Avanafil phosphate ester compounds, their production method and applications

Abstract

The present invention relates to the technical field of pharmaceutical compounds, and provides an avanafil phosphate compound, the structural formula of which is shown in Formula I, where R is hydrogen, phenyl, substituted phenyl, alkyl or substituted alkyl. The avanafil phosphate compound provided by the present invention has high water solubility, long drug action time, and excellent sustained release effect, and can be widely used in the preparation of drugs for the treatment of phosphodiesterase 5-related diseases. The present invention further provides a method for preparing the avanafil phosphate compound described in the above solution, and the method provided by the present invention has a simple procedure, is easy to operate, and is suitable for mass production. TIFF2025511592000038.tif4659 Formula I.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to a Chinese patent application filed with the China Patent Office on May 30, 2022, with application number CN202210595665.6 and title "Avanafil phosphate ester compounds and their manufacturing methods and applications," the entire contents of which are incorporated herein by reference. [Technical field]

[0002] The present invention relates to the technical field of pharmaceutical compounds, in particular to avanafil phosphate compounds and their preparation methods and applications. [Background technology]

[0003] Phosphodiesterase 5 (PDE5) is an enzyme belonging to the superfamily, which can catalyze the second messenger cGMP and convert it into GMP. PDE5 inhibitors are recommended as first-line drugs for treating erectile dysfunction (ED), and PDE5 inhibitors can also be used to treat diseases such as hypertension, coronary heart disease, and prostate hyperplasia (Non-Patent Document 1). According to survey statistics, about 15% of men aged 40 to 59 suffer from ED, and about 70% of men aged 60 and over 70 suffer from ED, and like many other chronic diseases, the incidence of ED also increases with age (Non-Patent Document 2).

[0004] Avanafil is a selective PDE5 inhibitor approved by the US FDA in April 2012 to treat ED. At present, the PDE5 inhibitors on the market are sildenafil, vardenafil, tadalafil, udenafil and mirodenafil. Clinical research data shows that many ED patients can successfully carry out their sexual life within 30 minutes of using avanafil, and the onset of action time after taking avanafil is about 90 minutes for sildenafil and vardenafil, and 2 hours for tadalafil (Non-Patent Document 3). Therefore, due to the advantage of fast acting, avanafil is preferred by ED patients, and has the same mechanism of action as other PDE5 inhibitors on the market, but has unique pharmacokinetic and pharmacological properties, faster oral absorption, more selective, fewer side effects, and in long-term clinical trials, the dropout rate of subjects of the product due to side effects is also low (Non-Patent Document 4). Accumulated data shows that avanafil has better pharmacological effects on ED and has good market response.

[0005] However, avanafil has the disadvantages of low water solubility and short duration of action. Therefore, it is of great value to develop water-soluble avanafil and avanafil prodrugs to extend the duration of action of the drug. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] [Chinese Journal of Medicinal Chemistry.2017.27.400-07] [Non-Patent Document 2] [Am J Med. 2021. 134. 310-16] [Non-Patent Document 3] [Pharmacology Advances. 2012.36.135-36] [Non-Patent Document 4] [The Annals of pharmacotherapy. 2013. 47. 1312-20] Summary of the Invention [Problem to be solved by the invention]

[0007] In view of this, the present invention provides an avanafil phosphate compound and its preparation and application. The avanafil phosphate compound provided by the present invention has high water solubility and long action time. [Means for solving the problem]

[0008] In order to achieve the above objectives, the present invention provides the following technical solutions: The structural formula of the avanafil phosphate compound or its pharma- ceutically acceptable salt is shown in Formula I. TIFF2025511592000002.tif4659 Formula I In formula I, R is hydrogen, a phenyl group, a substituted phenyl group, a benzyl group, an alkyl group, or a substituted alkyl group; The substituted phenyl group is a mono- or poly-substituted phenyl group at the ortho, meta or para position; the substituent in the substituted phenyl group is a halogen, a nitro group, or an alkyl group; The substituents in the substituted alkyl groups are halogen or cyano groups.

[0009] Preferably, when R is an alkyl group or a substituted alkyl group, the alkyl group or the substituted alkyl group has 1 to 18 carbon atoms, and when a substituent in the substituted alkyl group is a halogen, the halogen is fluorine, chlorine, or bromine.

