阅读说明：本技术 一种酰基胍类化合物及其制备方法与应用 (Acylguanidine compound and preparation method and application thereof ) 是由 陈蔚 穆帅 闫少杰 王浩 李树军 张慕军 雷勇胜 崔轶达 刘福景 孙靖 于玲丽 于 2020-07-27 设计创作，主要内容包括：本发明公开了一种具有式I结构的酰基胍类化合物及其药学上可接受的盐。本发明还公开了上述化合物的制备方法,并同时公开了以该化合物或其药学上可接受的盐作为活性有效成分的药物组合物,以及他们在预防或治疗与精氨酸加压素V1a受体、精氨酸加压素V1b受体、精氨酸加压素V2受体相关的疾病(如高血压、慢性充血性心力衰竭、抗利尿激素分泌紊乱综合症或慢性心力衰竭/肝硬化/抗利尿激素分泌紊乱引起的低钠血症)中的应用。(The invention discloses an acylguanidine compound with a structure shown in a formula I and pharmaceutically acceptable salts thereof. The invention also discloses a preparation method of the compound, and also discloses a pharmaceutical composition taking the compound or pharmaceutically acceptable salts thereof as active effective components, and application of the compound or pharmaceutically acceptable salts thereof in preventing or treating diseases (such as hypertension, chronic congestive heart failure, anti-diuretic hormone secretion disorder syndrome or hyponatremia caused by chronic heart failure/liver cirrhosis/anti-diuretic hormone secretion disorder) related to arginine vasopressin V1a receptor, arginine vasopressin V1b receptor and arginine vasopressin V2 receptor.)

1. A compound having the structure of formula I:

。

2. a pharmaceutically acceptable salt of a compound having the structure of formula I according to claim 1, wherein the compound having the structure of formula I and the corresponding acid form a hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, phosphate, acetate, propionate, butyrate, lactate, methanesulphonate, p-toluenesulphonate, maleate, benzoate, succinate, tartrate, citrate, fumarate, taurate, gluconate, amino acid salt.

3. A process for the preparation of a compound of formula I according to claim 1: the method comprises the following steps:

(1) reacting the compound of the formula II with the compound of the formula III or hydrochloride of the compound of the formula III to obtain a compound of a formula IV;

(2) reacting the compound shown in the formula IV with the compound shown in the formula III or hydrochloride of the compound shown in the formula III to obtain a compound shown in the formula I;

wherein the molar ratio of the compound of formula II to the compound of formula III or the hydrochloride salt of the compound of formula III is 1: 0.8 to 1.2;

the molar ratio of the compound of formula IV to the compound of formula III or the hydrochloride salt of the compound of formula III is 1: 0.8 to 1.2;

。

4. a pharmaceutical composition comprising a compound having the structure of formula i as claimed in claim 1 or 2 and pharmaceutically acceptable salts thereof, together with one or more pharmaceutically acceptable carriers.

5. The use of a compound having the structure of formula I as claimed in claims 1 or 2 and pharmaceutically acceptable salts thereof in the manufacture of a medicament for the prevention or treatment of hypertension, chronic congestive heart failure, antidiuretic hormone secretion disorder syndrome or hyponatremia caused by chronic heart failure/cirrhosis/antidiuretic hormone secretion disorder.

6. The use of claim 5, wherein the prevention or treatment of hypertension is characterized in that the compound having the structure of formula I binds to arginine vasopressin receptor, thereby antagonizing and exhibiting diuretic activity.

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a compound with an acylguanidine structure, a preparation method thereof, a pharmaceutical composition containing the compound and the pharmaceutical composition as an arginine vasopressin receptor antagonist, in particular to arginine vasopressin V₂Use of a receptor antagonist.

