JPH06192229A - 3,4-dihydrocarbostyril derivative - Google Patents
3,4-dihydrocarbostyril derivativeInfo
- Publication number
- JPH06192229A JPH06192229A JP36203592A JP36203592A JPH06192229A JP H06192229 A JPH06192229 A JP H06192229A JP 36203592 A JP36203592 A JP 36203592A JP 36203592 A JP36203592 A JP 36203592A JP H06192229 A JPH06192229 A JP H06192229A
- Authority
- JP
- Japan
- Prior art keywords
- dihydrocarbostyril
- formula
- compound
- nitro
- morpholino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Quinoline Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は医薬品として有用な３，
４−ジヒドロカルボスチリル誘導体に関するものであ
る。INDUSTRIAL APPLICABILITY The present invention is useful as a pharmaceutical product3.
It relates to 4-dihydrocarbostyryl derivatives.
【０００２】さらに詳しく述べれば、本発明は血小板凝
集抑制作用を有し、抗血小板剤等として有用な、一般式More specifically, the present invention has a general formula which has an inhibitory effect on platelet aggregation and is useful as an antiplatelet agent and the like.
【０００３】[0003]
【化２】 [Chemical 2]
【０００４】（式中のＲ１およびＲ２はどちらか一方が
ニトロ基であり、他方は水素原子であり、Ｚはスルホニ
ル基、スルフィニル基、硫黄原子または酸素原子であ
る）で表される３，４−ジヒドロカルボスチリル誘導体
およびその薬理学的に許容される塩に関するものであ
る。(In the formula, one of R 1 and R 2 is a nitro group, the other is a hydrogen atom, and Z is a sulfonyl group, a sulfinyl group, a sulfur atom or an oxygen atom). , 4-dihydrocarbostyril derivatives and pharmaceutically acceptable salts thereof.
【０００５】[0005]
【従来の技術】本発明の前記一般式（Ｉ）で表される
３，４−ジヒドロカルボスチリル誘導体のような化合物
として、式BACKGROUND OF THE INVENTION As a compound such as the 3,4-dihydrocarbostyryl derivative represented by the general formula (I) of the present invention, a compound of the formula
【０００６】[0006]
【化３】 [Chemical 3]
【０００７】で表される化合物が製造されており、強心
剤の製造中間体として有用である旨記載されているが、
それ自体の薬理作用については何ら報告されていない
（特開昭５７−７７６７６号）。It is described that the compound represented by the formula (3) is produced and is useful as an intermediate for the production of cardiotonic agents.
No report has been made on its own pharmacological action (JP-A-57-77676).
【０００８】[0008]
【発明が解決しようとする課題】本発明の目的は、血小
板凝集抑制作用を有し、抗血小板剤等として有用な３，
４−ジヒドロカルボスチリル誘導体を提供することであ
る。DISCLOSURE OF THE INVENTION The object of the present invention is to have an inhibitory effect on platelet aggregation and to be useful as an antiplatelet agent, etc.
It is to provide a 4-dihydrocarbostyril derivative.
【０００９】[0009]
【課題を解決するための手段】本発明者らは、抗血小板
剤等として有用な化合物を見出すべく鋭意研究した結
果、前記一般式（Ｉ）で表されるある種の３，４−ジヒ
ドロカルボスチリル誘導体が、強力な血小板凝集抑制作
用を発揮するという知見を得、本発明を成すに至った。Means for Solving the Problems As a result of intensive studies to find compounds useful as antiplatelet agents and the like, the present inventors have found that certain 3,4-dihydrocarbohydrates represented by the above general formula (I) are used. The present invention has been completed based on the finding that a styryl derivative exerts a strong inhibitory effect on platelet aggregation.
【００１０】本発明の一般式（Ｉ）で表される３，４−
ジヒドロカルボスチリル誘導体は新規な化合物であり、
以下のようにして製造することができる。すなわち、一
般式3,4-represented by the general formula (I) of the present invention
Dihydrocarbostyril derivatives are novel compounds,
It can be manufactured as follows. That is, the general formula
【００１１】[0011]
【化４】 [Chemical 4]
【００１２】（式中のＹは酸素原子または硫黄原子であ
る）で表される３，４−ジヒドロカルボスチリル誘導体
を、発煙硝酸、濃硝酸、亜硝酸ナトリウム、亜硝酸カリ
ウム、硝酸ナトリウムまたは硝酸カリウム等のニトロ化
剤を用いて、無溶媒または酢酸、トリフルオロ酢酸、塩
酸、硫酸等の溶媒中で反応させたのち、必要に応じてメ
タクロロ過安息香酸、過酸化水素等で処理することによ
り製造することができる。A 3,4-dihydrocarbostyryl derivative represented by the formula (Y is an oxygen atom or a sulfur atom) is prepared from fuming nitric acid, concentrated nitric acid, sodium nitrite, potassium nitrite, sodium nitrate or potassium nitrate. Producing by reacting with a nitrating agent without solvent or in a solvent such as acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, and then treating with metachloroperbenzoic acid, hydrogen peroxide, etc. if necessary. You can
【００１３】上記製造方法において出発原料として用い
られる前記一般式（ＩＩ）で表される３，４−ジヒドロ
カルボスチリル誘導体は、以下の方法により得ることが
できる。つまり、一般式The 3,4-dihydrocarbostyryl derivative represented by the general formula (II) used as a starting material in the above production method can be obtained by the following method. That is, the general formula
【００１４】[0014]
【化５】 [Chemical 5]
