JP3136609B2 - N-cyanoimino heterocyclic compounds - Google Patents
N-cyanoimino heterocyclic compoundsInfo
- Publication number
- JP3136609B2 JP3136609B2 JP04507512A JP50751292A JP3136609B2 JP 3136609 B2 JP3136609 B2 JP 3136609B2 JP 04507512 A JP04507512 A JP 04507512A JP 50751292 A JP50751292 A JP 50751292A JP 3136609 B2 JP3136609 B2 JP 3136609B2
- Authority
- JP
- Japan
- Prior art keywords
- cyanoimino
- compound
- group
- mixture
- nmr
- 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.)
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/18—Nitrogen atoms
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/28—Nitrogen atoms not forming part of a nitro radical
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】 技術分野 本発明は、血管拡張作用を有するＮ−シアノイミノ複
素環式化合物に関する。Description: TECHNICAL FIELD The present invention relates to an N-cyanoimino heterocyclic compound having a vasodilatory effect.
背景技術 従来、血管拡張剤としては、ニトログリセリン、硝酸
イソソルビッド、ジルチアゼム、ベラパミル、ニフェジ
ピン、ニコランジルなどが知られているが、本発明の化
合物に構造が類似するものはない。BACKGROUND ART Conventionally, as vasodilators, nitroglycerin, isosorbide dinitrate, diltiazem, verapamil, nifedipine, nicorandil and the like have been known, but none of the compounds of the present invention have a similar structure.
本発明の目的は、新しいタイプの血管拡張剤を提供す
ることにある。It is an object of the present invention to provide a new type of vasodilator.
発明の開示 本発明は、式 （式中、Ｘは酸素原子または硫黄原子を示し、Ａは炭素
原子数１〜５個のアルキレン基またはニトロオキシ基で
置換された炭素原子数１〜５個のアルキレン基を示
す。）で表されるＮ−シアノイミノ複素環式化合物及び
その塩である。DISCLOSURE OF THE INVENTION (In the formula, X represents an oxygen atom or a sulfur atom, and A represents an alkylene group having 1 to 5 carbon atoms or an alkylene group having 1 to 5 carbon atoms substituted with a nitrooxy group.) N-cyanoimino heterocyclic compounds and salts thereof.
本発明において、炭素原子数１〜５個のアルキレン基
とは、メチレン基、エチレン基、トリメチレン基、１−
メチルエチレン基、２−メチルエチレン基、テトラメチ
レン基、ペンタメチレン基などの直鎖状または分枝鎖状
のものをいう。また、ニトロオキシ基で置換された炭素
原子数１〜５個のアルキレン基とは、前記炭素原子数１
〜５個のアルキレン基の任意の位置に、一つのニトロオ
キシ基が置換しているものをいう。In the present invention, the alkylene group having 1 to 5 carbon atoms means a methylene group, an ethylene group, a trimethylene group,
It refers to a linear or branched one such as a methylethylene group, a 2-methylethylene group, a tetramethylene group, and a pentamethylene group. Further, an alkylene group having 1 to 5 carbon atoms substituted with a nitrooxy group refers to the alkylene group having 1 carbon atom.
It means that one nitrooxy group is substituted at an arbitrary position of ~ 5 alkylene groups.
なお、式（Ｉ）の化合物にはアンチ型，シン型の２種
の幾何異性体が存在するが、本発明においてはアンチ
型，シン型及びそれらの混合物のいずれをも含む。The compound of the formula (I) has two types of geometric isomers, anti-form and syn-form, and the present invention includes both anti-form, syn-form and mixtures thereof.
本発明の式（Ｉ）の化合物は、式 （式中、Ｘは前記と同意義である。）で表される化合物
と式 Ｙ−Ａ−ONO2 （III） （式中、Ａは前記と同意義であり、Ｙはハロゲン原子を
示す。）で表される化合物を、塩基存在下、有機溶媒中
反応させることにより製造することができる。The compounds of formula (I) of the present invention have the formula (Wherein X has the same meaning as described above) and a compound represented by the formula YA-ONO 2 (III) (wherein A has the same meaning as above, and Y represents a halogen atom). ) Can be produced by reacting the compound represented by the formula (1) in an organic solvent in the presence of a base.