[0010] Preferably, the substituted phenyl group is a mono-, di- or tri-substituted phenyl group, and when a substituent on the substituted phenyl group is a halogen, the halogen is preferably fluorine, chlorine or bromine, and when a substituent on the substituted phenyl group is an alkyl group, the alkyl group has 1 to 18 carbon atoms.

[0011] Preferably, R in formula I is H, The file is one of the following: TIFF2025511592000003.tif48156.

[0012] Preferably, the avanafil phosphate ester compound is any one of formulas II to IV. TIFF2025511592000004.tif3239 formula II, TIFF2025511592000005.tif3141 formula III, TIFF2025511592000006.tif3343 Formula IV.

[0013] The present invention also provides a method for producing the avanafil phosphate ester compound according to the above-mentioned solution, comprising method 1, method 2, method 3 or method 4: The method 1 is The method includes the steps of: mixing avanafil, an alkali, a solvent, and a compound having the structure shown in formula (a) to carry out a condensation reaction to obtain an avanafil phosphate compound having the structure shown in formula (I); TIFF2025511592000007.tif1422 formula a In formula a, R is a phenyl group, a substituted phenyl group, an alkyl group, or a substituted alkyl group. The method 2 is The method includes the steps of: mixing avanafil, an alkali, a solvent, and a compound having a structure shown in formula b to carry out a condensation reaction to obtain an intermediate reaction solution (an intermediate product in the intermediate reaction solution has a structure shown in formula c); and mixing the intermediate reaction solution with a metachloroperbenzoic acid solution to carry out an oxidation reaction to obtain an avanafil phosphate compound having a structure shown in formula I; TIFF2025511592000008.tif1619 formula b TIFF2025511592000009.tif3446 formula c In formulae b and c, R is a benzyl group, a phenyl group, an alkyl group or a substituted alkyl group.

[0014] The method 3 is Mixing (CH3O)3PO, POCl3 and avanafil to carry out an esterification reaction to obtain an avanafil phosphate compound having the structure shown in formula I, where R is hydrogen; The method 4 is The method includes the step of mixing a compound having the structure shown in formula III, BCl3 and a solvent to carry out a debenzylation reaction to obtain an avanafil phosphate ester compound having the structure shown in formula I, in which R is hydrogen.

[0015] Preferably, the solvents in Method 1 and Method 2 above are independently a non-polar solvent or a polar aprotic solvent.

[0016] Preferably, the alkali in the method 1 and the method 2 is independently an organic alkali or an inorganic alkali, the inorganic alkali includes an alkali metal carbonate or an alkali metal phosphate, and the organic alkali includes one or more of pyridine, 4-dimethylaminopyridine, triethylamine, trimethylamine, and tetrazole.

[0017] Preferably, in the method 1, the molar ratio of avanafil to alkali is 1:(1.1-1.3), and the molar ratio of avanafil to the compound having the structure shown in formula a is 1:(1.1-1.3).

[0018] Preferably, in the method 2, the molar ratio of avanafil to alkali is 1:(1.1-1.3), and the molar ratio of avanafil to the compound having the structure shown in formula b is 1:(1.1-1.3).

[0019] The alkali in the above method 1 and method 2 is independently an organic alkali or an inorganic alkali.

[0020] Preferably, the condensation reaction in the method 1 is carried out at room temperature for 12 to 24 hours, the condensation reaction in the method 2 is carried out at room temperature for 12 to 24 hours, and the oxidation reaction in the method 2 is carried out at room temperature for 4 to 12 hours.

[0021] Preferably, in the method 2, the mass ratio of metachloroperbenzoic acid to avanafil is (0.7-0.8:1).

[0022] Preferably, the esterification reaction in the method 3 is carried out at a temperature of 0° C. to 25° C. for a reaction time of 1 hour to 8 hours, and the debenzylation reaction in the method 4 is carried out at room temperature for a reaction time of 12 hours to 48 hours.

[0023] The present invention also provides the application of the avanafil phosphate compound or its pharma- ceutically acceptable salt according to the above solution in the preparation of a drug for the treatment of phosphodiesterase 5-related diseases.

[0024] Preferably, said phosphodiesterase 5 related disorders include erectile dysfunction related disorders, hypertension, coronary heart disease or prostatic hyperplasia.

[0025] Preferably, in the above applications, the avanafil phosphate compound or its pharma- ceutical acceptable salt is used alone or in combination with medicinal auxiliary materials.

[0026] Preferably, the dosage form of the drug for treating the phosphodiesterase 5-related disease is a tablet, a capsule, a granule or a syrup. Effect of the Invention

[0027] The present invention also provides the application of the avanafil phosphate compound or its physiologically acceptable salt according to the above-mentioned solution in treating phosphodiesterase 5-related diseases.

