JP2001106674A - Method for producing ipidacrine hydrochloride hydrate - Google Patents
Method for producing ipidacrine hydrochloride hydrateInfo
- Publication number
- JP2001106674A JP2001106674A JP2000138855A JP2000138855A JP2001106674A JP 2001106674 A JP2001106674 A JP 2001106674A JP 2000138855 A JP2000138855 A JP 2000138855A JP 2000138855 A JP2000138855 A JP 2000138855A JP 2001106674 A JP2001106674 A JP 2001106674A
- Authority
- JP
- Japan
- Prior art keywords
- hydrate
- ipidacrine hydrochloride
- ipidacrine
- water
- producing
- 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
Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は下式（Ｉ）TECHNICAL FIELD The present invention relates to the following formula (I)
【０００２】[0002]
【化１】 Embedded image
【０００３】で表される塩酸イピダクリン水和物（９−
アミノ−２，３，５，６，７，８−ヘキサヒドロ−１Ｈ
−シクロペンタ［ｂ］キノリン一塩酸塩一水和物）の製
造方法に関する。[0003] Ipidacrine hydrochloride hydrate (9-
Amino-2,3,5,6,7,8-hexahydro-1H
-Cyclopenta [b] quinoline monohydrochloride monohydrate).
【０００４】塩酸イピダクリン水和物は、コリンエステ
ラーゼ阻害作用を有することが知られており、老人の痴
呆、特にアルツハイマー型痴呆の治療薬として期待され
ている有用な化合物である。[0004] Ipidacrine hydrochloride hydrate is known to have a cholinesterase inhibitory action, and is a useful compound which is expected as a therapeutic drug for dementia of the elderly, particularly Alzheimer's dementia.
【０００５】塩酸イピダクリン水和物は抹消神経系統に
おける興奮伝達の刺戟効果がある化合物として報告され
ている［特公昭６３−３５６１１］。また、学習促進・
記憶増強効果がある化合物としても報告されている［特
公平３−５４９２２］。式（Ｉ）で表される化合物の製
造方法としては、例えば特許第２５１０５８６号公報が
知られている。本方法は、反応により得られた塩酸塩化
する前の９−アミノ−２，３，５，６，７，８−ヘキサ
ヒドロ−１Ｈ−シクロペンタ［ｂ］キノリン（以下、イ
ピダクリンという）の粗結晶をエタノール等の有機溶媒
に溶解し、塩化水素ガスを吹き込み塩酸塩化することに
より製造している。この塩酸塩化の工程によりイピダク
リンは塩酸が１分子付加した塩酸イピダクリンになり、
更に部分的に水が結合した塩酸イピダクリンの部分水和
物として得られる。得られた部分水和物は、２−プロパ
ノール、エタノール等のアルコール系溶媒、酢酸エチル
等のエステル系有機溶媒で再結晶をすることにより精製
することができる。[0005] Ipidacrine hydrochloride hydrate has been reported as a compound having a stimulatory effect on excitatory transmission in the peripheral nervous system [JP-B-63-35611]. In addition, learning promotion
It has also been reported as a compound having a memory enhancing effect [Japanese Patent Publication No. 3-54922]. As a method for producing the compound represented by the formula (I), for example, Japanese Patent No. 2510586 is known. The present method comprises the steps of: subjecting a crude crystal of 9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta [b] quinoline (hereinafter referred to as ipidacrine) obtained by the reaction to a salt with hydrochloric acid to ethanol. It is manufactured by dissolving in an organic solvent such as those described above and blowing hydrogen chloride gas to convert it into hydrochloric acid. This process of hydrochlorination turns ipidacrine into ipidacrine hydrochloride to which one molecule of hydrochloric acid has been added.
Further, it is obtained as a partial hydrate of ipidacrine hydrochloride partially bound to water. The obtained partial hydrate can be purified by recrystallization with an alcoholic solvent such as 2-propanol and ethanol or an ester organic solvent such as ethyl acetate.