ここで、ハロゲン原子とは塩素原子、臭素原子または
ヨウ素原子をいう。また、塩基としては水酸化ナトリウ
ム、水酸化カリウム、炭酸カリウムなどのアルカリ類、
ジメチルアミン、ジエチルアミン、ジイソプロピルアミ
ン、ピロリジン、ピペリジン、ピペラジン、Ｎ−メチル
ピペラジン、モルホリンなどのアミン類、ｎ−ブチルリ
チウム、リチウムジイソプロピルアミドなどの有機金属
類、ナトリウムメトキサイド、ナトリウムエトキサイド
などのアルコラート類及び水素化ナトリウムなどを用い
ることができる。有機溶媒としてはメタノール、エタノ
ール、ジクロルメタン、クロロホルム、N,N−ジメチル
ホルムアミド、テトラヒドロフラン、ジオキサン、ベン
ゼン、トルエンなどを用いることができる。反応温度は
５〜100℃、反応時間は２〜５時間である。Here, the halogen atom means a chlorine atom, a bromine atom or an iodine atom. Further, as the base, alkalis such as sodium hydroxide, potassium hydroxide, potassium carbonate,
Amines such as dimethylamine, diethylamine, diisopropylamine, pyrrolidine, piperidine, piperazine, N-methylpiperazine, and morpholine; organic metals such as n-butyllithium and lithium diisopropylamide; and alcoholates such as sodium methoxide and sodium ethoxide. And sodium hydride. As the organic solvent, methanol, ethanol, dichloromethane, chloroform, N, N-dimethylformamide, tetrahydrofuran, dioxane, benzene, toluene and the like can be used. The reaction temperature is 5 to 100 ° C, and the reaction time is 2 to 5 hours.
このようにして得られた式（Ｉ）の化合物は、必要に
応じて常法により塩酸塩、硝酸塩、ｐ−トルエンスルホ
ン酸塩などにすることができる。The compound of the formula (I) thus obtained can be converted into a hydrochloride, a nitrate, a p-toluenesulfonate or the like by a conventional method, if necessary.
本発明の化合物は、経口的または非経口的に慣用の投
与剤形で投与することができる。剤形としては、錠剤、
カプセル剤、注射剤、軟膏剤、テープ剤などであり、い
ずれも常法により製造することができる。人に対して例
えば抗狭心症剤あるいは抗高血圧症剤として用いる場
合、その投与量は症状、投与経路などによって異なる
が、通常１日当り20〜100mgである。The compounds of the present invention can be administered orally or parenterally in conventional dosage forms. Dosage forms include tablets,
Capsules, injections, ointments, tapes, etc., all of which can be produced by a conventional method. When used for humans, for example, as an antianginal agent or an antihypertensive agent, the dosage varies depending on the condition, administration route and the like, but is usually 20 to 100 mg per day.
発明を実施するための最良の形態 以下、実施例及び参考例を挙げて本発明を更に詳細に
説明する。BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail with reference to Examples and Reference Examples.
実施例１ ２−（Ｎ−シアノイミノ）−３−ニトロオキ
シエチルチアゾリジン（化合物１） Ｎ−シアノイミノチアゾリジン6.35g（0.05モル）及
び２−ニトロオキシエチルブロマイド8.50g（0.05モ
ル）をN,N−ジメチルホルムアミド30mlに溶解し、次い
で炭酸カリウム8.28g（0.06モル）を加え、室温で５時
間撹拌した。反応液に水を加え、ジクロルメタンで抽出
した。抽出液を水洗し、乾燥後、減圧濃縮した。残留物
をシリカゲルカラムクロマトグラフィー（展開溶媒；酢
酸エチル:n−ヘキサン＝1:1）に付し、得られた粗結晶
をメタノール−エーテル混合液から再結晶して標記化合
物11.80gを得た。Example 1 2- (N-cyanoimino) -3-nitrooxyethylthiazolidine (compound 1) 6.35 g (0.05 mol) of N-cyanoiminothiazolidine and 8.50 g (0.05 mol) of 2-nitrooxyethyl bromide were added to N, N- After dissolving in 30 ml of dimethylformamide, 8.28 g (0.06 mol) of potassium carbonate was added, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction solution, and extracted with dichloromethane. The extract was washed with water, dried and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (developing solvent; ethyl acetate: n-hexane = 1: 1), and the obtained crude crystals were recrystallized from a mixture of methanol and ether to give 11.80 g of the title compound.
