JPH05339263A - Dihydropyridine derivative - Google Patents
Dihydropyridine derivativeInfo
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- JPH05339263A JPH05339263A JP14751892A JP14751892A JPH05339263A JP H05339263 A JPH05339263 A JP H05339263A JP 14751892 A JP14751892 A JP 14751892A JP 14751892 A JP14751892 A JP 14751892A JP H05339263 A JPH05339263 A JP H05339263A
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Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は持続性のあるカルシウム
拮抗作用及び血圧降下作用を有し、狭心症や高血圧症の
治療薬として有用なジヒドロピリジン誘導体に関する。FIELD OF THE INVENTION The present invention relates to a dihydropyridine derivative having a persistent calcium antagonism and a hypotensive action and useful as a therapeutic drug for angina and hypertension.
【０００２】[0002]
【従来の技術】カルシウム拮抗薬は、心筋や血管平滑筋
の細胞膜にあるカルシウムチャンネルに直接作用し、細
胞外カルシウムイオンの細胞内流入を遮断する。その結
果、細胞内遊離カルシウムイオンの増加が抑制され、特
に血管平滑筋では筋の過収縮と不完全弛緩が緩解され、
血管の拡張と降圧がもたらされる。このような作用を有
するカルシウム拮抗薬としては、ニフェジピン、ニカル
ジピンに代表されるジヒドロピリジン誘導体が狭心症治
療剤、脳循環改善剤、高血圧症治療剤等として広く使用
されている。2. Description of the Related Art Calcium antagonists act directly on calcium channels in the cell membranes of myocardium and vascular smooth muscle, and block intracellular inflow of extracellular calcium ions. As a result, the increase of intracellular free calcium ion is suppressed, and especially in vascular smooth muscle, muscle hypercontraction and incomplete relaxation are relieved,
It causes vasodilation and blood pressure reduction. As a calcium antagonist having such an action, a dihydropyridine derivative represented by nifedipine and nicardipine is widely used as a therapeutic agent for angina, a cerebral circulation improving agent, a therapeutic agent for hypertension and the like.
【０００３】[0003]
【発明が解決しようとする課題】しかしながら、これら
のジヒドロピリジン誘導体は、作用持続時間が比較的短
く、また反射性頻脈の発生等の副作用の点で充分満足で
きるものではなかった。従って、本発明の目的は作用持
続時間が長く、副作用の少ない新たなカルシウム拮抗薬
を提供することにある。However, these dihydropyridine derivatives have not been sufficiently satisfactory in terms of side effects such as relatively short duration of action and occurrence of reflex tachycardia. Therefore, an object of the present invention is to provide a new calcium antagonist with long duration of action and few side effects.
【０００４】[0004]
【課題を解決するための手段】そこで、本発明者らはジ
ヒドロピリジン環の３位のエステル部に種々の含窒素複
素環を導入し、その薬理作用を検討してきた結果、下記
一般式（１）で表わされるジヒドロピリジン誘導体が強
力でかつ持続的なカルシウム拮抗作用を有することを見
出し、本発明を完成するに至った。Therefore, the present inventors have introduced various nitrogen-containing heterocycles into the ester moiety at the 3-position of the dihydropyridine ring, and studied the pharmacological action thereof. As a result, the following general formula (1) It was found that the dihydropyridine derivative represented by the formula (11) has a strong and persistent calcium antagonistic effect, and has completed the present invention.
【０００５】すなわち、本発明は次の一般式（１）That is, the present invention has the following general formula (1):
【０００６】[0006]
【化２】 [Chemical 2]
【０００７】（ここで、Ｒ2 は低級アルキル基、低級ア
ルケニル基、アラルキル基、アシル基、トルエンスルホ
ニル基又はエステル化されたカルボキシル基を示し、Ｒ
3 は水素原子又は低級アルコキシ基を示し、Ｒ4 は水素
原子又は低級アルキル基を示し、Ｒ5 は水素原子、フェ
ニル基、アラルキル基又は低級アルコキシ、低級アルケ
ニルオキシもしくはフェノキシで置換されていてもよい
低級アルキル基を示し、Ｒ6 は水素原子、低級アルキル
基又はフェニル基を示し、Ｒ7 は低級アルキル基、アラ
ルキル基又はフェニル基を示す）〕で表わされるジヒド
ロピリジン誘導体を提供するものである。(Wherein R 2 represents a lower alkyl group, a lower alkenyl group, an aralkyl group, an acyl group, a toluenesulfonyl group or an esterified carboxyl group, and R 2
3 represents a hydrogen atom or a lower alkoxy group, R 4 represents a hydrogen atom or a lower alkyl group, R 5 may be substituted with a hydrogen atom, a phenyl group, an aralkyl group or a lower alkoxy, a lower alkenyloxy or a phenoxy. A lower alkyl group, R 6 represents a hydrogen atom, a lower alkyl group or a phenyl group, and R 7 represents a lower alkyl group, an aralkyl group or a phenyl group)].
【０００８】本発明において、低級アルキル基として
は、炭素数１〜６の直鎖又は分岐鎖のアルキル基、例え
ばメチル基、エチル基、ｎ−プロピル基、ｉｓｏ−プロ
ピル基、ｎ−ブチル基、ｉｓｏ−ブチル基、ｓｅｃ−ブ
チル基、ｔｅｒｔ−ブチル基、ｎ−ペンチル基、ｎ−ヘ
キシル基等が挙げられる。低級アルケニル基としては、
炭素数２〜６の直鎖又は分岐鎖のアルケニル基、例えば
ビニル基、アリル基、３−ブテニル基等が挙げられる。
アラルキル基としては、ベンジル基、ジフェニルメチル
基、フェネチル基等が挙げられる。アシル基としては、
アセチル基、プロパノイル基、ブチリル基等のアルカノ
イル基及びベンゾイル基等のアロイル基が挙げられる。
エステル化されたカルボキシル基としては、例えばメト
キシカルボニル、エトキシカルボニル、ｔｅｒｔ−ブト
キシカルボニル等のアルコキシカルボニル基、ベンジル
オキシカルボニル、４−クロロベンジルオキシカルボニ
ル、フルオレニルメトキシカルボニル等のアラルキルオ
キシカルボニル基、フェノキシカルボニル、４−メトキ
シフェノキシカルボニル、４−ジメチルアミノフェノキ
シカルボニル、ナフチルオキシカルボニル等のアリール
オキシカルボニル基が挙げられる。低級アルコキシ基と
しては、炭素数１〜６の直鎖又は分岐鎖のアルコキシ
基、例えばメトキシ基、エトキシ基、ｎ−プロピルオキ
シ基、ｉｓｏ−プロピルオキシ基、ｎ−ブチルオキシ
基、ｎ−ヘキシルオキシ基等が挙げられる。低級アルケ
ニルオキシ基としては、炭素数２〜６の直鎖又は分岐鎖
のアルケニルオキシ基、例えばビニルオキシ基、アリル
オキシ基等が挙げられる。In the present invention, the lower alkyl group is a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl group, ethyl group, n-propyl group, iso-propyl group, n-butyl group, Examples thereof include an iso-butyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group and an n-hexyl group. As a lower alkenyl group,
Examples thereof include linear or branched alkenyl groups having 2 to 6 carbon atoms, such as vinyl group, allyl group and 3-butenyl group.
Examples of the aralkyl group include a benzyl group, a diphenylmethyl group, a phenethyl group and the like. As an acyl group,
Examples thereof include alkanoyl groups such as acetyl group, propanoyl group and butyryl group, and aroyl groups such as benzoyl group.
Examples of the esterified carboxyl group include alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl, aralkyloxycarbonyl groups such as benzyloxycarbonyl, 4-chlorobenzyloxycarbonyl and fluorenylmethoxycarbonyl, and phenoxy. Examples include aryloxycarbonyl groups such as carbonyl, 4-methoxyphenoxycarbonyl, 4-dimethylaminophenoxycarbonyl and naphthyloxycarbonyl. The lower alkoxy group is a linear or branched alkoxy group having 1 to 6 carbon atoms, for example, a methoxy group, an ethoxy group, an n-propyloxy group, an iso-propyloxy group, an n-butyloxy group, an n-hexyloxy group. Etc. Examples of the lower alkenyloxy group include linear or branched alkenyloxy groups having 2 to 6 carbon atoms, such as vinyloxy group and allyloxy group.
【０００９】一般式（１）中のＲ1 を示す前記（２）〜
（９）の基のうち、（２）、（４）及び／又は（５）が
特に好ましい。From the above (2) to R 1 in the general formula (1)
Among the groups of (9), (2), (4) and / or (5) are particularly preferable.
【００１０】本発明の一般式（１）で表わされる化合物
のうち塩基性基を有する化合物は、薬理学的に許容し得
る酸と塩を形成することができる。斯かる酸としては例
えば塩酸、臭化水素酸、ヨウ化水素酸、硫酸、硝酸、リ
ン酸等の鉱酸；ギ酸、酢酸、シュウ酸、クエン酸、コハ
ク酸、フマール酸、マレイン酸、リンゴ酸、酒石酸、メ
タンスルホン酸、エタンスルホン酸等の有機酸が挙げら
れる。また、本発明化合物（１）は不斉炭素原子を有す
るが、全ての光学活性体及びそれらの混合物は本発明の
範囲に包含されるものである。光学活性化合物は、光学
活性原料を用いて製造できる。また、光学活性な担体を
用いたクロマトグラフィーによりラセミ化合物を分離し
て得ることもできる。更に、一般式（１）で表わされる
化合物のうち塩基性を有するものである場合は、そのラ
セミ化合物と光学的に活性な酸（例えば酒石酸、ジアセ
チル酒石酸、ジトルオイル酸）とを作用させてジアステ
レオマーの塩を形成させ、次いで晶出、蒸留、クロマト
グラフィー等で分離し、分離した塩から光学的に活性な
化合物を得ることもできる。Among the compounds represented by the general formula (1) of the present invention, the compound having a basic group can form a salt with a pharmacologically acceptable acid. Examples of such acids include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid; formic acid, acetic acid, oxalic acid, citric acid, succinic acid, fumaric acid, maleic acid, malic acid. , Organic acids such as tartaric acid, methanesulfonic acid and ethanesulfonic acid. Further, the compound (1) of the present invention has an asymmetric carbon atom, but all the optically active substances and mixtures thereof are included in the scope of the present invention. The optically active compound can be produced using an optically active raw material. Alternatively, the racemic compound can be separated and obtained by chromatography using an optically active carrier. Further, in the case where the compound represented by the general formula (1) has basicity, the racemic compound and an optically active acid (eg tartaric acid, diacetyltartaric acid, ditoluoyl acid) are allowed to act on each other to give diastereos. It is also possible to form the mer salt and then separate by crystallization, distillation, chromatography, etc., and obtain the optically active compound from the separated salt.
