JPS61118366A - Intermediate of 2-methyldihydropyridine derivative - Google Patents
Intermediate of 2-methyldihydropyridine derivativeInfo
- Publication number
- JPS61118366A JPS61118366A JP60214152A JP21415285A JPS61118366A JP S61118366 A JPS61118366 A JP S61118366A JP 60214152 A JP60214152 A JP 60214152A JP 21415285 A JP21415285 A JP 21415285A JP S61118366 A JPS61118366 A JP S61118366A
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- compound
- methyl
- carboxylic acid
- dihydropyridine
- formula
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
- C07C205/56—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups bound to carbon atoms of six-membered aromatic rings and carboxyl groups bound to acyclic carbon atoms of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/55—Acids; Esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Cardiology (AREA)
- Animal Behavior & Ethology (AREA)
- Heart & Thoracic Surgery (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Pyridine Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
本発明は冠血管拡張作用及び血圧降下作用等の血管拡張
作用を有する新規な２−メチルジヒドロピリジン誘導体
の中間体に関するものである。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel 2-methyldihydropyridine derivative intermediate having vasodilatory effects such as coronary vasodilation and blood pressure lowering effects.
本発明で提供される２−メチルジヒドロピリジン誘導体
の中間体は下記の一般式で示される。The intermediate of the 2-methyldihydropyridine derivative provided by the present invention is represented by the following general formula.
ｎ
（式中、Ｒ１は３−ニトロフェニル、２−クロロフェニ
ルまたは２−トリプルオロメチルフェニ／Ｌ、Ｒ２はイ
ソプロピル、２−フェノキシエチル・ または２−ベ
ンジルオキシエチル、Ｒ３は低級アルキル、モしてＲ４
はジ（低級）アルコキシメチルまたはホルミルを意味し
、Ｒ１が３−二トロフェニルであるときは、Ｒ２はイソ
プロピルであるものとする）
上記（Ｉ＞式で示される２−メチルジヒドロピリジン誘
導体の中間体に関して、ジヒドロピリジン骨核の第４位
における不斉炭素原子に基づく２つの光学異性体が１対
存在しており、これらの型の異性体は本発明の範−内に
含まれ、且ついずれも同一の式（Ｉ）によって抱括的に
示きれる。n (wherein R1 is 3-nitrophenyl, 2-chlorophenyl or 2-triple omethylphenylene/L, R2 is isopropyl, 2-phenoxyethyl or 2-benzyloxyethyl, R3 is lower alkyl, and R4 is
means di(lower) alkoxymethyl or formyl, and when R1 is 3-nitrophenyl, R2 shall be isopropyl) An intermediate of the 2-methyldihydropyridine derivative represented by the above formula (I>) There is a pair of two optical isomers based on the asymmetric carbon atom at the 4th position of the dihydropyridine core, and these types of isomers are included within the scope of the present invention, and both are identical. This can be comprehensively shown by the formula (I).
本発明によれば、２−メチルジヒドロピリジン誘導体の
中間体（Ｉ）は以下に示す反応方式によって製造するこ
とができる。According to the present invention, the 2-methyldihydropyridine derivative intermediate (I) can be produced by the reaction method shown below.
（１）プロセス１
（１−１） （ＩＩ−１）（式中、Ｒ、
Ｒ及びＲ３は前と同じ意味であり、Ｒ４はジ（低級）ア
ルコキシメチルを意味する）
（２）プロセス２
（Ｉｆ−２＞ （Ｉ［−２）（式中、Ｒ
、Ｒ、Ｒ及びＲ４はそれぞれ前と同じ意味）
（３）プロセス３
（式中、ａ １ 、Ｒ２、Ｒ３及びＲ４はそれぞれ前と
同じ意味）
以下に、本明細書において使用される定義の詳細な説明
とそれらの具体例を列挙する。(1) Process 1 (1-1) (II-1) (wherein R,
R and R3 have the same meanings as before, R4 means di(lower) alkoxymethyl) (2) Process 2 (If-2> (I[-2) (in the formula, R
, R, R and R4 each have the same meaning as before) (3) Process 3 (wherein a 1 , R2, R3 and R4 each have the same meaning as before) Below are details of the definitions used in this specification. List detailed explanations and specific examples.
Ｒで示される１低級アルキル」とは０１〜Ｃ６のアルキ
ルを含み、好ましいものは０１〜Ｃ３アルキルで、更に
好ましいものは第１級直鎖状アルキル、例えばメチル、
エチル、プロピル等である。"1-lower alkyl represented by R" includes alkyl of 01 to C6, preferably 01 to C3 alkyl, and more preferably primary linear alkyl, such as methyl,
Ethyl, propyl, etc.
Ｒ４で示される「ジ（低級）アルフキジメチル」とは、
ジ（０１〜Ｃ６直鎖又は分岐状低級）アルフキジメチル
を含み、好ましくはＣ１〜Ｃ３のもの、例えば、ジメト
キシメチル、ジェトキシメチル、ジプロポキシメチル等
である。“Di(lower)alfkydimethyl” represented by R4 is
It includes di(01-C6 linear or branched lower)alfky dimethyl, preferably C1-C3, such as dimethoxymethyl, jetoxymethyl, dipropoxymethyl, and the like.
プロセス１及び２で用いられる出発物質（ＩＦ−１＞及
び（ＩＩ−２）は新規のもの及び公知のものを共に含む
が、新規物質は、下記反応式に示す如く常法に従って４
−置換アセト酢酸エステル（Ｉ［Ａ＞又は（Ｉ［Ａ’
）にアルデヒド（ＩＢ）を反応させることによって製造
することができる。The starting materials (IF-1> and (II-2) used in Processes 1 and 2 include both novel and known materials.
-Substituted acetoacetate (I[A> or (I[A')
) with aldehyde (IB).
（ＩＢ ） （Ｉ［Ａ ）
（式中、Ｒ、Ｒ及びＲ４はそれぞれ前と同じ意味）
（ＩＢ） （Ｉ［ム′）
（Ｉｆ−２）
（式中、Ｒ及びＲはそれぞれ前と同じ意味）プロセス１
及び２で用いられる他の出発物質＜ｌｌｌ−１）及び（
ＩＩＩ−２＞は、下記反応式で示す様に、４−置換アセ
ト酢酸化合物（ＩＩＩＡ＞又は（ＨＡ’ ）にアンモニ
ア又はその塩を反応きせることによって製造することが
できる。(IB) (I[A) (In the formula, R, R and R4 each have the same meaning as before) (IB) (I[mu') (If-2) (In the formula, R and R each have the same meaning as before) Meaning) Process 1
and other starting materials used in 2<lll-1) and (
III-2> can be produced by reacting a 4-substituted acetoacetic acid compound (IIIA> or (HA') with ammonia or a salt thereof, as shown in the reaction formula below.
■
（ＩＩ［Ａ）
（ＩＩ−１）
（式中、Ｒ２は前と同じ意味）
■
（Ｉｌ［Ａ’）
（式中、Ｒ及びＲ４はそれぞれ前と同じ意味）２−メチ
ルジヒドロピリジン誘導体の中間体（１）の製造方法を
詳述すると下記の通りである。■ (II[A) (II-1) (In the formula, R2 has the same meaning as before) ■ (Il[A') (In the formula, R and R4 each have the same meaning as before) Intermediate of 2-methyldihydropyridine derivative The method for producing body (1) is detailed below.
（１）プロセス１
このプロセスは、化合物（ＩＩ−１＞にアミノ化合物（
Ｉ［−１）を反応させることによって化合物（Ｉ−１）
を製造する方法に関するものである。(1) Process 1 This process involves adding an amino compound (
Compound (I-1) by reacting I[-1]
The present invention relates to a method for manufacturing.
