JPH037258A - Pyridinecarboxamide derivative - Google Patents

Pyridinecarboxamide derivative

Info

Publication number
JPH037258A
JPH037258A JP2027202A JP2720290A JPH037258A JP H037258 A JPH037258 A JP H037258A JP 2027202 A JP2027202 A JP 2027202A JP 2720290 A JP2720290 A JP 2720290A JP H037258 A JPH037258 A JP H037258A
Authority
JP
Japan
Prior art keywords
methyl
nicotinamide
piperazinyl
compound
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
JP2027202A
Other languages
Japanese (ja)
Other versions
JP2843632B2 (en
Inventor
Katsutoshi Miura
三浦　勝利
Hiroyasu Koyama
裕康 小山
Toshihisa Sugai
菅井　利寿
Hiroaki Yamada
博章 山田
Einosuke Sakurai
櫻井　英之助
Masato Horigome
堀米　正人
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nisshin Seifun Group Inc
Original Assignee
Nisshin Seifun Group Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nisshin Seifun Group Inc filed Critical Nisshin Seifun Group Inc
Priority to US07/483,532 priority Critical patent/US4994456A/en
Priority to EP90103703A priority patent/EP0385350B1/en
Priority to DE69014351T priority patent/DE69014351T2/en
Priority to KR1019900002605A priority patent/KR0130758B1/en
Publication of JPH037258A publication Critical patent/JPH037258A/en
Application granted granted Critical
Publication of JP2843632B2 publication Critical patent/JP2843632B2/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)

Abstract

NEW MATERIAL:A compound expressed by formula I [R1 is H, 1-6C alkyl, 3-6C cycloalkyl or diphenylmethyl; Y is -NH(CH2)n-R2 or formula II (R2 is OH or -ONO2; n is 2-8); 1 is 2 or 3; m is 0 or 1] and acid addition salt thereof. EXAMPLE:N-(2-Hydroxyethyl)-6-(4-methyl-1-piperazinyl)nicotinamide. USE:Useful for treating and preventing cerebral circulatory disorder, peripheral circulatory disorder, ischemic cardiopathy, hypertension, etc. PREPARATION:A compound expressed by formula III (R3 is H or 1-6C alkyl) is reacted with an amino compound expressed by formula IV and, as necessary, an amidation reaction product in which R2 is OH is converted into a nitric acid ester thereof to afford the compound expressed by formula I.

Description

【発明の詳細な説明】 〔産業上の利用分野〕 本発明は、新規なピリジンカルボン酸アミド誘導体、そ
の製造方法および該誘導体を含有する医薬組成物に関す
る。DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel pyridinecarboxylic acid amide derivative, a method for producing the same, and a pharmaceutical composition containing the derivative.

本発明によって提供されるピリジンカルボン酸アミド誘
導体、および、その生理学的に許容し得る塩は、椎骨動
脈、総頚動脈、大腿動脈の血流増加作用および血圧低下
作用を有し、脳循環障害、末梢循環障害、虚血性心疾患
および高血圧症の治療および予防において有効である。The pyridinecarboxylic acid amide derivatives and physiologically acceptable salts thereof provided by the present invention have the effect of increasing blood flow and lowering blood pressure in the vertebral artery, common carotid artery, and femoral artery, and are effective in reducing cerebral circulation disorders and peripheral blood pressure. Effective in the treatment and prevention of circulatory disorders, ischemic heart disease and hypertension.

〔従来の技術〕[Conventional technology]

循環器疾患治療剤として有用であるニコチン酸アミド誘
導体は、特開昭８２−２Ｈ９Ｂ８号に開示されている。Nicotinic acid amide derivatives useful as therapeutic agents for cardiovascular diseases are disclosed in JP-A-82-2H9B8.

また、血管拡張剤として有用である硝酸エステル誘導体
は、特開昭８２−２０５０５２号に開示されている。Additionally, nitrate ester derivatives useful as vasodilators are disclosed in Japanese Patent Application Laid-Open No. 82-205052.

〔発明が解決しようとする課題〕[Problem to be solved by the invention]

これらの化合物はその循環器疾患治療剤とじての薬効に
おいて必ずしも満足すべきものとはなし難いところから
新規でかつ薬効においてすぐれた化合物の発見が求めら
れている。Since these compounds are not always satisfactory in their medicinal efficacy as therapeutic agents for cardiovascular diseases, there is a demand for the discovery of novel compounds with excellent medicinal efficacy.

〔課題を解決するための手段〕[Means to solve the problem]

そこで本発明者らは薬理効果が高くしかも工業的に容易
に入手しつる実用上において充分満足できる化合物を開
発すべく鋭意研究を重ねた結果、次に述べる新規化合物
を見出し本発明を完成したのである。Therefore, the present inventors conducted extensive research in order to develop a compound that has high pharmacological effects, is easily available industrially, and is fully satisfactory in practical use.As a result, the present inventors discovered the following new compound and completed the present invention. be.

すなわち、本発明によれば、次の一般式（１）％式％ ） で表わされるピリジンカルボン酸アミド化合物およびそ
の生理学的に許容し得る酸付加塩が提供される。That is, according to the present invention, a pyridinecarboxylic acid amide compound represented by the following general formula (1) % formula % ) and a physiologically acceptable acid addition salt thereof are provided.

本発明の化合物は次の一般式（ｒｌ） （Ｉ） （式中、Ｒは水素、０１〜Ｃ６アルキル、０３〜Ｃ６ン
クロアルキルまたはジフェニルメチルであり、 （Ｉ［） （式中、Ｒ，、、Ｉｌｌおよびｎは上述したとおりであ
り、 Ｒ３は水素または０１〜Ｃ６アルキルである）で表わさ
れる化合物と、次の一般式（ＩＩＩ）ＮＨ２−（ＣＨ２
）　ｎ−Ｒ２（Ｉ［Ｉ）（式中、Ｒ２およびｎは上述し
たとおりである）で表わされるアミノ化合物とを反応さ
せ、場合によりＲ２がＯＨである得られたアミド化反応
生成物を硝酸エステル化して次の一般式（Ｉ）ｏＸ （式中、Ｒ１，Ｙ、ｆｌおよびｍは上記と同義である） で表わされる化合物を得るか、または必要によってこの
ようにして得られた化合物を生理学的に許容しうる酸付
加塩に変換することにより製造することができる。The compounds of the present invention have the following general formula (rl) (I) (wherein R is hydrogen, 01-C6 alkyl, 03-C6 chloroalkyl or diphenylmethyl, (I[) (wherein R,, , Ill and n are as described above, and R3 is hydrogen or 01-C6 alkyl) and the compound represented by the following general formula (III) NH2-(CH2
) n-R2(I[I), where R2 and n are as described above, and the resulting amidation reaction product, where R2 is OH, is treated with nitric acid. Esterification may be carried out to obtain a compound represented by the following general formula (I) o It can be produced by converting it into a legally acceptable acid addition salt.

別法として、−機成（Ｉ）においてＹが−ＮＨ（ＣＨ２
）。−Ｒ２（Ｒ２はＯＨまたは一０ＮＯ２であり、ｎは
５〜８である）およびＹ（式中、Ｘはハロゲンであり、
ｍはＯまたは１である）で表わされる化合物と、ＮＨ（
ＣＨ２）。Alternatively, in -organism (I), Y is -NH(CH2
). -R2 (R2 is OH or -NO2, n is 5 to 8) and Y (wherein X is halogen,
m is O or 1) and NH (
CH2).

