JPS59110690A - Benzopyran derivative - Google Patents

Abstract

NEW MATERIAL:A compound(salt) shown by the formula I [R<1> is H, lower alkyl, lower alkoxy, nitro, or amino; R<2> is H, lower or alkoxy: R<3> is H, or lower alkyl; R<4> is H, or lower alkyl; R<5> is mono- or diphenylalkyl, group shown by the formula II(R<6> is diphenylpropyl, cinnamoyl, etc.), group shown by the formula III(R<7> is H, or lower alkyl), etc.; n is 0-2]. EXAMPLE:N-(3,3-Diphenylpropionyl)-3,4-dihydro-2H-benzopyran-4-ylmethyl amine. USE:A coronary vasodilator. Having calcium antagonizing action, useful as a remedy for circulatory system, especially a preventive and remedy for ischemic heart disease. PROCESS:A compound shown by the formula IV is reacted with an acid chloride shown by the formula R<8>COX (R<8> is a group having methylene bonds less by one at the end group of R<5>) in a nonpolar solvent to give a result compound, which is reduced with a complex such as lithium aluminum hydride, etc. to give a compound shown by the formula I where the group R<1> is a group except amino group and the group R<5> is diphenylalkyl, etc.

Description

【発明の詳細な説明】 で示される新規ベンゾピラン誘導体およびその塩に関す
る。DETAILED DESCRIPTION OF THE INVENTION This invention relates to novel benzopyran derivatives and salts thereof.

上記式中Ｒ１は水素原子、低級アルキル基、低級アルフ
キシ基、ニトロ基又はアミノ基を、Ｒ２は水素原子又は
低級アルコキシ基を、′Ｒ３は水素原子又は低級アルキ
ル基を、Ｒ４は水素原子又は低級アルキル基を、Ｒ５は
モノあるいはジフェニルアルキル基、ベンゼン環に低級
アルコキシ基が置換することもあるフェノキシアルキル
基。In the above formula, R1 is a hydrogen atom, a lower alkyl group, a lower alkyl group, a nitro group, or an amino group, R2 is a hydrogen atom or a lower alkoxy group, 'R3 is a hydrogen atom or a lower alkyl group, and R4 is a hydrogen atom or a lower alkyl group. As for the alkyl group, R5 is a mono- or diphenyl alkyl group, or a phenoxyalkyl group in which a lower alkoxy group may be substituted on the benzene ring.

（式中Ｆｌ’はジフェニルプロピル基、ジフェニルプロ
ピオニル基又はシンナモイル基を意味し。(In the formula, Fl' means a diphenylpropyl group, a diphenylpropionyl group, or a cinnamoyl group.

シンナモイル基のベンゼン環は１〜３個の低級アルコキ
シ基で置換されていてもよい。）で示される基又は式（
１１） （式中Ｒ７は水素原子又は低級アルキル基を意味す。）
で示される基を、ｎは０〜２の整数を意味す。又、塩と
しては塩酸、硫酸のような無機酸、クエン酸、フマール
酸、マレイン酸、シュウ酸、酒石酸のような有機カルボ
ン酸およびパラトルエンスルホン酸、メタンスルホン酸
のような有機スルホン酸等があげられる。The benzene ring of the cinnamoyl group may be substituted with 1 to 3 lower alkoxy groups. ) Group or formula (
11) (In the formula, R7 means a hydrogen atom or a lower alkyl group.)
In the group represented by, n means an integer of 0 to 2. Examples of salts include inorganic acids such as hydrochloric acid and sulfuric acid, organic carboxylic acids such as citric acid, fumaric acid, maleic acid, oxalic acid, and tartaric acid, and organic sulfonic acids such as p-toluenesulfonic acid and methanesulfonic acid. can give.

本発明化合物は式（ト） で示される化合物を原料とし、下記方法により製される
。The compound of the present invention is produced by the following method using a compound represented by formula (g) as a raw material.

■　式（１）において置換基Ｒ１がアミン基以外であす
、　Ｒ５がモノあるいはジフェニルアルキル基又はフェ
ノキシアルキル基の場合： 式（Ｎ′）の化合物をベンゼン、トルエン等の非極性溶
媒中式（ｖ）　Ｒ８ｃｏｘ　（ｖ）　（Ｒ８はＲ５）末
端ノメチレン結合が一個少ない基を意味す。）で示され
る酸クロリドと溶媒の沸点以下で反応させ９次いで、得
られる成績体をテトラヒドロフラン。■ In the case where substituent R1 is other than an amine group in formula (1), and R5 is a mono- or diphenylalkyl group or a phenoxyalkyl group: The compound of formula (N') is mixed with formula (v) in a nonpolar solvent such as benzene or toluene. R8cox (v) (R8 means R5) a group having one less terminal methylene bond. ) with the acid chloride shown below at a temperature below the boiling point of the solvent.

ジオキサン等の溶媒中水素化リチウムアルミニウム、ア
セチルオキシ水素化ホウ素ナトリウム又はトリフルオロ
アセチルオキシ水素化ホウ素ナトリウムあるいは水素化
ホウ素ナトリウムと三沸化ホウ素エーテルとのコンプレ
ックスにより室温又は溶媒の沸点に不還元することによ
り製される。Lithium aluminum hydride, sodium acetyloxyborohydride or sodium trifluoroacetyloxyborohydride or a complex of sodium borohydride and boron trifluoride ether in a solvent such as dioxane to reduce the temperature to room temperature or the boiling point of the solvent. Manufactured by.

■　式（１）において置換基Ｒ１がアミノ基以外であり
、♂が前記式（Ｉ［）で示される場合：式（酌の化合物
をエタノール、メチルエチルケトン等の溶媒中炭酸アル
カリの存在下る−（２−ハロゲノエチル）ピベラチンー
１−カルボン酸低級アルキルエステルと反応させ、得ら
れる成績体を低級アルコール等の溶媒中アルカリにて加
水分解し式（Ｍ） （式中Ｈ１−Ｒ’およびｎは前記に同じ。）を製し。■ In the case where substituent R1 in formula (1) is other than an amino group and ♂ is represented by the above formula (I -halogenoethyl)piveratine-1-carboxylic acid lower alkyl ester, and the resulting product is hydrolyzed with an alkali in a solvent such as a lower alcohol to form the formula (M) (where H1-R' and n are the same as above). ).

次いで式（匂の化合物をベンゼン、トルエン等の溶媒中
、トリエチルアミン、ピリジン等の塩基の存在下に、ジ
フェニルプロピルハライド、ジフェニルプロピオニルハ
ライド又はシンナモイルハライドと反応させることによ
り製される。It is then produced by reacting a compound of formula (odor) with diphenylpropyl halide, diphenylpropionyl halide, or cinnamoyl halide in a solvent such as benzene or toluene in the presence of a base such as triethylamine or pyridine.

又、この場合の本発明化合物は式（菊の化合物と１・−
クロロアセチル−１＝（８，３−ジフェニルプロピオニ
ル）ピペラチン等とをアルコール溶媒中ヨー化す）　Ｉ
Ｊウム、炭酸アルカリ等の存在下に反応させ９次いで得
られる成績体をテトラヒドロフラン、ジオキサン等の溶
媒中水素化リチウムアルミニウム等で還元することによ
っても製しうる。In addition, the compound of the present invention in this case has the formula (chrysanthemum compound and 1.-
Iodination of chloroacetyl-1=(8,3-diphenylpropionyl)piperatine, etc. in an alcohol solvent) I
It can also be produced by reacting in the presence of hydrogen, alkali carbonate, etc., and then reducing the resulting product with lithium aluminum hydride or the like in a solvent such as tetrahydrofuran or dioxane.

■　式（４）において置換基Ｒ１がアミノ基以外であり
、Ｒ５が前記式（ＩＩＩ）で示される場合：■　Ｒ’−
Ｒ７−Ｈである場合； 式（Ｎ′）の化合物に＋Ｎ−（ａ、ａ−ジフェニルプロ
・ピオニル）グリシンとクロル蟻酸アルキルより製した
酸無水物をクロロホルム等の反応に関与しない溶媒中反
応させ、得られる成績体をテトラヒドロフラン、ジオキ
サン等の溶媒中水素化リチウムアルミニウム等にて還元
することにより製しうる。■ When the substituent R1 in formula (4) is other than an amino group and R5 is represented by the above formula (III): ■ R'-
In the case of R7-H; the compound of formula (N') is reacted with an acid anhydride prepared from +N-(a,a-diphenylpropionyl)glycine and an alkyl chloroformate in a solvent that does not participate in the reaction, such as chloroform. It can be produced by reducing the resulting product with lithium aluminum hydride or the like in a solvent such as tetrahydrofuran or dioxane.

＠Ｒ’−Ｒ７−低級アルキル基の場合；■で得られた化
合物をクロロホルム、ジクロロメタン等の溶媒中トリエ
チルアミン、ピリジン等の塩基の存在、下に例えばアセ
チルクロリド、プロピオニルクロリド等と反応させ。In the case of @R'-R7-lower alkyl group: The compound obtained in step (1) is reacted with, for example, acetyl chloride, propionyl chloride, etc. in a solvent such as chloroform or dichloromethane in the presence of a base such as triethylamine or pyridine.

得られる成績体をテトラヒドロフラン、ジオキサン等の
溶媒中水素化リチウムアルミニウム等の存在下還元する
ことにより製しうる。It can be produced by reducing the resulting product in the presence of lithium aluminum hydride in a solvent such as tetrahydrofuran or dioxane.

θ　か〜）（、Ｒ７−低級アルキル基である場合；式（
関の化合物とＮ−低級アルキル−Ｎ−（８，３−ジフェ
ニルプロピル）クリシンを用い、■の場合と同様に処理
して製することができる。θ or~)(, When R7-lower alkyl group; Formula (
It can be produced in the same manner as in the case of (2) using the compound of the above and N-lower alkyl-N-(8,3-diphenylpropyl)chrysine.

■　式（Ｉ）において置換基Ｒ１がアミ７基である場合 式（１）のＲ１がニトロ基である化合物をメタノール、
エタノール等のアルコール性ｍＫ中パラジウム炭素を触
媒とし接触還元して製しうる。■ When the substituent R1 in formula (I) is an ami7 group, a compound in which R1 in formula (1) is a nitro group is mixed with methanol,
It can be produced by catalytic reduction in alcoholic mK such as ethanol using palladium on carbon as a catalyst.

なお２式（Ｐ／）で示される本発明の原料化合物は既知
化合物（Ｒ１−Ｒ２−Ｈでｎ　−０又は１の場合および
Ｒ”−ＣＨ３０−でｎ−１の場合）と新規化合物とがあ
るが、新規化合物の場合は、既知化合物の製法に準じて
製造しえ、その代表例は後記参考例に示される。かくし
て製される本発明化合物は、持続性ある冠血管拡張作用
を有し、又。The starting compound of the present invention represented by formula 2 (P/) is a combination of a known compound (when R1-R2-H is n -0 or 1 and when R''-CH30- is n-1) and a new compound. However, in the case of a new compound, it can be manufactured according to the manufacturing method of a known compound, representative examples of which are shown in the reference examples below.The compound of the present invention thus manufactured has a sustained coronary vasodilator effect. ,or.

カルシウム拮抗作用を有することより循環器官治療剤な
かでも虚血性心疾患の予防および治療薬として有用なも
のである。Because it has a calcium antagonistic effect, it is useful as a prophylactic and therapeutic agent for ischemic heart disease among circulatory organ therapeutic agents.

本発明化合物の冠血管拡張作用は、ライフサイエンス２
８巻第１６０９頁（１９７８）記載の方法に準じモルモ
ット摘出心臓標本を使用し。The coronary vasodilator effect of the compound of the present invention is shown in Life Science 2.
A guinea pig isolated heart specimen was used according to the method described in Vol. 8, p. 1609 (1978).

ランゲンドルフ氏法により３０μり投与時の冠血管潅流
量を測定することにより確認された。This was confirmed by measuring the coronary vascular perfusion amount at the time of administration of 30μ by Langendorff's method.