出発物質（ＩＩ−１）及び（Ｉ［−１）はそれぞれ各分
子中の２Ｊｌ［結合に基づくシス及びトランスの各幾何
異性体を含み、本プロセスによれば、化合物（ＩＩ−１
）と化合物（ＩＩＩ−４）におけるいずれの幾何異性体
を用いても反応図式に従って化合物（Ｉ−１）を製造す
ることができる。従って出発物質（Ｉ−１）及び（Ｉ（
）のすべての異性体及びそれらの任意の混合物を用いて
も本プロセスの範囲中に含まれる。The starting materials (II-1) and (I[-1) each contain cis and trans geometric isomers based on the 2Jl bond in each molecule, and according to this process, compound (II-1
) and compound (III-4), compound (I-1) can be produced according to the reaction scheme using any geometric isomer of compound (III-4). Therefore, starting material (I-1) and (I(
) and any mixtures thereof are included within the scope of this process.
反応は室温、加温又は加熱下に遂行きれる０反応は好ま
しくは無溶媒で行なわれるが、適当な溶媒、例えば、ベ
ンゼン、トルエン、キシレン、クロロホルム、四塩化炭
素、塩化エチレン、塩化エチレン、あるいはその他の繁
用溶媒中で行なうこともできる。又反応は、酸（例えば
酢酸）や塩基（例えばピリジンやピッリン）又はその他
の繁用緩衝溶液との試剤によって反応を促進させて行な
うのが好ましい、これらの試剤は反応促進剤として作用
し、これらが液体であるときは溶媒の作用を兼ねきせる
こともできる。又反応は加温或は加熱によって促進する
こともできる０反応条件は、反応化合物、溶媒及び上記
他の試剤の種類に応じて選択できる。The reaction can be carried out at room temperature, with heating, or under heating. The reaction is preferably carried out without a solvent, but with a suitable solvent such as benzene, toluene, xylene, chloroform, carbon tetrachloride, ethylene chloride, ethylene chloride, or other solvents. It can also be carried out in commonly used solvents. The reaction is also preferably carried out by accelerating the reaction with acids (e.g. acetic acid), bases (e.g. pyridine or pyridine) or other commonly used buffer solutions; these agents act as reaction accelerators and When is a liquid, it can also serve as a solvent. The reaction may also be accelerated by heating or heating.The reaction conditions can be selected depending on the type of the reaction compound, solvent, and other reagents mentioned above.
本プロセスの反応様式について、例えば４−置換アセト
酢酸化合物（ＩＩＡ＋に、アミノ化合物（ＩＩＩ−１＞
の存在下アルデヒド（Ｉ［Ｂ）を反応させることによっ
ても遂行でき、このような場合もこのプロセスに含まれ
る。Regarding the reaction mode of this process, for example, a 4-substituted acetoacetic acid compound (IIA+, an amino compound (III-1>
It can also be accomplished by reacting aldehyde (I[B) in the presence of , and such cases are also included in this process.
（２）プロセス２
このプロセスは、化合物（Ｉｆ−２＞にアミン化合物（
ＤＩ−２）を反応させることによって化合物（Ｉ−１）
を得る方法に関するものである。(2) Process 2 This process involves adding an amine compound (If-2> to a compound (If-2>).
Compound (I-1) by reacting DI-2)
It is about how to obtain.
本プロセスはプロセス１と実質的に同じであり、化合物
（Ｉ［−２）と（ＩＩＩ−２）の反応をプロセス１と同
様の方法で遂行すればよい、即ち同一の反応条件（例え
ば反応温度、溶媒、反応促進剤等）及びプロセス１で述
べた反応の様式は、本プロセスにおいても適用できる。This process is substantially the same as Process 1, and the reaction of compounds (I[-2) and (III-2) may be carried out in the same manner as Process 1, that is, under the same reaction conditions (e.g., reaction temperature , solvent, reaction accelerator, etc.) and the reaction mode described in Process 1 can also be applied to this process.
但し、プロセス１で用いる化合物（Ｉ［−１）又は反応
試剤（Ｉ（Ａン並びに化合物（ＩＩＩ−１）はプロセス
２では化合物（ｌｌ−２＞又は反応試剤（ＩＡ）並びに
化合物（Ｉ［［−２）に置き換える。However, the compound (I[-1) or the reaction reagent (I(A) and the compound (III-1) used in Process 1 are replaced by the compound (I[-2> or the reaction reagent (IA) and the compound (III-1) in Process 2). -2).
（３）プロセス３
このプロセスは化合物（Ｉ−１）を加水分解して化合物
（Ｉ−２）を得る方法に関するものである。(3) Process 3 This process relates to a method of hydrolyzing compound (I-1) to obtain compound (I-2).
化合物（Ｉ−１）は上記プロセス（１及び２）で示した
方法によって製造される。Compound (I-1) is produced by the method shown in Processes (1 and 2) above.
このプロセスでは、Ｒ４で示されるジ（低級）アルコキ
シメチルがホルミルに変換される。In this process, di(lower)alkoxymethyl represented by R4 is converted to formyl.
力日水分解は、所謂アセタール結合を開裂して、対応す
るカルボニルに変換するときに用いられる常法に従って
行なわれるが、好ましいのは、酸例えば無機酸（例えば
塩酸、硫酸等）苦しくは有機酸（例えばぎ酸、酢酸、ト
リプルオロ酢酸、ｐ−トルエンスルホン酸等）、或は酸
性イオン交換樹脂等の酸の存在下に行なう酸性加水分解
である。Hydrolysis is carried out according to the conventional method used to cleave the so-called acetal bond and convert it into the corresponding carbonyl, but acids such as inorganic acids (e.g. hydrochloric acid, sulfuric acid, etc.) and organic acids are preferred. (for example, formic acid, acetic acid, triple oroacetic acid, p-toluenesulfonic acid, etc.), or acidic hydrolysis carried out in the presence of an acid such as an acidic ion exchange resin.
この加水分解は好適な常用溶媒、例えば水、アセトン、
メチルエチル・・ケトン、ジオキサン、エタノール、メ
タノール、Ｎ、Ｎ−ジメチルホルムアミド、ジメデルス
ルホキシド、或はこれらの任意の混合物或いは緩衝溶液
等の存在下で行なうことができる０反応温度の制限はな
く、通常は冷却下、室温下或は苦干の加温下で遂行きれ
る。This hydrolysis can be carried out using suitable conventional solvents such as water, acetone,
The reaction can be carried out in the presence of methyl ethyl ketone, dioxane, ethanol, methanol, N, N-dimethylformamide, dimedel sulfoxide, or any mixture thereof or buffer solution, etc. There is no limit to the reaction temperature. Usually, it can be carried out under cooling, room temperature, or slightly heated conditions.
上記プロセスにおいて、一般的な分離法及び精製法によ
って、反応混合物から目的物質を分離及び精製すること
ができる。上記一般法としては、好適溶媒による抽出、
クロマトグラフ、沈殿、再結晶等の手段があげられる。In the above process, the target substance can be separated and purified from the reaction mixture by common separation and purification methods. The above general methods include extraction with a suitable solvent,
Examples include means such as chromatography, precipitation, and recrystallization.
こうして得られる化合物（１）は、２−メチルジヒドロ
ピリジン骨核の第４位の不斉炭素原子に由来する少なく
とも１対の光学異性体をしばしば含み、これらは各異性
体単独で、又は混合物として存在する。ラセミ化合物は
、一般的なラセミ分割法に従って各光学異性体に分割す
ることができる。該分割法としては、一般的な光学活性
酸（例えば酒石酸、カンファースルホン酸等）とのジア
ステレオマー塩に導き化学分割する方法が挙げられる。The compound (1) thus obtained often contains at least one pair of optical isomers derived from the asymmetric carbon atom at the 4th position of the 2-methyldihydropyridine core, and these isomers exist alone or as a mixture. do. Racemic compounds can be resolved into each optical isomer according to general racemic resolution methods. Examples of the separation method include a method of chemically resolving diastereomer salts with general optically active acids (eg, tartaric acid, camphorsulfonic acid, etc.).
こノ発明の２−メチルジヒドロピリジン誘導体の中間体
（Ｉ）はそれ自体上記のような血管拡張作用を有するが
、より強力な血管拡張作用を有する下記の一般式（ｆｆ
＞で示される２−メチルジヒドロピリジン誘導体または
その塩を製造する合成中間体としても有用である。Intermediate (I) of the 2-methyldihydropyridine derivative of this invention itself has the above-mentioned vasodilatory effect, but it has the following general formula (ff
It is also useful as a synthetic intermediate for producing 2-methyldihydropyridine derivatives or salts thereof.