【００１１】本発明のジヒドロピリジン誘導体（１）
は、例えば次の反応式に従って製造される。The dihydropyridine derivative (1) of the present invention
Is produced, for example, according to the following reaction formula.
【００１２】[0012]
【化３】 [Chemical 3]
【００１３】すなわち、ジヒドロピリジン−３−カルボ
ン酸（２）又はその反応性誘導体にアルコール（１０）
を反応させることにより、ジヒドロピリジン誘導体
（１）が製造される。That is, alcohol (10) is added to dihydropyridine-3-carboxylic acid (2) or its reactive derivative.
The dihydropyridine derivative (1) is produced by reacting
【００１４】ジヒドロピリジン−３−カルボン酸（２）
の反応性誘導体としては、酸ハライドや混合酸無水物が
挙げられる。酸ハライドは、例えばジヒドロピリジン−
３−カルボン酸（２）に、ジクロルメタン、クロロホル
ム、四塩化炭素、クロルベンゼン等のハロゲン化炭化水
素類、ベンゼン、トルエン等の芳香族炭化水素類、テト
ラヒドロフラン、ジオキサン等のエーテル類、アセトニ
トリル、Ｎ，Ｎ−ジメチルホルムアミド等の非プロトン
性極性溶媒中、ピリジン、トリエチルアミン等のアミン
類の存在下又は非存在下に−７０℃〜１００℃、好まし
くは−２０℃〜５０℃で、塩化チオニル、シュウ酸ジク
ロリド、三塩化リン、五塩化リン、オキシ塩化リン、三
臭化リン等のハロゲン化試薬を反応させることにより得
られる。特に、ハロゲン化試薬として塩化チオニルを用
い、反応溶媒としてＮ，Ｎ−ジメチルホルムアミド又は
ジクロルメタンを単独あるいは混合して用いて氷冷下に
反応を行うことが好ましい。Dihydropyridine-3-carboxylic acid (2)
Examples of the reactive derivative of (1) include acid halides and mixed acid anhydrides. Acid halides are, for example, dihydropyridine-
3-Carboxylic acid (2), halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and chlorobenzene, aromatic hydrocarbons such as benzene and toluene, ethers such as tetrahydrofuran and dioxane, acetonitrile, N, Thionyl chloride, oxalic acid in an aprotic polar solvent such as N-dimethylformamide in the presence or absence of amines such as pyridine and triethylamine at -70 ° C to 100 ° C, preferably -20 ° C to 50 ° C. It can be obtained by reacting a halogenating reagent such as dichloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride and phosphorus tribromide. In particular, it is preferable to use thionyl chloride as a halogenating reagent and N, N-dimethylformamide or dichloromethane as a reaction solvent, either alone or in combination, to carry out the reaction under ice cooling.
【００１５】これらのジヒドロピリジン−３−カルボン
酸（２）の反応性誘導体とアルコール（１０）との反応
は、前述の溶媒と同様の溶媒中、ピリジン、ピコリン、
Ｎ，Ｎ−ジメチルアニリン、Ｎ−メチルモルホリン、ジ
メチルアミン等の塩基の存在下に−７０℃〜１００℃、
好ましくは−２０℃〜５０℃で行うことができる。The reaction of these reactive derivatives of dihydropyridine-3-carboxylic acid (2) with the alcohol (10) is carried out in the same solvent as the above-mentioned solvent, pyridine, picoline,
-70 ° C to 100 ° C in the presence of a base such as N, N-dimethylaniline, N-methylmorpholine, dimethylamine,
It can be preferably carried out at -20 ° C to 50 ° C.
【００１６】反応混合物から目的化合物を単離するに
は、常法、例えば溶媒留去、再結晶、カラムクロマトグ
ラフィー等により行われる。Isolation of the desired compound from the reaction mixture is carried out by a conventional method, for example, distillation of the solvent, recrystallization, column chromatography and the like.
【００１７】尚、原料化合物として用いられる化合物
（２）はＨａｎｔｚｓｃｈ合成法及び改良法（Ａ．Ａｓ
ｈｉｍｏｒｉ ｅｔ ａｌ．；Ｃｈｅｍ．Ｐｈａｒｍ．
Ｂｕｌｌ．，３９，１０８（１９９１））により容易に
製造することができる。The compound (2) used as a raw material compound is the Hantzsch synthesis method and the improved method (A.
himori et al. Chem .; Pharm.
Bull. , 39 , 108 (1991)).
【００１８】また、もう一方の原料化合物であるＲ1Ｏ
Ｈのうち、前記（２）、（３）、（５）、（６）又は
（７）の構造を有する化合物は、例えば対応するケトン
体を水素化リチウムアルミニウムや水素化ホウ素ナトリ
ウム等の還元剤を用いて還元する方法、当該還元反応後
に常法に従い置換基Ｒ2 を導入する方法等を組み合わせ
ることにより製造される。また、Ｒ1ＯＨのうち、前記
（４）の構造を有する化合物は、例えばテトラヒドロキ
ノリンにＨＯ−ＣＲ4Ｒ5−ＣＨＲ6−Ｂｒ又はエポキシ
化合物を反応させる方法、ブロモ酢酸エステルを反応さ
せた後還元する方法等により製造することができる。ま
た、Ｒ1ＯＨのうち、前記（８）又は（９）の構造を有
する化合物は、Ｎ−クロロプロピルベンズアゼピン体又
はＮ−クロロプロピルジベンズアゼピン体にＨＯＣＨ2
ＣＨ2ＮＨＲ7を反応させることにより製造される。Further, the other raw material compound R 1 O
Among H, the compound having the structure of (2), (3), (5), (6) or (7) is, for example, a corresponding ketone body which is a reducing agent such as lithium aluminum hydride or sodium borohydride. how to reduction with, it is produced by combining a method in which introducing a substituent R 2 according to a conventional method after the reduction reaction. Further, among R 1 OH, the compound having the structure of (4) is, for example, a method of reacting tetrahydroquinoline with HO-CR 4 R 5 —CHR 6 —Br or an epoxy compound, after reacting with bromoacetic acid ester. It can be produced by a reduction method or the like. In addition, among R 1 OH, the compound having the structure of (8) or (9) is an N-chloropropylbenzazepine body or an N-chloropropyldibenzazepine body in HOCH 2
It is produced by reacting CH 2 NHR 7 .
【００１９】[0019]
【発明の効果】かくして得られるジヒドロピリジン誘導
体（１）は、強力かつ持続的なカルシウム拮抗作用を有
し、また持続的な血圧降下作用を有する。従って、狭心
症治療剤、脳循環改善剤、高血圧症治療剤として有用で
ある。INDUSTRIAL APPLICABILITY The dihydropyridine derivative (1) thus obtained has a strong and persistent calcium antagonistic action and also a persistent blood pressure lowering action. Therefore, it is useful as a therapeutic agent for angina, a cerebral circulation improving agent, and a therapeutic agent for hypertension.
【００２０】[0020]
【実施例】次に実施例を挙げて本発明を更に詳細に説明
するが、本発明はこれらによって何ら制限されるもので
はない。The present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.
【００２１】実施例１ １，４−ジヒドロ−２，６−ジメチル−４−（３−ニト
ロフェニル）−３，５−ピリジンジカルボン酸 １−ベ
ンジル−１，２，３，４−テトラヒドロ−４−キノリル
メチル エステル（１）：１，４−ジヒドロ−２，６
−ジメチル−４−（３−ニトロフェニル）−３，５−ピ
リジンジカルボン酸水素メチル（２４４mg）を無水ジメ
チルホルムアミド−無水ジクロロメタン（１：４）（５
ml）混液に溶解させ、氷冷下、塩化チオニル（８８mg）
の無水ジクロロメタン（０．５ml）溶液を滴下し１時間
攪拌した後、１−ベンジル−１，２，３，４−テトラヒ
ドロ−４−キノリノール（１６０mg）の無水ジクロロメ
タン（１ml）溶液を滴下し、３時間攪拌を続けた。反応
液に水を加えクロロホルムで抽出後、有機層を飽和食塩
水で洗浄し、乾燥、溶媒を減圧留去して得られた残渣を
シリカゲルカラムクロマトグラフィー（ジクロロメタ
ン）で精製して、標題化合物（１）９５mgを得た。Example 1 1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 1-benzyl-1,2,3,4-tetrahydro-4- Quinolyl methyl ester (1): 1,4-dihydro-2,6
-Dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylate methyl hydrogen (244 mg) was added to anhydrous dimethylformamide-anhydrous dichloromethane (1: 4) (5
ml) mixed solution, and thionyl chloride (88 mg) under ice cooling.
Anhydrous dichloromethane (0.5 ml) solution was added dropwise and stirred for 1 hour, then 1-benzyl-1,2,3,4-tetrahydro-4-quinolinol (160 mg) in anhydrous dichloromethane (1 ml) was added dropwise. Stirring was continued for hours. Water was added to the reaction solution, the mixture was extracted with chloroform, the organic layer was washed with saturated brine, dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane) to give the title compound ( 1) Obtained 95 mg.
【００２２】褐色無晶形物質1 H-NMR(CDCl3)δ:1.68-2.13(2H,m),1.94(2.52H,s),1.96
(0.48H,s),2.34(3H,s),3.11-3.88(2H,m),3.62(0.48H,
s),3.63(2.52H,s),4.42-4.59(3H,m),5.34(0.84H,s),5.4
4(0.16H,s),6.08(1H,t,J=7Hz),6.43-8.17(13H,m). MS m/z:492(M+-NO2,CH3).Brown amorphous substance 1 H-NMR (CDCl 3 ) δ: 1.68-2.13 (2H, m), 1.94 (2.52H, s), 1.96
(0.48H, s), 2.34 (3H, s), 3.11-3.88 (2H, m), 3.62 (0.48H, s)
s), 3.63 (2.52H, s), 4.42-4.59 (3H, m), 5.34 (0.84H, s), 5.4
4 (0.16H, s), 6.08 (1H, t, J = 7Hz), 6.43-8.17 (13H, m) MS m / z:. 492 (M + -NO 2, CH 3).
