JPS62226970A - Production of isomelamine derivative and cardiotonic agent - Google Patents
Production of isomelamine derivative and cardiotonic agentInfo
- Publication number
- JPS62226970A JPS62226970A JP7166386A JP7166386A JPS62226970A JP S62226970 A JPS62226970 A JP S62226970A JP 7166386 A JP7166386 A JP 7166386A JP 7166386 A JP7166386 A JP 7166386A JP S62226970 A JPS62226970 A JP S62226970A
- Authority
- JP
- Japan
- Prior art keywords
- isomelamine
- formula
- derivative
- group
- compound
- 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.)
- Pending
Links
- JDSHMPZPIAZGSV-UHFFFAOYSA-N melamine Chemical class NC1=NC(N)=NC(N)=N1 JDSHMPZPIAZGSV-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 239000000496 cardiotonic agent Substances 0.000 title claims abstract description 11
- 238000004519 manufacturing process Methods 0.000 title claims description 10
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims abstract description 14
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 claims abstract description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 9
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 5
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 4
- 125000003118 aryl group Chemical group 0.000 claims abstract description 4
- 239000000126 substance Substances 0.000 claims description 9
- 239000004480 active ingredient Substances 0.000 claims description 8
- 239000012454 non-polar solvent Substances 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 abstract description 40
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 abstract description 36
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 abstract description 10
- 150000003141 primary amines Chemical class 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 3
- 239000002798 polar solvent Substances 0.000 abstract 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 26
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- 238000006243 chemical reaction Methods 0.000 description 13
- -1 alkyl cyanamide Chemical compound 0.000 description 12
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- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 7
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- 229960002105 amrinone Drugs 0.000 description 6
- SXDBWCPKPHAZSM-UHFFFAOYSA-M bromate Inorganic materials [O-]Br(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-M 0.000 description 6
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Substances [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 5
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- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 4
- NJPQVIOFDBFZGX-UHFFFAOYSA-N bromic acid;ethanamine Chemical compound CCN.OBr(=O)=O NJPQVIOFDBFZGX-UHFFFAOYSA-N 0.000 description 4
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- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 4
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明はイソメラミン誘導体の製造方法、並びにイソメ
ラミン誘導体を有効成分とする強心剤に関する。DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a method for producing an isomelamine derivative, and a cardiotonic agent containing an isomelamine derivative as an active ingredient.
イソメラミンは、今まで高価な出発原料、多段階にわた
る反応を必要とし、また低収率であり、工業的に製造す
ることが困難であった。イソメラミンの合成は、186
9年A、W、ホフマンによって最初に手掛けられた。(
Chem、 Ber、 2.600゜1869)Lかし
この文献においては、イソメラミンの構造が解明されて
いなかった。次いで1885年A、W、ホフマンはこの
物質に関する研究上で前述の文献の方法により合成した
物質はイソメラミン誘導体であることを解明した。(C
hem、 Ber。Until now, isomelamine has required expensive starting materials, multi-step reactions, and had a low yield, making it difficult to produce industrially. Synthesis of isomelamine is 186
It was first created in 1999 by A.W. Hoffman. (
Chem, Ber, 2.600°1869) However, in this document, the structure of isomelamine was not elucidated. Then, in 1885, A. W. Hoffmann conducted research on this substance and discovered that the substance synthesized by the method described in the above-mentioned literature was an isomelamine derivative. (C
hem, Ber.
18.2207.1885)その後、イソメラミン誘導
体は1896年M、 Frouid等によって(Che
m、 Ber、 29. 2499 、 1896 )
、1908年Pa1azzo等によって(Gazze
tta ChimicaHa]1ana、 38. 6
77. 1908)合成されているが、いずれも多段階
の反応と高価な出発原料を必要とするものであった。18.2207.1885) Subsequently, isomelamine derivatives were developed in 1896 by M. Frouid et al.
m, Ber, 29. 2499, 1896)
, 1908 by Pa1azzo et al. (Gazze
tta ChimicaHa] 1ana, 38. 6
77. 1908), but all required multi-step reactions and expensive starting materials.
また1983年、チバ・ガイギー社は特開昭58−15
7773においてN−シアノ−N(メタ)アルキルシア
ナミドを中間体として多段階の反応を必要とする製造方
法を開示しているが、より経済的で工業化に適した方法
が望まれていた。Also, in 1983, Ciba-Geigy Co., Ltd.
No. 7773 discloses a production method that requires a multi-step reaction using N-cyano-N(meth)alkyl cyanamide as an intermediate, but a more economical method suitable for industrialization has been desired.
これまで強心剤としては、ジギタリス等の強心配糖体、
キサンチン誘導体、アムリノン、アドレナリン等が使用
されて来たが、イソメラミン誘導体の医薬的効果につい
ては全く発見されていなかった。Until now, cardiac glycosides such as digitalis,
Although xanthine derivatives, amrinone, adrenaline, etc. have been used, no medicinal effects of isomelamine derivatives have been discovered.
本発明の目的は、安価に人手できる市販の臭化シアン〔
式(II)〕および第一級アミン〔式(■)]を出発原
料とし、■工程にて、簡単な後処理をすることでイソメ
ラミン誘導体〔式(■)〕を高収率(80%)で容易に
製造する方法を提供することにある。The object of the present invention is to use commercially available cyanogen bromide that can be done manually at low cost.
Formula (II)] and primary amine [Formula (■)] are used as starting materials, and by simple post-treatment in Step (2), isomelamine derivative [Formula (■)] can be obtained in high yield (80%). The purpose is to provide an easy manufacturing method.
また本発明の目的は、イソメラミン誘導体を有効成分と
する強心剤を提供することにある。Another object of the present invention is to provide a cardiotonic agent containing an isomelamine derivative as an active ingredient.
本発明は次式(I)及び(II)
:R−NH2(I)
BrCN (T1.)
(但し式(I)のRは低級アルキル基、アリル基、アリ
ール基、又はアラルキル基を表す。)を無水無極性溶媒
中で反応せし給ることによって次式(■):
H
(但し式(Jlll)のRは式(I)のRと同じ。)で
表されるイソメラミン誘導体を製造する方法からなる。The present invention relates to the following formulas (I) and (II): R-NH2(I) BrCN (T1.) (However, R in formula (I) represents a lower alkyl group, an allyl group, an aryl group, or an aralkyl group.) A method for producing an isomelamine derivative represented by the following formula (■): H (wherein R in formula (Jlll) is the same as R in formula (I)) by reacting in an anhydrous nonpolar solvent. Consisting of
また本発明は次式(IV):
H
]1
(但しRはエチル基又はアリル基を表す。)で表される
イソメラミン誘導体を有効成分とする強心剤からなる。The present invention also comprises a cardiotonic agent containing as an active ingredient an isomelamine derivative represented by the following formula (IV): H ]1 (wherein R represents an ethyl group or an allyl group).
本発明のイソメラミン誘導体の製造方法において、第1
級アミン〔式(I)〕の低級アルキル基は直釦若しくは
分枝、又は置換アルキル基であることができる。そのよ
うなアルキル基の例としては、メチル基、エチル基、n
−プロピル基、n−ブチル基、イソブチル基等があり、
置換基の例としては、シアノ基ならびに1ないし4個の
炭素原子を有するアルコキシ基、特にエトキシ基等があ
る。アリール基はフェニル基等ベンゼン誘導体を意味し
、アラルキル基はベンジル基、フェネチル基等を意味す
る。In the method for producing isomelamine derivatives of the present invention, the first
The lower alkyl group of the secondary amine [formula (I)] can be a straight or branched or substituted alkyl group. Examples of such alkyl groups include methyl, ethyl, n
-Propyl group, n-butyl group, isobutyl group, etc.
Examples of substituents include cyano groups and alkoxy groups having 1 to 4 carbon atoms, especially ethoxy groups. Aryl group means benzene derivatives such as phenyl group, and aralkyl group means benzyl group, phenethyl group, etc.
本発明のイソメラミン誘導体の製造方法は、一般に次の
ような工程で実施することができる。The method for producing isomelamine derivatives of the present invention can generally be carried out through the following steps.
】)無水無極性溶媒中で、臭化シアン1グラム当量に対
して2.0〜2.5グラム当量、好ましくは2.2〜2
.5グラム当量、更に好ましくは2.2グラム当量の第
1級アミンを加え、−10℃〜−1℃の温度範囲、好ま
しくは一5℃で30分〜2時間攪拌し、反応せしめる。]) 2.0 to 2.5 gram equivalents, preferably 2.2 to 2 gram equivalents per gram equivalent of cyanogen bromide in an anhydrous non-polar solvent.
.. Add 5 gram equivalents, more preferably 2.2 gram equivalents of primary amine, and stir at a temperature range of -10°C to -1°C, preferably -5°C, for 30 minutes to 2 hours to allow reaction.
ii)第1級アミン臭素酸塩の結晶を濾去する。ii) Filter off the primary amine bromate crystals.
111)反応濾液は15℃以下で溶媒を留去し、そのま
ま、又は水若しくはアルコール等の溶媒を加えて、室温
にて1〜20時間攪拌する。この際、塩基を触媒として
加えてもよい。111) The solvent of the reaction filtrate is distilled off at 15° C. or below, and the mixture is stirred as it is or with a solvent such as water or alcohol added thereto at room temperature for 1 to 20 hours. At this time, a base may be added as a catalyst.
iv) 更に30℃〜60℃まで昇温し、1〜5時間
反応せしめる。iv) The temperature is further raised to 30°C to 60°C and reacted for 1 to 5 hours.
