JPH05339271A - Quinoline derivative or its salt - Google Patents
Quinoline derivative or its saltInfo
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- JPH05339271A JPH05339271A JP14554592A JP14554592A JPH05339271A JP H05339271 A JPH05339271 A JP H05339271A JP 14554592 A JP14554592 A JP 14554592A JP 14554592 A JP14554592 A JP 14554592A JP H05339271 A JPH05339271 A JP H05339271A
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Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は強心作用、抗不整脈作用
及び血管拡張作用等の薬理作用を有する新規なキノリン
誘導体又はその塩に関する。FIELD OF THE INVENTION The present invention relates to a novel quinoline derivative having a pharmacological action such as cardiotonic action, antiarrhythmic action and vasodilator action or a salt thereof.
【０００２】[0002]
【従来の技術】うっ血性心不全は心臓の機能異常の為に
心拍出量が低下し、組織の代謝に必要なだけの血液を拍
出できない病的状態とされているが、最近、Ｊ．Ｎ．Ｃ
ｏｈｎは心不全を、１）運動耐容能の低下、２）心室性
不整脈の多発と、３）予後不良の徴候を伴った心機能不
全による症候群と記載している（Ｊ．Ｎ．Ｃｏｈｎ：Ｃ
ｉｒｃｕｌａｔｉｏｎ ７８，１０９９（１９８
８））。従来、これらの改善には利尿剤、血管拡張剤及
びジギタリス剤等の強心剤が用いられている。2. Description of the Related Art Congestive heart failure is a pathological condition in which the cardiac output is reduced due to the abnormal function of the heart, and it is not possible to pump enough blood for the metabolism of tissues. N. C
Ohn describes heart failure as 1) decreased exercise tolerance, 2) multiple ventricular arrhythmias, and 3) cardiac dysfunction syndrome with signs of poor prognosis (JN Cohn: C).
circulation 78 , 1099 (198
8)). Conventionally, cardiotonic agents such as diuretics, vasodilators and digitalis agents have been used for these improvements.
【０００３】今日、強心剤としては、ジギタリス剤が広
く用いられており、その一つであるジゴキシンは心臓の
駆出率を上げ、心不全の悪化を抑えていることは認めら
れており、さらに、心拍数が低下し、持続が長く、耐薬
性がなく、経口投与できるなど大変な利点を持っている
が、反面有効血中濃度と中毒量が近く、しばしば、不整
脈を誘発する等の欠点を持っていることもあって、近年
非グリコシド経口強心剤の開発が強力に進められてい
る。[0003] Today, a digitalis agent is widely used as a cardiotonic agent, and it is acknowledged that one of them, digoxin, increases the ejection fraction of the heart and suppresses the worsening of heart failure. The number is low, the duration is long, the drug is not resistant, and it can be orally administered, but on the other hand, the effective blood concentration and the amount of poisoning are close, and they often have the drawbacks of inducing arrhythmia. Therefore, the development of non-glycoside oral inotropic agents has been strongly promoted in recent years.
【０００４】[0004]
【発明が解決しようとする課題】従って、本発明の目的
は強心作用を有し、不整脈を抑制又は殆んど誘発せず、
心拍数を著しく増加させることなく血管拡張作用を有す
る等の心疾患治療剤として有用な化合物を提供すること
にある。Therefore, the object of the present invention is to have a cardiotonic action, suppress or hardly induce arrhythmia,
It is intended to provide a compound useful as a therapeutic agent for heart diseases such as having a vasodilatory action without significantly increasing the heart rate.
【０００５】[0005]
【課題を解決するための手段】かかる実状に鑑み、本発
明者らは数多くの化合物を合成し、強心作用、抗不整脈
作用、血管拡張作用等を指標としてスクリーニングして
きたところ、下記一般式（１）で表わされるキノリン誘
導体又はその塩がこれらの作用を有し、心疾患治療剤と
して有用であることを見出し、本発明を完成するに至っ
た。In view of the above situation, the present inventors have synthesized a large number of compounds and have screened them using the cardiotonic action, antiarrhythmic action, vasodilatory action, etc. as an index. It was found that the quinoline derivative represented by the formula (4) or a salt thereof has these actions and is useful as a therapeutic agent for heart disease, and has completed the present invention.
【０００６】すなわち、本発明は次の一般式（１）で表
わされるキノリン誘導体又はその塩を提供するものであ
る。That is, the present invention provides a quinoline derivative represented by the following general formula (1) or a salt thereof.
【０００７】[0007]
【化２】 [Chemical 2]
【０００８】〔式中、Ａは酸素原子又は単結合を示し、
Ａが酸素原子のときＢは単結合又はメチレン基を示し、
Ａが単結合のときＢは酸素原子を示す。Ｒ1 及びＲ2 は
水素原子又は低級アルキル基を示し、Ｒ3 は置換基を有
していてもよい低級アルキル基、低級アルカノイルオキ
シ基、水酸基、低級アルキルスルホニルオキシ基、アジ
ド基又はアミノ基を示し、破線は二重結合が存在しても
よいことを示す。〕[In the formula, A represents an oxygen atom or a single bond,
When A is an oxygen atom, B represents a single bond or a methylene group,
When A is a single bond, B represents an oxygen atom. R 1 and R 2 represent a hydrogen atom or a lower alkyl group, and R 3 represents a lower alkyl group which may have a substituent, a lower alkanoyloxy group, a hydroxyl group, a lower alkylsulfonyloxy group, an azido group or an amino group. The dashed line indicates that a double bond may be present. ]
【０００９】上記一般式（１）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、イソプロピル基、ｎ−
ブチル基、ｓｅｃ−ブチル基、ｎ−ペンチル基、ｎ−ヘ
キシル基等が挙げられ、低級アルキルスルホニルオキシ
基としてはメタンスルホニルオキシ基、エタンスルホニ
ルオキシ基等が挙げられ、低級アルカノイルオキシ基と
しては炭素数２〜６の直鎖又は分岐鎖のアルカノイルオ
キシ基、例えばアセトキシ基、プロパノイルオキシ基、
ブチリルオキシ基等が挙げられる。また、低級アルキル
基に置換し得る基としては、水酸基、低級アルキルスル
ホニルオキシ基、アジド基又はアミノ基等が挙げられ
る。In the above general formula (1), the lower alkyl group is a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl group, ethyl group, isopropyl group, n-
Butyl group, sec-butyl group, n-pentyl group, n-hexyl group and the like, lower alkylsulfonyloxy group such as methanesulfonyloxy group, ethanesulfonyloxy group and the like, lower alkanoyloxy group is carbon A straight-chain or branched-chain alkanoyloxy group of the number 2 to 6, for example, acetoxy group, propanoyloxy group,
Examples include butyryloxy group. Examples of the group that can be substituted on the lower alkyl group include a hydroxyl group, a lower alkylsulfonyloxy group, an azido group, an amino group and the like.
【００１０】また、本発明化合物（１）の塩としては、
例えば塩酸、硫酸、硝酸等の無機酸又はフマル酸、酒石
酸、マレイン酸、コハク酸等の有機酸との酸付加塩；カ
ルボキシル基のナトリウム塩、カリウム塩等のアルカリ
金属塩又はカルシウム塩、マグネシウム塩等のアルカリ
土類金属塩等が挙げられる。Further, as the salt of the compound (1) of the present invention,
For example, an acid addition salt with an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, or an organic acid such as fumaric acid, tartaric acid, maleic acid, succinic acid; an alkali metal salt such as a sodium salt or a potassium salt of a carboxyl group, a calcium salt, or a magnesium salt. Alkaline earth metal salts and the like.
【００１１】また、本発明化合物（１）には不斉炭素原
子が存在するため光学異性体があるが、その光学活性体
及びラセミ体のいずれも本発明に含まれる。Further, the compound (1) of the present invention has optical isomers due to the presence of an asymmetric carbon atom, and both the optically active form and the racemic form are included in the present invention.
【００１２】本発明化合物（１）は、例えば次に示す方
法に従って製造することができる。The compound (1) of the present invention can be produced, for example, according to the following method.
【００１３】〔方法１〕 フロ〔３，２−ｇ〕キノリン類の製造：[Method 1] Production of Furo [3,2-g] quinolines:
【００１４】[0014]
【化３】 [Chemical 3]
【００１５】[0015]
【化４】 [Chemical 4]
【００１６】〔式中、Ｒ4 は低級アルカノイル基を示
し、Ｒ5 は低級アルキルスルホニル基を示し、Ｘはハロ
ゲン原子を示し、Ｒ1 及びＲ2 は前記と同じ意味を有す
る。〕[In the formula, R 4 represents a lower alkanoyl group, R 5 represents a lower alkylsulfonyl group, X represents a halogen atom, and R 1 and R 2 have the same meanings as described above. ]
【００１７】３−アミノフェノール類（２）に桂皮酸ハ
ライド等の桂皮酸反応性誘導体を反応させて桂皮酸アミ
ド誘導体（３）を得、これをフリーデルクラフツ反応に
付してキノリン体（４）とし、これにアリルハライドを
反応させてアリルオキシキノリン（５）を得る。アリル
オキシキノリン（５）をクライゼン転移後無水酢酸等の
酸無水物を反応させて６−アリルキノリン（７）を得、
これに過酸を反応させてエポキシ体（８）を得る。次
に、このエポキシ体（８）をアルカリで処理すれば化合
物（１ａ）が得られる。この化合物（１ａ）に低級アル
キルスルホン酸ハライドを反応させれば化合物（１ｂ）
が得られ、化合物（１ｂ）にアジ化ナトリウムを反応さ
せれば化合物（１ｃ）が得られる。また化合物（１ｃ）
を還元すれば化合物（１ｄ）が得られる。A cinnamic acid amide derivative (3) is obtained by reacting a 3-aminophenol (2) with a cinnamic acid-reactive derivative such as cinnamic acid halide, which is subjected to Friedel-Crafts reaction to give a quinoline derivative (4). ) Is reacted with allyl halide to obtain allyloxyquinoline (5). After Claisen transfer of allyloxyquinoline (5), acid anhydride such as acetic anhydride is reacted to obtain 6-allylquinoline (7),
This is reacted with peracid to obtain an epoxy compound (8). Then, the epoxy body (8) is treated with alkali to obtain the compound (1a). When this compound (1a) is reacted with a lower alkyl sulfonic acid halide, the compound (1b) is obtained.
Is obtained, and the compound (1b) is reacted with sodium azide to obtain the compound (1c). Compound (1c)
Is reduced to obtain the compound (1d).
【００１８】〔方法２〕 ピラノ〔３，２−ｇ〕キノリン類の製造：[Method 2] Production of pyrano [3,2-g] quinolines:
【００１９】[0019]
【化５】 [Chemical 5]
【００２０】〔式中、Ｒ1 、Ｒ2 、Ｒ4 及びＲ5 は前記
と同じ意味を有する。〕[Wherein, R 1 , R 2 , R 4 and R 5 have the same meanings as described above. ]
【００２１】〔方法１〕で得られたエポキシ体（８）に
ヨウ化ナトリウム等のハロゲン化アルカリを反応させれ
ば化合物（１ｅ）が得られ、これを加水分解すれば化合
物（１ｆ）が得られる。また、〔方法１〕と同様に、化
合物（１ｆ）に低級アルキルスルホン酸ハライドを反応
させれば化合物（１ｇ）が得られ、次いでアジ化ナトリ
ウムを反応させれば化合物（１ｈ）が得られ、化合物
（１ｈ）を還元すれば化合物（１ｉ）が得られる。The compound (1e) is obtained by reacting the epoxy compound (8) obtained by [Method 1] with an alkali halide such as sodium iodide, and the compound (1f) is obtained by hydrolyzing it. Be done. Further, in the same manner as in [Method 1], the compound (1f) is reacted with a lower alkylsulfonic acid halide to obtain a compound (1 g), and then sodium azide is reacted to obtain a compound (1h). The compound (1i) is obtained by reducing the compound (1h).