【００２３】実施例２ 実施例１と同様にして表１に示す化合物（２）〜化合物
（３）を合成した。Example 2 Compounds (2) to (3) shown in Table 1 were synthesized in the same manner as in Example 1.
【００２４】[0024]
【表１】 [Table 1]
【００２５】実施例３ １，４−ジヒドロ−２，６−ジメチル−４−（３−ニト
ロフェニル）−３，５−ピリジンジカルボン酸 １−
（ベンジルオキシカルボニル）−１，２，３，４−テト
ラヒドロ−４−キノリル メチル エステル（４）：
１，４−ジヒドロ−２，６−ジメチル−４−（３−ニト
ロフェニル）−３，５−ピリジンジカルボン酸水素メチ
ル（３２１mg）を無水ジメチルホルムアミド−無水ジク
ロロメタン（１：４）（５ml）に溶解させ、氷冷下、塩
化チオニル（１１５mg）の無水ジクロロメタン溶液を滴
下し、１時間攪拌した。これに、１−（ベンジルオキシ
カルボニル）−１，２，３，４−テトラヒドロ−４−キ
ノリノール（２５０mg）の無水ジクロロメタン溶液を滴
下し、更にＮ−メチルモルホリン（８９mg）の無水ジク
ロロメタン（０．５ml）溶液を滴下して氷冷下２時間攪
拌を続けた。反応液に水を加えクロロホルムで抽出した
後、有機層を飽和食塩水で洗浄し、乾燥、溶媒を減圧留
去して得られた残渣をシリカゲルカラムクロマトグラフ
ィー（ジクロロメタン：アセトン＝５０：１）で精製
し、標題化合物（４）３６５mgを得た。Example 3 1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 1-
(Benzyloxycarbonyl) -1,2,3,4-tetrahydro-4-quinolyl methyl ester (4):
Methyl hydrogen 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylate (321 mg) was dissolved in anhydrous dimethylformamide-anhydrous dichloromethane (1: 4) (5 ml). Then, a solution of thionyl chloride (115 mg) in anhydrous dichloromethane was added dropwise under ice cooling, and the mixture was stirred for 1 hour. To this, a solution of 1- (benzyloxycarbonyl) -1,2,3,4-tetrahydro-4-quinolinol (250 mg) in anhydrous dichloromethane was added dropwise, and further N-methylmorpholine (89 mg) in anhydrous dichloromethane (0.5 ml). ) The solution was added dropwise and stirring was continued for 2 hours under ice cooling. After adding water to the reaction solution and extracting with chloroform, the organic layer was washed with saturated brine, dried, and the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (dichloromethane: acetone = 50: 1). Purification gave 365 mg of the title compound (4).
【００２６】黄色無晶形物質1 H-NMR(CDCl3)δ:1.79-2.19(2H,m),2.31-2.39(6H,m),3.
33-4.28(1H,m),3.60(3H,s),4.01-4.28(1H,m),4.99(0.5
H,s),5.01(0.5H,s),5.26(2H,ABq,JAB=13Hz),5.76(1H,
s),5.91(1H,s),6.71-8.10(13H,m). MS m/z:597(M+).Yellow amorphous substance 1 H-NMR (CDCl 3 ) δ: 1.79-2.19 (2H, m), 2.31-2.39 (6H, m), 3.
33-4.28 (1H, m), 3.60 (3H, s), 4.01-4.28 (1H, m), 4.99 (0.5
H, s), 5.01 (0.5H, s), 5.26 (2H, ABq, J AB = 13Hz), 5.76 (1H,
s), 5.91 (1H, s), 6.71-8.10 (13H, m) .MS m / z: 597 (M + ).
【００２７】実施例４ 実施例３と同様にして、表２〜表７に示す化合物（５）
〜化合物（１８）を合成した。Example 4 Compound (5) shown in Table 2 to Table 7 in the same manner as in Example 3.
~ Compound (18) was synthesized.
【００２８】[0028]
【表２】 [Table 2]
【００２９】[0029]
【表３】 [Table 3]
【００３０】[0030]
【表４】 [Table 4]
【００３１】[0031]
【表５】 [Table 5]
【００３２】[0032]
【表６】 [Table 6]
【００３３】[0033]
【表７】 [Table 7]
【００３４】実施例５ １，４−ジヒドロ−２，６−ジメチル−４−（３−ニト
ロフェニル）−３，５−ピリジンジカルボン酸 ２−ベ
ンジル−１，２，３，４−テトラヒドロ−４−イソキノ
リル メチル エステル（１９）：１，４−ジヒドロ−
２，６−ジメチル−４−（３−ニトロフェニル）−３，
５−ピリジンジカルボン酸水素メチル（３３２mg）を無
水ジメチルホルムアミド−無水ジクロロメタン（１：
４）（５ml）に溶解させ、氷冷下、塩化チオニル（１７
９mg）の無水ジクロロメタン（０．５ml）溶液を滴下し
１時間攪拌した。これに２−ベンジル−１，２，３，４
−テトラヒドロ−４−イソキノリノール（２３９mg）の
無水ジクロロメタン（１ml）溶液を滴下し、氷冷下２時
間攪拌を続けた。反応液に水を加え、ジクロロメタンで
抽出し、乾燥、溶媒を減圧下留去して得られた残渣をシ
リカゲルカラムクロマトグラフィー（ヘキサン：アセト
ン＝５：１）で精製し、標題化合物（１９）３２１mgを
得た。Example 5 1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 2-benzyl-1,2,3,4-tetrahydro-4- Isoquinolyl methyl ester (19): 1,4-dihydro-
2,6-dimethyl-4- (3-nitrophenyl) -3,
Methyl hydrogen 5-pyridinedicarboxylate (332 mg) was added to anhydrous dimethylformamide-anhydrous dichloromethane (1:
4) (5 ml) and thionyl chloride (17 ml) under ice cooling.
A solution of 9 mg) in anhydrous dichloromethane (0.5 ml) was added dropwise and the mixture was stirred for 1 hour. 2-benzyl-1,2,3,4
A solution of tetrahydro-4-isoquinolinol (239 mg) in anhydrous dichloromethane (1 ml) was added dropwise, and stirring was continued for 2 hours under ice cooling. Water was added to the reaction solution, which was extracted with dichloromethane, dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: acetone = 5: 1) to give 321 mg of the title compound (19). Got
【００３５】黄色無晶形物質1 H-NMR(CDCl3)δ:2.33(0.6H,s),2.36(2.4H,s),2.37(2.4
H,s),2.38(0.6H,s),2.74-2.98(2H,m),3.47-3.91(4H,m),
3.60(0.6H,s),3.61(2.4H,s),5.10(1H,s),5.77(0.8H,s),
5.80(0.2H,s),5.96(0.8H,t,J=3Hz),6.01(0.2H,t,J=5H
z),6.76-7.62(11H,m),7.83-7.99(1H,m),7.98(0.8H,t,J=
1.5Hz),8.05(0.2H,t,J=1.5Hz). MS m/z:553(M+).Yellow amorphous substance 1 H-NMR (CDCl 3 ) δ: 2.33 (0.6H, s), 2.36 (2.4H, s), 2.37 (2.4
H, s), 2.38 (0.6H, s), 2.74-2.98 (2H, m), 3.47-3.91 (4H, m),
3.60 (0.6H, s), 3.61 (2.4H, s), 5.10 (1H, s), 5.77 (0.8H, s),
5.80 (0.2H, s), 5.96 (0.8H, t, J = 3Hz), 6.01 (0.2H, t, J = 5H
z), 6.76-7.62 (11H, m), 7.83-7.99 (1H, m), 7.98 (0.8H, t, J =
1.5Hz), 8.05 (0.2H, t, J = 1.5Hz) .MS m / z: 553 (M + ).
【００３６】実施例６ １，４−ジヒドロ−２，６−ジメチル−４−（３−ニト
ロフェニル）−３，５−ピリジンジカルボン酸 １，
２，３，４−テトラヒドロ−２−メチル−４−イソキノ
リル メチル エステル（２０）：１，４−ジヒドロ−
２，６−ジメチル−４−（３−ニトロフェニル）−３，
５−ピリジンジカルボン酸水素メチル（４９３mg）をジ
メチルホルムアミド−ジクロロメタン（１：４）（５m
l）の混液に溶解させ、氷冷下、塩化チオニル（１７７m
g）のジクロロメタン（０．５ml）溶液を加え１時間攪
拌した。これに、２−メチル−１，２，３，４−テトラ
ヒドロ−４−イソキノリノール（２１８mg）のジクロロ
メタン（１ml）溶液を滴下し、更にＮ−メチルモルホリ
ン（１３６mg）のジクロロメタン（０．５ml）溶液を滴
下して氷冷下５時間攪拌を続けた。反応液に水を加えジ
クロロメタンで抽出し、乾燥、溶媒を減圧下留去して得
られた残渣をシリカゲルカラムクロマトグラフィー（ヘ
キサン：アセトン＝５：１）で精製して黄色無晶形物質
を得た。更にシリカゲルカラムクロマトグラフィー（ジ
クロロメタン：アセトン＝２０：１）でジアステレオマ
ーを分離して、先溶出物２０ａ（黄色無晶形物質）９５
mgと後溶出物２０ｂ（黄色無晶形物質）１２１mgを得
た。Example 6 1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 1,
2,3,4-Tetrahydro-2-methyl-4-isoquinolyl methyl ester (20): 1,4-dihydro-
2,6-dimethyl-4- (3-nitrophenyl) -3,
Methyl hydrogen 5-pyridinedicarboxylate (493 mg) was added to dimethylformamide-dichloromethane (1: 4) (5 m
l), and thionyl chloride (177m
A solution of g) in dichloromethane (0.5 ml) was added and stirred for 1 hour. To this, a solution of 2-methyl-1,2,3,4-tetrahydro-4-isoquinolinol (218 mg) in dichloromethane (1 ml) was added dropwise, and further a solution of N-methylmorpholine (136 mg) in dichloromethane (0.5 ml) was added. Was added dropwise and stirring was continued for 5 hours under ice cooling. Water was added to the reaction solution, extracted with dichloromethane, dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: acetone = 5: 1) to obtain a yellow amorphous substance. .. Further, the diastereomer was separated by silica gel column chromatography (dichloromethane: acetone = 20: 1) to obtain the eluate 20a (yellow amorphous substance) 95.
and 121 mg of the post-eluate 20b (yellow amorphous substance) were obtained.
