Selective beta1-adrenergic receptor and application thereof in cardiovascular disease medicines

A cardiovascular and drug technology, applied in the field of medicine, can solve the problems of loss of specificity, adverse effects of the respiratory system, etc., and achieve stable quality, excellent β1-adrenergic receptor inhibitory activity, and good physical and chemical properties

Active Publication Date: 2019-09-17
MUDANJIANG MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The first generation of β-adrenergic receptor inhibitor drugs, such as propranol, is non-specific. It blocks β1 and β2 receptors at the same time. It is widely used in hypertensive patients, but experiments have shown that it will produce many adverse reactions, mainly Adverse effects on the respiratory system due to beta2 adrenoceptor blockade
Second-generation β1-adrenergic receptor inhibitors, such as atenolol, metoprolol, and bisoprolol, have high affinity for β1 receptors, but specificity is largely lost at high doses
Such compounds, and their pharmaceutically acceptable salts are used as selective β1-adrenoceptor inhibitors, and as active compounds for the treatment of cardiovascular diseases have not been reported

Method used

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  • Selective beta1-adrenergic receptor and application thereof in cardiovascular disease medicines
  • Selective beta1-adrenergic receptor and application thereof in cardiovascular disease medicines
  • Selective beta1-adrenergic receptor and application thereof in cardiovascular disease medicines

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Example 1 The beneficial effects of active compounds of the present invention are further set forth below through in vitro pharmacological activity experiments, but this should not be interpreted as only having the following beneficial effects on the compounds of the present invention

[0034] The experimental rats were Wistar rats, male or female, weighing 300±25 g, provided by the Experimental Animal Center of Peking University Health Science Center.

[0035] Materials: The β1 receptor membrane protein is prepared from the heart tissue of Wistar rats, and the β2 receptor membrane protein is prepared from the lung tissue of Wistar rats. The preparation method can be prepared with reference to the method of Williams, LT (referring to Williams, LT: Science, 1976, 192:791). Specifically, rats were decapitated and bled, and the rat heart and lung tissues were quickly taken out and placed in pre-cooled centrifugation buffer at 0-4°C, and the envelope was peeled off. Then ad...

Embodiment 2

[0040] The effect of embodiment 2 formula I compound on SHR spontaneously hypertensive rat model

[0041] Based on the blocking results of the compound of formula I on β-receptor, we further used the model of spontaneously hypertensive rats (SHR rats) to evaluate the antihypertensive ability of the compound of formula (I) of the present invention.

[0042] Experimental method: 16-week-old SHR rats, male or female, were randomly divided into 4 groups: model group, positive drug group, and drug administration group, with 8 rats in each group. Rats in each group were reared in a conventional environment, free to drink water and ingest food, and began to administer intragastric administration after 3 days of feeding. The positive drug group was given atenolol at 5 mg / kg, the drug group was given the compound of formula I at 5 mg / kg, and the model group The same amount of normal saline was given once a day for 4 consecutive weeks.

[0043] Blood pressure measurement: The blood pre...

Embodiment 4

[0060] Embodiment 4 comprises the preparation of the pharmaceutical composition of formula (I) compound active ingredient

[0061] The pharmaceutical composition of this embodiment contains the following components by mass:

[0062]

[0063] The composition is prepared according to the following steps:

[0064]1) sieve the compound of formula (I) and cornstarch and mix into a homogeneous mixture;

[0065] 2) Granulate the mixture with water and allow to dry;

[0066] 3) the dried granules are mixed with sorbitol and calcium stearate to obtain lubricated granules;

[0067] 4) Compress the lubricated granules into tablet cores, each tablet core containing 25 mg of the compound of formula (I).

[0068] 5) The tablet core was coated with a sugar coating containing 2 wt% gum arabic / 77 wt% refined sugar / 20 wt% calcium sulfate / 1 wt% sodium carboxymethylcellulose.

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Abstract

The invention provides a compound of a formula (I) shown in the specification with selective beta1-adrenergic inhibitory activity, and the chemical name of the compound is clerodane-3,12E-di-double bond-15,16-dioctyl phthalate. The compound of the formula (1) has selective beta1-adrenergic receptor inhibitory activity, the inhibitory activity of the compound upon a beta1 receptor is 6 times or greater of that upon a beta2 receptor, cardiovascular diseases such as hypertension, myocardial ischemia, cardiomegaly, coronary heart diseases, myocardial infarction, stroke, atherosclerosis, cardiac failure and angina pectoris can be effectively treated, and in addition, side effects of a non-selective beta1-adrenergic receptor inhibitor can be avoided. The invention further relates to a pharmaceutically acceptable salt of the compound of the formula (I), a medicine composition and a preparation with the compound of the formula (I) and/or the pharmaceutically acceptable salt thereof, and application of the compounds and compositions in preparing medicines for treating cardiovascular diseases.

Description

technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to a β1-adrenergic receptor inhibitor, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising the β1-adrenergic receptor inhibitor. Background technique [0002] Cardiovascular disease is an important cause of morbidity and mortality worldwide, and according to the World Health Organization (WHO), the majority of deaths from cardiovascular disease occur in sub-middle-income countries. And WHO predicts that cardiovascular disease will become the main cause of death in developing countries, therefore, there is an urgent need for the treatment and prevention of cardiovascular disease. β-adrenergic receptor inhibitors are effective drugs for the treatment of cardiovascular diseases that have been proven effective in many years of clinical trials. The β-adrenergic receptors can be divided into 3 subtypes (β1, β2 and β3). β1 receptors are mai...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C57/26A61P9/12A61P9/10A61P9/04A61K31/194
CPCA61K31/194A61P9/04A61P9/10A61P9/12C07B2200/07C07C57/26C07C2602/10
Inventor 张琦李强李芳巍李永生徐建忠刘晓冬
Owner MUDANJIANG MEDICAL UNIV
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