又、カルシウム拮抗作用はマグヌス法によりモルモット
摘出心臓標本を用いて、１００ｍＭの塩化カリウムおよ
び１０　　Ｍ　　のフルエピネフリンの引き起こす収縮
に対する１　０−　Ｍ　の本発明化合物の抑制率を測定
することにより確認した。上述の本発明化合物の効果の
判定に際しては、パパベリンおよび優れたカルシウム拮
抗作用を有し狭心症の治療薬として知られるジルチアゼ
ムを対照として使用した。Further, the calcium antagonism was confirmed by the Magnus method using isolated guinea pig heart specimens, and by measuring the inhibition rate of the compound of the present invention at 10-M against the contraction induced by 100 mM potassium chloride and 10 M fluepinephrine. In evaluating the effects of the above-mentioned compounds of the present invention, papaverine and diltiazem, which has excellent calcium antagonistic activity and is known as a therapeutic agent for angina pectoris, were used as controls.

その結果９本発明化合物は、パバベリンに比べ持続性の
ある冠血管潅流量増加作用を有し。As a result, the compound of the present invention has a more sustained effect on increasing coronary vascular perfusion than pavaberine.

かつ又ジルチアゼムと同等以上の優れたカルシウム拮抗
作用があることが判明した。It was also found that it has an excellent calcium antagonistic effect equivalent to or superior to that of diltiazem.

以下参考例および実施例により本発明を説明する。説明
中油出液等の溶媒の乾燥は特記しない限り無水硫酸す）
　ＩＪウム上を意味する。The present invention will be explained below with reference to Reference Examples and Examples. In the explanation, drying of solvents such as oil exudates is done using anhydrous sulfuric acid unless otherwise specified)
It means on IJum.

参考例１ ３．４−ジヒドロ−２Ｈ−１−ベンゾピラン−４−イリ
デンアセトニトリル ２．３−ジヒドロ−４Ｈ−１−ベンゾピラン−４−オン
５０９とジエトキシフォスホノアセトニトリル５９．８
９をジクロロメタン１０７ｆｎ１．に溶かした溶液を５
０％力性ソーダ５　Ｑ、　７　ｍｌ、ジクロロメタン４
００１ｎｌの混液中に滴下する。８時間室温にて攪拌し
た後、水５０　Ｑｆｎｔを加え。Reference example 1 3.4-dihydro-2H-1-benzopyran-4-ylideneacetonitrile 2.3-dihydro-4H-1-benzopyran-4-one 509 and diethoxyphosphonoacetonitrile 59.8
9 to dichloromethane 107fn1. The solution dissolved in
0% strength soda 5 Q, 7 ml, dichloromethane 4
001nl of the mixed solution. After stirring at room temperature for 8 hours, 50 Qfnt of water was added.

ジクロロメタン層を分取し、水洗、乾燥後、減圧濃縮し
表題化合物の無色結晶５Ｂ、７９を得た。The dichloromethane layer was separated, washed with water, dried, and concentrated under reduced pressure to obtain colorless crystals of the title compound 5B, 79.

融点７７〜８２°Ｃ０ ８，４−ジヒドロ−２Ｈ−１−ベンゾビラン−４−アセ
トニトリル 上記で得た８、４−ジヒドロ−２Ｈ−１−ベンゾビラン
−４−イリデンアセトニトリル６７９ヲメタノール１．
１１中に溶がしマグネシウム３５９を２〜ｌＯ℃にて少
量づつ加える。加え終った後、５〜２０°Ｃに３時間攪
拌した後、水冷下に６Ｎ−塩酸ａＯＯ−を滴下する。析
出する不溶物を濾去し、濾液をクロロホルムで抽出する
。抽出液は水洗、乾燥後、減圧濃縮し淡黄色油状の粗製
の表題化合物６８．１９を得た。Melting point 77-82°C0 8,4-dihydro-2H-1-benzobylan-4-acetonitrile 679 of the above-obtained 8,4-dihydro-2H-1-benzobylan-4-ylideneacetonitrile Methanol 1.
Dissolved magnesium 359 in No. 11 was added little by little at 2 to 10°C. After the addition is complete, the mixture is stirred at 5-20°C for 3 hours, and then 6N-hydrochloric acid aOO- is added dropwise while cooling with water. The precipitated insoluble matter is filtered off, and the filtrate is extracted with chloroform. The extract was washed with water, dried, and concentrated under reduced pressure to obtain the title compound 68.19 as a pale yellow oil.

３．４−ジヒドロ−２Ｈ−１−ベンゾピラン−４−アセ
トアミド 前記ニトリル０．５９を三級ブタノール５ｆｎｌに溶か
し、これに粉末にした水酸化カリウム１ｇを加え００５
時間加熱還流する。今後、２Ｎ塩酸にて酸性とし、クロ
ロホルムにて抽出する。抽出液を水洗、乾燥後、減圧濃
縮すれば粉末の表題化合物０．３５９を得た。融点９８
〜ｌｏ４°ｃ０３．４−ジヒドロ−２Ｈ−１−ベンゾビ
ラン−４−イルメチルアミン塩酸塩 臭素１．５−を水酸化カリウム９．４９．水８１−の溶
液に滴下する。こ、れを氷冷し、上記８．４−ジヒドロ
ー２Ｈ−１−ベンゾピラン−４−アセトアミド８．７９
を加え、０．５時間室温にて続いて９０°Ｃにて１時間
攪拌する。次いで水酸化カリウム１８’　９を加え９０
°Ｃに８．５時間加熱攪拌する。今後、ベンゼンにて抽
出する。抽出液を水洗、乾燥後、減圧濃縮し表題化合物
の遊離塩基を油状物として得、これを２０％塩化水素の
エタノール溶液と混合し減圧濃縮する。残渣をエタノー
ル、エーテルより再結晶して表題化合物の無色針高１．
８９を得た。融点２２０〜２２２℃。3.4-dihydro-2H-1-benzopyran-4-acetamide 0.59 of the above nitrile was dissolved in 5fnl of tertiary butanol, and 1 g of powdered potassium hydroxide was added thereto.005
Heat to reflux for an hour. Afterwards, it is acidified with 2N hydrochloric acid and extracted with chloroform. The extract was washed with water, dried, and concentrated under reduced pressure to obtain 0.359 of the title compound as a powder. Melting point 98
~lo4°c03.4-dihydro-2H-1-benzobylan-4-ylmethylamine hydrochloride bromine 1.5- to potassium hydroxide 9.49. Drop into a solution of water 81-. This was cooled on ice, and the above 8.4-dihydro 2H-1-benzopyran-4-acetamide 8.79
and stirred for 0.5 h at room temperature and then at 90°C for 1 h. Next, add 18'9 of potassium hydroxide and
Heat and stir at °C for 8.5 hours. From now on, it will be extracted with benzene. The extract was washed with water, dried, and concentrated under reduced pressure to obtain the free base of the title compound as an oil, which was mixed with a 20% ethanolic solution of hydrogen chloride and concentrated under reduced pressure. The residue was recrystallized from ethanol and ether to give the title compound, a colorless needle height of 1.
I got 89. Melting point: 220-222°C.

元素分析値（％）　　Ｃ１ｏＨｔ　ｓＮｏ　ＨＨＧＩと
して計算値　Ｇ　　ｆｌＯ，１５，Ｈ７，０７，Ｎ　　
７．０１実測値　Ｇ　　［＋、００．　　Ｈ６，８７，
Ｎ　　７．０１参考例２ ３．４−ジヒドロ−２Ｈ−１−ベンゾビラン−４−カル
ボニトリル ２．８−ジヒドロ−４Ｈ−１−ベンゾビラン−４−オン
２０９とｐ−）ルエンスルホニルメチルイソシアニド４
０９をジメトキシエタン８００ゼに溶かし５°Ｃに冷却
する。これにナトリウム４，７５９をエタノール１３ｆ
ｌ艷にとがし。Elemental analysis value (%) C1oHt sNo Calculated value as HHGI G flO,15,H7,07,N
7.01 Actual value G [+, 00. H6,87,
N 7.01 Reference Example 2 3.4-dihydro-2H-1-benzobilan-4-carbonitrile 2.8-dihydro-4H-1-benzobilan-4-one 209 and p-)luenesulfonylmethylisocyanide 4
Dissolve 09 in dimethoxyethane 800 and cool to 5°C. Add 4,759 sodium to this and 13f ethanol.
Togashi on board.

更にジメトキシエタン２５０−で希釈した溶液を滴下す
る。室温にて３時間攪拌後９反応液をベンゼンにて抽出
する。抽出液を水洗、乾燥後減圧濃縮して得られる残渣
部シリカゲル２３０りを用いてカラムクロマトを行ない
、ベンゼン溶出液より無色油状の表題化合物１４．２９
を得た。Furthermore, a solution diluted with 250 ml of dimethoxyethane is added dropwise. After stirring at room temperature for 3 hours, the 9 reaction mixture was extracted with benzene. The extract was washed with water, dried, and concentrated under reduced pressure. The resulting residue was subjected to column chromatography using 230 ml of silica gel, and the title compound as a colorless oil was obtained from the benzene eluate.
I got it.

３．４−ジヒドロ−２Ｈ−１−ベンゾビラン−４−イル
メチルアミン塩酸塩 上記で得たシア／体０．３５ｇをテトラヒドロフラン５
−に溶がした溶液を水素化リチウムアルミ＝ウム０．３
９とテトラヒドロフラン１０ｔ／のけん濁液中に滴下し
３．５時間加熱還流する。3.4-dihydro-2H-1-benzobylan-4-ylmethylamine hydrochloride 0.35 g of the shea/isomer obtained above was added to 5 g of tetrahydrofuran.
- Lithium aluminum hydride = 0.3
The mixture was added dropwise to a suspension of 9 and 10 tons of tetrahydrofuran and heated under reflux for 3.5 hours.

今後水Ｑ、３ｇｎ１とテトラヒドロフラン３ｆｎｌの混
液を滴下し、続いて１５％力性ソーダ０．８ｆｔ／、水
１ｆｎｔを順次滴下し析出する不溶物を濾去し、濾液を
減圧濃縮する。残渣を２０％塩化水素エタノール溶液を
加え、得ら杆る粉末をエタノール。Thereafter, a mixture of 3gn1 of water Q and 3fnl of tetrahydrofuran was added dropwise, followed by 0.8ft/15% sodium hydroxide and 1fnt of water to be added dropwise in order to remove precipitated insoluble matter by filtration, and the filtrate was concentrated under reduced pressure. Add a 20% hydrogen chloride ethanol solution to the residue, and add ethanol to the resulting powder.

エーテルより再結晶し表題化合物の無色針高０．２５９
を得た。融点２２０〜２２２°ＣＯこのものは実施例１
で得られたものの融点。Colorless needle height of the title compound recrystallized from ether: 0.259
I got it. Melting point: 220-222°CO This is Example 1
The melting point of the obtained product.

赤外吸収スペクトル共に一致する０ 参考例８ エチル　６−メドキシー８，４−ジヒドロ−２Ｈ−１−
ベンゾビラン−４−イリデンアセテート ６−メトキシ−２，８−ジヒドロ−４Ｈ−１−ベンゾビ
ラン−４−オン１５９をベンゼン２５０−に溶かし、活
性化した亜鉛末１０りを加え加熱還流し、これにブロム
酢酸エチル５−とヨウ素５０１９を加える。３０分後に
亜鉛末１０ｇ、ブロム酢酸エチル５−とヨウ素５０Ｔｎ
９を加える。８０分加熱還流後再び亜鉛末１０９゜ブロ
ム酢酸エチル５−とヨウ素５０ｆ１１９を加える。Both infrared absorption spectra match 0 Reference Example 8 Ethyl 6-medoxy 8,4-dihydro-2H-1-
Benzobylane-4-ylidene acetate 6-methoxy-2,8-dihydro-4H-1-benzobilan-4-one 159 was dissolved in benzene 250, and 10 g of activated zinc powder was added and heated to reflux. Add ethyl acetate 5- and iodine 50-19. After 30 minutes, add 10g of zinc powder, 5-ethyl bromoacetate and 50Tn of iodine.
Add 9. After heating under reflux for 80 minutes, 109° of zinc powder, ethyl bromoacetate, and 50° of iodine were added again.