m.p. 88〜90℃ 1H−NMR（CDCl3,200MHz）δppm; 3.43（2H,t,J＝8Hz）,3.81（2H,t,J＝5Hz）， 4.00（2H,t,J＝8Hz）,4.78（2H,t,J＝5Hz） 上記実施例１において、２−ニトロオキシエチルブロ
マイドの代わりに対応する式（III）の化合物を用い、
実質的に実施例１と同様にして以下の化合物を得た。mp 88-90 ° C. 1 H-NMR (CDCl 3 , 200 MHz) δ ppm; 3.43 (2H, t, J = 8 Hz), 3.81 (2H, t, J = 5 Hz), 4.00 (2H, t, J = 8 Hz), 4.78 (2H, t, J = 5Hz) In Example 1 above, the corresponding compound of formula (III) was used instead of 2-nitrooxyethyl bromide,
The following compounds were obtained substantially in the same manner as in Example 1.
２−（Ｎ−シアノイミノ）−３−ニトロオキシプロピル
チアゾリジン（化合物２） m.p. 30〜32℃（ジクロルメタン−イソプロピルエー
テル，以下、融点の後の括弧内の溶媒は、その溶媒から
再結晶したことを示す。） 1H−NMR（CDCl3,200MHz）δppm; 2.08（2H,m）,3.47（2H,t,J＝8Hz）， 3.58（2H,t,J＝6Hz）,3.96（2H,t,J＝8Hz）， 4.55（2H,t,J＝6Hz） ２−（Ｎ−シアノイミノ）−３−（４−ニトロオキシ−
ｎ−ブチル）チアゾリジン（化合物３） 1H−NMR（CDCl3,200MHz）δppm; 1.79（4H,m）,3.44（2H,t,J＝8Hz）， 3.52（2H,t,J＝5Hz）,3.92（2H,t,J＝8Hz）， 4.53（2H,t,J＝5Hz） ２−（Ｎ−シアノイミノ）−３−（２−ニトロオキシプ
ロピル）チアゾリジン m.p. 125〜127℃（メタノール−ジエチルエーテル） 1H−NMR（DMSO−d6,200MHz）δppm; 1.31（3H,d,J＝6Hz）,3.49（2H,t,J＝8Hz）， 3.72（2H,m）,3.98（2H,m）,5.39（1H,m） ２−（Ｎ−シアノイミノ）−３−（2,3−ジニトロオキ
シプロピル）チアゾリジン m.p. 122〜124℃（ジクロルメタン−ジエチルエーテ
ル） 1H−NMR（CDCl3,200MHz）δppm; 3.46（2H,t,J＝6Hz）， 3.73（1H,dd,J＝14Hz,8Hz）， 3.88（1H,dd,J＝14Hz,5Hz）， 4.01（2H,t,J＝6Hz）， 4.55（1H,dd,J＝12Hz,5Hz） 4.95（1H,dd,J＝12Hz,4Hz）,5.55（1H,m） 実施例２ ２−（Ｎ−シアノイミノ）−３−ニトロオキ
シエチルオキサゾリジン（化合物４） N,N−ジメチルホルムアミド20mlに、室温で窒素気流
下、水素化ナトリウム1.32g（0.055モル）を加え30分間
撹拌した後、同温度でN,N−ジメチルホルムアミド10ml
に溶解したＮ−シアノイミノオキサゾリジン5.56g（0.0
5モル）を滴下したあと、さらに１時間撹拌した。この
溶液に２−ニトロオキシエチルブロマイド8.50g（0.05
モル）を滴下後、さらに同温度で５時間撹拌した。反応
液に水を加え、ジクロルメタンで抽出した。抽出液を水
洗し、乾燥後、減圧濃縮した。残留物をシリカゲルカラ
ムクロマトグラフィー（展開溶媒；酢酸エチル:n−ヘキ
サン＝1:1）に対し、得られた粗結晶をジクロルメタン
−イソプロピルエーテル混合液から再結晶して標記化合
物3.20gを得た。2- (N-cyanoimino) -3-nitrooxypropylthiazolidine (compound 2) mp 30-32 ° C. (dichloromethane-isopropyl ether; hereinafter, the solvent in parentheses after the melting point indicates that it was recrystallized from the solvent. .) 1 H-NMR (CDCl 3, 200MHz) δppm; 2.08 (2H, m), 3.47 (2H, t, J = 8Hz), 3.58 (2H, t, J = 6Hz), 3.96 (2H, t, J = 8 Hz), 4.55 (2H, t, J = 6 Hz) 2- (N-cyanoimino) -3- (4-nitrooxy-