【００１５】（式中のＸはハロゲン原子であり、Ｒ３お
よびＲ４は低級アルキル基または両者が結合して低級ア
ルキレン基を形成する）で表されるアセタール誘導体
を、モルホリンまたはチオモルホリンとトリエチルアミ
ン、ピリジン、１，８−ジアザビシクロ〔５，４，０〕
−７−ウンデセン、１，５−ジアザビシクロ〔４，３，
０〕−５−ノネン等の塩基の存在下または過剰の原料を
用いて、Ｎ，Ｎ−ジメチルホルムアミドやリン酸ヘキサ
メチルトリアミド等の不活性溶媒中または無溶媒で反応
させることにより、一般式(X in the formula is a halogen atom, R 3 and R 4 are lower alkyl groups or both are combined to form a lower alkylene group), and an acetal derivative represented by morpholine or thiomorpholine and triethylamine is used. , Pyridine, 1,8-diazabicyclo [5,4,0]
-7-Undecene, 1,5-diazabicyclo [4,3,
[0] -5-Nonene or the like in the presence or excess of a raw material, by reacting in an inert solvent such as N, N-dimethylformamide or hexamethyltriamide phosphate with or without a solvent, a compound of the general formula
【００１６】[0016]
【化６】 [Chemical 6]
【００１７】（式中のＹ、Ｒ３およびＲ４は前記と同じ
意昧をもつ）で表されるアセタール誘導体とし、塩酸ま
たは硫酸等の鉱酸を用いて含水アルコールまたは含水ア
セトン中でホルミル基の保護基を除去し、次いで、一般
式An acetal derivative represented by the formula (Y, R 3 and R 4 have the same meanings as described above), and a formyl group in hydrous alcohol or hydrous acetone using a mineral acid such as hydrochloric acid or sulfuric acid. The protecting group of
【００１８】[0018]
【化７】 [Chemical 7]
【００１９】（式中のＲ５は水素原子またはアルキル基
であり、Ｒ６は水素原子またはアルカリ金属である）で
表されるマロン酸誘導体と、ピペリジン、ピロリジン等
の塩基の存在下、ピリジン、酢酸、エタノール等の溶媒
中で脱水縮合させることにより製した、一般式、(Wherein R 5 is a hydrogen atom or an alkyl group, and R 6 is a hydrogen atom or an alkali metal), and a pyridine in the presence of a base such as piperidine or pyrrolidine. Made by dehydration condensation in a solvent such as acetic acid, ethanol, the general formula,
【００２０】[0020]
【化８】 [Chemical 8]
【００２１】（式中のＹおよびＲ５は前記と同じ意味を
もつ）で表されるケイ皮酸誘導体を、例えば、パラジウ
ム炭素等のパラジウム系触媒、酸化白金等の白金触媒ま
たはラネーニッケル等のニッケル触媒を用いて、メタノ
ール、エタノール、酢酸、テトラヒドロフラン等の溶媒
中で還元し、さらに、必要に応じて水素化ホウ素ナトリ
ウム等の還元剤を用いてメタノール、エタノール、酢
酸、テトラヒドロフラン等の溶媒中処理することにより
製造することができる。A cinnamic acid derivative represented by the formula (Y and R 5 have the same meanings as described above) is prepared, for example, by a palladium-based catalyst such as palladium carbon, a platinum catalyst such as platinum oxide, or a nickel such as Raney nickel. Reduce with a catalyst in a solvent such as methanol, ethanol, acetic acid, tetrahydrofuran, etc., and further, if necessary, treat with a reducing agent such as sodium borohydride in a solvent such as methanol, ethanol, acetic acid, tetrahydrofuran, etc. It can be manufactured.
【００２２】また、文献記載の方法またはそれと類似の
方法によっても製造することができる（特開昭５７−７
７６７６号）。It can also be produced by the method described in the literature or a method similar thereto (JP-A-57-7).
7676).
【００２３】本発明の前記一般式（Ｉ）で表される３，
４−ジヒドロカルボスチリル誘導体は常法に従い、薬理
学的に許容される塩とすることができる。例えば、塩酸
塩、臭化水素酸塩、硫酸塩、メタンスルホン酸塩、ベン
ゼンスルホン酸塩、ｐ−トルエンスルホン酸塩、酢酸
塩、クエン酸塩、コハク酸塩、酒石酸塩、フマル酸塩等
の酸付加塩とすることができる。これらの薬理学的に許
容される塩も血小板凝集抑制作用を示し、抗血小板剤等
として有用である。The compound represented by the general formula (I) of the present invention 3,
The 4-dihydrocarbostyryl derivative can be converted into a pharmacologically acceptable salt according to a conventional method. For example, hydrochloride, hydrobromide, sulfate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, acetate, citrate, succinate, tartrate, fumarate, etc. It can be an acid addition salt. These pharmacologically acceptable salts also exhibit a platelet aggregation inhibitory action and are useful as antiplatelet agents and the like.
【００２４】本発明の前記一般式（Ｉ）で表される３，
４−ジヒドロカルボスチリル誘導体およびその塩を実際
の治療に用いる場合、適当な医薬品組成物、例えば、錠
剤、散剤、顆粒剤、カプセル剤、注射剤などとして経口
的あるいは非経口的に投与される。これらの医薬品組成
物は一般の調剤において行われる製剤学的方法により調
整することができる。3, which is represented by the general formula (I) of the present invention.
When the 4-dihydrocarbostyril derivative and its salt are used for actual treatment, they are orally or parenterally administered as a suitable pharmaceutical composition such as tablets, powders, granules, capsules and injections. These pharmaceutical compositions can be prepared by a pharmaceutical method performed in a general preparation.
【００２５】その投与量は対象となる患者の性別、年
齢、体重、症状の度合などによって適宜決定されるが、
経口投与の場合、概ね成人１日当たり１０〜１０００ｍ
ｇ、非経口投与の場合、概ね成人１日当たり１〜１００
ｍｇの範囲内で投与される。The dose is appropriately determined according to the sex, age, weight, degree of symptoms, etc. of the subject patient.