【００２２】〔方法３〕 フロ〔２，３−ｇ〕キノリン類の製造：[Method 3] Production of Furo [2,3-g] quinolines:
【００２３】[0023]
【化６】 [Chemical 6]
【００２４】[0024]
【化７】 [Chemical 7]
【００２５】４−アミノフェノール類（９）に桂皮酸ハ
ライド等の桂皮酸反応性誘導体を反応させて桂皮酸アミ
ド誘導体（１０）を得、これをフリーデルクラフツ反応
に付して６−ヒドロキシキノリン体（１１）とし、これ
にアリルハライドを反応させて６−アリルオキシキノリ
ン（１２）を得る。６−アリルオキシキノリン（１２）
をクライゼン転移後無水酢酸等の酸無水物を反応させて
７−アリルキノリン（１４）を得、これに過酸を反応さ
せてエポキシ体（１５）を得る。次に、このエポキシ体
（１５）をアルカリで処理すれば化合物（１ｊ）が得ら
れる。この化合物（１ｊ）に低級アルキルスルホン酸ハ
ライドを反応させれば、化合物（１ｋ）が得られ、化合
物（１ｋ）にアジ化ナトリウムを反応させれば化合物
（１ｌ）が得られる。また化合物（１ｌ）を還元すれば
化合物（１ｍ）が得られる。The 4-aminophenols (9) are reacted with a cinnamic acid-reactive derivative such as cinnamic acid halide to obtain a cinnamic acid amide derivative (10), which is subjected to Friedel-Crafts reaction to give 6-hydroxyquinoline. The body (11) is reacted with allyl halide to obtain 6-allyloxyquinoline (12). 6-allyloxyquinoline (12)
After Claisen transfer, an acid anhydride such as acetic anhydride is reacted to obtain 7-allylquinoline (14), and this is reacted with peracid to obtain an epoxy compound (15). Next, the epoxy body (15) is treated with alkali to obtain the compound (1j). The compound (1j) is reacted with a lower alkyl sulfonic acid halide to obtain the compound (1k), and the compound (1k) is reacted with sodium azide to obtain the compound (1l). Further, the compound (1m) is obtained by reducing the compound (1l).
【００２６】また、かくして得られるキノリン体（１
ａ）〜（１ｍ）を接触還元に付すことにより、下記のテ
トラヒドロキノリン誘導体（１ｎ）が得られる。The quinoline derivative (1
By subjecting a) to (1m) to catalytic reduction, the following tetrahydroquinoline derivative (1n) is obtained.
【００２７】[0027]
【化８】 [Chemical 8]
【００２８】また、化合物（１ａ）、（１ｆ）又は（１
ｊ）を接触還元すれば対応するテトラヒドロキノリン誘
導体が得られ、当該テトラヒドロキノリン誘導体を前記
と同様に低級アルキルスルホニル化、アジド化、次いで
還元することにより化合物（１ｂ）〜（１ｄ）、化合物
（１ｇ）〜（１ｉ）、化合物（１ｋ）〜（１ｍ）のテト
ラヒドロキノリン誘導体が得られる。Further, the compound (1a), (1f) or (1
Corresponding tetrahydroquinoline derivative can be obtained by catalytic reduction of j), and the compound (1b) to (1d), compound (1g) can be obtained by subjecting the tetrahydroquinoline derivative to lower alkylsulfonylation, azidation and reduction in the same manner as above. ) To (1i), and tetrahydroquinoline derivatives of compounds (1k) to (1m) are obtained.
【００２９】上記反応において、反応混合物から目的化
合物を単離するには通常の手段、例えば抽出、再結晶、
カラムクロマトグラフィー等によればよい。In the above reaction, the desired compound can be isolated from the reaction mixture by a conventional method such as extraction, recrystallization,
Column chromatography or the like may be used.
【００３０】[0030]
【発明の効果】斯くして得られる本発明化合物（１）又
はその塩は、優れた抗不整脈作用、強心作用及び血管拡
張作用等を有し、心不全に代表される心疾患治療剤とし
て有用である。EFFECTS OF THE INVENTION The compound (1) of the present invention or a salt thereof thus obtained has excellent antiarrhythmic action, cardiotonic action, vasodilatory action and the like, and is useful as a therapeutic agent for heart diseases represented by heart failure. is there.
【００３１】[0031]
【実施例】以下、実施例を挙げて本発明をさらに詳細に
説明するが本発明はこれらに限定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.
【００３２】合成例１ Ｎ−（３−ヒドロキシ−２−メチルフェニル）シンナマ
ミドの合成：３−アミノ−ｏ−クレゾール３．０ｇ（２
４．７mmol）をアセトン５２mlに懸濁し、これにピリジ
ン２．３４ｇ（２９．６mmol）を加え氷水冷却下にシン
ナモイルクロリド４．５２ｇ（２７．１mmol）を加え常
温で２０分間撹拌した。反応後溶媒を減圧留去した残渣
に水を加え、不溶の固体を濾取し、水次いで酢酸エチル
で洗い標題化合物の白色粉末４．７２ｇ（７５．９％）
を得た。Synthesis Example 1 Synthesis of N- (3-hydroxy-2-methylphenyl) cinnamamide: 3-amino-o-cresol 3.0 g (2
(4.7 mmol) was suspended in 52 ml of acetone, 2.34 g (29.6 mmol) of pyridine was added thereto, 4.52 g (27.1 mmol) of cinnamoyl chloride was added under cooling with ice water, and the mixture was stirred at room temperature for 20 minutes. After the reaction, the solvent was distilled off under reduced pressure, water was added to the residue, the insoluble solid was collected by filtration, washed with water and then ethyl acetate, and 4.72 g (75.9%) of a white powder of the title compound was obtained.
Got
【００３３】IR(KBr)cm-1:3235,3015,1659,1621,1593,1
536,1446,1345,1248,12031 H-NMR(CDCl3:CD3OD=7:2)δ(ppm):2.17(3H,s),6.71(1H,
br.d,J=8),6.79(1H,br.d,J=16),7.03(1H,t,J=8),7.10(1
H,br.d,J=8),7.35-7.65(5H,m),7.70(1H,d,J=16)IR (KBr) cm -1 : 3235,3015,1659,1621,1593,1
536,1446,1345,1248,1203 1 H-NMR (CDCl 3 : CD 3 OD = 7: 2) δ (ppm): 2.17 (3H, s), 6.71 (1H,
br.d, J = 8), 6.79 (1H, br.d, J = 16), 7.03 (1H, t, J = 8), 7.10 (1
H, br.d, J = 8), 7.35-7.65 (5H, m), 7.70 (1H, d, J = 16)
【００３４】合成例２ １，２−ジヒドロ−７−ヒドロキシ−８−メチルキノリ
ン−２−オンの合成：Ｎ−（３−ヒドロキシ−２−メチ
ルフェニル）シンナマミド１．５７ｇ（６．２mmol）と
塩化アルミニウム４．１２ｇ（３０．９mmol）をクロル
ベンゼン２０mlに懸濁し、１２５℃で１時間撹拌した。
反応液を冷後、氷水に注ぎ不溶物を濾取し、水次いでｎ
−ヘキサンで洗い標題化合物の褐色固体０．７０ｇ（６
４．３％）を得た。Synthesis Example 2 Synthesis of 1,2-dihydro-7-hydroxy-8-methylquinolin-2-one: 1.57 g (6.2 mmol) of N- (3-hydroxy-2-methylphenyl) cinnamamide and chloride 4.12 g (30.9 mmol) of aluminum was suspended in 20 ml of chlorobenzene and stirred at 125 ° C. for 1 hour.
After cooling the reaction solution, it was poured into ice water and the insoluble matter was collected by filtration.
-Wash with hexane 0.70 g (6
4.3%) was obtained.
【００３５】IR(KBr)cm-1:3171,2908,1626,1597,1558,1
496,1386,1304,1247,11401 H-NMR(CDCl3:DMSO-d6=7:3)δ(ppm):2.26(3H,s),6.28(1
H,d,J=9),6.77(1H,d,J=8.5),7.23(1H,d,J=8.5),7.66(1
H,d,J=9),9.72(1H,s),10.39(1H,br.s,NH)IR (KBr) cm -1 : 3171,2908,1626,1597,1558,1
496,1386,1304,1247,1140 1 H-NMR (CDCl 3 : DMSO-d 6 = 7: 3) δ (ppm): 2.26 (3H, s), 6.28 (1
H, d, J = 9), 6.77 (1H, d, J = 8.5), 7.23 (1H, d, J = 8.5), 7.66 (1
H, d, J = 9), 9.72 (1H, s), 10.39 (1H, br.s, NH)
【００３６】合成例３ ７−アリルオキシ−１，２−ジヒドロ−８−メチルキノ
リン−２−オンの合成：１，２−ジヒドロ−７−ヒドロ
キシ−８−メチルキノリン−２−オン０．７０ｇ（４．
０mmol）、炭酸カリウム０．６９ｇ（５．０mmol）、沃
化アリル１．０１ｇ（６．０mmol）、ジメチルホルムア
ミド１４mlの懸濁液を５０℃で２時間撹拌した。反応液
を減圧濃縮した残渣に水を加え、不溶物を濾取し、水次
いでエーテルで洗い風乾し標題化合物の白色針状晶０．
７３ｇ（８４．９％）を得た。Synthesis Example 3 Synthesis of 7-allyloxy-1,2-dihydro-8-methylquinolin-2-one: 1,2-dihydro-7-hydroxy-8-methylquinolin-2-one 0.70 g (4 ．
0 mmol), 0.69 g (5.0 mmol) of potassium carbonate, 1.01 g (6.0 mmol) of allyl iodide, and 14 ml of dimethylformamide were stirred at 50 ° C. for 2 hours. Water was added to the residue obtained by concentrating the reaction solution under reduced pressure, the insoluble material was collected by filtration, washed with water and then with ether, and air-dried to give white needle crystals of the title compound.
73 g (84.9%) were obtained.
【００３７】IR(KBr)cm-1:3143,3010,1637,1616,1557,1
498,1309,1251,11411 H-NMR(CDCl3:DMSO-d6=7:2)δ(ppm):2.33(3H,s),4.65(2
H,d,J=5),5.31(1H,d,J=10),5.43(1H,d,J=18),6.02-6.17
(1H,m),6.36(1H,d,J=9),6.83(1H,d,J=9),7.38(1H,d,J=
9),7.69(1H,d,J=9),10.38(1H,br.s,NH)IR (KBr) cm -1 : 3143,3010,1637,1616,1557,1
498,1309,1251,1141 1 H-NMR (CDCl 3 : DMSO-d 6 = 7: 2) δ (ppm): 2.33 (3H, s), 4.65 (2
H, d, J = 5), 5.31 (1H, d, J = 10), 5.43 (1H, d, J = 18), 6.02-6.17
(1H, m), 6.36 (1H, d, J = 9), 6.83 (1H, d, J = 9), 7.38 (1H, d, J =
9), 7.69 (1H, d, J = 9), 10.38 (1H, br.s, NH)
【００３８】合成例４ ６−アリル−１，２−ジヒドロ−７−ヒドロキシ−８−
メチルキノリン−２−オンの合成：７−アリルオキシ−
１，２−ジヒドロ−８−メチルキノリン−２−オン２．
１６ｇ（１０mmol）をＮ，Ｎ−ジメチルアニリン４８ml
に懸濁し窒素雰囲気下２３０℃で９時間加熱撹拌した。
反応液に冷後ｎ−ヘキサンを加え析出した結晶を濾取
し、クロロホルムで洗い、標題化合物の黄色結晶１．４
０ｇ（６４．８％）を得た。クロロホルムの洗浄液より
７−アリルオキシ−１，２−ジヒドロ−８−メチルキノ
リン−２−オンの淡褐色個体０．６２ｇ（２８．７％）
を回収した。Synthesis Example 4 6-allyl-1,2-dihydro-7-hydroxy-8-
Synthesis of methylquinolin-2-one: 7-allyloxy-
1,2-dihydro-8-methylquinolin-2-one 2.
16 g (10 mmol) of N, N-dimethylaniline 48 ml
And was stirred under heating in a nitrogen atmosphere at 230 ° C. for 9 hours.
After cooling the reaction mixture, n-hexane was added and the precipitated crystals were collected by filtration and washed with chloroform to give 1.4 g of the title compound as yellow crystals.
0 g (64.8%) was obtained. From the chloroform washing solution, a light brown solid of 7-allyloxy-1,2-dihydro-8-methylquinolin-2-one 0.62 g (28.7%)
Was recovered.
