JPH0867681A - Apovincamic acid derivative and medicine containing the same - Google Patents
Apovincamic acid derivative and medicine containing the sameInfo
- Publication number
- JPH0867681A JPH0867681A JP6155644A JP15564494A JPH0867681A JP H0867681 A JPH0867681 A JP H0867681A JP 6155644 A JP6155644 A JP 6155644A JP 15564494 A JP15564494 A JP 15564494A JP H0867681 A JPH0867681 A JP H0867681A
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- Prior art keywords
- compound
- acid
- apovincamic
- formula
- ddd
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- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は新規なアポビンカミン酸
誘導体、更に詳細には、優れた血管拡張作用及び血小板
凝集阻害作用を有するアポビンカミン酸誘導体及びその
酸付加塩に関する。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel apovincamic acid derivative, and more particularly to an apovincamic acid derivative having excellent vasodilatory action and platelet aggregation inhibitory action and its acid addition salt.
【０００２】[0002]
【従来の技術】従来、アポビンカミン酸エステルが脳血
管障害、末梢血管障害、狭心症、高血圧症の治療に有効
であることが報告されており（特開昭５６−７１０９１
号、同５９−６２５９０号）、特にアポビンカミン酸エ
チルエステル（ビンポセチン）は臨床試験に供されてい
る。Conventionally, it has been reported that apovincamic acid ester is effective for treating cerebrovascular disorders, peripheral vascular disorders, angina pectoris, and hypertension (JP-A-56-71091).
No. 59-62590), especially apovincaminic acid ethyl ester (vinpocetine) has been subjected to clinical trials.
【０００３】[0003]
【発明が解決しようとする課題】しかしながら、従来公
知のアポビンカミン酸エステルの上記医薬効果はまだ充
分とは云えず、更に効果の優れたアポビンカミン酸誘導
体の開発が望まれていた。However, the above-mentioned medicinal effects of the conventionally known apovincamic acid ester are not yet sufficient, and there has been a demand for the development of an apovincamic acid derivative having further excellent effects.
【０００４】[0004]
【課題を解決するための手段】そこで、本発明者は鋭意
研究を行った結果、アポビンカミン酸骨格の１１位にス
ルホニルアミノ基を導入した新規なアポビンカミン酸誘
導体が優れた血管拡張作用と共に優れた血小板凝集阻害
作用を有することを見出し、本発明を完成した。従っ
て、本発明は、一般式（１）Therefore, as a result of earnest studies, the present inventors have found that a novel apovincamic acid derivative having a sulfonylamino group introduced at the 11-position of the apovincamic acid skeleton has excellent vasodilator action and excellent platelet expansion. The present invention has been completed by finding that it has an aggregation inhibitory action. Therefore, the present invention provides the general formula (1)
【０００５】[0005]
【化２】 Embedded image
【０００６】（式中、Ｒ1 は低級アルキル基を示し、Ｒ
2 はハロゲン原子、低級アルキル基、低級アルコキシ
基、低級アルコキシカルボニル基、アシルアミノ基又は
ニトロ基が置換していてもよいアリール基；ベンジル
基；キノリル基又はチエニル基を示す）(In the formula, R 1 represents a lower alkyl group,
2 represents a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, an acylamino group or an aryl group which may be substituted with a nitro group; a benzyl group; a quinolyl group or a thienyl group)
【０００７】で表わされるアポビンカミン酸誘導体又は
その酸付加塩を提供するものである。また、本発明は、
上記一般式（１）で表わされるアポビンカミン酸誘導体
又はその酸付加塩を含有する医薬を提供するものであ
る。The present invention provides an apovincamic acid derivative represented by: or an acid addition salt thereof. Also, the present invention
The present invention provides a medicament containing the apovincamic acid derivative represented by the general formula (1) or an acid addition salt thereof.
【０００８】本発明の一般式（１）において、低級アル
キル基は炭素数１〜６の直鎖状又は分枝鎖状のものであ
って、例えばメチル、エチル、ｎ−プロピル、イソプロ
ピル、ｎ−ブチル、ｓｅｃ−ブチル、ｔｅｒｔ−ブチ
ル、ｎ−ペンチル、イソペンチル、ｎ−ヘキシル、イソ
ヘキシル基等が挙げられる。ハロゲン原子としては弗
素、塩素、臭素又はヨウ素が挙げられる。低級アルコキ
シ基としては炭素数１〜６のアルコキシ基、例えばメト
キシ、エトキシ、プロポキシ、ブトオキシ基等が挙げら
れる。低級アルコキシカルボニル基としてはアルコキシ
基の炭素数が１〜６のもの、例えばメトキシカルボニ
ル、エトキシカルボニル、プロポキシカルボニル、ブト
キシカルボニル基等が挙げられる。アシルアミノ基とし
てはアシル基の炭素数が１〜６のもの、例えばアセチル
アミノ、プロピオニルアミノ、ブチリルアミノ、バレリ
ルアミノ基等が挙げられる。In the general formula (1) of the present invention, the lower alkyl group is a straight chain or branched chain having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl and n-. Examples thereof include butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl and isohexyl groups. Examples of the halogen atom include fluorine, chlorine, bromine and iodine. Examples of the lower alkoxy group include alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy and butoxy groups. Examples of the lower alkoxycarbonyl group include alkoxy groups having 1 to 6 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and butoxycarbonyl groups. Examples of the acylamino group include those having an acyl group having 1 to 6 carbon atoms, such as acetylamino, propionylamino, butyrylamino and valerylamino groups.
【０００９】本発明のアポビンカミン酸誘導体（１）の
酸付加塩としては、例えば塩酸、臭化水素酸、硫酸、リ
ン酸、硝酸等の無機酸塩；ギ酸、酢酸、プロピオン酸、
グルコール酸、マレイン酸、フマル酸、コハク酸、酒石
酸、アスコルビン酸、クエン酸、リンゴ酸、サリチル
酸、乳酸、安息香酸、ｐ−トルエンスルホン酸、メタン
スルホン酸等の有機酸塩等の医薬品として許容される塩
類が挙げられる。Examples of the acid addition salt of the apovincamic acid derivative (1) of the present invention include inorganic acid salts such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and nitric acid; formic acid, acetic acid, propionic acid,
Accepted as pharmaceuticals such as glycolic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, ascorbic acid, citric acid, malic acid, salicylic acid, lactic acid, benzoic acid, p-toluenesulfonic acid and methanesulfonic acid Salt.
【００１０】本発明のアポビンカミン酸誘導体（１）
は、例えば次の反応式によって示される方法により製造
される。Apovincamic acid derivative of the present invention (1)
Is produced, for example, by the method represented by the following reaction formula.
【００１１】[0011]
【化３】 [Chemical 3]
【００１２】（式中、Ｘはハロゲン原子を示し、Ｒ1 及
びＲ2 は前記と同じものを示す） すなわち、アポビンカミン酸エステル（２）をニトロ化
して１１−ニトロ−アポビンカミン酸エステル（３）と
なし、次いでこれを還元して１１−アミノ−アポビンカ
ミン酸エステル（４）となし、更にこれにスルホニルハ
ロゲニド類（５）を反応せしめてアポビンカミン酸誘導
体（１）を製造する。(In the formula, X represents a halogen atom, and R 1 and R 2 represent the same as described above.) That is, the apovincamic acid ester (2) is nitrated to obtain 11-nitro-apovincamic acid ester (3). None, and then it is reduced to 11-amino-apovincamic acid ester (4), which is further reacted with a sulfonyl halogenide (5) to produce an apovincamic acid derivative (1).
【００１３】原料のアポビンカミン酸エステルは、特開
昭５９−６２５９０号公報において公知のアポビンカミ
ン酸をエステル化することにより容易に製造することが
できる。The raw material apovincamic acid ester can be easily produced by esterifying apovincamic acid known in JP-A-59-62590.
【００１４】アポビンカミン酸エステル（２）のニトロ
化は濃硝酸を用いる一般的なニトロ化法によって行われ
る。このようにするとき、アポビンカミン骨格の９、１
０、１１位にニトロ基が置換した化合物の混合物が得ら
れるが、これらはカラムクロマトグラフィー等によって
容易に分離することができる。１１−ニトロ−アポビン
カミン酸エステル（３）の還元は二酸化白金、ラネーニ
ッケル、パラジウム等の触媒を用いる接触還元等によっ
て行われる。The nitration of apovincamic acid ester (2) is carried out by a general nitration method using concentrated nitric acid. When doing this, the apovincamine skeleton 9,1
A mixture of compounds having a nitro group at the 0- and 11-positions is obtained, which can be easily separated by column chromatography or the like. The reduction of 11-nitro-apovincamic acid ester (3) is performed by catalytic reduction using a catalyst such as platinum dioxide, Raney nickel, palladium or the like.
【００１５】１１−アミノ−アポビンカミン酸エステル
（４）とスルホニルハロゲニド類（５）との反応は、ピ
リジン、トリエチルアミン等の塩基の存在下、ピリジ
ン、テトラヒドロフラン、ジメチルホルムアミド、ジク
ロロメタン等の不活性溶媒中、氷冷下ないし室温で行わ
れる。The reaction of 11-amino-apovincamic acid ester (4) with sulfonylhalogenides (5) is carried out in the presence of a base such as pyridine and triethylamine in an inert solvent such as pyridine, tetrahydrofuran, dimethylformamide and dichloromethane. , Under ice-cooling to room temperature.
【００１６】本発明のアポビンカミン酸誘導体（１）は
血管拡張に基づく血流増加作用、血小板凝集阻害による
抗血栓作用を有することから、脳血管障害（脳梗塞後遺
症、脳出血後遺症、脳動脈硬化症）、虚血性心疾患（脳
血栓、心筋梗塞等）に伴う血栓・塞栓、慢性動脈閉塞症
等の治療剤及び血流障害の改善剤として使用できる。Since the apovincamic acid derivative (1) of the present invention has a blood flow increasing action based on vasodilation and an antithrombotic action due to inhibition of platelet aggregation, it has cerebrovascular disorders (aftereffects of cerebral infarction, aftereffects of cerebral hemorrhage, cerebral arteriosclerosis). It can be used as a therapeutic agent for thrombosis / embolism associated with ischemic heart disease (cerebral thrombosis, myocardial infarction, etc.), chronic arterial occlusion, etc., and an agent for improving blood flow disorders.
【００１７】上記の目的のために、本発明のアポビンカ
ミン酸誘導体（１）及びその酸付加塩は経口又は非経口
的に投与することができる。従って、アポビンカミン酸
誘導体は常法によって、錠剤、粉剤、顆粒剤、カプセル
剤、液剤、乳剤、懸濁剤、注射剤等に調製される。アポ
ビンカミン酸誘導体又はその酸付加塩の投与量は年令、
疾病の種類及び程度、投与方法等によっても異なるが、
一般に１日に１〜１００mgが好ましい。For the above purpose, the apovincamic acid derivative (1) of the present invention and its acid addition salt can be administered orally or parenterally. Therefore, the apovincamic acid derivative is prepared into tablets, powders, granules, capsules, solutions, emulsions, suspensions, injections and the like by a conventional method. The dose of apovincamic acid derivative or its acid addition salt is
Depending on the type and degree of disease, administration method, etc.,
Generally, 1-100 mg / day is preferred.