で表わされる化合物とを有機溶媒中で反応させて次の一
般式 一０ＮＯ２である）である本発明の化合物は、次の一般
式（ＩＶ） （式中、Ｘ、ｍおよびｎは上述したとおりである）で表
わされる化合物を生成させ、さらにこの化合物を酸結合
剤の存在下に次の一般式 （式中、Ｒ１は上述したとおりである）で表わされる化
合物と縮合させて一般式（１）においてＹが−ＮＨ（Ｃ
Ｈ２）　ｎ−ＯＨまたはいはこのようにして得られた化
合物を硝酸エステル化して一般式（１）においてＹが−
ＮＨ（ＣＨ）　　−０ＮＯ２または ｎ より製造することができる。The compound of the present invention which is the following general formula (10NO2) obtained by reacting with the compound represented by the following in an organic solvent can be obtained by the following general formula (IV) (wherein, This compound is further condensed with a compound represented by the following general formula (wherein R1 is as described above) in the presence of an acid binder to form a compound represented by the general formula (1). ), Y is -NH(C
H2) n-OH or the compound thus obtained is esterified with nitric acid so that Y in the general formula (1) is -
It can be produced from NH(CH)-0NO2 or n.

上記した一般式（１）の化合物におけるＲ１の具体例と
しては、水素；メチル、エチル、ｎ−プロピル、ｉ−プ
ロピル、ｉ−ブチル、５ｅｅ−ブチル、ｔｅｒｔ−ブチ
ル、ヘキシルなどの０１〜Ｃ６アルキル；シクロペンチ
ル、シクロヘキシルなどのＣ３〜Ｃｅシクロアルキル；
およびジフェニルメチルが挙げられる。Specific examples of R1 in the compound of general formula (1) above include hydrogen; 01-C6 alkyl such as methyl, ethyl, n-propyl, i-propyl, i-butyl, 5ee-butyl, tert-butyl, hexyl, etc. ;C3-Ce cycloalkyl such as cyclopentyl, cyclohexyl;
and diphenylmethyl.

一般式（ＩＩ）で表わされる化合物と一般式（ＩＩＩ）
で表わされる化合物との反応は、例えば一般式（ＩＩ）
で表わされる化合物がエステル型である場合には過剰量
の一般式（ＩＩＩ）で表わされる化合物と共に触媒例え
ば２−ヒドロキシピリジンの存在下に、または不在下に
、有機溶媒中または有機溶媒なしで行なわれる。この反
応は常温〜１５０℃の温度で数十分〜数十時間にわたっ
て撹拌することによって達成される。目的化合物の精製
単離は常法により行なわれる。すなわち、反応終了後有
機溶媒例えばジエチルエーテル、酢酸エチル、ジクロロ
メタンなどで抽出し、抽出液から抽出溶媒を留去し、残
留物を再結晶操作に付すかまたはクロマトグラフィーに
付して精製された縮合生成物を得る。Compounds represented by general formula (II) and general formula (III)
For example, the reaction with a compound represented by the general formula (II)
When the compound represented by is an ester type, the reaction is carried out in the presence or absence of a catalyst such as 2-hydroxypyridine together with an excess amount of the compound represented by general formula (III), in an organic solvent or without an organic solvent. It will be done. This reaction is achieved by stirring at a temperature of room temperature to 150° C. for several tens of minutes to several tens of hours. Purification and isolation of the target compound is carried out by conventional methods. That is, after the completion of the reaction, the condensation product is extracted with an organic solvent such as diethyl ether, ethyl acetate, dichloromethane, etc., the extraction solvent is distilled off from the extract, and the residue is purified by recrystallization or chromatography. Get the product.

得られた縮合生成物でＲ２がＯＨである場合には、これ
を有機溶媒中に溶解または懸濁させ、水冷下に発煙硝酸
または発煙硝酸と無水酢酸の混合物を加え、１〜４時間
撹拌することにより硝酸エステル化してＲが０ＮＯ２で
ある一般式（Ｉ）の化合物を得ることができる。When R2 is OH in the obtained condensation product, dissolve or suspend it in an organic solvent, add fuming nitric acid or a mixture of fuming nitric acid and acetic anhydride while cooling with water, and stir for 1 to 4 hours. By this, a compound of general formula (I) in which R is 0NO2 can be obtained by nitrate esterification.

また、一般式（Ｉｌ、）で表わされる化合物が遊離酸型
である化合物の場合は、この化合物と一般式（ＩＩＩ）
で表わされるアミノアルコール硝酸エステルとを適当な
アミド化剤の存在下または不存在下に有機溶媒中で縮合
反応させ、一般式（１）で表わされる化合物とされる。In addition, when the compound represented by the general formula (Il,) is a free acid type compound, this compound and the general formula (III)
A compound represented by the general formula (1) is obtained by condensing the amino alcohol nitric ester represented by the formula (1) in an organic solvent in the presence or absence of a suitable amidating agent.

これらの反応において、反応溶媒としては、ｎ−へキサ
ン、石油エーテルなどの脂肪族炭化水素、ベンゼン、ト
ルエン、キシレンなどの芳香族炭化水素、シクロヘキサ
ンなどの脂環式化合物、四塩化炭素、クロロホルム、ジ
クロロエタン、トリクロロエタンなどのハロゲン化炭化
水素、アセトン、メチルエチルケトンなどの脂肪族ケト
ン、アセトニトリル、Ｎ，Ｎ−ジメチルホルムアミド、
ジメチルスルホキシドなどを用いることができる。In these reactions, reaction solvents include aliphatic hydrocarbons such as n-hexane and petroleum ether, aromatic hydrocarbons such as benzene, toluene, and xylene, alicyclic compounds such as cyclohexane, carbon tetrachloride, chloroform, Halogenated hydrocarbons such as dichloroethane and trichloroethane, aliphatic ketones such as acetone and methyl ethyl ketone, acetonitrile, N,N-dimethylformamide,
Dimethyl sulfoxide and the like can be used.

この場合における目的化合物の精製、単離も常法により
行なわれる。すなわち、反応終了後溶媒を留去し、残留
物を炭酸水素ナトリウム水溶液に注ぎ、有機溶媒例えば
ジエチルエーテル、酢酸エチル、ジクロロメタンなどで
抽出し抽出液から抽出溶媒を留去し、残留物を再結晶操
作に付すかまたはクロマトグラフィーに付して精製され
た目的の縮合生成物を得る。Purification and isolation of the target compound in this case are also carried out by conventional methods. That is, after the reaction is complete, the solvent is distilled off, the residue is poured into an aqueous sodium bicarbonate solution, extracted with an organic solvent such as diethyl ether, ethyl acetate, dichloromethane, etc., the extraction solvent is distilled off from the extract, and the residue is recrystallized. The purified desired condensation product is obtained by manipulation or chromatography.

このようにして得られた一般式（Ｉ）の化合物は常法に
よりその酸付加塩に変換することができる。この酸付加
塩としては、塩酸、硫酸、リン酸、臭化水素酸、硝酸な
どの無機酸との酸付加塩、酢酸、プロピオン酸、コハク
酸、酪酸、リンゴ酸、クエン酸、フマル酸、酒石酸など
の有機酸との酸付加塩を挙げることができる。The compound of general formula (I) thus obtained can be converted into its acid addition salt by a conventional method. Examples of acid addition salts include acid addition salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, and nitric acid, acetic acid, propionic acid, succinic acid, butyric acid, malic acid, citric acid, fumaric acid, and tartaric acid. Examples include acid addition salts with organic acids such as.