【０００６】例えば、上記のアルコール系溶媒を用いて
再結晶を行い乾燥させた結晶は、塩酸イピダクリン１分
子に対して０．４〜０．８分子の水（結晶水）が結合し
た状態の化合物として得られる。一方、塩酸イピダクリ
ンは１分子の水を結晶水として有している状態（塩酸イ
ピダクリン水和物）が最も安定しているため、塩酸イピ
ダクリンの部分水和物は室内に放置すると長期間にわた
り徐々に水分を吸収して塩酸イピダクリン水和物にな
る。For example, recrystallized and dried crystals of the above-mentioned alcohol-based solvent are compounds having 0.4 to 0.8 molecules of water (water of crystallization) bound to 1 molecule of ipidacrine hydrochloride. Is obtained as On the other hand, ipidacrine hydrochloride is the most stable state in which one molecule of water is contained as water of crystallization (ipidacrine hydrochloride hydrate). Absorbs water to form ipidacrine hydrochloride hydrate.
【０００７】こうした現象は、結晶に再結晶溶媒が相当
量（２−プロパノールの場合は濃度が約２００〜３００
０ｐｐｍ程度）残留し、１分子の結晶水の付加を阻害す
ることが原因と考えられる。このため残留する溶媒を完
全に除去するには、乾燥時間の延長、高温処理、減圧乾
燥等の乾燥条件をより厳しく設定しなければならない
が、残留する溶媒が極微量の部分的な溶媒和を形成して
いると推定され、完全には溶媒を除去することが困難で
ある上、結晶水の放出、結晶の着色などが認められるこ
ともあり、決して好ましい方法とは言い難い。なお、再
結晶で得られた結晶は、長時間加湿（例えば、４０℃、
相対湿度７５％の条件下で１ヶ月以上）することによ
り、１分子の結晶水に完全に置換した水和物に変換する
ことができるが、このような長時間の加湿は、製造時間
上及び製造コスト上非常に不利である。[0007] This phenomenon is caused by the fact that a recrystallization solvent is added to the crystal in a considerable amount (in the case of 2-propanol, the concentration is about 200 to 300
This is considered to be caused by the fact that it remains and inhibits the addition of one molecule of crystallization water. For this reason, in order to completely remove the residual solvent, drying conditions such as extension of drying time, high-temperature treatment, and drying under reduced pressure must be set more strictly. It is presumed that it is formed, and it is difficult to completely remove the solvent. In addition, release of water of crystallization, coloring of the crystal, and the like may be observed, and it is hardly a preferable method. In addition, the crystal obtained by the recrystallization is humidified for a long time (for example, 40 ° C.,
(1 month or more under the condition of a relative humidity of 75%) can be converted into a hydrate completely substituted with one molecule of water of crystallization. It is very disadvantageous in manufacturing cost.
【０００８】[0008]
【発明が解決しようとする課題】再結晶で精製した化合
物を医薬品として使用する場合、最終の再結晶工程で使
用した有機溶媒の残留率について測定し、その品質規格
限度値を設定し、管理することが必須である。塩酸イピ
ダクリン水和物は再結晶で使用した溶媒の影響（残留溶
媒の影響）により赤外吸収スペクトル、熱分析（ＤＳ
Ｃ）、粉末Ｘ線回折スペクトルなどに変化が認められる
ことが知られている（医薬品研究 ２８，９，６４３−
６５３（１９９７））。これは、再結晶で使用したエタ
ノール等の溶媒が微量ではあるが塩酸イピダクリン水和
物の結晶水の一部分と置換した溶媒混合水和物を形成し
ているためと考えられる。この場合、僅かな残留溶媒に
より、結晶水の結合状態に影響を及ぼし、それに伴い赤
外吸収スペクトル等が変化する。このため、微量の残留
溶媒が含まれる塩酸イピダクリン水和物は、溶媒を完全
に除去しない限り、確認試験として赤外吸収スペクトル
の参照スペクトルチャートに一致するとの記載ができな
くなる。このような理由で、医薬品原料の場合、再結晶
で使用した有機溶媒を完全に除去することは極めて重要
である。When a compound purified by recrystallization is used as a drug, the residual ratio of the organic solvent used in the final recrystallization step is measured, and its quality standard limit is set and managed. It is essential. Ipidacrine hydrochloride hydrate has an infrared absorption spectrum and thermal analysis (DS) due to the effect of the solvent used for recrystallization (effect of residual solvent).