【００１８】[0018]
【発明の効果】本発明のアポビンカミン酸誘導体（１）
及びその酸付加塩は優れた血管拡張作用及び血小板凝集
阻害作用を有し、脳血管障害、血栓・塞栓、慢性動脈閉
塞症の治療及び血流障害の改善に使用することができ
る。The apovincamic acid derivative of the present invention (1)
And its acid addition salts have excellent vasodilatory action and platelet aggregation inhibitory action, and can be used for treatment of cerebrovascular disorders, thrombosis / embolism, chronic arterial occlusion, and improvement of blood flow disorders.
【００１９】[0019]
【実施例】次に実施例及び試験例を挙げて、本発明を更
に詳細に説明する。EXAMPLES The present invention will be described in more detail with reference to Examples and Test Examples.
【００２０】実施例１ （ｉ）アポビンカミン酸エチルエステルの合成：エタノ
ール１８０mlにビンカミン酸６．０ｇを加え、氷浴攪拌
下濃硫酸３４．５ｇ（３５２mmol）を注意深く加えた
後、８時間加熱還流した。反応液を減圧下濃縮し、氷水
１００mlを加え、１０％ＮａＯＨ水溶液で中和し、析出
結晶をジクロロメタンで抽出（５０ml×３）した。飽和
ＮａＣｌ水で洗浄後硫酸マグネシウムで乾燥し減圧下に
溶媒を留去して得た残渣にエタノールを加え結晶化さ
せ、濾取し、標記化合物４．９ｇ（収率７９％）を得
た。1 H-NMR(270MHz,CDCl3)δ：7.46(1H,d,J=8.6Hz), 7.24(1
H,d,J=8.6Hz), 7.18-7.08(2H,m), 6.11(1H,s),4.47-4.3
8(2H,m), 4.14(1H,brs), 3.35(1H,dd,J=13.7,5.4Hz),3.
25(1H,ddd,J=13.5,11.2,5.0Hz), 3.09-2.93(1H,m),2.62
(2H,dd,J=8.7,2.8Hz), 2.50(1H,brd,J=16.3Hz), 1.91(2
H,m),1.76-1.63(1H,m), 1.51(1H,brd,J=13.5Hz), 1.43-
1.32(1H,m),1.39(3H,t,J=7.3Hz), 1.01(3H,t,J=7.6Hz),
1.06-0.91(1H,m).Example 1 (i) Synthesis of apovincamic acid ethyl ester: 6.0 g of vincamic acid was added to 180 ml of ethanol, 34.5 g (352 mmol) of concentrated sulfuric acid was carefully added under stirring in an ice bath, and the mixture was heated under reflux for 8 hours. . The reaction mixture was concentrated under reduced pressure, 100 ml of ice water was added, the mixture was neutralized with 10% NaOH aqueous solution, and the precipitated crystals were extracted with dichloromethane (50 ml × 3). The mixture was washed with saturated aqueous NaCl solution, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethanol was added to the obtained residue for crystallization, and the crystals were collected by filtration to give the title compound (4.9 g, yield 79%). 1 H-NMR (270MHz, CDCl 3 ) δ: 7.46 (1H, d, J = 8.6Hz), 7.24 (1
H, d, J = 8.6Hz), 7.18-7.08 (2H, m), 6.11 (1H, s), 4.47-4.3
8 (2H, m), 4.14 (1H, brs), 3.35 (1H, dd, J = 13.7,5.4Hz), 3.
25 (1H, ddd, J = 13.5,11.2,5.0Hz), 3.09-2.93 (1H, m), 2.62
(2H, dd, J = 8.7,2.8Hz), 2.50 (1H, brd, J = 16.3Hz), 1.91 (2
H, m), 1.76-1.63 (1H, m), 1.51 (1H, brd, J = 13.5Hz), 1.43-
1.32 (1H, m), 1.39 (3H, t, J = 7.3Hz), 1.01 (3H, t, J = 7.6Hz),
1.06-0.91 (1H, m).
【００２１】（ii）１１−ニトロ−アポビンカミン酸エ
チルエステルの合成：無水酢酸１００mlに、氷浴攪拌
下、７０％硝酸１００mlを約２０分を要して滴下し、更
に濃硫酸を１滴加え、同条件下約１５ml攪拌した。その
溶液にアポビンカミン酸エチルエステル４０ｇを同条件
下少量ずつ加え、約２時間攪拌した。その後２０％Ｎａ
ＯＨ水で注意深く中和し、酢酸エチルで抽出（２００ml
×３）した。飽和ＮａＣｌ水で洗浄後、硫酸マグネシウ
ムで乾燥し、減圧下に溶媒を留去して得た残渣５９ｇを
２kgのシリカゲルを用いてカラムクロマトグラフィーに
付し、１％トリエチルアミンを含む酢酸エチルで溶出し
て標記化合物１８ｇ（収率４０％）を得た。1 H-NMR(270MHz,CDCl3)δ：8.28(1H,d,J=2.0Hz), 8.05(1
H,dd,J=8.6,2.0Hz), 7.49(1H,d,J=8.6Hz),6.34(1H,s),
4.53-4.44(2H,m), 4.16(1H,brs), 3.39(1H,dd,J=13.8,
5.6Hz),3.25(1H,ddd,J=13.8,11.0,5.1Hz), 3.13-2.98(1
H,m),2.72-2.48(3H,m), 1.94(2H,m), 1.77-1.67(1H,m),
1.57(1H,brd,J=13.5Hz),1.43(3H,t,J=7.1Hz), 1.46-1.
33(1H,m), 1.04(3H,t,J=7.4Hz),1.06-0.91(1H,m).(Ii) Synthesis of 11-nitro-apovincamic acid ethyl ester: To 100 ml of acetic anhydride, 100 ml of 70% nitric acid was added dropwise over about 20 minutes while stirring in an ice bath, and 1 drop of concentrated sulfuric acid was added. About 15 ml was stirred under the same conditions. To the solution, 40 g of apovincamic acid ethyl ester was added little by little under the same conditions, and the mixture was stirred for about 2 hours. Then 20% Na
Carefully neutralize with OH water and extract with ethyl acetate (200 ml).
X3). After washing with saturated NaCl water, drying with magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 59 g of the residue, which was subjected to column chromatography using 2 kg of silica gel and eluted with ethyl acetate containing 1% triethylamine. 18 g (40% yield) of the title compound were obtained. 1 H-NMR (270MHz, CDCl 3 ) δ: 8.28 (1H, d, J = 2.0Hz), 8.05 (1
H, dd, J = 8.6,2.0Hz), 7.49 (1H, d, J = 8.6Hz), 6.34 (1H, s),
4.53-4.44 (2H, m), 4.16 (1H, brs), 3.39 (1H, dd, J = 13.8,
5.6Hz), 3.25 (1H, ddd, J = 13.8,11.0,5.1Hz), 3.13-2.98 (1
H, m), 2.72-2.48 (3H, m), 1.94 (2H, m), 1.77-1.67 (1H, m),
1.57 (1H, brd, J = 13.5Hz), 1.43 (3H, t, J = 7.1Hz), 1.46-1.
33 (1H, m), 1.04 (3H, t, J = 7.4Hz), 1.06-0.91 (1H, m).
【００２２】（iii）１１−アミノ−アポビンカミン酸
エチルエステルの合成：１１−ニトロ−アポビンカミン
酸エチルエステル３．７ｇをエタノール２００mlに溶か
し、二酸化白金２００mgを加え、水素雰囲気下、常温常
圧で２時間攪拌した。ＴＬＣで反応の終了を確認後、セ
ライトを通して濾過し、減圧下に溶媒を留去して標記化
合物を得た。1 H-NMR(270MHz,CDCl3)δ：7.23(1H,dd,J=7.4,1.8Hz),
6.58(1H,s), 6.56(1H,dd,J=7.4,1.8Hz),6.06(1H,s), 4.
42(2H,dd,J=14.2,6.9Hz), 4.09(1H,brs), 3.61(2H,s),
3.32(1H,dd,J=13.5,5.3Hz), 3.21(1H,ddd,J=13.5,10.9,
5.0Hz),3.04-2.91(1H,m), 2.68-2.56(2H,m), 2.43(1H,b
rd), 1.89(2H,m),1.77-1.63(1H,m), 1.50(1H,brd,J=13.
5Hz), 1.40(3H,t,J=7.1Hz),1.43-1.35(1H,m), 1.00(3H,
t,J=7.4Hz), 1.07-0.90(1H,m).(Iii) Synthesis of 11-amino-apovincamic acid ethyl ester: 3.7-g of 11-nitro-apovincamic acid ethyl ester was dissolved in 200 ml of ethanol, 200 mg of platinum dioxide was added, and the mixture was added under hydrogen atmosphere at room temperature and atmospheric pressure for 2 hours. It was stirred. After confirming the completion of the reaction by TLC, the mixture was filtered through Celite and the solvent was evaporated under reduced pressure to give the title compound. 1 H-NMR (270MHz, CDCl 3 ) δ: 7.23 (1H, dd, J = 7.4,1.8Hz),
6.58 (1H, s), 6.56 (1H, dd, J = 7.4,1.8Hz), 6.06 (1H, s), 4.
42 (2H, dd, J = 14.2,6.9Hz), 4.09 (1H, brs), 3.61 (2H, s),
3.32 (1H, dd, J = 13.5,5.3Hz), 3.21 (1H, ddd, J = 13.5,10.9,
5.0Hz), 3.04-2.91 (1H, m), 2.68-2.56 (2H, m), 2.43 (1H, b
rd), 1.89 (2H, m), 1.77-1.63 (1H, m), 1.50 (1H, brd, J = 13.
5Hz), 1.40 (3H, t, J = 7.1Hz), 1.43-1.35 (1H, m), 1.00 (3H,
t, J = 7.4Hz), 1.07-0.90 (1H, m).
【００２３】（iv）１１−フェニルスルホニルアミノ−
アポビンカミン酸エチルエステル（化合物１）の合成：
１１−アミノ−アポビンカミン酸エチルエステル５００
mgをピリジン２０mlに溶解し、氷浴攪拌下、ベンゼンス
ルフォニルクロリド２７８mgを加え、同条件下２時間半
攪拌した。減圧下に溶媒を留去して得た残渣を塩化メチ
レンに溶解し、飽和ＮａＣｌ水で洗浄後、硫酸マグネシ
ウムで乾燥し、減圧下に溶媒を留去した。得られた残渣
を２０倍量のシリカゲルカラムに付し酢酸エチルで溶出
して標記化合物４７８mg（収率６９％）を得た。1 H-NMR(CDCl3,δppm)：7.78(2H,d,J=6.9Hz), 7.52(1H,
t,J=7.4Hz), 7.42(2H,t,J=7.4Hz),7.24(1H,d,J=8.2Hz),
7.15(1H,d,J=1.7Hz), 6.64(1H,dd,J=8.4,1.8Hz),6.41
(1H,br), 6.12(1H,s), 4.52-4.32(2H,m), 4.10(1H,br
s),3.33(1H,dd,J=13.5,5.9Hz), 3.20(1H,ddd,J=13.8,1
1.1,5.1Hz),3.03-2.91(1H,m), 2.61-2.53(1H,m), 2.54
(1H,dd,J=11.2,2.6Hz),2.43(1H,dd,J=16.8,3.3Hz), 1.9
0(2H,m), 1.79-1.68(1H,m),1.53(1H,brd,J=13.5Hz), 1.