【００３９】IR(KBr)cm-1:3155,1641,1620,1559,1391,1
171,11591 H-NMR(CDCl3:DMSO-d6=7:2)δ(ppm):2.34(3H,s),3.43(2
H,d,J=7),5.06(2H,br.d,J=13),5.90-6.09(1H,m),6.33(1
H,d,J=9),7.13(1H,s),7.63(1H,d,J=9),8.58(1H,s),10.1
2(1H,br.s,NH)IR (KBr) cm -1 : 3155,1641,1620,1559,1391,1
171,1159 1 H-NMR (CDCl 3 : DMSO-d 6 = 7: 2) δ (ppm): 2.34 (3H, s), 3.43 (2
H, d, J = 7), 5.06 (2H, br.d, J = 13), 5.90-6.09 (1H, m), 6.33 (1
H, d, J = 9), 7.13 (1H, s), 7.63 (1H, d, J = 9), 8.58 (1H, s), 10.1
2 (1H, br.s, NH)
【００４０】合成例５ ７−アセトキシ−６−アリル−１，２−ジヒドロ−８−
メチルキノリン−２−オンの合成：６−アリル−１，２
−ジヒドロ−７−ヒドロキシ−８−メチルキノリン−２
−オン１．６０ｇ（７．４３mmol）をピリジン２５mlに
とかし、これに無水酢酸２．１ml（２２．２mmol）を滴
下し常温で１時間撹拌した。反応液を減圧濃縮した残渣
をクロロホルムで洗い、標題化合物の白色粉末１．６９
ｇ（８８．３％）を得た。Synthesis Example 5 7-acetoxy-6-allyl-1,2-dihydro-8-
Synthesis of methylquinolin-2-one: 6-allyl-1,2
-Dihydro-7-hydroxy-8-methylquinoline-2
1.60 g (7.43 mmol) of -one was dissolved in 25 ml of pyridine, 2.1 ml (22.2 mmol) of acetic anhydride was added dropwise thereto, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was washed with chloroform, and the title compound was white powder 1.69.
g (88.3%) was obtained.
【００４１】IR(KBr)cm-1:3146,3001,1753,1668,1639,1
601,1369,1226,1204,11471 H-NMR(CDCl3)δ(ppm):2.26(3H,s),2.38(3H,s),3.32(2
H,d,J=6),5.06-5.99(3H,m),6.62(1H,d,J=10),7.29(1H,
s),7.70(1H,d,J=10),9.57(1H,br.s,NH)IR (KBr) cm -1 : 3146,3001,1753,1668,1639,1
601,1369,1226,1204,1147 1 H-NMR (CDCl 3 ) δ (ppm): 2.26 (3H, s), 2.38 (3H, s), 3.32 (2
H, d, J = 6), 5.06-5.99 (3H, m), 6.62 (1H, d, J = 10), 7.29 (1H,
s), 7.70 (1H, d, J = 10), 9.57 (1H, br.s, NH)
【００４２】合成例６ ７−アセトキシ−１，２−ジヒドロ−６−（２，３−エ
ポキシプロピル）−８−メチルキノリン−２−オンの合
成：７−アセトキシ−６−アリル−１，２−ジヒドロ−
８−メチルキノリン−２−オン１．６０ｇ（６．２２mm
ol）をクロロホルム６０mlにとかし、これにｍ−クロル
過安息香酸酸４．０２ｇ（１８．６mmol）を加え、常温
で２０時間撹拌した。反応液を５％亜硫酸ナトリウム水
溶液、飽和重曹水、食塩水で順次洗い芒硝で乾燥し、溶
媒を減圧留去した。残渣を少量のクロロホルムで洗い、
標題化合物の白色粉末１．６６ｇ（９８．２％）を得
た。Synthesis Example 6 Synthesis of 7-acetoxy-1,2-dihydro-6- (2,3-epoxypropyl) -8-methylquinolin-2-one: 7-acetoxy-6-allyl-1,2- Dihydro-
8-Methylquinolin-2-one 1.60 g (6.22 mm
ol) was dissolved in 60 ml of chloroform, 4.02 g (18.6 mmol) of m-chloroperbenzoic acid was added thereto, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was washed successively with 5% aqueous sodium sulfite solution, saturated aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. Wash the residue with a small amount of chloroform,
1.66 g (98.2%) of white powder of the title compound was obtained.
【００４３】IR(KBr)cm-1:3000,1749,1644,1600,1229,1
205,11471 H-NMR(CDCl3)δ(ppm):2.27(3H,s),2.42(3H,s),2.55(1
H,dd,J=5,2.5),2.77-3.19(4H,m),6.63(1H,d,J=9),7.41
(1H,s),7.72(1H,d,J=9),9.62(1H,br.s,NH)IR (KBr) cm -1 : 3000,1749,1644,1600,1229,1
205,1147 1 H-NMR (CDCl 3 ) δ (ppm): 2.27 (3H, s), 2.42 (3H, s), 2.55 (1
H, dd, J = 5,2.5), 2.77-3.19 (4H, m), 6.63 (1H, d, J = 9), 7.41
(1H, s), 7.72 (1H, d, J = 9), 9.62 (1H, br.s, NH)
【００４４】実施例１ ２−ヒドロキシメチル−９−メチル−２，３，７，８−
テトラヒドロフロ〔３，２−ｇ〕キノリン−７−オンの
合成：７−アセトキシ−１，２−ジヒドロ−６−（２，
３−エポキシプロピル）−８−メチルキノリン−２−オ
ン６．４６ｇ（２３．６mmol）をジメチルホルムアミド
２６０mlにとかし、これに１Ｎ−カセイソーダ溶液１０
６mlを加え５０℃で３０分間撹拌した。反応液を減圧濃
縮した残渣に水を加え、不溶物を濾取し、エーテルで洗
い、標題化合物の淡黄色針状晶３．３８ｇ（６１．８
％）〔ｍｐ２５９−２６１℃〕を得た。Example 1 2-Hydroxymethyl-9-methyl-2,3,7,8-
Synthesis of tetrahydrofuro [3,2-g] quinolin-7-one: 7-acetoxy-1,2-dihydro-6- (2,
6.46 g (23.6 mmol) of 3-epoxypropyl) -8-methylquinolin-2-one were dissolved in 260 ml of dimethylformamide, and 1N-caustic soda solution 10 was added thereto.
6 ml was added and the mixture was stirred at 50 ° C. for 30 minutes. Water was added to the residue obtained by concentrating the reaction solution under reduced pressure, the insoluble material was collected by filtration, washed with ether, and 3.38 g (61.8) of pale yellow needle crystals of the title compound were obtained.
%) [Mp 259-261 ° C.].
【００４５】元素分析 計算値 （C13H13NO3・1/5H2Oとして）:C,66.49;H,5.7
5;N,5.96 実測値 :C,66.52;H,5.7
0;N,6.05 IR(KBr)cm-1:3273,3169,2916,1636,1609,1567,1425,124
8,1159,10621 H-NMR(CDCl3:DMSO-d6=7:4)δ(ppm):2.28(3H,s),3.11(1
H,dd,J=16,7),3.20-3.32(1H,m),3.65(1H,dd,J=12,6),3.
72(1H,dd,J=12,5),4.84-4.95(2H,m),6.29(1H,d,J=9),7.
20(1H,s),7.65(1H,d,J=9),10.50(1H,s,NH)Calculated by elemental analysis (as C 13 H 13 NO 3 · 1 / 5H 2 O): C, 66.49; H, 5.7
5; N, 5.96 Found: C, 66.52; H, 5.7
0; N, 6.05 IR (KBr) cm -1 : 3273,3169,2916,1636,1609,1567,1425,124
8,1159,1062 1 H-NMR (CDCl 3 : DMSO-d 6 = 7: 4) δ (ppm): 2.28 (3H, s), 3.11 (1
H, dd, J = 16,7), 3.20-3.32 (1H, m), 3.65 (1H, dd, J = 12,6), 3.
72 (1H, dd, J = 12,5), 4.84-4.95 (2H, m), 6.29 (1H, d, J = 9), 7.
20 (1H, s), 7.65 (1H, d, J = 9), 10.50 (1H, s, NH)
【００４６】実施例２ ２−メタンスルホニルオキシメチル−９−メチル−２，
３，７，８−テトラヒドロフロ〔３，２−ｇ〕キノリン
−７−オンの合成：２−ヒドロキシメチル−９−メチル
−２，３，７，８−テトラヒドロフロ〔３，２−ｇ〕キ
ノリン−７−オン９０６mg（３．９２mmol）をピリジン
１８mlに懸濁し、これにメタンスルホニルクロリド０．
４０ml（５．１７mmol）を加え、常温で、１時間撹拌し
た。反応液を減圧濃縮した残渣をクロロホルムで洗い、
標題化合物の白色粉末９３３mg（７７．１％）を得た。Example 2 2-Methanesulfonyloxymethyl-9-methyl-2,
Synthesis of 3,7,8-tetrahydrofuro [3,2-g] quinolin-7-one: 2-hydroxymethyl-9-methyl-2,3,7,8-tetrahydrofuro [3,2-g] quinoline 906 mg (3.92 mmol) of -7-one was suspended in 18 ml of pyridine, and methanesulfonyl chloride (0.1 mg) was added thereto.
40 ml (5.17 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, the residue was washed with chloroform,
933 mg (77.1%) of a white powder of the title compound was obtained.
【００４７】IR(KBr)cm-1:3409,1642,1612,1345,1181,1
156,9901 H-NMR(CDCl3:DMSO-d6=7:1)δ(ppm):2.30(3H,s),3.09(3
H,s),3.14(1H,dd,J=16,6),3.44(1H,dd,J=16,9),4.41(1
H,dd,J=12,6),4.48(1H,dd,J=12,4),5.09-5.20(1H,m),6.
40(1H,d,J=10),7.22(1H,s),7.65(1H,d,J=10),10.05(1H,
br.s,NH)IR (KBr) cm -1 : 3409,1642,1612,1345,1181,1
156,990 1 H-NMR (CDCl 3 : DMSO-d 6 = 7: 1) δ (ppm): 2.30 (3H, s), 3.09 (3
H, s), 3.14 (1H, dd, J = 16,6), 3.44 (1H, dd, J = 16,9), 4.41 (1
H, dd, J = 12,6), 4.48 (1H, dd, J = 12,4), 5.09-5.20 (1H, m), 6.
40 (1H, d, J = 10), 7.22 (1H, s), 7.65 (1H, d, J = 10), 10.05 (1H,
br.s, NH)
【００４８】実施例３ ２−アジドメチル−９−メチル−２，３，７，８−テト
ラヒドロフロ〔３，２−ｇ〕キノリン−７−オンの合
成：２−メタンスルホニルオキシメチル−９−メチル−
２，３，７，８−テトラヒドロフロ〔３，２−ｇ〕キノ
リン−７−オン１．１２ｇ（３．６１mmol）とアジ化ナ
トリウム２．３５ｇをジメチルホルムアミド５０mlに懸
濁し、１２０℃で２時間撹拌した。冷後、反応液を水に
注ぎ、析出した結晶を濾取し、標題化合物の淡褐色結晶
０．９０ｇ（９７．０％）を得た。Example 3 Synthesis of 2-azidomethyl-9-methyl-2,3,7,8-tetrahydrofuro [3,2-g] quinolin-7-one: 2-methanesulfonyloxymethyl-9-methyl-
1.12 g (3.61 mmol) of 2,3,7,8-tetrahydrofuro [3,2-g] quinolin-7-one and 2.35 g of sodium azide were suspended in 50 ml of dimethylformamide, and the suspension was performed at 120 ° C for 2 hours. It was stirred. After cooling, the reaction solution was poured into water, and the precipitated crystals were collected by filtration to obtain 0.90 g (97.0%) of light brown crystals of the title compound.