本発明の化合物を合成するための出発原料の一般式（Ｉ
Ｉ）で示される化合物は、次の一般式（Ｖ）（式中、Ｘ
はハロゲンであり、Ｒ３は水素またはＣＩ−０６アルキ
ルである） で表わされる化合物と、次の一般式（ＶＴ）（式中、Ｒ
は水素、Ｃ１〜Ｃ６アルキル、シフ０アルキルまたはジ
フェニルメチルであり、ｇは２または３である）で表わ
される化合物とを、酸結合剤の存在下に縮合させて得ら
れる。この縮合反応によって得られる化合物でＲ１が水
素である場合には、必要によってこの化合物と式Ｒ’１
−Ｘ（式中、Ｒ′１は０１〜Ｃ６アルキルであり、Ｘは
ハロゲンである）で表わされる化合物とを酸結合剤の存
在下に有機溶媒中で反応させることによりＲ１がＣ１〜
Ｃ６アルキル基である一般式（ＩＩ）の化合物とするこ
ともできる。さらにまた−機成（ｎ）の化合物でＲ１が
水素である化合物についてはホルムアルデヒド−ｔｈ１
酸混合物と反応させてＲ１がメチルである一般式（ｎ）
の化合物に変換することができる。なお、この反応はＯ
ｒｇａｎｌｅＳｙｎｔｈｅｓｅｓ　ｖｏｌ、　３．７２
３〜７２５頁に記載の反応条件で行ないうる。General formula (I
The compound represented by I) has the following general formula (V) (wherein X
is halogen, R3 is hydrogen or CI-06 alkyl) and the compound represented by the following general formula (VT) (wherein R
is hydrogen, C1-C6 alkyl, Schiff-alkyl or diphenylmethyl, and g is 2 or 3) in the presence of an acid binder. When R1 is hydrogen in the compound obtained by this condensation reaction, if necessary, this compound and the formula R'1
-X (wherein, R'1 is 01-C6 alkyl and X is halogen) in an organic solvent in the presence of an acid binder, so that R1 is
It can also be a compound of general formula (II) which is a C6 alkyl group. Furthermore, for compounds of structure (n) in which R1 is hydrogen, formaldehyde-th1
General formula (n) in which R1 is methyl by reaction with an acid mixture
It can be converted into the compound of Note that this reaction is O
rganleSyntheses vol, 3.72
The reaction can be carried out under the reaction conditions described on pages 3 to 725.

本発明の一般式（１）で表わされる化合物は、以下に示
される薬理試験結果からも明らかなように、温血動物に
対して著しい血流増加作用および血圧低下作用を有し、
循環器疾患の治療および予防のために使用されうる。こ
の循環器疾患には例えば脳循環障害、末梢循環障害、虚
血性心疾患および高血圧症などがある。The compound represented by the general formula (1) of the present invention has a remarkable blood flow increasing effect and blood pressure lowering effect on warm-blooded animals, as is clear from the pharmacological test results shown below.
It can be used for the treatment and prevention of cardiovascular diseases. Such circulatory diseases include, for example, cerebral circulation disorders, peripheral circulation disorders, ischemic heart diseases, and hypertension.

従って本発明はさらに上記疾患の治療および予防のため
に使用される一般式（ｒ）の化合物またはその生理学的
に許容しうる酸付加塩を活性成分として含有する医薬組
成物にも関する。The invention therefore also relates to pharmaceutical compositions containing as active ingredient a compound of general formula (r) or a physiologically acceptable acid addition salt thereof, which is used for the treatment and prevention of the above-mentioned diseases.

本発明の医薬組成物は、通常薬学的製剤の形態で経口的
または非経口的に投与されうる。薬学的製剤の形態とし
ては、錠剤、カプセル剤、半割、トローチ剤、シロップ
剤、クリーム剤、軟膏剤、貼付剤、ハップ剤、顆粒剤、
散剤、注射剤、懸濁剤等がある。また他の薬剤とともに
二重層錠、多層錠とすることができる。さらに錠剤は、
必要に応じて通常の剤皮を施した錠剤、例えば糖衣錠、
腸溶被錠、フィルムコート錠とすることもできる。The pharmaceutical composition of the present invention can be administered orally or parenterally, usually in the form of a pharmaceutical preparation. Forms of pharmaceutical preparations include tablets, capsules, halves, troches, syrups, creams, ointments, patches, poultices, granules,
There are powders, injections, suspensions, etc. It can also be made into double-layer tablets or multi-layer tablets together with other drugs. Furthermore, the tablets
Tablets with conventional coatings, such as sugar-coated tablets, if necessary.
Enteric-coated tablets and film-coated tablets can also be used.

固体製剤とする場合は、例えば、乳糖、白糖、結晶セル
ロース、トウモロコシデンプン、リン酸カルシウム、ソ
ルビトール、グリシン、カルボキシメチルセルロース、
アラビアゴム、ポリビニルピロリドン、ヒドロキシプロ
ピルセルロース、グリセリン、ポリエチレングリコール
、ステアリン酸、ステアリン酸マグネシウム、タルク等
を添加剤として用いつる。In the case of a solid preparation, for example, lactose, sucrose, crystalline cellulose, corn starch, calcium phosphate, sorbitol, glycine, carboxymethyl cellulose,
Gum arabic, polyvinylpyrrolidone, hydroxypropyl cellulose, glycerin, polyethylene glycol, stearic acid, magnesium stearate, talc, etc. are used as additives.

半固体製剤とする場合は、植物性または合成ロウまたは
脂肪等が用いられる。In the case of semi-solid preparations, vegetable or synthetic waxes or fats are used.

液体製剤とする場合は、例えば、塩化ナトリウム水溶液
、ソルビトール、グリセリン、オリブ油、アーモンド油
、プロピレングリコール、エチルアルコール等を添加剤
として用いうる。When preparing a liquid preparation, for example, an aqueous sodium chloride solution, sorbitol, glycerin, olive oil, almond oil, propylene glycol, ethyl alcohol, etc. can be used as additives.

これらの製剤の成分の量は製剤の０．１〜１００重量％
であり、適当には経口投与のための製剤の場合には１〜
５０重量％であり、そして注射用製剤の場合には０．１
〜１０重量％である。The amount of ingredients in these formulations ranges from 0.1 to 100% by weight of the formulation.
and suitably 1 to 1 in the case of formulations for oral administration.
50% by weight and in the case of injectable formulations 0.1
~10% by weight.

本発明の薬剤の投与方法および投与量にはとくに制限は
なく、各種製剤形態、患者の年齢、性別、疾患の程度な
どにより適宜選択されるが、有効成分の１日あたりの投
与量は１〜１０００ａ＋ｇである。There are no particular restrictions on the administration method or dosage of the drug of the present invention, and it is selected appropriately depending on various formulation forms, patient age, sex, degree of disease, etc., but the daily dosage of the active ingredient is 1 to 1. It is 1000a+g.

本発明の化合物の代表的な例をあげれば次のとおりであ
る。Representative examples of the compounds of the present invention are as follows.