Background

Arginine Vasopressin (AVP) is a peptide hormone that plays an important role in regulating reabsorption of free water, osmotic pressure of body fluids, blood volume, blood pressure, cell contraction, cell proliferation, and secretion of adrenocortical hormone (ACTH). Arginine vasopressin through V_1a，V₂And V_1bThe regulation of three receptor subtypes plays a role. The distribution and physiological effects of AVP receptor subtypes are shown in the following table:

TABLE 1 distribution and physiological role of AVP receptor subtypes

Elevated levels of AVP are associated with clinical symptoms that produce abnormal water retention, such as heart failure, cirrhosis, and the syndrome of hypersecretion of antidiuretic hormone (SIADH), and may potentially be responsible for the pathogenesis and progression of these clinical symptoms.

Numerous studies have demonstrated that the arginine vasopressin receptor has an important role in the development, progression and treatment of congestive heart failure, cirrhosis, antidiuretic hormone secretion disorder syndrome, hypertension, hyponatremia. However, many drugs with arginine vasopressin receptor antagonistic activity are the best choice for treating hyponatremia caused by various reasons at present and in the future, such as tolvaptan and the like. However, due to the low water solubility of tolvaptan, intestinal absorption is insufficient, and the dosage form and route of administration are subject to many limitations.

Disclosure of Invention

It is an object of the present invention to provide compounds of formula (I) and pharmaceutically acceptable salts thereof.

It is another object of the present invention to provide processes for the preparation of compounds of formula (I) and pharmaceutically acceptable salts thereof.

It is a further object of the present invention to provide compounds of formula (I) and pharmaceutically acceptable salts thereof as active ingredients, as well as pharmaceutical compositions containing one or more pharmaceutically acceptable carriers, excipients or diluents, and their use as AVP receptor antagonists in the treatment of hypertension, chronic congestive heart failure, anti-diuretic hormone secretion disorder syndrome or hyponatremia caused by chronic heart failure/cirrhosis/anti-diuretic hormone secretion disorder. In particular to the application in the aspect of preparing the medicine for preventing or treating the hypertension; wherein the prevention or treatment of hypertension means that the compound of formula (I) binds to arginine vasopressin receptor, thereby producing antagonism and exhibiting diuretic activity.

The acylguanidine compound of the invention has the following structural formula:

the MS spectrum of the compound of formula (I) is shown in figure 1.

The compounds of formula (I) have a guanidino group and can therefore form salts with organic and inorganic acids, including but not limited to hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, phosphate, acetate, propionate, butyrate, lactate, methanesulfonate, p-toluenesulfonate, maleate, benzoate, succinate, tartrate, citrate, fumarate, taurate, gluconate, amino acid salts.

The compounds of formula (I) may be prepared by the following process:

in a solvent, the compound (II) and the compound (III) are subjected to esterification reaction to obtain a compound (IV), and the compound (IV) is continuously reacted with the compound (III) to obtain the compound of the formula (I).

The solvent is acetonitrile, acetone, dichloromethane, tetrahydrofuran, N-dimethylformamide, dimethyl sulfoxide, toluene, pyridine, dioxane, and a condensing agent such as Dicyclohexylcarbodiimide (DCC) and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) is used in the condensation process, or the compound (III) is converted into the corresponding acid chloride by thionyl chloride or oxalyl chloride and then reacted.

The two-step reaction can be realized in the same reaction system by using a one-pot method.

The compound (III) is usually available as a hydrochloride salt, and does not interfere with the progress of the reaction.

The resulting compound of formula (I) may be suspended or dissolved in a solvent and salified dropwise with an organic or inorganic acid as described above. The salifying solvent is methanol, ethanol, isopropanol, N-butanol, tert-butanol, water, ethyl acetate, acetonitrile, acetone, dichloromethane, tetrahydrofuran, N-dimethylformamide, dimethyl sulfoxide, toluene, pyridine, dioxane, diethyl ether, isopropyl ether and methyl tert-butyl ether.

The compounds of formula (I) may also be prepared by the following process:

in a solvent, the compound (III) is subjected to amidation reaction to obtain a compound (V), and the compound (V) is continuously reacted with a compound (II) to obtain a compound of formula (I).