In the case of oral administration, about 10 to 1000 m per day for an adult
g, in the case of parenteral administration, it is generally 1 to 100 per adult per day
It is administered within the range of mg.
【００２６】[0026]
【実施例】本発明の内容を以下の実施例および参考例で
さらに詳細に説明する。なお、各実施例および参考例中
の化合物の融点はすべで未補正である。The contents of the present invention will be described in more detail with reference to the following examples and reference examples. The melting points of the compounds in the examples and reference examples are all uncorrected.
【００２７】参考例 １ ５−モルホリノ−２−ニトロベンズアルデヒド ジメチ
ルアセタール ５−クロロ−２−ニトロベンズアルデヒド ジメチルア
セタール１．０ｇとモルホリン０．３８ｍ１を１，８−
ジアザビシクロ〔５．４．０〕−７−ウンデセン０．６
４ｍｌに溶解し、１００℃で３時間加熱撹拌した。反応
終了後、水を加え酢酸エチルで抽出した。水洗の後、硫
酸マグネシウムで乾燥し溶媒を減圧留去した。残渣をシ
リカゲルカラムクロマトグラフィーにて精製し、５−モ
ルホリノ−２−ニトロベンズアルデヒドジメチルアセタ
ール１．０ｇを得た。Reference Example 1 5-morpholino-2-nitrobenzaldehyde dimethyl acetal 5-chloro-2-nitrobenzaldehyde dimethyl acetal 1.0 g and morpholine 0.38 ml 1,8-
Diazabicyclo [5.4.0] -7-undecene 0.6
It was dissolved in 4 ml and heated with stirring at 100 ° C. for 3 hours. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. After washing with water, it was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.0 g of 5-morpholino-2-nitrobenzaldehyde dimethyl acetal.
【００２８】形 状：黄色油状物 ＮＭＲ（ＣＤＣｌ３，２７０ＭＨｚ） δ： ３．３０〜３．４２（４Ｈ，ｍ），３．４６（６
Ｈ，ｓ），３．８２〜３．９０（４Ｈ，ｍ），６．０７
（１Ｈ，ｓ），６．７８（１Ｈ，ｄｄ，Ｊ＝８．９Ｈ
ｚ，Ｊ＝３．０Ｈｚ），７．２１（１Ｈ，ｄ，Ｊ＝３．
０ＨＺ），８．０２（１Ｈ，ｄ，Ｊ＝９．０Ｈｚ）Form: Yellow oily matter NMR (CDCl 3 , 270 MHz) δ: 3.30 to 3.42 (4H, m), 3.46 (6)
H, s), 3.82 to 3.90 (4H, m), 6.07.
(1H, s), 6.78 (1H, dd, J = 8.9H
z, J = 3.0 Hz), 7.21 (1H, d, J = 3.
0HZ), 8.02 (1H, d, J = 9.0Hz)
【００２９】参考例 ２ ５−モルホリノ−２−ニトロベンズアルデヒド ５−モルホリノ−２−ニトロベンズアルデヒド ジメチ
ルアセタール５４０ｍｇをアセトン２０ｍｌに溶解し、
２Ｎ−塩酸５ｍｌを加え１時間加熱還流した。反応終了
後、水を加え酢酸エチルで抽出した。水洗の後、硫酸マ
グネシウムで乾燥し溶媒を減圧留去し、５−モルホリノ
−２−ニトロベンズアルデヒド３６８ｍｇを得た。Reference Example 2 5-morpholino-2-nitrobenzaldehyde 5-morpholino-2-nitrobenzaldehyde 540 mg of dimethyl acetal was dissolved in 20 ml of acetone,
5 ml of 2N hydrochloric acid was added, and the mixture was heated under reflux for 1 hour. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. After washing with water, it was dried over magnesium sulfate and the solvent was distilled off under reduced pressure to obtain 368 mg of 5-morpholino-2-nitrobenzaldehyde.
【００３０】形 状：黄色針状晶 ＮＭＲ（ＣＤＣｌ３，２７０ＭＨｚ） δ： ３．４２（４Ｈ，ｄｄ，Ｊ＝５．０Ｈｚ，Ｊ＝
４．５Ｈｚ），３．８７（４Ｈ，ｄｄ，Ｊ＝５．０Ｈ
ｚ，Ｊ＝４．９Ｈｚ），６．９６（１Ｈ，ｄｄ，Ｊ＝
９．０Ｈｚ，Ｊ＝３．０Ｈｚ），７．１７（１Ｈ，ｄ，
Ｊ＝３．０Ｈｚ），８．１３（１Ｈ，ｄ，Ｊ＝９．０Ｈ
ｚ），１０．５３（１Ｈ，ｓ） 融 点： １６７〜１６８℃Shape: Yellow needle crystal NMR (CDCl 3 , 270 MHz) δ: 3.42 (4H, dd, J = 5.0 Hz, J =)
4.5Hz), 3.87 (4H, dd, J = 5.0H
z, J = 4.9 Hz), 6.96 (1H, dd, J =
9.0 Hz, J = 3.0 Hz), 7.17 (1H, d,
J = 3.0 Hz), 8.13 (1H, d, J = 9.0H)
z), 10.53 (1H, s) Melting point: 167 to 168 ° C
【００３１】参考例 ３ ５−モルホリノ−２−ニトロケイ皮酸 ５−モルホリノ−２−ニトロベンズアルデヒド３５０ｍ
ｇとピペリジン０．１８ｍｌをピリジン１０ｍｌに加え
加熱し、マロン酸２１６ｍｇを加えさらに３０分加熱還
流した。反応終了後、溶媒を減圧留去し、塩酸酸性条件
下で生じた析出物をろ取した。これを水洗した後、減圧
下で乾燥し、５−モルホリノ−２−ニトロケイ皮酸２０
５ｍｇを得た。Reference Example 3 5-morpholino-2-nitrocinnamic acid 5-morpholino-2-nitrobenzaldehyde 350 m
g and 0.18 ml of piperidine were added to 10 ml of pyridine and heated, 216 mg of malonic acid was added, and the mixture was heated under reflux for 30 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitate formed under acidic conditions of hydrochloric acid was collected by filtration. This is washed with water and then dried under reduced pressure to give 5-morpholino-2-nitrocinnamic acid 20.