【００３７】20a:1H-NMR(CDCl3)δ:2.36(9H,s),2.52-2.
74(2H,m),3.45(1H,d,J=15Hz),3.59(3H,s),3.69(1H,d,J=
15Hz),5.08(1H,s),5.82(1H,s),6.01(1H,t,J=5.5Hz),7.1
0(1H,d,J=7.5Hz),7.17-7.32(3H,m),7.32(1H,t,J=8Hz),
7.66(1H,dt,J=2.8Hz),7.98-8.03(1H,m),8.07(1H,t,J=2H
z). 20b:1H-NMR(CDCl3)δ:2.34(3H,s),2.41(3H,s),2.45(3H,
s),2.83(2H,d,J=5Hz), 3.44(1H,d,J=15Hz), 3.59(3H,
s),3.74(1H,d,J=15Hz),5.05(1H,s),5.80(1H,s),5.91(1
H,t,J=5Hz),6.67(1H,d,J=7.5Hz),6.98(1H,t,J=7.5Hz),
7.06(1H,d,J=7.5Hz),7.19(1H,t,J=7.5Hz),7.24(1H,t,J=
7.5Hz),7.48(1H,dt,J=1.5,7.5Hz),7.94-7.99(2H,m).20a: 1 H-NMR (CDCl 3 ) δ: 2.36 (9H, s), 2.52-2.
74 (2H, m), 3.45 (1H, d, J = 15Hz), 3.59 (3H, s), 3.69 (1H, d, J =
15Hz), 5.08 (1H, s), 5.82 (1H, s), 6.01 (1H, t, J = 5.5Hz), 7.1
0 (1H, d, J = 7.5Hz), 7.17-7.32 (3H, m), 7.32 (1H, t, J = 8Hz),
7.66 (1H, dt, J = 2.8Hz), 7.98-8.03 (1H, m), 8.07 (1H, t, J = 2H
z) .20b: 1 H-NMR (CDCl 3 ) δ: 2.34 (3H, s), 2.41 (3H, s), 2.45 (3H,
s), 2.83 (2H, d, J = 5Hz), 3.44 (1H, d, J = 15Hz), 3.59 (3H,
s), 3.74 (1H, d, J = 15Hz), 5.05 (1H, s), 5.80 (1H, s), 5.91 (1
H, t, J = 5Hz), 6.67 (1H, d, J = 7.5Hz), 6.98 (1H, t, J = 7.5Hz),
7.06 (1H, d, J = 7.5Hz), 7.19 (1H, t, J = 7.5Hz), 7.24 (1H, t, J =
7.5Hz), 7.48 (1H, dt, J = 1.5,7.5Hz), 7.94-7.99 (2H, m).
【００３８】実施例７ １，４−ジヒドロ−２，６−ジメチル−４−（３−ニト
ロフェニル）−３，５−ピリジンジカルボン酸 ２−
（ベンジルオキシカルボニル）−１，２，３，４−テト
ラヒドロ−４−イソキノリル メチル エステル（２
１）：１，４−ジヒドロ−２，６−ジメチル−４−（３
−ニトロフェニル）−３，５−ピリジンジカルボン酸水
素メチル（２８９mg）を無水ジメチルホルムアミド−無
水ジクロロメタン（１：４）（５ml）の混液に溶解さ
せ、氷冷下塩化チオニル（１０３mg）の無水ジクロロメ
タン（０．５ml）溶液を加え１時間攪拌した。これに２
−（ベンジルオキシカルボニル）−１，２，３，４−テ
トラヒドロ−４−イソキノリノール（２２２mg）の無水
ジクロロメタン（０．５ml）溶液を滴下し、氷冷下２時
間攪拌を続けた。反応液に水を加えジクロロメタンで抽
出し、乾燥、溶媒を減圧下留去して得られた残渣をシリ
カゲルカラムクロマトグラフィー（ヘキサン：アセトン
＝５：１）で精製して標題化合物（２１）１７１mgを得
た。Example 7 1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 2-
(Benzyloxycarbonyl) -1,2,3,4-tetrahydro-4-isoquinolyl methyl ester (2
1): 1,4-dihydro-2,6-dimethyl-4- (3
Methyl nitrophenyl-3,5-pyridinedicarboxylate (289 mg) was dissolved in a mixture of anhydrous dimethylformamide-anhydrous dichloromethane (1: 4) (5 ml), and thionyl chloride (103 mg) in anhydrous dichloromethane ( 0.5 ml) solution was added and stirred for 1 hour. 2 to this
A solution of-(benzyloxycarbonyl) -1,2,3,4-tetrahydro-4-isoquinolinol (222 mg) in anhydrous dichloromethane (0.5 ml) was added dropwise, and stirring was continued for 2 hours under ice cooling. Water was added to the reaction solution, extracted with dichloromethane, dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: acetone = 5: 1) to give 171 mg of the title compound (21). Obtained.
【００３９】黄色無晶形物質1 H-NMR(CDCl3)δ:2.17-2.37(6H,m),3.43-3.62(4H,m),4.
18-4.62(2H,m),4.77-5.33(4H,m), 5.64-5.99(2H,m,),
6.83-7.50(11H,m),7.82-7.99(2H,m). MS m/z:597(M+).Yellow amorphous substance 1 H-NMR (CDCl 3 ) δ: 2.17-2.37 (6H, m), 3.43-3.62 (4H, m), 4.
18-4.62 (2H, m), 4.77-5.33 (4H, m), 5.64-5.99 (2H, m,),
6.83-7.50 (11H, m), 7.82-7.99 (2H, m) .MS m / z: 597 (M + ).
【００４０】実施例８ 実施例７と同様にして表８〜表９に示す化合物（２２）
〜化合物（２６）を合成した。Example 8 Compound (22) shown in Table 8 to Table 9 in the same manner as in Example 7.
~ Compound (26) was synthesized.
【００４１】[0041]
【表８】 [Table 8]
【００４２】[0042]
【表９】 [Table 9]
【００４３】実施例９ １，４−ジヒドロ−２，６−ジメチル−４−（３−ニト
ロフェニル）−３，５−ピリジンジカルボン酸 １，
２，４，５−テトラヒドロ−３−（ｐ−トリルスルホニ
ル）−３Ｈ−３−ベンズアゼピン−１−イル メチル
エステル（２７）：１，４−ジヒドロ−２，６−ジメチ
ル−４−（３−ニトロフェニル）−３，５−ピリジンジ
カルボン酸水素メチル（３５７mg）を無水ジメチルホル
ムアミド−無水ジクロロメタン（１：４）（５ml）の混
液に溶解させ、氷冷下、塩化チオニル（１２９mg）の無
水ジクロロメタン（０．５ml）溶液を滴下し１時間攪拌
した。これに１，２，４，５−テトラヒドロ−３−（ｐ
−トリルスルホニル）−３Ｈ−３−ベンズアゼピン−１
−オール（３１０mg）の無水ジクロロメタン（１ml）溶
液を滴下し、更にＮ−メチルモルホリン（９９mg）の無
水ジクロロメタン（０．５ml）溶液を滴下して、氷冷下
２時間攪拌を続けた。反応液に水を加えジクロロメタン
で抽出し、乾燥、溶媒を減圧下留去して得られた残渣を
シリカゲルカラムクロマトグラフィー（ヘキサン：アセ
トン＝５：１）で精製して標題化合物（２７）２３５mg
を得た。Example 9 1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 1,
2,4,5-Tetrahydro-3- (p-tolylsulfonyl) -3H-3-benzazepin-1-yl methyl
Ester (27): 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylate methyl hydrogen (357 mg) was added to anhydrous dimethylformamide-anhydrous dichloromethane (1: 4). The mixture was dissolved in a mixed solution of (5 ml), a solution of thionyl chloride (129 mg) in anhydrous dichloromethane (0.5 ml) was added dropwise under ice cooling, and the mixture was stirred for 1 hour. 1,2,4,5-tetrahydro-3- (p
-Tolylsulfonyl) -3H-3-benzazepine-1
A solution of -ol (310 mg) in anhydrous dichloromethane (1 ml) was added dropwise, and a solution of N-methylmorpholine (99 mg) in anhydrous dichloromethane (0.5 ml) was added dropwise, and stirring was continued for 2 hours under ice cooling. Water was added to the reaction solution, extracted with dichloromethane, dried, and the solvent was distilled off under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane: acetone = 5: 1) to give 235 mg of the title compound (27).
Got
【００４４】黄色無晶形物質1 H-NMR(CDCl3)δ:2.35(2.35H,s),2.36(0.75H,s),2.39(3
H,s),2.41(0.75H,s),2.46(2.25H,s),2.78-3.67(1.5H,
m),2.84(0.75H,dd,J=7,15Hz),2.94(0.75H,dd,J=10,14H
z),3.12(0.75H,d,J=13Hz),3.23(0.75H,dd,J=10,15Hz),
3.67(0.75H,s),3.68(2.25H,s),3.77(0.75H,J=6.5,13H
z),4.00(0.75H,dd,J=7,14Hz),5.15(0.75H,s),5.20(0.25
H,s),5.81(0.75H,d,J=6.5Hz),5.93(0.75H,s),5.94(0.25
H,d,J=6.5Hz),6.07(0.25H,s),6.85(0.75H,d,J=7Hz),6.9
7-8.29(6H,m),7.44(0.25H,t,J=8.5Hz),7.53(0.75H,d,J=
8.5Hz),7.54(0.5H,d,J=8.5Hz),7.63(1.5H,d,J=8.5Hz),
7.74(0.25H,d,J=8.5Hz),7.89-7.94(0.75H,m),8.00-8.04
(0.25H,m),8.02(0.75H,t,J=2Hz),8.09(0.25H,t,J=2Hz). MS m/z:630(M+-1).Yellow amorphous substance 1 H-NMR (CDCl 3 ) δ: 2.35 (2.35H, s), 2.36 (0.75H, s), 2.39 (3
H, s), 2.41 (0.75H, s), 2.46 (2.25H, s), 2.78-3.67 (1.5H,
m), 2.84 (0.75H, dd, J = 7,15Hz), 2.94 (0.75H, dd, J = 10,14H
z), 3.12 (0.75H, d, J = 13Hz), 3.23 (0.75H, dd, J = 10,15Hz),
3.67 (0.75H, s), 3.68 (2.25H, s), 3.77 (0.75H, J = 6.5,13H
z), 4.00 (0.75H, dd, J = 7,14Hz), 5.15 (0.75H, s), 5.20 (0.25
H, s), 5.81 (0.75H, d, J = 6.5Hz), 5.93 (0.75H, s), 5.94 (0.25
H, d, J = 6.5Hz), 6.07 (0.25H, s), 6.85 (0.75H, d, J = 7Hz), 6.9
7-8.29 (6H, m), 7.44 (0.25H, t, J = 8.5Hz), 7.53 (0.75H, d, J =
8.5Hz), 7.54 (0.5H, d, J = 8.5Hz), 7.63 (1.5H, d, J = 8.5Hz),
7.74 (0.25H, d, J = 8.5Hz), 7.89-7.94 (0.75H, m), 8.00-8.04
(0.25H, m), 8.02 (0.75H, t, J = 2Hz), 8.09 (0.25H, t, J = 2Hz) .MS m / z: 630 (M + -1).