44-1.36(1H,m), 1.38(3H,t,J=7.2Hz),1.03-0.86(1H,m),
1.00(3H,t,J=7.4Hz)(Iv) 11-phenylsulfonylamino-
Synthesis of apovincamic acid ethyl ester (Compound 1):
11-Amino-apovincamic acid ethyl ester 500
mg was dissolved in 20 ml of pyridine, 278 mg of benzenesulfonyl chloride was added with stirring in an ice bath, and the mixture was stirred for 2 hours and a half under the same conditions. The solvent was distilled off under reduced pressure, the obtained residue was dissolved in methylene chloride, washed with saturated aqueous NaCl, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was applied to a 20-fold amount silica gel column and eluted with ethyl acetate to obtain 478 mg (yield 69%) of the title compound. 1 H-NMR (CDCl 3 , δppm): 7.78 (2H, d, J = 6.9Hz), 7.52 (1H,
t, J = 7.4Hz), 7.42 (2H, t, J = 7.4Hz), 7.24 (1H, d, J = 8.2Hz),
7.15 (1H, d, J = 1.7Hz), 6.64 (1H, dd, J = 8.4,1.8Hz), 6.41
(1H, br), 6.12 (1H, s), 4.52-4.32 (2H, m), 4.10 (1H, br
s), 3.33 (1H, dd, J = 13.5,5.9Hz), 3.20 (1H, ddd, J = 13.8,1
1.1,5.1Hz), 3.03-2.91 (1H, m), 2.61-2.53 (1H, m), 2.54
(1H, dd, J = 11.2,2.6Hz), 2.43 (1H, dd, J = 16.8,3.3Hz), 1.9
0 (2H, m), 1.79-1.68 (1H, m), 1.53 (1H, brd, J = 13.5Hz), 1.
44-1.36 (1H, m), 1.38 (3H, t, J = 7.2Hz), 1.03-0.86 (1H, m),
1.00 (3H, t, J = 7.4Hz)
【００２４】実施例２〜２４ 実施例１と同様にして以下の化合物を得た。Examples 2 to 24 The following compounds were obtained in the same manner as in Example 1.
【００２５】化合物２： １１−フェニルスルホニルア
ミノ−アポビンカミン酸メチルエステル1 H-NMR(CDCl3,δppm)：7.76(2H,d,J=6.9Hz), 7.53(1H,
t,J=7.4Hz), 7.42(2H,t,J=7.4Hz),7.25(1H,d,J=8.6Hz),
7.15(1H,d,J=1.7Hz), 6.63(1H,dd,J=8.2,2.0Hz),6.49
(1H,br), 6.16(1H,s), 4.11(1H,brs), 3.93(3H,s),3.35
(1H,dd,J=13.8,6.1Hz), 3.21(1H,ddd,J=13.5,11.2,5.0H
z),3.03-2.89(1H,m), 2.70-2.54(1H,m), 2.56(1H,dd,J=
10.9,2.6Hz),2.45(1H,dd,J=16.2,2.9Hz), 1.90(2H,m),
1.78-1.62(1H,m),1.53(1H,brs,J=13.2Hz), 1.44-1.39(1
H,m), 1.01(3H,t,J=7.4Hz),1.03-0.86(1H,m).Compound 2: 11-phenylsulfonylamino-apovincamic acid methyl ester 1 H-NMR (CDCl 3 , δppm): 7.76 (2H, d, J = 6.9Hz), 7.53 (1H,
t, J = 7.4Hz), 7.42 (2H, t, J = 7.4Hz), 7.25 (1H, d, J = 8.6Hz),
7.15 (1H, d, J = 1.7Hz), 6.63 (1H, dd, J = 8.2,2.0Hz), 6.49
(1H, br), 6.16 (1H, s), 4.11 (1H, brs), 3.93 (3H, s), 3.35
(1H, dd, J = 13.8,6.1Hz), 3.21 (1H, ddd, J = 13.5,11.2,5.0H
z), 3.03-2.89 (1H, m), 2.70-2.54 (1H, m), 2.56 (1H, dd, J =
10.9,2.6Hz), 2.45 (1H, dd, J = 16.2,2.9Hz), 1.90 (2H, m),
1.78-1.62 (1H, m), 1.53 (1H, brs, J = 13.2Hz), 1.44-1.39 (1
H, m), 1.01 (3H, t, J = 7.4Hz), 1.03-0.86 (1H, m).
【００２６】化合物３： １１−（４−クロロフェニ
ル）スルホニルアミノ−アポビンカミン酸メチルエステ
ル1 H-NMR(CDCl3,δppm)：（NHがきれいに出ていない） 7.70(2H,d,J=7.6Hz), 7.36(2H,d,J=7.6Hz), 7.25(1H,d,
J=8.3Hz),7.13(1H,d,J=2.0Hz), 6.68(1H,dd,J=8.3,2.0H
z), 6.17(1H,s),4.10(1H,brs), 3.94(3H,s), 3.32(1H,d
d,J=13.5,5.6Hz),3.20(1H,ddd,J=13.5,11.2,5.3Hz), 3.
04-2.87(1H,m), 2.65-2.59(1H,m),2.54(1H,dd,J=11.2,
2.6Hz), 2.43(1H,ddd,J=16.5,6.2,2.3Hz), 1.89(2H,m),
1.82-1.62(1H,m), 1.51(1H,brd,J=13.5Hz), 1.40(1H,
m),1.00(3H,t,J=7.3Hz), 1.02-0.90(1H,m).Compound 3: 11- (4-chlorophenyl) sulfonylamino-apovincamic acid methyl ester 1 H-NMR (CDCl 3 , δppm): (NH is not cleanly emitted) 7.70 (2H, d, J = 7.6Hz) , 7.36 (2H, d, J = 7.6Hz), 7.25 (1H, d,
J = 8.3Hz), 7.13 (1H, d, J = 2.0Hz), 6.68 (1H, dd, J = 8.3,2.0H
z), 6.17 (1H, s), 4.10 (1H, brs), 3.94 (3H, s), 3.32 (1H, d
d, J = 13.5,5.6Hz), 3.20 (1H, ddd, J = 13.5,11.2,5.3Hz), 3.
04-2.87 (1H, m), 2.65-2.59 (1H, m), 2.54 (1H, dd, J = 11.2,
2.6Hz), 2.43 (1H, ddd, J = 16.5,6.2,2.3Hz), 1.89 (2H, m),
1.82-1.62 (1H, m), 1.51 (1H, brd, J = 13.5Hz), 1.40 (1H,
m), 1.00 (3H, t, J = 7.3Hz), 1.02-0.90 (1H, m).
【００２７】化合物４： １１−（４−ブロモフェニ
ル）スルホニルアミノ−アポビンカミン酸エチルエステ
ル1 H-NMR(CDCl3,δppm)：7.64(2H,d,J=8.9Hz), 7.54(2H,
d,J=8.9Hz), 7.25(1H,d,J=8.2Hz),7.14(1H,d,J=2.0Hz),
6.85(1H,br), 6.68(1H,dd,J=8.2,2.0Hz),6.14(1H,s),
4.50-4.29(2H,m), 4.09(1H,brs), 3.32(1H,dd,J=13.6,
5.6Hz),3.19(1H,ddd,J=13.6,11.2,5.0Hz), 3.02-2.91(1
H,m), 2.59(1H,brs),2.53(1H,dd,J=11.0,3.0Hz), 2.43
(1H,ddd,J=18.2,4.6,2.0Hz),1.94-1.84(2H,m), 1.79-1.
69(1H,m), 1.49(1H,m), 1.38(3H,t,J=7.1Hz),1.26-1.25
(1H,m), 0.99(3H,t,J=7.4Hz), 0.92-0.85(1H,m).Compound 4: 11- (4-Bromophenyl) sulfonylamino-apovincamic acid ethyl ester 1 H-NMR (CDCl 3 , δppm): 7.64 (2H, d, J = 8.9Hz), 7.54 (2H,
d, J = 8.9Hz), 7.25 (1H, d, J = 8.2Hz), 7.14 (1H, d, J = 2.0Hz),
6.85 (1H, br), 6.68 (1H, dd, J = 8.2,2.0Hz), 6.14 (1H, s),
4.50-4.29 (2H, m), 4.09 (1H, brs), 3.32 (1H, dd, J = 13.6,
5.6Hz), 3.19 (1H, ddd, J = 13.6,11.2,5.0Hz), 3.02-2.91 (1
H, m), 2.59 (1H, brs), 2.53 (1H, dd, J = 11.0,3.0Hz), 2.43
(1H, ddd, J = 18.2,4.6,2.0Hz), 1.94-1.84 (2H, m), 1.79-1.
69 (1H, m), 1.49 (1H, m), 1.38 (3H, t, J = 7.1Hz), 1.26-1.25
(1H, m), 0.99 (3H, t, J = 7.4Hz), 0.92-0.85 (1H, m).