5 mg was obtained.
【００３２】形 状：黄色粉末 ＮＭＲ（ＤＭＳＯ−ｄ６，２７０ＭＨｚ） δ： ３．４０〜３．５０（４Ｈ，ｍ），３．６５〜
３．８０（４Ｈ，ｍ），６．４７（１Ｈ，ｄ，Ｊ＝１６
Ｈｚ），７．０５〜７．１５（２Ｈ，ｍ），８．００〜
８．１５（２Ｈ，ｍ），１２．６２（１Ｈ，ｂｒｓ） 融 点： ２５６〜２６０℃ （分解）Form: yellow powder NMR (DMSO-d 6 , 270 MHz) δ: 3.40 to 3.50 (4H, m), 3.65
3.80 (4H, m), 6.47 (1H, d, J = 16
Hz), 7.05 to 7.15 (2H, m), 8.00
8.15 (2H, m), 12.62 (1H, brs) Melting point: 256-260 ° C (decomposition)
【００３３】参考例 ４ ６−モルホリノ−３，４−ジヒドロカルボスチリル ５−モルホリノ−２−ニトロケイ皮酸１９０ｍｇ、５％
パラジウムカーボン粉末８０ｍｇを酢酸４ｍｌとメタノ
ール４０ｍ１の混液に懸濁し、水素気流中室温で２時間
撹拌した。反応終了後、５％パラジウムカーボン粉末を
ろ取し、ろ液を減圧留去した。残渣をシリカゲルカラム
クロマトグラフィーにて精製し、６−モルホリノ−３，
４−ジヒドロカルボスチリル１３３ｍｇを得た。Reference Example 4 6-morpholino-3,4-dihydrocarbostyril 5-morpholino-2-nitrocinnamic acid 190 mg, 5%
80 mg of palladium carbon powder was suspended in a mixed solution of 4 ml of acetic acid and 40 ml of methanol, and stirred in a hydrogen stream at room temperature for 2 hours. After completion of the reaction, 5% palladium carbon powder was collected by filtration, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give 6-morpholino-3,
133 mg of 4-dihydrocarbostyril was obtained.
【００３４】形 状：無色針状晶 ＮＭＲ（ＣＤＣｌ３，２７０ＭＨｚ） δ： ２．５５〜２，７０（２Ｈ，ｍ），２．９４（２
Ｈ，ｄｄ，Ｊ＝８．２Ｈｚ，Ｊ＝６．６Ｈｚ），３．０
５〜３．１５（４Ｈ，ｍ），３．８０〜３．９５（４
Ｈ，ｍ）６．６８（１Ｈ，ｄ，Ｊ＝９．４Ｈｚ），６．
７０〜６．８５（２Ｈ，ｍ），７．８３（１Ｈ，ｂｒ
ｓ） 融 点： １８１〜１８２℃Form: colorless needle crystal NMR (CDCl 3 , 270 MHz) δ: 2.55 to 2,70 (2H, m), 2.94 (2
H, dd, J = 8.2 Hz, J = 6.6 Hz), 3.0
5 to 3.15 (4H, m), 3.80 to 3.95 (4
H, m) 6.68 (1H, d, J = 9.4 Hz), 6.
70 to 6.85 (2H, m), 7.83 (1H, br
s) Melting point: 181 to 182 ° C
【００３５】参考例 ５ ２−ニトロ−５−チオモルホリノケイ皮酸エチル チオモルホリンを出発原料にして参考例１および参考例
２と同様の方法により得られた２−ニトロ−５−チオモ
ルホリノベンズアルデヒドとマロン酸エチルカリウム
を、参考例３と同様の方法によって反応させ、２−ニト
ロ−５−チオモルホリノケイ皮酸エチルを得た。Reference Example 5 Ethyl 2-nitro-5-thiomorpholinocinnamate 2-nitro-5-thiomorpholinobenzaldehyde obtained by the same method as in Reference Examples 1 and 2 using thiomorpholine as a starting material. Ethyl potassium malonate was reacted in the same manner as in Reference Example 3 to obtain ethyl 2-nitro-5-thiomorpholinocinnamate.