更に３０分加熱還流後に亜鉛末５９．ブロム酢酸エチル
２．５−とヨウ素５０Ｔｎ９を加えた後１．５時間還流
させ、テトラヒドロフラン３０−を加え更に８時間加熱
還流する。今後１反発液に酢酸２０−、メタノール２０
−と水１０−の混液を滴下し過剰の亜鉛末を濾去する。After further heating and refluxing for 30 minutes, zinc powder 59. After adding 2.5-years of ethyl bromoacetate and 50Tn9 of iodine, the mixture was refluxed for 1.5 hours, and 30-years of tetrahydrofuran was added, and the mixture was further heated under reflux for 8 hours. From now on, 1 repulsion liquid contains 20% acetic acid and 20% methanol.
A mixture of - and 10 parts of water is added dropwise and excess zinc powder is filtered off.

濾液に水１００−を加えかきまぜ、有機層を分取し水洗
。Add 100% water to the filtrate and stir, separate the organic layer and wash with water.

乾燥後減圧濃縮して得られた油状物にギ酸（１００％）
２５−を加え４０分間加熱還流する。今後、減圧濃縮し
て表題化合物を油状物として１８．！を得た。After drying, concentrate under reduced pressure and add formic acid (100%) to the obtained oil.
Add 25- and heat to reflux for 40 minutes. 18. From now on, the title compound will be concentrated under reduced pressure as an oil. ! I got it.

エチル　６−メドキシー３，４−ジヒドロ−２Ｈ−１−
ベンゾビラン−４−アセテート前記で得たエステル体１
８．７９をエタノール２００−に溶かし、５％パラジウ
ム炭２ｇを用いて常圧、室温にて接触還元を行なう。水
素の吸収終了後触媒を濾去し、濾液を減圧濃縮し表題化
合物を油状物として１８．８９を得た。Ethyl 6-medoxy-3,4-dihydro-2H-1-
Benzobilane-4-acetate ester obtained above 1
8.79 was dissolved in 200% ethanol, and catalytic reduction was performed using 2 g of 5% palladium on charcoal at normal pressure and room temperature. After the hydrogen absorption was completed, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 18.89 of the title compound as an oil.

６−メドキシー３．４−ジヒドロ−２Ｈ−１−ベンゾビ
ラン−４−酢酸 上記で得たエステル体１８．８９を水酸化カリウム２０
ｇ、水１８０−およびエタノール１５０ｇｎｔと共に８
時間加熱還流する。減圧濃縮し残渣に２Ｎ塩酸を加え酸
性とし、クロロホルムにて抽出する。抽出筒は一水洗し
、乾燥後減圧濃縮すれば表題化合物を油状物として１５
．．３９を得た。6-Medoxy 3.4-dihydro-2H-1-benzobilane-4-acetic acid 18.89 of the ester obtained above was mixed with 20% of potassium hydroxide.
g, along with 180 g of water and 150 gnt of ethanol.
Heat to reflux for an hour. Concentrate under reduced pressure, acidify the residue with 2N hydrochloric acid, and extract with chloroform. The extraction column is washed once with water, dried and concentrated under reduced pressure to obtain the title compound as an oily substance.
．． ．． I got 39.

６−メドキシー３，４−ジヒドロ−２Ｈ−１−ベンゾビ
ラン−４−アセトアミド 上記で得られたカルボン酸１０．４ｇをジクロロメタン
１５０−とトリエチルアミン５．２９の混液に加え外よ
り氷冷し、これにクロルギ酸エチル５．２９とジクロロ
メタン２５−の混液を滴下する。３時間水冷下に攪拌し
た後１７％アンモニアのエタノール溶液１０ｏ−を加え
水冷下に８時間攪拌する。反応液を減圧濃縮し残渣をク
ロロホルムに溶かし、２Ｎ力性ソーダ、２Ｎ塩酸、水の
順に洗浄し、乾燥後減圧乾固し表題化合物の粉末７．４
９（７２％）を得た。融点１８９〜１４４°Ｃ８ ６−メドキシー８，４−ジヒドロ−２Ｈ−１−ベンゾビ
ラン−４−イルメチルアミン 前記で得たアミド体６．４ｇより参考例１の後段と同じ
方法にて行ない１表題化合物を油状物として５．０９を
得。6-Medoxy 3,4-dihydro-2H-1-benzobilane-4-acetamide 10.4 g of the carboxylic acid obtained above was added to a mixture of 150 g of dichloromethane and 5.29 g of triethylamine, cooled on ice from the outside, and added with chloride. A mixture of 5.29 kg of ethyl acid and 25 kg of dichloromethane is added dropwise. After stirring under water-cooling for 3 hours, 10 °C of a 17% ammonia ethanol solution was added, and the mixture was stirred for 8 hours under water-cooling. The reaction solution was concentrated under reduced pressure, the residue was dissolved in chloroform, washed successively with 2N sodium hydroxide, 2N hydrochloric acid, and water, dried, and then evaporated to dryness under reduced pressure to obtain a powder of the title compound (7.4).
9 (72%). Melting point 189-144°C8 6-Medoxy 8,4-dihydro-2H-1-benzobylan-4-ylmethylamine From 6.4 g of the amide compound obtained above, the same method as in the latter part of Reference Example 1 was carried out to obtain 1 the title compound. Obtained 5.09 as an oil.

参考例４ ６．７−シメトキシー４−トリメチルシリルオキシ−８
，４−ジヒドロ−２Ｈ−１−ベンゾビラン−４−カルボ
ニトリル ６．７−シメトキシー２，３−ジヒドロ−４Ｈ−１−ベ
ンゾビラン−４−オン４．１６９をジクロロメタン１５
−に溶がす。この中にトリメチルシリルシアニド２．１
８９とヨウ化亜鉛０．１９を加え室温にて８日間攪拌す
る。反応液を２Ｎ−力性ソーダ、水の順に洗浄し、乾燥
後減圧濃縮して表題化合物を油状物として５．４９を得
。Reference example 4 6.7-simethoxy4-trimethylsilyloxy-8
, 4-dihydro-2H-1-benzobilan-4-carbonitrile 6.7-simethoxy 2,3-dihydro-4H-1-benzobilan-4-one 4.169 dichloromethane 15
-Dissolve in. In this, trimethylsilyl cyanide 2.1
89 and zinc iodide 0.19 were added and stirred at room temperature for 8 days. The reaction solution was washed successively with 2N sodium hydroxide and water, dried and concentrated under reduced pressure to obtain 5.49 of the title compound as an oil.

６．７−シメトキシー３．４−ジヒドロ−２Ｈ−１−ベ
ンゾビラン−４−イルメチルアミン塩酸塩 上記で得たニトリル体５゜ｏ９をテトラヒドロフラン７
０−に溶かし、これに水素化ホウ素ナトリウム１．８５
ｇを加え、水冷下に三フッ化ホウ素ジエチルエーテルコ
ンプレックス９．２５９を滴下する。−夜室温にて攪拌
後メタノールを発泡がおさまるまで滴下し続いて濃塩酸
５ｇｎｔを滴下した後１時間還流させた後、水で希釈し
クロロホルム抽出する。水層を分取しこれを４０％力性
ソーダにてアルカリ性とした後クロロホルム抽出する。6.7-Simethoxy3.4-dihydro-2H-1-benzobylan-4-ylmethylamine hydrochloride The nitrile compound 5°o9 obtained above was dissolved in tetrahydrofuran 7
0-, and add 1.85% of sodium borohydride to this.
g, and 9.259 g of boron trifluoride diethyl ether complex was added dropwise while cooling with water. - After stirring at room temperature at night, methanol was added dropwise until the bubbling subsided, and then 5 gnt of concentrated hydrochloric acid was added dropwise. After refluxing for 1 hour, the mixture was diluted with water and extracted with chloroform. The aqueous layer was separated, made alkaline with 40% sodium chloride, and then extracted with chloroform.

この抽出液を水洗、乾燥後減圧濃縮し、残渣をシリカゲ
ル９０りを用いてカラムクロマトにて精製し、クロロホ
ルム溶出液ヨり表題化合物の遊離塩基を２．１Ｇ’を得
た。これをエタノールにとかし２０％塩化水素エタノー
ル溶液を加え減圧濃縮し、残渣を酢酸エチルより再結晶
して表題化合物の無色粉末を得た。融点１４９〜１５１
．５℃。This extract was washed with water, dried and concentrated under reduced pressure, and the residue was purified by column chromatography using 90% silica gel to obtain 2.1G' of the free base of the title compound from the chloroform eluate. This was dissolved in ethanol, a 20% hydrogen chloride solution in ethanol was added, and the mixture was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to obtain the title compound as a colorless powder. Melting point 149-151
．． 5℃.

元素分析値（イ）　Ｏ１２Ｈ７Ｎ　０３・ＨＣｌ−＋Ｈ
２０として計算値　Ｇ　　５３．ｆｉ３．　　Ｈ７，１
３，Ｎ　　５．２１実測値　Ｃ５３，ｆｉ４．　　Ｈ６
，８０，Ｎ　　５．１６参考例５ Ｎ−アセチル−３，４−ジヒドロ−２）１−１−ベンゾ
ビラン−４−イルメチルアミン ３．４−ジヒドロ−２Ｈ−１−ベンゾビラン−４−イル
メチルアミン３９を無水酢酸２０ｆｆ＋７゜酢酸５−と
共に８０’Ｃに４時間加熱する。減圧濃縮し残渣をベン
ゼンに溶がし水洗、乾燥後減圧濃縮して淡黄色油状の表
題化合物を２．３９を得た。Elemental analysis value (a) O12H7N 03.HCl-+H
Calculated value as 20 G 53. fi3. H7,1
3, N 5.21 actual measurement value C53, fi4. H6
,80,N 5.16 Reference Example 5 N-acetyl-3,4-dihydro-2) 1-1-benzobylan-4-ylmethylamine 3,4-dihydro-2H-1-benzobylan-4-ylmethylamine 39 is heated to 80'C with 20ff of acetic anhydride + 7° acetic acid 5- for 4 hours. After concentration under reduced pressure, the residue was dissolved in benzene, washed with water, dried, and concentrated under reduced pressure to obtain 2.39 of the title compound as a pale yellow oil.

Ｎ−エチル−８，４−ジヒドロ−２Ｈ−１−ベンゾビラ
ン−４−イルメチルアミン 上記で得たアセチル体１．８９をテトラヒドロフラン３
０ｒｎ１．にとがし、水素化ホウ素ナトリウム１．６６
９を加え続いて水冷下に酢酸２Ｊ３ｇとテトラヒドロフ
ラン４−の混液を滴下した後３時間加熱還流する。今後
、減圧濃縮し残液に水を加え、２Ｎ力性ソーダにてアル
カリ性としベンゼンにて抽出する。抽出液は水洗、乾燥
後減圧濃縮し、無色油状の表題化合物１．４９を得た。N-Ethyl-8,4-dihydro-2H-1-benzobylan-4-ylmethylamine 1.89 of the acetyl compound obtained above was dissolved in tetrahydrofuran 3
0rn1. Togashi, sodium borohydride 1.66
9 was added thereto, and then a mixed solution of 2J3 g of acetic acid and 4-tetrahydrofuran was added dropwise under water cooling, and the mixture was heated under reflux for 3 hours. Afterwards, concentrate under reduced pressure, add water to the residual liquid, make alkaline with 2N sodium hydroxide, and extract with benzene. The extract was washed with water, dried, and concentrated under reduced pressure to obtain 1.49 of the title compound as a colorless oil.