（式中、ＲＬ 、Ｒ２およびＲ３はそれぞれ前と同じ意
味であり、Ｒ５はヒドロキシメチル又はシアノを意味す
る）
上記の２−メチルジヒドロピリジン誘導体（ＩＶ）は例
えば、本発明の化合物（Ｉ）を出発原料として下記に示
す方法により製造でき、これらの方法については後述す
る参考例において具体的に説明する。(In the formula, RL, R2 and R3 each have the same meaning as before, and R5 means hydroxymethyl or cyano) The above 2-methyldihydropyridine derivative (IV) can be obtained, for example, starting from the compound (I) of the present invention. It can be produced by the methods shown below as raw materials, and these methods will be specifically explained in the reference examples described below.
１迭ユ
（式中、Ｒ，Ｒ及びＲ３はそれぞれ前と同じ意味）
１亘ユ
、１
（式中、Ｒ１、Ｒ２及びＲ３はそれぞれ前と同じ意味）
２−メチルジヒドロピリジン誘導体の中間体（Ｉ）及び
それか、ら誘導きれるジヒドロピリジン誘導体（ＩＶ）
の好適な塩としては、医薬として利用できる塩、例えば
無機酸塩（例えば塩酸塩、臭化水Ｓ酸塩、燐酸塩、硫酸
塩等）や有機酸塩（例えばぎ酸塩、酢酸塩、フマル酸塩
、マレイン酸塩、アスパラギン酸塩、グルタミン酸塩等
）等が挙げられる。1 (in the formula, R, R and R3 each have the same meaning as before) 1 (in the formula, R1, R2 and R3 each have the same meaning as before) Intermediate of 2-methyldihydropyridine derivative (I ) and dihydropyridine derivatives (IV) derived therefrom
Suitable salts include pharmaceutically usable salts, such as inorganic acid salts (e.g., hydrochloride, hydrobromide, sulfate, phosphate, sulfate, etc.) and organic acid salts (e.g., formate, acetate, fumarate, etc.). salts, maleates, aspartates, glutamates, etc.).
本発明の化合物（■）痴ら得られる２−メチルジヒドロ
ピリジン誘導体（ＩＶ）またはその塩は、強い冠血管拡
張作用、降圧作用等の血管拡張作用を有し、心不全、狭
心症、心筋梗泰症の様な冠状血管疾患又は高血圧症の治
療に効果的である。The 2-methyldihydropyridine derivative (IV) or its salt obtained from the compound (■) of the present invention has vasodilatory effects such as strong coronary vasodilatory effect and antihypertensive effect, and is effective against heart failure, angina pectoris, and myocardial infarction. It is effective in treating coronary vascular diseases such as schizophrenia or hypertension.
化合物（Ｉ）の中間体としての有用性を示す為に、２−
メチルジヒドロピリジン誘導体（ＩＶ）の代表的な化合
物についての薬理試験結果を示す。In order to demonstrate the usefulness of compound (I) as an intermediate, 2-
The results of pharmacological tests on representative compounds of methyldihydropyridine derivatives (IV) are shown.
５匹のウィスターラットで１群を構成し、体長に合わせ
たケージ中に固定した。圧カドランスデューサーによっ
て大腿動脈の血圧を測定し、平均動脈圧の積分値を電気
的に記録し、心拍数はパルス波検出器で測定した。エー
テルでの軽麻酔下にカテーテルを挿入し、挿入後３時間
で試験化合物を経口投与した。One group consisted of five Wistar rats and were fixed in a cage adjusted to body length. Blood pressure in the femoral artery was measured using a pressure transducer, the integral value of the mean arterial pressure was recorded electrically, and heart rate was measured using a pulse wave detector. A catheter was inserted under light anesthesia with ether, and the test compound was orally administered 3 hours after insertion.
佐狭±皇璽工
化合物Ａ−に
フエジピン（比較化合物）
化合物Ｂ
６−ジアツー５−メトキシカルボニル−２−メチル−４
−（３−ニトロフェニル）−１，４−ジヒドロピリジン
−３−カルボン酸のイソプロピルエステル
化合物Ｃ
４−（２−クロロフェニル）−６−シアツー５−メドキ
シ力ルボニル−２−メチル−１，４−ジヒドロピリジン
−３−カルボン酸のイソプロピルエステル
化合物Ｄ
６−ジアツー４−（２７１−リフルオロメチルフェニル
）−５−メトキシカルボニル−２−メチル−１，４−ジ
ヒドロピリジン−３−カルボン酸のイソプロピルエステ
ル
化合物Ｅ
６−ジアツー４−（２−トリプルオロメチルフェニル）
−５−エトキシカルボニル−２−メチル−１，４−ジヒ
ドロピリジン−３−カルボン酸の２−フェノキシエチル
エステル
化合物Ｆ
４−（２−ｈリフルオロメチルフェニル）−６−ヒドロ
キシメチル−５−メトキシカルボニル−２−メチル−１
，４−ジヒドロピリジン−３−カルボン酸のイソプロピ
ルエステル
化合物Ｇ
４− （２−ト１，１フルオロメチルフェニル）−５−
ニトキシ力ルボニル−６−ヒドロキシメチルー２−メチ
ル−１，４−ジヒドロピリジン−３−カルボン酸の２−
フェノキシエチルエステル試験結果
下記の表に血圧の最大降下量（ｍｍＨｇ）の平均値を示
す。Sasa±English compound A- and fuedipine (comparative compound) Compound B 6-dia-2-5-methoxycarbonyl-2-methyl-4
-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid isopropyl ester compound C 4-(2-chlorophenyl)-6-cyatoxycarbonyl-2-methyl-1,4-dihydropyridine- Isopropyl ester of 3-carboxylic acid Compound D 6-Diatu 4-(271-lifluoromethylphenyl)-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid Isopropyl ester Compound E 6-Diatu 4-(2-triple omethylphenyl)
2-phenoxyethyl ester compound of -5-ethoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid F 4-(2-hlifluoromethylphenyl)-6-hydroxymethyl-5-methoxycarbonyl- 2-methyl-1
, 4-dihydropyridine-3-carboxylic acid isopropyl ester compound G 4- (2-to-1,1 fluoromethylphenyl)-5-
Nitoxycarbonyl-6-hydroxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid 2-
Phenoxyethyl ester test results The table below shows the average value of the maximum decrease in blood pressure (mmHg).
第１表
冠血管流に対する
体重８〜１５ｋｇの雑種犬にベントパルビタールナトリ
ウム３５ｍｇ／ｋｔｔを腹腔内投与して麻酔した．人工
呼吸下に胸部を切開し、冠動脈左回旋技に血流計のプロ
ーブを固定した．大腿動脈の血圧を測定し、本発明の目
的物質を静脈注射して血流量のピーク値を測定した。Table 1 Coronary Vascular Flow A mongrel dog weighing 8 to 15 kg was anesthetized by intraperitoneal administration of sodium bentoparbital at 35 mg/ktt. Under artificial respiration, an incision was made in the chest, and a blood flow meter probe was fixed to the left coronary artery. The blood pressure of the femoral artery was measured, and the target substance of the present invention was intravenously injected, and the peak value of blood flow was measured.
ス簾塁１工
第２表
冠動脈血流量の増加
（正常時の血流量に対する百分率で示す）以下本発明を
説明する為の実施例を掲げる。Screen Ruins 1st Table 2 Increase in Coronary Artery Blood Flow (expressed as a percentage of normal blood flow) Examples for explaining the present invention will be given below.
虫ｍ已鼾二裂】 製造例１ １）３−ニトロベンズアルデヒド（７．５６ｇ）と４。Insects m snoring two splits] Manufacturing example 1 1) 3-nitrobenzaldehyde (7.56g) and 4.