C), it is known that there is a change in the powder X-ray diffraction spectrum, etc. (Pharmaceutical Research 28, 9, 643-
653 (1997)). This is presumably because the solvent such as ethanol used in the recrystallization was a trace amount, but formed a mixed solvent hydrate in which a part of the water of crystallization of ipidacrine hydrochloride hydrate was substituted. In this case, the slight residual solvent affects the bonding state of the water of crystallization, and the infrared absorption spectrum and the like change accordingly. Therefore, unless the solvent is completely removed, it is impossible to describe that ipidacrine hydrochloride hydrate containing a trace amount of the residual solvent coincides with the reference spectrum chart of the infrared absorption spectrum as a confirmation test. For these reasons, in the case of pharmaceutical raw materials, it is extremely important to completely remove the organic solvent used in the recrystallization.
【０００９】[0009]
【課題を解決するための手段】本発明者らは、再結晶に
使用した有機溶媒を除去する方法について種々検討を行
った結果、残留溶媒のない水和物を簡単な方法で短時間
に得ることができる製造方法を見出し本発明を完成する
に至った。本発明は、１）再結晶により得られた残留溶
媒の存在する塩酸イピダクリンの部分水和物に水を加え
て混合し、得られた混合物を乾燥するか、２）該塩酸イ
ピダクリンの部分水和物を高温高湿下に放置することを
特徴とする残留溶媒の含まれない塩酸イピダクリン水和
物の製造方法である。The present inventors have conducted various studies on a method for removing the organic solvent used for recrystallization, and as a result, obtained a hydrate having no residual solvent by a simple method in a short time. The present invention has been completed by finding a manufacturing method that can be used. The present invention relates to 1) partial addition of water to a partial hydrate of ipidacrine hydrochloride in the presence of a residual solvent obtained by recrystallization, followed by mixing and drying of the resulting mixture, or 2) partial hydration of the ipidacrine hydrochloride. A method for producing ipidacrine hydrochloride hydrate containing no residual solvent, wherein the product is left under high temperature and high humidity.
【００１０】[0010]
【発明の実施の形態】以下、本発明を更に詳細に説明す
る。上記１）の方法は、残留溶媒の存在する塩酸イピダ
クリンの部分水和物に適当量の水、通常、重量比で２倍
〜０．０１倍量、好ましくは１．５倍〜０．０５倍量の
水を加えて、均一に混合し、クリーム状態あるいは結晶
が少し湿った状態にし、次いで、過剰の水分を減圧下あ
るいは常圧下で乾燥させることにより行われる。この処
理により結晶中に残留している溶媒は、過剰の水と共に
速やかに除去され、分子中に１分子の結晶水を含有し、
有機溶媒が全く残留していない塩酸イピダクリン水和物
となる。過剰の水分を加えずそのまま放置した結晶では
数ヶ月単位で溶媒が残留するのに対して、水を添加する
方法では、過剰の水分が蒸発した時点で残留溶媒はほと
んど消失する。BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail. The method of the above 1) is a method in which a partial hydrate of ipidacrine hydrochloride in which a residual solvent is present has an appropriate amount of water, usually 2 to 0.01 times, preferably 1.5 to 0.05 times by weight. This is done by adding an amount of water and mixing uniformly to make the cream or crystals slightly wet, and then drying the excess water under reduced pressure or normal pressure. The solvent remaining in the crystal by this treatment is promptly removed together with excess water, and contains one molecule of crystal water in the molecule.