以上の1)〜iv )の各工程によって本発明の製造方
法によるイソメラミン誘導体を得ることができるが、こ
こで後に比較例1にも示すように、原料の第1級アミン
を臭化シアン1グラム当量に対して2.2〜2.5グラ
ム当量使用すれば、工程iii )において用いる水又
はアルコール等の溶媒の存在、塩基触媒は必須のもので
はなく、また、工業的に製造する場合には水が最も好適
な溶媒となることを見出した。また上記各工程に示した
温度及び反応時間の条件は、反応速度や収率に関係する
ものであり、本発明を限定するものではない。The isomelamine derivative according to the production method of the present invention can be obtained through each of the above steps 1) to iv), but as shown later in Comparative Example 1, 1 gram of cyanogen bromide is added to the primary amine as the raw material. If 2.2 to 2.5 gram equivalents are used, the presence of a solvent such as water or alcohol used in step iii) and the base catalyst are not essential, and in the case of industrial production. We have found that water is the most suitable solvent. Further, the conditions of temperature and reaction time shown in each of the above steps are related to the reaction rate and yield, and do not limit the present invention.
更に閉環反応における触媒効果としては、比較例2に示
すように塩基の存在がとりわけ反応時間短縮に重要な効
果を有することを見出した。Furthermore, as a catalytic effect in the ring-closing reaction, as shown in Comparative Example 2, the presence of a base was found to have an important effect, particularly in shortening the reaction time.
本発明者は、イソメラミン誘導体の薬理学的作用につい
て種々の研究を行った結果、上記イソメラミン誘導体の
構造式において、Rがエチル基若しくは、アリル基であ
る化合物(以下、化合物(rV)と言う)が有効な強心
作用を有することを発見し、本発明を完成するに至った
。As a result of conducting various studies on the pharmacological effects of isomelamine derivatives, the present inventor has discovered a compound (hereinafter referred to as compound (rV)) in which R is an ethyl group or an allyl group in the structural formula of the above isomelamine derivative. The present inventors have discovered that this has an effective cardiotonic effect, and have completed the present invention.
本発明の強心剤は、経口及び非経口投与のいずれも使用
可能であり、経口投与する場合は、カプセル剤又は錠剤
、顆粒剤、細粒剤、散剤として投与され、非経口投与す
る場合は、注射剤又は粘膜吸収での串刺又は、経皮吸収
を目的としたパップ剤又は軟膏剤とてして投与され得る
。The cardiotonic agent of the present invention can be administered either orally or parenterally; when administered orally, it is administered as a capsule, tablet, granule, fine granule, or powder; when administered parenterally, it is administered by injection. It can be administered as a skewer for mucosal absorption, or as a poultice or ointment for transdermal absorption.
本発明の強心剤組成物の有効成分の割合は、剤形によっ
て変更し得るが、通常、経口又は粘膜吸収あるいは経皮
吸収で投与されるとき、はぼ0.05〜10.0重量%
が適当であり、注射剤として適用される場合は、0.0
1〜10.0重量%が適当である。Although the proportion of the active ingredient in the cardiotonic composition of the present invention may vary depending on the dosage form, it is usually about 0.05 to 10.0% by weight when administered orally or by mucosal absorption or transdermal absorption.
is appropriate and when applied as an injection, 0.0
1 to 10.0% by weight is suitable.
また、本発明の有効成分を製剤化するに当っては、化合
物(IV)は常法に従い、水溶性注射液、あるいは、温
時溶解する粉末注射剤などにして、皮下、筋肉内或いは
静脈注射用製剤とすることができる他、カプセル剤、錠
剤(たとえば舌下錠、フィルムコート錠等)、顆粒剤等
の剤形に製剤化して経口用に供することができる。さら
に、パップ剤、軟膏剤、串刺等の剤形化も可能である。Furthermore, when formulating the active ingredient of the present invention, compound (IV) can be prepared into a water-soluble injection solution or a powder injection solution that dissolves when warmed, and can be injected subcutaneously, intramuscularly, or intravenously. In addition to being formulated into dosage forms such as capsules, tablets (eg, sublingual tablets, film-coated tablets, etc.), and granules, they can be administered orally. Furthermore, formulations such as poultices, ointments, and skewers are also possible.
本発明の有効成分の製剤化に用いられる賦形剤、結合剤
、崩壊剤滑沢剤、基剤及び医薬的に許容し得る皮膜形成
物質等を挙げれば、次のとおりである。Examples of excipients, binders, disintegrants, lubricants, bases, pharmaceutically acceptable film-forming substances, etc. used in formulating the active ingredient of the present invention are as follows.
賦形剤としては、例えば、グリコース、デンゾン、乳糖
、マンニトール、ソルビトール、白糖、カオリン、テ′
キストリン、シクロテ゛キストリン、酸化チタン無水リ
ン酸カルシウム、軽質無水ケイ酸、タルク(天然含水ケ
イ酸マグネシウム)沈降炭酸カルシウム、メタケイ酸ア
ルミン酸マグネシウム、結晶セルロース、カルボキシメ
チルセルロースカルシウム等の1種又は2種以上を組合
せて添加することができる。Examples of excipients include glycose, denzone, lactose, mannitol, sorbitol, white sugar, kaolin, and lactose.
One or a combination of two or more of kistrin, cyclotextrin, titanium oxide anhydrous calcium phosphate, light anhydrous silicic acid, talc (natural hydrated magnesium silicate) precipitated calcium carbonate, magnesium aluminate metasilicate, crystalline cellulose, carboxymethylcellulose calcium, etc. Can be added.
結合剤としては、例えば、デンプン、デキストリン、ト
ラガントガム、ゼラチン、ポリビニルピロリドン、ポリ
ビニルアルコール、メチルセルロース、エチルセル臼−
ス、ヒドロキシエチルセルロース、ヒドロキシプロピル
セルロース、ヒビロキシプロピルメチルセルロース、ヒ
ドロキシプロピルスターチ、結晶セルロースペクチン、
ポリペクチン酸、ポリペクチン酸ナトリウム、ポリアク
リル酸、承りアクリル酸ナトリウム、ポリアクリル酸共
重合体、ポリメタアクリル酸、ポリメタアクリル酸ナト
リウム、ポリヒドロキシエチルメタアクリレート、カル
ボキシメチルセルロース、力ルボキシメチルセルロース
ナトリウム、アラビアゴム、アルギン酸ナトリウム等の
1種又は2種以上を組合せて添加することができる。Examples of binders include starch, dextrin, gum tragacanth, gelatin, polyvinylpyrrolidone, polyvinyl alcohol, methyl cellulose, and ethyl cellulose.
hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropyl starch, crystalline cellulose pectin,
Polypectic acid, sodium polypectate, polyacrylic acid, sodium acrylate, polyacrylic acid copolymer, polymethacrylic acid, sodium polymethacrylate, polyhydroxyethyl methacrylate, carboxymethylcellulose, sodium carboxymethylcellulose , gum arabic, sodium alginate, etc., or a combination of two or more thereof can be added.
崩壊剤としては、例えばデンプン、結晶セルロース、カ
ルボキシメチルセルロース、カルボキシメチルセルロー
スカルシウム、カルボキシメチルスターチ、ヒドロキシ
プロピルスターチカンテン末、マンナン等の1種又は2
種以上を組合せて添加することができる。Examples of the disintegrating agent include one or two of starch, crystalline cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch, hydroxypropyl starch, agar powder, mannan, etc.
A combination of more than one species can be added.
滑沢剤としては、例えば、タルク、ステアリン酸、ステ
アリン酸マグネシウム及びカルシウム、硬化油、ゴマ油
、パラフィン等の1種又は2種以上を組合せて添加する
ことができ、また矯味矯臭剤として、食塩、サッカリン
糖、マンニット、メントール、クエン酸、フマール酸、
酒石酸、リンゴ酸、カンゾウエキス、オレンジ油、ロー
ズ油、ユーカリ油、レモン油等の甘味剤、香料、着色剤
保存料等を含有させてもよい。As the lubricant, for example, one or a combination of two or more of talc, stearic acid, magnesium and calcium stearate, hydrogenated oil, sesame oil, paraffin, etc. can be added, and as the flavoring agent, salt, Saccharin sugar, mannitol, menthol, citric acid, fumaric acid,
Sweeteners such as tartaric acid, malic acid, licorice extract, orange oil, rose oil, eucalyptus oil, and lemon oil, fragrances, coloring agents, and preservatives may also be included.
基剤としては、例えばパラフィン、ワセリン、ゴマ油、
牛脂、コレステロールイソステアリン酸、ミリスチン酸
、ミリスチン酸亜鉛、ミリスチン酸イソプロピルミリス
チン酸オクチルドデシル、ミリスチン酸ミリスチル、ラ
ノリン、オリーブ油、マクロゴール、プロピレングリコ
ール、ポリヒ゛ニルアルコール、ポリブテン、オレイン
アルコール、オレイン酸、オレイン酸エチル、ウイテプ
ゾール、サポシーレニトロセルロース、酸化亜鉛、乳酸
セチル、乳酸ミリスチル、グリセリン、ラウリルアルコ
ール等の1種又は2種以上を組合せて添加することがで
きる。Examples of bases include paraffin, petrolatum, sesame oil,
Beef tallow, cholesterol isostearic acid, myristic acid, zinc myristate, isopropyl myristate, octyldodecyl myristate, myristyl myristate, lanolin, olive oil, macrogol, propylene glycol, polyvinyl alcohol, polybutene, oleic alcohol, oleic acid, ethyl oleate, One type or a combination of two or more types of such as Witepsol, sapocyrenitrocellulose, zinc oxide, cetyl lactate, myristyl lactate, glycerin, and lauryl alcohol can be added.