【００４５】実施例１０ １，４−ジヒドロ−２，６−ジメチル−４−（３−ニト
ロフェニル）−３，５−ピリジンジカルボン酸 １，
２，４，５−テトラヒドロ−３−メチル−３Ｈ−ベンズ
アゼピン−１−イル メチル エステル（２８）：１，
２，４，５−テトラヒドロ−３−メチル−３Ｈ−ベンズ
アゼピン−１−オールを用い実施例９と同様の方法によ
り黄色結晶（塩酸塩）を得た。この結晶に飽和炭酸ナト
リウムを加えクロロホルムで抽出し、乾燥、溶媒を減圧
下留去して黄色無晶形物質を得た。このジアステレオマ
ーの混合物をシリカゲルカラムクロマトグラフィー（ヘ
キサン：アセトン＝５：１）で分離し、先溶出物質２８
ａ（黄色無晶形物質）を７９mg、後溶出物質２８ｂ（黄
色無晶形物質）を２３０mg得た。 混合物：MS m/z:492(M++1).Example 10 1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 1,
2,4,5-Tetrahydro-3-methyl-3H-benzazepin-1-yl methyl ester (28): 1,
Yellow crystals (hydrochloride) were obtained by the same method as in Example 9 using 2,4,5-tetrahydro-3-methyl-3H-benzazepin-1-ol. Saturated sodium carbonate was added to the crystals, extracted with chloroform, dried and the solvent was distilled off under reduced pressure to obtain a yellow amorphous substance. The mixture of diastereomers was separated by silica gel column chromatography (hexane: acetone = 5: 1), and the previously eluted substance 28
79 mg of a (yellow amorphous substance) and 230 mg of post-eluting substance 28b (yellow amorphous substance) were obtained. Mixture: MS m / z: 492 (M + +1).
【００４６】28a:1H-NMR(CDCl3)δ:2.31(3H,s),2.37-2.
48(1H,m),2.38(3H,s),2.39(3H,s),2.59(2H,d,J=5Hz),2.
74(1H,dt,J=4.5,12.5Hz),2.98(0.52H,2H,t,J=4.5Hz),3.
67(3H,s),5.28(1H,s),5.80(1H,s),5.99(1H,t,J=5Hz),7.
08-7.24(4H,m),7.38(1H,t,J=8Hz),7.76(1H,d,J=8Hz),8.
00-8.04(1H,m),8.15(1H,t,J=2Hz). 28b:1H-NMR(CDCl3)δ:2.34(3H,s),2.40(3H,s),2.42(3H,
s),2.43-3.07(6H,m),3.66(3H,s),5.17(1H,s),5.92(1H,
t,J=5Hz),6.03(1H,s),6.51(1H,d,J=7.5Hz),6.90(1H,dt,
J=1.5,7.5Hz),7.03-7.14(2H,m),7.25(1H,t,J=8Hz),7.53
(1H,d,J=8Hz),7.94-7.99(1H,m),8.09(1H,t,J=2Hz).28a: 1 H-NMR (CDCl 3 ) δ: 2.31 (3H, s), 2.37-2.
48 (1H, m), 2.38 (3H, s), 2.39 (3H, s), 2.59 (2H, d, J = 5Hz), 2.
74 (1H, dt, J = 4.5,12.5Hz), 2.98 (0.52H, 2H, t, J = 4.5Hz), 3.
67 (3H, s), 5.28 (1H, s), 5.80 (1H, s), 5.99 (1H, t, J = 5Hz), 7.
08-7.24 (4H, m), 7.38 (1H, t, J = 8Hz), 7.76 (1H, d, J = 8Hz), 8.
00-8.04 (1H, m), 8.15 (1H, t, J = 2Hz) .28b: 1 H-NMR (CDCl 3 ) δ: 2.34 (3H, s), 2.40 (3H, s), 2.42 (3H,
s), 2.43-3.07 (6H, m), 3.66 (3H, s), 5.17 (1H, s), 5.92 (1H,
t, J = 5Hz), 6.03 (1H, s), 6.51 (1H, d, J = 7.5Hz), 6.90 (1H, dt,
J = 1.5,7.5Hz), 7.03-7.14 (2H, m), 7.25 (1H, t, J = 8Hz), 7.53
(1H, d, J = 8Hz), 7.94-7.99 (1H, m), 8.09 (1H, t, J = 2Hz).
【００４７】実施例１１ 実施例９と同様にして表１０〜表１１に示す化合物（２
９）〜化合物（３１）、表１２に示す化合物（３２）及
び表１３に示す化合物（３３）〜化合物（３４）を合成
した。Example 11 Compounds (2) shown in Tables 10 to 11 were prepared in the same manner as in Example 9.
9) to compound (31), compound (32) shown in Table 12 and compound (33) to compound (34) shown in Table 13 were synthesized.
【００４８】[0048]
【表１０】 [Table 10]
【００４９】[0049]
【表１１】 [Table 11]
【００５０】[0050]
【表１２】 [Table 12]
【００５１】[0051]
【表１３】 [Table 13]
【００５２】実施例１２ １，４−ジヒドロ−２，６−ジメチル−４−（３−ニト
ロフェニル）−３，５−ピリジンジカルボン酸メチル
２−（１，２，３，４−テトラヒドロ−１−キノリル）
エチル エステル（３５）：１，４−ジヒドロ−２，６
−ジメチル−４−（３−ニトロフェニル）−３，５−ピ
リジンジカルボン酸水素メチル（６６４mg）を無水ジメ
チルホルムアミド−無水ジクロロメタン（１：４）（１
０ml）の混液に溶解し、氷冷下塩化チオニル（０．２m
l）を滴下し１時間攪拌した。これに、１，２，３，４
−テトラヒドロ−１−（２−ヒドロキシエチル）キノリ
ン（２９０mg）の無水ジクロロメタン（１ml）溶液を滴
下し、更にＮ−メチルモルホリン（２０２mg）の無水ジ
クロロメタン（０．５ml）溶液を滴下し氷冷下２時間攪
拌を続けた。溶媒を減圧下留去し、残渣にクロロホルム
を加えシリカゲルで濾過して大部分の不要物を除去し、
濾液を減圧下留去して得られた残渣をシリカゲルカラム
クロマトグラフィー（ヘキサン：アセトン＝１０：１）
で精製して標題化合物（３５）６９１mgを得た。Example 12 Methyl 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylate
2- (1,2,3,4-tetrahydro-1-quinolyl)
Ethyl ester (35): 1,4-dihydro-2,6
Methyl dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylate (664 mg) was added to anhydrous dimethylformamide-anhydrous dichloromethane (1: 4) (1
0 ml) and thionyl chloride (0.2 m
l) was added dropwise and stirred for 1 hour. To this, 1, 2, 3, 4
A solution of tetrahydro-1- (2-hydroxyethyl) quinoline (290 mg) in anhydrous dichloromethane (1 ml) was added dropwise, and further a solution of N-methylmorpholine (202 mg) in anhydrous dichloromethane (0.5 ml) was added dropwise. Stirring was continued for hours. The solvent was distilled off under reduced pressure, chloroform was added to the residue and the mixture was filtered through silica gel to remove most unnecessary substances,
The residue obtained by evaporating the filtrate under reduced pressure was subjected to silica gel column chromatography (hexane: acetone = 10: 1).
The title compound (35) (691 mg) was obtained after purification.
【００５３】黄色結晶 mp １３１−１３３℃1 H-NMR(CDCl3)δ:1.82-1.92(2H,m),2.34(6H,s),2.71(2
H,t,J= 6.5Hz),3.24(2H,t,J=6Hz),3.47(2H,t,J=6.5Hz),
3.65(3H,s),4.19-4.28(2H,m),5.12(1H,s),6.54(1H,t,J=
7.5Hz),6.56(1H,d,J=8.5Hz),6.68-6.79(1H,br),6.91(1
H,d,J=7.5Hz),6.97-7.02(1H,m),7.33(1H,t,J=8Hz),7.61
(1H,d,J=8Hz),7.95-8.00(1H,m),8.11(1H,t,J=2Hz). MS m/z：491(M+).Yellow crystal mp 131-133 ° C. 1 H-NMR (CDCl 3 ) δ: 1.82-1.92 (2H, m), 2.34 (6H, s), 2.71 (2
H, t, J = 6.5Hz), 3.24 (2H, t, J = 6Hz), 3.47 (2H, t, J = 6.5Hz),
3.65 (3H, s), 4.19-4.28 (2H, m), 5.12 (1H, s), 6.54 (1H, t, J =
7.5Hz), 6.56 (1H, d, J = 8.5Hz), 6.68-6.79 (1H, br), 6.91 (1
H, d, J = 7.5Hz), 6.97-7.02 (1H, m), 7.33 (1H, t, J = 8Hz), 7.61
(1H, d, J = 8Hz), 7.95-8.00 (1H, m), 8.11 (1H, t, J = 2Hz) .MS m / z: 491 (M + ).