[0028] The present invention provides an vanafil phosphate compound, the structural formula of which is shown in Formula I. The vanafil phosphate compound provided by the present invention has an increased polarity and high water solubility due to its phosphate structure, and the sustained release effect of the phosphate extends the drug's action time, making it widely applicable in the treatment of phosphodiesterase 5-related diseases.

[0029] The present invention also provides a method for preparing the avanafil phosphate ester compound described in the above solution, and the preparation method provided by the present invention has simple steps, is easy to operate, and is suitable for mass production. [Brief description of the drawings]

[0030] [Figure 1] 1 is a comparison of the drug release effects of avanafil and the compounds of the structures shown in formula II and formula III upon intragastric administration. [Diagram 2] 1 is a comparison of the drug release effects of intragastric injection of avanafil and the compound of the structure shown in formula IV. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0031] The present invention provides an avanafil phosphate compound or a pharma- ceutically acceptable salt thereof, the structural formula of the avanafil phosphate compound is as shown in Formula I: TIFF2025511592000010.tif4659 Formula I In formula I, R is hydrogen, a phenyl group, a substituted phenyl group, an alkyl group, or a substituted alkyl group; The substituted phenyl group is a mono- or poly-substituted phenyl group at the ortho, meta or para position; the substituent in the substituted phenyl group is a halogen, a nitro group, or an alkyl group; The substituents in the substituted alkyl groups are halogen or cyano groups.

[0032] In the present invention, the substituted phenyl group is preferably a mono-substituted phenyl group, a di-substituted phenyl group or a tri-substituted phenyl group, and when a substituent on the substituted phenyl group is a halogen, the halogen is preferably fluorine, chlorine or bromine, and when a substituent on the substituted phenyl group is an alkyl group, the number of carbon atoms of the alkyl group is preferably 1 to 18, more preferably 1 to 5, and specifically, the alkyl group is preferably a methyl group or an isobutyl group.

[0033] In the present invention, when R is an alkyl group or a substituted alkyl group, the alkyl group or the substituted alkyl group preferably has 1 to 18 carbon atoms, more preferably 1 to 10 carbon atoms, and the substituent in the substituted alkyl group is preferably a halogen or a cyano group, and the halogen is preferably fluorine, chlorine, or bromine.

[0034] In the present invention, R in formula I is preferably H, The file is one of the following: TIFF2025511592000011.tif48156.

[0035] In the present invention, the avanafil phosphate ester compound is preferably any one of formulas II to IV. TIFF2025511592000012.tif3239 Formula II TIFF2025511592000013.tif3141 formula III TIFF2025511592000014.tif3343 Formula IV

[0036] In the present invention, the chemical name of the compound having the structure shown in the formula II is (S)-(1-(4-((3-chloro-4-methoxybenzyl)amino)5-((pyrimidine-2-methylene)carbamoyl)-2-pyrimidinyl)-2-pyrrolidinyl)dimethylmethylphosphonate, the chemical name of the compound having the structure shown in the formula III is (S)-(1-(4-((3-chloro-4-methoxybenzyl)amino)5-((pyrimidine-2-methylene)carbamoyl)-2-pyrimidinyl)-2-pyrrolidinyl)dibenzylmethylphosphonate, and the chemical name of the compound having the structure shown in the formula IV is (S)-(1-(4-((3-chloro-4-methoxybenzyl)amino)5-((pyrimidine-2-methylene)carbamoyl)-2-pyrimidinyl)-2-pyrrolidinyl)methylphosphate. In a specific embodiment of the present invention, the avanafil phosphate compound is most preferably a compound having the structure shown in Formula IV.

[0037] The present invention also provides a method for preparing avanafil phosphate compound according to the above-mentioned solution, including method 1, method 2, method 3 and method 4, in which method 1 is used for preparing avanafil phosphate compound when R is phenyl group, substituted phenyl group, alkyl group or substituted alkyl group, method 2 is used for preparing avanafil phosphate compound when R is benzyl group, phenyl group, alkyl group or substituted alkyl group, and method 3 and method 4 are used for preparing avanafil phosphate compound when R is hydrogen (i.e., avanafil phosphate compound shown in formula IV). Each will be described in detail below.