【００３６】形 状：橙色粉末 ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ） δ： １．３４（３Ｈ，ｔ，Ｊ＝７．１Ｈｚ），２．７
０〜２．７５（４Ｈ，ｍ），３．８０〜３．９０（４
Ｈ，ｍ），４．２９（２Ｈ，ｑ，Ｊ＝７．１Ｈｚ），
６．２１（１Ｈ，ｄ，Ｊ＝１６Ｈｚ），６．７５（１
Ｈ，ｄ，Ｊ＝２．９Ｈｚ），６．７９（１Ｈ，ｄｄ，Ｊ
＝９．３Ｈｚ，Ｊ＝２．９Ｈｚ），８．１２（１Ｈ，
ｄ，Ｊ＝９．３Ｈｚ），８．１２（１Ｈ，ｄ，Ｊ＝１６
Ｈｚ） 融 点： １１６〜１１８℃Form: orange powder NMR (CDCl 3 , 400 MHz) δ: 1.34 (3H, t, J = 7.1 Hz), 2.7
0 to 2.75 (4H, m), 3.80 to 3.90 (4
H, m), 4.29 (2H, q, J = 7.1 Hz),
6.21 (1H, d, J = 16Hz), 6.75 (1
H, d, J = 2.9 Hz), 6.79 (1H, dd, J
= 9.3 Hz, J = 2.9 Hz), 8.12 (1H,
d, J = 9.3 Hz), 8.12 (1H, d, J = 16)
Hz) Melting point: 116 to 118 ° C
【００３７】参考例 ６ ２−アミノ−５−チオモルホリノケイ皮酸エチル ２−ニトロ−５−チオモルホリノケイ皮酸エチル８６ｍ
ｇ、５％パラジウムカーボン粉末１０ｍｇをエタノール
２ｍｌに懸濁し、水素気流中室温で２４時間撹拌した。
反応終了後、５％パラジウムカーボン粉末をろ取し、ろ
液を減圧留去した。残査をシリカゲルカラムクロマトグ
ラフィーにて精製し、２−アミノ−５−チオモルホリノ
ケイ皮酸エチル７３ｍｇを得た。Reference Example 6 Ethyl 2-amino-5-thiomorpholinocinnamate 86 m Ethyl 2-nitro-5-thiomorpholinocinnamate
g, 10% of 5% palladium carbon powder was suspended in 2 ml of ethanol, and the mixture was stirred in a hydrogen stream at room temperature for 24 hours.
After completion of the reaction, 5% palladium carbon powder was collected by filtration, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 73 mg of ethyl 2-amino-5-thiomorpholinocinnamate.
【００３８】形 状：橙色粉末 ＮＭＲ（ＣＤＣｌ３，２７０ＭＨｚ） δ： １．３７（３Ｈ，ｔ，Ｊ＝７Ｈｚ），２．７０〜
２．８５（４Ｈ，ｍ），３．３０〜３．４０（４Ｈ，
ｍ），３．７０〜３．８０（２Ｈ，ｍ），４．２６（２
Ｈ，ｑ，Ｊ＝７Ｈｚ），６．３４（１Ｈ，ｄ，Ｊ＝１６
Ｈｚ）６．６７（１Ｈ，ｄ，Ｊ＝９Ｈｚ），６．８７
（１Ｈ，ｄｄ，Ｊ＝９Ｈｚ，Ｊ＝３Ｈｚ），６．９７
（１Ｈ，ｄ，Ｊ＝３Ｈｚ），７．８０（１Ｈ，ｄ，Ｊ＝
１６Ｈｚ） 融 点： １２１〜１２２℃Shape: orange powder NMR (CDCl 3 , 270 MHz) δ: 1.37 (3H, t, J = 7 Hz), 2.70-
2.85 (4H, m), 3.30 to 3.40 (4H,
m), 3.70 to 3.80 (2H, m), 4.26 (2
H, q, J = 7 Hz), 6.34 (1H, d, J = 16)
Hz) 6.67 (1H, d, J = 9 Hz), 6.87
(1H, dd, J = 9Hz, J = 3Hz), 6.97
(1H, d, J = 3Hz), 7.80 (1H, d, J =
16Hz) Melting point: 121 to 122 ° C
【００３９】参考例 ７ ６−チオモルホリノ−３，４−ジヒドロカルボスチリル ２−アミノ−５−チオモルホリノケイ皮酸エチル２２ｍ
ｇをメタノール０．５ｍｌに懸濁し、室温下で水素化ホ
ウ素ナトリウム６ｍｇを加え４時間撹拌した。反応終了
後、溶媒を減圧留去し、飽和重曹水を加え塩化メチレン
で抽出した。飽和食塩水で洗浄後、硫酸マグネシウムで
乾燥し溶媒を減圧留去した。残査をシリカゲルカラムク
ロマトグラフィーにて精製し、６−チオモルホリノ−
３，４−ジヒドロカルボスチリル７ｍｇを得た。Reference Example 7 6-Thiomorpholino-3,4-dihydrocarbostyryl 2-amino-5-thiomorpholino ethyl cinnamate 22 m
g was suspended in 0.5 ml of methanol, 6 mg of sodium borohydride was added at room temperature, and the mixture was stirred for 4 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with methylene chloride. The extract was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and 6-thiomorpholino-
7 mg of 3,4-dihydrocarbostyril was obtained.
【００４０】形 状：無色粉末 ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ） δ： ２．５５〜２．６５（２Ｈ，ｍ），２．７４〜
２．８０（４Ｈ，ｍ），２．８８〜２．９５（２Ｈ，
ｍ），３．４０〜３．４５（４Ｈ，ｍ），６．６３（１
Ｈ，ｄ，Ｊ＝８．８Ｈｚ），６．７０〜６．７６（２
Ｈ，ｍ），７．３７（１Ｈ，ｂｒｓ） 融 点： ２０８〜２０９℃Form: colorless powder NMR (CDCl 3 , 400 MHz) δ: 2.55 to 2.65 (2H, m), 2.74 to
2.80 (4H, m), 2.88 to 2.95 (2H,
m), 3.40 to 3.45 (4H, m), 6.63 (1
H, d, J = 8.8 Hz), 6.70 to 6.76 (2
H, m), 7.37 (1H, brs) Melting point: 208 to 209 ° C
【００４１】実施例 １ ６−モルホリノ−７−ニトロ−３，４−ジヒドロカルボ
スチリル ６−モルホリノ−３，４−ジヒドロカルボスチリル７６
ｍｇを酢酸４ｍｌとトリフルオロ酢酸１ｍｌの混液に溶
解し硝酸ナトリウム３１ｍｇを加え室温で３０分撹拌し
た。反応終了後、溶媒を減圧下にて留去した。残渣をシ
リカゲルカラムクロマトグラフィーで精製し、６−モル
ホルノ−７−ニトロ−３，４−ジヒドロカルボスチリル
５８ｍｇを得た。Example 1 6-morpholino-7-nitro-3,4-dihydrocarbostyril 6-morpholino-3,4-dihydrocarbostyril 76
mg was dissolved in a mixed solution of 4 ml of acetic acid and 1 ml of trifluoroacetic acid, 31 mg of sodium nitrate was added, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 58 mg of 6-molforno-7-nitro-3,4-dihydrocarbostyril.