【００４９】IR(KBr)cm-1:3145,2986,2095,1639,1609,1
473,1422,1289,12491 H-NMR(CDCl3)δ(ppm):2.30(3H,s),3.08(1H,ddd,J=16,
6,1),3.40(1H,ddd,J=16,9,1),3.47(1H,dd,J=13,6),3.54
(1H,dd,J=13,4),5.02-5.14(1H,m),6.47(1H,d,J=9),7.20
(1H,s),7.64(1H,d,J=9),9.24(1H,bs.s,NH)IR (KBr) cm -1 : 3145,2986,2095,1639,1609,1
473,1422,1289,1249 1 H-NMR (CDCl 3 ) δ (ppm): 2.30 (3H, s), 3.08 (1H, ddd, J = 16,
6,1), 3.40 (1H, ddd, J = 16,9,1), 3.47 (1H, dd, J = 13,6), 3.54
(1H, dd, J = 13,4), 5.02-5.14 (1H, m), 6.47 (1H, d, J = 9), 7.20
(1H, s), 7.64 (1H, d, J = 9), 9.24 (1H, bs.s, NH)
【００５０】実施例４ ２−アミノメチル−９−メチル−２，３，７，８−テト
ラヒドロフロ〔３，２−ｇ〕キノリン−７−オンの合
成：２−アジドメチル−９−メチル−２，３，７，８−
テトラヒドロフロ〔３，２−ｇ〕キノリン−７−オン
１．０８ｇ（４．２１mmol）をテトラヒドロフラン３６
mlとメタノール３６mlの混合溶液にとかし、これに１０
％パラジウム炭素０．９０ｇを加え、水素気流中常温で
２時間撹拌した。反応液よりパラジウム炭素を濾別し濾
液を減圧留去して、標題化合物の白色粉末０．３６ｇ
（３７．５％）を得た。Example 4 Synthesis of 2-aminomethyl-9-methyl-2,3,7,8-tetrahydrofuro [3,2-g] quinolin-7-one: 2-azidomethyl-9-methyl-2, 3,7,8-
Tetrahydrofuro [3,2-g] quinolin-7-one (1.08 g, 4.21 mmol) was added to tetrahydrofuran 36
Mix with 10 ml of methanol and 36 ml of methanol,
% 0.9% palladium carbon was added, and the mixture was stirred in a hydrogen stream at room temperature for 2 hours. Palladium carbon was separated from the reaction solution by filtration, and the filtrate was evaporated under reduced pressure to give the title compound (0.36 g) as a white powder.
(37.5%) was obtained.
【００５１】1H-NMR(CDCl3)δ(ppm):1.45(2H,br.s,NH
2),2.28(3H,s),2.93-3.09(3H,m),3.33(1H,dd,J=16,9),
4.83-4.96(1H,m),6.45(1H,d,J=9),7.18(1H,s),7.63(1H,
d,J=9),9.10(1H,br.s,NH) 得られた標題化合物０．３６ｇをメタノールにとかし、
４Ｎ−塩酸−ジオキサン溶液０．４９mlを加え溶媒を減
圧留去した残留物をメタノール−エーテルで再結晶し、
標題化合物の塩酸塩０．２８ｇ（６６．６％）を淡黄色
プリズム晶〔ｍｐ＞２８０℃〕として得た。 1 H-NMR (CDCl 3 ) δ (ppm): 1.45 (2H, br.s, NH
2 ), 2.28 (3H, s), 2.93-3.09 (3H, m), 3.33 (1H, dd, J = 16,9),
4.83-4.96 (1H, m), 6.45 (1H, d, J = 9), 7.18 (1H, s), 7.63 (1H,
d, J = 9), 9.10 (1H, br.s, NH) Dissolve 0.36 g of the obtained title compound in methanol,
0.49 ml of 4N hydrochloric acid-dioxane solution was added and the solvent was distilled off under reduced pressure. The residue was recrystallized from methanol-ether,
0.28 g (66.6%) of the hydrochloride of the title compound was obtained as pale yellow prism crystals [mp> 280 ° C.].
【００５２】塩酸塩： 元素分析 計算値 （C13H14N2O2・HCl・7/10H2Oとして）:C,55.9
0;H,5.92;N,10.03 実測値 :C,56.2
0;H,5.90;N,9.85 IR(KBr)cm-1:3378,3176,2916,1642,1611,1567,1438,124
3,11581 H-NMR(CD3OD)δ(ppm):2.37(3H,s),3.12(1H,ddd,J=16,
7,2),3.22(1H,dd,J=14,9),3.28-3.42(1H,m),3.56(1H,dd
d,J=16,9,2),5.11-5.22(1H,m),6.52(1H,d,J=9),7.43(1
H,s),7.96(1H,d,J=9)Hydrochloride: Calculated by elemental analysis (as C 13 H 14 N 2 O 2 .HCl.7 / 10H 2 O): C, 55.9
0; H, 5.92; N, 10.03 Actual value: C, 56.2
0; H, 5.90; N, 9.85 IR (KBr) cm -1 : 3378,3176,2916,1642,1611,1567,1438,124
3,1158 1 H-NMR (CD 3 OD) δ (ppm): 2.37 (3H, s), 3.12 (1H, ddd, J = 16,
7,2), 3.22 (1H, dd, J = 14,9), 3.28-3.42 (1H, m), 3.56 (1H, dd
d, J = 16,9,2), 5.11-5.22 (1H, m), 6.52 (1H, d, J = 9), 7.43 (1
H, s), 7.96 (1H, d, J = 9)
【００５３】実施例５ ２，３，５，６，７，８−ヘキサヒドロ−２−ヒドロキ
シメチル−９−メチルフロ〔３，２−ｇ〕キノリン−７
−オンの合成：２−ヒドロキシメチル−９−メチル−
２，３，７，８−テトラヒドロフロ〔３，２−ｇ〕キノ
リン−７−オン１．６４ｇ（７．０８mmol）を酢酸８０
mlにとかし、これに１０％パラジウム炭素１．６４ｇを
加え、水素気流中７０℃で４時間撹拌した。触媒を濾別
した溶液を減圧乾固して標題化合物の白色粉末１．４４
ｇ（８７．２％）を得た。これをクロロホルム−メタノ
ール−ｎ−ヘキサンで再結晶し、標題化合物の無色針状
晶〔ｍｐ２２５−２２７℃〕を得た。Example 5 2,3,5,6,7,8-hexahydro-2-hydroxymethyl-9-methylfuro [3,2-g] quinoline-7
Synthesis of 1-one: 2-hydroxymethyl-9-methyl-
2,3,7,8-Tetrahydrofuro [3,2-g] quinolin-7-one 1.64 g (7.08 mmol) was added to 80% acetic acid.
It was dissolved in ml, 1.64 g of 10% palladium carbon was added thereto, and the mixture was stirred at 70 ° C. for 4 hours in a hydrogen stream. The solution obtained by filtering off the catalyst was dried under reduced pressure to give a white powder of the title compound 1.44.
g (87.2%) were obtained. This was recrystallized from chloroform-methanol-n-hexane to obtain colorless needle crystals of the title compound [mp225-227 ° C].
【００５４】元素分析 計算値 （C13H15NO3・1/5H2Oとして）:C,65.92;H,6.5
5;N,5.91 実測値 :C,65.76;H,6.3
3;N,5.82 IR(KBr)cm-1:3341,3219,1642,1470,1398,1213,1188,110
7,10591 H-NMR(CDCl3:DMSO-d6=7:2)δ(ppm):2.09(3H,s),2.43-
2.85(4H,m),2.98(1H,dd,J=16,7),3.15(1H,dd,J=16,9),
3.66(2H,t,J=6),4.68(1H,t,J=6,OH),4.74-4.85(1H,m),
6.78(1H,s),8.85(1H,s,NH)Elemental analysis calculated value (as C 13 H 15 NO 3 · 1 / 5H 2 O): C, 65.92; H, 6.5
5; N, 5.91 Found: C, 65.76; H, 6.3
3; N, 5.82 IR (KBr) cm -1 : 3341,3219,1642,1470,1398,1213,1188,110
7,1059 1 H-NMR (CDCl 3 : DMSO-d 6 = 7: 2) δ (ppm): 2.09 (3H, s), 2.43-
2.85 (4H, m), 2.98 (1H, dd, J = 16,7), 3.15 (1H, dd, J = 16,9),
3.66 (2H, t, J = 6), 4.68 (1H, t, J = 6, OH), 4.74-4.85 (1H, m),
6.78 (1H, s), 8.85 (1H, s, NH)
【００５５】実施例６ ２，３，５，６，７，８−ヘキサヒドロ−２−メタンス
ルホニルオキシメチル−９−メチルフロ〔３，２−ｇ〕
キノリン−７−オンの合成：２，３，５，６，７，８−
ヘキサヒドロ−２−ヒドロキシメチル−９−メチルフロ
〔３，２−ｇ〕キノリン−７−オン１．３５ｇ（５．７
９mmol）をピリジン２７mlに懸濁し、メタンスルホニル
クロリド０．５４ml（７．０mmol）を加え常温で１時間
撹拌したのち、溶媒を減圧留去し、残渣をクロロホルム
で洗い、標題化合物の白色粉末１．４６ｇ（８１．１
％）を得た。Example 6 2,3,5,6,7,8-hexahydro-2-methanesulfonyloxymethyl-9-methylfuro [3,2-g]
Synthesis of quinolin-7-one: 2,3,5,6,7,8-
Hexahydro-2-hydroxymethyl-9-methylfuro [3,2-g] quinolin-7-one 1.35 g (5.7
(9 mmol) was suspended in 27 ml of pyridine, 0.54 ml (7.0 mmol) of methanesulfonyl chloride was added, and the mixture was stirred at room temperature for 1 hour. Then, the solvent was distilled off under reduced pressure, the residue was washed with chloroform, and a white powder of the title compound (1. 46 g (81.1
%) Was obtained.
【００５６】IR(KBr)cm-1:3216,1673,1622,1471,1383,1
349,1176,11061 H-NMR(CDCl3)δ(ppm):2.07(3H,s),2.55-2.91(4H,m),3.
02(1H,dd,J=16,7),3.07(3H,s),3.31(1H,dd,J=16,10),4.
34-5.09(3H,m),6.83(1H,s),7.41(1H,s,NH)IR (KBr) cm -1 : 3216,1673,1622,1471,1383,1
349,1176,1106 1 H-NMR (CDCl 3 ) δ (ppm): 2.07 (3H, s), 2.55-2.91 (4H, m), 3.
02 (1H, dd, J = 16,7), 3.07 (3H, s), 3.31 (1H, dd, J = 16,10), 4.
34-5.09 (3H, m), 6.83 (1H, s), 7.41 (1H, s, NH)
【００５７】実施例７ ２−アジドメチル−２，３，５，６，７，８−ヘキサヒ
ドロ−９−メチルフロ〔３，２−ｇ〕キノリン−７−オ
ンの合成：２，３，５，６，７，８−ヘキサヒドロ−２
−メタンスルホニルオキシメチル−９−メチルフロ
〔３，２−ｇ〕キノリン−７−オン０．７３ｇ（２．３
４mmol）、アジ化ナトリウム１．５２ｇ（２３．４mmo
l）をジメチルホルムアミド３０mlに懸濁し、１２０℃
で２時間反応したのち反応液を氷水に注ぎ、析出した結
晶を濾取し、標題化合物の淡黄色粉末０．６０４ｇ（定
量的）を得た。Example 7 Synthesis of 2-azidomethyl-2,3,5,6,7,8-hexahydro-9-methylfuro [3,2-g] quinolin-7-one: 2,3,5,6,6 7,8-hexahydro-2
-Methanesulfonyloxymethyl-9-methylfuro [3,2-g] quinolin-7-one 0.73 g (2.3
4 mmol), sodium azide 1.52 g (23.4 mmo)
l) is suspended in 30 ml of dimethylformamide at 120 ° C.
After reacting for 2 hours with ice water, the reaction solution was poured into ice water, and the precipitated crystals were collected by filtration to obtain 0.604 g (quantitative) of a pale yellow powder of the title compound.
【００５８】IR(KBr)cm-1:3202,2080,1663,1624,1470,1
383,1270,1211,11821 H-NMR(CDCl3)δ(ppm):2.09(3H,s),2.55-2.92(4H,m),2.
95(1H,dd,J=16,6),3.29(1H,dd,J=16,9),3.44(2H,d,J=
5),4.92-5.04(1H,m),6.82(1H,s),7.41(1H,br.s,NH)IR (KBr) cm -1 : 3202,2080,1663,1624,1470,1
383,1270,1211,1182 1 H-NMR (CDCl 3 ) δ (ppm): 2.09 (3H, s), 2.55-2.92 (4H, m), 2.
95 (1H, dd, J = 16,6), 3.29 (1H, dd, J = 16,9), 3.44 (2H, d, J =
5), 4.92-5.04 (1H, m), 6.82 (1H, s), 7.41 (1H, br.s, NH)
【００５９】実施例８ ２−アミノメチル−２，３，５，６，７，８−ヘキサヒ
ドロ−９−メチルフロ〔３，２−ｇ〕キノリン−７−オ
ンの合成：２−アジドメチル−２，３，５，６，７，８
−ヘキサヒドロ−９−メチルフロ〔３，２−ｇ〕キノリ
ン−７−オン０．６０８ｇ（２．３１mmol）を酢酸１２
mlにとかし、１０％パラジウム炭素０．６０ｇを加え水
素気流中、常温で１５時間反応したのち、触媒を除き、
溶媒を減圧留去して、標題化合物の白色粉末０．３１３
ｇ（５８．１％）を得た。Example 8 Synthesis of 2-aminomethyl-2,3,5,6,7,8-hexahydro-9-methylfuro [3,2-g] quinolin-7-one: 2-azidomethyl-2,3 , 5, 6, 7, 8
-Hexahydro-9-methylfuro [3,2-g] quinolin-7-one 0.608 g (2.31 mmol) in acetic acid 12
Dissolve in ml, add 0.60 g of 10% palladium on carbon and react for 15 hours at room temperature in a hydrogen stream, then remove the catalyst,
The solvent was evaporated under reduced pressure to give the title compound as a white powder 0.313
g (58.1%) was obtained.