４−ジメトキシアセト酢酸メチル（７．９３ｇ）の乾燥
ベンゼン（ ３ｏｍＱ）溶液に酢酸（０．１８ｇ）とピ
ペリジン（０．１７ｇ）を加えて還流下に３．５時間加
熱し、その間生成する水を共沸的に除去した．その反応
混合物にベンゼンを加えた後、水、炭酸水素ナトリウム
の希薄水溶液、水及び塩化ナトリウムの飽和水溶液で順
次洗浄し、乾燥した。減圧下に溶媒を留去すると油状の
残渣（１５．７４［）が得られ、これをベンゼンと酢酸
エチル（容量比２５：１）を用いてシリカゲル（ ４７
ｏｇ ）でクロマトグラフを行ない、溶出物から黄色油
状の４．４−ジメトキシ−２−（３−ニトロベンジリデ
ン）アセト酢酸メチル（ ８．０６ｇ ） （シス及び
トランス異性体の混合物）を得た。Acetic acid (0.18 g) and piperidine (0.17 g) were added to a solution of methyl 4-dimethoxyacetoacetate (7.93 g) in dry benzene (3omQ) and heated under reflux for 3.5 hours, during which time the water produced was evaporated. It was removed azeotropically. Benzene was added to the reaction mixture, which was then washed successively with water, a dilute aqueous solution of sodium bicarbonate, water and a saturated aqueous solution of sodium chloride, and dried. The solvent was distilled off under reduced pressure to obtain an oily residue (15.74), which was purified using silica gel (47) using benzene and ethyl acetate (volume ratio 25:1).
chromatography was carried out at 8.06 g of methyl 4,4-dimethoxy-2-(3-nitrobenzylidene) acetoacetate (mixture of cis and trans isomers) as a yellow oil from the eluate.
７、２５−８．４ （５Ｈ，ｍ）。7, 25-8.4 (5H, m).
上記１）と実質的に同様の方法で下記の化合物を得た。The following compound was obtained in substantially the same manner as in 1) above.
２）２−（２−クロロベンジリデン）−４．４−ジメト
キシアセト酢酸メチル（シス及びトランス異性体の混合
物）。2) Methyl 2-(2-chlorobenzylidene)-4,4-dimethoxyacetoacetate (mixture of cis and trans isomers).
３）２−（２−トリプルオロメチルベンジリデン）−４
．４−ジメトキシアセト酢酸メチル（シス及びトランス
異性体の混合物）。3) 2-(2-triple omethylbenzylidene)-4
．． Methyl 4-dimethoxyacetoacetate (mixture of cis and trans isomers).
７．２−７．８ （４Ｌｍ）、８．０−８．１４
（ＩＨ，ｍ）。7.2-7.8 (4Lm), 8.0-8.14
(IH, m).
４）２−（２−トリフルオロメチルベンジリデン）アセ
ト酢酸の２−フェノキシエチルエステル（シス及びトラ
ンス異性体の混合物）。4) 2-phenoxyethyl ester of 2-(2-trifluoromethylbenzylidene)acetoacetic acid (mixture of cis and trans isomers).
５）２−（２−トリフルオロメチルベンジリデン）アセ
ト酢酸の２−ベンジルオキシエチルエステル（シス及び
トランス異性体の混合物）。5) 2-benzyloxyethyl ester of 2-(2-trifluoromethylbenzylidene)acetoacetic acid (mixture of cis and trans isomers).
７．２−８．０ （１０Ｈ，ｍ）。7.2-8.0 (10H, m).
実施例１
１）４．４−ジメトキシ−２−（３−ニトロベンジリデ
ン）アセト酢酸゛メチル（’８．０ｇ）と３−アミノク
ロトン酸イソプロピル（４，０７ｇ）の混合物を攪拌し
つつ７０℃で１時間加熱し、引き続いて１００℃で１時
間及び１２０℃で２．５時間攪拌した。得られた反応物
を酢酸エチルに溶解した後、水及び塩化ナトリウム水溶
液で洗浄し、硫酸マグネシウムで乾燥した後減圧下に濃
縮して、黄橙色油状の５−メトキシカルボニル−６−ジ
メトキシメチル−２−メチル−４−（３−ニトロフェニ
ル）−１，４−ジヒドロピリジン−３−カルボン酸のイ
ソプロピルエステル（１１，０３ｇ ）を得た。Example 1 1) A mixture of methyl 4-dimethoxy-2-(3-nitrobenzylidene)acetoacetate (8.0 g) and isopropyl 3-aminocrotonate (4,07 g) was heated at 70°C with stirring. Heating was carried out for 1 hour, followed by stirring at 100°C for 1 hour and at 120°C for 2.5 hours. The obtained reaction product was dissolved in ethyl acetate, washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 5-methoxycarbonyl-6-dimethoxymethyl-2 as a yellow-orange oil. -Methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid isopropyl ester (11.03 g) was obtained.
Ｎ、 Ｍ、 Ｒ，ｌ； ｐｐｍ（ＣＤＣ１ａ） ：３．
６９ （３Ｈ，ｓ）、 ５．０ （ＩＨ，７重線。N, M, R, l; ppm (CDC1a): 3.
69 (3H, s), 5.0 (IH, 7-fold line.
Ｊ＝７．０Ｈｚ）、 ５．１７ （ＩＨ，ｓ）。J=7.0Hz), 5.17 (IH, s).
６．０４ （ＩＨ，ｓ）、 ６．９２ （１１，
ブロード ｓ）。6.04 (IH,s), 6.92 (11,
Broad s).
７．２−８．２ （４Ｈ，ａ＋）。7.2-8.2 (4H, a+).
上記１）と実質的に同様の方法で下記化合物を得た。The following compound was obtained in substantially the same manner as in 1) above.
２）４−（２−クロロフェニル）−５−メトキシカルボ
ニル−６−ジメトキシメチル−２−メチル−１，４−ジ
ヒドロピリジン−３−カルボン酸のイソプロピルエステ
ル。2) Isopropyl ester of 4-(2-chlorophenyl)-5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid.
ｍｐ ８６〜８７．５℃
３）４−′Ｃ２−トリフルオロメチルフェニル）−５−
メトキシカルボニル−６−シメトキシメチル３−カルボ
ン酸のイソプロピルエステル。mp 86-87.5°C 3) 4-'C2-trifluoromethylphenyl)-5-
Isopropyl ester of methoxycarbonyl-6-simethoxymethyl 3-carboxylic acid.
ｍｐ ９２〜９４℃
４）５−エトキシカルボニル−６−ジェトキシメチル−
４−（２−トリプルオロメチルフェニル）−２−メチル
−１．４−ジヒドロピリジン−３−カルボン酸の２−フ
ェノキシエチルエステル。mp 92-94°C 4) 5-ethoxycarbonyl-6-jethoxymethyl-
2-phenoxyethyl ester of 4-(2-tripleomethylphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylic acid.
Ｎ．Ｍ．Ｒ． Ｓｐｐｍ（ＣＤＣｌ２） ： １．０−
１．５ （９Ｈ，ｍ）。N. M. R. Sppm (CDCl2): 1.0-
1.5 (9H, m).
２、３７ （３Ｈ．ｓ）、 ３．５−４．６ （１０Ｈ
．ｍ）。2, 37 (3H.s), 3.5-4.6 (10H
．． m).
５、６７ （ＩＨ，ｓ）、 ７．１２ （ＩＨ．ｓ）。5, 67 (IH,s), 7.12 (IH.s).
６、７−７、８ （１０Ｈ．ｍ）。6, 7-7, 8 (10H.m).
５）５−エトキシカルボニル−６−ジェトキシメチル−
４−（ ２−トリプルオロメチルフェニル）−２−メチ
ル−１．４−ジヒドロピリジン−３−カルボン酸の２−
ベンジルオキシエチルエステル。5) 5-ethoxycarbonyl-6-jethoxymethyl-
2-(2-tripleomethylphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylic acid
Benzyloxyethyl ester.
Ｎ．Ｍ．Ｒ． ＆ｐｐｍ（ＣＤＣｌ２） ： １．０−
１．６ （９Ｈ．ｍ）。N. M. R. &ppm(CDCl2): 1.0-
1.6 (9H.m).
２、３２ （３Ｈ．ｓ）、 ３。４−４．４ （ＩＯＨ
，ｍ）。2, 32 (3H.s), 3.4-4.4 (IOH
, m).