【００５４】実施例１３ １，４−ジヒドロ−２，６−ジメチル−４−（３−ニト
ロフェニル）−３，５−ピリジンジカルボン酸 メチル
１−メチル−２−（１，２，３，４−テトラヒドロ−
１−キノリル）エチル エステル（３６）：１，４−ジ
ヒドロ−２，６−ジメチル−４−（３−ニトロフェニ
ル）−３，５−ピリジンジカルボン酸水素メチル（３３
２mg）を無水ジメチルホルムアミド−無水ジクロロメタ
ン（１：４）（５ml）の混液に溶解し、氷冷下塩化チオ
ニル（１ml）を滴下し１時間攪拌した。これに、１，
２，３，４−テトラヒドロ−１−（２−ヒドロキシプロ
ピル）キノリン（２６７mg）の無水ジクロロメタン（１
ml）溶液を滴下し、更にＮ−メチルモルホリン（３０３
mg）の無水ジクロロメタン（０．５ml）を滴下し氷冷下
３時間攪拌した。溶媒を減圧下留去し、残渣にクロロホ
ルムを加えシリカゲルで濾過した後、濾液を減圧下留去
して得られた残渣をシリカゲルカラムクロマトグラフィ
ー（ヘキサン：アセトン＝８：１）で精製して標題化合
物（３６）３４４mgを得た。EXAMPLE 13 1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid methyl 1-methyl-2- (1,2,3,4-) Tetrahydro-
1-Quinolyl) ethyl ester (36): 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid methyl hydrogen (33)
2 mg) was dissolved in a mixed solution of anhydrous dimethylformamide-anhydrous dichloromethane (1: 4) (5 ml), thionyl chloride (1 ml) was added dropwise under ice cooling, and the mixture was stirred for 1 hour. To this, 1,
2,3,4-Tetrahydro-1- (2-hydroxypropyl) quinoline (267 mg) in anhydrous dichloromethane (1
ml) solution was added dropwise, and N-methylmorpholine (303
Anhydrous dichloromethane (0.5 ml) (mg) was added dropwise and the mixture was stirred for 3 hours under ice cooling. The solvent was evaporated under reduced pressure, chloroform was added to the residue, and the mixture was filtered through silica gel. The filtrate was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane: acetone = 8: 1) to give the title. 344 mg of the compound (36) was obtained.
【００５５】1H-NMR(CDCl3)δ:1.12(1.5H,d,J=6.5Hz),
1.31(1.5H,d,J=6.5Hz),1.70-1.95(2H,m),2.31(1.5H,s),
2.32(3H,s),2.34(1.5H,s),2.62-2.72(2H,m),2.94-3.59
(4H,m),3.65(1.5H,s),3.67(1.5H,s),5.08(0.5H,s),5.10
(0.5H,s),5.15-5.28(1H,m),6.23(0.5H,s),6.29(0.5H,
s),6.49-6.55(1.5H,m),6.67(0.5H,d,J=8Hz),6.88(1H,t,
J=8Hz),6.93-7.03(1H,m),7.35(0.5H,t,J=8Hz),7.36(0.5
H,t,J=8Hz),7.59-7.66(1H,m),7.96-8.01(1H,m),8.12(1
H,t,J=2Hz). MS m/z:505(M+). 1 H-NMR (CDCl 3 ) δ: 1.12 (1.5H, d, J = 6.5Hz),
1.31 (1.5H, d, J = 6.5Hz), 1.70-1.95 (2H, m), 2.31 (1.5H, s),
2.32 (3H, s), 2.34 (1.5H, s), 2.62-2.72 (2H, m), 2.94-3.59
(4H, m), 3.65 (1.5H, s), 3.67 (1.5H, s), 5.08 (0.5H, s), 5.10
(0.5H, s), 5.15-5.28 (1H, m), 6.23 (0.5H, s), 6.29 (0.5H,
s), 6.49-6.55 (1.5H, m), 6.67 (0.5H, d, J = 8Hz), 6.88 (1H, t,
J = 8Hz), 6.93-7.03 (1H, m), 7.35 (0.5H, t, J = 8Hz), 7.36 (0.5
H, t, J = 8Hz), 7.59-7.66 (1H, m), 7.96-8.01 (1H, m), 8.12 (1
H, t, J = 2Hz) .MS m / z: 505 (M + ).
【００５６】実施例１４ １，４−ジヒドロ−２，６−ジメチル−４−（３−ニト
ロフェニル）−３，５−ピリジンジカルボン酸 １−エ
チル−２−（１，２，３，４−テトラヒドロ−１−キノ
リル）エチル メチル エステル（３７）：１，４−ジ
ヒドロ−２，６−ジメチル−４−（３−ニトロフェニ
ル）−３，５−ピリジンジカルボン酸水素メチル（３３
２mg）を無水ジメチルホルムアミド−無水ジクロロメタ
ン（１：４）（５ml）の混液に溶解し、氷冷下塩化チオ
ニル（１４３mg）の無水ジクロロメタン（０．５ml）溶
液を滴下し１時間攪拌した。これに１，２，３，４−テ
トラヒドロ−１−（２−ヒドロキシブチル）キノリン
（２４６mg）の無水ジクロロメタン（１ml）溶液を滴下
し、更にＮ−メチルモルホリン（３０３mg）の無水ジク
ロロメタン（０．５ml）溶液をを滴下し氷冷下２時間攪
拌を続けた。反応液に水を加えジクロロメタンで抽出
し、乾燥、溶媒を減圧下留去して得られた残渣をシリカ
ゲルカラムクロマトグラフィー（ヘキサン：アセトン＝
１０：１）で精製して標題化合物（３７）を得た。Example 14 1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 1-ethyl-2- (1,2,3,4-tetrahydro) -1-Quinolyl) ethyl methyl ester (37): 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylate methyl hydrogen (33)
2 mg) was dissolved in a mixed solution of anhydrous dimethylformamide-anhydrous dichloromethane (1: 4) (5 ml), and a solution of thionyl chloride (143 mg) in anhydrous dichloromethane (0.5 ml) was added dropwise under ice cooling and the mixture was stirred for 1 hour. A solution of 1,2,3,4-tetrahydro-1- (2-hydroxybutyl) quinoline (246 mg) in anhydrous dichloromethane (1 ml) was added dropwise thereto, and further N-methylmorpholine (303 mg) in anhydrous dichloromethane (0.5 ml). ) The solution was added dropwise and stirring was continued for 2 hours under ice cooling. Water was added to the reaction solution, extracted with dichloromethane, dried, and the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (hexane: acetone =).
Purification with 10: 1) gave the title compound (37).
【００５７】褐色無晶形物質1 H-NMR(CDCl3)δ:0.55(1.5H,t,J=7.5Hz),0.97(1.5H,t,J
=7.5Hz),1.38-1.90(4H,m),2.32(1.5H,s),2.33(1.5H,s),
2.34(1.5H,s),2.35(1.5H,s),2.61-2.71(2H,m),2.89-3.5
6(4H,m),3.66(3H,s),5.06-5.17(1H,m),5.08(1H,s),5.92
(0.5H,s),5.92(0.5H,s),6.49-6.57(1.5H,m),6.70(0.5H,
d,J=8Hz),6.84-6.90(1H,m),6.93-7.03(1H,m),7.35(1H,
t,J=8Hz),7.60-7.66(1H,m),7.97-8.01(1H,m),8.11(0.5
H,t,J=2Hz),8.12(0.5H,t,J=2Hz). MS m/z:519(M+).Brown amorphous substance 1 H-NMR (CDCl 3 ) δ: 0.55 (1.5H, t, J = 7.5Hz), 0.97 (1.5H, t, J
= 7.5Hz), 1.38-1.90 (4H, m), 2.32 (1.5H, s), 2.33 (1.5H, s),
2.34 (1.5H, s), 2.35 (1.5H, s), 2.61-2.71 (2H, m), 2.89-3.5
6 (4H, m), 3.66 (3H, s), 5.06-5.17 (1H, m), 5.08 (1H, s), 5.92
(0.5H, s), 5.92 (0.5H, s), 6.49-6.57 (1.5H, m), 6.70 (0.5H, s)
d, J = 8Hz), 6.84-6.90 (1H, m), 6.93-7.03 (1H, m), 7.35 (1H,
t, J = 8Hz), 7.60-7.66 (1H, m), 7.97-8.01 (1H, m), 8.11 (0.5
H, t, J = 2Hz), 8.12 (0.5H, t, J = 2Hz) .MS m / z: 519 (M + ).
【００５８】実施例１５ 実施例１４と同様の方法により表１４〜１８に示す化合
物（３８）〜化合物（４７）を合成した。Example 15 Compounds (38) to (47) shown in Tables 14 to 18 were synthesized in the same manner as in Example 14.
【００５９】[0059]
【表１４】 [Table 14]
【００６０】[0060]
【表１５】 [Table 15]
【００６１】[0061]
【表１６】 [Table 16]
【００６２】[0062]
【表１７】 [Table 17]
【００６３】[0063]
【表１８】 [Table 18]
【００６４】実施例１６ １，４−ジヒドロ−２，６−ジメチル−４−（３−ニト
ロフェニル）−３，５−ピリジンジカルボン酸メチル
１−（フェノキシメチル）−２−（１，２，３，４−テ
トラヒドロキノリン−１−イル）エチル エステル（４
８）：実施例１４と同様の方法により標題化合物（４
８）３６３mgを得た。この一部をとり、シリカゲルカラ
ムクロマトグラフィー（ベンゼン：アセトン＝３０：
１）でジアステレオマーを分離した。先溶出物質４８ａ
（黄色結晶）と後溶出物質４８ｂ（黄色結晶）の比率
は、４：３であった。Example 16 Methyl 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylate
1- (phenoxymethyl) -2- (1,2,3,4-tetrahydroquinolin-1-yl) ethyl ester (4
8): By a method similar to that in Example 14, the title compound (4
8) Obtained 363 mg. A part of this was taken and subjected to silica gel column chromatography (benzene: acetone = 30:
The diastereomers were separated in 1). Pre-eluted substance 48a
The ratio of (yellow crystals) to post-eluted substance 48b (yellow crystals) was 4: 3.