参考例６ Ｎ−エチル−６−メチル−３，４−ジヒドロ−２Ｈ−１
−ベンゾビラン−４−イルメチルアミン 三フッ化ホウ素エチルエーテルコンプレックスローとエ
ーテル１２イの混液にエヒリロルヒドリン３−を滴下し
、１時間加熱還流する。氷冷し析出する結晶を濾集する
。この結晶をジクロロメタンｌＯ艷に加え、更に実施例
２の前段と同様な方法にて製造した６−メチル−３，４
−ジヒドロ−２Ｈ−１−ベンゾビラン−４−カルボニト
リル３９を加えて窒素ガス気流下に３日間加熱還流する
。今後、エタノール３−を加え水冷下に１０分間攪拌し
た後、減圧濃縮する。Reference example 6 N-ethyl-6-methyl-3,4-dihydro-2H-1
-Benzobylan-4-ylmethylamine boron trifluoride ethyl ether complex Ethyrolhydrin 3- is added dropwise to a mixture of slaw and ether 12-i, and the mixture is heated under reflux for 1 hour. Cool on ice and collect the precipitated crystals by filtration. These crystals were added to dichloromethane (1O2), and 6-methyl-3,4 produced in the same manner as in the first part of Example 2 was added.
-Dihydro-2H-1-benzobyrane-4-carbonitrile 39 is added and heated under reflux for 3 days under a nitrogen gas stream. After that, ethanol 3- was added and the mixture was stirred for 10 minutes while cooling with water, and then concentrated under reduced pressure.

残渣にメタノール３０−を加え、水冷下に水素化ホウ素
す）　ＩＪウム４９を加え、１時間攪拌後６Ｎ塩酸を加
え酸性となし減圧濃縮する。残渣に水５０−を加え、６
Ｎ力性ソーダにてアルカリ性とし、ベンゼンにて抽出す
る。抽出液を２Ｎ塩酸で抽出し、塩酸層を炭酸水素す）
　ＩＪウムにて中和しクロロホルムにて抽出する。クロ
ロホルム層を水洗、乾燥後、減圧濃縮し油状の表題化合
物２．３９を得た。Add 30 methanol to the residue, add 49 ml of borohydride under water cooling, and stir for 1 hour, acidify by adding 6N hydrochloric acid, and concentrate under reduced pressure. Add 50% of water to the residue,
Make alkaline with N-hydrocarbon soda and extract with benzene. Extract the extract with 2N hydrochloric acid, and remove the hydrochloric acid layer with hydrogen carbonate)
Neutralize with IJum and extract with chloroform. The chloroform layer was washed with water, dried, and concentrated under reduced pressure to obtain the title compound 2.39 as an oil.

参考例７ Ｎ−アセチル−６，８−ジニトロ−３，４−ジヒドロ−
２８−１−ベンゾビラン−４−イルメチルアミン Ｎ−アセチル−３，４−ジヒドロ−２Ｈ−１−ベンゾビ
ラン−４−イルメチルアミン２ｇを濃硫酸５−に溶かし
、これを水冷下比重１．５の発煙硝酸０．ｆｌ記と濃硫
酸２−の混液を滴下した後室温にて５分間攪拌し氷水中
に圧加し、クロロホ・ルムで抽出する。抽出液を水洗、
乾燥後、減圧乾固し表題化合物の淡黄色針状晶１．４２
９を得た。Reference example 7 N-acetyl-6,8-dinitro-3,4-dihydro-
28-1-Benzobylan-4-ylmethylamine N-acetyl-3,4-dihydro-2H-1-benzobylan-4-ylmethylamine (2 g) was dissolved in concentrated sulfuric acid 5-, and this was dissolved under water cooling to a solution with a specific gravity of 1.5. Fuming nitric acid 0. After adding dropwise a mixture of 2-fl and concentrated sulfuric acid, the mixture was stirred at room temperature for 5 minutes, pressurized into ice water, and extracted with chloroform. Wash the extract with water,
After drying, it was dried under reduced pressure to give pale yellow needle crystals of the title compound (1.42 kg).
I got a 9.

Ｎ−・アセチル−（８−アミノ−６−ニトロ−３，４−
ジヒドロ−２Ｈ−１−ベンゾビラン−４−イル）メチル
アミン 上記で得たジニトロ体１ｇを水６−、エタノール８−の
混液に加え、加熱還流し硫化ナトリウム８１６１ｎ９と
硫黄２０９■と水４−の混合物を少しづつ加える。３０
分間加熱還流後、減圧濃縮し水ＩＱｉで希釈した後クロ
ロホルムにて抽出する。抽出液は水洗、乾燥後、減圧濃
縮し橙色結晶の表題化合物６２０■を得た。N-acetyl-(8-amino-6-nitro-3,4-
Dihydro-2H-1-benzobylan-4-yl) methylamine 1 g of the dinitro compound obtained above was added to a mixture of 6- water and 8-ethanol, and the mixture was heated under reflux to form a mixture of 8161 n9 sodium sulfide, 209 sulfur, and 4- water. Add little by little. 30
After heating under reflux for a minute, the mixture was concentrated under reduced pressure, diluted with water IQi, and extracted with chloroform. The extract was washed with water, dried, and concentrated under reduced pressure to obtain the title compound 620cm as orange crystals.

Ｎ−アセチル−Ｊ（６−ニトロ−８，４−ジヒドロ−２
Ｈ−１−ベンゾビラン−４−イル）メチルアミン 上記アミノ体８８０１ｎ９をエタノール３記にとかし、
氷冷下濃硫酸Ｑ、５ｇｎｔを加える。亜硝酸ナトリウム
１０９■を加え６０°Ｃに加熱し３０分後、８０°Ｃに
して１時間加熱する。今後、水を加え、クロロホルムに
て抽出する。抽出液を水洗、乾燥後、減圧濃縮して黄色
針高の表題化合物ａｏｏＴｎ９を得た。N-acetyl-J(6-nitro-8,4-dihydro-2
H-1-benzobylan-4-yl)methylamine The above amino compound 8801n9 was dissolved in ethanol 3,
Add 5 gnt of concentrated sulfuric acid Q under ice cooling. Add 109 cm of sodium nitrite and heat to 60°C for 30 minutes, then raise to 80°C and heat for 1 hour. From now on, add water and extract with chloroform. The extract was washed with water, dried, and concentrated under reduced pressure to obtain the title compound aooTn9 with yellow needle height.

６−ニトロ−３，４−ジヒドロ−２Ｈ−１−ベンゾビラ
ン−４−イルメチルアミン 上記で得たアセチル体２．２５９　を製塩＠３〇−とエ
タノール８０−の混液と共に２４・時間加熱還流する。6-Nitro-3,4-dihydro-2H-1-benzobylan-4-ylmethylamine The acetyl compound 2.259 obtained above is heated under reflux for 24 hours together with a mixture of salt preparation @30 and ethanol 80.

反応液を減圧濃縮し残渣に水を加え２Ｎ力性ソーダにて
中和しクロロホルム抽出する。抽出液を水洗、乾燥後減
圧濃縮して淡黄色油状の表題化合物１．５ｇを得た。The reaction solution was concentrated under reduced pressure, water was added to the residue, neutralized with 2N sodium hydroxide, and extracted with chloroform. The extract was washed with water, dried, and concentrated under reduced pressure to obtain 1.5 g of the title compound as a pale yellow oil.

実施例１ Ｎ−（８，３−ジフェニルプロピオニル）−３，４−ジ
ヒドロ−２Ｈ−１−ベンゾビラン−４−イルメチルアミ
ン ３．８−ジフェニルプロピオン酸１．１９９を塩化チオ
ニル１．　Ｒｍｌ　、ベンゼン８−と共に２．５時間加
熱還流した後減圧濃縮して得られる粗製の３．３−ジフ
ェニルプロピオニルクロリドをベンゼン１５−に溶かし
、これを８，４−ジヒドロ−２Ｈ−１−ベンゾビラン−
４−イルメチルアミン０．８２９を）リエチルアミン２
９とベンゼン１６ｆｎ！、の混液中にとかした溶液中に
滴下する。Example 1 N-(8,3-diphenylpropionyl)-3,4-dihydro-2H-1-benzobylan-4-ylmethylamine 3.8-diphenylpropionic acid 1.199 was converted to thionyl chloride 1. Rml, crude 3,3-diphenylpropionyl chloride obtained by heating under reflux with benzene 8- for 2.5 hours and then concentrating under reduced pressure is dissolved in benzene 15-, and this is dissolved in 8,4-dihydro-2H-1-benzobilane-
4-ylmethylamine 0.829) ethylamine 2
9 and benzene 16fn! , into the solution dissolved in the mixture.

滴下後、３．５時間加熱還流し、今後１反応液を希塩酸
、水、２Ｎカセイソーダ、水で順次洗らい。After dropping, the mixture was heated under reflux for 3.5 hours, and one reaction solution was washed successively with dilute hydrochloric acid, water, 2N caustic soda, and water.

乾燥後、減圧乾固すれば融点１ｆｉ７〜１７０’Ｃの無
色結晶１．７りを得る。After drying, the mixture is dried under reduced pressure to obtain colorless crystals having a melting point of 1fi7 to 170'C.

Ｎ−（３，３−ジフェニルプロピル）−３，４−ジヒド
ロ−２Ｈ−，１−ベンゾビラン−４−イルメチルアミン
塩酸塩 上記で得られたアミド１．７ｇをテトラヒドロフラン４
０−に溶かし、これに水素化ホウ素ナトリウム１ｇを加
え氷水で冷却し、氷酢酸１．６り、テトラヒドロフラン
７ｍｌの混液を滴下する。N-(3,3-diphenylpropyl)-3,4-dihydro-2H-,1-benzobylan-4-ylmethylamine hydrochloride 1.7 g of the amide obtained above was dissolved in tetrahydrofuran 4
0-, add 1 g of sodium borohydride, cool with ice water, and dropwise add a mixture of 1.6 g of glacial acetic acid and 7 ml of tetrahydrofuran.

３時間加熱還流した後、減圧下に溶媒を留去する。残渣
に水を加えかきまぜ２Ｎ力性ソーダにてアルカリ性とし
クロロホルムにて抽出する。After heating under reflux for 3 hours, the solvent was distilled off under reduced pressure. Add water to the residue, stir, make alkaline with 2N sodium hydroxide, and extract with chloroform.

抽出液は水洗、乾燥後、減圧濃縮する。残渣を少量のエ
タノールに溶かし、塩化水素の２０％エタノール溶液５
−を加え、減圧下に濃縮して得られる残渣をエタノール
−エーテルの混液より再結晶して無色針状晶の表題化合
物１．０３９を得た。融点２１４〜２１５°ｃ。The extract is washed with water, dried, and concentrated under reduced pressure. Dissolve the residue in a small amount of ethanol and make a 20% ethanolic solution of hydrogen chloride.
- was added and concentrated under reduced pressure, and the resulting residue was recrystallized from a mixture of ethanol and ether to obtain the title compound 1.039 in the form of colorless needles. Melting point 214-215°c.

元素分析値（％）−５Ｈ２７Ｎｏ−ＨＣｌとして計算値
　Ｃ７６，２２，Ｈ７，１６，Ｎ　　３．５ｆ’を実測
値　Ｇ　　７６．０２．　　Ｈ７，２０，Ｎ　　３．５
６実施例２〜１４ 以下の化合物を実施例１と同様な方法にて製造した。Elemental analysis value (%) - Calculated value as 5H27No-HCl C76,22,H7,16,N 3.5f' Actual value G 76.02. H7, 20, N 3.5
6 Examples 2 to 14 The following compounds were produced in the same manner as in Example 1.