４、４７ （２Ｈ．ｓ）、 ５．６−５．７ （ＬＨ．
ｍ）。4, 47 (2H.s), 5.6-5.7 (LH.
m).
６、１１ （ＩＨ．ｓ）、 ６．６−６、８ （
ＩＨ．ブロード ｓ）。6, 11 (IH.s), 6.6-6, 8 (
IH. Broad s).
７、２−７．７ （９Ｈ，ｍ）。7, 2-7.7 (9H, m).
実施例２
１）２−（２−トリフルオロメチルベンジリデン）アセ
ト酢酸の２−フェノキシエチルエステル（１９，６２ｇ
）と２−アミノ−４，４−ジェトキシクロトン酸エチ
ル（１１，９５ｇ ）の混合物を１００〜１１０℃で２
時間加熱し、更に１２０〜１３０℃で１２時間加熱した
。得られた混合物を酢酸エチルに溶解し、水洗後無水硫
酸マグネシウムで乾燥した。溶媒を留去して粗製の油状
物（２７，７ｇ）を得、これをベンゼンと酢酸エチルの
混合物（容量比５０：１）を用いシリカゲルでクロマト
グラフを行ない、溶出物からＳ−エトキシカルボニル−
６−ジェトキシメチル−４−（２−）リフルオロメチル
フェニル）−２−メチル−１゜４−ジヒドロピリジン−
３−カルボン酸の２−フェノキシエチルエステル（１９
，ｓ４ｇ ）を得た。Example 2 1) 2-phenoxyethyl ester of 2-(2-trifluoromethylbenzylidene)acetoacetic acid (19,62 g
) and ethyl 2-amino-4,4-jethoxycrotonate (11.95 g) at 100-110°C.
The mixture was heated for an additional 12 hours at 120 to 130°C. The resulting mixture was dissolved in ethyl acetate, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain a crude oil (27.7 g), which was chromatographed on silica gel using a mixture of benzene and ethyl acetate (volume ratio 50:1).
6-jethoxymethyl-4-(2-)lifluoromethylphenyl)-2-methyl-1゜4-dihydropyridine-
2-phenoxyethyl ester of 3-carboxylic acid (19
, s4g) was obtained.
Ｎ、Ｍ、Ｒ，ｌ； ｐｐｍ（ＣＤＣＩｓン ： Ｌ、
Ｏ−１，５（９Ｈ，ｍ＞。N, M, R, l; ppm (CDCIson: L,
O-1,5 (9H, m>.
２．３７ （３１，ｓ）、 ３．５−４．６ （ＩＯＨ
，ｍ）。2.37 (31,s), 3.5-4.6 (IOH
, m).
５．６７ （ＩＨ，ｓ）、 ７．１２ （ＩＨ，ｓ）。5.67 (IH, s), 7.12 (IH, s).
６．７−７．８ （ｔｏｕ、ｍ＞。6.7-7.8 (tou, m>.
上記１）と実質的に同様の方法で下記の化合物を得た。The following compound was obtained in substantially the same manner as in 1) above.
２）、５−エトキシカルボニル−６−ジェトキシメチル
−
ル）−２−メチル−１．４−ジヒドロピリジン−３−カ
ルボン酸の２−ベンジルオキシエチルエステル。2) 2-benzyloxyethyl ester of 5-ethoxycarbonyl-6-jethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid.
Ｎ．Ｍ．Ｒ． Ｅ ｐｐｍ（ＣＤＣＩｓ）： １
．０（、６ （９Ｈ．ｍ）。N. M. R. E ppm (CDCIs): 1
．． 0(, 6 (9H.m).
２、３２ （３Ｈ．ｓ）、 ３．４−４．４ （１０
Ｈ．ｍ）。2, 32 (3H.s), 3.4-4.4 (10
H. m).
４、４７ （２Ｈ．ｓ）、 ５．６−５．７ （ＩＨ．
ｍ）。4, 47 (2H.s), 5.6-5.7 (IH.
m).
６、１１ （ＩＨ．ｓ）、 ６．６−６、８ （
ＩＨ．ブロード Ｓ）。6, 11 (IH.s), 6.6-6, 8 (
IH. Broad S).
７、２−７．７ （９Ｈ．ｍ）。7, 2-7.7 (9H.m).
３）５−メトキシカルボニル−６−ジメトキシメチル−
２−メチル−４−（３−ニトロフェニＮ． Ｍ． Ｒ．
δｐｐｍ（ＣＤＣＩｓ） ：３、６９ （３Ｈ．ｓ）、
５．０ （ＬＨ．ｈｅｐｔａｔ。3) 5-methoxycarbonyl-6-dimethoxymethyl-
2-Methyl-4-(3-nitrophenyN.M.R.
δppm (CDCIs): 3, 69 (3H.s),
5.0 (LH. heptat.
Ｊ＝７．０Ｈｚ＞、 ５、１７ （１１，ｓ）。J=7.0Hz>, 5, 17 (11, s).
６、０４ （ＬＨ．ｓ）、 ６．９２ （ＬＭ．
ブロード ｓ）。6, 04 (LH.s), 6.92 (LM.
Broad s).
７、２−８．２ （４Ｈ．ｍ）。7, 2-8.2 (4H.m).
４）４−（２−クロロフェニル）−５−メトキシカルボ
ニル−６−ジメトキシメチル−
ル−１．４−ジヒドロピリジン−３−カルボン酸のイソ
プロピルエステル。4) Isopropyl ester of 4-(2-chlorophenyl)-5-methoxycarbonyl-6-dimethoxymethyl-1,4-dihydropyridine-3-carboxylic acid.
ｍｐ ８６〜８７．５℃
５）４−（２−トリフルオロメチルフェニル）−５−メ
トキシカルボニル−６−シメトキシメチル３〜カルボン
酸のイソプロピルエステル。mp 86-87.5°C 5) Isopropyl ester of 4-(2-trifluoromethylphenyl)-5-methoxycarbonyl-6-simethoxymethyl 3-carboxylic acid.
１、Ｒ．レヌジ３−ル： ３４００， １７２０，
１６９０， １６５３。1.R. Renuji 3-ru: 3400, 1720,
1690, 1653.
１４９３、 １３１９， １３１０． １２７Ｂ。1493, 1319, 1310. 127B.
１２０６、 １０９５． １０３５． ９５１。1206, 1095. 1035. 951.
７６８ ａｍ’ 。768 am'.
実施例３
１）５−エトキシカルボニル−６−ジェトキシメチル−
４−（２−）リフルオロメチルフェニル）−２−メチル
−１．４−ジヒドロピリジン−３−カルボン酸の２−フ
ェノキシエチルエステル（ １５．８５ｇ ）のアセト
ン（１５９賊）溶液に、室温で攪拌しつつ６Ｎの塩酸（
１５． ８５ｍＱ ）を加え、１．５時間攪拌を統け
た．反応物を炭酸水素ナトリウムの飽和水溶液で中和し
た後、アセトンを減圧留去し、残渣を酢酸エチルに溶解
した後、水洗し乾燥した．溶媒を除去し、油状の５−エ
トキシカルボニル−４−（２−トリフルオロメチルフェ
ニル）−６−ホルミル−２−メチル−１．４−ジヒドロ
ピリジン−３−カルボン酸の２−フェノキシエチルエス
テル（１３．５６ｇ）を得た。Example 3 1) 5-ethoxycarbonyl-6-jethoxymethyl-
A solution of 2-phenoxyethyl ester of 4-(2-)lifluoromethylphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylic acid (15.85 g) in acetone (159%) was stirred at room temperature. 6N hydrochloric acid (
15. 85 mQ) was added and stirring was continued for 1.5 hours. After neutralizing the reaction product with a saturated aqueous solution of sodium hydrogen carbonate, acetone was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate, washed with water, and dried. The solvent was removed and the oily 2-phenoxyethyl ester of 5-ethoxycarbonyl-4-(2-trifluoromethylphenyl)-6-formyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid (13. 56g) was obtained.
Ｎ． Ｍ． Ｒ． ｌ； ｐｐｍ（ＣＤＣＩｓ） ：１
、２２ ＜３Ｈ．ｔ，Ｊニア、５Ｈｚ＞、 ２．４０
（３Ｈ，ｓ）。N. M. R. l; ppm (CDCIs): 1
, 22 <3H. t, J near, 5Hz>, 2.40
(3H, s).