The solvent is acetonitrile, acetone, dichloromethane, tetrahydrofuran, N-dimethylformamide, dimethyl sulfoxide, toluene, pyridine, dioxane, and a condensing agent such as Dicyclohexylcarbodiimide (DCC) and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) is used in the condensation process, or one half of compound (III) is converted into corresponding acid chloride by thionyl chloride or oxalyl chloride and then reacted.

The two-step reaction can be realized in the same reaction system by using a one-pot method.

The compound (III) is usually available as a hydrochloride salt, and does not interfere with the progress of the reaction.

The resulting compound of formula (I) may be suspended or dissolved in a solvent and salified dropwise with an organic or inorganic acid as described above. The salifying solvent is methanol, ethanol, isopropanol, N-butanol, tert-butanol, water, ethyl acetate, acetonitrile, acetone, dichloromethane, tetrahydrofuran, N-dimethylformamide, dimethyl sulfoxide, toluene, pyridine, dioxane, diethyl ether, isopropyl ether and methyl tert-butyl ether.

Although the compounds of the present invention may be administered directly without any formulation, the various compounds described are preferably used in the form of pharmaceutical preparations, the route of administration may be parenteral (e.g., intravenous, intramuscular) as well as oral.

Pharmaceutical compositions of the compounds of the invention are prepared as follows: the compounds of the present invention are combined with pharmaceutically acceptable solid or liquid carriers and optionally with pharmaceutically acceptable adjuvants and excipients using standard and conventional techniques to prepare microparticles or microspheres. Solid dosage forms include tablets, dispersible granules, capsules, sustained release tablets, sustained release pellets and the like. A solid carrier can be at least one substance that can act as a diluent, flavoring agent, solubilizing agent, lubricant, suspending agent, binder, disintegrant, and encapsulating agent. Inert solid carriers include magnesium phosphate, magnesium stearate, powdered sugar, lactose, pectin, propylene glycol, polysorbate 80, dextrin, starch, gelatin, cellulosic materials such as methyl cellulose, microcrystalline cellulose, low melting paraffin, polyethylene glycol, mannitol, cocoa butter, and the like. Liquid dosage forms include solvents, suspensions such as injections, powders, and the like.

The amount of active ingredient (compound of the invention) contained in the pharmaceutical composition and unit dosage form may be specifically adapted to the condition of the patient, the condition diagnosed by the physician, and the amount or concentration of the compound used may be adjusted over a wide range. Generally, the amount of active compound ranges from 0.5 to 90% by weight of the composition, another preferred range being from 0.5 to 70%.

Solubility studies have shown that the hydrochloride, sulfate and mesylate salts of the compounds of formula (I) are slightly soluble in water and have good formulation potential. Meanwhile, although the compound of the formula (I) is difficult to dissolve in water, the solubility of the compound is remarkably increased in an acidic aqueous solution, which suggests that the dissolution and absorption in the stomach have certain advantages.

The radioligand binding assay was performed as follows:

uni-filter 96 GF/C filter plates were soaked with 100 μ L/well 0.5% PEI (polyethylenimine, Sigma-Aldrich, cat. No. # 408727, dissolved in milli-Q water) and placed at 4 ℃ for about 30-60 min. The PEI in the plate was removed by suction using a vacuum filtration device (8-15 mmHg) and the remaining PEI was washed off at 1 mL/well with 4 ℃ elution buffer. A reaction system containing membrane protein, tritium-labeled ligand and unlabeled ligand is prepared in a 24-well plate, and incubated for 2 hours at 25 ℃ and at the rotating speed of 350 RPM. The reaction was transferred to a filter plate (8-15 mmHg), washed with 2 mL/well of cooled elution buffer, and then dried at room temperature for 120 min. The plate Bottom was sealed with a Bottom seal (TM) (opaque, Perkin elmer). 50 μ L MicroScint 20TM (Perkin elmer) was added per well. A sealing film, Topseal A (Perkin elmer), was applied to the plate and counted at 1 min/well on TopCount NXT.