＊　Ｃａ　Ｈ４０４−マレイン酸 実施例１５ Ｎ−（３，３−ジフェニルプロピオニル）−６，７−シ
メトキシー３，４−ジヒドロ−２Ｈ−１−ペンゾビラン
−４−イルメチルアミン８．３−ジフェニルプロピオン
酸１．２５９を塩化チオニル２りと共に１．５時間加熱
還流後、減圧濃縮し残渣をベンゼン１０−に溶がす。こ
の溶液を６，７−シメトキシー３，４−ジヒドロ−２Ｈ
−１−ベンゾビラン−４−イルメチルアミン１．１２９
．）リエチルアミン２．５１ｎ１．およびベンゼン５０
−よりなる溶液に滴下する。滴下後４０分間加熱還流す
る。冷後２反応液を２Ｎ塩酸、水、２Ｎ力性ソーダ、水
にて順次洗浄し無水硫酸す）　ＩＪウム上乾燥した後、
減圧濃縮すれば表題化合物の無色粉末２．１．２９を得
た。融点１４８〜１５５℃。*Ca H404-Maleic acid Example 15 N-(3,3-diphenylpropionyl)-6,7-simethoxy3,4-dihydro-2H-1-penzobylan-4-ylmethylamine 8.3-diphenylpropionic acid 1 After heating and refluxing .259 with 2 parts of thionyl chloride for 1.5 hours, it was concentrated under reduced pressure and the residue was dissolved in benzene 10-. Add this solution to 6,7-simethoxy-3,4-dihydro-2H
-1-benzobyran-4-ylmethylamine 1.129
．． ) ethylamine 2.51n1. and benzene 50
- dropwise into a solution consisting of. After dropping, heat and reflux for 40 minutes. After cooling, the two reaction solutions were sequentially washed with 2N hydrochloric acid, water, 2N sodium hydroxide, and water, and dried over anhydrous sulfuric acid.
Concentration under reduced pressure gave the title compound as a colorless powder 2.1.29. Melting point 148-155°C.

Ｎ−（３，３−ジフェニルプロピル）−６，７−シメト
キシー８，４−ジヒドロ−２ｉ−１−ベンゾピラン−４
−イル−メチルアミン塩酸塩上で得たアミド体２．０６
９をテトラヒドロフラン２５−に溶かす。これに水素化
ホウ素ナトリウム０．４４９を加え、続いて三フッ化ホ
ウ素エチルエーテルコンプレックス２゜１８９とトリエ
チルアミン１５−の溶液を滴加する。室温にて８日間攪
拌する。反応液に濃塩酸１０−を加え９発泡がおさまっ
てから５０°Ｃに２．５時間加温し、減圧下に濃縮し残
渣を５％炭酸水素ナトリウムにて処理しクロロホルムに
て抽出する。N-(3,3-diphenylpropyl)-6,7-simethoxy8,4-dihydro-2i-1-benzopyran-4
Amide 2.06 obtained on -yl-methylamine hydrochloride
9 is dissolved in tetrahydrofuran 25-. To this is added 0.449 g of sodium borohydride, followed by dropwise addition of a solution of boron trifluoride ethyl ether complex 2.189 g and triethylamine 15. Stir at room temperature for 8 days. Concentrated hydrochloric acid (10) was added to the reaction solution, and after the foaming subsided, the mixture was heated to 50°C for 2.5 hours, concentrated under reduced pressure, and the residue was treated with 5% sodium bicarbonate and extracted with chloroform.

抽出液は水洗、乾燥後、減圧濃縮する。残渣を塩化水素
のエタノール溶液（２０％）３０−に溶かし、減圧濃縮
する残渣を酢酸エチルより再結晶して無色結晶の表題化
合物１．６５りを得た。The extract is washed with water, dried, and concentrated under reduced pressure. The residue was dissolved in an ethanol solution (20%) of hydrogen chloride and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to obtain 1.65 of the title compound as colorless crystals.

融点１６５〜１６７°Ｃ６ 元素分析値（イ）　（ｚ７Ｈ３ｓｏｓＮ−ＨＯＩとして
計算値　Ｃ’、７１．４２．　　Ｈ７，１０，Ｎ　　３
．０９実測値　Ｇ　　７０．９６．　　Ｈ７，０８，Ｎ
　　３．１１実施例１６ Ｎ、（３，３−ジフェニルプロピオニル）−６−メドキ
シー８，４−ジヒドロ−２Ｈ−１−ベンゾビラン−４−
イルメチルアミン ３．３−ジフェニルプロピオン酸０．５　ｑ　ヲ塩化チ
オニル３−と共に２．５時間加熱還流した後。Melting point 165-167°C6 Elemental analysis value (A) (Calculated value as z7H3sosN-HOI C', 71.42. H7,10,N3
．． 09 actual measurement value G 70.96. H7,08,N
3.11 Example 16 N,(3,3-diphenylpropionyl)-6-medoxy8,4-dihydro-2H-1-benzobilane-4-
After heating 3-diphenylpropionic acid (0.5 q) and 3-thionyl chloride under reflux for 2.5 hours.

減圧濃縮し残渣をベンゼンｌＯ−に溶かし、これを６−
メドキシー３．４−ジヒドロ−２Ｈ−１−ベンゾビラン
−４−イルメチルアミン０．４Ｇ’。Concentrate under reduced pressure, dissolve the residue in benzene lO-, and add 6-
Medoxy 3.4-dihydro-2H-1-benzobylan-4-ylmethylamine 0.4G'.

トリエチルアミン２−、ベンゼン２５−の混液中に滴下
した後３時間加熱還流する。今後９反発液を２Ｎ塩酸、
水、２Ｎ力性ソーダ、水の順に洗浄し、硫酸す）　ＩＪ
ウム上乾燥後減圧濃縮し油状、粗製の表題アミドを０．
７９を得た。The mixture was added dropwise to a mixture of 2-triethylamine and 25-benzene, and then heated under reflux for 3 hours. From now on, add 9 repulsion liquid to 2N hydrochloric acid,
Wash with water, 2N hydric soda, water in that order, and add sulfuric acid) IJ
After drying over aluminum, the crude title amide was concentrated under reduced pressure to give 0.0% oil.
I got 79.

Ｎ　−（３，３−ジフェニルプロピル）−６−メドキシ
ー３．４−ジヒドロ−２Ｈ−１−ペンゾビプンー４−イ
ルメチルアミンモノマレエート上記で得た粗アミド０．
７りをテトラヒドロ７ラン１５ｆｎｔに溶かし、これを
水素化リチウムアルミニウム０．７９のテトラヒドロ７
ラン４〇−にけん濁した中に滴下する。滴下後、４時間
加熱還流した後水冷する。これに水Ｑ、７　ｍｌ　、テ
トラヒドロフラン１５−の混液を滴加する。更に１５％
力性ソーダ０１７−２水２．１−を順次滴下し不溶物を
濾去する。濾液を減圧濃縮し、残渣をクロロホルムに溶
がし水洗、乾燥後減圧濃縮し、残渣をメタノールに溶が
し、マレイン酸３５　ＱＴｎ９を加え減圧濃縮する。得
られる粉末をメタ／−ルより再結晶して無色鱗片晶の表
題化合物０．５９を得た。融点２１０〜２１２°ｃ０元
素分析値（＄）　　Ｃ２ｇＨｚ９ＮＯｒＧ４Ｈ４０４と
して計算値　Ｇ　　７１．５５．　　Ｈ６，６１，Ｎ　
　２．７８実測値　Ｃ７１，８１，Ｈ６，６０，Ｎ　　
２．９１実施例１７〜８゜ 以下の化合物を実施例１６と同様な方法にて製造した。N-(3,3-diphenylpropyl)-6-medoxy 3.4-dihydro-2H-1-benzobipun-4-ylmethylamine monomaleate Crude amide obtained above0.
7 is dissolved in 15 fnt of tetrahydro 7, and this is dissolved in 0.79 lithium aluminum hydride of tetrahydro 7.
Drop into the suspension of Run 40-. After the addition, the mixture was heated under reflux for 4 hours and then cooled with water. A mixed solution of 7 ml of water Q and 15% of tetrahydrofuran was added dropwise to this. Another 15%
Hydrogen soda 017-2 and water 2.1-2 are added dropwise one after another, and insoluble matter is filtered off. The filtrate is concentrated under reduced pressure, the residue is dissolved in chloroform, washed with water, dried and concentrated under reduced pressure. The residue is dissolved in methanol, maleic acid 35QTn9 is added and concentrated under reduced pressure. The obtained powder was recrystallized from methanol to obtain 0.59 g of the title compound as colorless scale crystals. Melting point 210-212°c0 Elemental analysis value ($) Calculated value as C2gHz9NOrG4H404 G 71.55. H6,61,N
2.78 actual measurement value C71,81,H6,60,N
2.91 Example 17 Compounds below 8° were prepared in the same manner as in Example 16.

＊モノマレイン酸ｍ、＊＊モノシュウ酸塩実施例３１ Ｎ−エチル−Ｎ−（２−（４−エトキシカルボニル−１
−ビペラチ／）エチル）−８，４−ジヒドロ−２Ｈ−１
−ベンゾピラン−４−イルメチルアミン エチル　４−（２−クロロエチル）ビベラチンー１−カ
ルボキシレート塩酸塩１７３Ｔｎ９を２Ｎ力性ソーダ３
−と混合しクロロホルムにて抽出、抽出液を減圧濃縮し
て得られる遊離塩基を８．４−ジヒドロ−２Ｈ−１−ベ
ンゾピラン−４−イルメチルアミン＋９１１ｎ９．炭酸
ナトリウム１１０ｍ９．ヨウ化ナトリウム１５０■、エ
タノール３０−と共に１０．５時間加熱還流する。減圧
濃縮し残渣をクロロホルムにて抽出し、抽出液は水洗、
乾燥後、減圧濃縮して油状の表題化合物０．３１１を得
た。*Monomaleic acid m, **Monoxalate Example 31 N-ethyl-N-(2-(4-ethoxycarbonyl-1)
-biperati/)ethyl)-8,4-dihydro-2H-1
-Benzopyran-4-ylmethylamine ethyl 4-(2-chloroethyl)viveratin-1-carboxylate hydrochloride 173Tn9 2N hydric soda 3
-, extracted with chloroform, concentrated the extract under reduced pressure, and the resulting free base was 8.4-dihydro-2H-1-benzopyran-4-ylmethylamine+911n9. Sodium carbonate 110m9. Heat under reflux for 10.5 hours with 150 μm of sodium iodide and 30 μm of ethanol. Concentrate under reduced pressure, extract the residue with chloroform, wash the extract with water,
After drying, the residue was concentrated under reduced pressure to obtain 0.311 of the title compound as an oil.

Ｎ−エチル−Ｎ−（２−（１−ピペラチ７）エチル）　
−３，４−ジヒドロ−２Ｈ−１−ベンゾピラン−４−イ
ルメチルアミンニ塩酸塩七／水和物 上記で得た粗製のエトキシカルボニル体０．８１ｇを１
５％力性ソーダＢ、　５　ｗｌ、　、エタノール８−と
共に８時間加熱還流する。冷接、減圧濃縮し残渣をクロ
ロホルムにて抽出する。クロロホルム層を水洗、乾燥後
、減圧濃縮し粗製の表題化合物を油状物として０゜２２
９を得る。N-ethyl-N-(2-(1-piperati7)ethyl)
-3,4-dihydro-2H-1-benzopyran-4-ylmethylamine dihydrochloride hepta/hydrate 0.81 g of the crude ethoxycarbonyl compound obtained above was
Heat under reflux for 8 hours with 5% hydric soda B, 5 ml, and 8 liters of ethanol. The mixture was cooled and concentrated under reduced pressure, and the residue was extracted with chloroform. The chloroform layer was washed with water, dried, and concentrated under reduced pressure to obtain the crude title compound as an oil at 0°22
Get 9.

Ｎ−エチル−Ｎ−（２−（４−（３，３−ジフェニルフ
ロピオニル）−１−ピペラチノ）エチル）−３，４−ジ
ヒドロ−２）（−１−ベンゾピラン−４−イルメチルア
ミンニ塩酸塩−水和物前記アミン０．４ｇ、）リエチル
アミン１．５１ｒＬｌ。N-Ethyl-N-(2-(4-(3,3-diphenylfuropionyl)-1-piperatino)ethyl)-3,4-dihydro-2)(-1-benzopyran-4-ylmethylamine di Hydrochloride-hydrate 0.4 g of the above amine,) 1.51 rLl of ethylamine.