また皮膜形成物質としては、セルロースの誘導体として
エチルセルロース(EC)、カルボキシメチルエチルセ
ルロース(CMEC)、酢酸セルロース(CA)、酢酸
フタル酸セルロース(CへP)、ヒドロキシプロピルメ
チルセルロース(HPMC) 、ビトロキシプロピル
メチルセルロースフタレート(HPMCP)、メチルセ
ルロース(MC)、ヒドロキシプロピルセルロース(H
PC)、またポリビニル誘導体としてポリビニルアセタ
ールジエチルアミノアセテテート、メタアリクル酸アク
リル酸エチルコポリマー、メタアクリル酸メタアクリル
酸メチルコポリマー、メタアクリル酸エチル・メタアク
リル酸塩化トリメチルアンモニウムエチルコポリマー、
メタアクリル酸ジメチルアミノエチル・メタアクリル酸
メチルコポリマーが挙げられる。Film-forming substances include cellulose derivatives such as ethylcellulose (EC), carboxymethylethylcellulose (CMEC), cellulose acetate (CA), cellulose acetate phthalate (C to P), hydroxypropylmethylcellulose (HPMC), and bitroxypropylmethylcellulose. Phthalate (HPMCP), Methylcellulose (MC), Hydroxypropylcellulose (H
PC), and as polyvinyl derivatives, polyvinyl acetal diethylaminoacetate, methacrylic acid ethyl acrylate copolymer, methacrylic acid methyl methacrylate copolymer, ethyl methacrylate/methacrylic acid trimethylammonium ethyl chloride copolymer,
Examples include dimethylaminoethyl methacrylate/methyl methacrylate copolymer.
また、上記皮膜形成物質をコーティングするに際し、通
常使用されるコーティング助剤、例えば可塑剤の他、コ
ーティング操作時の薬剤相互の付着防止のための各種添
加剤を添加することによって皮膜形成剤の性質を改良し
たり、コーティング操作をより容易ならしめることがで
きる。In addition, when coating the above-mentioned film-forming substances, in addition to commonly used coating aids such as plasticizers, the properties of the film-forming agent can be improved by adding various additives to prevent the chemicals from adhering to each other during coating operations. This can improve the coating process and make coating operations easier.
また、投与量は、所望の治療効果及び治療期間によって
左右されるが、大人では通常、体重1 kg1日当り、
有効成分となる化合物(TV)を0.01〜20mg含
む形で投与する。The dosage depends on the desired therapeutic effect and duration of treatment, but for adults it is usually 1 kg body weight per day.
The compound (TV) serving as the active ingredient is administered in a form containing 0.01 to 20 mg.
次に上記化合物(IV)の強心作用を確認した薬効試験
について述べる。Next, a drug efficacy test in which the inotropic effect of the above compound (IV) was confirmed will be described.
イソメラミン誘導体の一般式(IV)でRがエチル基又
はアリル基である化合物(IV)の強心剤としての有用
性を、標準の薬理学的テスト方法で摘出モルモットの心
房と乳頭筋を用いる試験において、収縮力の著しい増大
を測定し、実証した。これらのテスト方法を以下に記載
する。The usefulness of compound (IV), an isomelamine derivative of general formula (IV) in which R is an ethyl group or an allyl group, as a cardiotonic agent was evaluated in a test using isolated guinea pig atrium and papillary muscle using standard pharmacological test methods. A significant increase in contractile force was measured and demonstrated. These test methods are described below.
(摘出したモルモットの心房と乳頭筋とを用いる方法)
体重350〜400gの雄性モルモットを放血致死させ
各モルモットを開胸し、心臓を摘出してタイロード液で
洗浄し左右の心房および右心室から1個ないし数個の乳
頭筋を切り取った。これらの組織を5%C02+ 95
%02 の混合ガスで通気しているタイロード液槽中に
移した。ついで容量10mj!の滑車つきのゴムを敷い
たマグヌス管に移して、組織の端を2個の白金電極付き
のピンで留めた。次にもう一方の端を糸でしばり、滑車
を通してFDピックアップに吊、した。液温は32℃に
保持し、常時5%CO2+95%02の混合ガスで通気
した。(Method using isolated atria and papillary muscles of guinea pigs) Male guinea pigs weighing 350 to 400 g were killed by exsanguination, each guinea pig's chest was opened, the heart was removed and washed with Tyrode's solution, and the heart was extracted from the left and right atria and the right ventricle. One or several papillary muscles were excised. These tissues were treated with 5% C02+ 95
The sample was transferred to a Tyrode bath which was vented with a mixed gas of 0.2%. Then the capacity is 10mj! The tissue was transferred to a rubber-lined Magnus tube with a pulley, and the ends of the tissue were secured with two platinum electrode pins. Next, I tied the other end with a string, passed it through a pulley, and hung it from the FD pickup. The liquid temperature was maintained at 32°C, and a mixed gas of 5% CO2 + 95% 02 was constantly aerated.
標本には1〜2gの負荷を与え、収縮曲線は直配式ポリ
グラフに記録した。右心房は洞房結節の存在に起因して
自然に脈打ち、左心房と乳頭筋は白金電極を介して超最
大電圧1 m5ec 、 2 Hzの条件で電気的に刺
激した。標本を入れたタイロード液は、次の組成(g/
Jりであった。A load of 1-2 g was applied to the specimen and the shrinkage curve was recorded on a stand-up polygraph. The right atrium beat spontaneously due to the presence of the sinoatrial node, and the left atrium and papillary muscles were electrically stimulated via platinum electrodes at a supermaximal voltage of 1 m5ec and 2 Hz. The Tyrode solution containing the specimen has the following composition (g/
It was Juri.
Nap! 8,0. KO2,2,Caα20.2゜
Mgα20.1. Na112P040,05. Gl
ucose 1.0゜Nat(CO31,0
標本は安定になるまで数回タイロード液で洗浄した。生
理食塩水に溶解した本発明の化合物(IV)をタイロー
ド液槽中に滴下して実応答を記録した。Nap! 8,0. KO2,2, Caα20.2°Mgα20.1. Na112P040,05. Gl
ucose 1.0°Nat (CO31,0) The specimen was washed several times with Tyrode's solution until it became stable.The compound (IV) of the present invention dissolved in physiological saline was dropped into the Tyrode's solution bath, and an actual response was performed. was recorded.
上記に示した単離したモルモットの心房と乳頭筋とを用
いる方法により試験した時、本化合物は右心房の試験で
10−’g/m(の投薬量で25%以上、左心房の試験
で5 x 10−5g/lnlの投薬量で25%以上、
乳頭筋の試験で10−”g/meの投薬量で30%以上
、それぞれ収縮力を増大した。When tested using the isolated guinea pig atrium and papillary muscle method described above, the compound showed greater than 25% at a dosage of 10-'g/m (in the right atrium test) and 25% in the left atrium test. 25% or more at a dosage of 5 x 10-5 g/lnl,
In tests on papillary muscles, doses of 10-''g/me each increased contractile force by more than 30%.
一方、右心房の心拍数は、左右心房又は乳頭筋における
収縮力の増加率の約1/3程度の増加率が引き起こされ
たのみであった。On the other hand, the rate of increase in the heart rate of the right atrium was only about 1/3 of the rate of increase in the contractile force in the left and right atria or papillary muscles.
また、一般式(IV)でRがエチル基、アリル基、であ
る化合物の気管支拡張剤としての有用性を標準の薬理学
的テスト方法で摘出モルモットの気管平滑筋を用いる試
験により、気管平滑筋を著しく弛緩することを実証した
。これらのテスト方法を以下に記載する。In addition, the usefulness of compounds of general formula (IV) in which R is an ethyl group or an allyl group as a bronchodilator was investigated using standard pharmacological test methods using isolated guinea pig tracheal smooth muscle. was demonstrated to significantly relax the body. These test methods are described below.
摘出モルモットの気管平滑筋を用いる方法体重350〜
400gの雄性モルモットを後頭部打撲後放血致死させ
、頚部の喉頭蓋軟骨より左右分岐部までの気管を、背側
の平滑筋を傷つけないようにして摘出した。5%Co2
+95%02の混合ガスで通気しているタイロード液
中に移して周囲の組織をできるだけ取り除いた後、前面
を縦に切開して軟骨にそって靭帯部を横方向に切断し、
切片を長軸方向に3個糸で連結し、セルフインをつけ、
タイロード液を満たした容量50m1!のマグヌス管に
移してアイソトニックトランスジューサーに吊した。液
温は37℃に保持し、常時5%CO2+95%02 の
混合ガスで通気した。標本には0.5gの負荷を与え、
収縮曲線は直配式ポリグラフに記録した。標本は安定に
なるまで数回タイロード液で洗浄した。生理食塩水に溶
解した本発明の化合物(IV)をタイロード液槽中に滴
下して実応答を記録した。Method using isolated guinea pig tracheal smooth muscle Body weight: 350~
A 400 g male guinea pig was beaten to the back of the head and exsanguinated to death, and the trachea from the epiglottis cartilage in the neck to the right and left carina was removed without damaging the dorsal smooth muscle. 5%Co2
After transferring it into Tyrode's solution aerated with +95% 02 mixed gas and removing as much surrounding tissue as possible, the front surface was longitudinally incised and the ligament section was cut transversely along the cartilage.
Connect three sections in the longitudinal direction with thread, attach a self-in,
Capacity 50ml filled with Tyrode's liquid! was transferred to a Magnus tube and hung on an isotonic transducer. The liquid temperature was maintained at 37°C, and a mixed gas of 5% CO2 + 95% CO2 was constantly aerated. A load of 0.5 g was applied to the specimen.
The shrinkage curve was recorded on a stand-up polygraph. The specimens were washed with Tyrode's solution several times until stable. Compound (IV) of the present invention dissolved in physiological saline was dropped into a Tyrode bath, and the actual response was recorded.
上記の方法で試験した時、本化合物はアセチルコリン2
X10−8g/ml!の収縮に対して5 Xl0−6g
/mi!で50%、10−5g/mi!で100%弛緩
した。また対照として用いたアミノフィリンは2×10
−8g/mi!の収縮に対して10−5g/mfで50
%、5 x 10−”g/mlで100%弛緩し、化合
物■は、対照薬アミノフィリンの約5倍の薬効をボした
。When tested using the method described above, this compound showed acetylcholine 2
X10-8g/ml! 5 Xl0-6g for the contraction of
/mi! 50%, 10-5g/mi! It was 100% relaxed. In addition, aminophylline used as a control was 2 × 10
-8g/mi! 50 at 10-5 g/mf for shrinkage of
%, 100% relaxation at 5 x 10-''g/ml, and Compound II had approximately 5 times the efficacy of the control drug, aminophylline.