【００６０】1H-NMR(CDCl3)δ(ppm):1.43(2H,br.s,NH
2),2.08(3H,s),2.54-3.02(7H,m),3.22(1H,dd,J=15,9),
4.73-4.85(1H,m),6.81(1H,s),7.38(1H,br.s,NH) 得られた標題化合物０．３１３ｇを塩酸塩としたのち、
メタノール−エーテルで再結晶し、標題化合物の塩酸塩
０．２６３ｇ（７２．３％）、無色プリズム晶〔ｍｐ＞
２８０℃〕を得た。 1 H-NMR (CDCl 3 ) δ (ppm): 1.43 (2H, br.s, NH
2 ), 2.08 (3H, s), 2.54-3.02 (7H, m), 3.22 (1H, dd, J = 15,9),
4.73-4.85 (1H, m), 6.81 (1H, s), 7.38 (1H, br.s, NH) After 0.313 g of the obtained title compound was made into hydrochloride,
The crystals were recrystallized from methanol-ether to give the hydrochloride of the title compound 0.263 g (72.3%), colorless prism crystals [mp>
280 ° C.] was obtained.
【００６１】塩酸塩： 元素分析 計算値 （C13H16N2O2・HClとして）:C,58.10;H,6.38;
N,10.42;Cl,13.19 実測値 :C,57.93;H,6.32;
N,10.41;Cl,13.19 IR(KBr)cm-1:3416,3232,2890,1668,1623,1469,1373,135
9,1214,11861 H-NMR(CD3OD)δ(ppm):2.14(3H,s),2.46-2.88(4H,m),2.
94(1H,dd,J=16,7),3.14(1H,dd,J=13,9),3.23-3.44(2H,
m),4.94-5.05(1H,m),6.89(1H,s)Hydrochloride: Calculated by elemental analysis (as C 13 H 16 N 2 O 2 .HCl): C, 58.10; H, 6.38;
N, 10.42; Cl, 13.19 Found: C, 57.93; H, 6.32;
N, 10.41; Cl, 13.19 IR (KBr) cm -1 : 3416,3232,2890,1668,1623,1469,1373,135
9,1214,1186 1 H-NMR (CD 3 OD) δ (ppm): 2.14 (3H, s), 2.46-2.88 (4H, m), 2.
94 (1H, dd, J = 16,7), 3.14 (1H, dd, J = 13,9), 3.23-3.44 (2H,
m), 4.94-5.05 (1H, m), 6.89 (1H, s)
【００６２】実施例９ ３−アセトキシ−１０−メチル−２，３，８，９−テト
ラヒドロピラノ〔３，２−ｇ〕キノリン−８−オンの合
成：７−アセトキシ−１，２−ジヒドロ−６−（２，３
−エポキシプロピル）−８−メチルキノリン−２−オン
１．６１ｇ（５．８９mmol）と沃化ナトリウム０．４４
ｇ（２．９５mmol）をアセトン９７mlとイソプロパノー
ル１２９mlの混合溶液にとかし、７５℃で２時間撹拌し
た。反応後、溶媒を減圧留去し残留物を水及びクロロホ
ルムで洗い、標題化合物の白色針状晶１．６１ｇ（定量
的）〔ｍｐ２６０−２６１℃〕を得た。Example 9 Synthesis of 3-acetoxy-10-methyl-2,3,8,9-tetrahydropyrano [3,2-g] quinolin-8-one: 7-acetoxy-1,2-dihydro- 6- (2,3
-Epoxypropyl) -8-methylquinolin-2-one 1.61 g (5.89 mmol) and sodium iodide 0.44
g (2.95 mmol) was dissolved in a mixed solution of 97 ml of acetone and 129 ml of isopropanol, and the mixture was stirred at 75 ° C. for 2 hours. After the reaction, the solvent was distilled off under reduced pressure, and the residue was washed with water and chloroform to obtain 1.61 g (quantitative) of white needle crystals of the title compound [mp 260-261 ° C].
【００６３】元素分析 計算値 （C15H15NO4・1/5H2Oとして）:C,65.07;H,5.6
1;N,5.06 実測値 :C,65.25;H,5.5
9;N,5.10 IR(KBr)cm-1:3160,1724,1644,1599,1248,1161,1063,103
11 H-NMR(CDCl3)δ(ppm):2.07(3H,s),2.27(3H,s),2.97(1
H,br.d,J=17),3.21(1H,dd,J=17,5),4.22(1H,d,J=12),4.
38(1H,br.d,J=12),5.27-5.33(1H,m),6.48(1H,d,J=9),7.
12(1H,s),7.62(1H,d,J=9),8.87(1H,br.s,NH)[0063] Analysis Calculated (as C 15 H 15 NO 4 · 1 / 5H 2 O): C, 65.07; H, 5.6
1; N, 5.06 Found: C, 65.25; H, 5.5
9; N, 5.10 IR (KBr) cm -1 : 3160,1724,1644,1599,1248,1161,1063,103
1 1 H-NMR (CDCl 3 ) δ (ppm): 2.07 (3H, s), 2.27 (3H, s), 2.97 (1
H, br.d, J = 17), 3.21 (1H, dd, J = 17,5), 4.22 (1H, d, J = 12), 4.
38 (1H, br.d, J = 12), 5.27-5.33 (1H, m), 6.48 (1H, d, J = 9), 7.
12 (1H, s), 7.62 (1H, d, J = 9), 8.87 (1H, br.s, NH)
【００６４】実施例１０ ３−ヒドロキシ−１０−メチル−２，３，８，９−テト
ラヒドロピラノ〔３，２−ｇ〕キノリン−８−オンの合
成：３−アセトキシ−１０−メチル−２，３，８，９−
テトラヒドロピラノ〔３，２−ｇ〕キノリン−８−オン
０．７０９ｇ（２．５９mmol）をクロロホルム３２mlと
メタノール４８mlの混合溶液にとかし、２Ｎ−カセイソ
ーダ溶液２．６mlを加え、常温で１時間撹拌した。反応
液を減圧濃縮し、不溶の固体を濾取し水及びエーテルで
洗い、標題化合物の白色粉末０．５４３ｇ（９０．６
％）を得た。クロロホルム−メタノール−ｎ−ヘキサン
で再結晶し、標題化合物の無色針状晶〔ｍｐ２６１−２
６２℃〕を得た。Example 10 Synthesis of 3-hydroxy-10-methyl-2,3,8,9-tetrahydropyrano [3,2-g] quinolin-8-one: 3-acetoxy-10-methyl-2, 3,8,9-
Tetrahydropyrano [3,2-g] quinolin-8-one 0.709 g (2.59 mmol) was dissolved in a mixed solution of 32 ml of chloroform and 48 ml of methanol, 2.6 ml of 2N-caustic soda solution was added, and the mixture was stirred at room temperature for 1 hour. did. The reaction mixture was concentrated under reduced pressure, the insoluble solid was collected by filtration, washed with water and ether, and 0.543 g (90.6 g) of a white powder of the title compound was obtained.
%) Was obtained. Recrystallized from chloroform-methanol-n-hexane to give the title compound as colorless needles [mp261-2].
62 ° C.] was obtained.
【００６５】元素分析 計算値 （C13H13NO3として）:C,67.52;H,5.67;N,6.06 実測値 :C,67.50;H,5.68;N,6.12 IR(KBr)cm-1:3304,3153,1635,1599,1559,1457,1410,128
7,12571 H-NMR(CDCl3:DMSO-d6=7:4)δ(ppm):2.24(3H,s),2.75(1
H,dd,J=16,6),3.04(1H,dd,J=16,4),3.97-4.22(3H,m),5.
10(1H,d,J=4.0),6.28(1H,d,J=9),7.13(1H,s),7.63(1H,
d,J=9),10.45(1H,br.s,NH)Elemental analysis calculated (as C 13 H 13 NO 3 ): C, 67.52; H, 5.67; N, 6.06 Found: C, 67.50; H, 5.68; N, 6.12 IR (KBr) cm −1 : 3304,3153,1635,1599,1559,1457,1410,128
7,1257 1 H-NMR (CDCl 3 : DMSO-d 6 = 7: 4) δ (ppm): 2.24 (3H, s), 2.75 (1
H, dd, J = 16,6), 3.04 (1H, dd, J = 16,4), 3.97-4.22 (3H, m), 5.
10 (1H, d, J = 4.0), 6.28 (1H, d, J = 9), 7.13 (1H, s), 7.63 (1H,
d, J = 9), 10.45 (1H, br.s, NH)
【００６６】実施例１１ ３−メタンスルホニルオキシ−１０−メチル−２，３，
８，９−テトラヒドロピラノ〔３，２−ｇ〕キノリン−
８−オンの合成：３−ヒドロキシ−１０−メチル−２，
３，８，９−テトラヒドロピラノ〔３，２−ｇ〕キノリ
ン−８−オン０．３８２ｇ（１．６５mmol）をピリジン
１６mlにとかし、メタンスルホニルクロリド０．１６６
ml（２．１５mmol）を加え、常温で１時間撹拌したの
ち、溶媒を減圧留去し、残渣をクロロホルムで洗い、標
題化合物の白色結晶０．４２ｇ（８２．１％）を得た。Example 11 3-Methanesulfonyloxy-10-methyl-2,3,3
8,9-Tetrahydropyrano [3,2-g] quinoline-
Synthesis of 8-one: 3-hydroxy-10-methyl-2,
0.38 g (1.65 mmol) of 3,8,9-tetrahydropyrano [3,2-g] quinolin-8-one was dissolved in 16 ml of pyridine to give methanesulfonyl chloride 0.166.
After adding ml (2.15 mmol) and stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure and the residue was washed with chloroform to obtain 0.42 g (82.1%) of white crystals of the title compound.
【００６７】IR(KBr)cm-1:3420,1647,1603,1343,1162,9
351 H-NMR(CDCl3:DMSO-d6=7:3)δ(ppm):2.28(3H,s),3.18(3
H,s),3.06-3.37(2H,m),4.30(1H,d,J=12),4.49(1H,br.d,
J=12),5.25-5.31(1H,m),6.33(1H,d,J=9),7.18(1H,s),7.
65(1H,d,J=9),10.53(1H,s,NH)IR (KBr) cm -1 : 3420,1647,1603,1343,1162,9
35 1 H-NMR (CDCl 3 : DMSO-d 6 = 7: 3) δ (ppm): 2.28 (3H, s), 3.18 (3
H, s), 3.06-3.37 (2H, m), 4.30 (1H, d, J = 12), 4.49 (1H, br.d,
J = 12), 5.25-5.31 (1H, m), 6.33 (1H, d, J = 9), 7.18 (1H, s), 7.
65 (1H, d, J = 9), 10.53 (1H, s, NH)
【００６８】実施例１２ ３−アジド−１０−メチル−２，３，８，９−テトラヒ
ドロピラノ〔３，２−ｇ〕キノリン−８−オンの合成：
３−メタンスルホニルオキシ−１０−メチル−２，３，
８，９−テトラヒドロピラノ〔３，２−ｇ〕キノリン−
８−オン０．８４６ｇ（２．７４mmol）とアジ化ナトリ
ウム１．７８ｇ（２７．４mmol）をジメチルホルムアミ
ド３３mlに懸濁し、１２０℃で２時間撹拌した。反応液
を氷水に注ぎ、析出した固体を濾取し、標題化合物の淡
黄色結晶０．２２９ｇ（３２．７％）を得た。Example 12 Synthesis of 3-azido-10-methyl-2,3,8,9-tetrahydropyrano [3,2-g] quinolin-8-one:
3-Methanesulfonyloxy-10-methyl-2,3
8,9-Tetrahydropyrano [3,2-g] quinoline-
8-one 0.846 g (2.74 mmol) and sodium azide 1.78 g (27.4 mmol) were suspended in dimethylformamide 33 ml and stirred at 120 ° C. for 2 hours. The reaction solution was poured into ice water and the precipitated solid was collected by filtration to obtain 0.229 g (32.7%) of pale yellow crystals of the title compound.