ベンゼン２０−の混液に３，３−ジフェニルプロピオニ
ルクロリドＯ，：３７９．ベンゼン８−の溶液を加え８
時間加熱還流後１反応液を２Ｎ力性ソーダ、水で洗浄、
乾燥後減圧濃縮する。残渣を塩化水素のエタノール溶液
を加え減圧濃縮しエーテルで処理して得られる粉末をエ
タノール。3,3-diphenylpropionyl chloride O,:379. Add a solution of benzene 8-
After heating under reflux for an hour, the reaction solution was washed with 2N sodium hydroxide and water.
After drying, concentrate under reduced pressure. Add an ethanol solution of hydrogen chloride to the residue, concentrate under reduced pressure, and treat with ether to obtain a powder in ethanol.

ゴーチルで再結晶し、無色粉末の表題化合物を得た。融
点１７２〜１７８°Ｃ０ 元素分析値い）　　Ｇ３３Ｈ４１Ｎ３０２・２ＨＧｔ・
Ｈ２Ｏとして計算値　０　６５．７７、　　Ｈ７，５８
，Ｎ　　６．９７実測値　Ｃ６５，６７、Ｈ７，５３，
Ｎ　　７．１６実施例８２〜３６ 以下の化合物を実施例８１と同様な方法で製実施例３７ Ｎ−エチル−Ｎ−（２−（−ｉ−（ａ、ａ−ジフェニル
プロピル）−１−ピペラチノ）エチル〕−３，４−ジヒ
ドロ−２Ｈ−１−ベンゾピラン−４−イルメチルアミン
三塩酸塩・土水和物実施例３１で得たＮ−エチル−Ｎ−
（２−（４−（３，３−ジフェニルプロピオニル）−１
−ビベラチノ）エチル）−３，４−ジヒドロ−２Ｈ−１
−ベンゾピラン−４−イルメチルアミンの遊離塩基０．
９２９をテトラヒドロフランｌＯ−に溶かし、これを水
素化リチウムアルミニウム０．８９とテトラヒドロフラ
ン４０−のけん濁液中に滴下した後、４．５時間加熱還
流した後氷水で冷やし、水０゜８−、テトラヒドロフラ
ンｌＯ−の混液を滴下する。続いて１５％Ｎａ０ＨＱ、
　８ｖｔｌ　、更に水２．４−を順に滴下し析出不溶物
を濾去し、濾液を減圧濃縮する。残渣をクロロホルムに
溶かし、水洗、乾燥後減圧濃縮する。Recrystallization with Gothyl gave the title compound as a colorless powder. Melting point 172-178°C0 Elemental analysis value) G33H41N302・2HGt・
Calculated value as H2O 0 65.77, H7,58
, N 6.97 Actual measurement C65,67, H7,53,
N 7.16 Examples 82-36 The following compounds were prepared in the same manner as in Example 81. Example 37 N-ethyl-N-(2-(-i-(a,a-diphenylpropyl)-1-piperatino) ) Ethyl]-3,4-dihydro-2H-1-benzopyran-4-ylmethylamine trihydrochloride/earth hydrate N-ethyl-N- obtained in Example 31
(2-(4-(3,3-diphenylpropionyl)-1
-biveratino)ethyl)-3,4-dihydro-2H-1
- Free base of benzopyran-4-ylmethylamine 0.
929 was dissolved in tetrahydrofuran lO-, this was added dropwise to a suspension of lithium aluminum hydride 0.89- and tetrahydrofuran 40-, heated under reflux for 4.5 hours, cooled with ice water, and dissolved in water 0°8- and tetrahydrofuran. A mixture of lO− is added dropwise. followed by 15% Na0HQ,
8 vtl and further 2.4 m of water were added dropwise in order to remove the precipitated insoluble matter by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in chloroform, washed with water, dried, and concentrated under reduced pressure.

残渣に２０％塩化水素エタノール溶液１０イを加え減圧
濃縮しアセトンにて結晶化させ、続いてエタノール、エ
ーテル混液にて再結晶して無色粉末の表題化合物０．４
５９を得。To the residue was added 10 g of a 20% hydrogen chloride solution in ethanol, concentrated under reduced pressure, and crystallized from acetone, followed by recrystallization from a mixture of ethanol and ether to obtain the title compound as a colorless powder.
Got 59.

元素分析値（％）　　Ｇ５５Ｈ４３Ｎ３０・３Ｈ２０・
＋Ｈ２０として計算値　Ｃ６４，３３，Ｈ７，６９，Ｎ
　　６．８２実測値　０　６４．８４．　　Ｈ７，５９
，Ｎ　　６．７９実施例８８〜４０ 以下の化合物を実施例３１と実施例３７に示した方法と
同様な方法にて製造した。　　。Elemental analysis value (%) G55H43N30・3H20・
Calculated value as +H20 C64, 33, H7, 69, N
6.82 Actual value 0 64.84. H7,59
, N 6.79 Examples 88-40 The following compounds were prepared in a manner similar to that shown in Examples 31 and 37. .

＊マレイン酸塩 実施例４１ ４−（（３，４−ジヒドロ−２Ｈ−１−ベンゾピラン−
４−イル）メチルアミノアセチル〕−１−（３，３−ジ
フェニルプロピオニル）−ビペラチン ３．４−ジヒドロ−２Ｈ−１−ベンゾピラン−４−イル
メチルアミン塩酸塩１．１９を２Ｎ力性／−１”１ｏｏ
−と混合しり四ロホルムで抽出する。抽出液を水洗、乾
燥後、減圧濃縮する。残渣をエタノール１００−に溶か
し４−（３，３−ジフェニルプロピオニル）−１−クロ
ロアセチルビペラチン２．０４９．ヨウ化ナトリウム０
．８３９および炭酸ソーダ０．５８４９を加え。*Maleate Example 41 4-((3,4-dihydro-2H-1-benzopyran-
4-yl)methylaminoacetyl]-1-(3,3-diphenylpropionyl)-biperatine 3.4-dihydro-2H-1-benzopyran-4-ylmethylamine hydrochloride 1.19 to 2N strength/-1 ”1oo
- Extract with shirishiroform mixed with. The extract is washed with water, dried, and concentrated under reduced pressure. Dissolve the residue in 100% of ethanol and 2.049% of 4-(3,3-diphenylpropionyl)-1-chloroacetylbiperatine. Sodium iodide 0
．． Add 839 and 0.5849 of soda.

１３時間加熱還流する。減圧濃縮し残渣をクロロホルム
１５　Ｑｌｎｌ、にて抽出する。抽出液は水洗。Heat to reflux for 13 hours. Concentrate under reduced pressure and extract the residue with 15 Qlnl of chloroform. Wash the extract with water.

乾燥後減圧濃縮し油状の表題化合物２．８９を得た。After drying, the residue was concentrated under reduced pressure to obtain 2.89 of the title compound as an oil.

Ｎ−（２−（＋−（ｓ、ａ−ジフェニルプロピル）−１
−ビペラチノ）エチル）−３，４−ジヒドロ−２Ｈ−１
−ベンゾピラン−４−イルーメチルアミン三マレイン酸
塩 上記了ミド体２．．８９をテトラヒドロフラン３０−に
溶かし、これを水素化リチウムアルミニウム２りとテト
ラヒドロ７ラン１５０−のけん濁液に滴下した後８．５
時間加熱還流する。今後実施例３７に示した方法の後処
理と同様に行ない１表題化合物の遊離塩基とする。これ
をエタノール中計算量のマレイン酸と処理し減圧濃縮す
る。残渣をエタ／−ルーエーテルの混液より再結晶して
無色粉末の表題化合物０．４ｊ９を得た。融点１６７〜
１６８°Ｃ０ 元素分析値（％）　　Ｃ３１Ｈ３９Ｎ３０・３　Ｃ４Ｈ
４０４として計算値　Ｃ６＆１５．　　Ｈ６，２９，Ｎ
　　５．１４実測値　ＣＬ３．４５．　　Ｈ６，３４，
Ｎ　　５．３７実施例４２〜４７ 以下の化合物を実施例４１と同様な方法で製本マレイン
酸塩 実施例４８ Ｎ−（Ｎ　−（３，８−ジフェニルプロピオニル）グリ
シル）−３，４−ジヒドロ−２Ｈ−１−ベンゾピラン−
４−イル−メチルアミン Ｎ−（３，３−ジフェニルプロピオニル）グリシン２．
５５２をクロロホルム３０−に溶かし。N-(2-(+-(s,a-diphenylpropyl)-1
-biperatino)ethyl)-3,4-dihydro-2H-1
-Benzopyran-4-yl-methylamine trimaleate The above-mentioned compound 2. ．． 89 was dissolved in 30% of tetrahydrofuran, and this was added dropwise to a suspension of 2% of lithium aluminum hydride and 150% of tetrahydrofuran.
Heat to reflux for an hour. The free base of the title compound is then prepared in the same way as the work-up described in Example 37. This is treated with a calculated amount of maleic acid in ethanol and concentrated under reduced pressure. The residue was recrystallized from a mixture of ether and ether to obtain the title compound 0.4j9 as a colorless powder. Melting point 167~
168°C0 Elemental analysis value (%) C31H39N30・3 C4H
Calculated value as 404 C6&15. H6, 29, N
5.14 Actual value CL3.45. H6, 34,
N 5.37 Examples 42 to 47 The following compounds were prepared in the same manner as in Example 41. Maleate Example 48 N-(N-(3,8-diphenylpropionyl)glycyl)-3,4-dihydro- 2H-1-benzopyran-
4-yl-methylamine N-(3,3-diphenylpropionyl)glycine2.
Dissolve 552 in chloroform 30-.

−１０’Ｃに冷却し、これにクロルギ酸エチル０．９８
９とクロロホルム１５−の溶液を滴下する。−１０°Ｃ
前後にて１時間攪拌した後、この中に８．４−ジヒドロ
−２Ｈ−１−ベンゾピラン−４−イル−メチルアミン塩
酸塩１．５９．）リエチルアミン８．８７ｇをクロロホ
ルム３Ｑ７！中に混合した溶液を滴下する。滴下後、−
５°Ｃ前後で１時間攪拌し９次に５℃にて３日間放置し
反応を完結させる。反応液を２Ｎ塩酸、ＩＮ炭酸水素す
）　ＩＪウム、水の順に洗浄し、乾燥後。Cool to -10'C and add 0.98 ethyl chloroformate to it.
A solution of 9 and chloroform 15- is added dropwise. -10°C
After stirring back and forth for 1 hour, 8.4-dihydro-2H-1-benzopyran-4-yl-methylamine hydrochloride 1.59. ) 8.87g of ethylamine in chloroform 3Q7! Drop the mixed solution inside. After dropping, -
The mixture was stirred at around 5°C for 1 hour and then left at 5°C for 3 days to complete the reaction. The reaction solution was washed with 2N hydrochloric acid, IN hydrogen carbonate, and water in this order, and dried.

減圧濃縮し、油状の表題化合物３．５１９を得た。Concentration under reduced pressure gave the title compound 3.519 as an oil.

Ｎ−（２−（３，３−ジフェニルプロピルアミン）エチ
ル）−１，４−ジヒドロ−２Ｈ−１−ベンゾピラン−４
−イルーメチルアミンニマレイン酸塩 上記で得たアミド体８．４９をテトラヒドロフラン２５
−に溶かした溶液を水素化リチウムアルミニウム１．８
７９のテトラヒドロフラン３〇−にけん濁した中に滴下
する。４時間加熱還流した後、氷冷し、水４ｔｎｌ、テ
トラヒドロ７ラン３０−の混液を滴下した後２Ｎ力性ソ
ーダを滴下する。析出する不溶物を濾去し、濾液を減圧
濃縮する。残渣をクロロホルムに溶かし、水洗。N-(2-(3,3-diphenylpropylamine)ethyl)-1,4-dihydro-2H-1-benzopyran-4
-yl-methylamine nimalate The amide compound 8.49 obtained above was added to 25% of tetrahydrofuran.
- a solution of 1.8 lithium aluminum hydride
79 suspended in 30% of tetrahydrofuran. After heating under reflux for 4 hours, the mixture was cooled on ice, and a mixed solution of 4 tnl of water and 30 cm of tetrahydrochloride was added dropwise, followed by dropwise addition of 2N hydric soda. The precipitated insoluble matter is filtered off, and the filtrate is concentrated under reduced pressure. Dissolve the residue in chloroform and wash with water.