１）Ｎ−（２−ヒドロキシエチル）−６−（４−メチル
−１−ピペラジニル）ニコチンアミド２）Ｎ−（２−ヒ
ドロキシエチル）−６−（１ピペラジニル）ニコチンア
ミド ３）Ｎ−（２−ヒドロキシエチル）−６−（４−ジフェ
ニルメチル−１−ピペラジニル）ニコチンアミド ４）Ｎ−（２−ヒドロキシエチル）−６−（４−エチル
−１−ピペラジニル）ニコチンアミド５）Ｎ−（２−ヒ
ドロキシエチル）−６−（４−シクロベンチルー１−ピ
ペラジニル）ニコチンアミド ６）Ｎ−（２−ヒドロキシエチル）−６−（４−メチル
−１−ホモピペラジニル）ニコチンアミ７）Ｎ−（２−
ヒドロキシエチル）−２−（４−メチル−１−ピペラジ
ニル）ニコチンアミド８）Ｎ−（２−ヒドロキシエチル
）−６−（４−メチル−１−ピペラジニルメチル）ニコ
チンアミ　ド ９）Ｎ−（２−ヒドロキシエチル）−６−（４−ジフェ
ニルメチル−１−ピペラジニルメチル）ニコチンアミド １（１）Ｎ−（３−ヒドロキシプロピル）−６・（４−
メチル−１−ピペラジニル）ニコチンアミド １１）Ｎ−（２−二トロキンエチル）−６−（４−メチ
ル−１−ピペラジニル）ニコチンアミド１２）Ｎ−（２
−ニトロキシエチル）−６−（４−メチル−１−ピペラ
ジニル）ニコチンアミド・２塩酸塩 １３）Ｎ−（２−二トロキシエチル）−６−（４−エチ
ル−１−ピペラジニル）ニコチンアミド・２塩酸塩 １４）Ｎ−（２−二トロキシエチル）−６−（４−メチ
ル−１−ホモピペラジニル）ニコチンアミド・２塩酸塩 １５）Ｎ−（２−二トロキシエチル）−６−（４−メチ
ル−１−ピペラジニルメチル）ニコチンアミ　ド １Ｂ）Ｎ−（２−二トロキシエチル）−６−（４−ジフ
ェニルメチル−１−ピペラジニルメチル）ニコチンアミ
ド １７）Ｎ−（２−二トロキシエチル）−２−（４−メチ
ル−１−ピペラジニル）ニコチンアミド１ｇ）Ｎ−（２
−ニトロキシエチル）−２−（４−メチル−１−ピペラ
ジニル）ニコチンアミド・２塩酸塩 １９）Ｎ−（２−二トロキシエチル）−６−（４−ジフ
ェニルメチル−１−ピペラジニル）ニコチンアミド ２０）Ｎ−（２−ニトロキシエチル）−６−（４−ジフ
ェニルメチル−１−ピペラジニル）ニコチンアミド・２
塩酸塩 ２１）Ｎ−（３−ニトロキシプロピル）−６−（４−メ
チル−１−ピペラジニル）ニコチンアミド ２２）Ｎ−（３−ニトロキシプロピル）−６−（４−メ
チル−１−ピペラジニル）ニコチンアミド・２塩酸塩 ２３）Ｎ−（４−ヒドロキシブチル）−６−（４−メチ
ル−１−ピペラジニル）ニコチンアミド２４）Ｎ−（４
−ニトロキシブチル）−６−（４−メチル−１−ピペラ
ジニル）ニコチンアミド２５）Ｎ−（５−ヒドロキシペ
ンチル）−６−（４−メチル−１−ピペラジニル）ニコ
チンアミド ２６）Ｎ−（６−ヒドロキシヘキシル）−６−（４−メ
チル−１−ピペラジニル）ニコチンアミド ２７）Ｎ−（８−ヒドロキシオクチル）−６−（４−メ
チル−１−ピペラジニル）ニコチンアミド ２８）４−ヒドロキシ−１−（６−（４−メチル−１−
ピペラジニル）ニコチニルコピペリジン２９）Ｎ−（５
−ニトロキシペンチル）−６−（４−メチル−１−ピペ
ラジニル）ニコチンアミド ３０）Ｎ−（６−ニトロキシヘキシル）−６−（４−メ
チル−１−ピペラジニル）ニコチンアミ　ド ３１）Ｎ−（８−ニトロキシオクチル）−６＝（４−メ
チル−１−ピペラジニル）ニコチンアミド ３２）１−　（６−（４−メチル−１−ピペラジニル）
ニコチニル〕　−４−二トロキシピベリジン以下に本発
明を実施例によりさらに説明するが、本発明はこれらに
限定されるものではない。1) N-(2-hydroxyethyl)-6-(4-methyl-1-piperazinyl)nicotinamide 2) N-(2-hydroxyethyl)-6-(1-piperazinyl)nicotinamide 3) N-(2- hydroxyethyl)-6-(4-diphenylmethyl-1-piperazinyl)nicotinamide 4) N-(2-hydroxyethyl)-6-(4-ethyl-1-piperazinyl)nicotinamide 5) N-(2-hydroxy ethyl)-6-(4-cycloben-1-piperazinyl)nicotinamide 6) N-(2-hydroxyethyl)-6-(4-methyl-1-homopiperazinyl)nicotinamide 7) N-(2-
hydroxyethyl)-2-(4-methyl-1-piperazinyl)nicotinamide 8) N-(2-hydroxyethyl)-6-(4-methyl-1-piperazinylmethyl)nicotinamide 9) N-( 2-hydroxyethyl)-6-(4-diphenylmethyl-1-piperazinylmethyl)nicotinamide 1(1)N-(3-hydroxypropyl)-6・(4-
Methyl-1-piperazinyl) nicotinamide 11) N-(2-nitroquinethyl)-6-(4-methyl-1-piperazinyl) nicotinamide 12) N-(2
-Nitroxyethyl)-6-(4-methyl-1-piperazinyl)nicotinamide dihydrochloride 13) N-(2-nitroxyethyl)-6-(4-ethyl-1-piperazinyl)nicotinamide dihydrochloride Salt 14) N-(2-nitroxyethyl)-6-(4-methyl-1-homopiperazinyl)nicotinamide dihydrochloride 15) N-(2-nitroxyethyl)-6-(4-methyl-1-pipe Radinylmethyl) Nicotinamide 1B) N-(2-nitroxyethyl)-6-(4-diphenylmethyl-1-piperazinylmethyl) Nicotinamide 17) N-(2-nitroxyethyl)-2-(4 -Methyl-1-piperazinyl)nicotinamide 1g)N-(2
-Nitroxyethyl)-2-(4-methyl-1-piperazinyl)nicotinamide dihydrochloride 19) N-(2-nitroxyethyl)-6-(4-diphenylmethyl-1-piperazinyl)nicotinamide 20) N-(2-nitroxyethyl)-6-(4-diphenylmethyl-1-piperazinyl)nicotinamide 2
Hydrochloride 21) N-(3-nitroxypropyl)-6-(4-methyl-1-piperazinyl) Nicotinamide 22) N-(3-nitroxypropyl)-6-(4-methyl-1-piperazinyl) Nicotinamide dihydrochloride 23) N-(4-hydroxybutyl)-6-(4-methyl-1-piperazinyl)nicotinamide 24) N-(4
-Nitroxybutyl)-6-(4-methyl-1-piperazinyl)nicotinamide25)N-(5-hydroxypentyl)-6-(4-methyl-1-piperazinyl)nicotinamide26)N-(6- hydroxyhexyl)-6-(4-methyl-1-piperazinyl)nicotinamide 27) N-(8-hydroxyoctyl)-6-(4-methyl-1-piperazinyl)nicotinamide 28) 4-hydroxy-1-( 6-(4-methyl-1-
piperazinyl) nicotinylcopiperidine 29) N-(5
-nitroxypentyl)-6-(4-methyl-1-piperazinyl)nicotinamide 30) N-(6-nitroxyhexyl)-6-(4-methyl-1-piperazinyl)nicotinamide 31) N-( 8-nitroxyoctyl)-6=(4-methyl-1-piperazinyl)nicotinamide 32) 1-(6-(4-methyl-1-piperazinyl)
Nicotinyl]-4-nitroxypiveridine The present invention will be further explained below with reference to Examples, but the present invention is not limited thereto.