【００６９】IR(KBr)cm-1:3100,2102,1659,1625,1599,1
320,1215,11571 H-NMR(CDCl3)δ(ppm):2.26(3H,s),2.96(1H,dd,J=17,
6),3.22(1H,dd,J=17,5),4.02-4.34(3H,m),6.48(1H,d,J=
10),7.14(1H,s),7.62(1H,d,J=10),8.95(1H,br.s,NH)IR (KBr) cm -1 : 3100,2102,1659,1625,1599,1
320,1215,1157 1 H-NMR (CDCl 3 ) δ (ppm): 2.26 (3H, s), 2.96 (1H, dd, J = 17,
6), 3.22 (1H, dd, J = 17,5), 4.02-4.34 (3H, m), 6.48 (1H, d, J =
10), 7.14 (1H, s), 7.62 (1H, d, J = 10), 8.95 (1H, br.s, NH)
【００７０】実施例１３ ３−アミノ−１０−メチル−２，３，８，９−テトラヒ
ドロピラノ〔３，２−ｇ〕キノリン−８−オンの合成：
３−アジド−１０−メチル−２，３，８，９−テトラヒ
ドロピラノ〔３，２−ｇ〕キノリン−８−オン０．４５
１ｇ（１．７６mmol）をジメチルホルムアミド１００ml
にとかし、１０％パラジウム炭素０．６５ｇを加え、水
素気流中、常温で４時間反応したのち、反応液より触媒
を除き、溶媒を減圧留去して、標題化合物の淡黄色粉末
０．３２ｇ（７８．８％）を得た。これをクロロホルム
−メタノール−ｎ−ヘキサンで再結晶し標題化合物の無
色プリズム晶０．２６９ｇ〔ｍｐ２３５−２３９℃〕を
得た。Example 13 Synthesis of 3-amino-10-methyl-2,3,8,9-tetrahydropyrano [3,2-g] quinolin-8-one:
3-Azido-10-methyl-2,3,8,9-tetrahydropyrano [3,2-g] quinolin-8-one 0.45
1 g (1.76 mmol) of 100 ml of dimethylformamide
, 10% palladium-carbon (0.65 g) was added, the mixture was reacted in a hydrogen stream at room temperature for 4 hours, the catalyst was removed from the reaction solution, and the solvent was evaporated under reduced pressure to give 0.32 g of a pale yellow powder of the title compound ( 78.8%) was obtained. This was recrystallized from chloroform-methanol-n-hexane to obtain 0.269 g of the title compound as colorless prism crystals [mp 235-239 ° C].
【００７１】元素分析 計算値 （C13H14N2O2・1/5H2Oとして）:C,66.77 H,6.2
1;N,11.98 実測値 :C,66.66;H,6.1
0;N,11.89 IR(KBr)cm-1:3400,3160,2983,1653,1600,1479,1457,141
0,1291,12171 H-NMR(CDCl3)δ(ppm):2.24(3H,s),2.69(1H,dd,J=16,
8),3.09(1H,dd,J=16,5),3.20-3.45(1H,m),3.52(2H,br.
s,NH2),3.93(1H,dd,J=10,7),4.27(1H,br.d,J=10),6.46
(1H,d,J=9),7.11(1H,s),7.61(1H,d,J=9),8.79(1H,br.s,
NH)Elemental analysis calculated value (as C 13 H 14 N 2 O 2 · 1 / 5H 2 O): C, 66.77 H, 6.2
1; N, 11.98 Found: C, 66.66; H, 6.1
0; N, 11.89 IR (KBr) cm -1 : 3400,3160,2983,1653,1600,1479,1457,141
0,1291,1217 1 H-NMR (CDCl 3 ) δ (ppm): 2.24 (3H, s), 2.69 (1H, dd, J = 16,
8), 3.09 (1H, dd, J = 16,5), 3.20-3.45 (1H, m), 3.52 (2H, br.
s, NH 2 ), 3.93 (1H, dd, J = 10,7), 4.27 (1H, br.d, J = 10), 6.46
(1H, d, J = 9), 7.11 (1H, s), 7.61 (1H, d, J = 9), 8.79 (1H, br.s,
(NH)
【００７２】合成例７ Ｎ−（２，５−ジメチル−４−ヒドロキシフェニル）シ
ンナマミドの合成：４−アミノ−２，５−ジメチルフェ
ノール１０ｇ（７２．９mmol）とピリジン７．１mlをア
セトン１６０mlにとかし、これにシンナモイルクロリド
１３．４ｇ（８０．４mmol）を加え常温で１５時間撹拌
した。反応液を減圧濃縮し、不溶の固体を濾取し、水及
びアセトンで洗い、標題化合物の灰色粉末１４．５ｇ
（７４．６％）〔ｍｐ２７８−２８０℃（分解）〕を得
た。Synthesis Example 7 Synthesis of N- (2,5-dimethyl-4-hydroxyphenyl) cinnamamide: 4-amino-2,5-dimethylphenol 10 g (72.9 mmol) and pyridine 7.1 ml were dissolved in acetone 160 ml. Then, 13.4 g (80.4 mmol) of cinnamoyl chloride was added thereto, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, the insoluble solid was collected by filtration, washed with water and acetone, and 14.5 g of the title compound as a gray powder.
(74.6%) [mp 278-280 ° C. (decomposition)] was obtained.
【００７３】IR(KBr)cm-1:3328,1651,1605,1529,1448,1
405,1348,12241 H-NMR(DMSO-d6)δ(ppm):2.08(3H,s),2.10(3H,s),6.64
(1H,s),6.91(1H,d,J=16),7.12(1H,s),7.54(1H,d,J=16),
7.35-7.70(5H,m),9.13(1H,br.s,NH),9.30(1H,s,OH)IR (KBr) cm -1 : 3328,1651,1605,1529,1448,1
405,1348,1224 1 H-NMR (DMSO-d 6 ) δ (ppm): 2.08 (3H, s), 2.10 (3H, s), 6.64
(1H, s), 6.91 (1H, d, J = 16), 7.12 (1H, s), 7.54 (1H, d, J = 16),
7.35-7.70 (5H, m), 9.13 (1H, br.s, NH), 9.30 (1H, s, OH)
【００７４】合成例８ １，２−ジヒドロ−５，８−ジメチル−６−ヒドロキシ
キノリン−２−オンの合成：Ｎ−（２，５−ジメチル−
４−ヒドロキシフェニル）シンナマミド１４．２ｇ（５
３．１mmol）と塩化アルミニウム３５．４ｇ（０．２７
mol ）をクロルベンゼン１００mlに懸濁し１２５℃で１
時間撹拌した。冷後、反応液を氷水に注ぎ、析出した固
体を濾取し、水及びエーテルで洗い、標題化合物の褐色
粉末８．５８ｇ（８５．４％）〔ｍｐ＞２８０℃〕を得
た。Synthesis Example 8 Synthesis of 1,2-dihydro-5,8-dimethyl-6-hydroxyquinolin-2-one: N- (2,5-dimethyl-
4-hydroxyphenyl) cinnamamide 14.2 g (5
3.1 mmol) and 35.4 g (0.27) of aluminum chloride
(mol) in 100 ml of chlorobenzene,
Stir for hours. After cooling, the reaction solution was poured into ice water, and the precipitated solid was collected by filtration and washed with water and ether to obtain 8.58 g (85.4%) of a brown powder of the title compound [mp> 280 ° C.].
【００７５】IR(KBr)cm-1:1640,1598,1559,1441,1395,1
313,1280,11021 H-NMR(DMSO-d6)δ(ppm):2.29(3H,s),2.34(3H,s),6.48
(1H,d,J=10),6.92(1H,s),8.00(1H,d,J=10),9.17(1H,s,O
H),10.60(1H,br.s,NH)IR (KBr) cm -1 : 1640,1598,1559,1441,1395,1
313,1280,1102 1 H-NMR (DMSO-d 6 ) δ (ppm): 2.29 (3H, s), 2.34 (3H, s), 6.48
(1H, d, J = 10), 6.92 (1H, s), 8.00 (1H, d, J = 10), 9.17 (1H, s, O
H), 10.60 (1H, br.s, NH)
【００７６】合成例９ ６−アリルオキシ−１，２−ジヒドロ−５，８−ジメチ
ルキノリン−２−オンの合成：１，２−ジヒドロ−５，
８−ジメチル−６−ヒドロキシキノリン−２−オン２
４．６ｇ（０．１４mol ）、炭酸カリウム３８．８ｇ
（０．２８mol ）、沃化アリル３３．０ｇ（０．２０mo
l ）、ジメチルホルムアミド４００mlの混合溶液を５０
℃で２時間撹拌した。反応液を減圧濃縮した残渣に水を
加え、不溶の固体を濾取し、水及びｎ−ヘキサンで洗
い、標題化合物の褐色粉末７．９８ｇ（２６．４％）
〔ｍｐ１８０−１８４℃〕を得た。Synthesis Example 9 Synthesis of 6-allyloxy-1,2-dihydro-5,8-dimethylquinolin-2-one: 1,2-dihydro-5
8-dimethyl-6-hydroxyquinolin-2-one 2
4.6 g (0.14 mol), potassium carbonate 38.8 g
(0.28 mol), allyl iodide 33.0 g (0.20 mol)
l) and 50 ml of a mixed solution of 400 ml of dimethylformamide.
The mixture was stirred at 0 ° C for 2 hours. Water was added to the residue obtained by concentrating the reaction solution under reduced pressure, the insoluble solid was collected by filtration, washed with water and n-hexane, and 7.98 g (26.4%) of a brown powder of the title compound.
[Mp 180-184 ° C.] was obtained.
【００７７】元素分析 計算値 （C14H15NO2として）:C,73.34;H,6.59;N,6.11 実測値 :C,72.96;H,6.59;N,6.07 IR(KBr)cm-1:1673,1609,1447,1309,1280,11061 H-NMR(CDCl3)δ(ppm):2.43(3H,s),2.46(3H,s),4.56(2
H,dt,J=5,2),5.29(1H,dq,J=11,2),5.44(1H,dq,J=17,2),
6.08(1H,ddt,J=17,11,5),6.68(1H,d,J=10),6.99(1H,s),
7.99(1H,d,J=10),9.42(1H,br.s,NH)Elemental analysis calculated (as C 14 H 15 NO 2 ): C, 73.34; H, 6.59; N, 6.11 Found: C, 72.96; H, 6.59; N, 6.07 IR (KBr) cm −1 : 1673,1609,1447,1309,1280,1106 1 H-NMR (CDCl 3 ) δ (ppm): 2.43 (3H, s), 2.46 (3H, s), 4.56 (2
H, dt, J = 5,2), 5.29 (1H, dq, J = 11,2), 5.44 (1H, dq, J = 17,2),
6.08 (1H, ddt, J = 17,11,5), 6.68 (1H, d, J = 10), 6.99 (1H, s),
7.99 (1H, d, J = 10), 9.42 (1H, br.s, NH)
【００７８】合成例１０ ７−アリル−１，２−ジヒドロ−５，８−ジメチル−６
−ヒドロキシキノリン−２−オンの合成：６−アリルオ
キシ−１，２−ジヒドロ−５，８−ジメチルキノリン−
２−オン２．６０ｇ（１１．３mmol）をＮ，Ｎ−ジメチ
ルアニリン３０mlに懸濁し窒素雰囲気下２００℃で１０
時間撹拌した。反応液をそのままシリカゲルカラムクロ
マトグラフィーに付し、クロロホルム：メタノール（４
０：１）で溶出し、標題化合物の褐色結晶０．９５６ｇ
（３６．８％）〔ｍｐ２２０−２２３℃（分解）〕を得
た。また原料化合物０．７９８ｇ（３０．７％）とその
脱アリル体０．４１５ｇ（１９．３％）を回収した。Synthesis Example 10 7-allyl-1,2-dihydro-5,8-dimethyl-6
-Synthesis of hydroxyquinolin-2-one: 6-allyloxy-1,2-dihydro-5,8-dimethylquinoline-
2.60 g (11.3 mmol) of 2-one was suspended in 30 ml of N, N-dimethylaniline and the suspension was stirred at 200 ° C. under nitrogen atmosphere for 10 hours.