[0038] In the present invention, the method 1 includes: The method includes the step of mixing avanafil, an alkali, a solvent, and a compound having the structure shown in formula a to carry out a condensation reaction to obtain an avanafil phosphate compound having the structure shown in formula I. TIFF2025511592000015.tif1422 formula a In formula a, R is a phenyl group, a substituted phenyl group, an alkyl group, or a substituted alkyl group. The types of the substituted phenyl and alkyl groups are consistent with the above solutions and will not be further described here.

[0039] In the present invention, the synthetic route of the method 1 is shown in the following formula: JPEG2025511592000016.jpg46150 In the present invention, the solvent used in the method 1 is preferably a non-polar solvent or a polar aprotic solvent, more preferably one or more of dichloromethane, 1,2-dichloroethane, dioxane, tetrahydrofuran, N,N-dimethylacetamide and dimethylsulfoxide; the alkali is preferably an inorganic alkali or an organic alkali; the inorganic alkali preferably comprises an alkali metal carbonate or an alkali metal phosphate; the alkali metal carbonate preferably comprises one or more of potassium carbonate, cesium carbonate and sodium carbonate; the alkali metal phosphate preferably comprises one or two of potassium phosphate and sodium phosphate; and the organic alkali preferably comprises one or more of pyridine, 4-dimethylaminopyridine, triethylamine, trimethylamine and tetrazole.

[0040] In the present invention, in the method 1, the molar ratio of avanafil to alkali is preferably 1: (1.1-1.3), more preferably 1: 1.2, and the molar ratio of avanafil to the compound having the structure shown in formula a is preferably 1: (1.1-1.3), more preferably 1: 1.2. The present invention has no special requirements for the source of the compound having the structure shown in formula a, and the above-mentioned compound may be commercially available or may be synthesized by a method well known to those skilled in the art. The present invention has no special requirements for the amount of the solvent used, and only requires that the reaction proceed smoothly.

[0041] In the present invention, the temperature of the condensation reaction in the method 1 is preferably room temperature, the reaction time is preferably 12-24h, and the condensation reaction is preferably carried out under nitrogen gas protection conditions. In a specific embodiment of the present invention, preferably, avanafil is first dissolved in a solvent, then an alkali is added, and then cooled in an ice-water bath under nitrogen gas protection conditions for 15min, and a compound having the structure shown in formula a is added to the reaction solution using a syringe, and then the reaction is allowed to naturally rise to room temperature. The present invention preferably monitors the reaction by TLC, and the reaction is stopped after the raw materials are completely reacted, and the reagent used in the TLC monitoring is a mixed solvent of methanol and dichloromethane, and the volume fraction of methanol in the mixed solvent is preferably 5%, and is recorded as 5%MeOH / DCM.

[0042] After the reaction is completed, the present invention preferably evaporates and dries the solvent in the obtained reaction sample solution to obtain a crude product, and then purifies the crude product by silica gel column chromatography to obtain an avanafil phosphate ester compound having the structure shown in formula I. In the present invention, the eluent used in the purification by silica gel column chromatography is a mixed solvent of methanol and dichloromethane, and the volume ratio of methanol and dichloromethane in the mixed solvent is preferably 1:(20-30).

[0043] In the present invention, the method 2 comprises: Mixing avanafil, an alkali, a solvent and a compound having a structure shown in formula b to carry out a condensation reaction to obtain an intermediate reaction solution (an intermediate product in the intermediate reaction solution has a structure shown in formula c); and mixing the intermediate reaction solution with an m-CPBA solution to carry out an oxidation reaction to obtain an avanafil phosphate compound having the structure shown in Formula I. TIFF2025511592000017.tif1619 formula b TIFF2025511592000018.tif3446 formula c (In formulas b and c, R is a benzyl group, a phenyl group, an alkyl group, or a substituted alkyl group.)

[0044] In the present invention, the synthetic route of the method 2 is shown in the following formula: JPEG2025511592000019.jpg95150First, the present invention mixes avanafil, an alkali, a solvent and a compound having the structure shown in formula b to carry out a condensation reaction to obtain an intermediate reaction liquid. In the present invention, the solvent used in the method 2 is preferably a non-polar solvent or a polar aprotic solvent, more preferably one or more of dichloromethane, 1,2-dichloroethane, dioxane, tetrahydrofuran, N,N-dimethylacetamide and dimethylsulfoxide, the alkali is preferably an inorganic alkali or an organic alkali, the inorganic alkali preferably includes an alkali metal carbonate or an alkali metal phosphate, the alkali metal carbonate preferably includes one or more of potassium carbonate, cesium carbonate and sodium carbonate, the alkali metal phosphate preferably includes one or two of potassium phosphate and sodium phosphate, and the organic alkali preferably includes one or more of pyridine, 4-dimethylaminopyridine, triethylamine, trimethylamine and tetrazole.