(急性毒性試験)
急性毒性試験の結果は、一般式のRがエチル基の場合で
、LD、。=547.73mg/kg(i、v。(Acute toxicity test) The results of the acute toxicity test are when R in the general formula is an ethyl group, and LD. =547.73mg/kg (i, v.
マウス♂)であった。またRがアリル基“の場合で、L
Dso= 358.00mg/kg (i 、 v、
7ウス♂)であった。It was a female mouse). In addition, when R is an allyl group, L
Dso = 358.00mg/kg (i, v,
It was a 7-year-old male).
他の標準薬理学的テスト法でスクリーニングした時に、
化合物(IV)のRがn−ブチル、イソブチル、ベンジ
ル、アリルである化合物に強心作用以外の活性があるこ
とがわかった。When screened with other standard pharmacological test methods,
It has been found that compounds in which R in compound (IV) is n-butyl, isobutyl, benzyl, or allyl have activities other than cardiac inotropy.
例えば化合物(IV)のRがn−ブチル、イソブチル、
アリルの化合物は、メタコリンで収縮させた潅流モルモ
ット心肺標本において、気管支拡張活性をもつことがわ
かった。For example, R in compound (IV) is n-butyl, isobutyl,
The allyl compound was found to have bronchodilator activity in perfused guinea pig heart-lung preparations contracted with methacholine.
また、化合物(IV)のRがn−ブチル、イソブチルの
化合物は、摘出モルモット回腸におけるアセチルコリン
(0,1mcg /mi! )の収縮効果の阻害活性を
もつことがわかった。It was also found that the compound (IV) in which R is n-butyl or isobutyl has an inhibitory activity on the contractile effect of acetylcholine (0.1 mcg/mi!) in isolated guinea pig ileum.
また、化合物(IV)のRがn−ブチルの化合物は、絶
食ラットのエタノールによる潰瘍を抑制した。Further, the compound (IV) in which R is n-butyl inhibited ethanol-induced ulcers in fasted rats.
さらに化合物(IV)のRがベンジルの化合物は高コL
、 ステロールマウスの血清コレステロール濃度を減少
させ血清LDL、VLDL、β−リポプロティンを減少
させた。Furthermore, the compound (IV) in which R is benzyl has a high co-L
, decreased serum cholesterol concentration and decreased serum LDL, VLDL, and β-lipoprotein in sterol mice.
また化合物(rV)のRがアリルの化合物は利尿作用が
あった。Further, the compound (rV) in which R is allyl had a diuretic effect.
本発明の製造方法によれば、経済的かつ容易にイソメラ
ミン誘導体を製造することができる。According to the production method of the present invention, isomelamine derivatives can be produced economically and easily.
本発明の強心剤は、モルモットの左心房を電気刺激し、
収縮力を測定する実験で、対照薬のアムリノン(Amr
inone )の10倍の薬効を示した。The cardiotonic agent of the present invention electrically stimulates the left atrium of a guinea pig,
In an experiment to measure contractile force, the control drug amrinone (Amr
Inone) showed 10 times the medicinal efficacy.
以下に示す実施例は、本発明を更に例示するものであり
それに限定するものではない。The following examples further illustrate the invention and do not limit it thereto.
実施例1
臭化シアン10.0 gを無水エーテル200m1に溶
解し、10%エチルアミン無水エーテル溶液93.4m
l!(2,2当量)を−5℃にて滴下し、完全無水条件
下1時間撹拌する。反応終了後エチルアミン臭素酸塩の
結晶を濾去し、エーテルを15℃以下で留去する。得ら
れる残液に水68m1!を加え、室温にて2時間撹拌後
、50℃に昇温しさらに2時間加温した後冷蔵庫に放置
する。析出する結晶を吸引ろ過し、冷水で洗浄後真空中
60℃で乾燥し、4.86g(理論量の73.6%)を
得た。さらに母液を濃縮し、析串する結晶を熱水に溶解
させ冷蔵庫に放置する。析出する結晶を吸引ろ取し、冷
水で洗浄後、真空中60℃で乾燥させ0.43 g(理
論量の6.5%)を得た。総収量5.29g(理論量の
80.2%)
熱水より再結晶し、真空中60℃で乾燥する。Example 1 10.0 g of cyanogen bromide was dissolved in 200 ml of anhydrous ether, and 93.4 ml of 10% ethylamine anhydrous ether solution was dissolved.
l! (2.2 equivalents) was added dropwise at -5°C and stirred for 1 hour under completely anhydrous conditions. After the reaction is completed, the ethylamine bromate crystals are filtered off, and the ether is distilled off at a temperature below 15°C. The resulting residual liquid contains 68ml of water! After stirring at room temperature for 2 hours, the mixture was heated to 50°C, further heated for 2 hours, and then left in the refrigerator. The precipitated crystals were suction-filtered, washed with cold water, and dried in vacuo at 60°C to obtain 4.86 g (73.6% of the theoretical amount). Further, the mother liquor is concentrated, and the crystals to be precipitated are dissolved in hot water and left in the refrigerator. The precipitated crystals were collected by suction filtration, washed with cold water, and dried in vacuo at 60°C to obtain 0.43 g (6.5% of the theoretical amount). Total yield 5.29 g (80.2% of theory) Recrystallized from hot water and dried at 60° C. in vacuo.
融点94〜95℃〔文献値91〜92℃ A、 Ill
。Melting point 94-95°C [Literature value 91-92°C A, Ill
.
Hofmann、 Chem、 Ber、 18.
2784 (1885) ]元素分析(%) C9
H,J6 (分子量−210)計算値: C,51,4
0、H,8,63; N、39.97゜実測値: C,
50,99、H,8,63; N、39.84゜IRV
am−’ :3340. 2980. 160
0. 1480. 1380゜1275、1220.1
150.10?0.990゜860、780.760.
715
’H−NMR(DMSOd6) δ: L 09 (
3H,t、 −C)12cL) 。Hofmann, Chem, Ber, 18.
2784 (1885)] Elemental analysis (%) C9
H, J6 (molecular weight - 210) calculated value: C, 51,4
0, H, 8,63; N, 39.97° Actual value: C,
50,99, H, 8,63; N, 39.84°IRV
am-' :3340. 2980. 160
0. 1480. 1380°1275, 1220.1
150.10?0.990°860, 780.760.
715'H-NMR (DMSOd6) δ: L 09 (
3H,t, -C)12cL).
3.68−4.20(2H,m、 CLCH3) 、
6.37(18゜br s >C=Nl(、020置
換により消失)” C−NMII (DMSO−d6)
δ: 11.8 (Q、 −[:’1I2c11.
) 。3.68-4.20 (2H, m, CLCH3),
6.37 (18゜br s > C=Nl (, disappeared by 020 substitution)" C-NMII (DMSO-d6)
δ: 11.8 (Q, -[:'1I2c11.
).
38、2(t、 −Ct12CH3)、 144.6
(br s >c =NH)MS(m/z) :
210(M”) 。38, 2(t, -Ct12CH3), 144.6
(br s > c = NH) MS (m/z):
210 (M”).
実施例2
臭化シアン10.0 gを無水エーテル200m1!に
溶解し、10%エチルアミン無水エーテル溶液93.4
ml!(2,2当量)を−5℃にて滴下し、完全無水条
件下1時間撹拌する。反応終了後エチルアミン臭素酸塩
の結晶をろ去し、エーテルを15℃以下で留去する。得
られる残液に水68m1!を加え、室温にて19時間撹
拌後析出する結晶を加熱によって再び溶解させ冷蔵庫に
放置する。析出する結晶を吸引ろ取し冷水で洗浄後真空
中60℃で乾燥し4.86g(理論量の73,6%)を
得た。さらに母液を濃縮し、熱水より結晶化後、実施例
1と同様に処理し、0.11 g (理論量の1.7%
)を得た。Example 2 10.0 g of cyanogen bromide was added to 200 ml of anhydrous ether! 10% ethylamine solution in anhydrous ether 93.4
ml! (2.2 equivalents) was added dropwise at -5°C and stirred for 1 hour under completely anhydrous conditions. After the reaction is complete, the ethylamine bromate crystals are filtered off, and the ether is distilled off at a temperature below 15°C. The resulting residual liquid contains 68ml of water! After stirring at room temperature for 19 hours, the precipitated crystals are redissolved by heating and left in the refrigerator. The precipitated crystals were collected by suction filtration, washed with cold water, and dried in vacuo at 60°C to obtain 4.86 g (73.6% of the theoretical amount). The mother liquor was further concentrated, crystallized from hot water, and treated in the same manner as in Example 1 to yield 0.11 g (1.7% of the theoretical amount).
) was obtained.
総収量4.97g(理論量の75.3%)実施例3
臭化シアン10.0 gを無水エーテル200−に溶解
し、10%エチルアミン無水エーテル溶液93.4ml
!(2,2当量)を−5℃にて滴下し、完全無水条件下
1時間撹拌する。反応終了後エチルアミン臭素酸塩の結
晶を濾去し、エーテルを15℃以下で留去する。得られ
る残液を室温にて溶媒なしで5時間攪拌後、析出する結
晶を加熱によって再び溶解させ冷蔵庫に放置する。析出
する結晶を吸引ろ取し、冷水で洗浄し真空中60℃で乾
燥し4.79g(理論量の726%)を得た。さらに母
液を濃縮し熱水より結晶化後、実施例1と同様に処理し
0.31g(理論量の4.7%)を得た。総収量5.1
0g(理論量の77.3%)
実施例4
臭化シアン10.0 gを熱水エーテル200ml!に
溶解し、10%エチルアミン無水エーテル溶液85、O
me(2,0当量)を−5℃にて滴下し、完全無水条件
下1時間撹拌する。反応終了後エチルアミン臭素酸塩の
結晶を濾去し、エーテルを15℃以下で留去する。得ら
れる残液に水64m1!を加え、その溶液に水酸化ナト
リウム398 mg (0,1mol)の水溶液4ml
!を滴下し、室温にて2時間撹拌した後50℃にて0.