【００４２】形 状：橙色粉末 ＮＭＲ（ＣＤＣｌ３，２７０ＭＨｚ） δ： ２．６７（２Ｈ，ｄｄ，Ｊ＝８．１Ｈｚ，Ｊ＝
７．０Ｈｚ），３．０２（６Ｈ，ｍ），３．８４（４
Ｈ，ｄｄ，Ｊ＝４．６Ｈｚ，Ｊ＝４．４Ｈｚ），７．０
１（１Ｈ，ｓ），７．０３（１Ｈ，ｓ），８．９１（１
Ｈ，ｂｒｓ） 融 点： ２１０〜２１２℃Shape: orange powder NMR (CDCl 3 , 270 MHz) δ: 2.67 (2H, dd, J = 8.1 Hz, J =)
7.0 Hz), 3.02 (6 H, m), 3.84 (4
H, dd, J = 4.6 Hz, J = 4.4 Hz), 7.0
1 (1H, s), 7.03 (1H, s), 8.91 (1
H, brs) Melting point: 210 to 212 ° C.
【００４３】実施例 ２ ７−ニトロ−６−チオモルホリノ−３，４−ジヒドロカ
ルボスチリル ６−チオモルホリノ−３，４−ジヒドロカルボスチリル
を出発原料にして実施例１と同様の方法により、７−ニ
トロ−６−チオモルホリノ−３，４−ジヒドロカルボス
チリルを得た。Example 2 7-Nitro-6-thiomorpholino-3,4-dihydrocarbostyril 6-Thiomorpholino-3,4-dihydrocarbostyril was used as a starting material in the same manner as in Example 1 to give 7-. Nitro-6-thiomorpholino-3,4-dihydrocarbostyril was obtained.
【００４４】形 状：橙色粉末 ＮＭＲ（ＣＤＣｌ３，２７０ＭＨｚ） δ： ２．６７（２Ｈ，ｍ），２．７５〜２．８５（４
Ｈ，ｍ），３．０１（２Ｈ，ｍ），３．２０〜３．３０
（４Ｈ，ｍ），７．０３（１Ｈ，ｓ），７．２５（１
Ｈ，ｓ），８．５０（１Ｈ，ｂｒｓ） 融 点： ２１０〜２１１℃Shape: orange powder NMR (CDCl 3 , 270 MHz) δ: 2.67 (2H, m), 2.75 to 2.85 (4
H, m), 3.01 (2H, m), 3.20 to 3.30.
(4H, m), 7.03 (1H, s), 7.25 (1
H, s), 8.50 (1H, brs) Melting point: 210 to 211 ° C
【００４５】実施例 ３ ７−ニトロ−６−（１−オキソ−チオモルホリノ）−
３，４−ジヒドロカルボスチリル ７−ニトロ−６−チオモルホリノ−３，４−ジヒドロカ
ルボスチリル２１ｍｇをクロロホルム１ｍｌとメタノー
ル０．５ｍｌの混液に溶解し、メタクロロ過安息香酸
（８０％）１６ｍｇを加え氷冷下で１５分撹拌した。反
応終了後、溶媒を減圧留去した。残渣をシリカゲルカラ
ムクロマトグラフィーにて精製し、７−ニトロ−６−
（１−オキソーチオモルホリノ）−３，４−ジヒドロカ
ルボスチリル１７ｍｇを得た。Example 3 7-Nitro-6- (1-oxo-thiomorpholino)-
21 mg of 3,4-dihydrocarbostyril 7-nitro-6-thiomorpholino-3,4-dihydrocarbostyril was dissolved in a mixed solution of 1 ml of chloroform and 0.5 ml of methanol, 16 mg of metachloroperbenzoic acid (80%) was added, and the mixture was iced. Stir for 15 minutes under cold conditions. After the reaction was completed, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography, 7-nitro-6-
17 mg of (1-oxo-thiomorpholino) -3,4-dihydrocarbostyril was obtained.
【００４６】形 状：淡橙色針状晶 ＮＭＲ（ＣＤＣｌ３，２７０ＭＨｚ） δ： ２６７（２Ｈ，ｍ），２．９０〜３．１０（６
Ｈ，ｍ），３．１２（２Ｈ，ｍ），３．８２（２Ｈ，
ｍ），７．１８（１Ｈ，ｓ），７．３０（１Ｈ，ｓ），
８．３０（１Ｈ，ｂｒｓ） 融 点： ２８４〜２８６℃ （分解）Form: pale orange needle crystal NMR (CDCl 3 , 270 MHz) δ: 267 (2H, m), 2.90 to 3.10 (6
H, m), 3.12 (2H, m), 3.82 (2H,
m), 7.18 (1H, s), 7.30 (1H, s),
8.30 (1H, brs) Melting point: 284 to 286 ° C (decomposition)
【００４７】実施例 ４ ６−モルホリノ−５−ニトロ−３，４−ジヒドロカルボ
スチリル 参考例１から参考例４および実施例１の方法を実施し、
シリカゲルカラムクロマトグラフィーを用いて分離精製
することにより、６−モルホリノ−５−ニトロ−３，４
−ジヒドロカルボスチリルを得た。Example 4 6-morpholino-5-nitro-3,4-dihydrocarbostyril The methods of Reference Examples 1 to 4 and Example 1 were carried out,
By separating and purifying using silica gel column chromatography, 6-morpholino-5-nitro-3,4
-Dihydrocarbostyril was obtained.