【００６５】48a:mp136-138℃.1 H-NMR(CDCl3)δ:1.80-1.89(2H,m),2.33(3H,s),2.35(3
H,s),2.70(2H,t,J=6.5Hz),3.33(2H,t,J=6Hz),3.60-3.65
(2H,m),3.64(3H,s),3.90(1H,dd,J=3.5,1.0Hz),3.98(1H,
dd,J=4,10Hz),5.12(1H,s),5.37-5.45(1H,m),6.16(1H,
s),6.55(1H,dt,J=1,7.5Hz),6.77-6.82(3H,m),6.88-7.05
(4H,m),7.22-7.29(2H,m),7.57-7.61(1H,m),7.82(1H,dd
d,J=1,2,8Hz),8.04(1H,t,J=2Hz). MS m/z:597(M+). 48b:1H-NMR(CDCl3)δ:1.71-1.80(2H,m),2.34(3H,s),2.3
6(3H,s),2.66(2H,t,J=6.5Hz),3.11(1H,t,J=5Hz),3.13-
(1H,t,J=5Hz),3.28(1H,dd,J=5.5,14.5Hz),3.47(1H,dd,J
=8.5,14.5Hz),3.60(3H,s),4.14(2H,d,J=3.5Hz),5.09(1
H,s),5.35-5.43(1H,m),6.06(1H,s),6.54(1H,t,J=7.5H
z),6.68(1H,d,J=8Hz),6.89(1H,dd,J=1.5,7.5Hz),6.93-
7.00(4H,m),7.27-7.32(2H,m),7.38(1H,t,J=8Hz),7.66-
7.71(1H,m),8.00(1H,ddd,J=1,2,8Hz),8.17(1H,t,J=2H
z).48a: mp 136-138 ° C. 1 H-NMR (CDCl 3 ) δ: 1.80-1.89 (2H, m), 2.33 (3H, s), 2.35 (3
H, s), 2.70 (2H, t, J = 6.5Hz), 3.33 (2H, t, J = 6Hz), 3.60-3.65
(2H, m), 3.64 (3H, s), 3.90 (1H, dd, J = 3.5,1.0Hz), 3.98 (1H,
dd, J = 4,10Hz), 5.12 (1H, s), 5.37-5.45 (1H, m), 6.16 (1H,
s), 6.55 (1H, dt, J = 1,7.5Hz), 6.77-6.82 (3H, m), 6.88-7.05
(4H, m), 7.22-7.29 (2H, m), 7.57-7.61 (1H, m), 7.82 (1H, dd
d, J = 1,2,8Hz), 8.04 (1H, t, J = 2Hz) .MS m / z: 597 (M + ). 48b: 1 H-NMR (CDCl 3 ) δ: 1.71-1.80 (2H , m), 2.34 (3H, s), 2.3
6 (3H, s), 2.66 (2H, t, J = 6.5Hz), 3.11 (1H, t, J = 5Hz), 3.13-
(1H, t, J = 5Hz), 3.28 (1H, dd, J = 5.5,14.5Hz), 3.47 (1H, dd, J
= 8.5,14.5Hz), 3.60 (3H, s), 4.14 (2H, d, J = 3.5Hz), 5.09 (1
H, s), 5.35-5.43 (1H, m), 6.06 (1H, s), 6.54 (1H, t, J = 7.5H
z), 6.68 (1H, d, J = 8Hz), 6.89 (1H, dd, J = 1.5,7.5Hz), 6.93-
7.00 (4H, m), 7.27-7.32 (2H, m), 7.38 (1H, t, J = 8Hz), 7.66-
7.71 (1H, m), 8.00 (1H, ddd, J = 1,2,8Hz), 8.17 (1H, t, J = 2H
z).
【００６６】実施例１７ １，４−ジヒドロ−２，６−ジメチル−４−（３−ニト
ロフェニル）−３，５−ピリジンジカルボン酸 ２−
｛〔３−（１，２，４，５−テトラヒドロ−７，８−ジ
メトキシ−２−オキソ−３Ｈ−３−ベンズアゼピン−３
−イル）プロピル〕−メチルアミノ｝エチル メチル
エステル（４９）：１，４−ジヒドロ−２，６−ジメチ
ル−４−（３−ニトロフェニル）−３，５−ピリジンジ
カルボン酸水素メチル（５４８mg）を無水ジメチルホル
ムアミド−無水ジクロロメタン混液（１：４）（５ml）
に溶かし、これに氷冷下、塩化チオニル（１９６mg）の
無水ジクロロメタン（０．５ml）溶液を滴下し、０℃で
１時間攪拌した。この溶液に、４，５−ジヒドロ−３−
｛３−〔（２−ヒドロキシエチル）メチルアミノ〕プロ
ピル｝−７，８−ジメトキシ−３Ｈ−３−ベンズアゼピ
ン−２（１Ｈ）−オン（５０４mg）の無水ジクロロメタ
ン（１ml）溶液を滴下した後、更にＮ−メチルモルホリ
ン（１５２mg）の無水ジクロロメタン（０．５ml）溶液
を滴下し、氷冷下、２時間攪拌を続けた。反応液に水を
加えジクロロメタンで抽出し、乾燥、溶媒を減圧留去し
て得られた残渣をシリカゲルカラムクロマトグラフィー
（クロロホルム：メタノール＝１０：１）で精製して、
標題化合物（４９）５５３mgを得た。Example 17 1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 2-
{[3- (1,2,4,5-Tetrahydro-7,8-dimethoxy-2-oxo-3H-3-benzazepine-3
-Yl) propyl] -methylamino} ethyl methyl
Ester (49): Methyl hydrogen (548 mg) of 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylate was mixed with anhydrous dimethylformamide-anhydrous dichloromethane (1: 4). ) (5 ml)
The resulting solution was dissolved in water and thionyl chloride (196 mg) in anhydrous dichloromethane (0.5 ml) was added dropwise thereto under ice cooling, followed by stirring at 0 ° C. for 1 hour. To this solution, 4,5-dihydro-3-
After a solution of {3-[(2-hydroxyethyl) methylamino] propyl} -7,8-dimethoxy-3H-3-benzazepin-2 (1H) -one (504 mg) in anhydrous dichloromethane (1 ml) was added dropwise, A solution of N-methylmorpholine (152 mg) in anhydrous dichloromethane (0.5 ml) was added dropwise, and stirring was continued for 2 hours under ice cooling. Water was added to the reaction solution, extracted with dichloromethane, dried, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1).
553 mg of the title compound (49) was obtained.
【００６７】黄色無晶形物質1 H-NMR(CDCl3)δ:1.66-1.78(2H,m),2.21(3H,s),2.35(3
H,s),2.36(3H,s),2.37-2.45(2H,m),2.51-2.67(2H,m),3.
03(2H,t,J=6Hz),3.42(2H,t,J=7Hz),3.63(3H,s),3.72(2
H,t,J=6Hz),3.81(2H,s),3.84(3H,s),3.85(3H,s),4.13(2
H,t,J=5.5Hz),5.11(1H,s),5.94(1H,s),6.56(1H,s),6.60
(1H,s),7.38(1H,t,J=8Hz),7.65(1H,dt,J=2,8Hz),7.99(1
H,dt,J=2,8Hz),8.11(1H,t,J=2Hz). MS m/z:650(M+).Yellow amorphous substance 1 H-NMR (CDCl 3 ) δ: 1.66-1.78 (2H, m), 2.21 (3H, s), 2.35 (3
H, s), 2.36 (3H, s), 2.37-2.45 (2H, m), 2.51-2.67 (2H, m), 3.
03 (2H, t, J = 6Hz), 3.42 (2H, t, J = 7Hz), 3.63 (3H, s), 3.72 (2
H, t, J = 6Hz), 3.81 (2H, s), 3.84 (3H, s), 3.85 (3H, s), 4.13 (2
H, t, J = 5.5Hz), 5.11 (1H, s), 5.94 (1H, s), 6.56 (1H, s), 6.60
(1H, s), 7.38 (1H, t, J = 8Hz), 7.65 (1H, dt, J = 2,8Hz), 7.99 (1
H, dt, J = 2,8Hz), 8.11 (1H, t, J = 2Hz) .MS m / z: 650 (M + ).
【００６８】実施例１８ 実施例１７と同様にして、表１９〜表２１に示す化合物
（５０）〜化合物（５３）を得た。Example 18 In the same manner as in Example 17, compounds (50) to (53) shown in Tables 19 to 21 were obtained.
【００６９】[0069]
【表１９】 [Table 19]
【００７０】[0070]
【表２０】 [Table 20]
【００７１】[0071]
【表２１】 [Table 21]
【００７２】実施例１９ １，４−ジヒドロ−２，６−ジメチル−４−（３−ニト
ロフェニル）−３，５−ピリジンジカルボン酸 ２−
｛〔３−（１０，１１−ジヒドロ−５Ｈ−ジベンズ
［ｂ，ｆ］アゼピン−５−イル）プロピル〕メチルアミ
ノ｝エチル メチルエステル（５４）：１，４−ジヒド
ロ−２，６−ジメチル−４−（３−ニトロフェニル）−
３，５−ピリジンジカルボン酸水素メチル（４７５mg）
を無水ジメチルホルムアミド−無水ジクロロメタン
（１：４）（５ml）の混液に溶解させ、氷冷下、塩化チ
オニル（１７０mg）の無水ジクロロメタン（０．５ml）
溶液を滴下し１時間攪拌した。この溶液に、１０，１１
−ジヒドロ−５−｛３−〔（２−ヒドロキシエチル）メ
チルアミノ〕プロピル｝−５Ｈ−ジベンズ［ｂ，ｆ］ア
ゼピン（３８５mg）の無水ジクロロメタン（１ml）溶液
を滴下し、更にＮ−メチルモルホリン（１３１mg）の無
水ジクロロメタン（０．５ml）溶液を加え、氷冷下４時
間攪拌を続けた。反応液に水を加えジクロロメタンで抽
出し、乾燥、溶媒を減圧留去して得られた残渣をシリカ
ゲルカラムクロマトグラフィー（ヘキサン：アセトン＝
５：１）で精製して、標題化合物（５４）１８０mgを得
た。Example 19 1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 2-
{[3- (10,11-Dihydro-5H-dibenz [b, f] azepin-5-yl) propyl] methylamino} ethyl methyl ester (54): 1,4-dihydro-2,6-dimethyl-4 -(3-Nitrophenyl)-
Methyl hydrogen 3,5-pyridinedicarboxylate (475 mg)
Was dissolved in a mixed solution of anhydrous dimethylformamide-anhydrous dichloromethane (1: 4) (5 ml), and thionyl chloride (170 mg) in anhydrous dichloromethane (0.5 ml) under ice cooling.
The solution was added dropwise and stirred for 1 hour. In this solution 10,11
A solution of -dihydro-5- {3-[(2-hydroxyethyl) methylamino] propyl} -5H-dibenz [b, f] azepine (385 mg) in anhydrous dichloromethane (1 ml) was added dropwise, and N-methylmorpholine ( A solution of 131 mg) in anhydrous dichloromethane (0.5 ml) was added, and stirring was continued for 4 hours under ice cooling. Water was added to the reaction solution, extracted with dichloromethane, dried, and the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (hexane: acetone =
Purification by 5: 1) gave 180 mg of the title compound (54).