5時間加温する。反応終了後冷蔵庫に放置し結晶化機生
成物を吸引ろ取し、冷水で洗浄後真空中60℃で乾燥し
3.54g(理論量の53.6%)を得た。さらに母液
を濃縮後熱水より結晶化後、実施例1と同様に処理し0
.5’ 8 g (理論量の8.8%)を得た。総収量
4.12 g (理論量の62.4%)
実施例5
一般式(III)においてR=n−ブチル(口15H3
ON6Mw、 294 )
臭化シアン10.0 gを無水エーテル200mj!に
溶解し2.2当量のn−ブチルアミン無水エーテル溶液
100mi!4−5℃にて滴下し、同温度にて1時間撹
拌する。反応終了後n−ブチルアミンの臭素酸塩を濾去
し、エーテルを15℃以下で留去する。得られる残液に
水60m1!、エタノール30m1を加え、50℃にて
2時間加温した後、溶媒を留去し得られる残液をシリカ
ゲルカラムクロマトグラフィーに付す。n−ヘキザンー
酢酸エチル;7:3流出部より6.78 gを無色油状
物として得る。(理論量の73.4%)
元素分析(%) C,5113oN6(分子量−29
4)計算値:C,6]、、18 H,10,27N、
28.55゜実測値: C,61,21H,10,4
3N、 28.53゜1080、 740゜
’H−NMR(D8SO−66) δ: 0.88
〜0.97 (9H,m ) 。Total yield 4.97 g (75.3% of theory) Example 3 10.0 g of cyanogen bromide was dissolved in 200 g of anhydrous ether and 93.4 ml of a 10% ethylamine solution in anhydrous ether was added.
! (2.2 equivalents) was added dropwise at -5°C and stirred for 1 hour under completely anhydrous conditions. After the reaction is completed, the ethylamine bromate crystals are filtered off, and the ether is distilled off at a temperature below 15°C. After stirring the resulting residual liquid at room temperature for 5 hours without a solvent, the precipitated crystals are redissolved by heating and left in a refrigerator. The precipitated crystals were collected by suction filtration, washed with cold water, and dried in vacuo at 60° C. to obtain 4.79 g (726% of the theoretical amount). Further, the mother liquor was concentrated and crystallized from hot water, and then treated in the same manner as in Example 1 to obtain 0.31 g (4.7% of the theoretical amount). Total yield 5.1
0 g (77.3% of theoretical amount) Example 4 10.0 g of cyanogen bromide and 200 ml of hot water ether! 10% ethylamine solution in anhydrous ether, dissolved in 85% O
me (2.0 equivalents) was added dropwise at -5°C and stirred for 1 hour under completely anhydrous conditions. After the reaction is completed, the ethylamine bromate crystals are filtered off, and the ether is distilled off at a temperature below 15°C. The resulting residual liquid contains 64ml of water! and add 4 ml of an aqueous solution of 398 mg (0.1 mol) of sodium hydroxide to the solution.
! was added dropwise, stirred at room temperature for 2 hours, and then heated to 50°C for 0.
Warm for 5 hours. After the reaction was completed, the crystallizer product was left in a refrigerator and collected by suction filtration, washed with cold water, and dried at 60° C. in vacuo to obtain 3.54 g (53.6% of the theoretical amount). Further, the mother liquor was concentrated and crystallized from hot water, and then treated in the same manner as in Example 1.
.. 8 g (8.8% of theory) of 5' was obtained. Total yield 4.12 g (62.4% of theory) Example 5 In general formula (III), R=n-butyl (15H3
ON6Mw, 294) 10.0 g of cyanogen bromide and 200 mj of anhydrous ether! 2.2 equivalents of n-butylamine dissolved in anhydrous ether solution 100mi! It was added dropwise at 4-5°C and stirred at the same temperature for 1 hour. After the reaction is completed, the bromate of n-butylamine is filtered off, and the ether is distilled off at a temperature below 15°C. The resulting residual liquid contains 60ml of water! After adding 30 ml of ethanol and heating at 50°C for 2 hours, the solvent was distilled off and the resulting residue was subjected to silica gel column chromatography. n-hexane-ethyl acetate; 6.78 g was obtained as a colorless oil from the 7:3 outflow. (73.4% of theoretical amount) Elemental analysis (%) C, 5113oN6 (molecular weight -29
4) Calculated value: C, 6], 18 H, 10, 27 N,
28.55°Actual measurement: C, 61, 21H, 10, 4
3N, 28.53°1080, 740°'H-NMR (D8SO-66) δ: 0.88
~0.97 (9H, m).
1.38 (6H,m )、 3.90 (6
H,m )。1.38 (6H, m), 3.90 (6
H,m).
6.31 (3H,br s 020置換にて消失)
。6.31 (3H, disappeared by br s 020 substitution)
.
13C−NMR(DBSO−c16) δ: 13
.6 (q、 )。13C-NMR (DBSO-c16) δ: 13
.. 6 (q, ).
、 19.5(t)、 28.6(t)、 4
3.1(t)。, 19.5(t), 28.6(t), 4
3.1(t).
145、8 (s) 。145, 8 (s).
MS(m/ z) + 294 (M+ )
。MS (m/z) + 294 (M+)
.
実施例6
一般式(III)において、R=i−ブチル(C,5H
3,N6Mw、 294 )臭化シアン10.0 gを
無水エーテル200m1に溶解し、2.2当景の1−ブ
チルアミン無水エーテル溶液100m1!を一5℃にて
滴下し、同温度にて1時間撹拌する。反応終了後1−ブ
チルアミンの臭素酸塩を濾去し、エーテルを15℃以下
で留去する。得られる残液に水60m1!、エタノール
乙0
30m!!を加え、50tにて3時間加温した後溶媒を
留去し、水を加え、ベンゼンにて抽出を行う。Example 6 In general formula (III), R=i-butyl (C, 5H
3, N6Mw, 294) Dissolve 10.0 g of cyanogen bromide in 200 ml of anhydrous ether, and 100 ml of the 1-butylamine anhydrous ether solution of 2.2! was added dropwise at -5°C and stirred at the same temperature for 1 hour. After the reaction is completed, the bromate of 1-butylamine is filtered off, and the ether is distilled off at a temperature below 15°C. The resulting residual liquid contains 60ml of water! , Ethanol Otsu 0 30m! ! After heating at 50 t for 3 hours, the solvent was distilled off, water was added, and extraction was performed with benzene.
溶媒乾燥後留去し、得られる結晶をベンゼン−n−ヘキ
サンより再結晶を行い7.20 gを得る。The solvent was dried and evaporated, and the resulting crystals were recrystallized from benzene-n-hexane to obtain 7.20 g.
(理論量の77.9%)mp95〜96℃〔文献値mp
91〜93℃(特開昭58−157773))元素分析
(%) C15H3ON6 <分子量=294)計算
値:C,61,18H,10,27N、 28.55゜
実測値: C,60,81H,10,71N、 28.
19゜1460、 1390. 1310. 1200
゜1140、1090.1080.970゜715、5
60゜
’H−NMR(DBSO−d6)δ: 0,835 (
9H,d)。(77.9% of theoretical amount) mp95-96℃ [Literature value mp
Elemental analysis (%) C15H3ON6 <molecular weight = 294) Calculated value: C,61,18H,10,27N, 28.55° Actual value: C,60,81H, 10,71N, 28.
19°1460, 1390. 1310. 1200
゜1140, 1090.1080.970゜715, 5
60°'H-NMR (DBSO-d6) δ: 0,835 (
9H, d).
1.67〜2.33 (3tl、 m ) 、 3.5
0〜4.00 (6ft、mL6.46 (3H,br
s 020 にて消失)。1.67-2.33 (3tl, m), 3.5
0~4.00 (6ft, mL6.46 (3H, br
Disappeared at s 020).
I3C−NMR(D[ESO−d6)δ: 19.6
(q、 )。I3C-NMR(D[ESO-d6)δ: 19.6
(q, ).
26.1(d)、 49.5(t)、 146.6(
t) 。26.1(d), 49.5(t), 146.6(
t).
MS(m/z) : 295(M” +1)。MS (m/z): 295 (M”+1).
実施例7
一般式(III)において R−ベンジル臭化シアン1
0.0 gを無水エーテル200m1!に溶解し、2.
2当量のベンジルアミン無水エーテル溶液100rI1
1を一5℃にて滴下し、同温度にて1時間撹拌する。反
応終了後ベンジルアミンの臭素酸塩を濾去し、エーテル
を15℃以下で留去する。Example 7 In general formula (III), R-benzyl cyanogen bromide 1
0.0 g to 200ml of anhydrous ether! Dissolved in 2.
2 equivalents of benzylamine in anhydrous ether 100 rI1
1 was added dropwise at -5°C, and the mixture was stirred at the same temperature for 1 hour. After the reaction is completed, the bromate of benzylamine is filtered off, and the ether is distilled off at a temperature below 15°C.
得られる残液に水60ml、エタノール60m1!を加
え、50℃にて2時間加温した後溶媒を留去し、得られ
る結晶をトルエン−シクロヘキサンより再結晶を行い9
.34 gを得る。(理論量の75.0%)mp131
〜132℃〔文献値”’ mpl 29〜130℃)。The resulting residual liquid contains 60 ml of water and 60 ml of ethanol! After heating at 50°C for 2 hours, the solvent was distilled off, and the resulting crystals were recrystallized from toluene-cyclohexane.
.. Obtain 34 g. (75.0% of theoretical amount) mp131
~132°C (literature value “'mpl 29-130°C)”.
