JPS625905B2 - - Google Patents
Info
- Publication number
- JPS625905B2 JPS625905B2 JP8350485A JP8350485A JPS625905B2 JP S625905 B2 JPS625905 B2 JP S625905B2 JP 8350485 A JP8350485 A JP 8350485A JP 8350485 A JP8350485 A JP 8350485A JP S625905 B2 JPS625905 B2 JP S625905B2
- Authority
- JP
- Japan
- Prior art keywords
- biguanide
- carboxylic acid
- acid salt
- formula
- represented
- 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.)
- Expired
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】
技術分野
本発明は新規なビグアナイド誘導体複素五員環
カルボン酸塩及びその製造方法に関する。DETAILED DESCRIPTION OF THE INVENTION Technical Field The present invention relates to a novel five-membered heterocyclic carboxylic acid salt of a biguanide derivative and a method for producing the same.
発明の背景
現在一般的に糖尿病はインシユリンの作用不足
によつて起こる代謝障害であると理解されている
が、従来糖尿病における代謝異常は糖質代謝の障
害が主で、その他の障害は二次的の如く考えられ
てきた面がある。しかし近年ランドル及びウエー
バーらにより糖質代謝と脂質代謝の相互作用が明
らかにされ（Randle P.J.、Lancet１785
（1963）、Weber G.、Science1541357（1966））、
糖尿病における脂質代謝の占める役割の大きさが
認識されてきた。Background of the Invention Diabetes is currently generally understood to be a metabolic disorder caused by insufficient action of insulin, but conventionally the metabolic abnormalities in diabetes are primarily disorders of carbohydrate metabolism, with other disorders being secondary. In some ways, it has been thought that However, in recent years Randle and Weber et al. have clarified the interaction between carbohydrate metabolism and lipid metabolism (Randle PJ, Lancet 1 785
(1963), Weber G., Science 154 1357 (1966)),
The important role that lipid metabolism plays in diabetes has been recognized.
今日、ビグアナイド系糖尿病治療薬として、フ
エネチルビグアナイド、ブチルビグアナイド及び
ジメチルビグアナイドが塩酸塩として臨床的に使
用されているが、これらのビグアナイド誘導体塩
酸塩は比較的毒性が強く、また脂質に対する作用
は非常に弱いことから知られている。 Today, phenethyl biguanide, butyl biguanide, and dimethyl biguanide are used clinically as hydrochlorides as biguanide antidiabetic drugs, but these biguanide derivative hydrochlorides are relatively toxic and have no effect on lipids. It is known for being extremely weak.
本発明者はビグアナイド誘導体の顕著な血糖低
下作用に更に脂質に対する作用をも兼ね合わせて
有し、しかもより低毒性の化合物から得られれば
極めて有利な糖尿病治療薬が得られるという知見
に基づいて研究を重ねた結果、ビグアナイド誘導
体と複素五員環カルボン酸を結合せしめることに
より、その目的が達成されることを見い出した。 The present inventor conducted research based on the knowledge that biguanide derivatives have a remarkable hypoglycemic effect and also an effect on lipids, and that if obtained from a compound with lower toxicity, an extremely advantageous antidiabetic drug could be obtained. As a result of repeated research, it was discovered that this objective could be achieved by combining a biguanide derivative with a five-membered heterocyclic carboxylic acid.
発明の開示
本発明のビグアナイド誘導体複素五員環カルボ
ン酸塩は一般式
（式中R1及びR2は一方が水素原子、低級アルキル
基又はアラルキル基を、他方が低級アルキル基又
はアラルキル基を表わす）で示される化合物であ
る。式中R1及びR2で示される低級アルキル基と
しては例えばメチル、エチル、プロピル、ブチル
基等が挙げられ、アラルキル基としては例えばベ
ンジル、フエネチル基等が挙げられる。Disclosure of the Invention The biguanide derivative hetero5-membered carboxylic acid salt of the present invention has the general formula (In the formula, one of R 1 and R 2 represents a hydrogen atom, a lower alkyl group, or an aralkyl group, and the other represents a lower alkyl group or an aralkyl group.) Examples of lower alkyl groups represented by R 1 and R 2 in the formula include methyl, ethyl, propyl, and butyl groups, and examples of aralkyl groups include benzyl and phenethyl groups.
本発明の上記化合物は新規化合物であつて、優
れた血糖低下作用、遊離脂肪酸低下作用を有す
る。また連続投与においてもその効力は減じるこ
となく、糖尿病治療薬として有用なものである。 The above compound of the present invention is a new compound and has excellent hypoglycemic and free fatty acid lowering effects. In addition, its efficacy remains unchanged even after continuous administration, making it useful as a therapeutic agent for diabetes.