【００２８】化合物５： １１−（４−クロロフェニ
ル）スルホニルアミノ−アポビンカミン酸イソプロピル
エステル1 H-NMR(CDCl3,δppm)：7.73(2H,d,J=8.6Hz), 7.39(2H,
d,J=8.9Hz), 7.28(1H,d,J=8.9Hz),7.14(1H,d,J=6.2Hz),
6.70(1H,dd,J=8.2,2.0Hz), 6.58(1H,br),6.09(1H,s),
5.24(1H,m), 4.09(1H,brs), 3.32(1H,dd,J=13.5,5.6H
z),3.18(1H,ddd,J=16.2,13.5,5.0Hz), 3.02-2.89(1H,
m), 2.60(1H,brs),2.52(1H,dd,J=10.9,8.3Hz), 2.40(1
H,ddd,J=14.2,4.6,2.4Hz),1.98-1.81(2H,m), 1.78-1.63
(1H,m), 1.51(1H,br), 1.41(3H,d,J=6.2Hz),1.37(3H,d,
J=6.2Hz), 1.29-1.22(1H,m), 0.99(3H,t,J=7.3Hz),0.93
-0.85(1H,m)Compound 5: 11- (4-chlorophenyl) sulfonylamino-apovincamic acid isopropyl ester 1 H-NMR (CDCl 3 , δppm): 7.73 (2H, d, J = 8.6Hz), 7.39 (2H,
d, J = 8.9Hz), 7.28 (1H, d, J = 8.9Hz), 7.14 (1H, d, J = 6.2Hz),
6.70 (1H, dd, J = 8.2,2.0Hz), 6.58 (1H, br), 6.09 (1H, s),
5.24 (1H, m), 4.09 (1H, brs), 3.32 (1H, dd, J = 13.5,5.6H
z), 3.18 (1H, ddd, J = 16.2,13.5,5.0Hz), 3.02-2.89 (1H,
m), 2.60 (1H, brs), 2.52 (1H, dd, J = 10.9,8.3Hz), 2.40 (1
H, ddd, J = 14.2,4.6,2.4Hz), 1.98-1.81 (2H, m), 1.78-1.63
(1H, m), 1.51 (1H, br), 1.41 (3H, d, J = 6.2Hz), 1.37 (3H, d,
J = 6.2Hz), 1.29-1.22 (1H, m), 0.99 (3H, t, J = 7.3Hz), 0.93
-0.85 (1H, m)
【００２９】化合物６： １１−（４−クロロフェニ
ル）スルホニルアミノ−アポビンカミン酸プロピルエス
テル1 H-NMR(CDCl3,δppm)：7.71(2H,d,J=8.5Hz), 7.38(2H,
d,J=8.5Hz), 7.26(1H,d,J=5.6Hz),7.12(1H,brs), 6.85
(1H,br), 6.68(1H,dd,J=8.2,1.6Hz), 6.14(1H,s),4.40-
4.21(2H,m), 4.10(1H,s), 3.32(1H,dd,J=13.6,6.0Hz),
3.19(1H,ddd,J=13.6,11.2,5.9Hz), 3.02-2.90(1H,m),
2.60(1H,br),2.55(1H,dd,J=10.9,8.3Hz), 2.43(1H,dd,J
=16.2,2.6Hz),1.98-1.79(2H,m), 1.77-1.70(2H,m), 1.5
1(1H,d,J=13.6Hz),1.41(1H,dd,J=13.2,3.0Hz), 1.25(1
H,brs), 1.01(3H,t,J=5.0Hz),0.98(3H,t,J=5.0Hz), 0.9
3-0.85(1H,m)Compound 6: 11- (4-chlorophenyl) sulfonylamino-apovincamic acid propyl ester 1 H-NMR (CDCl 3 , δppm): 7.71 (2H, d, J = 8.5Hz), 7.38 (2H,
d, J = 8.5Hz), 7.26 (1H, d, J = 5.6Hz), 7.12 (1H, brs), 6.85
(1H, br), 6.68 (1H, dd, J = 8.2,1.6Hz), 6.14 (1H, s), 4.40-
4.21 (2H, m), 4.10 (1H, s), 3.32 (1H, dd, J = 13.6,6.0Hz),
3.19 (1H, ddd, J = 13.6,11.2,5.9Hz), 3.02-2.90 (1H, m),
2.60 (1H, br), 2.55 (1H, dd, J = 10.9,8.3Hz), 2.43 (1H, dd, J
= 16.2, 2.6Hz), 1.98-1.79 (2H, m), 1.77-1.70 (2H, m), 1.5
1 (1H, d, J = 13.6Hz), 1.41 (1H, dd, J = 13.2,3.0Hz), 1.25 (1
H, brs), 1.01 (3H, t, J = 5.0Hz), 0.98 (3H, t, J = 5.0Hz), 0.9
3-0.85 (1H, m)
【００３０】化合物７： １１−（４−フルオロフェニ
ル）スルホニルアミノ−アポビンカミン酸エチルエステ
ル1 H-NMR(CDCl3,δppm)：7.82-7.73(2H,m), 7.26(1H,d,J=
8.3Hz), 7.15(1H,d,J=2.0Hz),7.09(2H,t,J=8.9Hz), 6.6
5(1H,dd,J=8.3,2.0Hz), 6.53(1H,br),6.14(1H,s), 4.51
-4.33(2H,m), 4.10(1H,brs),3.33(1H,dd,J=13.5,5.9H
z), 3.19(1H,ddd,J=13.5,11.2,5.0Hz),3.03-2.90(1H,
m), 2.60-2.51(2H,m), 2.44(1H,ddd,J=16.5,6.2,2.0H
z),1.90(2H,m), 1.76-1.61(1H,m), 1.52(1H,brd,J=13.5
Hz),1.40(3H,t,J=7.0Hz), 1.42-1.32(1H,m), 1.00(3H,
t,J=7.4Hz),0.99-0.89(1H,m)Compound 7: 11- (4-Fluorophenyl) sulfonylamino-apovincamic acid ethyl ester 1 H-NMR (CDCl 3 , δppm): 7.82-7.73 (2H, m), 7.26 (1H, d, J =
8.3Hz), 7.15 (1H, d, J = 2.0Hz), 7.09 (2H, t, J = 8.9Hz), 6.6
5 (1H, dd, J = 8.3,2.0Hz), 6.53 (1H, br), 6.14 (1H, s), 4.51
-4.33 (2H, m), 4.10 (1H, brs), 3.33 (1H, dd, J = 13.5,5.9H
z), 3.19 (1H, ddd, J = 13.5,11.2,5.0Hz), 3.03-2.90 (1H,
m), 2.60-2.51 (2H, m), 2.44 (1H, ddd, J = 16.5,6.2,2.0H
z), 1.90 (2H, m), 1.76-1.61 (1H, m), 1.52 (1H, brd, J = 13.5
Hz), 1.40 (3H, t, J = 7.0Hz), 1.42-1.32 (1H, m), 1.00 (3H,
t, J = 7.4Hz), 0.99-0.89 (1H, m)
【００３１】化合物８： １１−（４−ヨウドフェニ
ル）スルホニルアミノ−アポビンカミン酸エチルエステ
ル1 H-NMR(CDCl3,δppm)：7.77(2H,d,J=8.9Hz), 7.50(2H,
d,J=8.9Hz), 7.28(1H,s),7.14(1H,d,J=2.0Hz), 6.65(1
H,d,J=2.0Hz), 6.41(1H,brs), 6.14(1H,s),4.51-4.35(2
H,m), 4.11(1H,brs), 3.33(1H,dd,J=5.6,3.6Hz),3.20(1
H,ddd,J=13.5,11.3,5.3Hz), 3.05-2.89(1H,m), 2.61(1
H,brs),2.57-2.53(1H,m), 2.46-2.41(1H,m), 1.95-1.82
(2H,m), 1.57(2H,brs),1.39(3H,t,J=7.2Hz), 1.28-1.26
(1H,m), 1.00(3H,t,J=7.2Hz),0.93-0.92(1H,m)Compound 8: 11- (4-iodophenyl) sulfonylamino-apovincamic acid ethyl ester 1 H-NMR (CDCl 3 , δppm): 7.77 (2H, d, J = 8.9Hz), 7.50 (2H,
d, J = 8.9Hz), 7.28 (1H, s), 7.14 (1H, d, J = 2.0Hz), 6.65 (1
H, d, J = 2.0Hz), 6.41 (1H, brs), 6.14 (1H, s), 4.51-4.35 (2
H, m), 4.11 (1H, brs), 3.33 (1H, dd, J = 5.6,3.6Hz), 3.20 (1
H, ddd, J = 13.5,11.3,5.3Hz), 3.05-2.89 (1H, m), 2.61 (1
H, brs), 2.57-2.53 (1H, m), 2.46-2.41 (1H, m), 1.95-1.82
(2H, m), 1.57 (2H, brs), 1.39 (3H, t, J = 7.2Hz), 1.28-1.26
(1H, m), 1.00 (3H, t, J = 7.2Hz), 0.93-0.92 (1H, m)
【００３２】化合物９： １１−（２，５−ジクロロフ
ェニル）スルホニルアミノ−アポビンカミン酸エチルエ
ステル1 H-NMR(CDCl3,δppm)：7.96(1H,d,J=2.3Hz), 7.45(1H,
d,J=8.6Hz), 7.40(1H,dd,J=8.6,2.3Hz),7.26(1H,d,J=8.
2Hz), 7.15(1H,d,J=2.0Hz), 7.00(1H,br),6.81(1H,dd,J
=8.3,2.0Hz), 6.13(1H,s), 4.57-4.37(2H,m), 4.07(1H,
brs),3.31(1H,dd,J=13.8,5.9Hz), 3.18(1H,ddd,J=13.8,
11.5,5.6Hz),3.02-2.86(1H,m), 2.63-2.55(1H,m), 2.54
(1H,dd,J=11.2,2.6Hz),2.42(1H,dd,J=15.8,2.0Hz), 1.8
9(2H,m), 1.78-1.62(1H,m),1.59-1.51(1H,m), 1.45(3H,
t,J=7.1Hz), 1.47-1.36(1H,m),0.99(3H,t,J=7.4Hz), 1.
02-0.92(1H,m)Compound 9: 11- (2,5-dichlorophenyl) sulfonylamino-apovincamic acid ethyl ester 1 H-NMR (CDCl 3 , δppm): 7.96 (1H, d, J = 2.3Hz), 7.45 (1H,
d, J = 8.6Hz), 7.40 (1H, dd, J = 8.6,2.3Hz), 7.26 (1H, d, J = 8.
2Hz), 7.15 (1H, d, J = 2.0Hz), 7.00 (1H, br), 6.81 (1H, dd, J
= 8.3,2.0Hz), 6.13 (1H, s), 4.57-4.37 (2H, m), 4.07 (1H,
brs), 3.31 (1H, dd, J = 13.8,5.9Hz), 3.18 (1H, ddd, J = 13.8,
11.5,5.6Hz), 3.02-2.86 (1H, m), 2.63-2.55 (1H, m), 2.54
(1H, dd, J = 11.2,2.6Hz), 2.42 (1H, dd, J = 15.8,2.0Hz), 1.8
9 (2H, m), 1.78-1.62 (1H, m), 1.59-1.51 (1H, m), 1.45 (3H,
t, J = 7.1Hz), 1.47-1.36 (1H, m), 0.99 (3H, t, J = 7.4Hz), 1.
02-0.92 (1H, m)
【００３３】化合物１０： １１−（１−ナフタレン）
スルホニルアミノ−アポビンカミン酸エチルエステル1 H-NMR(CDCl3,δppm)：8.74(1H,d,J=8.9Hz), 8.14(1H,d
d,J=7.6,1.3Hz),8.01(1H,d,J=8.3Hz), 7.93(1H,dd,J=8.
3,1.3Hz), 7.70-7.56(2H,m),7.41(1H,dd,J=8.3,7.6Hz),
7.12(1H,d,J=8.3Hz), 6.93(1H,d,J=1.6Hz),6.85(1H,b
r), 6.52(1H,dd,J=8.3,1.6Hz), 6.06(1H,s), 4.38-4.08
(2H,m),4.04(1H,brs), 3.28(1H,dd,J=13.5,5.6Hz),3.15
(1H,ddd,J=13.5,11.0,5.3Hz), 2.97-2.83(1H,m),2.56(1
H,dd,J=5.2,2.6Hz), 2.49(1H,dd,J=11.2,2.6Hz),2.36(1
H,ddd,J=16.5,6.2,2.0Hz), 1.86(2H,m), 1.75-1.59(1H,
m),1.47(1H,brd,J=13.5Hz), 1.42-1.33(1H,m), 1.29(3
H,t,J=7.2Hz),0.97(3H,t,J=7.3Hz), 0.98-0.85(1H,m)Compound 10: 11- (1-naphthalene)
Sulfonylamino-apovincamic acid ethyl ester 1 H-NMR (CDCl 3 , δppm): 8.74 (1H, d, J = 8.9Hz), 8.14 (1H, d
d, J = 7.6,1.3Hz), 8.01 (1H, d, J = 8.3Hz), 7.93 (1H, dd, J = 8.
3,1.3Hz), 7.70-7.56 (2H, m), 7.41 (1H, dd, J = 8.3,7.6Hz),
7.12 (1H, d, J = 8.3Hz), 6.93 (1H, d, J = 1.6Hz), 6.85 (1H, b
r), 6.52 (1H, dd, J = 8.3,1.6Hz), 6.06 (1H, s), 4.38-4.08
(2H, m), 4.04 (1H, brs), 3.28 (1H, dd, J = 13.5,5.6Hz), 3.15
(1H, ddd, J = 13.5,11.0,5.3Hz), 2.97-2.83 (1H, m), 2.56 (1
H, dd, J = 5.2,2.6Hz), 2.49 (1H, dd, J = 11.2,2.6Hz), 2.36 (1
H, ddd, J = 16.5,6.2,2.0Hz), 1.86 (2H, m), 1.75-1.59 (1H,
m), 1.47 (1H, brd, J = 13.5Hz), 1.42-1.33 (1H, m), 1.29 (3
H, t, J = 7.2Hz), 0.97 (3H, t, J = 7.3Hz), 0.98-0.85 (1H, m)
【００３４】化合物１１： １１−（４−トルエン）ス
ルホニルアミノ−アポビンカミン酸エチルエステル1 H-NMR(CDCl3,δppm)：7.66(2H,d,J=8.6Hz), 7.25(1H,
d,J=9.2Hz), 7.21(2H,d,J=9.2Hz),7.15(1H,d,J=1.7Hz),
6.64(1H,dd,J=8.4,1.8Hz), 6.42(1H,br),6.12(1H,s),
4.52-4.32(2H,m), 4.11(1H,brs), 3.33(1H,dd,J=13.6,
5.6Hz),3.20(1H,ddd,J=13.5,11.2,5.1Hz), 3.03-2.91(1
H,m), 2.68-2.53(1H,m),2.54(1H,dd,J=11.2,2.6Hz), 2.