元素分析(%) C2,H2,N6(分子量−396
)計算値:(:、 72.70 H,6,10N、
21.20゜実測値: C,72,77H,6,00N
、 21.39゜’ H−NMR(DMSO−d6)δ
: 5,30 (611,s ) 。Elemental analysis (%) C2, H2, N6 (molecular weight -396
) Calculated value: (:, 72.70H, 6,10N,
21.20°Actual measurement: C, 72,77H, 6,00N
, 21.39゜' H-NMR (DMSO-d6) δ
: 5,30 (611,s).
6.59 (3H,br s D20 にて消失)。6.59 (disappeared at 3H, brs D20).
7.28 (15H,br s)。7.28 (15H, br s).
13C−NMR(DI!5O−d6) δ: 46
.9 (t)。13C-NMR (DI!5O-d6) δ: 46
.. 9 (t).
126.6(d)、 126.8(d)、 128
.3(d)。126.6(d), 126.8(d), 128
.. 3(d).
137.2(s)、 146.3(s)。137.2 (s), 146.3 (s).
MS(m / Z ) + 396 (M+)
。MS (m/Z) + 396 (M+)
.
実施例8
一般式(I)において R=アリル
(C,2H,、N6MtI1246 )臭化シアン10
.0 gを無水エーテル200ml!に溶解し、2.2
当量のアリルアミン無水エーテル溶液100m1!を一
5℃にて滴下し、同温度にて1時間撹拌する。反応終了
後アリルアミンンの臭素酸塩を濾去し、エーテルを15
℃以下で留去する。Example 8 In general formula (I), R=allyl (C, 2H,, N6MtI1246) cyanogen bromide 10
.. 0 g in 200 ml of anhydrous ether! Dissolved in 2.2
Equivalent amount of allylamine anhydrous ether solution 100ml! was added dropwise at -5°C and stirred at the same temperature for 1 hour. After the reaction was completed, the bromate of allylamine was removed by filtration, and 15% of the ether was removed.
Distill at temperatures below ℃.
得られる残液に水60ml!、エタノール30m1’を
加え、50℃にて2時間加温した後溶媒を留去し、シリ
カゲルカラムクロマトグラフィーに付し、n−ヘキサン
−酢酸エチル1:1流出部より5.79gの無色油状物
を得る。(理論量の74.8%)。Add 60ml of water to the remaining liquid! , 30ml of ethanol was added, and after heating at 50°C for 2 hours, the solvent was distilled off and subjected to silica gel column chromatography, and 5.79g of a colorless oil was obtained from the n-hexane-ethyl acetate 1:1 outflow. get. (74.8% of theory).
元素分析(%) C,28,8N6 (分子量−24
6)計算値:[:、 58.51 H,7,37N、
34.12 。Elemental analysis (%) C, 28, 8N6 (molecular weight -24
6) Calculated value: [:, 58.51H, 7,37N,
34.12.
実測値: C,58,34H,7,65N、 34.0
5゜1460、 1315. 1250. 1140゜
1000、 920. 880. 750゜’H−NM
R(DMSO−d6 ) δ: 4.64 (6
H,br s)。Actual value: C, 58, 34H, 7, 65N, 34.0
5°1460, 1315. 1250. 1140°1000, 920. 880. 750°'H-NM
R(DMSO-d6) δ: 4.64 (6
H, br s).
5.00 〜5.26 (6N、 m )、
5.49〜6.15 (3ft、m)。5.00 ~ 5.26 (6N, m),
5.49-6.15 (3ft, m).
6.32(3H,br s 020 にて消失)。6.32 (disappeared at 3H, br s 020).
13C−NMR(DMSO−d6) δ: 45.
5 (t)。13C-NMR (DMSO-d6) δ: 45.
5 (t).
115.9(t)、 132.7(d)、 145
.3(s)。115.9(t), 132.7(d), 145
.. 3(s).
MS(m/ z ) : 246 (M+) 。MS (m/z): 246 (M+).
比較例1
実施例1と同じ方法で、前記工程出)の溶媒を種々の溶
媒に代えて実施した。結果として溶媒を使用しなくても
イソメラミン誘導体を得るこ七ができた(第1表)。Comparative Example 1 The same method as in Example 1 was carried out, except that the solvent in step (a) was replaced with various solvents. As a result, it was possible to obtain an isomelamine derivative without using a solvent (Table 1).
ン 8
比較例2
実施例3と同じ方法で、ただし原料としてn −ブチル
アミンの代わりに蒸留精製したエチルシアナミドを用い
て、室温にて種々の触媒(塩基)を検討した(第2表)
。塩基の存在がとりわけ反応時間短縮に重要であること
を見出した。Comparative Example 2 Various catalysts (bases) were investigated at room temperature using the same method as in Example 3, but using distilled ethyl cyanamide instead of n-butylamine as the raw material (Table 2).
. It has been found that the presence of a base is especially important for shortening the reaction time.
製剤例1(水溶性注射液)
上記化合物(IV)を2.5gと塩化す) IJウム4
5、 Ogをとり、注射用蒸留水にて5,000m+!
とする。また0、0INHα液にてpHを7.5に調製
する。Formulation Example 1 (Water-soluble injection solution) The above compound (IV) is chlorinated with 2.5 g) IJum 4
5. Take Og and add distilled water for injection to 5,000m+!
shall be. Also, adjust the pH to 7.5 using 0.0 INHα solution.
この液を、メンブランフィルタ−でろ過し、ガラス製ア
ンプルに1ml!分注する。この際、窒素ガスを封入し
ながら溶閉し、常法に従がい滅菌した。Filter this liquid with a membrane filter and put 1ml into a glass ampoule! Dispense. At this time, it was fused and sealed while enclosing nitrogen gas, and sterilized according to the usual method.
本注射液は、1+ui!中上記化合物(IV)0.5m
gを含有する。This injection solution is 1+ui! Above compound (IV) 0.5m
Contains g.
製剤例2(用時溶解粉末注射剤)
上記化合物(IV)0.5gと塩化ナトリウム18.0
gをとり、注射用蒸留水にて1000mi!とじ、0.
0INHa液でpHを7.5に調製する。この液をメン
ブランフィルタ−にてろ過し、バイアルビンに1mi!
ずつ分注し、凍結乾燥装置を用いて、常法に従い凍結乾
燥品を得た。このものに、窒素ガスを封入後、ゴム栓を
施こし、用時溶解して使用する粉末注射剤を得た。水晶
は、1バイアル中0.5 mgの上記化合物(rV)を
含有し、使用時には、2−の注射用蒸留水にて溶解し使
用する。Formulation Example 2 (Powder injection to dissolve before use) 0.5 g of the above compound (IV) and 18.0 g of sodium chloride
Take g and add 1000 mi with distilled water for injection! Binding, 0.
Adjust pH to 7.5 with 0INHa solution. This liquid was filtered with a membrane filter and placed in a vial of 1 mi!
A freeze-dried product was obtained using a freeze-drying apparatus according to a conventional method. After filling this with nitrogen gas, a rubber stopper was applied, and a powder injection was obtained which was dissolved before use. Each vial of crystal contains 0.5 mg of the above compound (rV), and when used, it is dissolved in 2-distilled water for injection.
製剤例3(舌下錠)
上記化合物(IV)1.0g、コーンスターチ82.0
g、乳糖5°5.Og、結晶セルロース39.0 gを
とり、混合機にてよく混合した後、タルク2.、Og。Formulation example 3 (sublingual tablet) 1.0 g of the above compound (IV), cornstarch 82.0
g, lactose 5°5. After taking 39.0 g of crystalline cellulose and mixing it well with a mixer, add 2.0 g of talc. , Og.
ステアリン酸マグネシウム1.0gを加えて再混合し、
緊密な粉体を得た。これを通常の打錠機を用いて打錠す
る事により、重量約180mg、直径約8111mの舌
下錠を製した。Add 1.0 g of magnesium stearate and mix again.
A compact powder was obtained. This was compressed using an ordinary tablet machine to produce sublingual tablets weighing approximately 180 mg and having a diameter of approximately 8111 m.
製剤例4(腸溶性フィルムコート錠)
上記化合物(IV)1.0g、ツーシスター9フ9.0
混合機にてよく混合した後、ヒドロキシプロピルセルロ
ース8.0gをエタノールにて溶解して加え、良く練合
する。このものを直径0. 5 m+nのスクリーンを
用いて押出し造粒機で造粒する。得られた造粒物を常法
に従がい乾燥し、この乾bN eUにタルク2、 O
g 、ステアリン酸マグネシウム1. 0 gを加え、
混合後、通常の打錠機にて打錠する事により、重量約1
85mg,直径約8 mmの錠剤を得た。Formulation example 4 (enteric film coated tablet) 1.0 g of the above compound (IV), Two Sister 9f 9.0
After mixing well with a mixer, 8.0 g of hydroxypropyl cellulose dissolved in ethanol is added and kneaded well. This thing has a diameter of 0. Granulate with an extrusion granulator using a 5 m+n screen. The obtained granules were dried according to a conventional method, and talc 2, O
g, magnesium stearate 1. Add 0 g,
After mixing, tablets are compressed using a regular tablet machine to reduce the weight to approximately 1
Tablets weighing 85 mg and having a diameter of about 8 mm were obtained.
次に、メタアクリル酸・メタアクリ酸メチルjと
110、0g,ポリエチレングリコール−600010
g1タルク30gをエタノール5 0 0m+!に溶解
したコーテイング液を調製し、上記方法で得た錠剤に常
法に従かいスプレーコーティングを施こし、重量約20
0mgのフィルムコート錠剤を得た。Next, methacrylic acid/methyl methacrylate j and 110, 0g, polyethylene glycol-600010
G1 Talc 30g to ethanol 500m+! The tablets obtained by the above method were spray coated according to a conventional method, and the tablets weighed approximately 20%.
A 0 mg film-coated tablet was obtained.
