CN111732524B - Acylguanidine compound and preparation method and application thereof - Google Patents
Acylguanidine compound and preparation method and application thereof Download PDFInfo
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- C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
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Abstract
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.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a compound with an acylguanidine structure and a preparation method thereofMethods, pharmaceutical compositions containing them and use as arginine vasopressin receptor antagonists, especially 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 V1a，V2And V1bThe 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 showed that the compound of formula (I) is on AVP V2The receptor has strong affinity and is simultaneously used for V1aHas 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.
Example 1
30g of compound (II), 500ml of acetonitrile, 27g of compound (III), and 29g of EDCI (1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride) were charged into a reaction flask, and the mixture was heated to reflux and reacted for 5 hours. After the reaction, the reaction mixture was evaporated to dryness to obtain an oily substance. 500ml of water is added, the mixture is stirred vigorously and filtered to obtain a crude compound of the formula (IV). The crude product was purified by flash preparative chromatography to give 38.2g of compound (IV).
The compound of the formula (IV) was added to 500ml of acetonitrile, 27g of the compound (III) and 29g of EDCI were added thereto, and the mixture was heated to reflux and reacted for 48 hours. After the reaction, the reaction mixture was evaporated to dryness to obtain an oily substance. 500ml of water is added, the mixture is stirred vigorously and filtered to obtain a crude compound of the formula (I). The crude product was purified by flash preparative chromatography to give 45.5g of compound (I).1H NMR：8.11(d, 2H, J=8.8Hz), 7.96(d, 2H, J=8.4Hz), 7.85(d, 2H, J=84Hz), 7.39(d, 2H, J=8.4Hz), 7.23(dd, 2H, J=2Hz, 6.4Hz), 6.84(d, 2H, J=8.4Hz), 5.44(br s), 4.82(s, 2H), 3.81(s, 2H), 2.91(s, 3H), 2.91(s, 3H)。ESI-MS ：560.3。
Example 2
30g of compound (II), 500ml of toluene and 58g of EDCI were put into a reaction flask, heated to reflux, 54g of compound (III) was added in two portions, and reacted for 9 hours. After the reaction, the reaction mixture was evaporated to dryness to obtain an oily substance. 1000ml of water is added, stirred vigorously and filtered to give the crude compound of formula (I). The crude product was purified by flash preparative chromatography to give 49.3 g of compound (I).1H NMR：8.11(d, 2H, J=8.8Hz), 7.96(d, 2H, J=8.4Hz), 7.85(d, 2H, J=84Hz), 7.39(d, 2H, J=8.4Hz), 7.23(dd, 2H, J=2Hz, 6.4Hz), 6.84(d, 2H, J=8.4Hz), 5.44(br s), 4.82(s, 2H), 3.81(s, 2H), 2.91(s, 3H), 2.91(s, 3H)。ESI-MS ：560.3。
Example 3
100ml of thionyl chloride and 27g of the compound (III) were put into a reaction flask, stirred under reflux for 4 hours, evaporated to dryness, entrained with toluene, and the thionyl chloride was removed. 500ml of methylene chloride and 27g of the compound (III) were added, and the reaction was refluxed for 12 hours. Evaporated to dryness to give an oil (V), which was taken to the next reaction without further treatment.
And (3) adding 30g of the compound (II) and 29g of EDCI into tetrahydrofuran of the solution (V) obtained above, refluxing for 48h, stopping the reaction, adding 1000ml of water after evaporation to dryness, stirring vigorously, and filtering to obtain a crude product of the compound of the formula (I). The crude product was purified by flash preparative chromatography to give 52.8 g of compound (I).1H NMR：8.11(d, 2H, J=8.8Hz), 7.96(d, 2H, J=8.4Hz), 7.85(d, 2H, J=84Hz), 7.39(d, 2H, J=8.4Hz), 7.23(dd, 2H, J=2Hz, 6.4Hz), 6.84(d, 2H, J=8.4Hz), 5.44(br s), 4.82(s, 2H), 3.81(s, 2H), 2.91(s, 3H), 2.91(s, 3H)。ESI-MS ：560.3。
Example 4:
suspending the compound of the formula (I) in acetone, dripping methanesulfonic acid, adjusting the pH to about 2, stirring for 1h at room temperature, and filtering to obtain the methanesulfonic acid salt of the compound of the formula (I).
Example 5:
suspending the compound shown in the formula (I) in N, N-dimethylformamide, dripping glacial acetic acid, adjusting the pH value to about 3, stirring at room temperature for 1h, dissolving, cooling to-5 ℃, crystallizing for 2h, and filtering to obtain the acetate of the compound shown in the formula (I).
Example 6:
tablets were prepared with the following ingredients:
the preparation process comprises the following steps: drying the raw and auxiliary materials in advance, and sieving the dried raw and auxiliary materials with a 80-mesh sieve for later use. The auxiliary materials with the prescription amount are fully and evenly mixed. Adding the raw material medicines into the auxiliary materials by an incremental dilution method, fully and uniformly mixing for 2-3 times each time, ensuring that the medicines and the auxiliary materials are fully and uniformly mixed, sieving with a 20-mesh sieve, drying for 1h in a 60-DEG C ventilation oven, sieving with a 16-mesh sieve for grading, uniformly mixing, and tabletting on a tabletting machine.
Example 7
An injection was prepared from the following ingredients:
the preparation method comprises the following steps: adding the active ingredients into water for injection in which polysorbate and propylene glycol are dissolved, and adding medicinal alkali to adjust the pH value to 4-8 for dissolving. Fine filtering, bottling, and sterilizing.
Claims (6)
1. A compound having the structure of formula I:
（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 of formula i as described in claim 1 and one or more pharmaceutically acceptable carriers.
5. The use of a compound having the structure of formula I as defined in claim 1 for the manufacture of a medicament for the prevention or treatment of hypertension, chronic congestive heart failure, antidiuretic hormone secretion disorder syndrome or chronic heart failure/cirrhosis/hyponatremia caused by 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.
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Non-Patent Citations (5)
| Title |
|---|
| Highly potent and orally active non-peptide arginine vasopressin antagonists for both V1a and V2 receptors:synthesis and pharmacological properties of 4"-［(4，4-difluoro-5-methylidene-2，3，4，5-tetratetrahydro-1H-1-benzoazepin-1-yl)carbonyl]-2-phenyl;Yoshiaki SHIMADA 等;《chem.pharm.bull》;20001231;第48卷(第11期);第1644-1651页 * |
| Linda Åkerbladh 等.Palladium(0)-Catalyzed Carbonylative One-Pot Synthesis of N‑Acylguanidines.《J. Org. Chem》.2017,第82卷第12520-12529页. * |
| Nonpeptide arginine vasopressin antagonists for both V1a and V2 receptors: synthesis and pharmacological properties of 4"-［5-( substituted methylidene -2，3，4，5-tetrahydro-1H-l-benzoazepine-l-carbonyl］benzanilide and 4"-［5-( substituted methyl);Akira MATSUHISA 等;《Chem.Pharm.Bull》;19990331;第47卷(第3期);第329-339页 * |
| 精氨酸加压素受体拮抗剂治疗低钠血症的研究进展;柳鑫 等;《临床药物治疗杂志》;20191031;第17卷(第10期);第24-27页 * |
| 非肽类精氨酸加压素受体拮抗剂的研究进展;张大帅 等;《中国药物化学杂志》;20140430;第24卷(第2期);第103-115页 * |
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