（実　施　例〕 実施例　Ｉ Ｎ−（２−ヒドロキシエチル）−６−（４−メチル−１
−ピペラジニル）ニコチンアミド（化合物１）の製造 ６−　（４−メチル−１−ピペラジニル）ニコチン酸メ
チル（ｎ）３．２９ｇ、２−アミノエタノール（Ｉ［Ｉ
）　２．０２ｇ−及び２−ヒドロキシピリジン１．００
ｇの混合物を１２０〜１３０℃に加熱し、７時間撹拌す
る。(Example) Example I N-(2-hydroxyethyl)-6-(4-methyl-1
-Piperazinyl)nicotinamide (Compound 1) 6- 3.29 g of methyl (4-methyl-1-piperazinyl)nicotinate (n), 2-aminoethanol (I[I
) 2.02g- and 2-hydroxypyridine 1.00
The mixture of g is heated to 120-130°C and stirred for 7 hours.

この混合物をカラムクロマトグラフィー（シリカゲル；
クロロホルム：メタノール−５：　１）により精製し、
Ｎ−（２−ヒドロキシエチル）６−　（４−メチル−１
−ピペラジニル）ニコチンアミド３．０２ｇ　（９４％
）を得た。This mixture was subjected to column chromatography (silica gel;
Purified by chloroform:methanol-5:1),
N-(2-hydroxyethyl)6-(4-methyl-1
-piperazinyl) nicotinamide 3.02g (94%
) was obtained.

実施例　２〜１０ 上記の６−　（４−メチル−１−ピペラジニル）ニコチ
ン酸メチルの代わりに６−　（１−ピペラジニル）ニコ
チン酸メチル、６−（４−ジフェニルメチル−１−ピペ
ラジニル）ニコチン酸メチル、６−　（４−エチル−１
−ピペラジニル）ニコチン酸メチル、６−（４−シクロ
ペンチル−１−ピペラジニル）ニコチン酸メチル、６−
　（４−メチル−１−ホモピペラジニル）ニコチン酸メ
チル、２−　（４−メチル−１−ピペラジニル）ニコチ
ン酸メチル、６−（４−メチル−１−ピペラジニルメチ
ル）ニコチン酸メチル、６−　（４−ジフェニルメチル
−１−ピペラジニルメチル）ニコチン酸メチルを用いて
、同様にして各々Ｎ−（２−ヒドロキシエチル）−６−
（１−ピペラジニル）ニコチンアミド（化合物２）、Ｎ
−（２−ヒドロキシエチル）−６−（４−ジフェニルメ
チル−１−ピペラジニル）ニコチンアミド（化合物３）
、Ｎ−（２−ヒドロキシエチル）−６−（４−エチル１
−ピペラジニル）ニコチンアミド（化合物４）、Ｎ−（
２−ヒドロキシエチル）−６−（４−シクロペンチル−
１−ピペラジニル）ニコチンアミド（化合物５）、Ｎ−
（２−ヒドロキシエチル）６−　（４−メチル−１−ホ
モピペラジニル）ニコチンアミド（化合物６）、Ｎ−（
２−ヒドロキシエチル）−２−（４−メチル−１−ピペ
ラジニル）ニコチンアミド（化合物７）、Ｎ−（２−ヒ
ドロキシエチル）−６−（４−メチル−１−ピペラジニ
ルメチル）ニコチンアミド（化合物８）、Ｎ−（２−ヒ
ドロキシエチル）−６−（４−ジフェニルメチル−１−
ピペラジニルメチル）ニコチンアミド（化合物９）を合
成した。また、上記の２−アミノエタノールの代わりに
３−アミノプロパツールを用いて同様にしてＦＪ−（３
−ヒドロキシプロピル）−６−（４−メチル−１−ピペ
ラジニル）ニコチンアミド（化合物１０）を合成した。Examples 2 to 10 Methyl 6-(1-piperazinyl)nicotinate, methyl 6-(4-diphenylmethyl-1-piperazinyl)nicotinate in place of the above methyl 6-(4-methyl-1-piperazinyl)nicotinate ,6-(4-ethyl-1
-piperazinyl) methyl nicotinate, 6-(4-cyclopentyl-1-piperazinyl) methyl nicotinate, 6-
(4-Methyl-1-homopiperazinyl)methyl nicotinate, 2-(4-methyl-1-piperazinyl)methyl nicotinate, 6-(4-methyl-1-piperazinylmethyl)methyl nicotinate, 6- (4-methyl-1-piperazinylmethyl)methyl nicotinate, -diphenylmethyl-1-piperazinylmethyl) methyl nicotinate, respectively N-(2-hydroxyethyl)-6-
(1-piperazinyl)nicotinamide (compound 2), N
-(2-hydroxyethyl)-6-(4-diphenylmethyl-1-piperazinyl)nicotinamide (compound 3)
, N-(2-hydroxyethyl)-6-(4-ethyl 1
-piperazinyl) nicotinamide (compound 4), N-(
2-hydroxyethyl)-6-(4-cyclopentyl-
1-piperazinyl) nicotinamide (compound 5), N-
(2-hydroxyethyl)6-(4-methyl-1-homopiperazinyl)nicotinamide (compound 6), N-(
2-hydroxyethyl)-2-(4-methyl-1-piperazinyl)nicotinamide (compound 7), N-(2-hydroxyethyl)-6-(4-methyl-1-piperazinylmethyl)nicotinamide ( Compound 8), N-(2-hydroxyethyl)-6-(4-diphenylmethyl-1-
Piperazinylmethyl)nicotinamide (Compound 9) was synthesized. Further, in the same manner, FJ-(3
-hydroxypropyl)-6-(4-methyl-1-piperazinyl)nicotinamide (Compound 10) was synthesized.

実施例　１１〜１２ Ｎ−（２−ニトロキシエチル）−６−（４−メチル−１
−ピペラジニル）ニコチンアミド（化合物１１）及びそ
の２塩酸塩（化合物１２）の製造実施例１で得られた化
合物１１．００ｇを塩化メチレン２０ｍ１に溶解し氷冷
する。撹拌しなから０℃以下で発煙硝酸５ｍｌを滴下し
、２時間撹拌する。これを炭酸水素ナトリウム水溶液に
あけ塩化メチレンで抽出した後、水洗（２回）飽和食塩
水洗（１回）の後無水硫酸マグネシウムで乾燥し濃縮す
ることにより、Ｎ−（２−二トロキシエチル）−６−（
４−メチル−１−ピペラジニル）ニコチンアミドを得た
。これをエタノールに溶かし、水冷下塩化水素飽和エタ
ノールを加えて塩酸塩とし、エタノールから再結晶して
Ｎ−（２−ニトロキシエチル）−６−（４−メチル−１
−ピペラジニル）ニコチンアミド・２塩酸塩０．５４ｇ
　（３４％）を得た。Examples 11-12 N-(2-nitroxyethyl)-6-(4-methyl-1
-Piperazinyl)nicotinamide (Compound 11) and its dihydrochloride (Compound 12) 11.00 g of the compound obtained in Example 1 was dissolved in 20 ml of methylene chloride and cooled on ice. While stirring, 5 ml of fuming nitric acid is added dropwise at below 0°C, and the mixture is stirred for 2 hours. This was poured into an aqueous solution of sodium hydrogen carbonate, extracted with methylene chloride, washed with water (twice), washed with saturated saline (once), dried over anhydrous magnesium sulfate, and concentrated to obtain N-(2-nitroxyethyl)-6. −(
4-Methyl-1-piperazinyl) nicotinamide was obtained. Dissolve this in ethanol, add hydrogen chloride saturated ethanol under water cooling to obtain a hydrochloride salt, recrystallize from ethanol, and N-(2-nitroxyethyl)-6-(4-methyl-1
-piperazinyl) nicotinamide dihydrochloride 0.54g
(34%).

