Derivatives of isosorbid mononitrate, utilization as vasodilator agents with reduced tolerance

A technology of isosorbide and nitrate, applied in the direction of cardiovascular system diseases, drug combinations, active ingredients of heterocyclic compounds, etc., can solve the problems of low vasodilation activity and high tolerance

Inactive Publication Date: 2001-11-14
LACER SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] The nitrated organic compounds described in the above-mentioned documents do not solve the problem of tolerance originating from the nitrated organic compounds by themselves, since they still have problems such as low vasodilatory activity, high tolerance, etc.

Method used

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  • Derivatives of isosorbid mononitrate, utilization as vasodilator agents with reduced tolerance

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 2

[0059] (CH 2 ), 23.84 (CH 2 -S), 14.31 (CH 3 ). Example 2 Obtaining 5-(2'-ethylthio) nicotinate 2-mononitrate hydrochloride of isosorbide

[0060] Step 1. The same method as in Step 2 in Example 1 was used, and 2-mononitrate of isosorbide was used as the starting compound. The chemical yield of the expected compound was obtained in 88%.

[0061] Step 2. In the 500 milliliters of three-neck glass flasks of the reflux condenser of calcium chloride tube sealing, magnetic stirrer and constant pressure dropping funnel, 7.0 grams (19.66 millimoles) the product that last step obtains is dissolved in 200 milliliters A mixed solution of EtOEt and 100 ml of dichloromethane. The solution was stirred at room temperature, and 30 ml of hydrogen chloride-saturated EtOEt solution (prepared by passing hydrogen chloride gas directly into EtOEt until saturation) was added drop by drop, and a white solid was precipitated. The solid was filtered off, washed with excess EtOEt, and dried unde...

Embodiment 3

[0074] 23.67 (CH 2 ), 14.14 (CH 3 ). Example 3 Obtaining 2-(2'-mercapto) nicotinic acid ester 5-mononitrate (3) of isosorbide

[0075] Step 1. In a 100-ml glass flask equipped with a calcium chloride tube-sealed reflux condenser and a magnetic stirrer, 3.0 g (19.35 mmol) of 2-mercaptonicotinic acid was suspended in 30 ml of thionyl chloride (1.64 g / ml, 431.4 mmol). The mixture was continued to reflux for 2 hours, during which time dissolution of the solid was observed. The mixture was cooled and excess thionyl chloride was removed under reduced pressure with addition of portions of toluene. After drying under reduced pressure, 3.35 g of an orange-yellow solid was obtained, which was the expected acid chloride. Yield: 100%.

[0076]Step 2. In a 250 ml glass flask equipped with a reflux condenser and a magnetic stirrer, 3.0 g (17.29 mmol) of the acid chloride obtained in the previous step was suspended in 75 ml of pyridine under an argon atmosphere. The suspension was c...

Embodiment 7

[0099] 13 C-NMR (50MHz, DMSO-d 6 ): 163.91 (C=O), 161.64 (C ar-COO), 152.80 (CH ar ), 139.27 (CH ar ), 122.20 (C ar -S), 118.83 (CH ar ), 85.97 (CH-ONO 2 ), 82.41(CH), 81.53(CH), 77.87(CH-O-CO), 72.67(CH 2 ), 69.07 (CH 2 ), 13.34 (CH 3 ). Embodiment 7 Obtain 5-(2'-methylthio)nicotinate 2-mononitrate hydrochloride of isosorbide ( 7 )

[0100] In a 50 mL glass flask equipped with a magnetic stirrer and a reflux condenser, 2.00 g (10.7 mmol) of 2-methylthionicotinoyl chloride was suspended in 12 mL of pyridine under an argon atmosphere. The mixture was cooled in an ice bath, and 2.04 g (10.7 mmol) of 5-mononitrate of isosorbide were added. The reaction mixture was stirred at room temperature under an atmosphere of argon for 15 hours. Thereafter, the solvent was removed under reduced pressure, the residue was dissolved in 50 ml of chloroform and washed: first with 50 ml of water, then with 50 ml of 5% aqueous hydrochloric acid and finally with 50 ml of water again. ...

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Abstract

Disclosed are derivatives of isosorbid mononitrate and pharmaceutically acceptable salts thereof which have a vasodilator activity with a reduced tolerance effect, having the general formula (I) wherein A and B represent independently any of the groups NO2 and-CO-R, Z being an atom of oxygen or sulfur, and R being optionally substituted C1-C4 alkyl, aryl or aralkyl group or the group (a) wherein R<1> is hydrogen or optionally substituted C1-C4 alkyl, aryl or aralkyl group,so that always either A or B is NO2 but never both at the same time, when Z is a sulfur atom R is optionally substituted C1-C4 alkyl, aryl or aralkyl group, and when Z is an oxygen atom R is the group (a).

Description

field of invention [0001] The present invention relates to novel derivatives of isosorbide mononitrate, which possess potent vasodilatory activity and at the same time have significantly reduced tolerability properties. technical background [0002] Nitrate esters of organic compounds, commonly referred to as nitrated organic compounds, are known and have been used as vasodilators. Of these vasodilators, the effectiveness of mononitrated and dinitrated isosorbide is well known, and it has been described as a compound with vascular and coronary activity, based on the activity of isosorbide mononitrate Substitution of free hydroxyl groups of esters. For example, US-A-4891373 patent describes derivatives of aminopropanol corresponding to the formula below for the treatment of angina pectoris, systemic and pulmonary hypertension. [0003] US-A-5665766 patent describes isosorbide 5-mononitrate 2-acetylsalicylate of the following structural formula, and its antiplatelet aggreg...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/34A61P9/10C07D493/04
CPCC07D493/04A61P9/00A61P9/08A61P9/10
Inventor 何塞·雷波里斯·莫利纳尔弗朗西斯科·帕比尔·科伊莉迪亚·卡韦萨·略伦特马塞利·卡尔沃·巴纽斯克里斯蒂纳·内格里·罗夫斯胡安·安东尼奥·塞尔达·里达维茨艾丽西亚·费雷尔·西索马雷克·W·拉多姆斯基爱德华多·萨拉斯·佩雷斯-拉西利亚胡安·马丁内斯·伯尼恩
Owner LACER SA
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