【００４８】形 状：黄色粉末 ＮＭＲ（ＣＤＣｌ３，２７０ＭＨｚ） δ： ２．６０〜２．７０（２Ｈ，ｍ），２．８０〜
２．９５（６Ｈ，ｍ），３．７０〜３．８０（４Ｈ，
ｍ），６．８８（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．１６
（１Ｈ，ｄ，Ｊ＝９Ｈｚ），８．２９（１Ｈ，ｂｒｓ） 融 点： ２４４〜２４７℃Shape: Yellow powder NMR (CDCl 3 , 270 MHz) δ: 2.60 to 2.70 (2H, m), 2.80 to
2.95 (6H, m), 3.70 to 3.80 (4H,
m), 6.88 (1H, d, J = 9Hz), 7.16
(1H, d, J = 9Hz), 8.29 (1H, brs) Melting point: 244 to 247 ° C
【００４９】実施例 ５ ６−（１，１−ジオキソ−チオモルホリノ）−７−ニト
ロ−３，４−ジヒドロカルボスチリル７−ニトロ−６−
チオモルホリノ−３，４−ジヒドロカルボスチリル２１
ｍｇをクロロホルム１ｍｌとメタノール０．５ｍｌの混
液に溶解し、メタクロロ過安息香酸（８０％）３５ｍｇ
を加え室温で１．５時間撹拌した。反応終了後、溶媒を
減圧留去した。残渣をシリカゲルカラムクロマトグラフ
ィーにて精製し、６−（１，１−ジオキソ−チオモルホ
リノ）−７−ニトロ−３，４−ジヒドロカルボスチリル
１８ｍｇを得た。Example 5 6- (1,1-dioxo-thiomorpholino) -7-nitro-3,4-dihydrocarbostyril 7-nitro-6-
Thiomorpholino-3,4-dihydrocarbostyril 21
mg was dissolved in a mixed solution of 1 ml of chloroform and 0.5 ml of methanol, and 35 mg of metachloroperbenzoic acid (80%) was dissolved.
Was added and the mixture was stirred at room temperature for 1.5 hours. After the reaction was completed, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 6- (1,1-dioxo-thiomorpholino) -7-nitro-3,4-dihydrocarbostyril 18 mg.
【００５０】形 状：黄色粉末 ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ） δ： ２．６５（２Ｈ，ｍ），３．０１（２Ｈ，ｍ），
３．２０〜３．２５（４Ｈ，ｍ），３．５０〜３．５５
（４Ｈ，ｍ），７．１０（１Ｈ，ｓ），７．３４（１
Ｈ，ｓ），８．６９（１Ｈ，ｂｒｓ） 融 点： ２７７〜２８０℃Form: yellow powder NMR (CDCl 3 , 400 MHz) δ: 2.65 (2H, m), 3.01 (2H, m),
3.20-3.25 (4H, m), 3.50-3.55
(4H, m), 7.10 (1H, s), 7.34 (1
H, s), 8.69 (1H, brs) Melting point: 277 to 280 ° C
【００５１】実施例 ６ アデノシン二リン酸（ＡＤＰ）誘発血小板凝集阻害作用Example 6 Adenosine diphosphate (ADP) -induced platelet aggregation inhibitory action
【００５２】日本白色雄性家兎の総頚動脈より、無麻酔
下に３．８％クエン酸ナトリウム溶液１容に対して血液
９容を採取し、１０００ｒｐｍで１０分間遠心分離して
得た上澄を多血小板血漿（ＰＲＰ）とした。このＰＲＰ
を用いて、ＡＤＰ２０μＭによる血小板の凝集をアグリ
ゴメーター（二光バイオサイエンス社製）によって測定
した。From the common carotid artery of a Japanese white male rabbit, 9 volumes of blood were collected for 1 volume of 3.8% sodium citrate solution without anesthesia, and the supernatant obtained by centrifugation at 1000 rpm for 10 minutes was used. Platelet rich plasma (PRP) was used. This PRP
Was used to measure the aggregation of platelets by ADP of 20 μM with an aggregometer (manufactured by Nikko Bioscience).
【００５３】結果は本発明化合物を１分間前処置した場
合に、６−モルホリノ−７−ニトロ−３，４−ジヒドロ
カルボスチリルは６５μＭ、６−モルホリノ−５−ニト
ロ−３，４−ジヒドロカルボスチリルは２００μＭ、７
−ニトロ−６−チオモルホリノ−３，４−ジヒドロカル
ボスチリルは１２０μＭ、７−ニトロ−６−（１−オキ
ソーチオモルホリノ）−３，４−ジヒドロカルボスチリ
ルは４２μＭ、６−（１，１，ジオキソ−チオモルホリ
ノ）−７−ニトロ−３，４−ジヒドロカルボスチリルは
４２μＭ、６−（１，１−ジオキソーチオモルホリノ）
−７−ニトロ−３，４−ジヒドロカルボスチリルは２１
０μＭで血小板の凝集を５０％阻害した。The results show that 6-morpholino-7-nitro-3,4-dihydrocarbostyril was 65 μM, 6-morpholino-5-nitro-3,4-dihydrocarbostyril when the compound of the present invention was pretreated for 1 minute. Is 200 μM, 7
-Nitro-6-thiomorpholino-3,4-dihydrocarbostyril is 120 µM, 7-nitro-6- (1-oxo-thiomorpholino) -3,4-dihydrocarbostyril is 42 µM, 6- (1,1,1, Dioxo-thiomorpholino) -7-nitro-3,4-dihydrocarbostyril is 42 μM, 6- (1,1-dioxo-thiomorpholino)
-7-Nitro-3,4-dihydrocarbostyril is 21
At 0 μM it inhibited platelet aggregation by 50%.