n-butyl) thiazolidine (compound 3) 1 H-NMR (CDCl 3 , 200 MHz) δ ppm; 1.79 (4H, m), 3.44 (2H, t, J = 8 Hz), 3.52 (2H, t, J = 5 Hz), 3.92 (2H, t, J = 8Hz), 4.53 (2H, t, J = 5Hz) 2- (N-cyanoimino) -3- (2-nitrooxypropyl) thiazolidine mp 125-127 ° C (methanol-diethyl ether) 1 H-NMR (DMSO-d 6, 200MHz) δppm; 1.31 (3H, d, J = 6Hz), 3.49 (2H, t, J = 8Hz), 3.72 (2H, m), 3.98 (2H, m), 5.39 (1H, m) 2- ( N- cyanoimino) -3- (2,3-dinitrophenyl propyl) thiazolidine mp 122 to 124 ° C. (dichloromethane - diethyl ether) 1 H-NMR (CDCl 3 , 200MHz) δppm; 3.46 (2H, t, J = 6Hz), 3.73 (1H, dd, J = 14Hz, 8Hz), 3.88 (1H, dd, J = 14Hz, 5Hz), 4.01 (2H, t, J = 6Hz), 4.55 (1H , dd, J = 12Hz, 5Hz) 4.95 (1H, dd, J = 12Hz, 4Hz), 5.55 (1H, m) Example 2 2- (N-cyanoimino) -3-nitrooxyethylo Xazolidine (compound 4) 1.32 g (0.055 mol) of sodium hydride was added to 20 ml of N, N-dimethylformamide at room temperature under a nitrogen stream, and the mixture was stirred for 30 minutes, and then 10 ml of N, N-dimethylformamide at the same temperature.
5.56 g of N-cyanoiminooxazolidine dissolved in
5 mol), and the mixture was further stirred for 1 hour. 8.50 g (0.05 g) of 2-nitrooxyethyl bromide was added to this solution.
Mol), and the mixture was further stirred at the same temperature for 5 hours. Water was added to the reaction solution, and extracted with dichloromethane. The extract was washed with water, dried and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (developing solvent; ethyl acetate: n-hexane = 1: 1) to recrystallize the obtained crude crystals from a mixture of dichloromethane and isopropyl ether to obtain 3.20 g of the title compound.
m.p. 86〜88℃ 1H−NMR（CDCl3,200MHz）δppm; 3.73（2H,t,J＝5Hz）,3.91（2H,t,J＝8Hz）， 4.68（2H,t,J＝8Hz）,4.70（2H,t,J＝5Hz） 上記実施例２において、２−ニトロオキシエチルブロ
マイドの代わりに対応する式（III）の化合物を用い、
実質的に実施例２と同様にして以下の化合物を得た。mp 86-88 ° C 1 H-NMR (CDCl 3 , 200 MHz) δ ppm; 3.73 (2H, t, J = 5 Hz), 3.91 (2H, t, J = 8 Hz), 4.68 (2H, t, J = 8 Hz), 4.70 (2H, t, J = 5Hz) In Example 2 above, the corresponding compound of formula (III) was used in place of 2-nitrooxyethyl bromide,
The following compounds were obtained substantially in the same manner as in Example 2.