実施例　１３〜１Ｂ 化合物１の代わりに化合物４．　６．　８．　９を用い
て同様にしてＮ−（２−ニトロキシエチル）６−　（４
−エチル−１−ピペラジニル）ニコチンアミド・２塩酸
塩（化合物１３）、Ｎ−（２−ニトロキシエチル）−６
−（４−メチル−１−ホモピペラジニル）ニコチンアミ
ド・２塩酸塩（化合物１４）、Ｎ−（２−ニトロキシエ
チル）−６−（４−メチル−１−ピペラジニルメチル）
ニコチンアミド（化合物１５）、Ｎ−（２−ニトロキシ
エチル）−６−（４−ジフェニルメチル−１−ピペラジ
ニルメチル）ニコチンアミド（化合物１Ｂ）を合成した
。Examples 13-1B Compound 4. in place of Compound 1. 6. 8. Similarly, N-(2-nitroxyethyl)6-(4
-ethyl-1-piperazinyl) nicotinamide dihydrochloride (compound 13), N-(2-nitroxyethyl)-6
-(4-Methyl-1-homopiperazinyl)nicotinamide dihydrochloride (compound 14), N-(2-nitroxyethyl)-6-(4-methyl-1-piperazinylmethyl)
Nicotinamide (Compound 15) and N-(2-nitroxyethyl)-6-(4-diphenylmethyl-1-piperazinylmethyl)nicotinamide (Compound 1B) were synthesized.

実施例　１７〜１８ Ｎ−（２−ニトロキシエチル）−２−（４−メチル−１
−ピペラジニル）ニコチンアミド（化合物１７）及びそ
の２塩酸塩（化合物１８）の製造 実施例２〜１０で得られた化合物７　１．２７ｇをアセ
トニトリル１３ｍ１に溶解し一１０℃以下で発煙硝酸２
、Ｏｇと無水酢酸１．４ｇの混液を滴下し、４時間撹拌
する。これを炭酸水素ナトリウム水溶液にあけ塩化メチ
レンで抽出した後、水洗（２回）飽和食塩水洗（１回）
の後無水硫酸マグネシウムで乾燥し濃縮することにより
、Ｎ−（２−ニトロキシエチル）−２−（４−メチル−
１−ピペラジニル）ニコチンアミド（化合物１７）を得
た。これをエタノールに溶かし、水冷上塩化水素飽和エ
タノールを加えて塩酸塩とし、エタノールから再結晶し
てＮ−（２−二トロキシエチル）−２−（４−メチル−
１−ピペラジニル）ニコチンアミド・２塩酸塩（化合物
１８）　１．３２ｇ　（６８％）を得た。Examples 17-18 N-(2-nitroxyethyl)-2-(4-methyl-1
-piperazinyl) nicotinamide (compound 17) and its dihydrochloride (compound 18) 1.27 g of compound 7 obtained in Examples 2 to 10 was dissolved in 13 ml of acetonitrile and heated to -10°C or below with fuming nitric acid 2.
, Og and 1.4 g of acetic anhydride were added dropwise, and the mixture was stirred for 4 hours. After pouring this into an aqueous sodium hydrogen carbonate solution and extracting with methylene chloride, washing with water (twice) and saturated salt water (once)
Then, by drying with anhydrous magnesium sulfate and concentrating, N-(2-nitroxyethyl)-2-(4-methyl-
1-piperazinyl) nicotinamide (compound 17) was obtained. Dissolve this in ethanol, add hydrogen chloride saturated ethanol over water to obtain a hydrochloride salt, recrystallize from ethanol and N-(2-nitroxyethyl)-2-(4-methyl-
1.32 g (68%) of nicotinamide (1-piperazinyl) dihydrochloride (compound 18) was obtained.

実施例　１９〜２２ 上記の代わりに化合物３，１０を用いて同様にしてＮ−
（２−ニトロキシエチル）−６−（４−ジフェニルメチ
ル−１−ピペラジニル）ニコチンアミド（化合物１９）
及びその２塩酸塩（化合物２０）、Ｎ−（３−ニトロキ
シプロピル）−６−（４−メチル−１−ピペラジニル）
ニコチンアミド（化合物２１）及びその２塩酸塩（化合
物２２）を合成した。Examples 19-22 N-
(2-Nitroxyethyl)-6-(4-diphenylmethyl-1-piperazinyl)nicotinamide (Compound 19)
and its dihydrochloride (compound 20), N-(3-nitroxypropyl)-6-(4-methyl-1-piperazinyl)
Nicotinamide (Compound 21) and its dihydrochloride (Compound 22) were synthesized.

実施例　２３ Ｎ−（４−ヒドロキシブチル）−６−（４−メチル−１
−ピペラジニル）ニコチンアミド（化合物２３）の製造 ２−アミノエタノールの代わりに４−アミノブタノール
を用いた以外には実施例１と同様な方法を繰り返してＮ
−（４−ヒドロキシブチル）６−　（４−メチル−１−
ピペラジニル）ニコチンアミドを得た。Example 23 N-(4-hydroxybutyl)-6-(4-methyl-1
-Piperazinyl) Nicotinamide (Compound 23) The same method as in Example 1 was repeated except that 4-aminobutanol was used instead of 2-aminoethanol.
-(4-hydroxybutyl)6- (4-methyl-1-
piperazinyl) nicotinamide was obtained.

実施例　２４ 実施例２３で得られた化合物を実施例１７と同様にして
エステル化してＮ−（４−ニトロキシブチル）−６−（
４−メチル−１−ピペラジニル）ニコチンアミド（化合
物２４）を得た。Example 24 The compound obtained in Example 23 was esterified in the same manner as in Example 17 to give N-(4-nitroxybutyl)-6-(
4-Methyl-1-piperazinyl)nicotinamide (compound 24) was obtained.

実施例　２５ Ｎ−（５−ヒドロキシペンチル）−６−（４メチル−１
−ピペラジニル）ニコチンアミド（化合物２５）の製造 ６−クロロニコチン酸７．８８Ｋに、塩化チオニル７．
３ｍｌおよびＤＭＦ数滴を加え、この混合物を２時間加
熱還流した後過剰の塩化チオニルを留去して６−クロロ
ニコチン酸クロライドの結晶を得た。この結晶をテトラ
ヒドロフラン６０ｍ１に溶解し、この溶液をテトラヒド
ロフラン２００ｍ１中の５−アミノペンタノール１５．
４７ｉの溶液に０℃以下で滴下し、室温まで徐々に昇温
しながら一晩撹拌した。Example 25 N-(5-hydroxypentyl)-6-(4methyl-1
-Piperazinyl) Nicotinamide (Compound 25) 6-Chloronicotinic acid 7.88K was added to thionyl chloride 7.
3 ml and several drops of DMF were added, and the mixture was heated under reflux for 2 hours, and then excess thionyl chloride was distilled off to obtain crystals of 6-chloronicotinic acid chloride. The crystals were dissolved in 60 ml of tetrahydrofuran and the solution was dissolved in 15.0 ml of 5-aminopentanol in 200 ml of tetrahydrofuran.
The mixture was added dropwise to a solution of 47i at 0° C. or below, and stirred overnight while gradually heating up to room temperature.

溶媒を留去して残留物に水を加え酢酸エチルで抽出した
。次いで抽出物を水および飽和食塩水で洗浄し、無水硫
酸マグネシウムで乾燥した後溶媒を留去した。得られた
残渣を酢酸エチルより再結晶させて１１．２４＋ｒ　（
９３％）のＮ−（５−ヒドロキシペンチル）−６−クロ
ロニコチンアミドを得た。The solvent was distilled off, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was then washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The obtained residue was recrystallized from ethyl acetate to give 11.24+r (
93%) of N-(5-hydroxypentyl)-6-chloronicotinamide was obtained.