フロントページの続き (72)発明者 鎌田 晃爾 長野県南安曇郡穂高町大字柏原4509 キッ セイ第三青友寮Front Page Continuation (72) Inventor Akira Kamata 4509 Kashiwara, Hotaka-cho, Minami-Azumi-gun, Nagano Kissei Daisan Seiyu Dormitory
Claims (1)
り、他方は水素原子であり、Ｚはスルホニル基、スルフ
ィニル基、硫黄原子または酸素原子である）で表される
３，４−ジヒドロカルボスチリル誘導体およびその薬理
学的に許容される塩。1. A general formula: (In the formula, one of R 1 and R 2 is a nitro group, the other is a hydrogen atom, and Z is a sulfonyl group, a sulfinyl group, a sulfur atom or an oxygen atom) 3,4- Dihydrocarbostyril derivatives and pharmaceutically acceptable salts thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4362035A JP2826790B2 (en) | 1992-12-26 | 1992-12-26 | 3,4-dihydrocarbostyril derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4362035A JP2826790B2 (en) | 1992-12-26 | 1992-12-26 | 3,4-dihydrocarbostyril derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH06192229A true JPH06192229A (en) | 1994-07-12 |
| JP2826790B2 JP2826790B2 (en) | 1998-11-18 |
Family
ID=18475693
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP4362035A Expired - Lifetime JP2826790B2 (en) | 1992-12-26 | 1992-12-26 | 3,4-dihydrocarbostyril derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2826790B2 (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS51125390A (en) * | 1975-04-17 | 1976-11-01 | Otsuka Pharmaceut Co Ltd | A process for preparing carbostyril derivatives |
| JPS5649363A (en) * | 1979-09-28 | 1981-05-02 | Otsuka Pharmaceut Co Ltd | Carbostyril derivative |
| JPS5777676A (en) * | 1980-10-31 | 1982-05-15 | Otsuka Pharmaceut Co Ltd | Carbostyril derivative |
| JPS5883677A (en) * | 1981-11-11 | 1983-05-19 | Otsuka Pharmaceut Co Ltd | Carbostyril derivative |
-
1992
- 1992-12-26 JP JP4362035A patent/JP2826790B2/en not_active Expired - Lifetime
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS51125390A (en) * | 1975-04-17 | 1976-11-01 | Otsuka Pharmaceut Co Ltd | A process for preparing carbostyril derivatives |
| JPS5649363A (en) * | 1979-09-28 | 1981-05-02 | Otsuka Pharmaceut Co Ltd | Carbostyril derivative |
| JPS5777676A (en) * | 1980-10-31 | 1982-05-15 | Otsuka Pharmaceut Co Ltd | Carbostyril derivative |
| JPS5883677A (en) * | 1981-11-11 | 1983-05-19 | Otsuka Pharmaceut Co Ltd | Carbostyril derivative |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2826790B2 (en) | 1998-11-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2019141250A1 (en) | Pyridone-pyrimidine derivative acting as krasg12c mutein inhibitor | |
| RU2142946C1 (en) | Derivatives of pyrazole and pharmaceutical composition containing thereof | |
| JPH07509726A (en) | Pyrrolopyrimidines as CRF antagonists | |
| JP2810236B2 (en) | Naphthalene derivative | |
| JPH08500121A (en) | Substituted pyrazoles as CRF antagonists | |
| JPH05507687A (en) | Quinuclidine derivative | |
| JPH0586391B2 (en) | ||
| JP2001512118A (en) | Pyridyl- and pyrimidyl heterocyclic compounds that inhibit oxidosqualene-cyclase | |
| TW200902006A (en) | Fast dissociating dopamine 2 receptor antagonists | |
| US9416143B2 (en) | Griseofulvin derivatives | |
| JPH0523269B2 (en) | ||
| JPH03170465A (en) | Pyridazine derivative, its preparation and pharmaceutical composition containing said derivative | |
| JPS60214778A (en) | N-substituted 3,4-dihydropyrimidine derivative, its preparation and use | |
| JPH07505394A (en) | Bridged bisaryl carbinol derivatives, compositions and uses | |
| JPS60248672A (en) | Use of 5,6,7,8-tetrahydroquinolines and 5,6-dihydropyridinesas leukotriene and lipxygenase inhibitor and their novel 3-substituted compounds | |
| JP2686887B2 (en) | Piperidino-3,4-dihydrocarbostyril derivative | |
| JPH06192229A (en) | 3,4-dihydrocarbostyril derivative | |
| JPH08151366A (en) | 1-hydroxyindole derivative | |
| JPS5825678B2 (en) | Oxazole powder | |
| JPS63310880A (en) | Novel 5-methoxyalkylammoniumtetrahydrofurans and tetrahydrothiophenes, manufacture and medicinal composition | |
| JP2002518386A (en) | Production of heteroaryl compounds | |
| JP2875605B2 (en) | 3-exomethylenepyrrolo [2,1-b] thiazole derivatives | |
| JPS6296489A (en) | Tetraoxo compound, manufacture and central nervous system activator | |
| JPH06298756A (en) | Piperidino-3,4-dihydrocarbostyryl derivative | |
| JPH06298757A (en) | Piperidino-3,4-dihydrocarbostyryl derivative |