乾燥後、減圧濃縮し無色油状の表題化合物の遊離塩基１
．８２９を得た。After drying, concentrate under reduced pressure to obtain the free base 1 of the title compound as a colorless oil.
．． I got 829.

この油状物８６０ｍｇをメタノールに溶かし。860 mg of this oil was dissolved in methanol.

琳 ２当量のマレイン酸を加え析出する粉末を濾集し２表題
化合物を無色板状晶として４７６町を得た。融点２０９
〜２１０９ＣＯ 元素分析値Ｃ％）Ｃ２７Ｈ３２Ｎ２ｏ・２Ｃ４Ｈ４０４
トシテ計算値　Ｃ６６，４４，Ｈ６，３７，Ｎ　　４．
４３実測値　Ｇ　　６６．０．７．　　Ｈ６，１１，Ｎ
　４，４１実施例４９ Ｎ−アセチル−Ｎ−〔２−（Ｎ−アセチル−Ｎ−（３，
３−ジフェニルプロピル）アミノ）エチル）−３，４−
ジヒドロ−２Ｈ−１−ベンゾピラン−４−イルメチルア
ミン 実施例４８にて得られたＮ−（２−（３，８−ジフェニ
ルプロピルアミノ）エチル”Ｊ−３，４−ジヒドロ−２
Ｈ−１−ベンゾピラン−４−イルメチルアミンの遊離塩
基５ｏｏＴｎ９をクロロホルム８０−に溶かしトリエチ
ルアミン１．２６−を加える。続いてこの中にアセチル
クロリド４７１■を滴下した後、２時間室温にて攪拌す
る。反応液を２Ｎ塩酸、２Ｎ−力性ソーダ、水の順に洗
浄、乾燥後減圧濃縮すれば油状の表題化合物９８８Ｑを
得たＯ Ｎ−エチル−Ｎ　７　（２−＜　Ｎ−エチル−Ｎ−（３
，３−ジフェニルプロピル）アミン）エチル〕−８，４
−ジヒドロ−２Ｈ−１−ベン４ビラン−４−イルメチル
アミン・ニマレイン酸塩上記で得たアセチル体８７６ｍ
９をテトラヒドロ７ラン１５−に溶かした溶液を水素化
リチウムアルミニウム５４９■のテトラヒドロフランＩ
Ｑｇｎｔにけん濁した中に滴加した後３時間加熱還流す
る。今後、水１　ｆｎｔ、テトラヒドロフラン９−の混
液を滴下し、続いて２Ｎ力性ソーダを加え析出不溶物を
濾別し濾液を減圧濃縮する。Two equivalents of maleic acid were added and the precipitated powder was collected by filtration to obtain 476 pieces of the title compound as colorless plate crystals. Melting point 209
~2109CO Elemental analysis value C%) C27H32N2o・2C4H404
Toshite calculation value C66, 44, H6, 37, N 4.
43 Actual value G 66.0.7. H6, 11, N
4,41 Example 49 N-acetyl-N-[2-(N-acetyl-N-(3,
3-diphenylpropyl)amino)ethyl)-3,4-
Dihydro-2H-1-benzopyran-4-ylmethylamine N-(2-(3,8-diphenylpropylamino)ethyl"J-3,4-dihydro-2 obtained in Example 48
H-1-benzopyran-4-ylmethylamine free base 5ooTn9 is dissolved in chloroform 80- and triethylamine 1.26- is added. Subsequently, 471 cm of acetyl chloride was added dropwise to the mixture, and the mixture was stirred at room temperature for 2 hours. The reaction solution was sequentially washed with 2N hydrochloric acid, 2N sodium hydroxide, and water, dried, and then concentrated under reduced pressure to obtain the oily title compound 988Q.
,3-diphenylpropyl)amine)ethyl]-8,4
-dihydro-2H-1-ben4bilan-4-ylmethylamine nimalate Acetyl compound obtained above 876m
A solution of 9 dissolved in tetrahydrofuran 15- was dissolved in 549 cm of lithium aluminum hydride in tetrahydrofuran I.
The mixture was added dropwise to the suspension in Qgnt and heated under reflux for 3 hours. Thereafter, a mixture of 1 fnt of water and 9 g of tetrahydrofuran was added dropwise, followed by addition of 2N hydric soda, the precipitated insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure.

残渣をシリカゲル１０ｇを用いてカラムクロマトにて精
製する。クロロホルムにて溶出分より表題化合物の遊離
塩基を無色油状として５４２■を得。The residue is purified by column chromatography using 10 g of silica gel. From the fraction eluted with chloroform, the free base of the title compound was converted into a colorless oil to obtain 542.

これをメタノール５−に溶かしマレイン酸２８９ＷＩ９
を加え、減圧濃縮しエーテルにて結晶化させ、無色粉末
の表題化合物９０Ｂ”’９を得た。Dissolve this in methanol 5-maleic acid 289WI9
was added, concentrated under reduced pressure, and crystallized from ether to obtain the title compound 90B"'9 as a colorless powder.

元素分析値（％）　　Ｃ３１Ｈ４ＯＮ２０４Ｃ４Ｈ４０
＜とじて計算値　Ｃ６８，００，Ｈ７，０２，・Ｎ　　
４．０７実測値　Ｃ６７，７８，Ｈ７，１６，Ｎ　　４
．１６実施例５Ｏ Ｎ−（Ｎ−エチル−Ｎ−（３，８−ジフェニルプロピル
）グリシル）　−３１４−ジヒドロ−２Ｈ−１−ベンゾ
ビラン−４−イルメチルアミンＮ−エチル−Ｎ−（８，
８−ジフェニルプロピル）グリシン１．８３９とトリエ
チルアミン０．５りをテトラヒドロ７ラン２５−に溶か
す。この溶液を−１６°Ｃに冷却し、これにクロルギ酸
イソブチル６１０１ｎ９とテトラヒドロフラン２５−の
溶液を滴下する。８時間−１０〜−８°Ｃにて攪拌した
後、３，４−ジキドロー２Ｈ−１−ベンゾビラン・−４
−イルメチルアミン７３０”’９．）リエチルアミ７０
．５９をテトラヒドロ７ラン１ｏ−に溶かした溶液を滴
下する。−１０〜０℃にて１時間更に室温にて１時間攪
拌した抜水２−を加え減圧濃縮する。濃縮液に２Ｎ力性
ソーダを加えアルカリ性としベンゼンにて抽出する。抽
出液を水洗、乾燥後減圧濃縮して油状の表題化合物を１
．６９９を得た。Elemental analysis value (%) C31H4ON204C4H40
<Calculated value C68,00, H7,02,・N
4.07 actual measurement value C67,78,H7,16,N 4
．． 16 Example 5O N-(N-ethyl-N-(3,8-diphenylpropyl)glycyl)-314-dihydro-2H-1-benzobylan-4-ylmethylamine N-ethyl-N-(8,
Dissolve 1.839 g of (8-diphenylpropyl)glycine and 0.5 g of triethylamine in 25 g of tetrahydro7ran. This solution is cooled to -16°C, and a solution of isobutyl chloroformate 6101n9 and tetrahydrofuran 25 is added dropwise thereto. After stirring at -10 to -8°C for 8 hours, 3,4-diquidrow 2H-1-benzobilane-4
-ylmethylamine 730'''9.) Liethylamine 70
．． A solution of 59 dissolved in tetrahydro7ran 1o- is added dropwise. After stirring at -10 to 0°C for 1 hour and at room temperature for 1 hour, drained water 2- is added and concentrated under reduced pressure. Add 2N sodium hydroxide to the concentrated solution to make it alkaline and extract with benzene. The extract was washed with water, dried and concentrated under reduced pressure to obtain the oily title compound.
．． I got 699.

Ｎ−（２−（Ｎ−エチル−Ｎ−（３，３−ジフェニルプ
ロピル）アミン）エチル）−３，４−ジヒド０−２Ｈ−
１−ベンゾピラン−４−イルメチルアミン・ニマレイン
酸塩 上記で得た粗製のアミド体１．６５りをテトラヒドロフ
ラン１５−にとかし、これを水素化リチウムアルミニウ
ム４２０Ｔｎ９とテトラヒドロ７ラン８０ｗｔ／のけん
濁液中に滴下した後、８時間加熱還流する。氷冷し、こ
れに水１−とテトラヒドロ７ラン５０−の混液を滴下す
る。析出する不溶物を濾去し、濾液を減圧濃縮し残渣を
クロロホルムにて抽出し、抽出液を水洗、乾燥し減圧濃
縮する。残渣をシリカゲル２６９を用いてカラムクロマ
トにて精製し、２％メタノール含有クロロホルム溶出液
より表題化合物の遊離塩基を無色油状物として６９４１
ｎ９を得た。N-(2-(N-ethyl-N-(3,3-diphenylpropyl)amine)ethyl)-3,4-dihydro0-2H-
1-benzopyran-4-ylmethylamine nimalate 1.65% of the crude amide compound obtained above was dissolved in 15-tetrahydrofuran, and this was dissolved in a suspension of lithium aluminum hydride 420Tn9 and tetrahydro7rane 80wt/. After adding dropwise to the solution, the mixture was heated under reflux for 8 hours. The mixture is cooled on ice, and a mixed solution of 1-liter of water and 50-liter of tetrahydro 7-ran is added dropwise thereto. The precipitated insoluble matter is filtered off, the filtrate is concentrated under reduced pressure, the residue is extracted with chloroform, the extract is washed with water, dried, and concentrated under reduced pressure. The residue was purified by column chromatography using silica gel 269, and the free base of the title compound was obtained as a colorless oil from the chloroform eluate containing 2% methanol.
I got n9.

これをメタノールに溶かし、マレイン酸不 ３３２９を加えかきまぜ析出する結晶を濾肇しメタノー
ルより再結晶すれば無色結晶の表題化合物を７４５■を
得た。融点１７６〜１７６５°Ｃ０元素分析値（％）　
　Ｃ２９Ｈ３６Ｎ２０・２０４Ｈ４０４として計算値　
Ｇ　　６７．２５．　　Ｈ６，７１，Ｎ　　４．２４実
測値　ｃ　　６７．４６．　　Ｈ６，６６、Ｎ　４．１
５実施例５１ Ｎ−（３，３−ジフェニルプロピオニル）−６−二トロ
ー３．４−ジヒドロ−２Ｈ−１−ベンゾピラン−４−イ
ルメチルアミン ３．３−ジフェニルプロピオン酸１．９６９を塩化チオ
ニル４−と共に２時間加熱還流後、減圧濃縮する。残渣
をベンゼン１５ｔｎ１．に溶かし、６−ニトロ−３，４
−ジヒドｏ−２Ｈ−１−ベンゾビラン−４−イルメチル
アミ＞１．５９．トリエチルアミン１．０２９．ベンゼ
ン４０ｆｒＬｔの混液中に滴下した後、１４時間加熱還
流する。今後。This was dissolved in methanol, mixed with maleic acid 3329, stirred, and the precipitated crystals were filtered and recrystallized from methanol to obtain 745 ml of the title compound as colorless crystals. Melting point 176-1765°C0 elemental analysis value (%)
Calculated value as C29H36N20/204H404
G 67.25. H6,71,N 4.24 Actual value c 67.46. H6, 66, N 4.1
5 Example 51 N-(3,3-diphenylpropionyl)-6-nitro3.4-dihydro-2H-1-benzopyran-4-ylmethylamine 3.3-diphenylpropionic acid 1.969 to thionyl chloride 4 - After heating under reflux for 2 hours, concentrate under reduced pressure. The residue was dissolved in benzene 15tn1. Dissolved in 6-nitro-3,4
-dihydro-2H-1-benzobylan-4-ylmethylami>1.59. Triethylamine 1.029. After dropping the mixture into a mixed solution of 40 frLt of benzene, the mixture was heated under reflux for 14 hours. from now on.