この錠剤について日本薬局方(以下「日周」という。)
崩壊試験法、腸溶性製剤の項に従かい試験を行なったと
ころ、第1液(人工胃液pH 1. 2 ’)中で1時
間振盪しても崩壊せず、第2液(人工腸液p86.8)
中においては約゛8〜10分で崩壊した。About this tablet Japanese Pharmacopoeia (hereinafter referred to as "diurnal")
When a test was conducted according to the disintegration test method and enteric-coated preparation section, it did not disintegrate even after shaking for 1 hour in the first liquid (artificial gastric fluid pH 1.2'), and the second liquid (artificial intestinal fluid pH 1.2') did not disintegrate. 8)
Inside, it disintegrated in about 8 to 10 minutes.
本腸溶性フィルムコート錠は1銑中上記化合物(IV)
1mgを含有する。This enteric film-coated tablet contains the above compound (IV) in one pig.
Contains 1mg.
製剤例5(腸溶性顆粒剤)
上記化合物(IV)1.0g、コーンスターチ2 9
4、 0 g乳糖4 9 0. 0 gをとり混合機を
用いて良く混合した後、ヒドロキシプロピルセルロース
15、0gをエタノールにて溶解して加え、良く練合す
る。このものを常法に従って粒状に成形しそれをよく乾
燥して篩別し、適した顆粒を製した。Formulation example 5 (enteric coated granules) 1.0 g of the above compound (IV), cornstarch 2 9
4. 0 g lactose 4 9 0. After taking 0 g and mixing well using a mixer, add 15.0 g of hydroxypropyl cellulose dissolved in ethanol and knead well. This product was formed into granules according to a conventional method, thoroughly dried and sieved to produce suitable granules.
次にメタアクリル酸・メタアクリル酸メチル110.0
g1ポリエチレングリコール−600010g、タルク
30gをエタノール500m1に溶解したコーテイング
液を調製し、先に製した顆粒を約800gフローコータ
ー中に入れ、コーテイング液を°スプレーしながらコー
ティングし、約LOOOgのフィルムコート腸溶性顆粒
を得た。この顆粒 剤は、日周の崩壊試験器を用いて崩
壊試験を行なったところ、p++ 1.2の人工胃液中
では1時間振盪しても崩壊せず、pH6,8の人工腸液
中では6〜8分で崩壊した。Next, methacrylic acid/methyl methacrylate 110.0
Prepare a coating solution by dissolving 10 g of g1 polyethylene glycol-6000 and 30 g of talc in 500 ml of ethanol, put about 800 g of the previously prepared granules into a flow coater, coat with the coating solution while spraying, and obtain about LOOO g of film coated intestine. Soluble granules were obtained. When this granule was subjected to a disintegration test using a diurnal disintegration tester, it did not disintegrate even after shaking for 1 hour in artificial gastric fluid with a p++ of 1.2, and it did not disintegrate in artificial intestinal fluid with a pH of 6 to 8. It collapsed in eight minutes.
氷晶は1g中上記化合物(IV)を1 mg含有する。1 g of ice crystals contains 1 mg of the above compound (IV).
製剤例6(腸溶性カプセル剤)
上記化合物(rV)1.0g、コーンスターチ36.0
g、乳糖80.0 gをとり混合機を用いて良く混合し
た後、ヒドロキシプロピルセルロース3.0gをエタノ
ールにて溶解して加え、良く練合する。以下、腸溶性顆
粒と同様の操作にて顆粒剤を製し、この顆粒剤約120
gに腸溶性顆粒に用いた同一組成のコーテイング液を同
様操作にてコーティングし約140gのコーティング顆
粒を得た。このコーティング顆粒を、常法に従がい、1
力プセル約140mgずつ充填し、腸溶性カプセルとし
た。Formulation example 6 (enteric-coated capsule) 1.0 g of the above compound (rV), 36.0 g of corn starch
After taking 80.0 g of lactose and mixing well using a mixer, 3.0 g of hydroxypropylcellulose dissolved in ethanol was added and kneaded well. Hereinafter, granules were prepared in the same manner as the enteric-coated granules, and the granules had approximately 120%
g was coated with a coating liquid having the same composition as that used for enteric-coated granules in the same manner to obtain about 140 g of coated granules. The coated granules were coated with 1
Approximately 140 mg of each capsule was filled to form enteric-coated capsules.
このカプセルは、日周の崩壊試験器を用いて崩壊試験を
行なったところ、p+ 1.、2の人工胃液中に1時間
振盪しても崩壊または溶出を認めず、pH6,8の人工
腸液では、8〜10分で崩壊または全量が溶出した。When this capsule was subjected to a disintegration test using a diurnal disintegration tester, it showed p+ 1. No disintegration or elution was observed even after shaking for 1 hour in artificial gastric fluid of pH 6.8, and disintegration or elution of the entire amount occurred in 8 to 10 minutes in artificial intestinal fluid of pH 6.8.
本カプセルは、1力プセル中上記化合物(IV)を1
mg含有する。This capsule contains 1 portion of the above compound (IV) in 1 capsule.
Contains mg.
製剤例7(″パップ剤) ゼラチン22.0g、ポリビニルアルコ−5,0g。Formulation example 7 (“Poultice”) 22.0 g of gelatin, 5.0 g of polyvinyl alcohol.
メチルセルロース2.0gをとり混合機にて混合後、こ
の粉末にグリセリン26.0 gを加えて乳鉢を用いて
良く混合分散を行ない、次に精製水19.0 gを加え
て60℃で加温溶解する。このものに、カオリン1’
8.0 gを加え混合後、ポリアクリル酸ナトリウム1
. Ogをグリセリン4.0gに混合して加え混合を行
なう。さらに、このものにポリブテン3.0gを加温し
ながら加え良く混合する。そして、最後に上記化合物(
TV)0.1gを加えてさらに良く混合しペースト状物
を得た。これを木綿布に延展し使用する。After taking 2.0 g of methyl cellulose and mixing it with a mixer, add 26.0 g of glycerin to this powder, mix and disperse well using a mortar, then add 19.0 g of purified water and heat at 60°C. dissolve. This one has 1' kaolin.
After adding 8.0 g and mixing, add 1 part of sodium polyacrylate.
.. A mixture of Og and 4.0 g of glycerin is added and mixed. Furthermore, 3.0 g of polybutene was added to this mixture while heating and mixed well. And finally, the above compound (
TV) 0.1 g was added and mixed well to obtain a paste-like product. Spread this on cotton cloth and use it.
本ペースト状物質1gあたり上記化合物(IV)をL
Omg含有する。L of the above compound (IV) per 1 g of this pasty substance
Contains Omg.
製剤例8(軟膏剤)
マクロゴール−150023g、マクロゴール−400
023gプロピレングリコール53.5gをとり、約8
5°前後に加温しながら混合する。Formulation example 8 (ointment) Macrogol-150023g, Macrogol-400
Take 53.5g of 023g propylene glycol and add about 8
Mix while heating to around 5°.
これに上記化合物(TV)を0.5 g加えて同様に加
温混合後、徐々に冷却しながら混合し均一な水溶性軟膏
剤を得た。To this, 0.5 g of the above compound (TV) was added and mixed under heating in the same manner, followed by mixing while gradually cooling to obtain a uniform water-soluble ointment.
本軟膏剤は1g中5 mgの上記化合物(IV)を含有
する。This ointment contains 5 mg of the above compound (IV) per 1 g.
製剤例9(串刺)
マクロゴール−600090,0g、マクロゴール−1
50070,0g、マクロゴール−400039、05
gをとり約70°で加温混合し、これを混合しながら5
0℃まで冷却し、上記化合物(rV)を0.05 g加
えてさらに良く混合する。この液を40℃まで冷却し、
串刺形成用金型に2gずつ分b
注し、これを15〜18°まで冷却した。冷後金型を開
いて串刺を得た。Formulation Example 9 (Skewer) Macrogol-600090.0g, Macrogol-1
50070,0g, macrogol-400039,05
Take g, heat and mix at about 70°, and while mixing,
Cool to 0°C, add 0.05 g of the above compound (rV), and mix well. Cool this liquid to 40°C,
2g portions were poured into a mold for forming skewers, and the mixture was cooled to 15-18°. After cooling, the mold was opened to obtain skewers.
木串刺は、2g71個中0.5 mgの上記化合物(T
V)を含有する。Wooden skewers contain 0.5 mg of the above compound (T
V).
比較例3
化合物(TV)でRがエチル基である場合の強心作用に
ついて、モルモットの左心房を電気刺激し、収縮力を測
定する実験を行った。対照薬としてアムリノンを使用し
、第3表の結果を得た。化合物(IV)は、対照薬アム
リノンの約10倍の薬効を示した。Comparative Example 3 Regarding the inotropic effect of the compound (TV) in which R is an ethyl group, an experiment was conducted in which the left atrium of a guinea pig was electrically stimulated and the contractile force was measured. Amrinone was used as a control drug and the results shown in Table 3 were obtained. Compound (IV) exhibited approximately 10 times the efficacy of the control drug amrinone.
第3表(陽性変力作用試験)
比較例4
モルモットの心臓摘出の24時間前にモルモットにレセ
ルピン(reserpine) 3 mg / kg
腹腹腔膜投与、心カテコールアミンを枯渇させた後、比
較例3の試験と同様に行うと対照薬アムリノン(Amr
inone)の10倍の薬効を示した。(第4表)第
4 表
手続補正書
1、事件の表示 昭和61年特許願第71663号
3、補正をする者
事件との関係 出願人
名称 メクト株式会社
4、代理人
5゜補正命令の日付 自 発
1、 明細書中下記の個所を各々訂正する。Table 3 (Positive inotropic effect test) Comparative Example 4 Reserpine 3 mg/kg administered to guinea pigs 24 hours before heart extraction
After intraperitoneal administration to deplete cardiac catecholamines, the test was conducted in the same manner as in Comparative Example 3.
It was 10 times more effective than inone). (Table 4) No.
4 Written amendment to the procedure 1, Indication of the case 1985 Patent Application No. 71663 3, Relationship with the case of the person making the amendment Name of applicant Mekto Co., Ltd. 4, Agent 5゜Date of amendment order Initiation 1, Specification Please correct each of the following points.