このようにして得られたアミド４．１３ｇ、１−メチル
ビペラジン８．５１ｇおよびジイソプロピルアン１．７
２．をｐ−キシレンｌ１０ｍ１に溶解し、この溶液に触
媒量のＮａｌを加え、混合物を１２０〜１３０℃に加熱
し４時間撹拌した。この反応混合物を水に注ぎ、クロロ
ホルムで抽出した。抽出物を水および飽和食塩水で洗浄
した後無水硫酸マグネシウムで乾燥し濃縮した。濃縮物
をカラムクロマトグラフィー（シリカゲル、クロロホル
ム：メタノール−４：１）により精製して４．８５ｇ　
（８９％）のＮ−（５−ヒドロキシペンチル）−６−（
４−メチル−１−ピペラジニル）ニコチンアミドを得た
。4.13 g of the amide thus obtained, 8.51 g of 1-methylbiperazine and 1.7 g of diisopropylune.
2. was dissolved in 10 ml of p-xylene, a catalytic amount of Nal was added to this solution, and the mixture was heated to 120-130° C. and stirred for 4 hours. The reaction mixture was poured into water and extracted with chloroform. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The concentrate was purified by column chromatography (silica gel, chloroform:methanol-4:1) to give 4.85 g.
(89%) of N-(5-hydroxypentyl)-6-(
4-Methyl-1-piperazinyl) nicotinamide was obtained.

実施例　２６〜２８ 実施例２５で用いた５−アミノペンタノールの代わりに
それぞれ６−アミノヘキサノール、８−アミノオクタツ
ールおよび４−ヒドロキシピペリジンを用いた以外には
実施例２５と同様にしてそれぞれＮ−（６−ヒドロキシ
ヘキシル）−６−（４−メチル−１−ピペラジニル）ニ
コチンアミド（化合物２Ｂ）、Ｎ−（８−ヒドロキンオ
クチル）６−　（４−メチル−１−ピペラジニル）ニコ
チンアミド（化合物２７）および４−ヒドロキシ−１（
６−（４−メチル−１−ピペラジニル）ニコチニルコピ
ペリジン（化合物２８）を得た。Examples 26 to 28 Each of the N -(6-hydroxyhexyl)-6-(4-methyl-1-piperazinyl)nicotinamide (compound 2B), N-(8-hydroquinoctyl)6-(4-methyl-1-piperazinyl)nicotinamide (compound 27) and 4-hydroxy-1 (
6-(4-Methyl-1-piperazinyl)nicotinylcopiperidine (Compound 28) was obtained.

実施例　２９〜３２ 実施例２６〜２８で得られた化合物を実施例１７と同様
にしてエステル化してそれぞれＮ−（５−ニトロキシペ
ンチル）−６−（４−メチル−１−ピペラジニル）ニコ
チンアミド（化合物２９）　、Ｎ　−（６−ニトロキシ
ヘキシル）−６−（４−メチル−１−ピペラジニル）ニ
コチンアミド（化合物３０）、Ｎ−（８−ニトロキシオ
クチル）−６−（４−メチル−１−ピペラジニル）ニコ
チンアミド（化合物３１）および１−（６−（４−メチ
ル−１−ピペラジニル）ニコチニル〕　−４−ニトロキ
ンピペリジン（化合物３２）を得た。Examples 29-32 The compounds obtained in Examples 26-28 were esterified in the same manner as in Example 17 to obtain N-(5-nitroxypentyl)-6-(4-methyl-1-piperazinyl)nicotinamide, respectively. (Compound 29), N-(6-nitroxyhexyl)-6-(4-methyl-1-piperazinyl)nicotinamide (Compound 30), N-(8-nitroxyoctyl)-6-(4-methyl- 1-Piperazinyl)nicotinamide (Compound 31) and 1-(6-(4-methyl-1-piperazinyl)nicotinyl]-4-nitroquinepiperidine (Compound 32) were obtained.

次の表１は上記のようにして製造した化合物１〜化合物
３２についてその化学構造、収率および諸物性を表にし
て示したものである。The following Table 1 shows the chemical structures, yields, and various physical properties of Compounds 1 to 32 produced as described above.

本発明の代表的な化合物の血流増加作用および血圧低下
作用を、以下の方法により評価した。The blood flow increasing effect and blood pressure lowering effect of representative compounds of the present invention were evaluated by the following method.

（実験方法） ベンドパルビタールで麻酔をかけた大の右椎骨動脈血流
、右椎骨動脈血流、左大腿動脈血流を非観血的に電磁血
流計にてｐ１定した。大腿動脈平均血圧を圧トランスデ
ユーサにて測定した。供試化合物は生理食塩水に溶解し
て１ｍｇ／ｋｇを静脈内へ投与した。試験結果は供試化
合物投与後の変化を投与前の値に対する百分率であられ
した。(Experimental Method) Blood flow in the right vertebral artery, right vertebral artery, and left femoral artery were non-invasively determined using an electromagnetic blood flow meter. Femoral artery mean blood pressure was measured using a pressure transducer. The test compound was dissolved in physiological saline and administered intravenously at 1 mg/kg. The test results were expressed as a percentage of the change after administration of the test compound relative to the value before administration.

その測定結果を以下の表２に示す。The measurement results are shown in Table 2 below.

表 ＋１０ ＋１３７ ＋１５８ ＋６９ ＋５６ ＋３６ ＋１４０ ＋８０ ＋１０６ ＋９７ ＋４１ ＋５５ ＋５０ ＋１８ 十　　９ ＋　１１ ＋３０ ＋５０ ＋１１３ ＋１００ ＋８０ ＋９５ ＋２２ ＋４６ ＋２ ＋９７ １０ １６ ０ ２ １２ １７ ２５ ３７ 次に本発明の製剤例を示す。table +10 +137 +158 +69 +56 +36 +140 +80 +106 +97 +41 +55 +50 +18 Ten 9 +11 +30 +50 +113 +100 +80 +95 +22 +46 +2 +97 10 16 0 2 12 17 25 37 Next, examples of formulations of the present invention will be shown.

製剤例　１　　錠　剤（１錠） Ｎ−（２−ニトロキシエチル） ６−　（４−メチル−１−ピペラジ ニル）ニコチンアミド ０ｍｇ 乳　　　糖 結晶セルロース トウモロコシデンプン ステアリン酸マグネシウム ７ｆｆ１ｇ ５ｍｇ ｍｇ ｍｇ ００ｍｇ 各成分を均一に混合し直打用粉末とする。これをロータ
リー式打錠機で直径６１！ｌｌ１１重ｆｆ１１００ｍｇ
の錠剤に成型する。Formulation example 1 Tablet (1 tablet) N-(2-nitroxyethyl) 6-(4-methyl-1-piperazinyl)nicotinamide 0 mg Lactose crystalline cellulose corn starch Magnesium stearate 7ff 1 g 5 mg mg mg 00 mg Uniformly distribute each ingredient Mix it to make a powder for direct application. This was made using a rotary tablet press with a diameter of 61 mm! ll11 heavy ff1100mg
Form into tablets.

製剤例　２　　顆粒剤（１分包） Ｎ−（２−二トロキシエチル） Ａの成分を均一に混合した後、Ｂの溶液を加えて練合し
、押出造粒法で整粒し、次いで５０℃の乾燥機で乾燥す
る。乾燥上がり顆粒を粒度２９７間〜１４６０μｓにふ
るい分けたものを顆粒剤とする。１分包量を２００ｍｇ
とする。Formulation Example 2 Granules (1 sachet) N-(2-nitroxyethyl) After uniformly mixing the components of A, the solution of B was added and kneaded, the particles were sized by extrusion granulation, and then heated at 50°C. Dry in a dryer. The dried granules are sieved to a particle size of 297 to 1460 μs and used as granules. 1 sachet amount is 200mg
shall be.