本発明の一般式〔１〕で示される化合物は一般
式
（式中R1及びR2は前記に同じ）で示される化合物
と式
で示される化合物を反応させことにより製造する
ことができる。 The compound represented by the general formula [1] of the present invention has the general formula (wherein R 1 and R 2 are the same as above) and the formula It can be produced by reacting the compound shown below.
本発明を詳細に説明すれば本発明原料として用
いられる化合物〔２〕及び化合物〔３〕は公知化
合物であり、化合物〔２〕としては例えばジメチ
ルビグアナイド、ブチルビグアナイド、フエネチ
ルビグアナイド等が挙げられる。化合物〔２〕は
通常反応に際しては遊離型を使用するのが好まし
いが、その鉱酸塩を使用することもできる。後者
の鉱酸塩を用いる場合は、例えば等モルの金属ナ
トリウムを無水アルコールに溶かした中へ該鉱酸
塩を加えて析出した無機塩を過して後使用する
ことが出来るが、反応に際しては必ずしも単離す
る必要はない。 To explain the present invention in detail, compound [2] and compound [3] used as raw materials of the present invention are known compounds, and examples of compound [2] include dimethyl biguanide, butyl biguanide, phenethyl biguanide, etc. . Compound [2] is usually preferably used in its free form during the reaction, but its mineral acid salt can also be used. When using the latter mineral salt, for example, the mineral salt can be added to an equimolar amount of sodium metal dissolved in anhydrous alcohol, and the precipitated inorganic salt can be filtered and used later. It does not necessarily have to be isolated.
化合物〔２〕と化合物〔３〕の反応は通常溶媒
中で行なうのが好ましい。溶媒としては反応に関
与しないものである限り特に限定されないが、一
般にメタノール、エタノール、アセトン等が好適
に使用される。化合物〔２〕と化合物〔３〕の割
合は適宜選択すればよいが一般に等モル使用する
のが有利である。反応温度も適宜選択すればよい
が一般に室温〜100℃において有利に進行する。 The reaction between compound [2] and compound [3] is usually preferably carried out in a solvent. The solvent is not particularly limited as long as it does not participate in the reaction, but methanol, ethanol, acetone, etc. are generally preferably used. The ratio of compound [2] and compound [3] may be selected as appropriate, but it is generally advantageous to use equimolar amounts. Although the reaction temperature may be selected appropriately, the reaction generally proceeds advantageously at room temperature to 100°C.
上記反応により新規化合物〔１〕が生成し、こ
れは蒸留、クロマトグラフイー、再結晶等の通常
の分離手段により単離可能である。 The above reaction produces a new compound [1], which can be isolated by conventional separation means such as distillation, chromatography, recrystallization, etc.
実施例
次に本発明の実施例を挙げて具体的に説明す
る。EXAMPLES Next, the present invention will be specifically explained by giving examples.
実施例 １
無水メタノール80mlに金属ナトリウム1.38ｇを
溶解したのち、１・１−ジメチルビグアナイド硫
酸塩6.81ｇを加える。室温で１時間、還流下に１
時間撹拌する。冷時不溶物を除去した後、３−メ
チルピラゾール−５−カルボン酸3.79ｇを加え
る。室温で１時間撹拌し、溶媒を減圧留去する。
残渣をイソプロピルアルコール−水から再結晶す
るとmp233〜235℃の１・１−ジメチルビグアナ
イドの３−メチルピラゾール−５−カルボン酸塩
5.7ｇを得る。（収率75.0％）
元素分析（C9H17N7O2）
Ｃ Ｈ Ｎ
計算値（％） 42.35 6.71 38.41
分析値（％） 41.97 6.67 38.12
実施例 ２
実施例１における１・１−ジメチルビグアナイ
ド硫酸塩にかえ１−ｎ−ブチルビグアナイド硫酸
塩を使用し、同様に操作を行ないイソプロピルア
ルコールから再結晶するとmp155〜156℃の１−
ｎ−ブチルビグアナイドの３−メチルピラゾール
−５−カルボン酸塩を得る。（収率72.6％）
元素分析（C11H21N7O2）
Ｃ Ｈ Ｎ
計算値（％） 46.63 7.47 34.61
分析値（％） 46.87 7.61 34.44
実施例 ３
実施例１における１・１−ジメチルビグアナイ
ド硫酸塩にかえ１−フエネチルビグアナイド塩酸
塩を使用し、同様に操作を行ないエタノール−エ
ーテル−アセトンから再結晶するとmp155〜158
℃の１−フエネチルビグアナイドの３−メチルピ
ラゾール−５−カルボン酸塩を得る。（収率70.5
％）
元素分析（C15H21N7O2）
Ｃ Ｈ Ｎ
計算値（％） 54.37 6.39 29.59
分析値（％） 54.16 6.39 29.24Example 1 After dissolving 1.38 g of metallic sodium in 80 ml of anhydrous methanol, 6.81 g of 1,1-dimethyl biguanide sulfate is added. 1 hour under reflux at room temperature.