反応液を２Ｎ塩酸、２Ｎ力性ソーダ、水の順に洗浄し、
乾燥後減圧濃縮する。残渣を酢酸エチル、石油エーテル
の混液より再結晶し黄色プリズム晶の表題化合物１．９
９９を得た。融点１７１〜１７４℃０ Ｎ−（３，３−ジフェニルプロピル）−６−二トロー３
．４−ジヒドロ−２Ｈ−１−ベンゾピラン−４−イルメ
チルアミンマレイン酸塩上記で得たアミド体８５０”９
をテトラヒドロ７ラン３０−に溶かし、窒素ガス下にこ
の中にジボランのテＦラヒドロフラン１モル溶液９”を
滴下し、８日間室温にて攪拌する。水を加え続いて塩酸
にて酸性とした後減圧濃縮する。残液を２Ｎ力性ソーダ
にて中和しクロロホルム抽出する。抽出液を水洗、乾燥
後減圧濃縮い残渣をシリカゲル３０９を用いてカラムク
ロマトに付い　１％メタノール含有クロロホルム溶出液
より表題化合物の遊離塩基を黄色油状物として８０２１
”９を得た。The reaction solution was washed with 2N hydrochloric acid, 2N sodium hydroxide, and water in this order.
After drying, concentrate under reduced pressure. The residue was recrystallized from a mixture of ethyl acetate and petroleum ether to give the title compound 1.9 as yellow prism crystals.
I got 99. Melting point 171-174℃0 N-(3,3-diphenylpropyl)-6-nitro 3
．． 4-dihydro-2H-1-benzopyran-4-ylmethylamine maleate Amide compound obtained above 850''9
was dissolved in tetrahydrofuran 30%, and a 1 molar solution of diborane in tetrahydrofuran (9") was added dropwise into the solution under nitrogen gas, and the mixture was stirred at room temperature for 8 days. After adding water and making it acidic with hydrochloric acid, Concentrate under reduced pressure. Neutralize the residual liquid with 2N hydric soda and extract with chloroform. The extract is washed with water, dried, and concentrated under reduced pressure. The residue is subjected to column chromatography using silica gel 309. From the chloroform eluate containing 1% methanol, the title 8021 as the free base of the compound as a yellow oil
“I got a 9.

これをエタノールにとかし計算量のマレイン酸を加え減
圧濃縮しエーテルより粉末となし。Dissolve this in ethanol, add the calculated amount of maleic acid, concentrate under reduced pressure, and make a powder with ether.

エタノール、エーテルより再結晶して淡黄色粉東の表題
化合物７００■を得た。融点１９４〜元素分析値（イ）
　Ｃｒｚ　ｓ　Ｔｏａ　Ｎ２０３・Ｇ４　Ｈ４０４とし
て計算値　Ｃ６７，１７，Ｈ５，８３，Ｎ　　５．４０
実測値　Ｃ６６，９７，Ｈ６，０８，Ｎ　　５．８８実
施例５２ ４−（Ｎ−（３，３−ジフェニルプロピル）アミ／メチ
ルツー６−アミノ−３，４−ジヒドロ−２Ｈ−１−ベン
ゾビラン二塩酸塩・十水和物実施例５１で得たＮ−（３
，３−ジフェニルプロピル）−６−ニトロ−３，４−ジ
ヒドロ−２Ｈ−１−、ベンゾピラン−４−イルメチルア
ミンの遊離塩基３１２ｍｇを酢酸エチル５ｆｎｌ、エタ
ノール１５−に溶かし、１０％パラジウム炭９０■を加
え常圧にて接触還元する。水素の吸収が終了したところ
で触媒を濾去し、濾液を減圧濃縮する残渣をクロロホル
ムに溶かし水洗、乾燥後減圧濃縮する。残液をエタノー
ルに溶かし２０％塩化水素エタノール溶液を加え減圧濃
縮する。Recrystallization from ethanol and ether gave the title compound 700cm as a pale yellow powder. Melting point 194 ~ elemental analysis value (a)
Calculated value as Crz s Toa N203/G4 H404 C67, 17, H5, 83, N 5.40
Actual value C66,97, H6,08, N 5.88 Example 52 4-(N-(3,3-diphenylpropyl)ami/methyl-6-amino-3,4-dihydro-2H-1-benzobilane dihydrochloride Salt/decahydrate N-(3
,3-diphenylpropyl)-6-nitro-3,4-dihydro-2H-1-, 312 mg of the free base of benzopyran-4-ylmethylamine was dissolved in 5fnl of ethyl acetate and 15ml of ethanol, and dissolved in 90ml of 10% palladium on charcoal. and catalytic reduction at normal pressure. When hydrogen absorption is completed, the catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure.The residue is dissolved in chloroform, washed with water, dried, and concentrated under reduced pressure. Dissolve the residual liquid in ethanol, add 20% hydrogen chloride ethanol solution, and concentrate under reduced pressure.

残渣をエタノール、エーテル混液より再結晶して無色針
状の表題化合物１８０■を得た。融点２１８〜２２４℃
（分解）。The residue was recrystallized from a mixture of ethanol and ether to obtain 180 ml of the title compound as colorless needles. Melting point 218-224℃
(Disassembly).

元素分析値（％）　　Ｃ２５ＨｚａＮ２０　・２ＨＧｌ
−４Ｈｚｏとして計算値　０　６６．０７．　　Ｈ６゜
８８．　　Ｎ　　６．１６実測値　Ｃ６６，５（１，Ｈ
６，８５，Ｎ　　６．２１実施例５３ 体重２５０〜４００ｇの雄性モルモットの大動脈を摘出
し、９５％酸素と５％炭酸ガスの混合ガス気流下に標本
（摘出した大動脈にポリエチレン管を挿入し９両端を糸
で結びカミソリを用いて２ｍ１ｌＬＸ２．０〜２．５Ｃ
ｆ１１のラセン状標本）を作成した。標本の両端に糸を
結び一方をガラス固定支持棒に固定し、マグヌス管中に
懸垂させたのち、他方をＦＤピックアップ（日本光電）
に結び、ひずみ圧力アンプを介してポリグラフ上に標本
の収縮を等尺性に記録した。実験はマグヌス法（栄養液
はタレブス液５０ｙ４．温度８７°Ｃ１９５％酸素と５
％炭酸ガス混合ガス通気下）で行なった。Elemental analysis value (%) C25HzaN20 ・2HGl
Calculated value as -4Hz 0 66.07. H6°88. N 6.16 Actual value C66,5(1,H
6,85,N 6.21 Example 53 The aorta of a male guinea pig weighing 250 to 400 g was removed, and the specimen was placed under a mixed gas flow of 95% oxygen and 5% carbon dioxide (a polyethylene tube was inserted into the removed aorta). Tie both ends with thread and use a razor to make 2ml 1lL x 2.0~2.5C
f11 spiral specimen) was prepared. Tie a string to both ends of the specimen, fix one end to a glass fixed support rod, suspend it in a Magnus tube, and then attach the other end to an FD pickup (Nihon Kohden).
The contraction of the specimen was recorded isometrically on a polygraph via a strain pressure amplifier. The experiment was carried out using the Magnus method (the nutrient solution was Taleb's solution 50y4, temperature 87°C, 195% oxygen and 50% oxygen).
% carbon dioxide mixed gas).

標本には］、、５９の負荷を与え約１時間安定させる。The specimen was loaded with .59 and allowed to stabilize for approximately 1 hour.

安定Ｌ　１ｏ　　モルのノルエピネフリンを添加し標本
の反応性を試みるＯ１Ｏ分間程度反応を見て標本の反応
性を確認の後、標本を３回栄養液で洗浄し、負荷がフル
エピネフリン添加前値に戻った後、塩化カリウムｌＯモ
ル添加し、その収縮を記録する。収縮が最大に達した時
点（約３０分後）に試験検体１０　モルを添加し、その
抑制効果を調べた。検体の効果は添加後４０分までの抑
制反応を変化率（％）で表わした。またノルエピネフリ
ン１０　モルでも同様に行ない、検体１０−５モルによ
る抑制反応（支））を求めた。After confirming the reactivity of the specimen by observing the reaction for about 10 minutes by adding 10 moles of norepinephrine, the specimen was washed three times with nutrient solution, and the load returned to the value before adding fluepinephrine. After that, 10 mol of potassium chloride is added and the contraction is recorded. At the time when the contraction reached its maximum (approximately 30 minutes later), 10 mol of the test specimen was added, and its inhibitory effect was investigated. The effect of the sample was expressed as the rate of change (%) in the inhibition reaction up to 40 minutes after addition. The same procedure was carried out using 10 moles of norepinephrine to determine the inhibitory reaction (support) caused by 10-5 moles of the specimen.

本発明の冠血管潅流量増加作用とカルシウム拮抗作用を
以下に表示する。The coronary vascular perfusion increasing effect and calcium antagonizing effect of the present invention are shown below.

＊　化合物Ａ＝対応する実施例点にて得られた化合物。*Compound A = compound obtained in the corresponding example.

ｎ　　モルモット摘出心臓　ランゲンドルフ氏法にて測
定。検体量は３０μりを使用。n Guinea pig isolated heart Measured by Langendorff's method. The sample amount used was 30μ.

ＣｏＦ−冠血管潅流量増加作用　パパベリンの作用を１
００とした時の相対比。CoF - Coronary vascular perfusion increasing effect: Increases the effect of papaverine by 1
Relative ratio when set to 00.

ＣｏＦｘＴ４−上記冠血管潅流量増加作用にその最大増
加量の十を維持する時間（秒）を乗じたものでパパベリ
ンのそれを １００とした時の相対比。CoFxT4 - Relative ratio of the above-mentioned coronary vascular perfusion increasing effect multiplied by the time (seconds) to maintain the maximum increase in 10, when that of papaverine is set as 100.

＊＃そルモット摘出大動脈標本でマグヌス法にて測定　
検体濃度は１０−５Ｍであり、その塩化カリウムとノル
エピネフリンの引き起こす収縮を抑制する抑制率（％）
。*#Measurement using the Magnus method using a Lemotte removed aorta specimen
The sample concentration is 10-5M, and the inhibition rate (%) of suppressing the contraction caused by potassium chloride and norepinephrine.
.

Claims (1)

【特許請求の範囲】 で示されるベンゾピラン誘導体およびその塩。 上記式中Ｒ１は水素原子、低級アルキル基、低級アルコ
キシ基、ニトロ基又はアミ７基を　Ｒ２は水素原子又は
低級アルコキシ基を　１３は水素原子又は低級アルキル
基を　Ｒ４は水素原子又は低級アルキル基を　ＢＳはモ
ノあるいはジフェニルアルキル基、ベンゼン環に低級ア
ルコキシ基が置換することもあるフェノキシアルキル基
。 オ （式中Ｉ’ｌ’はジフェニルプロピル基、ジフェニルフ
ロヒオニル基又はシンナモイル基を意味シ。 シンナモイル基のベンゼン環は１〜８個の低級アルコキ
シ基で置換されていてもよい。）で示（式中Ｒ７は水素
原子又は低級アルキル基を意味す。）で示される基を、
ｎはＯ〜２の整数を意味す。[Claims] A benzopyran derivative and a salt thereof. In the above formula, R1 is a hydrogen atom, a lower alkyl group, a lower alkoxy group, a nitro group, or an amide group. R2 is a hydrogen atom or a lower alkoxy group. 13 is a hydrogen atom or a lower alkyl group. R4 is a hydrogen atom or a lower alkyl group. BS is a mono- or diphenylalkyl group, or a phenoxyalkyl group in which a lower alkoxy group may be substituted on the benzene ring. (In the formula, I'l' means a diphenylpropyl group, a diphenylfurohionyl group, or a cinnamoyl group. The benzene ring of the cinnamoyl group may be substituted with 1 to 8 lower alkoxy groups.) (In the formula, R7 means a hydrogen atom or a lower alkyl group.)
n means an integer of 0 to 2.