２−（Ｎ−シアノイミノ）−３−ニトロオキシプロピル
オキサゾリジン（化合物５） m.p. 72〜74℃（ジクロルメタン−ジエチルエーテ
ル） 1H−NMR（CDCl3,200MHz）δppm; 2.09（2H,m）,3.49（2H,t,J＝5Hz）， 3.82（2H,t,J＝8Hz）,4.56（2H,t,J＝5Hz）， 4.66（2H,t,J＝8Hz） ２−（Ｎ−シアノイミノ）−３−（４−ニトロオキシ−
ｎ−ブチルオキサゾリジン（化合物６） 1H−NMR（CDCl3,200MHz）δppm; 1.77（4H,m）,3.40（2H,t,J＝5Hz）， 3.80（2H,t,J＝8Hz）,4.53（2H,t,J＝5Hz）， 4.64（2H,t,J＝8Hz） 参考例１ Ｎ−シアノイミノチアゾリジン エタノール500mlに、S,S′−ジメチルＮ−シアノジチ
オイミノカルボネート146.24g（１モル）及び２−アミ
ノエタンチオール77.15g（１モル）を加え、３時間撹拌
下、加熱還流した。反応終了後、室温まで冷却し、析出
した結晶を過した。得られた結晶をエタノールで洗浄
後、乾燥して標記化合物85.25gを得た。2- (N-cyanoimino) -3-nitrooxypropyloxazolidine (compound 5) mp 72-74 ° C (dichloromethane-diethyl ether) 1 H-NMR (CDCl 3 , 200 MHz) δ ppm; 2.09 (2H, m), 3.49 ( 2H, t, J = 5Hz), 3.82 (2H, t, J = 8Hz), 4.56 (2H, t, J = 5Hz), 4.66 (2H, t, J = 8Hz) 2- (N-cyanoimino) -3 -(4-nitrooxy-
n-Butyloxazolidine (compound 6) 1 H-NMR (CDCl 3 , 200 MHz) δ ppm; 1.77 (4H, m), 3.40 (2H, t, J = 5 Hz), 3.80 (2H, t, J = 8 Hz), 4.53 (2H, t, J = 5Hz), 4.64 (2H, t, J = 8Hz) Reference Example 1 N-cyanoiminothiazolidine In 500 ml of ethanol, 146.24 g (1 mol) of S, S'-dimethyl N-cyanodithioiminocarbonate ) And 77.15 g (1 mol) of 2-aminoethanethiol were added, and the mixture was heated under reflux with stirring for 3 hours. After completion of the reaction, the mixture was cooled to room temperature, and the precipitated crystals were collected. The obtained crystals were washed with ethanol and dried to obtain 85.25 g of the title compound.
m.p. 156.3〜156.9℃ 1H−NMR（DMSO−d6,200MHz）δppm; 3.36（1H,br.s）,3.56（2H,t,J＝6Hz）， 3.79（2H,t,J＝6Hz） 参考例２ Ｎ−シアノイミノオキサゾリジン エタノール500mlに、S,S′−ジメチルＮ−シアノジチ
オイミノカルボネート146.24g（１モル）及び２−アミ
ノエタノール61.08g（１モル）を加え、３時間撹拌下、
加熱還流した。反応終了後、室温まで冷却し、析出した
結晶を過した。得られた結晶をエーテルで洗浄後、乾
燥して標記化合物72.35gを得た。mp 156.3 to 156.9 ° C 1 H-NMR (DMSO-d 6 , 200 MHz) δppm; 3.36 (1H, br.s), 3.56 (2H, t, J = 6 Hz), 3.79 (2H, t, J = 6 Hz) Reference Example 2 N-cyanoiminooxazolidine To 500 ml of ethanol, 146.24 g (1 mol) of S, S'-dimethyl N-cyanodithioiminocarbonate and 61.08 g (1 mol) of 2-aminoethanol were added, and the mixture was stirred for 3 hours.