43(1H,dd,J=16.5,3.0Hz), 2.37(3H,s),1.90(2H,m), 1.7
8-1.63(1H,m), 1.52(1H,brd,J=13.5Hz),1.38(3H,t,J=7.
3Hz), 1.43-1.32(1H,m), 1.00(3H,t,J=7.6Hz),1.03-0.9
1(1H,m)Compound 11: 11- (4-toluene) sulfonylamino-apovincamic acid ethyl ester 1 H-NMR (CDCl 3 , δppm): 7.66 (2H, d, J = 8.6Hz), 7.25 (1H,
d, J = 9.2Hz), 7.21 (2H, d, J = 9.2Hz), 7.15 (1H, d, J = 1.7Hz),
6.64 (1H, dd, J = 8.4,1.8Hz), 6.42 (1H, br), 6.12 (1H, s),
4.52-4.32 (2H, m), 4.11 (1H, brs), 3.33 (1H, dd, J = 13.6,
5.6Hz), 3.20 (1H, ddd, J = 13.5,11.2,5.1Hz), 3.03-2.91 (1
H, m), 2.68-2.53 (1H, m), 2.54 (1H, dd, J = 11.2,2.6Hz), 2.
43 (1H, dd, J = 16.5,3.0Hz), 2.37 (3H, s), 1.90 (2H, m), 1.7
8-1.63 (1H, m), 1.52 (1H, brd, J = 13.5Hz), 1.38 (3H, t, J = 7.
3Hz), 1.43-1.32 (1H, m), 1.00 (3H, t, J = 7.6Hz), 1.03-0.9
1 (1H, m)
【００３５】化合物１２： １１−メジチレンスルホニ
ルアミノ−アポビンカミン酸エチルエステル1 H-NMR(CDCl3,δppm)：7.23(1H,d,J=8.6Hz), 7.01(1H,
d,J=1.7Hz), 6.91(2H,s),6.63(1H,dd,J=8.4,1.8Hz), 6.
45(1H,br), 6.11(1H,s), 4.45-4.31(2H,m),4.08(1H,br
s), 3.33(1H,dd,J=13.6,5.6Hz),3.20(1H,ddd,J=13.5,1
1.2,5.1Hz), 3.03-2.88(1H,m), 2.75-2.62(1H,m),2.57
(6H,s), 2.57-2.49(1H,m), 2.48-2.30(1H,m), 2.27(3H,
s),1.89(2H,m), 1.77-1.63(1H,m), 1.58-1.47(1H,m),
1.38(3H,t,J=7.2Hz),1.48-1.35(1H,m), 0.99(3H,t,J=7.
4Hz), 1.02-0.88(1H,m)Compound 12: 11-Mediethylenesulfonylamino-apovincamic acid ethyl ester 1 H-NMR (CDCl 3 , δppm): 7.23 (1H, d, J = 8.6Hz), 7.01 (1H,
d, J = 1.7Hz), 6.91 (2H, s), 6.63 (1H, dd, J = 8.4,1.8Hz), 6.
45 (1H, br), 6.11 (1H, s), 4.45-4.31 (2H, m), 4.08 (1H, br
s), 3.33 (1H, dd, J = 13.6,5.6Hz), 3.20 (1H, ddd, J = 13.5,1
1.2,5.1Hz), 3.03-2.88 (1H, m), 2.75-2.62 (1H, m), 2.57
(6H, s), 2.57-2.49 (1H, m), 2.48-2.30 (1H, m), 2.27 (3H,
s), 1.89 (2H, m), 1.77-1.63 (1H, m), 1.58-1.47 (1H, m),
1.38 (3H, t, J = 7.2Hz), 1.48-1.35 (1H, m), 0.99 (3H, t, J = 7.
4Hz), 1.02-0.88 (1H, m)
【００３６】化合物１３： １１−ベンジルスルホニル
アミノ−アポビンカミン酸エチルエステル1 H-NMR(CDCl3,δppm)：7.39(1H,d,J=8.2Hz), 7.34(5H,
s), 7.28(1H,d,J=2.0Hz),6.89(1H,dd,J=8.2,2.0Hz), 6.
73(1H,br), 6.17(1H,s), 4.55-4.33(2H,m),4.33(2H,s),
4.13(1H,brs), 3.32(1H,dd,J=13.5,5.6Hz),3.22(1H,dd
d,J=13.5,5.2,2.6Hz), 3.06-2.95(1H,m), 2.67-2.63(1
H,m),2.58(1H,dd,J=11.2,2.6Hz), 2.48(1H,ddd,J=16.5,
6.2,2.0Hz), 1.92(2H,m),1.83-1.64(1H,m), 1.54(1H,br
d,J=13.5Hz), 1.45-1.37(1H,m),1.40(3H,t,J=7.3Hz),
1.08-0.98(1H,m), 1.01(3H,t,J=7.3Hz)Compound 13: 11-benzylsulfonylamino-apovincamic acid ethyl ester 1 H-NMR (CDCl 3 , δppm): 7.39 (1H, d, J = 8.2Hz), 7.34 (5H,
s), 7.28 (1H, d, J = 2.0Hz), 6.89 (1H, dd, J = 8.2,2.0Hz), 6.
73 (1H, br), 6.17 (1H, s), 4.55-4.33 (2H, m), 4.33 (2H, s),
4.13 (1H, brs), 3.32 (1H, dd, J = 13.5,5.6Hz), 3.22 (1H, dd
d, J = 13.5,5.2,2.6Hz), 3.06-2.95 (1H, m), 2.67-2.63 (1
H, m), 2.58 (1H, dd, J = 11.2,2.6Hz), 2.48 (1H, ddd, J = 16.5,
6.2,2.0Hz), 1.92 (2H, m), 1.83-1.64 (1H, m), 1.54 (1H, br
d, J = 13.5Hz), 1.45-1.37 (1H, m), 1.40 (3H, t, J = 7.3Hz),
1.08-0.98 (1H, m), 1.01 (3H, t, J = 7.3Hz)
【００３７】化合物１４： １１−（４−アセチルアミ
ノフェニル）スルホニルアミノ−アポビンカミン酸エチ
ルエステル1 H-NMR(CDCl3,δppm)：8.12(1H,brs), 7.60(1H,br), 7.
59(2H,d,J=8.6Hz), 7.43(2H,d,J=8.6Hz),7.19(1H,d,J=
2.0Hz), 7.13(1H,d,J=8.3Hz), 6.62(1H,dd,J=8.3,2.0H
z),6.10(1H,s), 4.51-4.28(2H,m), 4.05(1H,brs), 3.28
(1H,dd,J=13.5,5.6Hz),3.15(1H,ddd,J=13.5,11.2,5.3H
z), 2.98-2.82(1H,m), 2.60-2.55(1H,m),2.51(1H,dd,J=
11.2,2.6Hz), 2.46(1H,ddd,J=16.5,6.2,2.0Hz), 2.10(3
H,s),1.87(2H,m), 1.80-1.60(1H,m), 1.48(1H,brd,J=1
3.2Hz),1.35(3H,t,J=7.2Hz), 1.40-1.32(1H,m), 0.98(3
H,t,J=7.3Hz),1.00-0.89(1H,m)Compound 14: 11- (4-acetylaminophenyl) sulfonylamino-apovincamic acid ethyl ester 1 H-NMR (CDCl 3 , δppm): 8.12 (1H, brs), 7.60 (1H, br), 7.
59 (2H, d, J = 8.6Hz), 7.43 (2H, d, J = 8.6Hz), 7.19 (1H, d, J =
2.0Hz), 7.13 (1H, d, J = 8.3Hz), 6.62 (1H, dd, J = 8.3,2.0H
z), 6.10 (1H, s), 4.51-4.28 (2H, m), 4.05 (1H, brs), 3.28
(1H, dd, J = 13.5,5.6Hz), 3.15 (1H, ddd, J = 13.5,11.2,5.3H
z), 2.98-2.82 (1H, m), 2.60-2.55 (1H, m), 2.51 (1H, dd, J =
11.2,2.6Hz), 2.46 (1H, ddd, J = 16.5,6.2,2.0Hz), 2.10 (3
H, s), 1.87 (2H, m), 1.80-1.60 (1H, m), 1.48 (1H, brd, J = 1
3.2Hz), 1.35 (3H, t, J = 7.2Hz), 1.40-1.32 (1H, m), 0.98 (3
H, t, J = 7.3Hz), 1.00-0.89 (1H, m)
【００３８】化合物１５： １１−（８−キノリン）ス
ルホニルアミノ−アポビンカミン酸エチルエステル1 H-NMR(CDCl3,δppm)：9.17(1H,dd,J=4.3,1.7Hz), 8.40
(1H,brs), 8.33-8.28(2H,m),8.00(1H,dd,J=8.3,1.3Hz),
7.62(1H,dd,J=8.3,4.3Hz),7.54(1H,dd,J=7.3,8.3Hz),
7.11(1H,d,J=8.3Hz), 7.03(1H,d,J=2.0Hz),6.62(1H,dd,
J=8.3,2.0Hz), 6.04(1H,s), 4.46-4.23(2H,m), 4.02(1
H,brs),3.27(1H,dd,J=13.5,5.7Hz), 3.11(1H,ddd,J=13.
5,11.2,5.3Hz),2.95-2.81(1H,m), 2.59-2.45(2H,m), 2.
34(1H,ddd,J=16.2,6.2,2.6Hz),1.85(2H,m), 1.73-1.64
(1H,m), 1.47(1H,brd,J=13.9Hz),1.39(3H,t,J=7.1Hz),
1.42-1.31(1H,m), 0.96(3H,t,J=7.6Hz),1.01-0.90(1H,
m)Compound 15: 11- (8-quinoline) sulfonylamino-apovincamic acid ethyl ester 1 H-NMR (CDCl 3 , δppm): 9.17 (1H, dd, J = 4.3,1.7Hz), 8.40
(1H, brs), 8.33-8.28 (2H, m), 8.00 (1H, dd, J = 8.3,1.3Hz),
7.62 (1H, dd, J = 8.3,4.3Hz), 7.54 (1H, dd, J = 7.3,8.3Hz),
7.11 (1H, d, J = 8.3Hz), 7.03 (1H, d, J = 2.0Hz), 6.62 (1H, dd,
J = 8.3,2.0Hz), 6.04 (1H, s), 4.46-4.23 (2H, m), 4.02 (1
H, brs), 3.27 (1H, dd, J = 13.5,5.7Hz), 3.11 (1H, ddd, J = 13.
5,11.2,5.3Hz), 2.95-2.81 (1H, m), 2.59-2.45 (2H, m), 2.