Stir for an hour. After removing insoluble materials during cooling, 3.79 g of 3-methylpyrazole-5-carboxylic acid is added. Stir at room temperature for 1 hour and remove the solvent under reduced pressure.
Recrystallization of the residue from isopropyl alcohol-water yields 3-methylpyrazole-5-carboxylate of 1,1-dimethylbiguanide with a mp of 233 to 235°C.
Obtain 5.7g. (Yield 75.0%) Elemental analysis (C 9 H 17 N 7 O 2 ) C H N Calculated value (%) 42.35 6.71 38.41 Analysis value (%) 41.97 6.67 38.12 Example 2 1,1-dimethyl biguanide in Example 1 Using 1-n-butyl biguanide sulfate instead of sulfate and recrystallizing from isopropyl alcohol results in 1-n-butyl biguanide sulfate with mp 155-156℃.
A 3-methylpyrazole-5-carboxylic acid salt of n-butyl biguanide is obtained. (Yield 72.6%) Elemental analysis (C 11 H 21 N 7 O 2 ) C H N Calculated value (%) 46.63 7.47 34.61 Analysis value (%) 46.87 7.61 34.44 Example 3 1,1-dimethyl biguanide in Example 1 Using 1-phenethyl biguanide hydrochloride instead of sulfate and recrystallizing from ethanol-ether-acetone results in mp155-158.
3-methylpyrazole-5-carboxylic acid salt of 1-phenethyl biguanide at a temperature of 1-phenethyl biguanide is obtained. (yield 70.5
%) Elemental analysis (C 15 H 21 N 7 O 2 ) C H N Calculated value (%) 54.37 6.39 29.59 Analysis value (%) 54.16 6.39 29.24
Claims (1)
基又はアラルキル基を、他方が低級アルキル基又
はアラルキル基を表わす）で示されるビグアナイ
ド誘導体複素五員環カルボン酸塩。 ２ 式 で示される特許請求の範囲第１項記載のビグアナ
イド誘導体複素五員環カルボン酸塩。 ３ 式 で示される特許請求の範囲第１項記載のビグアナ
イド誘導体複素五員環カルボン酸塩。 ４ 式 で示される特許請求の範囲第１項記載のビグアナ
イド誘導体複素五員環カルボン酸塩。 ５ 一般式 （式中R1及びR2は一方が水素原子、低級アルキル
基又はアラルキル基を、他方が低級アルキル基又
はアラルキル基を表わす）で示される化合物と式 で示される化合物を反応させることを特徴とする
一般式 （式中R1及びR2は前記に同じ）で示されるビグア
ナイド誘導体複素五員環カルボン酸塩の製造方
法。[Claims] 1. General formula (In the formula, one of R 1 and R 2 represents a hydrogen atom, a lower alkyl group, or an aralkyl group, and the other represents a lower alkyl group or an aralkyl group.) A biguanide derivative hetero5-membered ring carboxylic acid salt. 2 formulas The biguanide derivative hetero5-membered ring carboxylic acid salt according to claim 1, which is represented by: 3 formulas The biguanide derivative hetero5-membered ring carboxylic acid salt according to claim 1, which is represented by: 4 formula The biguanide derivative hetero5-membered ring carboxylic acid salt according to claim 1, which is represented by: 5 General formula (In the formula, one of R 1 and R 2 represents a hydrogen atom, a lower alkyl group, or an aralkyl group, and the other represents a lower alkyl group or an aralkyl group.) A general formula characterized by reacting a compound represented by A method for producing a biguanide derivative hetero five-membered carboxylic acid salt represented by the formula (wherein R 1 and R 2 are the same as above).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8350485A JPS6122071A (en) | 1985-04-18 | 1985-04-18 | Biguanide derivative 5-membered ring heterocyclic carboxylic acid salt and its preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8350485A JPS6122071A (en) | 1985-04-18 | 1985-04-18 | Biguanide derivative 5-membered ring heterocyclic carboxylic acid salt and its preparation |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP7920877A Division JPS6047263B2 (en) | 1977-07-01 | 1977-07-01 | Biguanide derivative hetero5-membered ring carboxylic acid salt and method for producing the same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6122071A JPS6122071A (en) | 1986-01-30 |
| JPS625905B2 true JPS625905B2 (en) | 1987-02-07 |
Family
ID=13804309
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP8350485A Granted JPS6122071A (en) | 1985-04-18 | 1985-04-18 | Biguanide derivative 5-membered ring heterocyclic carboxylic acid salt and its preparation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS6122071A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1299185B1 (en) | 2000-07-12 | 2011-03-02 | Albemarle Netherlands B.V. | Mixed metal catalyst comprising a combustible binder |
-
1985
- 1985-04-18 JP JP8350485A patent/JPS6122071A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6122071A (en) | 1986-01-30 |
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