Heated to reflux. After completion of the reaction, the mixture was cooled to room temperature, and the precipitated crystals were collected. The obtained crystals were washed with ether and dried to obtain 72.35 g of the title compound.
m.p. 112.0〜113.3℃ 1H−NMR（DMSO−d6,200MHz）δppm; 3.38（1H,br.s）,3.70（2H,t,J＝8Hz）， 4.64（2H,t,J＝8Hz） 産業上の利用可能性 本発明の化合物は強い血管拡張作用を示し、また、持
続性がよく、さらには吸収性もよいため、抗狭心症剤あ
るいは抗高血圧症剤として有用である。mp 112.0-113.3 ° C 1 H-NMR (DMSO-d 6 , 200 MHz) δppm; 3.38 (1H, br.s), 3.70 (2H, t, J = 8 Hz), 4.64 (2H, t, J = 8 Hz) The compounds of the present invention exhibit a strong vasodilatory effect, have a long-lasting effect, and have a good absorbability, and thus are useful as antianginal or antihypertensive agents.
以下、本発明化合物の効果を試験例により説明する。 Hereinafter, the effects of the compound of the present invention will be described with reference to Test Examples.
試験例［血管拡張作用試験］ N.Miyataら［ジェネラル・ファーマコロジー（Gen.Ph
armac.），第21巻，第５号，第665〜669ページ（1990
年）］の方法に準じて以下の試験を行った。Test example [Vasodilation test] N. Miyata et al. [General Pharmacology (Gen. Ph.
armac.), Vol. 21, No. 5, pp. 665-669 (1990)
Year)], the following test was conducted.
雄性ウィスター系ラット（体重250〜400g）を１群３
〜４匹として試験に供した。このラットから胸部大動脈
を摘出後、摘出した血管に付着した脂肪組織を除去し、
２〜3mm×20mmのラセン状片を作成し、95％酸素と５％
二酸化炭素の混合ガスを通気した37℃のKrebs−Hensele
it液（KH液）5mlを含む栄養槽に1gの負荷をかけて懸垂
固定した。20〜30分毎にKH液を交換して60〜90分間放置
し、標本を安定させた。なお、KH液の組成（mM）は以下
の通りである。Male Wistar rats (body weight 250-400g), 3 per group
Tested as ~ 4 animals. After removing the thoracic aorta from this rat, remove the adipose tissue attached to the removed blood vessels,
Make a helical piece of 2-3mm x 20mm, 95% oxygen and 5%
Krebs-Hensele at 37 ° C with a gas mixture of carbon dioxide aerated
A 1 g load was applied to a nutrient tank containing 5 ml of the it solution (KH solution) for suspension and fixation. The KH solution was changed every 20 to 30 minutes and left for 60 to 90 minutes to stabilize the specimen. The composition (mM) of the KH solution is as follows.
NaCl 118.0,KCl 4.7,NaHCO3 25.0,CaCl2 1.8,NaH
2PO4 1.2,MgSO4 1.2,dextrose 11.0 ラセン状にしたラット大動脈が懸垂されている栄養槽
内に血管収縮作用を有する化合物として知られているノ
ルエピネフリンを10-7MまたはプロスタグランジンＦ
２αを10-6Mの濃度になるように加えた。この後、試料
（本発明化合物及び比較としてニコランジル）をジメチ
ルスルホキシドに溶解し、前記溶液中に10-6Mの濃度と
なるように加え、ノルエピネフリンまたはプロスタグラ
ンジンＦ２αによる血管収縮の抑制作用を調べた。収縮
力はFDピックアップ（TB−612T,日本光電）を用いてひ
ずみ圧力用アンプ（AP−621G,日本光電）に導き、等尺
性に測定した。NaCl 118.0, KCl 4.7, NaHCO 3 25.0, CaCl 2 1.8, NaH
2 PO 4 1.2, MgSO 4 1.2, dextrose 11.0 Norepinephrine known as a compound having a vasoconstrictor action in a nutrient tank in which a spiral rat aorta is suspended is 10 -7 M or prostaglandin F
2α was added to a concentration of 10 −6 M. Thereafter, a sample (compound of the present invention and nicorandil for comparison) is dissolved in dimethyl sulfoxide, and added to the solution to a concentration of 10 −6 M to inhibit the action of norepinephrine or prostaglandin F 2α to suppress vasoconstriction. Examined. The contraction force was guided to a strain pressure amplifier (AP-621G, Nihon Kohden) using an FD pickup (TB-612T, Nihon Kohden) and measured isometrically.