34 (1H, ddd, J = 16.2,6.2,2.6Hz), 1.85 (2H, m), 1.73-1.64
(1H, m), 1.47 (1H, brd, J = 13.9Hz), 1.39 (3H, t, J = 7.1Hz),
1.42-1.31 (1H, m), 0.96 (3H, t, J = 7.6Hz), 1.01-0.90 (1H,
m)
【００３９】化合物１６： １１−（４−メトキシフェ
ニル）スルホニルアミノ−アポビンカミン酸エチルエス
テル1 H-NMR(CDCl3,δppm)：7.71(2H,d,J=8.9Hz), 7.25(1H,
d,J=6.9Hz), 7.15(1H,d,J=1.7Hz),6.88(2H,d,J=8.9Hz),
6.66(1H,dd,J=8.3,2.0Hz), 6.43(1H,brs),6.12(1H,s),
4.53-4.33(2H,m), 4.14(1H,brs), 3.81(3H,s),3.35(1
H,dd,J=13.8,5.9Hz), 3.22(1H,ddd,J=13.8,11.2,5.6H
z),3.04-2.88(1H,m), 2.72-2.62(1H,m), 2.58(1H,dd,J=
11.2,2.6Hz),2.48(1H,dd,J=16.2,2.9Hz), 1.92(2H,m),
1.78-1.60(1H,m),1.53(1H,brd,J=13.5Hz), 1.39(3H,t,J
=7.3Hz), 1.45-1.36(1H,m),1.01(3H,t,J=7.6Hz), 1.04-
0.88(1H,m)Compound 16: 11- (4-Methoxyphenyl) sulfonylamino-apovincamic acid ethyl ester 1 H-NMR (CDCl 3 , δppm): 7.71 (2H, d, J = 8.9Hz), 7.25 (1H,
d, J = 6.9Hz), 7.15 (1H, d, J = 1.7Hz), 6.88 (2H, d, J = 8.9Hz),
6.66 (1H, dd, J = 8.3,2.0Hz), 6.43 (1H, brs), 6.12 (1H, s),
4.53-4.33 (2H, m), 4.14 (1H, brs), 3.81 (3H, s), 3.35 (1
H, dd, J = 13.8,5.9Hz), 3.22 (1H, ddd, J = 13.8,11.2,5.6H
z), 3.04-2.88 (1H, m), 2.72-2.62 (1H, m), 2.58 (1H, dd, J =
11.2,2.6Hz), 2.48 (1H, dd, J = 16.2,2.9Hz), 1.92 (2H, m),
1.78-1.60 (1H, m), 1.53 (1H, brd, J = 13.5Hz), 1.39 (3H, t, J
= 7.3Hz), 1.45-1.36 (1H, m), 1.01 (3H, t, J = 7.6Hz), 1.04-
0.88 (1H, m)
【００４０】化合物１７： １１−（２，５−ジメチル
フェニル）スルホニルアミノ−アポビンカミン酸エチル
エステル1 H-NMR(CDCl3,δppm)：7.86(1H,d,J=1.3Hz), 7.21(1H,
d,J=8.3Hz), 7.15(1H,br),7.16(1H,dd,J=8.0,1.3Hz),
7.13(1H,d,J=8.0Hz), 7.05(1H,d,J=2.0Hz),6.70(1H,dd,
J=8.3,2.0Hz), 6.09(1H,s), 4.51-4.25(2H,m), 4.08(1
H,brs),3.31(1H,dd,J=13.5,5.9Hz), 3.18(1H,ddd,J=13.
5,11.2,5.3Hz),2.99-2.84(1H,m), 2.60(3H,s), 2.63-2.
56(1H,m),2.51(1H,dd,J=11.2,2.7Hz), 2.40(1H,ddd,J=1
6.5,6.2,2.0Hz), 2.29(3H,s),1.88(2H,m), 1.78-1.60(1
H,m), 1.49(1H,brd,J=13.5Hz), 1.43-1.34(1H,m),1.37
(3H,t,J=7.2Hz), 0.98(3H,t,J=7.3Hz), 1.01-0.87(1H,
m)Compound 17: 11- (2,5-Dimethylphenyl) sulfonylamino-apovincamic acid ethyl ester 1 H-NMR (CDCl 3 , δppm): 7.86 (1H, d, J = 1.3Hz), 7.21 (1H,
d, J = 8.3Hz), 7.15 (1H, br), 7.16 (1H, dd, J = 8.0,1.3Hz),
7.13 (1H, d, J = 8.0Hz), 7.05 (1H, d, J = 2.0Hz), 6.70 (1H, dd,
J = 8.3,2.0Hz), 6.09 (1H, s), 4.51-4.25 (2H, m), 4.08 (1
H, brs), 3.31 (1H, dd, J = 13.5,5.9Hz), 3.18 (1H, ddd, J = 13.
5,11.2,5.3Hz), 2.99-2.84 (1H, m), 2.60 (3H, s), 2.63-2.
56 (1H, m), 2.51 (1H, dd, J = 11.2,2.7Hz), 2.40 (1H, ddd, J = 1
6.5,6.2,2.0Hz), 2.29 (3H, s), 1.88 (2H, m), 1.78-1.60 (1
H, m), 1.49 (1H, brd, J = 13.5Hz), 1.43-1.34 (1H, m), 1.37
(3H, t, J = 7.2Hz), 0.98 (3H, t, J = 7.3Hz), 1.01-0.87 (1H,
m)
【００４１】化合物１８： １１−（２−チオフェン）
スルホニルアミノ−アポビンカミン酸エチルエステル1 H-NMR(CDCl3,δppm)：7.52-7.49(2H,m), 7.29(1H,d,J=
8.3Hz), 7.21(1H,d,J=2.0Hz),6.98(1H,t,J=4.3Hz), 6.7
3(1H,dd,J=8.3,2.0Hz), 6.68(1H,br),6.13(1H,s), 4.54
-4.31(2H,m), 4.14(1H,brs), 3.36(1H,dd,J=13.5,5.9H
z),3.23(1H,ddd,J=13.5,11.2,5.3Hz), 3.05-2.89(1H,
m), 2.72-2.62(1H,m),2.58(1H,dd,J=11.5,2.6Hz), 2.48
(1H,dd,J=16.5,2.0Hz), 1.92(2H,m),1.78-1.68(1H,m),
1.53(1H,brd,J=13.5Hz), 1.39(3H,t,J=7.3Hz),1.45-1.3
6(1H,m), 1.01(3H,t,J=7.4Hz), 1.03-0.86(1H,m)Compound 18: 11- (2-thiophene)
Sulfonylamino-apovincamic acid ethyl ester 1 H-NMR (CDCl 3 , δppm): 7.52-7.49 (2H, m), 7.29 (1H, d, J =
8.3Hz), 7.21 (1H, d, J = 2.0Hz), 6.98 (1H, t, J = 4.3Hz), 6.7
3 (1H, dd, J = 8.3,2.0Hz), 6.68 (1H, br), 6.13 (1H, s), 4.54
-4.31 (2H, m), 4.14 (1H, brs), 3.36 (1H, dd, J = 13.5,5.9H
z), 3.23 (1H, ddd, J = 13.5,11.2,5.3Hz), 3.05-2.89 (1H,
m), 2.72-2.62 (1H, m), 2.58 (1H, dd, J = 11.5,2.6Hz), 2.48
(1H, dd, J = 16.5,2.0Hz), 1.92 (2H, m), 1.78-1.68 (1H, m),
1.53 (1H, brd, J = 13.5Hz), 1.39 (3H, t, J = 7.3Hz), 1.45-1.3
6 (1H, m), 1.01 (3H, t, J = 7.4Hz), 1.03-0.86 (1H, m)
【００４２】化合物１９： １１−（２−カルボメトキ
シフェニル）スルホニルアミノ−アポビンカミン酸エチ
ルエステル1 H-NMR(CDCl3,δppm)：7.95(1H,brs), 7.83(1H,dd,J=7.
6,1.5Hz), 7.81(1H,dd,J=7.6,1.5Hz),7.55(1H,dt,J=7.
6,1.5Hz), 7.44(1H,dt,J=7.6,1.5Hz),7.21(1H,d,J=8.2H
z), 7.18(1H,d,J=1.5Hz), 6.77(1H,dd,J=8.2,1.5Hz),6.
08(1H,s), 4.54-4.32(2H,m), 4.08(1H,brs), 4.05(3H,
s),3.32(1H,dd,J=13.8,5.7Hz), 3.17(1H,ddd,J=13.8,1
1.2,5.3Hz),3.01-2.90(1H,m), 2.60-2.55(2H,m), 2.41
(1H,ddd,J=16.3,6.2,2.8Hz),1.89(2H,m), 1.74-1.62(1
H,m), 1.51(1H,brd,J=13.9Hz),1.40(3H,t,J=7.3Hz), 1.
42-1.37(1H,m), 1.00(3H,t,J=7.5Hz),1.02-0.95(1H,m)Compound 19: 11- (2-carbomethoxyphenyl) sulfonylamino-apovincamic acid ethyl ester 1 H-NMR (CDCl 3 , δppm): 7.95 (1H, brs), 7.83 (1H, dd, J = 7.
6,1.5Hz), 7.81 (1H, dd, J = 7.6,1.5Hz), 7.55 (1H, dt, J = 7.
6,1.5Hz), 7.44 (1H, dt, J = 7.6,1.5Hz), 7.21 (1H, d, J = 8.2H
z), 7.18 (1H, d, J = 1.5Hz), 6.77 (1H, dd, J = 8.2,1.5Hz), 6.
08 (1H, s), 4.54-4.32 (2H, m), 4.08 (1H, brs), 4.05 (3H,
s), 3.32 (1H, dd, J = 13.8,5.7Hz), 3.17 (1H, ddd, J = 13.8,1
1.2,5.3Hz), 3.01-2.90 (1H, m), 2.60-2.55 (2H, m), 2.41
(1H, ddd, J = 16.3,6.2,2.8Hz), 1.89 (2H, m), 1.74-1.62 (1
H, m), 1.51 (1H, brd, J = 13.9Hz), 1.40 (3H, t, J = 7.3Hz), 1.
42-1.37 (1H, m), 1.00 (3H, t, J = 7.5Hz), 1.02-0.95 (1H, m)
【００４３】化合物２０： １１−（２，４，６−トリ
イソプロピルフェニル）スルホニルアミノ−アポビンカ
ミン酸エチルエステル1 H-NMR(CDCl3,δppm)：7.27(1H,d,J=8.3Hz), 7.09(2H,
s), 7.00(1H,d,J=2.0Hz),6.75(1H,dd,J=8.3,2.0Hz), 6.
58(1H,brs), 6.13(1H,s), 4.42-4.24(2H,m),4.10(1H,br
s), 3.96(2H,m), 3.33(1H,dd,J=13.5,5.6Hz),3.21(1H,d
dd,J=13.5,11.2,5.0Hz), 3.02-2.90(1H,m), 2.87(1H,
m),2.60(1H,dd,J=5.2,2.6Hz), 2.53(1H,dd,J=11.2,2.6H
z),2.44(1H,ddd,J=16.5,6.2,2.0Hz), 1.89(2H,m), 1.64
-2.00(1H,m),1.49(1H,brd,J=13.9Hz), 1.41-1.31(1H,
m), 1.34(3H,t,J=7.3Hz),1.23(6H,d,J=6.9Hz), 1.13(6
H,d,J=6.9Hz), 1.09(6H,d,J=6.9Hz),0.99(3H,t,J=7.3H
z), 0.95-0.83(1H,m)Compound 20: 11- (2,4,6-Triisopropylphenyl) sulfonylamino-apovincamic acid ethyl ester 1 H-NMR (CDCl 3 , δppm): 7.27 (1H, d, J = 8.3Hz), 7.09 (2H,
s), 7.00 (1H, d, J = 2.0Hz), 6.75 (1H, dd, J = 8.3,2.0Hz), 6.