It becomes ipidacrine hydrochloride hydrate in which no organic solvent remains. In a crystal that has been left as it is without adding excess water, the solvent remains in a unit of several months, whereas in the method of adding water, the residual solvent almost disappears when the excess water evaporates.
【００１１】上記２）の方法は、残留溶媒の存在する塩
酸イピダクリンの部分水和物を高温高湿下、通常、６０
〜９０℃、相対湿度６０〜１００％の雰囲気下、好まし
くは７０〜８５℃、相対湿度７０〜９５％の雰囲気下に
残留溶媒が消失するまで放置することにより行われる。
例えば、８０℃相対湿度８０％の雰囲気下では、１時間
程度で赤外吸収スペクトルに変化が現れ、処理を行う結
晶を薄い層状で放置した場合では約８時間程度で結晶中
の残留溶媒が消失し処理が完結する。残留溶媒の存在す
る塩酸イピダクリンの部分水和物及び塩酸イピダクリン
水和物の結晶は、この様な高湿な条件下においても吸湿
性（あるいは潮解性）を示さず安定である。In the above method 2), a partial hydrate of ipidacrine hydrochloride in which a residual solvent is present is dissolved under high temperature and high humidity, usually at 60.degree.
This is carried out by leaving the mixture in an atmosphere at a temperature of about 90 ° C. and a relative humidity of 60 to 100%, preferably at an atmosphere of 70 to 85 ° C. and a relative humidity of 70 to 95% until the residual solvent disappears.
For example, in an atmosphere at a temperature of 80 ° C. and a relative humidity of 80%, the infrared absorption spectrum changes in about 1 hour, and when the crystal to be processed is left in a thin layer, the residual solvent in the crystal disappears in about 8 hours. The process is completed. The partial hydrate of ipidacrine hydrochloride and the crystals of hydrate of ipidacrine hydrochloride in which a residual solvent is present are stable without exhibiting hygroscopicity (or deliquescent) even under such high humidity conditions.
【００１２】塩酸イピダクリン水和物は、１分子の水を
結晶水として含有している状態が最も安定しているた
め、通常室温下で空気中に保存している限りは、結晶に
吸湿性や結晶水の脱離現象は認められないが、減圧下で
は徐々に結晶水の一部が蒸発し、部分水和物になること
がある。このため、上記１）の場合に過剰の水分の乾燥
処理を減圧下で加熱を行う方法で処理した場合、乾燥時
間が長いと結晶水の一部脱離現象が確認されるため、注
意が必要となる。Ipidacrine hydrochloride hydrate is most stable when it contains one molecule of water as water of crystallization. Therefore, as long as it is stored in the air at room temperature, it usually has a hygroscopic property. Although no desorption phenomenon of the water of crystallization is observed, a part of the water of crystallization may gradually evaporate under reduced pressure to form a partial hydrate. For this reason, in the case of the above 1), when the drying treatment of excess moisture is performed by heating under reduced pressure, if the drying time is long, a partial desorption phenomenon of the crystallization water is confirmed, so care must be taken. Becomes
【００１３】また、本発明では乾燥し過ぎた場合（過剰
乾燥の場合）、水の含量が１分子未満の化合物が得られ
る場合があるが、この化合物は、残留溶媒を全く含まな
いため、該化合物を加湿下に放置することにより、すみ
やかに水を吸収し１分子の結晶水を有する塩酸イピダク
リン水和物に変換することができる。本発明で製造され
る塩酸イピダクリン水和物は、下記実施例にて示す通り
赤外吸収スペクトルが残留溶媒の含まれないパターン
（Ａ型）を示す。また、塩酸イピダクリン水和物は、必
要であれば粉砕篩過することによって医薬品として用い
ることができる。In the present invention, when the composition is excessively dried (excessive drying), a compound having a water content of less than one molecule may be obtained. By leaving the compound under humidification, water can be rapidly absorbed and converted to ipidacrine hydrochloride hydrate having one molecule of water of crystallization. The ipidacrine hydrochloride hydrate produced by the present invention has a pattern (type A) in which the infrared absorption spectrum does not include the residual solvent as shown in the following Examples. In addition, ipidacrine hydrochloride hydrate can be used as a medicine by pulverizing and sieving if necessary.