４、０−４．６ （６Ｈ．ｍ＞、 ５．７１ （ＩＨ．
ｓ）。4, 0-4.6 (6H.m>, 5.71 (IH.
s).
６、７−７、７ （１０Ｈ．ｍ＞、 １０．２６ （Ｉ
Ｈ，ｓ）。6, 7-7, 7 (10H.m>, 10.26 (I
H,s).
上記１）と実質的に同様の方法で下記の化合物を製造し
た。The following compounds were produced in substantially the same manner as in 1) above.
２）４−（２−クロロフェニル）−６−ホルミル−５−
メトキシカルボニル−２−メチル−１゜４−ジヒドロピ
リジン−３−カルボン酸のイソプロピルエステル。2) 4-(2-chlorophenyl)-6-formyl-5-
Isopropyl ester of methoxycarbonyl-2-methyl-1°4-dihydropyridine-3-carboxylic acid.
ｍｐ、 １０２〜１０３℃
３）４−（２−トリフルオロメチルフェニル）−６−ホ
ルミル−
メチル−１，４−ジヒドロピリジン−３−カルボン酸の
イソプロピルエステル。mp, 102-103°C 3) Isopropyl ester of 4-(2-trifluoromethylphenyl)-6-formyl-methyl-1,4-dihydropyridine-3-carboxylic acid.
ｍｐ． ８３〜８５℃
４）６−ホルミル−５−エトキシカルボニル−２−メチ
ル−４−（２−トリフルオロメチルフェニル）−１．４
−ジヒドロピリジン−３−カルボン酸の２−ベンジルオ
キシエチルエステル。mp. 83-85°C 4) 6-formyl-5-ethoxycarbonyl-2-methyl-4-(2-trifluoromethylphenyl)-1.4
-2-benzyloxyethyl ester of dihydropyridine-3-carboxylic acid.
Ｎ． Ｍ． Ｒ− ８ ｐｐＩＩＩ（ＣＣ１４） ：１
、２３ （３Ｈ．ｔ．Ｊ＝７．５Ｈｚ）、 ２．４
０ （３Ｈ．ｓ）。N. M. R-8 ppIII (CC14): 1
, 23 (3H.t.J=7.5Hz), 2.4
0 (3H.s).
３、４−４．５ （６Ｈ．ｍ）、 ４．４１ （２Ｈ．
ｓ）。3, 4-4.5 (6H.m), 4.41 (2H.m)
s).
５、 ７−５．８ （ＬＨ．ｍ）、 ６．８−６．９
（ＩＨ，ｍ）。5, 7-5.8 (LH.m), 6.8-6.9
(IH, m).
７、２−７．８ （９Ｈ．ｍ＞、 １０．２８ （Ｉ
Ｈ．ｓ）。7, 2-7.8 (9H.m>, 10.28 (I
H. s).
実施例４
５−メトキシカルボニル−６−ジメトキシメチル−２−
メチル−４−（３−ニトロフェニル）−１、４〜ジヒド
ロピリジン−３−カルボン酸のイソプロピルエステル（
１１．０ｇ）と６Ｎの塩酸（１１戒）のアセトン（ １
ｔｏｍＩｌ）混合溶液を室温で４時間攪拌した。アセト
ンを除去した後、反応混合物に水を加え、炭酸水素ナト
リウムの飽和水溶液でｐＨ７． ５に調整した。得られ
た水溶液を酢酸エチルで抽出し、抽出液を水洗した後、
無水硫酸マグネシウムで乾燥した．次いで溶媒を除去し
て油状残渣を得、これを直ちに凝固させて、粗製の橙黄
色結晶状の６−ホルミル−５−メトキシカルボニル−２
−メチル−４〜（３−ニトロフェニル）−１、４−ジヒ
ドロピリジン−３−カルボン酸のイソプロピルエステル
を得た。Example 4 5-methoxycarbonyl-6-dimethoxymethyl-2-
Isopropyl ester of methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (
11.0g) and 6N hydrochloric acid (11 precepts) in acetone (1
toml) mixed solution was stirred at room temperature for 4 hours. After removing the acetone, water was added to the reaction mixture and the pH was adjusted to 7.0 with a saturated aqueous solution of sodium bicarbonate. Adjusted to 5. The resulting aqueous solution was extracted with ethyl acetate, and the extract was washed with water.
It was dried with anhydrous magnesium sulfate. The solvent was then removed to give an oily residue which immediately solidified to give crude orange-yellow crystalline 6-formyl-5-methoxycarbonyl-2.
The isopropyl ester of -methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid was obtained.
Ｎ． Ｍ． Ｒ． ８ ｐｐｍ（ＣＤＣｌ２） ：１、
１３ （３Ｈ．ｄ．Ｊ＝７Ｈｚ）、 １．２８ （３Ｈ
．ｄ。N. M. R. 8 ppm (CDCl2): 1,
13 (3H.d.J=7Hz), 1.28 (3H.d.J=7Hz), 1.28 (3H.d.J=7Hz)
．． d.
Ｊ＝７Ｈｚ）、 １．７９ （３Ｈ．ｓ）、 ３．８０
（３Ｈ．ｓ）。J=7Hz), 1.79 (3H.s), 3.80
(3H.s).
５、０２ （ＩＨ．ｈａｐｔａｔ，Ｊ＝７Ｈｚ）。5, 02 (IH.haptat, J=7Hz).
５、２７ （ＩＨ．ｓ）、 ７．１１ （ＩＨ．
ブロード Ｓ）。5, 27 (IH.s), 7.11 (IH.s).
Broad S).
７、４−８．２ （４Ｈ．ｍ）、 １０．６０ （Ｌ
Ｈ．ｓ）。7, 4-8.2 (4H.m), 10.60 (L
H. s).
２−メチルジヒドロピリジン誘導体（ＩＶ）の 造参考
例１
１）６−ホルミル−５−メトキシカルボニル−−メチル
−４−（３−ニトロフェニル）−１。Reference Example 1 for Preparation of 2-Methyldihydropyridine Derivative (IV) 1) 6-formyl-5-methoxycarbonyl--methyl-4-(3-nitrophenyl)-1.
４−ジヒドロピリジン−３−カルボン酸のイソプロピル
エステル（４．２ｇ）のエタノール（８５誰）溶液に、
攪拌下Ｏ℃に冷却しつつ水素化はう素ナトリウム（０．
４０９ｇ）を３０分を要して徐々に加えた。反応混合物
を酢酸の５０％水溶液で酸性にした後、エタノールを減
圧除去し、得られた水性懸濁液を水で希釈し、沈殿した
淡黄色粉末を濾取水洗後、乾燥した。この粉末（３．８
９ｇ）をエタノールで再結晶し、黄色粉末状の６−ヒド
ロキシメチル−５−メトキシカルボニル−２−メチル−
４−（３−ニトロフェニル）−１．４−ジヒドロピリジ
ン−３−カルボン酸のイソプロピルエステル（ ３．０
５ｇ ） ヲ得た。In a solution of isopropyl ester of 4-dihydropyridine-3-carboxylic acid (4.2 g) in ethanol (85 g),
Sodium borohydride (0.5%) was added while stirring and cooling to 0°C.
409 g) was gradually added over 30 minutes. After the reaction mixture was made acidic with a 50% aqueous solution of acetic acid, ethanol was removed under reduced pressure, the resulting aqueous suspension was diluted with water, and the precipitated pale yellow powder was filtered, washed with water, and dried. This powder (3.8
9g) was recrystallized from ethanol to obtain a yellow powder of 6-hydroxymethyl-5-methoxycarbonyl-2-methyl-
Isopropyl ester of 4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (3.0
5g) I got it.
ｆｆｌｐ． １６４〜１６６℃
参考例１−１〉と実質的に同様の方法で下記の化合物を
製造した。fflp. 164-166°C The following compound was produced in substantially the same manner as in Reference Example 1-1>.