58 (1H, brs), 6.13 (1H, s), 4.42-4.24 (2H, m), 4.10 (1H, br
s), 3.96 (2H, m), 3.33 (1H, dd, J = 13.5,5.6Hz), 3.21 (1H, d
dd, J = 13.5,11.2,5.0Hz), 3.02-2.90 (1H, m), 2.87 (1H,
m), 2.60 (1H, dd, J = 5.2,2.6Hz), 2.53 (1H, dd, J = 11.2,2.6H
z), 2.44 (1H, ddd, J = 16.5,6.2,2.0Hz), 1.89 (2H, m), 1.64
-2.00 (1H, m), 1.49 (1H, brd, J = 13.9Hz), 1.41-1.31 (1H,
m), 1.34 (3H, t, J = 7.3Hz), 1.23 (6H, d, J = 6.9Hz), 1.13 (6
H, d, J = 6.9Hz), 1.09 (6H, d, J = 6.9Hz), 0.99 (3H, t, J = 7.3H)
z), 0.95-0.83 (1H, m)
【００４４】化合物２１： １１−（４−メトキシ−２
−ニトロフェニル）スルホニルアミノ−アポビンカミン
酸エチルエステル1 H-NMR(CDCl3,δppm)：7.78(1H,d,J=8.9Hz), 7.32(1H,
d,J=2.5Hz), 7.28(1H,d,J=8.3Hz),7.21(1H,d,J=2.0Hz),
7.13(1H,br), 6.94(1H,dd,J=8.9,2.5Hz),6.85(1H,dd,J
=8.3,2.0Hz), 6.12(1H,s), 4.52-4.31(2H,m), 4.09(1H,
brs),3.87(3H,s), 3.33(1H,dd,J=13.5,5.6Hz),3.18(1H,
ddd,J=13.5,11.2,5.1Hz), 3.02-2.91(1H,m), 2.65-2.52
(2H,m),2.42(1H,ddd,J=16.2,6.2,2.3Hz), 1.89(2H,m),
1.78-1.62(1H,m),1.52(1H,brd,J=13.2Hz), 1.41(3H,t,J
=7.1Hz), 1.45-1.36(1H,m),1.00(3H,t,J=7.4Hz), 1.03-
0.95(1H,m)Compound 21: 11- (4-methoxy-2)
-Nitrophenyl) sulfonylamino-apovincamic acid ethyl ester 1 H-NMR (CDCl 3 , δppm): 7.78 (1H, d, J = 8.9Hz), 7.32 (1H,
d, J = 2.5Hz), 7.28 (1H, d, J = 8.3Hz), 7.21 (1H, d, J = 2.0Hz),
7.13 (1H, br), 6.94 (1H, dd, J = 8.9,2.5Hz), 6.85 (1H, dd, J
= 8.3,2.0Hz), 6.12 (1H, s), 4.52-4.31 (2H, m), 4.09 (1H,
brs), 3.87 (3H, s), 3.33 (1H, dd, J = 13.5,5.6Hz), 3.18 (1H,
ddd, J = 13.5,11.2,5.1Hz), 3.02-2.91 (1H, m), 2.65-2.52
(2H, m), 2.42 (1H, ddd, J = 16.2,6.2,2.3Hz), 1.89 (2H, m),
1.78-1.62 (1H, m), 1.52 (1H, brd, J = 13.2Hz), 1.41 (3H, t, J
= 7.1Hz), 1.45-1.36 (1H, m), 1.00 (3H, t, J = 7.4Hz), 1.03-
0.95 (1H, m)
【００４５】化合物２２： １１−（２−ナフタレン）
スルホニルアミノ−アポビンカミン酸エチルエステル1 H-NMR(CDCl3,δppm)：8.41(1H,brs), 7.89-7.75(6H,
m), 7.61-7.50(2H,m), 7.20(1H,d,J=8.3Hz),7.19(1H,d,
J=2.0Hz), 6.70(1H,dd,J=8.3,2.0Hz), 6.09(1H,s),4.44
-4.20(2H,m), 4.07(1H,brs), 3.30(1H,dd,J=13.5,5.9H
z),3.17(1H,ddd,J=13.5,11.2,5.2Hz), 2.97-2.84(1H,
m), 2.62-2.55(1H,m),2.53(1H,dd,J=11.2,2.6Hz), 2.39
(1H,ddd,J=16.5,6.2,2.0Hz), 1.88(2H,m),1.78-1.60(1
H,m), 1.49(1H,brd,J=13.5Hz), 1.37(1H,m),1.32(3H,t,
J=7.3Hz), 0.98(3H,t,J=7.3Hz), 1.01-0.88(1H,m)Compound 22: 11- (2-naphthalene)
Sulfonylamino-apovincamic acid ethyl ester 1 H-NMR (CDCl 3 , δppm): 8.41 (1H, brs), 7.89-7.75 (6H,
m), 7.61-7.50 (2H, m), 7.20 (1H, d, J = 8.3Hz), 7.19 (1H, d,
J = 2.0Hz), 6.70 (1H, dd, J = 8.3,2.0Hz), 6.09 (1H, s), 4.44
-4.20 (2H, m), 4.07 (1H, brs), 3.30 (1H, dd, J = 13.5,5.9H
z), 3.17 (1H, ddd, J = 13.5,11.2,5.2Hz), 2.97-2.84 (1H,
m), 2.62-2.55 (1H, m), 2.53 (1H, dd, J = 11.2,2.6Hz), 2.39
(1H, ddd, J = 16.5,6.2,2.0Hz), 1.88 (2H, m), 1.78-1.60 (1
H, m), 1.49 (1H, brd, J = 13.5Hz), 1.37 (1H, m), 1.32 (3H, t,
J = 7.3Hz), 0.98 (3H, t, J = 7.3Hz), 1.01-0.88 (1H, m)
【００４６】化合物２３： １１−（２，３，４，５，
６−ペンタフルオロフェニル）スルホニルアミノ−アポ
ビンカミン酸エチルエステル1 H-NMR(CDCl3,δppm)：7.35(1H,d,J=8.3Hz), 7.03(1H,
d,J=2.0Hz), 6.97(1H,dd,J=8.3,2.0Hz),6.19(1H,s), 4.
88(1H,br), 4.50-4.33(2H,m), 4.07(1H,brs),3.33(1H,d
d,J=13.5,5.6Hz), 3.19(1H,ddd,J=13.5,11.2,5.3Hz),3.
03-2.91(1H,m), 2.61(1H,dd,J=5.2,2.6Hz), 2.54(1H,d
d,J=11.2,2.6Hz),2.45(1H,ddd,J=16.5,6.2,2.0Hz), 1.8
9(2H,m), 1.78-1.62(1H,m),1.51(1H,brd,J=13.9Hz), 1.
42(3H,t,J=7.0Hz), 1.45-1.36(1H,m),0.99(3H,t,J=7.3H
z), 1.02-0.89(1H,m)Compound 23: 11- (2,3,4,5,5
6-Pentafluorophenyl) sulfonylamino-apovincamic acid ethyl ester 1 H-NMR (CDCl 3 , δppm): 7.35 (1H, d, J = 8.3Hz), 7.03 (1H,
d, J = 2.0Hz), 6.97 (1H, dd, J = 8.3,2.0Hz), 6.19 (1H, s), 4.
88 (1H, br), 4.50-4.33 (2H, m), 4.07 (1H, brs), 3.33 (1H, d
d, J = 13.5,5.6Hz), 3.19 (1H, ddd, J = 13.5,11.2,5.3Hz), 3.
03-2.91 (1H, m), 2.61 (1H, dd, J = 5.2,2.6Hz), 2.54 (1H, d
d, J = 11.2,2.6Hz), 2.45 (1H, ddd, J = 16.5,6.2,2.0Hz), 1.8
9 (2H, m), 1.78-1.62 (1H, m), 1.51 (1H, brd, J = 13.9Hz), 1.
42 (3H, t, J = 7.0Hz), 1.45-1.36 (1H, m), 0.99 (3H, t, J = 7.3H
z), 1.02-0.89 (1H, m)
【００４７】化合物２４： １１−（３−ニトロフェニ
ル）スルホニルアミノ−アポビンカミン酸エチルエステ
ル1 H-NMR(CDCl3,δppm)：（NHがきれいに出ていない） 8.66(1H,dd,J=2.0,1.6Hz), 8.33(1H,ddd,J=8.3,2.0,1.0
Hz),8.06(1H,ddd,J=8.2,1.6,1.0Hz), 7.59(1H,dd,J=8.
3,8.2Hz),7.25(1H,d,J=8.3Hz), 7.09(1H,d,J=2.0Hz),
6.75(1H,dd,J=8.3,2.0Hz),6.15(1H,s), 4.49-4.27(2H,
m), 4.09(1H,brs), 3.32(1H,dd,J=13.5,5.6Hz),3.20(1
H,ddd,J=13.5,11.2,5.3Hz), 3.03-2.87(1H,m), 2.66-2.
59(1H,m),2.54(1H,dd,J=11.2,2.6Hz), 2.44(1H,ddd,J=1
6.5,6.2,2.0Hz), 1.89(2H,m),1.80-1.62(1H,m), 1.51(1
H,brd,J=13.5Hz), 1.42-1.35(1H,m),1.38(3H,t,J=7.2H
z), 0.99(3H,t,J=7.3Hz), 1.01-0.89(1H,m),Compound 24: 11- (3-Nitrophenyl) sulfonylamino-apovincamic acid ethyl ester 1 H-NMR (CDCl 3 , δppm): (NH is not cleanly extracted) 8.66 (1H, dd, J = 2.0, 1.6Hz), 8.33 (1H, ddd, J = 8.3,2.0,1.0
Hz), 8.06 (1H, ddd, J = 8.2,1.6,1.0Hz), 7.59 (1H, dd, J = 8.
3,8.2Hz), 7.25 (1H, d, J = 8.3Hz), 7.09 (1H, d, J = 2.0Hz),
6.75 (1H, dd, J = 8.3,2.0Hz), 6.15 (1H, s), 4.49-4.27 (2H,
m), 4.09 (1H, brs), 3.32 (1H, dd, J = 13.5,5.6Hz), 3.20 (1
H, ddd, J = 13.5,11.2,5.3Hz), 3.03-2.87 (1H, m), 2.66-2.
59 (1H, m), 2.54 (1H, dd, J = 11.2,2.6Hz), 2.44 (1H, ddd, J = 1
6.5,6.2,2.0Hz), 1.89 (2H, m), 1.80-1.62 (1H, m), 1.51 (1
H, brd, J = 13.5Hz), 1.42-1.35 (1H, m), 1.38 (3H, t, J = 7.2H
z), 0.99 (3H, t, J = 7.3Hz), 1.01-0.89 (1H, m),
【００４８】試験例１ 急性毒性 ６〜７週齢、体重１８〜３６ｇの雄性Ｓｌｃ：ＩＣＲマ
ウスを１群３匹用いて試験を行った。５％グルコース水
溶液に溶解した本発明化合物及び被覆薬物（ビポセチン
・リン酸塩）の所定量をマウス尾静脈内に単回投与し、
一般状態及び死亡状況を観察した。おおよそのＬＤ50値
は観察期間終了時にプロビット法などにより算出した。
その結果は表１に示すとおりである。Test Example 1 Acute toxicity A test was conducted using 3 male Slc: ICR mice of 6 to 7 weeks of age and a weight of 18 to 36 g per group. A predetermined dose of the compound of the present invention and a coated drug (biposetine phosphate) dissolved in a 5% aqueous glucose solution was administered once into the tail vein of a mouse,
The general condition and mortality were observed. The approximate LD 50 value was calculated by the probit method or the like at the end of the observation period.