【００１４】本発明では塩酸イピダクリン水和物が残留
溶媒の含まれない結晶として得られる。この結晶は赤外
吸収スペクトルが標準スペクトルチャートと一致してお
り、Ｘ線構造解析による結晶形も標準品と同一である。In the present invention, ipidacrine hydrochloride hydrate is obtained as crystals containing no residual solvent. This crystal has an infrared absorption spectrum consistent with the standard spectrum chart, and the crystal form by X-ray structural analysis is the same as the standard product.
【００１５】[0015]
【実施例】以下に、参考例及び実施例を示し、本発明を
更に詳細に説明するが、本発明の範囲はこれらに限定さ
れるものではない。 参考例１ 塩酸イピダクリンの部分水和物を２−プロパノールから
再結晶し、溶媒を留去した後、６０℃で減圧にて３日間
乾燥した化合物を試料として用いた（水分量：３．０１
％）。EXAMPLES The present invention will be described in more detail with reference to the following Reference Examples and Examples, which should not be construed as limiting the scope of the present invention. Reference Example 1 A partial hydrate of ipidacrine hydrochloride was recrystallized from 2-propanol, and after distilling off the solvent, a compound dried at 60 ° C. under reduced pressure for 3 days was used as a sample (water content: 3.01).
%).
【００１６】実施例１ 参考例１で得た試料１５ｇに水を１５ｇまたは２０ｇ加
えて混合しクリーム状態とした。次いで、得られたクリ
ーム状混合物を層の厚さを変え、それぞれ減圧下、６０
℃で２４時間〜７２時間乾燥した。これらの条件で得ら
れた化合物の水分量及び赤外吸収スペクトル(ＩＲ)を測
定した結果を第１表に示した。Example 1 15 g or 20 g of water was added to 15 g of the sample obtained in Reference Example 1 and mixed to form a cream. Next, the obtained creamy mixture was changed in layer thickness,
Dry at 24 ° C. for 24-72 hours. Table 1 shows the results of measuring the water content and the infrared absorption spectrum (IR) of the compound obtained under these conditions.
【００１７】[0017]
【表１】 [Table 1]
【００１８】実施例２ 乾燥を室温で２４時間〜７２時間行うこと以外は実施例
１と同様に処理し、得られた化合物の水分量及び赤外吸
収スペクトル（ＩＲ）を測定し、その結果を第２表に示
した。Example 2 The same treatment as in Example 1 was conducted except that drying was performed at room temperature for 24 hours to 72 hours. The obtained compound was measured for water content and infrared absorption spectrum (IR). The results are shown in Table 2.
【００１９】[0019]
【表２】 [Table 2]
【００２０】参考例２ 塩酸イピダクリンの部分水和物１８８．８ｇを２−プロ
パノール１２５０ｍＬから再結晶し、結晶を濾過した
後、付着溶媒を空気中で乾燥させることにより得た化合
物（１１０．５ｇ）を実施例３の試料とした。Reference Example 2 A compound (110.5 g) obtained by recrystallizing 188.8 g of partial hydrate of ipidacrine hydrochloride from 1250 mL of 2-propanol, filtering the crystals, and drying the attached solvent in the air. Was used as the sample of Example 3.
【００２１】実施例３ 参考例２で得た化合物（試料）を３００ｍＬビーカに層
の厚さが５ｃｍ程度になるように入れ、８０℃、相対湿
度８０％の環境下に１〜４８時間放置した。放置時間の
違う結晶毎に赤外吸収スペクトル（ＩＲ）を測定し、そ
の結果を第３表に示した。Example 3 The compound (sample) obtained in Reference Example 2 was placed in a 300 mL beaker so that the thickness of the layer became about 5 cm, and left in an environment of 80 ° C. and a relative humidity of 80% for 1 to 48 hours. . An infrared absorption spectrum (IR) was measured for each crystal having a different standing time, and the results are shown in Table 3.