製剤例　３ シロップ剤 Ｎ−（２−ニトロキシエチル） ６−　（４−メチル−１−ピペラジ ニル）ニコチンアミド Ｌ、０００ｇ 白　　　　　糖　　　　　　　　　　　　　　　　　　
３０．０００ｇＤ−ソルビトール７０ｗ／ｖ％２５．０
００ｇバラオキシ安息香酸エチル　　　　０．０３０ｇ
バラオキシ安息香酸プロピル　　　０．０１５ｇ香　　
　味　　　料　　　　　　　　　　　　　０．２００ｇ
グ　リ　セ　リ　　ン　　　　　　　　　　　　　　　
　　　Ｏ，１５０ｇ９Ｇ％−１−９　／　−）Ｉｉ　　
　　　　　　　　　０．５００ｇ蒸　　　溜　　　水　
　　　　　　　　　　　適　　　量白糖、Ｄ−ソルビト
ール、パラオキシ安息香酸メチル、パラオキシ安息香酸
メチルおよび上記の有効成分を温水６０ｇに溶解する。Formulation example 3 Syrup N-(2-nitroxyethyl) 6-(4-methyl-1-piperazinyl)nicotinamide L, 000g White sugar
30.000gD-Sorbitol 70w/v%25.0
00g rose ethyl oxybenzoate 0.030g
Propyl roseoxybenzoate 0.015g scent
Flavoring 0.200g
Glycerin
O, 150g9G%-1-9/-)Ii
0.500g distilled water
Appropriate amounts of white sugar, D-sorbitol, methyl paraoxybenzoate, methyl paraoxybenzoate, and the above active ingredients are dissolved in 60 g of warm water.

冷却後グリセリンおよびエタノールに溶解した香味料の
溶液を加える。つぎにこの混合物に水を加えて１００ｍ
１にする。After cooling, a solution of flavoring dissolved in glycerin and ethanol is added. Next, add water to this mixture and add 100 m
Set it to 1.

製剤例　４　　注射液 Ｎ−（２−ニトロキシエチル） ６−　（４−メチル−１−ピペラジ　　１ｍｇニル）ニ
コチンアミド 塩化ナトリウム　　　　　　　　ｌｏｍｇ蒸　　　溜　
　　水　　　　　　　　　　　　適量全量　１．０ｍｌ 塩化ナトリウムおよび有効成分を蒸溜水を加えて溶解し
、全量を１．Ｏｍｌとする。Formulation Example 4 Injection N-(2-nitroxyethyl) 6-(4-methyl-1-piperazide 1mg nyl)nicotinamide sodium chloride lomg distillation
Water Appropriate amount total volume 1.0ml Add distilled water to dissolve sodium chloride and the active ingredient, and add the total volume to 1.0ml. Let it be Oml.

製剤例　５　　坐　剤 Ｎ−（２−ニトロキシエチル） ６−　（４−メチル−１−ピペラジ　　　２ｇニル）ニ
コチンアミド ポリエチレングリコール４０００　　　　　２０　ｇグ
　　リ　　セ　　リ　　ン　　　　　　　　　　　　　
　　　　　７８ｇ全量ＩＱＯｇ グリセリンを有効成分に加えて溶解する。そこへ、ポリ
エチレングリコール４０００を加えて加温し溶解後、半
割型に注入して冷却固化し、１個当たり１．５ｇの串刺
を製造する。Formulation example 5 Suppository N-(2-nitroxyethyl) 6-(4-methyl-1-piperazine 2g nyl)nicotinamide polyethylene glycol 4000 20g glycerin
78g total amount IQOg Add glycerin to the active ingredients and dissolve. Polyethylene glycol 4000 is added thereto, heated and dissolved, poured into half-split molds, cooled and solidified to produce skewers weighing 1.5 g each.

Claims (1)

【特許請求の範囲】 次の一般式（ I ） ▲数式、化学式、表等があります▼（ I ） （式中、Ｒ＿１は水素、Ｃ＿１〜Ｃ＿６アルキル、Ｃ＿
３〜Ｃ＿６シクロアルキルまたはジフェニルメチルであ
り、 Ｙは−ＮＨ（ＣＨ＿２）＿ｎ−Ｒ＿２または▲数式、化
学式、表等があります▼であり、Ｒ＿２はＯＨまたは−
ＯＮＯ＿２であり、 ｌは２または３であり、ｍは０または１であり、ｎは２
〜８である） で表わされるピリジンカルボン酸アミド化合物およびそ
の生理学的に許容し得る酸付加塩。[Claims] The following general formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R_1 is hydrogen, C_1 to C_6 alkyl, C_
3~C_6 cycloalkyl or diphenylmethyl, Y is -NH(CH_2)_n-R_2 or ▲Numerical formula, chemical formula, table, etc. are available▼, and R_2 is OH or -
ONO_2, l is 2 or 3, m is 0 or 1, n is 2
~8) A pyridinecarboxylic acid amide compound and a physiologically acceptable acid addition salt thereof.
JP2027202A 1989-03-01 1990-02-08 Pyridinecarboxamide derivatives Expired - Fee Related JP2843632B2 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US07/483,532 US4994456A (en) 1989-03-01 1990-02-22 Pyridinecarboxylic acid amide derivatives and pharmaceutical compositions comprising same
EP90103703A EP0385350B1 (en) 1989-03-01 1990-02-26 Pyridinecarboxylic acid amide derivatives and pharmaceutical compositions comprising same
DE69014351T DE69014351T2 (en) 1989-03-01 1990-02-26 Pyridinecarboxamide derivatives and pharmaceutical compositions containing them.
KR1019900002605A KR0130758B1 (en) 1989-03-01 1990-02-28 Pyridinecarboxylic acid amide derivatives and pharmaceutical compositions comprising same

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP1-46648 1989-03-01
JP4664889 1989-03-01

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CA (1) CA2011143C (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998022439A1 (en) * 1996-11-19 1998-05-28 Nisshin Flour Milling Co., Ltd. Novel pyridinecarboxamide derivatives
JP2001521025A (en) * 1997-10-27 2001-11-06 ニューロサーチ、アクティーゼルスカブ Heteroaryldiazacycloalkanes as cholinergic ligands at the nicotinic acetylcholine receptor
JP5841529B2 (en) * 2010-05-27 2016-01-13 あすか製薬株式会社 Heterocyclic compounds and H1 receptor antagonists

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998022439A1 (en) * 1996-11-19 1998-05-28 Nisshin Flour Milling Co., Ltd. Novel pyridinecarboxamide derivatives
WO1998022440A1 (en) * 1996-11-19 1998-05-28 Nisshin Flour Milling Co., Ltd. Pyridinecarboxamide derivatives
US5972943A (en) * 1996-11-19 1999-10-26 Nisshin Flour Milling Co., Ltd. Pyridinecarboxamide derivatives
US6046201A (en) * 1996-11-19 2000-04-04 Nisshin Flour Milling Co., Ltd. Pyridinecarboxamide derivatives
JP2001521025A (en) * 1997-10-27 2001-11-06 ニューロサーチ、アクティーゼルスカブ Heteroaryldiazacycloalkanes as cholinergic ligands at the nicotinic acetylcholine receptor
JP5841529B2 (en) * 2010-05-27 2016-01-13 あすか製薬株式会社 Heterocyclic compounds and H1 receptor antagonists

Also Published As

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KR900014360A (en) 1990-10-23
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CA2011143C (en) 1999-02-23
KR0130758B1 (en) 1998-04-09

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