【００７３】黄色無晶形物質1 H-NMR(CDCl3)δ:1.64-1.76(2H,m),2.15(3H,s),2.32(3
H,s),2.37(3H,s),2.42(2H,t,J=7Hz),2.53(2H,dt,J=3,7H
z),3.15(4H,s),3.63(3H,s),3.74(2H,t,J=7Hz),4.09(2H,
dt,J=3,7Hz),5.10(1H,s),5.78(1H,s),6.90(2H,dt,J=1.
5,7Hz),7.04-7.15(6H,m),7.34(1H,t,J=8Hz),7.65(1H,d,
J=8Hz),7.96-8.02(1H,m),8.09(1H,t,J=1Hz). MS m/z:607(M+).Yellow amorphous substance 1 H-NMR (CDCl 3 ) δ: 1.64-1.76 (2H, m), 2.15 (3H, s), 2.32 (3
H, s), 2.37 (3H, s), 2.42 (2H, t, J = 7Hz), 2.53 (2H, dt, J = 3,7H
z), 3.15 (4H, s), 3.63 (3H, s), 3.74 (2H, t, J = 7Hz), 4.09 (2H,
dt, J = 3,7Hz), 5.10 (1H, s), 5.78 (1H, s), 6.90 (2H, dt, J = 1.
5,7Hz), 7.04-7.15 (6H, m), 7.34 (1H, t, J = 8Hz), 7.65 (1H, d,
J = 8Hz), 7.96-8.02 (1H, m), 8.09 (1H, t, J = 1Hz) .MS m / z: 607 (M + ).
【００７４】実施例２０ 実施例１９と同様にして表２２〜表２３に示す化合物
（５５）〜化合物（５８）を合成した。Example 20 In the same manner as in Example 19, the compounds (55) to (58) shown in Tables 22 to 23 were synthesized.
【００７５】[0075]
【表２２】 [Table 22]
【００７６】[0076]
【表２３】 [Table 23]
【００７７】試験例１（カルシウム拮抗作用） 体重３５０〜４００ｇのモルモットを放血致死後、開腹
し、回腸を摘出し、この回腸よりＲｏｓｅｎｂｅｒｇｅ
ｒらの方法〔Ｒｏｓｅｎｂｅｒｇｅｒ ｅｔａｌ．，Ｃ
ａｎ．Ｊ．Ｐｈｙｓｉｏｌ．Ｐｈａｒｍａｃｏｌ．５
７，３３３−３４７（１９７９）〕に従って、縦走筋標
本を作成した。そして、９５％酸素及び５％二酸化炭素
の混合ガスを通気し、３７℃に保ち、２０ml Ｔｙｒａ
ｄｅ溶液を入れたマグヌス管に摘出回腸縦走筋標本を入
れ、０．５ｇの張力をかけて懸垂した。対照として、Ｋ
Ｃｌ ８０mMを投与して縦走筋を収縮させた。次いで、
被検薬投与（１０-8Ｍ）６０分後に、再びＫＣｌの収縮
を得、ＫＣｌ ８０mM投与によって得られた収縮高を１
００％とし、これに対する抑制率を求めた。結果を表２
４に示す。Test Example 1 (Calcium Antagonistic Action) A guinea pig having a body weight of 350 to 400 g was exsanguinated by bleeding, the abdomen was opened, and the ileum was excised. From this ileum, Rosenberg
r et al. [Rosenberger et al. , C
an. J. Physiol. Pharmacol. 5
7, 333-347 (1979)]. Then, a mixed gas of 95% oxygen and 5% carbon dioxide was aerated, and the temperature was maintained at 37 ° C., and 20 ml Tyra was used.
The extirpated ileum longitudinal muscle specimen was placed in the Magnus tube containing the de solution, and suspended with a tension of 0.5 g. As a control, K
The longitudinal muscle was contracted by administration of Cl 80 mM. Then
60 minutes after administration of the test drug (10 -8 M), contraction of KCl was obtained again, and the contraction height obtained by administration of 80 mM of KCl was 1
The inhibition rate was determined to be 00%. The results are shown in Table 2.
4 shows.
【００７８】[0078]
【表２４】 [Table 24]
【００７９】試験例２（血圧降下作用） 高血圧自然発症ラット（以下、「ＳＨＲ」と略す）に被
検薬を経口投与し、血圧降下作用を検討した。すなわ
ち、ＷｅｅｋｓとＪｏｎｅｓの方法（Ｗｅｅｋｓ Ｊ．
Ｒ．ａｎｄ Ｊｏｎｅｓ Ｊ．Ａ．，Ｐｒｏｃ．Ｓｏ
ｃ．Ｅｘｐｔｌ．Ｂｉｌ．Ｍｅｄ．，１０４巻，６４６
−６４８頁（１９６０年））に準じて、２５〜４０週齢
のＳＨＲの腹部大動脈にカテーテルを留置した。術後２
〜３日経過してから、背頸部から体外に導出したカテー
テルを血圧測定装置（ポリグラフＲＭ−６０００：日本
光電）に接続し、無麻酔・無拘束の条件下で、血圧及び
心拍数を測定した。被検薬は、０．５％カルボキシメチ
ルセルロースに懸濁して経口投与した。４時間以上の血
圧測定によって得られた基準血圧に対し、被検薬によっ
て最も低下した時の血圧をもって次式により降圧率を求
めた。Test Example 2 (Hypertensive action) The test drug was orally administered to spontaneously hypertensive rats (hereinafter abbreviated as "SHR") to examine the hypotensive action. That is, the method of Weeks and Jones (Weeks J. et al.
R. and Jones J. A. , Proc. So
c. Exptl. Bil. Med. , Volume 104 , 646
-648 (1960)), a catheter was placed in the abdominal aorta of SHR aged 25 to 40 weeks. 2 after surgery
~ After 3 days, connect the catheter derived from the back neck to the outside of the body and connect it to a blood pressure measurement device (Polygraph RM-6000: Nihon Kohden) to measure blood pressure and heart rate under unanesthetized and unrestrained conditions. did. The test drug was suspended in 0.5% carboxymethylcellulose and orally administered. With respect to the reference blood pressure obtained by measuring the blood pressure for 4 hours or more, the blood pressure at the time when it was most lowered by the test drug was used to determine the blood pressure reduction rate by the following formula.
【００８０】[0080]
【数１】 [Equation 1]
【００８１】結果を表２５に示す。尚、表中の化合物番
号は実施例に示したとおりである。The results are shown in Table 25. The compound numbers in the table are as shown in the examples.
【００８２】[0082]
【表２５】 [Table 25]
───────────────────────────────────────────────────── フロントページの続き (72)発明者 柿本 雅範 広島県高田郡甲田町下甲立1624 湧永製薬 株式会社内 (72)発明者 田村 浩一 広島県高田郡甲田町下甲立1624 湧永製薬 株式会社内 (72)発明者 平田 晃陰 広島県高田郡甲田町下甲立1624 湧永製薬 株式会社内 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Masanori Kakimoto 1624 Shimodate, Koda-cho, Takada-gun, Hiroshima Prefecture Yunaga Pharmaceutical Co., Ltd. (72) Inventor, Koin Hirata, 1624 Shimodateru, Koda-cho, Takada-gun, Hiroshima Prefecture Yunai Pharmaceutical Co., Ltd.
Claims (1)
アラルキル基、アシル基、トルエンスルホニル基又はエ
ステル化されたカルボキシル基を示し、Ｒ3 は水素原子
又は低級アルコキシ基を示し、Ｒ4 は水素原子又は低級
アルキル基を示し、Ｒ5 は水素原子、フェニル基、アラ
ルキル基又は低級アルコキシ、低級アルケニルオキシも
しくはフェノキシで置換されていてもよい低級アルキル
基を示し、Ｒ6 は水素原子、低級アルキル基又はフェニ
ル基を示し、Ｒ7 は低級アルキル基、アラルキル基又は
フェニル基を示す）〕で表わされるジヒドロピリジン誘
導体。1. The following general formula (1): (Here, R 2 is a lower alkyl group, a lower alkenyl group,
An aralkyl group, an acyl group, a toluenesulfonyl group or an esterified carboxyl group is shown, R 3 is a hydrogen atom or a lower alkoxy group, R 4 is a hydrogen atom or a lower alkyl group, R 5 is a hydrogen atom, phenyl Group, an aralkyl group or a lower alkyl group which may be substituted with lower alkoxy, lower alkenyloxy or phenoxy, R 6 represents a hydrogen atom, a lower alkyl group or a phenyl group, and R 7 represents a lower alkyl group or an aralkyl group. Or a phenyl group)].
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP14751892A JPH05339263A (en) | 1992-06-08 | 1992-06-08 | Dihydropyridine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP14751892A JPH05339263A (en) | 1992-06-08 | 1992-06-08 | Dihydropyridine derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH05339263A true JPH05339263A (en) | 1993-12-21 |
Family
ID=15432149
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP14751892A Pending JPH05339263A (en) | 1992-06-08 | 1992-06-08 | Dihydropyridine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH05339263A (en) |
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| US7365071B2 (en) | 2002-09-05 | 2008-04-29 | Branislav Musicki | Heterocyclic compounds, preparation process and intermediates, and use as medicaments, in particular as β-lactamase inhibitors and antibacterials |
| US7612087B2 (en) | 2002-01-28 | 2009-11-03 | Novexel | Heterocyclic compounds as inhibitors of beta-lactamases |
| US7704993B2 (en) | 2003-06-17 | 2010-04-27 | Arena Pharmaceuticals, Inc. | Benzazepine derivatives and methods of prophylaxis or treatment of 5ht2c receptor associated diseases |
| JP2012006939A (en) * | 2005-10-04 | 2012-01-12 | Mitsubishi Tanabe Pharma Corp | Optically active cyclic alcohol compound and method for producing the same |
| US8153621B2 (en) | 2004-12-23 | 2012-04-10 | Arena Pharmaceuticals, Inc. | 5ht2C receptor modulator compositions |
| US8168782B2 (en) | 2006-04-03 | 2012-05-01 | Arena Pharmaceuticals, Inc. | Processes for the preparation of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and intermediates related thereto |
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-
1992
- 1992-06-08 JP JP14751892A patent/JPH05339263A/en active Pending
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