この結果を収縮抑制率で示し、表１にまとめた。 The results are shown as shrinkage suppression rates and are summarized in Table 1.
───────────────────────────────────────────────────── フロントページの続き (72)発明者 畑山 勝男 埼玉県大宮市堀崎町1200−215 (56)参考文献 特開 昭50−103326（ＪＰ，Ａ) 特公 昭48−32657（ＪＰ，Ｂ１) (58)調査した分野(Int.Cl.7，ＤＢ名) C07D 263/28 C07D 277/18 ──────────────────────────────────────────────────続 き Continuation of the front page (72) Katsuo Hatayama, Inventor 1200-215 Horisaki-cho, Omiya-shi, Saitama (56) References JP-A-50-103326 (JP, A) JP-48-32657 (JP, B1) (58) Field surveyed (Int. Cl. 7 , DB name) C07D 263/28 C07D 277/18
Claims (1)
原子数１〜５個のアルキレン基またはニトロオキシ基で
置換された炭素原子数１〜５個のアルキレン基を示
す。）で表されるＮ−シアノイミノ複素環式化合物及び
その塩。(1) Expression (In the formula, X represents an oxygen atom or a sulfur atom, and A represents an alkylene group having 1 to 5 carbon atoms or an alkylene group having 1 to 5 carbon atoms substituted with a nitrooxy group.) N-cyanoimino heterocyclic compounds and salts thereof.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3-154214 | 1991-04-04 | ||
| JP15421491 | 1991-04-04 | ||
| PCT/JP1992/000412 WO1992017462A1 (en) | 1991-04-04 | 1992-04-03 | N-cyanoimino heterocyclic compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JP3136609B2 true JP3136609B2 (en) | 2001-02-19 |
Family
ID=15579339
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP04507512A Expired - Fee Related JP3136609B2 (en) | 1991-04-04 | 1992-04-03 | N-cyanoimino heterocyclic compounds |
Country Status (2)
| Country | Link |
|---|---|
| JP (1) | JP3136609B2 (en) |
| WO (1) | WO1992017462A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102418451B (en) * | 2011-12-27 | 2013-06-19 | 马维理 | Ancient book essence storage cabinet |
| KR102612166B1 (en) * | 2022-05-02 | 2023-12-11 | (주)금상 | Guard for cargo protection of trucks |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4427539A1 (en) * | 1994-08-04 | 1996-02-08 | Sueddeutsche Kalkstickstoff | 2-cyano:imino-thiazolidine prodn. from 2-aminoethane thiol |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1963193A1 (en) * | 1969-12-17 | 1971-06-24 | Bayer Ag | N-substituted 2-arylimino-oxazolidines, process for their preparation and their use as ectoparasiticides |
| JPS5540855B2 (en) * | 1974-01-14 | 1980-10-21 |
-
1992
- 1992-04-03 JP JP04507512A patent/JP3136609B2/en not_active Expired - Fee Related
- 1992-04-03 WO PCT/JP1992/000412 patent/WO1992017462A1/en active Application Filing
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102418451B (en) * | 2011-12-27 | 2013-06-19 | 马维理 | Ancient book essence storage cabinet |
| KR102612166B1 (en) * | 2022-05-02 | 2023-12-11 | (주)금상 | Guard for cargo protection of trucks |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1992017462A1 (en) | 1992-10-15 |
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