2゜ 同書中第28頁第10行と第11行の間に下記の
文を挿入する。2゜ Insert the following sentence between lines 10 and 11 on page 28 of the same book.
[実施例9
一般式(2)において、R=n−プロピル臭化シアン1
0.0 gを無水エーテル20〇−に溶解し、2.2当
量のn−プロピルアミン無水エーテル溶液100m1を
一5℃にて滴下し、同温度にて、1時間撹拌する。反応
終了後、n−プロピルアミンの臭素酸塩をろ去し、エー
テルを15℃以下で留去する。得られる残液に水50r
d、エタノール50−を加え、50℃にて3時間加温し
た後、溶媒を留去し、得られる結晶をエタノール−水よ
り再結晶を行い、吸引ろ取した後、真空中60℃で乾燥
し、4.84 gを得た(理論量の61.1%)。[Example 9 In general formula (2), R=n-propyl cyanogen bromide 1
0.0 g was dissolved in 200 ml of anhydrous ether, 100 ml of a 2.2 equivalent solution of n-propylamine in anhydrous ether was added dropwise at -5°C, and the mixture was stirred at the same temperature for 1 hour. After the reaction is completed, the bromate of n-propylamine is filtered off, and the ether is distilled off at a temperature below 15°C. Add 50 r of water to the resulting residual liquid.
d. After adding 50% of ethanol and heating at 50°C for 3 hours, the solvent was distilled off, and the resulting crystals were recrystallized from ethanol-water, collected by suction filtration, and then dried in vacuo at 60°C. 4.84 g (61.1% of theory) was obtained.
mp87〜89℃。mp87-89°C.
元素分析(%) CI2824 NB (分子量−2
52)計算値:C,57,11; H,9,59; N
、 33.30゜実測値:C,57,12; H,9,
72、N、 33.40 。Elemental analysis (%) CI2824 NB (molecular weight -2
52) Calculated value: C, 57, 11; H, 9, 59; N
, 33.30° Actual value: C, 57, 12; H, 9,
72, N, 33.40.
1460、 1240. 1130. 1080゜94
0、 880. 740゜
’H−NMR(DMSO−d、)δ: 0.86 (9
1(、t)、0.91〜1.83(68,m) 、3.
60〜4.26(6H,m)、6.39(3N、 br
S D20にて消失)。1460, 1240. 1130. 1080°94
0, 880. 740°'H-NMR (DMSO-d,) δ: 0.86 (9
1 (, t), 0.91-1.83 (68, m), 3.
60-4.26 (6H, m), 6.39 (3N, br
Disappeared at SD20).
13C−NMR(DMSO−d6)δ:10.9(q)
、19.8(t)、45、0 (t) 、145.8
(S)。13C-NMR (DMSO-d6) δ: 10.9 (q)
, 19.8 (t), 45, 0 (t) , 145.8
(S).
MS (’/z) : 253 (M”+ 1 )。MS (’/z): 253 (M”+1).
」手続補正書
62、4.−3
昭和 年 月 日
も
特許庁長官 黒 1)明 雄 殿
1、事件の表示 昭和61年特許願第71663号
2、発明の名称 イソメラミン誘導体の製造方法及
び強心剤
3、補正をする者
事件との関係 出願人
名称 メクト株式会社
4、代理人
5、補正命令の日付 自 発
6、補正の対象 明細書の発明の詳細な説明の欄
1、 明細書第38頁第5行及び第39頁第4〜5行の
“比較例3”を「実施例9」と訂正する。” Procedural Amendment 62, 4. -3 Mr. Kuro, Commissioner of the Japan Patent Office, 1989 1) Mr. Akihiro 1, Indication of the case 1988 Patent Application No. 71663 2, Title of the invention Process for producing isomelamine derivatives and cardiotonic agent 3, Amendment with the person making the amendment Relationship: Name of applicant: Mekto Co., Ltd. 4, Agent: 5, Date of amendment order: Proprietor: 6, Subject of amendment: Detailed explanation of the invention in the specification, column 1, page 38, line 5 of the specification, and page 39, line 4 "Comparative Example 3" in lines 5 to 5 is corrected to "Example 9."
2、 同書第39頁第1行の“比較例4”を「実施例1
0」と訂正する。2. Replace “Comparative Example 4” on page 39, line 1 of the same book with “Example 1”.
0” and corrected.
3、 同書第39頁第1に、以下の文を挿入する。3. Insert the following sentence in the first page of page 39 of the same book.
「実施例11
化合物動で、Rがアリル基である場合の強心作用につい
て、モルモットの左心房を電気刺激し、収縮力を測定す
る実験を行った。対照薬としてアムリノンを使用し、第
5表の結果を得た。本化合物は、対照薬アムリノンの約
4倍の薬効を示した。Example 11 An experiment was conducted to examine the inotropic effect of a compound in which R is an allyl group by electrically stimulating the left atrium of a guinea pig and measuring the contractile force.Amrinone was used as a control drug, and Table 5 This compound showed approximately 4 times the efficacy of the control drug amrinone.
第 5 表(陽性変力作用試験)
尚、本試験において、収縮力の増加が40%以上である
とき、陽性変力ありと判断する。Table 5 (Positive inotropic effect test) In this test, when the increase in contractile force is 40% or more, it is determined that there is positive inotropy.
実施例12
(イヌ摘出血液潅流洞房結節、並びに乳頭筋標本による
、変時作用、変力作用の検討)雑種成人をベンドパルビ
クール麻酔(30mg / kg 静脈内)し、ヘパ
リン投与後脱血し、心臓を摘出し、低温タイロード液中
にて標本を作成した。洞房結節標本は、右心房より成り
、洞結節動脈に、右冠動脈を介してカニユーレを挿入し
た。右心房に縫合した双極電極より、心房エレクトロダ
ラムを導出し、心拍計を駆動し、洞調律数を計測記録し
た。Example 12 (Study of chronotropic and inotropic effects using isolated canine blood-perfused sinoatrial node and papillary muscle specimens) An adult mongrel was anesthetized with bendoparvicur (30 mg/kg intravenously), and heparin was administered, followed by exsanguination. The heart was removed and specimens were prepared in cold Tyrode's solution. The sinoatrial node preparation consisted of the right atrium, and a cannula was inserted into the sinus node artery via the right coronary artery. An atrial electrodrum was derived from a bipolar electrode sutured to the right atrium, a heart rate monitor was driven, and the sinus rhythm rate was measured and recorded.
乳頭筋標本は、右室前乳頭筋を含む心室中隔より成り、
前中隔動脈にカニユーレを挿入した。乳頭筋の発生張力
及び−次微分を張力計にて記録した。The papillary muscle specimen consists of the ventricular septum, including the right ventricular anterior papillary muscle;
A cannula was inserted into the anterior septal artery. The generated tension and −th order differential of the papillary muscles were recorded using a tensiometer.
供血犬として、大型雑種成人をベンドパルビタール麻酔
(初回、30mg/kg 静脈内、後、1時間毎に、
5■/ kg 静脈内)し、へバリン化し、(初回5
00V/kg 静脈内、その後1時間毎に200V/
kg 静脈内)、頚動脈よりポンプを介して動脈血を
導き、通気抵抗(pnenmatic resista
nce)を介して120 mmHgの定圧にて標本を交
叉潅流した。As a donor dog, an adult large mongrel was anesthetized with bendoparbital (initial dose: 30 mg/kg intravenously, then every hour.
5■/kg intravenously), hebalinized, (initial 5
00V/kg intravenously, then 200V/kg every hour thereafter.
kg (intravenous), the arterial blood is guided from the carotid artery via a pump, and the aeration resistance (pnenmatic resista) is
The specimens were cross-perfused at a constant pressure of 120 mmHg through a 100-mm Hg tube.
洞房結節標本の右冠動脈を流れる血流量及び乳頭筋標本
の前中隔動脈を流れる血流量を電磁血流計にて計測した
。The blood flow flowing through the right coronary artery of the sinoatrial node specimen and the blood flow flowing through the anterior septal artery of the papillary muscle specimen were measured using an electromagnetic blood flow meter.
標本を流れた静脈血は頚動脈より供血犬に戻した。The venous blood that had flowed through the specimen was returned to the donor dog via the carotid artery.
Claims (2)
リール基、又はアラルキル基を表す。)を無水無極性溶
媒中で反応せしめることによって次式(III): ▲数式、化学式、表等があります▼(III) (但し式(III)のRは式( I )のRと同じ。)で表さ
れるイソメラミン誘導体を製造する方法。(1) The following formulas (I) and (II): R-NH_2(I) BrCN(II) (wherein R in formula (I) represents a lower alkyl group, allyl group, aryl group, or aralkyl group) By reacting in an anhydrous nonpolar solvent, the following formula (III): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (III) (However, R in formula (III) is the same as R in formula (I).) A method for producing an isomelamine derivative.
イソメラミン誘導体を有効成分とする強心剤。(2) The following formula (IV): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (IV) A cardiotonic agent whose active ingredient is an isomelamine derivative represented by (where R represents an ethyl group or an allyl group).
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP7166386A JPS62226970A (en) | 1986-03-28 | 1986-03-28 | Production of isomelamine derivative and cardiotonic agent |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP7166386A JPS62226970A (en) | 1986-03-28 | 1986-03-28 | Production of isomelamine derivative and cardiotonic agent |
Publications (1)
Publication Number | Publication Date |
---|---|
JPS62226970A true JPS62226970A (en) | 1987-10-05 |
Family
ID=13467067
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP7166386A Pending JPS62226970A (en) | 1986-03-28 | 1986-03-28 | Production of isomelamine derivative and cardiotonic agent |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS62226970A (en) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS4917272A (en) * | 1972-06-02 | 1974-02-15 |
-
1986
- 1986-03-28 JP JP7166386A patent/JPS62226970A/en active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS4917272A (en) * | 1972-06-02 | 1974-02-15 |
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