【００２２】[0022]
【表３】 [Table 3]
【００２３】参考例３（従来法） 参考例１で得た試料１５ｇを加湿条件下（４０℃、７５
％）で２４〜７２時間放置することにより塩酸イピダク
リン水和物を得た。得られた塩酸イピダクリン水和物に
ついて、その水分量及び赤外吸収スペクトル（ＩＲ）を
測定した。その結果を前記実施例１及び実施例２の結果
並びに標準品のデータと合わせて第４表に示した。Reference Example 3 (Conventional Method) 15 g of the sample obtained in Reference Example 1 was humidified (40 ° C., 75
%) To obtain ipidacrine hydrochloride hydrate. The water content and infrared absorption spectrum (IR) of the obtained ipidacrine hydrochloride hydrate were measured. The results are shown in Table 4 together with the results of Examples 1 and 2 and the data of the standard product.
【００２４】[0024]
【表４】 [Table 4]
【００２５】[0025]
【発明の効果】本発明は、再結晶により精製した塩酸イ
ピダクリンの部分水和物より、簡単な方法で短時間に残
留有機溶媒のない塩酸イピダクリン水和物を得ることが
できるため極めて有用な方法である。Industrial Applicability The present invention is an extremely useful method since it is possible to obtain ipidacrine hydrochloride hydrate free of residual organic solvent in a short time from a partial hydrate of ipidacrine hydrochloride purified by recrystallization. It is.
【００２６】[0026]
【図１】塩酸イピダクリン水和物のＡ型の赤外吸収スペ
クトルを示す図である。FIG. 1 is a view showing an infrared absorption spectrum of Form A of ipidacrine hydrochloride hydrate.
【図２】塩酸イピダクリン水和物のＢ型の赤外吸収スペ
クトルを示す図である。FIG. 2 is a view showing an infrared absorption spectrum of Form B of ipidacrine hydrochloride hydrate.
Claims (4)
分水和物に水を加えて混合し、得られた混合物を乾燥す
ることを特徴とする塩酸イピダクリン水和物（９−アミ
ノ−２，３，５，６，７，８−ヘキサヒドロ−１Ｈ−シ
クロペンタ［ｂ］キノリン一塩酸塩一水和物）の製造方
法。1. A method comprising adding water to a partial hydrate of ipidacrine hydrochloride in which a residual solvent is present, mixing the resulting mixture, and drying the resulting mixture. , 5,6,7,8-Hexahydro-1H-cyclopenta [b] quinoline monohydrochloride monohydrate).
分水和物を高温高湿下に放置することを特徴とする塩酸
イピダクリン水和物の製造方法。2. A method for producing ipidacrine hydrochloride hydrate, wherein a partial hydrate of ipidacrine hydrochloride having a residual solvent is left under high temperature and high humidity.
度６０〜１００％の雰囲気下であることを特徴とする請
求項２記載の塩酸イピダクリン水和物の製造方法。3. The method for producing ipidacrine hydrochloride hydrate according to claim 2, wherein the conditions under high temperature and high humidity are an atmosphere of 60 to 90 ° C. and a relative humidity of 60 to 100%.
