社島津製作所製）を用いた。その
結果、アルドース還元酵素に対する阻害活性は第２表に
示したように１×10-8（Ｍ）で阻害活性（IC50）が認め
られた。Aldose reductase activity is measured by KADOA
The method was carried out according to the method described above (see Biophysical Chemistry 8 (1978) 81-85). That is, 0.1 mM NADP as coenzyme
H (reduced nicotinamide adenine dinucleotide phosph
ate) and 100 mM sodium-potassium-phosphate buffer containing 2.0 mM DL-glyceraldehyde as substrate (pH 6.
2) To 970 μl, 10 μl of various concentrations of the compound of the present invention was added, and then 20 μl of the above-mentioned sample was added, and the reaction was carried out at 25 ° C. Using a control lacking only the substrate, the decrease in absorbance at 340 nm was measured for 200 seconds. In addition, instead of adding the sample solution, only the solvent was added, and the reaction was performed in the same manner as described above. The absorbance was measured using UV-260 (manufactured by Shimadzu Corporation). As a result, the inhibitory activity against aldose reductase was 1 × 10 −8 (M), as shown in Table 2, and the inhibitory activity (IC 50 ) was observed.
急性毒性 上記各例で得られた式（Ｉ）化合物の経口投与での急
性毒性試験のddv系マウス（体重23〜25g）を用いて行っ
たところ、2g/kgの経口投与でも死亡例は認められなか
った。 Acute toxicity Acute toxicity test by oral administration of the compound of formula (I) obtained in each of the above examples was performed using ddv mice (body weight: 23 to 25 g). I couldn't.
以上の結果から明らかなように、本発明の７−カルボ
キシメトキシ−４−フェニルクマリン誘導体はアルドー
ス還元酵素阻害作用を有し、かつ安全性の高い糖尿病合
併治療薬として有用である。As is clear from the above results, the 7-carboxymethoxy-4-phenylcoumarin derivative of the present invention has an aldose reductase inhibitory effect and is useful as a highly safe therapeutic drug for diabetes.
フロントページの続き (72)発明者 寺島 恵 富山県富山市上富居92番地 (72)発明者 鈴井 明男 兵庫県尼崎市宮内町２―42―302 (58)調査した分野(Int.Cl.6，ＤＢ名) C07D 311/00 - 311/74 ＲＥＧＩＳＴＲＹ（ＳＴＮ) ＣＡ（ＳＴＮ)Continued on the front page (72) Inventor Megumi Terashima 92 Kamitomi, Toyama City, Toyama Prefecture (72) Inventor Akio Suzui 2-42-302, Miyauchicho, Amagasaki City, Hyogo Prefecture (58) Field surveyed (Int.Cl. 6 , DB name) C07D 311/00-311/74 REGISTRY (STN) CA (STN)
Claims (3)
は水素原子，ハロゲン原子，低級アルキル基，低級アル
コキシ基，ジ低級アルキルアミノ基，パーフルオロ低級
アルキル基を表わす） で示される７−カルボキシメトキシ−４−フェニルクマ
リン誘導体。(1) Formula (I) (Where R 1 , R 2 , R 3 and R 1 ′, R 2 ′, R 3 ′, R 4 ′, R 5 ′
Represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a di-lower alkylamino group, or a perfluoro-lower alkyl group).
は上記式（Ｉ）と同様の意味を表わす） で示される７−ヒドロキシ−４−フェニルクマリン誘導
体をグリコール酸エーテル化することを特徴とする上記
式（Ｉ）で示される７−カルボキシメトキシ−４−フェ
ニルクマリン誘導体の製法。2. Formula (II) (Where R 1 , R 2 , R 3 and R 1 ′, R 2 ′, R 3 ′, R 4 ′, R 5 ′
Represents the same meaning as in the above formula (I). 7-carboxymethoxy-4 represented by the above formula (I), wherein a 7-hydroxy-4-phenylcoumarin derivative represented by the following formula is etherified with glycolic acid. -Preparation of phenylcoumarin derivatives.
トキシ−４−フェニルクマリン誘導体を有効成分として
含有するアルドース還元酵素阻害剤。3. An aldose reductase inhibitor comprising a 7-carboxymethoxy-4-phenylcoumarin derivative represented by the above formula (I) as an active ingredient.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP26673188 | 1988-10-22 | ||
| JP63-266731 | 1988-10-22 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH02191269A JPH02191269A (en) | 1990-07-27 |
| JP2876129B2 true JP2876129B2 (en) | 1999-03-31 |
Family
ID=17434905
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP12353889A Expired - Lifetime JP2876129B2 (en) | 1988-10-22 | 1989-05-17 | 7-carboxymethoxy-4-phenylcoumarin derivatives and their preparation and use |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2876129B2 (en) |
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| WO2004101543A1 (en) * | 2003-05-15 | 2004-11-25 | Shanghai Institute Of Organic Chemistry, Chinese Academy Of Sciences | Coumarins compounds, the preparation and the use thereof |
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| CN106674176B (en) * | 2016-12-21 | 2019-12-24 | 西安交通大学 | 7-substituted-4-aryl coumarin compound and preparation method and application thereof |
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Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004101543A1 (en) * | 2003-05-15 | 2004-11-25 | Shanghai Institute Of Organic Chemistry, Chinese Academy Of Sciences | Coumarins compounds, the preparation and the use thereof |
| US7259265B2 (en) | 2003-05-15 | 2007-08-21 | Shanghai Institute Of Organic Chemistry, Chinese Academy Of Sciences | Coumarin compounds and method for preparing and using the same |
| AU2016312305B2 (en) * | 2015-08-21 | 2021-02-18 | AMO Ireland | Compounds for optically active devices |
| WO2017032442A1 (en) * | 2015-08-21 | 2017-03-02 | Merck Patent Gmbh | Compounds for optically active devices |
| JP2018529659A (en) * | 2015-08-21 | 2018-10-11 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ | Compounds for optically active devices |
| US10457658B2 (en) | 2015-08-21 | 2019-10-29 | Merck Patent Gmbh | Compounds for optically active devices |
| US10723713B2 (en) | 2015-08-21 | 2020-07-28 | Merck Patent Gmbh | Hydrophilic compounds for optically active devices |
| US10829451B2 (en) | 2015-08-21 | 2020-11-10 | Merck Patent Gmbh | Compounds for optically active devices |
| EP3133065A1 (en) * | 2015-08-21 | 2017-02-22 | Merck Patent GmbH | Compounds for optically active devices |
| US11078177B2 (en) | 2015-08-21 | 2021-08-03 | Merck Patent Gmbh | Compounds for optically active devices |
| US11111226B2 (en) | 2015-08-21 | 2021-09-07 | Merck Patent Gmbh | Hydrophilic compounds for optically active devices |
| US11958819B2 (en) | 2015-08-21 | 2024-04-16 | Johnson & Johnson Surgical Vision, Inc. | Compounds for optically active devices |
| US11702396B2 (en) | 2017-02-15 | 2023-07-18 | Johnson & Johnson Surgical Vision, Inc. | Hydrophobic compounds for optically active devices |
| US11753387B2 (en) | 2017-02-15 | 2023-09-12 | Johnson & Johnson Surgical Vision, Inc. | Compounds for optically active devices |
| US10703735B2 (en) * | 2018-07-25 | 2020-07-07 | Lead Discovery Center Gmbh | 4-phenyl-coumarin derivatives, processes for their preparation and uses thereof for the treatment of cancer |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH02191269A (en) | 1990-07-27 |
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