２〉６−ヒドロキシメチル−５−メトキシカルボニル−
２−メチル−４−Ｃ２−クロロフェニル）− １．４−
ジヒドロピリジン−３−カルボン酸のイソプロピルエス
テル。2>6-hydroxymethyl-5-methoxycarbonyl-
2-Methyl-4-C2-chlorophenyl)-1.4-
Isopropyl ester of dihydropyridine-3-carboxylic acid.
ｍｐ． １２２〜１２３℃
３）６−ヒドロキシメチル−５−メトキシカルボニル−
２−メチル−４−（２−トリフルオロメチルフェニル）
−１．４−ジヒドロピリジン−３−カルボン酸のイソプ
ロピルエステル。mp. 122-123℃ 3) 6-Hydroxymethyl-5-methoxycarbonyl-
2-Methyl-4-(2-trifluoromethylphenyl)
- Isopropyl ester of 1,4-dihydropyridine-3-carboxylic acid.
ｍｐ． １２３〜１２５℃
４）６−ヒドロキシメチル−５−エトキシカルボニル−
２−メチル−４−（２−トリフルオロメチルフェニル）
−１．４−ジヒドロピリジン−３−カルボン酸の２−フ
ェノキシエチルエステル。mp. 123-125℃ 4) 6-Hydroxymethyl-5-ethoxycarbonyl-
2-Methyl-4-(2-trifluoromethylphenyl)
-2-phenoxyethyl ester of 1,4-dihydropyridine-3-carboxylic acid.
ｍｐ．１４８〜１４９℃
５〉６−ヒトロキシメデルー５−エトキシカルボニル−
２−メチル−４−（２−トリフルオロメチルフェニル）
−１，４−ジヒドロピリジン−３−カルボン酸の２−ベ
ンジルオキシエチルエステル。mp. 148-149℃ 5〉6-Hydroximedel-5-ethoxycarbonyl-
2-Methyl-4-(2-trifluoromethylphenyl)
2-benzyloxyethyl ester of -1,4-dihydropyridine-3-carboxylic acid.
ｍｐ、 １０４〜１０６℃
参考例２
１）６−ホルミル−５−メトキシカルボニル−２−メチ
ル−４−（３−ニトロフェニル）−１゜４−ジヒドロピ
リジン−３−カルボン酸のイソプロピルエステル（４，
５ｇ）の酢酸（３５１１Ｌｌｌ ）溶液にヒドロキシル
アミン塩酸塩（ｏ、９ｙｇ）と酢酸ナトリウム（１，４
３ｇ）を加え、室温で２．５時間攪拌した。得られた反
応混合物に無水酢酸（４，１４ｇ）を加えた後、室温で
１，５時間攪拌し、更に９５〜１００℃で４時間攪拌し
た。酢酸と過剰の無水酢酸を減圧下に除去し、次いで残
渣に水を加えた後、炭酸水素ナトリウムの飽和水溶液で
中和した。得られた水性懸濁液を２倍量の酢酸エチルで
抽出し、抽出液を水洗し無水硫酸マグネシウムで乾燥し
た後、減圧濃縮して、赤褐色油状物（４，ｓｓｇ）を得
た。これをベンゼンと酢酸エチル（容量比１０：１）を
用いシリカゲル（１５０ｇ）でクロマトグラフを行ない
、溶出物から粗製の結晶（２，９９ｇ）を得た。これを
エタノールで再結晶し、黄色プリズム結晶状の６−ジア
ツー５−メトキシカルボニル−２−メチル−４−（３−
ニトロフェニル）−１，４−ジヒドロピリジン−３−カ
ルボン酸のイソプロピルエステル（１８９ｇ）を得た。mp, 104-106°C Reference Example 2 1) Isopropyl ester of 6-formyl-5-methoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1°4-dihydropyridine-3-carboxylic acid (4,
Hydroxylamine hydrochloride (o, 9yg) and sodium acetate (1,4
3 g) was added thereto, and the mixture was stirred at room temperature for 2.5 hours. After adding acetic anhydride (4.14 g) to the resulting reaction mixture, the mixture was stirred at room temperature for 1.5 hours and further stirred at 95-100°C for 4 hours. Acetic acid and excess acetic anhydride were removed under reduced pressure, then water was added to the residue, which was then neutralized with a saturated aqueous solution of sodium bicarbonate. The resulting aqueous suspension was extracted with twice the amount of ethyl acetate, the extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a reddish-brown oil (4, ssg). This was chromatographed on silica gel (150 g) using benzene and ethyl acetate (volume ratio 10:1), and crude crystals (2.99 g) were obtained from the eluate. This was recrystallized from ethanol to give yellow prismatic crystals of 6-dia2-5-methoxycarbonyl-2-methyl-4-(3-
Isopropyl ester of (nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (189 g) was obtained.
ｍｐ、 １４８〜１５０℃
参考例２−１）と実質的に同様の方法で下記の化合物を
製造した。mp, 148-150°C The following compound was produced in substantially the same manner as in Reference Example 2-1).
２）６−ジアツー５−メトキシカルボニル−２−メチル
−４−（２−クロロフェニル）−１，４−シヒドロビリ
ジン−３−カルボン酸のイソプロピルエステル。2) Isopropyl ester of 6-diatwo-5-methoxycarbonyl-2-methyl-4-(2-chlorophenyl)-1,4-cyhydrobiridine-3-carboxylic acid.
ｍｐ、 １７６〜１７７℃
３）６−ジアツー５−メトキシカルボニル−メチル−４
−（２−トリフルオロメチルフェニル）−１．４−ジヒ
ドロピリジン−３−カルボン酸のイソプロピルエステル
。mp, 176-177°C 3) 6-dia-5-methoxycarbonyl-methyl-4
Isopropyl ester of -(2-trifluoromethylphenyl)-1,4-dihydropyridine-3-carboxylic acid.
ｍｐ． １７２〜１７３℃
４〉６−ジアツー５−エトキシカＪレボニル−２−メチ
ル−４−（ ２− ）リフルオロメチルフェニル）−１
．４−ジヒドロピリジン−３−カルボン酸の２−フェノ
キシエチルエステル。mp. 172-173℃ 4〉6-dia2-5-ethoxycaJ levonyl-2-methyl-4-(2-)lifluoromethylphenyl)-1
．． 2-phenoxyethyl ester of 4-dihydropyridine-3-carboxylic acid.
ｍｐ． １１８〜１１９℃
５）６−ジアツー５−エトキシカルボニル−２−メチル
−４−（２−１−リフルオロメチルフェニル）−１．４
−ジヒドロピリジン−３−カルボン酸の２−ベンジルオ
キシエチルエステル。mp. 118-119°C 5) 6-dia-5-ethoxycarbonyl-2-methyl-4-(2-1-lifluoromethylphenyl)-1.4
-2-benzyloxyethyl ester of dihydropyridine-3-carboxylic acid.
ｍｐ． ０６〜１４７．５℃mp. 06～147.5℃
Claims (5)
ニルまたは２−トリフルオロメチルフェニル、Ｒ＾２は
イソプロピル、２−フェノキシエチルまたは２−ベンジ
ルオキシエチル、Ｒ＾３は低級アルキル、そしてＲ＾４
はジ（低級）アルコキシメチルまたはホルミルを意味し
、Ｒ＾１が３−ニトロフェニルであるときは、Ｒ＾２は
イソプロピルであるものとする） で示される２−メチルジヒドロピリジン誘導体の中間体
またはその塩。(1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. 2-benzyloxyethyl, R^3 is lower alkyl, and R^4
means di(lower) alkoxymethyl or formyl, and when R^1 is 3-nitrophenyl, R^2 is isopropyl) or an intermediate of the 2-methyldihydropyridine derivative represented by salt.
囲第（１）項に記載の化合物。(2) The compound according to claim (1), wherein R^3 is methyl or ethyl.
囲第（２）項に記載の化合物。(3) The compound according to claim (2), wherein R^1 is 3-nitrophenyl.
−２−メチル−４−（３−ニトロフェニル）−１，４−
ジヒドロピリジン−３−カルボン酸のイソプロピルエス
テルである特許請求の範囲第（３）項に記載の化合物。(4) 5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-4-(3-nitrophenyl)-1,4-
The compound according to claim (3), which is an isopropyl ester of dihydropyridine-3-carboxylic acid.