Stir for hours. The reaction solution was directly subjected to silica gel column chromatography, and chloroform: methanol (4
Elution with 0: 1), 0.956 g of brown crystals of the title compound
(36.8%) [mp 220-223 ° C. (decomposition)] was obtained. Further, 0.798 g (30.7%) of the raw material compound and 0.415 g (19.3%) of the deallylated product thereof were recovered.
【００７９】元素分析 計算値 （C14H15NO2・1/5H2Oとして）:C,72.21;H,6.6
7;N,6.01 実測値 :C,72.08;H,6.5
3;N,6.07 IR(KBr)cm-1:3191,1643,1606,1588,1405,1273,1240,119
1,11801 H-NMR(CDCl3:CD3OD=10:1)δ(ppm):2.38(3H,s),2.46(3
H,s),3.63(2H,dt,J=6,2),4.95(1H,dq,J=17,2),5.05(1H,
dq,J=10,2),5.98(1H,ddt,J=17,10,6),6.65(1H,d,J=10),
8.06(1H,d,J=10)Elemental analysis calculated value (as C 14 H 15 NO 2 · 1 / 5H 2 O): C, 72.21; H, 6.6
7; N, 6.01 Found: C, 72.08; H, 6.5
3; N, 6.07 IR (KBr) cm -1 : 3191,1643,1606,1588,1405,1273,1240,119
1,1180 1 H-NMR (CDCl 3 : CD 3 OD = 10: 1) δ (ppm): 2.38 (3H, s), 2.46 (3
H, s), 3.63 (2H, dt, J = 6,2), 4.95 (1H, dq, J = 17,2), 5.05 (1H,
dq, J = 10,2), 5.98 (1H, ddt, J = 17,10,6), 6.65 (1H, d, J = 10),
8.06 (1H, d, J = 10)
【００８０】合成例１１ ６−アセトキシ−７−アリル−１，２−ジヒドロ−５，
８−ジメチルキノリン−２−オンの合成：７−アリル−
１，２−ジヒドロ−５，８−ジメチル−６−ヒドロキシ
キノリン−２−オン１．２２ｇ（５．３２mmol）をピリ
ジン１２mlにとかし、無水酢酸０．８１ｇ（７．９３mm
ol）を加え常温で１時間撹拌した。反応液を減圧濃縮し
た残渣をクロロホルムで洗い、標題化合物の白色結晶
１．２６ｇ（８７．４％）〔ｍｐ２２４℃（分解）〕を
得た。Synthesis Example 11 6-acetoxy-7-allyl-1,2-dihydro-5
Synthesis of 8-dimethylquinolin-2-one: 7-allyl-
1.22 g (5.32 mmol) of 1,2-dihydro-5,8-dimethyl-6-hydroxyquinolin-2-one was dissolved in 12 ml of pyridine, and 0.81 g (7.93 mm) of acetic anhydride was dissolved.
ol) was added and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and the residue was washed with chloroform to obtain 1.26 g (87.4%) of white crystals of the title compound [mp 224 ° C. (decomposition)].
【００８１】元素分析 計算値 （C16H17NO3として）:C,70.83;H,6.32;N,5.16 実測値 :C,71.09;H,6.41;N,5.28 IR(KBr)cm-1:1759,1647,1608,1368,1276,1210,11871 H-NMR(CDCl3)δ(ppm):2.32(3H,s),2.38(3H,s),2.39(3
H,s),3.20-3.68(2H,br.),4.96(1H,dq,J=17,2),5.07(1H,
dq,J=10,2),5.86(1H,ddt,J=17,10,6),6.70(1H,d,J=9),
7.98(1H,d,J=9),9.43(1H,br.s,NH)Elemental analysis calculated (as C 16 H 17 NO 3 ): C, 70.83; H, 6.32; N, 5.16 Found: C, 71.09; H, 6.41; N, 5.28 IR (KBr) cm −1 : 1759,1647,1608,1368,1276,1210,1187 1 H-NMR (CDCl 3 ) δ (ppm): 2.32 (3H, s), 2.38 (3H, s), 2.39 (3
H, s), 3.20-3.68 (2H, br.), 4.96 (1H, dq, J = 17,2), 5.07 (1H,
dq, J = 10,2), 5.86 (1H, ddt, J = 17,10,6), 6.70 (1H, d, J = 9),
7.98 (1H, d, J = 9), 9.43 (1H, br.s, NH)
【００８２】合成例１２ ６−アセトキシ−７−（２，３−エポキシプロピル）−
１，２−ジヒドロ−５，８−ジメチルキノリン−２−オ
ンの合成：６−アセトキシ−７−アリル−１，２−ジヒ
ドロ−５，８−ジメチルキノリン−２−オン１．２０ｇ
（４．４２mmol）をクロロホルム２０mlにとかし、ｍ−
クロル過安息香酸３．０６ｇ（１７．７mmol）を加え、
常温で１５時間撹拌した。反応液を５％亜硫酸ナトリウ
ム水溶液、飽和重曹水、食塩水で順次洗い、芒硝で乾燥
ののち溶媒を減圧留去し、標題化合物の白色粉末１．２
３ｇ（９６．８％）〔ｍｐ２２７−２２９℃（分解）〕
を得た。Synthesis Example 12 6-acetoxy-7- (2,3-epoxypropyl)-
Synthesis of 1,2-dihydro-5,8-dimethylquinolin-2-one: 6-acetoxy-7-allyl-1,2-dihydro-5,8-dimethylquinolin-2-one 1.20 g
(4.42 mmol) was dissolved in 20 ml of chloroform and m-
Add 3.06 g (17.7 mmol) of chloroperbenzoic acid,
The mixture was stirred at room temperature for 15 hours. The reaction mixture was washed successively with 5% aqueous sodium sulfite solution, saturated aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate and evaporated under reduced pressure to give the title compound as a white powder 1.2.
3 g (96.8%) [mp 227-229 ° C (decomposition)]
Got
【００８３】元素分析 計算値 （C16H17NO4・1/2H2Oとして）:C,64.85;H,6.1
2;N,4.73 実測値 :C,65.11;H,5.8
1;N,4.74 IR(KBr)cm-1:3169,3039,1741,1652,1610,13731 H-NMR(CDCl3:CD3OD=10:1)δ(ppm):2.33(3H,s),2.41(3
H,s),2.44(3H,s),2.42-3.18(5H,m),6.71(1H,d,J=10),8.
00(1H,d,J=10)Elemental analysis calculated value (as C 16 H 17 NO 4 · 1 / 2H 2 O): C, 64.85; H, 6.1
2; N, 4.73 Found: C, 65.11; H, 5.8
1; N, 4.74 IR (KBr) cm -1 : 3169,3039,1741,1652,1610,1373 1 H-NMR (CDCl 3 : CD 3 OD = 10: 1) δ (ppm): 2.33 (3H, s ), 2.41 (3
H, s), 2.44 (3H, s), 2.42-3.18 (5H, m), 6.71 (1H, d, J = 10), 8.
00 (1H, d, J = 10)
【００８４】実施例１４ ４，９−ジメチル−２−ヒドロキシメチル−２，３，
５，６−テトラヒドロフロ〔２，３−ｇ〕キノリン−６
−オンの合成：６−アセトキシ−７−（２，３−エポキ
シプロピル）−１，２−ジヒドロ−５，８−ジメチルキ
ノリン−２−オン１．２１ｇ（４．２１mmol）をジメチ
ルホルムアミド１５mlにとかし、１Ｎ−カセイソーダ溶
液１０mlを加え、５０℃で３０分間撹拌した。反応液を
減圧濃縮した残渣を水で洗い、標題化合物の淡黄色粉末
０．７６１ｇ（６９．３％）〔ｍｐ２５９−２６２℃
（分解）〕を得た。Example 14 4,9-Dimethyl-2-hydroxymethyl-2,3
5,6-Tetrahydrofuro [2,3-g] quinoline-6
Synthesis of 1-one: 6-acetoxy-7- (2,3-epoxypropyl) -1,2-dihydro-5,8-dimethylquinolin-2-one 1.21 g (4.21 mmol) was dissolved in 15 ml of dimethylformamide. 10 ml of 1N-caustic soda solution was added, and the mixture was stirred at 50 ° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure and the residue was washed with water to give 0.761 g (69.3%) of a pale yellow powder of the title compound [mp 259-262 ° C.
(Decomposition)] was obtained.
【００８５】元素分析 計算値 （C14H15NO3として）:C,68.56;H,6.16;N,5.71 実測値 :C,68.36;H,6.26;N,5.85 IR(KBr)cm-1:3304,1645,1607,1559,1432,1400,1256,110
61 H-NMR(CDCl3:CD3OD=5:1)δ(ppm):2.37(3H,s),2.39(3H,
s),3.15(1H,dd,J=17,7),3.25-3.45(1H,m),3.76(1H,dd,J
=12,6),3.81(1H,dd,J=12,4),4.85-5.02(1H,m),6.63(1H,
d,J=10),8.04(1H,d,J=10)Elemental analysis calculated value (as C 14 H 15 NO 3 ): C, 68.56; H, 6.16; N, 5.71 actual value: C, 68.36; H, 6.26; N, 5.85 IR (KBr) cm −1 : 3304,1645,1607,1559,1432,1400,1256,110
6 1 H-NMR (CDCl 3 : CD 3 OD = 5: 1) δ (ppm): 2.37 (3H, s), 2.39 (3H,
s), 3.15 (1H, dd, J = 17,7), 3.25-3.45 (1H, m), 3.76 (1H, dd, J
= 12,6), 3.81 (1H, dd, J = 12,4), 4.85-5.02 (1H, m), 6.63 (1H,
d, J = 10), 8.04 (1H, d, J = 10)
【００８６】実施例１５ ４，９−ジメチル−２−メタンスルホニルオキシメチル
−２，３，５，６−テトラヒドロフロ〔２，３−ｇ〕キ
ノリン−６−オンの合成：４，９−ジメチル−２−ヒド
ロキシメチル−２，３，５，６−テトラヒドロフロ
〔２，３−ｇ〕キノリン−６−オン０．７０ｇ（２．８
５mmol）をピリジン４０mlにとかし、メタンスルホニル
クロリド０．４９ｇ（４．２８mmol）を加え、常温で１
時間反応後、溶媒を減圧留去し、残留物をクロロホルム
で洗い、標題化合物の白色粉末０．６７ｇ（７２．６
％）〔ｍｐ１９８−２００℃（分解）〕を得た。Example 15 Synthesis of 4,9-dimethyl-2-methanesulfonyloxymethyl-2,3,5,6-tetrahydrofuro [2,3-g] quinolin-6-one: 4,9-dimethyl- 2-Hydroxymethyl-2,3,5,6-tetrahydrofuro [2,3-g] quinolin-6-one 0.70 g (2.8
(5 mmol) is dissolved in 40 ml of pyridine, 0.49 g (4.28 mmol) of methanesulfonyl chloride is added, and 1 is added at room temperature.
After reacting for an hour, the solvent was distilled off under reduced pressure, the residue was washed with chloroform, and 0.67 g (72.6) of a white powder of the title compound was obtained.
%) [Mp 198-200 ° C. (decomposition)].
【００８７】元素分析 計算値 （C15H17NO5Sとして）:C,55.72;H,5.30;N,4.33 実測値 :C,55.93;H,5.31;N,4.32 IR(KBr)cm-1:1654,1614,1443,1399,1343,1285,1176,9901 H-NMR(CDCl3:CD3OD=10:1)δ(ppm):2.36(6H,s),3.10(3
H,s),3.18(1H,dd,J=17,7),3.47(1H,dd,J=17,9),4.42(1
H,dd,J=11,6),4.49(1H,dd,J=11,4),5.04-5.20(1H,m),6.
68(1H,d,J=10),7.96(1H,d,J=10)Elemental analysis Calculated value (as C 15 H 17 NO 5 S): C, 55.72; H, 5.30; N, 4.33 Actual value: C, 55.93; H, 5.31; N, 4.32 IR (KBr) cm -1 : 1654,1614,1443,1399,1343,1285,1176,990 1 H-NMR (CDCl 3 : CD 3 OD = 10: 1) δ (ppm): 2.36 (6H, s), 3.10 (3
H, s), 3.18 (1H, dd, J = 17,7), 3.47 (1H, dd, J = 17,9), 4.42 (1
H, dd, J = 11,6), 4.49 (1H, dd, J = 11,4), 5.04-5.20 (1H, m), 6.