溶媒が含まれない赤外吸収スペクトル（Ａ型）を示すも
のであることを特徴する請求項１〜請求項３記載の塩酸
イピダクリン水和物の製造方法。4. The hydrate of ipidacrine hydrochloride according to claim 1, wherein the hydrate of ipidacrine hydrochloride produced has an infrared absorption spectrum (type A) containing no residual solvent. Method of manufacturing a product.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2000138855A JP2001106674A (en) | 1999-05-13 | 2000-05-11 | Method for producing ipidacrine hydrochloride hydrate |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13219099 | 1999-05-13 | ||
| JP11-216564 | 1999-07-30 | ||
| JP21656499 | 1999-07-30 | ||
| JP11-132190 | 1999-07-30 | ||
| JP2000138855A JP2001106674A (en) | 1999-05-13 | 2000-05-11 | Method for producing ipidacrine hydrochloride hydrate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JP2001106674A true JP2001106674A (en) | 2001-04-17 |
Family
ID=27316452
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2000138855A Pending JP2001106674A (en) | 1999-05-13 | 2000-05-11 | Method for producing ipidacrine hydrochloride hydrate |
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| JP (1) | JP2001106674A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001081075A (en) * | 1999-07-09 | 2001-03-27 | Nikken Chem Co Ltd | Production of ipidacrine and ipidacrine hydrochloride hydrate |
| EP1201656A4 (en) * | 1999-07-09 | 2002-10-09 | Nikken Chemicals Co Ltd | Processes for the preparation of ipidacrine or ipidacrine hydrochloride hydrate |
| JP2005533836A (en) * | 2002-07-16 | 2005-11-10 | バイエル・ヘルスケア・アクチェンゲゼルシャフト | Drugs containing vardenafil hydrochloride trihydrate |
| JP2009280510A (en) * | 2008-05-20 | 2009-12-03 | Daicel Chem Ind Ltd | METHOD FOR PRODUCING beta-KETOAMIDE DERIVATIVE HAVING NITROGEN-CONTAINING HETEROCYCLE |
| RU2659783C1 (en) * | 2018-04-05 | 2018-07-04 | АО "Щелково Агрохим" | Process of preparation of 9-amino-2,3,5,6,7,8-hexahydro-1h-cyclopenta[b]quinoline chlorohydrate, hydrate |
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| WO2001004094A1 (en) * | 1999-07-09 | 2001-01-18 | Nikken Chemicals Co., Ltd. | Processes for the preparation of ipidacrine or ipidacrine hydrochloride hydrate |
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| US4550113A (en) * | 1982-08-19 | 1985-10-29 | Nauchno-Issledovatelsky Institut Po Biologicheskikm Ispytaniyam Khimicheskikh Soedineny | 9-Amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta(b)quinoline monohydrate hydrochloride as stimulant of neuro-muscular transmission of smooth muscles |
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| WO2001004094A1 (en) * | 1999-07-09 | 2001-01-18 | Nikken Chemicals Co., Ltd. | Processes for the preparation of ipidacrine or ipidacrine hydrochloride hydrate |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001081075A (en) * | 1999-07-09 | 2001-03-27 | Nikken Chem Co Ltd | Production of ipidacrine and ipidacrine hydrochloride hydrate |
| EP1201656A4 (en) * | 1999-07-09 | 2002-10-09 | Nikken Chemicals Co Ltd | Processes for the preparation of ipidacrine or ipidacrine hydrochloride hydrate |
| JP4587529B2 (en) * | 1999-07-09 | 2010-11-24 | 興和創薬株式会社 | Method for producing ipidacrine and ipidacrine hydrochloride hydrate |
| JP2005533836A (en) * | 2002-07-16 | 2005-11-10 | バイエル・ヘルスケア・アクチェンゲゼルシャフト | Drugs containing vardenafil hydrochloride trihydrate |
| JP2013063982A (en) * | 2002-07-16 | 2013-04-11 | Bayer Pharma AG | Medicament containing vardenafil hydrochloride trihydrate |
| JP2009280510A (en) * | 2008-05-20 | 2009-12-03 | Daicel Chem Ind Ltd | METHOD FOR PRODUCING beta-KETOAMIDE DERIVATIVE HAVING NITROGEN-CONTAINING HETEROCYCLE |
| RU2659783C1 (en) * | 2018-04-05 | 2018-07-04 | АО "Щелково Агрохим" | Process of preparation of 9-amino-2,3,5,6,7,8-hexahydro-1h-cyclopenta[b]quinoline chlorohydrate, hydrate |
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