The results are as shown in Table 1.
【００４９】[0049]
【表１】 [Table 1]
【００５０】試験例２血管平滑筋弛緩作用 家兎を放血致死させ開腹し、摘出した上腸間膜動脈を常
法に従い螺旋状に切開し、条片標本としたのち、５％の
炭酸ガスを含む酸素ガスを通した３７±０．５℃のＫｒ
ｃｂｓ−Ｈｅｎｓｅｌｅｉｔ液中に張力を負荷して懸垂
した。この条片標本を塩化カリウムで収縮させ、一定の
張力を保ったのち、被験化合物を累積的に投与した。弛
緩作用は塩化カリウムによる収縮張力を１００％とし
て、５０％弛緩される濃度（ＥＤ50）を表示した。その
結果は表２に示すとおりである。Test Example 2 Relaxing Action of Vascular Smooth Muscles Rabbits were exsanguinated and laparotomized, and the excised superior mesenteric artery was spirally dissected according to a conventional method to prepare a strip sample, and 5% carbon dioxide gas was added. Kr of 37 ± 0.5 ℃ through oxygen gas containing
Tension was applied and suspended in the cbs-Henseleit solution. This strip specimen was contracted with potassium chloride to maintain a constant tension, and then the test compound was cumulatively administered. The relaxation action was represented by the concentration (ED 50 ) at which the contraction tension due to potassium chloride was 100% and the relaxation was 50%. The results are shown in Table 2.
【００５１】試験例３血小板凝集阻害作用 洗浄血小板の調製（遠心洗浄法） 健康人より採取し、直ちに1/10量の０．３８％クエン酸
ナトリウムと混和した血液を、遠心操作（７００×Ｇ、
１０分間）により多血小板血漿（ＰＲＰ）とし、このＰ
ＲＰに1/6量のＡＣＤ液（クエン酸ナトリウム２．２
％、クエン酸０．８％、グルコース２．２％−用時調
製）を加え、遠心操作（１５００×Ｇ、１０分間）によ
り得られた血小板ペレットを、修正ＨＥＰＥＳタイロー
ド溶液（食塩１３５mM、塩化カリウム２．７mM、塩化マ
グネシウム１mM、グルコース０．１mg／ml、ＨＥＰＥＳ
２０mM；pH７．４）に浮遊させた。これに1/6量のＡＣ
Ｄ液を添加後、更に遠心操作（１５００×Ｇ、５分間）
して得た血小板ペレットを修正ＨＥＰＥＳタイロード溶
液に浮遊させ、約３０万個／μｌの洗浄血小板浮遊液と
する。 血小板凝集反応の測定（比濁法） 上で得た洗浄血小板浮遊液２７０μｌに、適当な溶媒に
溶解した各濃度の被験化合物３μｌを加え、３７℃で２
分間予備加温ののち、コラーゲン２０μｇ／mlの溶液３
０μｌを加えてから、４チャンネル凝集測定機（ＨＥＭ
Ａトレイサー６０１；二光バイオサイエンス社製）にて
吸光度を測定する。 被験化合物の効果の判定 対照として、その被験化合物に用いた溶媒存在下でコラ
ーゲンによる最大凝集時の吸光度を１００とし、コラー
ゲン添加前の吸光度を０とする。次いで被験化合物を加
えたときのコラーゲンによる最大凝集時の吸光度から、
阻害の百分率を算出し、５０％阻害を与える被験化合物
の濃度ＩＣ50とし表示した。その結果は表２に示すとお
りである。Test Example 3 Preparation of Platelet Aggregation Inhibitory Action Washed Platelets (Centrifugal Washing Method) Blood collected from a healthy person and immediately mixed with 1/10 volume of 0.38% sodium citrate was centrifuged (700 × G). ,
Platelet-rich plasma (PRP) by 10 minutes)
1/6 volume of ACD solution in RP (sodium citrate 2.2
%, Citric acid 0.8%, glucose 2.2% -prepared before use, and the platelet pellet obtained by centrifugation (1500 × G, 10 minutes) was added to a modified HEPES Tyrode's solution (salt 135 mM, chloride). Potassium 2.7 mM, magnesium chloride 1 mM, glucose 0.1 mg / ml, HEPES
It was suspended in 20 mM; pH 7.4). 1/6 amount of AC
Centrifugal operation (1500 × G, 5 minutes) after adding D solution
The platelet pellet thus obtained is suspended in a modified HEPES Tyrode solution to prepare a washed platelet suspension of about 300,000 cells / μl. Measurement of Platelet Aggregation Reaction (Nephelometry) To 270 μl of the washed platelet suspension obtained above, 3 μl of each test compound dissolved in an appropriate solvent was added, and the mixture was allowed to stand at 37 ° C. for 2 hours.
After pre-warming for 3 minutes, collagen 20μg / ml solution 3
After adding 0 μl, 4-channel aggregometer (HEM
The absorbance is measured with A tracer 601; manufactured by Nikko Bioscience. Determination of effect of test compound As a control, the absorbance at the time of maximum aggregation by collagen in the presence of the solvent used for the test compound is 100, and the absorbance before the addition of collagen is 0. Then from the absorbance at the time of maximum aggregation by collagen when adding the test compound,
The percentage of inhibition was calculated and expressed as the concentration of the test compound giving 50% inhibition, IC 50 . The results are shown in Table 2.
【００５２】[0052]
【表２】 [Table 2]
【００５３】試験例４血流量増加試験 ペントバルビタールナトリウム（２５〜３０mg／kg）に
より麻酔した９〜１３カ月齢、体重９〜１０kgの雄性ビ
ーグル犬を１群４匹用いて試験を行った。５％グルコー
ス水溶液に溶解した被験化合物０．１〜１．０mg／kgを
イヌの大腿静脈内に投与し、椎骨動脈血流量及び大腿動
脈血流量を電磁血流計を用いて測定した。その結果を表
３に示す。Test Example 4 Blood Flow Increase Test A test was carried out using 4 male Beagle dogs 9 to 13 months old and weighing 9 to 10 kg anesthetized with sodium pentobarbital (25 to 30 mg / kg) per group. 0.1-1.0 mg / kg of the test compound dissolved in a 5% glucose aqueous solution was administered into the femoral vein of a dog, and the vertebral artery blood flow and the femoral artery blood flow were measured using an electromagnetic blood flow meter. Table 3 shows the results.
【００５４】[0054]
【表３】 [Table 3]
【００５５】試験例５血小板凝集阻害試験 ５〜７週齢、体重２７４〜５５４ｇの雄性Ｓｌｃ：Ｈａ
ｒｔｌｅｙ系モルモットを１群５匹用いて試験を行っ
た。５％グルコース溶液に溶解した被験化合物を１００
mg／kg経口投与し、投与１時間後に腹大動脈より採血
し、多血小板血漿（ＰＲＰ）を調製した。このＰＲＰに
血小板凝集惹起剤としてコラーゲン（２．５μｇ／ml）
又はアラキドン酸（０．１mM）を加えたときの最大凝集
を測定し、阻害率（％）を算出した。その結果を表４に
示す。Test Example 5 Platelet aggregation inhibition test Male Slc: Ha 5 to 7 weeks old and weighing 274 to 554 g
The test was conducted using 5 rtley-type guinea pigs per group. 100 test compounds dissolved in 5% glucose solution
Oral administration of mg / kg was performed, and 1 hour after the administration, blood was collected from the abdominal aorta to prepare platelet-rich plasma (PRP). Collagen (2.5 μg / ml) was added to this PRP as a platelet aggregation inducer.
Alternatively, the maximum aggregation when arachidonic acid (0.1 mM) was added was measured, and the inhibition rate (%) was calculated. The results are shown in Table 4.
【００５６】[0056]
【表４】 [Table 4]
フロントページの続き (72)発明者 井上 勗 千葉県船橋市二和西１−８−２−201Continuation of front page (72) Inoue Inou 1-8-2-201 Fuwabashi, Chiba
Claims (2)
原子、低級アルキル基、低級アルコキシ基、低級アルコ
キシカルボニル基、アシルアミノ基、又はニトロ基が置
換していてもよいアリール基；ベンジル基；キノリル基
又はチエニル基を示す）で表わされるアポビンカミン酸
誘導体又はその酸付加塩。1. The following general formula (1): (In the formula, R 1 represents a lower alkyl group, R 2 represents a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, an acylamino group, or an aryl group which may be substituted with a nitro group; a benzyl group. An apovincamic acid derivative represented by a quinolyl group or a thienyl group) or an acid addition salt thereof.
又はその酸付加塩を含有する医薬。2. A medicament containing the apovincamic acid derivative according to claim 1 or an acid addition salt thereof.
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP6155644A JPH0867681A (en) | 1994-06-24 | 1994-07-07 | Apovincamic acid derivative and medicine containing the same |
| PCT/JP1995/002434 WO1997019945A1 (en) | 1994-07-07 | 1995-11-29 | Apovincaminic acid derivative and medicine containing the same |
| EP95938607A EP0864571A4 (en) | 1994-07-07 | 1995-11-29 | Apovincaminic acid derivative and medicine containing the same |
| CA002238488A CA2238488A1 (en) | 1994-07-07 | 1995-11-29 | Apovincaminic acid derivatives and drugs containing the same |
| TW084113171A TW349099B (en) | 1994-06-24 | 1995-12-11 | Apovincamine derivatives and the pharmaceutical composition thereof |
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP14303494 | 1994-06-24 | ||
| JP6-143034 | 1994-06-24 | ||
| JP6155644A JPH0867681A (en) | 1994-06-24 | 1994-07-07 | Apovincamic acid derivative and medicine containing the same |
| PCT/JP1995/002434 WO1997019945A1 (en) | 1994-07-07 | 1995-11-29 | Apovincaminic acid derivative and medicine containing the same |
| CA002238488A CA2238488A1 (en) | 1994-07-07 | 1995-11-29 | Apovincaminic acid derivatives and drugs containing the same |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0867681A true JPH0867681A (en) | 1996-03-12 |
Family
ID=27170696
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP6155644A Pending JPH0867681A (en) | 1994-06-24 | 1994-07-07 | Apovincamic acid derivative and medicine containing the same |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0867681A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2018506582A (en) * | 2015-02-04 | 2018-03-08 | ▲は▼薬集団製薬総廠Ｈａｒｂｉｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｇｒｏｕｐ Ｃｏ．， Ｌｔｄ． Ｇｅｎｅｒａｌ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｆａｃｔｏｒｙ | Diaza-benzofluoranthene compounds |
-
1994
- 1994-07-07 JP JP6155644A patent/JPH0867681A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2018506582A (en) * | 2015-02-04 | 2018-03-08 | ▲は▼薬集団製薬総廠Ｈａｒｂｉｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｇｒｏｕｐ Ｃｏ．， Ｌｔｄ． Ｇｅｎｅｒａｌ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｆａｃｔｏｒｙ | Diaza-benzofluoranthene compounds |
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