68 (1H, d, J = 10), 7.96 (1H, d, J = 10)
【００８８】実施例１６ ２−アジドメチル−４，９−ジメチル−２，３，５，６
−テトラヒドロフロ〔２，３−ｇ〕キノリン−６−オン
の合成：４，９−ジメチル−２−メタンスルホニルオキ
シメチル−２，３，５，６−テトラヒドロフロ〔２，３
−ｇ〕キノリン−６−オン０．２５ｇ（０．７７３mmo
l）とアジ化ナトリウム０．５０ｇ（７．７４mmol）を
ジメチルホルムアミド５mlに懸濁し、１２０℃で２時間
反応したのち、氷水に注ぎ析出した結晶を濾取し、標題
化合物の淡黄色粉末０．２１ｇ（定量的）〔ｍｐ２０９
−２１０℃（分解）〕を得た。Example 16 2-Azidomethyl-4,9-dimethyl-2,3,5,6
-Synthesis of tetrahydrofuro [2,3-g] quinolin-6-one: 4,9-dimethyl-2-methanesulfonyloxymethyl-2,3,5,6-tetrahydrofuro [2,3
-G] quinolin-6-one 0.25 g (0.773 mmo
l) and 0.50 g (7.74 mmol) of sodium azide were suspended in 5 ml of dimethylformamide, reacted at 120 ° C. for 2 hours, poured into ice water, and the precipitated crystals were collected by filtration to give a pale yellow powder of the title compound (0.1%). 21 g (quantitative) [mp209
-210 ° C (decomposition)] was obtained.
【００８９】元素分析 計算値 （C14H14N4O2として）:C,62.21;H,5.22;N,20.7
3 実測値 :C,62.08;H,5.20;N,20.5
2 IR(KBr)cm-1:2085,1681,1652,1444,1401,1297,12681 H-NMR(CDCl3)δ(ppm):2.36(3H,s),2.38(3H,s),3.09(1
H,dd,J=17,6),3.42(1H,dd,J=17,9),3.46(1H,dd,J=13,
6),3.56(1H,dd,J=13,4),4.97-5.12(1H,m),6.66(1H,d,J=
10),7.94(1H,d,J=10),9.51(1H,br.s,NH)Elemental analysis calculated (as C 14 H 14 N 4 O 2 ): C, 62.21; H, 5.22; N, 20.7
3 Measured value: C, 62.08; H, 5.20; N, 20.5
2 IR (KBr) cm -1 : 2085,1681,1652,1444,1401,1297,1268 1 H-NMR (CDCl 3 ) δ (ppm): 2.36 (3H, s), 2.38 (3H, s), 3.09 (1
H, dd, J = 17,6), 3.42 (1H, dd, J = 17,9), 3.46 (1H, dd, J = 13,
6), 3.56 (1H, dd, J = 13,4), 4.97-5.12 (1H, m), 6.66 (1H, d, J =
10), 7.94 (1H, d, J = 10), 9.51 (1H, br.s, NH)
【００９０】実施例１７ ２−アミノメチル−４，９−ジメチル−２，３，５，６
−テトラヒドロフロ〔２，３−ｇ〕キノリン−６−オン
の合成：２−アジドメチル−４，９−ジメチル−２，
３，５，６−テトラヒドロフロ〔２，３−ｇ〕キノリン
−６−オン０．１６ｇ（０．５９mmol）をジメチルホル
ムアミド４mlにとかし、１０％パラジウム炭素０．１６
ｇを加え、水素気流中、常温で２時間反応したのち、触
媒を除き、溶媒を減圧留去して、標題化合物の淡黄色粉
末０．１０６ｇ（７３．３％）〔ｍｐ＞２９０℃〕を得
た。Example 17 2-Aminomethyl-4,9-dimethyl-2,3,5,6
-Synthesis of tetrahydrofuro [2,3-g] quinolin-6-one: 2-azidomethyl-4,9-dimethyl-2,
0.16 g (0.59 mmol) of 3,5,6-tetrahydrofuro [2,3-g] quinolin-6-one was dissolved in 4 ml of dimethylformamide, and 10% palladium-carbon 0.16 was added.
g, and after reacting for 2 hours at room temperature in a hydrogen stream, the catalyst was removed and the solvent was distilled off under reduced pressure to obtain 0.106 g (73.3%) of a pale yellow powder of the title compound [mp> 290 ° C.]. Obtained.
【００９１】IR(KBr)cm-1:1647,1608,1562,1522,1394,1
2571 H-NMR(DMSO-d6)δ(ppm):2.32(3H,s),2.34(3H,s),3.06
(1H,dd,J=14,8),3.10-3.28(1H,m),3.47(1H,dd,J=14,6),
4.96-5.13(1H,m),6.48(1H,d,J=10),7.98(1H,d,J=10),8.
25(3H,br.s,NH+NH2) 得られた標題化合物０．１０６ｇを塩酸塩としたのちメ
タノール−エーテルで再結晶し、標題化合物の塩酸塩８
８mg（７２．５％）を淡褐色プリズム晶〔ｍｐ＞２９０
℃〕として得た。IR (KBr) cm -1 : 1647,1608,1562,1522,1394,1
257 1 H-NMR (DMSO-d 6 ) δ (ppm): 2.32 (3H, s), 2.34 (3H, s), 3.06
(1H, dd, J = 14,8), 3.10-3.28 (1H, m), 3.47 (1H, dd, J = 14,6),
4.96-5.13 (1H, m), 6.48 (1H, d, J = 10), 7.98 (1H, d, J = 10), 8.
25 (3H, br.s, NH + NH 2 ) 0.106 g of the obtained title compound was converted into hydrochloride and recrystallized from methanol-ether to give the hydrochloride of the title compound 8
8 mg (72.5%) of light brown prism crystals [mp> 290
° C].
【００９２】塩酸塩： 元素分析 計算値 （C14H16N2O2・HCl・1/2H2Oとして）:C,58.03;
H,6.26;N,9.67;Cl,12.23 実測値 :C,57.86;
H,6.21;N,9.40;Cl,12.26 IR(KBr)cm-1:1645,1608,1557,1389,1253,11051 H-NMR(CD3OD)δ(ppm):2.38(3H,s),2.41(3H,s),3.10-3.
42(2H,m),3.12(1H,dd,J=17,8),3.54(1H,dd,J=17,9),5.0
0-5.19(1H,m),6.64(1H,d,J=10),8.18(1H,d,J=10)Hydrochloride: Calculated by elemental analysis (as C 14 H 16 N 2 O 2 .HCl.1 / 2H 2 O): C, 58.03;
H, 6.26; N, 9.67; Cl, 12.23 Found: C, 57.86;
H, 6.21; N, 9.40; Cl, 12.26 IR (KBr) cm -1 : 1645,1608,1557,1389,1253,1105 1 H-NMR (CD 3 OD) δ (ppm): 2.38 (3H, s) , 2.41 (3H, s), 3.10-3.
42 (2H, m), 3.12 (1H, dd, J = 17,8), 3.54 (1H, dd, J = 17,9), 5.0
0-5.19 (1H, m), 6.64 (1H, d, J = 10), 8.18 (1H, d, J = 10)
───────────────────────────────────────────────────── フロントページの続き (72)発明者 北村 崇博 東京都清瀬市野塩３−15−５ レジデンス 松村202号 (72)発明者 神谷 一博 東京都立川市西砂町５−66−15 (72)発明者 山口 隆 埼玉県浦和市皇山町７−32 (72)発明者 小野木 和弘 埼玉県入間市扇台６−２−７ (72)発明者 佐藤 精一 東京都杉並区上荻４−４−１ アビターレ 西荻202号 (72)発明者 大田 富夫 埼玉県狭山市鵜ノ木４−41 (72)発明者 内田 康美 千葉県市川市大野３−1739 ─────────────────────────────────────────────────── ─── Continued Front Page (72) Inventor Takahiro Kitamura 3-15-5 Noshio, Kiyose-shi, Tokyo Residence Matsumura No. 202 (72) Inventor Kazuhiro Kamiya 5-66-15 Nishisuna-cho, Tachikawa-shi, Tokyo (72) Inventor Takashi Yamaguchi 7-32 Oyamayama-cho, Urawa City, Saitama Prefecture (72) Inventor Kazuhiro Onoki 6-2-7 Ogidai, Iruma City, Saitama Prefecture (72) Inventor Seiichi Sato 4-4-1 Kamiogi, Suginami-ku, Tokyo Abitare Nishi-Ogi No. 202 (72) Inventor Tomio Ota 4-41 Unoki, Sayama City, Saitama Prefecture (72) Inventor Yasumi Uchida 3-1739 Ono, Ichikawa City, Chiba Prefecture
Claims (1)
のときＢは単結合又はメチレン基を示し、Ａが単結合の
ときＢは酸素原子を示す。Ｒ1 及びＲ2 は水素原子又は
低級アルキル基を示し、Ｒ3 は置換基を有していてもよ
い低級アルキル基、低級アルカノイルオキシ基、水酸
基、低級アルキルスルホニルオキシ基、アジド基又はア
ミノ基を示し、破線は二重結合が存在してもよいことを
示す。〕で表わされるキノリン誘導体又はその塩。1. The following general formula (1): [In the formula, A represents an oxygen atom or a single bond, B represents a single bond or a methylene group when A is an oxygen atom, and B represents an oxygen atom when A is a single bond. R 1 and R 2 represent a hydrogen atom or a lower alkyl group, and R 3 represents a lower alkyl group which may have a substituent, a lower alkanoyloxy group, a hydroxyl group, a lower alkylsulfonyloxy group, an azido group or an amino group. The dashed line indicates that a double bond may be present. ] The quinoline derivative or its salt represented by these.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP14554592A JP3153335B2 (en) | 1992-06-05 | 1992-06-05 | Quinoline derivatives or salts thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP14554592A JP3153335B2 (en) | 1992-06-05 | 1992-06-05 | Quinoline derivatives or salts thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH05339271A true JPH05339271A (en) | 1993-12-21 |
| JP3153335B2 JP3153335B2 (en) | 2001-04-09 |
Family
ID=15387662
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP14554592A Expired - Lifetime JP3153335B2 (en) | 1992-06-05 | 1992-06-05 | Quinoline derivatives or salts thereof |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3153335B2 (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001014384A1 (en) * | 1999-08-20 | 2001-03-01 | Takeda Chemical Industries, Ltd. | Tricyclic dihydrobenzofuran derivatives, process for the preparation thereof and agents |
| WO2005040146A1 (en) * | 2003-10-24 | 2005-05-06 | Wyeth | Dihydrobenzofuranyl alkanamines and pharmaceutical compositions containing them |
| WO2006047228A1 (en) * | 2004-10-21 | 2006-05-04 | Wyeth | Asymmetric synthesis of substituted dihydrobenzofurans |
| US7435837B2 (en) | 2003-10-24 | 2008-10-14 | Wyeth | Dihydrobenzofuranyl alkanamine derivatives and methods for using same |
| CN100448861C (en) * | 2003-10-24 | 2009-01-07 | 惠氏公司 | Dihydrobenzofuranyl alkanamines and pharmaceutical compositions containing them |
-
1992
- 1992-06-05 JP JP14554592A patent/JP3153335B2/en not_active Expired - Lifetime
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001014384A1 (en) * | 1999-08-20 | 2001-03-01 | Takeda Chemical Industries, Ltd. | Tricyclic dihydrobenzofuran derivatives, process for the preparation thereof and agents |
| WO2005040146A1 (en) * | 2003-10-24 | 2005-05-06 | Wyeth | Dihydrobenzofuranyl alkanamines and pharmaceutical compositions containing them |
| US7435837B2 (en) | 2003-10-24 | 2008-10-14 | Wyeth | Dihydrobenzofuranyl alkanamine derivatives and methods for using same |
| CN100448861C (en) * | 2003-10-24 | 2009-01-07 | 惠氏公司 | Dihydrobenzofuranyl alkanamines and pharmaceutical compositions containing them |
| US7728155B2 (en) | 2003-10-24 | 2010-06-01 | Wyeth Llc | Dihydrobenzofuranyl alkanamines and methods for using same as cns agents |
| WO2006047228A1 (en) * | 2004-10-21 | 2006-05-04 | Wyeth | Asymmetric synthesis of substituted dihydrobenzofurans |
Also Published As
| Publication number | Publication date |
|---|---|
| JP3153335B2 (en) | 2001-04-09 |
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