The rat diuresis experiment was performed as follows: male SD rats (BW 260 +/-20 g) are raised in a metabolism cage, the environment is constant, the humidity is 60-80%, water is freely drunk, the illumination is carried out (the light and dark cycle is about 12 hours), and the rats are fasted for 12 hours before the experiment. The male SD rats were randomly divided into groups (including a blank control group and a positive control group), and 5 rats were orally administered by gavage (10 mg/kg). The positive control group is respectively dosed with tolvaptan and lixivaptan, the blank control group is only intragastrically dosed with the same amount of solvent, and the experimental group is dosed with the target compound to be tested. Rats were housed in metabolic cages and spontaneous urine was collected. Before administration, the stomach was gavaged with physiological saline (5% BW) to increase the water load. Recording the urine volume of 0-20 h in each group.

TABLE 2 results of Activity Studies

Ligand binding experiments show thatThe compound of formula (I) to AVP V₂The receptor has strong affinity and is simultaneously used for V_1aHas weaker affinity and certain selectivity. Animal experiment results show that compared with a control group, the compounds have obvious diuretic effect. The experiment further shows that the compound shown in the formula (I) can be combined with arginine vasopressin receptor to generate antagonism, and the compound also finds that the urine volume is increased in animal experiments, shows certain diuretic activity, thereby reducing the liquid volume load in vivo and reducing the blood pressure. At the same time as the urine volume increases, there is little increase in sodium or potassium in the urine. Thus, the compounds of formula (I) also have some corrective effect on hyponatremia.

Rats were subjected to left coronary ligation to cause large-area left ventricular infarction, and survived for 5 weeks, and left ventricle, femoral artery and femoral vein were cannulated, and their Mean Blood Pressure (MBP), Heart Rate (HR), left ventricular peak pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), left ventricular maximum rising rate (+ dp/dt), left ventricular maximum falling rate (-dp/dt) were determined. Rats were randomized into two groups, one group for the compound of formula (I) and one group for oral gavage (10 mg/kg) and the other group for an equal amount of the blank solvent. The research result shows that the compound has a certain effect of reducing the average blood pressure of rats, improving the contraction and relaxation functions of cardiac muscle and has a certain effect of treating congestive heart failure. The relevant data measured 5 weeks after dosing are shown in the following table:

TABLE 3 rat Heart failure model study results

The in vivo and in vitro clinical experiments show that the compound has arginine vasopressin receptor antagonistic activity and diuretic effect, but does not influence the metabolism of sodium and potassium, thereby correcting hyponatremia. Furthermore, the compound has a certain therapeutic effect on heart failure (CHF) rats, thereby correcting hypertension and heart failure.

In addition, many documents report that compounds having arginine vasopressin receptor antagonistic action have a potential use for the prophylaxis or treatment of diseases such as hypertension, reye's syndrome, dysmenorrhea, premature labor, corticotropin-releasing hormone secretion disorder, adrenal hyperplasia, depression, chronic congestive heart failure, liver cirrhosis, antidiuretic hormone secretion disorder syndrome, or hyponatremia caused by chronic heart failure/liver cirrhosis/antidiuretic hormone secretion disorder. Therefore, the compound has remarkable medicinal value.

Drawings

FIG. 1 is a MS spectrum of a compound of formula (I) 1;

FIG. 2 is a structural diagram of the acylguanidine compound (I) of the present invention.

Detailed Description

The invention is described below by means of specific embodiments. Unless otherwise specified, the technical means used in the present invention are well known to those skilled in the art. In addition, the embodiments should be considered illustrative, and not restrictive, of the scope of the invention, which is defined solely by the claims. It will be apparent to those skilled in the art that various changes or modifications in the components and amounts of the materials used in these embodiments can be made without departing from the spirit and scope of the invention. The raw materials and reagents used in the present invention are commercially available. Wherein the compounds (II) and (III) are commercially available from EDCI, Oenokay technologies, Inc., Beijing.