チル−４−（３−ニトロフェニル）−１，４−ジヒドロ
ピリジン−３−カルボン酸のイソプロピルエステルであ
る特許請求の範囲第（３）項に記載の化合物。(5) Claim (3) which is isopropyl ester of 6-formyl-5-methoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid Compounds described.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB7839978 | 1978-10-10 | ||
| GB39978/78 | 1978-10-10 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP13053079A Division JPS5562065A (en) | 1978-10-10 | 1979-10-09 | 2-methyldihydropyridine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS61118366A true JPS61118366A (en) | 1986-06-05 |
| JPS6143343B2 JPS6143343B2 (en) | 1986-09-26 |
Family
ID=10500226
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP13053079A Granted JPS5562065A (en) | 1978-10-10 | 1979-10-09 | 2-methyldihydropyridine derivative |
| JP60214152A Granted JPS61118366A (en) | 1978-10-10 | 1985-09-26 | Intermediate of 2-methyldihydropyridine derivative |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP13053079A Granted JPS5562065A (en) | 1978-10-10 | 1979-10-09 | 2-methyldihydropyridine derivative |
Country Status (10)
| Country | Link |
|---|---|
| JP (2) | JPS5562065A (en) |
| BE (1) | BE879263A (en) |
| CA (1) | CA1117117A (en) |
| CH (1) | CH642353A5 (en) |
| DE (1) | DE2940833A1 (en) |
| FR (1) | FR2438654A1 (en) |
| GB (1) | GB2036722B (en) |
| IT (1) | IT1125469B (en) |
| NL (1) | NL7907482A (en) |
| SE (2) | SE446265B (en) |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE7910521L (en) * | 1979-12-20 | 1981-06-21 | Haessle Ab | NEW 2-METHYL-6-SUBSTITUTED-4- (2,3-DISUBSTITUTED PHENYL) -1,4-DIHYDROPYRIDINE-3,5-DIESTERS WITH HYPOTHESIVE PROPERTIES, AND PROCEDURES FOR THEIR PREPARATION AND PHARMACEUTICAL PREPARATION |
| JPS57175164A (en) * | 1981-04-18 | 1982-10-28 | Banyu Pharmaceut Co Ltd | 1,4-dihydropyridine derivative and its preparation |
| DE3269219D1 (en) * | 1981-11-17 | 1986-03-27 | Fisons Plc | Dihydropyridines, methods for their production and their formulation and use as pharmaceuticals |
| ZA83959B (en) * | 1982-03-10 | 1984-09-26 | Sandoz Ltd | 1,4-dihydropyridine derivatives,their preparation and pharmaceutical compositions containing them |
| CH655110A5 (en) * | 1982-09-03 | 1986-03-27 | Otsuka Pharma Co Ltd | CARBOSTYRILE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THEM. |
| DE3312216A1 (en) * | 1983-04-05 | 1984-10-11 | Bayer Ag, 5090 Leverkusen | METHOD FOR PRODUCING SYMMETRIC 1,4-DIHYDROPYRIDINE CARBONIC ACID ESTERS |
| JPS6038322A (en) * | 1983-08-11 | 1985-02-27 | Fujisawa Pharmaceut Co Ltd | Easily soluble solid preparation containing dihydropyridine-a substance |
| GB8412208D0 (en) * | 1984-05-12 | 1984-06-20 | Pfizer Ltd | Quinolone inotropic agents |
| GB8431119D0 (en) * | 1984-12-10 | 1985-01-16 | Fujisawa Pharmaceutical Co | Anti-arteriosclerotic composition |
| GB8602518D0 (en) * | 1986-02-01 | 1986-03-05 | Wyeth John & Brother Ltd | 1 4-dihydropyridines |
| JPS63115890A (en) * | 1986-10-31 | 1988-05-20 | Nippon Shinyaku Co Ltd | 2-substituted 1,4-dihydropyridine derivative |
| US5114946A (en) * | 1987-06-12 | 1992-05-19 | American Cyanamid Company | Transdermal delivery of pharmaceuticals |
| ES2043719T3 (en) * | 1987-06-12 | 1994-01-01 | American Cyanamid Co | DRUG ADMINISTRATION BY VIA PERCUTANEA. |
| US5045553A (en) * | 1987-06-24 | 1991-09-03 | Fujisawa Pharmaceutical Company, Ltd. | Pharmaceutical composition for percutaneous drug absorption and percutaneous drug absorption promoter |
| ATE105476T1 (en) * | 1987-12-29 | 1994-05-15 | Fujisawa Pharmaceutical Co | DIHYDROPYRIDIN COMPOUND TO IMPROVE VENETIC DILONATION AND INHIBIT CARDIAC HYPERTROPHY. |
| DE3888144T2 (en) * | 1987-12-29 | 1994-06-23 | Fujisawa Pharmaceutical Co | Brain neuron protective agent containing a dihydropyridine compound. |
| JP2007230869A (en) * | 2004-04-05 | 2007-09-13 | Takeda Chem Ind Ltd | Aldosterone receptor antagonist |
| CN101987833B (en) * | 2009-08-04 | 2014-07-30 | 北京利乐生制药科技有限公司 | Novel nilvaldipine crystal types and preparation method thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1552911A (en) * | 1975-07-02 | 1979-09-19 | Fujisawa Pharmaceutical Co | 1,4 dihydropyridine derivatives and the preparation thereof |
| GB1591089A (en) * | 1976-12-17 | 1981-06-10 | Fujisawa Pharmaceutical Co | 1,4-dihydropyridine derivatives and process for preparation thereof |
| DE2658183A1 (en) * | 1976-12-22 | 1978-07-06 | Bayer Ag | 2-POSITION SUBSTITUTED 1,4-DIHYDROPYRIDINE DERIVATIVES, PROCESS FOR THEIR PRODUCTION AND THEIR USE AS A MEDICINAL PRODUCT |
-
1979
- 1979-09-21 CA CA000336130A patent/CA1117117A/en not_active Expired
- 1979-10-08 FR FR7925007A patent/FR2438654A1/en active Granted
- 1979-10-08 BE BE0/197526A patent/BE879263A/en not_active IP Right Cessation
- 1979-10-09 GB GB7935022A patent/GB2036722B/en not_active Expired
- 1979-10-09 JP JP13053079A patent/JPS5562065A/en active Granted
- 1979-10-09 NL NL7907482A patent/NL7907482A/en active Search and Examination
- 1979-10-09 SE SE7908367A patent/SE446265B/en not_active IP Right Cessation
- 1979-10-09 IT IT26362/79A patent/IT1125469B/en active Protection Beyond IP Right Term
- 1979-10-09 DE DE19792940833 patent/DE2940833A1/en active Granted
- 1979-10-10 CH CH912879A patent/CH642353A5/en not_active IP Right Cessation
-
1984
- 1984-02-09 SE SE8400689A patent/SE446096B/en not_active IP Right Cessation
-
1985
- 1985-09-26 JP JP60214152A patent/JPS61118366A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| DE2940833A1 (en) | 1980-04-30 |
| JPS6125711B2 (en) | 1986-06-17 |
| FR2438654A1 (en) | 1980-05-09 |
| GB2036722A (en) | 1980-07-02 |
| FR2438654B1 (en) | 1983-01-14 |
| SE7908367L (en) | 1980-04-11 |
| SE8400689L (en) | 1984-02-09 |
| IT7926362A0 (en) | 1979-10-09 |
| BE879263A (en) | 1980-04-08 |
| NL7907482A (en) | 1980-04-14 |
| SE446265B (en) | 1986-08-25 |
| JPS6143343B2 (en) | 1986-09-26 |
| CA1117117A (en) | 1982-01-26 |
| DE2940833C2 (en) | 1989-01-26 |
| IT1125469B (en) | 1986-05-14 |
| SE446096B (en) | 1986-08-11 |
| GB2036722B (en) | 1982-12-01 |
| SE8400689D0 (en) | 1984-02-09 |
| CH642353A5 (en) | 1984-04-13 |
| JPS5562065A (en) | 1980-05-10 |
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