[0045] In the present invention, in the method 2, the molar ratio of avanafil to alkali is preferably 1: (1.1-1.3), more preferably 1: 1.2, and the molar ratio of avanafil to the compound having the structure shown in formula b is preferably 1: (1.1-1.3), more preferably 1: 1.2, and the present invention has no special requirements for the source of the compound having the structure shown in formula b, and the above-mentioned compound may be commercially available or may be synthesized by a method well known to those skilled in the art. The present invention has no special requirements for the amount of the solvent used, and only requires that the reaction proceed smoothly.

[0046] In the present invention, the temperature of the condensation reaction in the method 2 is preferably room temperature, the reaction time is preferably 12-24h, and the condensation reaction is preferably carried out under nitrogen gas protection conditions. In a specific embodiment of the present invention, preferably, avanafil is first dissolved in a solvent, then an alkali is added, and then the mixture is stirred for 5 minutes under nitrogen gas protection conditions, and a compound having the structure shown in formula b is added to the reaction solution using a syringe, and the reaction is carried out under stirring conditions. After the reaction is completed, there is no need to carry out any treatment, and the reaction of the next step can be carried out directly.

[0047] In the present invention, after obtaining the intermediate reaction solution, the intermediate reaction solution is mixed with m-CPBA (metachloroperbenzoic acid) solution to carry out oxidation reaction to obtain an avanafil phosphate compound having the structure shown in formula I. In the present invention, the solvent used in the m-CPBA solution is preferably the same as the solvent used in the condensation reaction step, and is not further described here. The concentration of the m-CPBA solution is preferably 0.143 g / mL, and the mass ratio of the m-CPBA to avanafil is preferably (0.7-0.8):1, more preferably 0.715:1.

[0048] In the present invention, the temperature of the oxidation reaction is preferably room temperature, and the reaction time is preferably 4-12 hours. In a specific embodiment of the present invention, the intermediate reaction liquid is preferably first transferred to a cooling trap at -78°C and cooled and stirred for 15 minutes, and then the m-CPBA solution is added using a constant pressure dropping funnel. After the dropwise addition is completed, the temperature is naturally raised to room temperature to carry out the oxidation reaction. The present invention preferably monitors the reaction by TLC, and the reaction is stopped after the raw materials are completely reacted. The reagent used in the TLC monitoring is a mixed solvent of methanol and dichloromethane, and the volume fraction of methanol in the mixed solvent is preferably 5%, and is recorded as 5%MeOH / DCM.

[0049] After the oxidation reaction is completed, the present invention preferably mixes the solid liquid of the obtained product with water, and then separates it. The aqueous layer is extracted using an organic solvent. The obtained organic layer is washed with saturated sodium chloride, dried with anhydrous sodium sulfate, and evaporated to dryness to obtain a crude product. The obtained crude product is purified by silica gel column chromatography to obtain an avanafil phosphate compound having the structure shown in formula I. In the present invention, the organic solvent for extraction is preferably dichloromethane, the number of extractions is preferably two, and the eluent used in the purification by silica gel column chromatography is a mixed solvent of methanol and dichloromethane, and the volume ratio of methanol and dichloromethane in the mixed solvent is preferably 1:(20-30).

[0050] In the present invention, the method 3 comprises: The method includes the step of mixing (CH3O)3PO, POCl3 and avanafil to carry out an esterification reaction to obtain an avanafil phosphate ester compound having the structure shown in Formula IV.

[0051] In the present invention, the synthetic route of the above-mentioned method 3 is shown in the following formula: TIFF2025511592000020.tif35110In the present invention, the ratio of the amounts of (CH3O)3PO, POCl3 and avanafil used is preferably 6mL:6mL:1mol, the temperature of the esterification reaction is preferably 0-25°C, and the reaction time is preferably 1-8h. In a specific embodiment of the present invention, avanafil is added to the mixture of (CH3O)3PO and POCl3, preferably at 5°C, and then stirred rapidly until the reaction is complete. After the reaction is completed, the present invention preferably quenches the reaction with ice water, adjusts the pH value of the resulting aqueous solution to 4-6 with NaOH, and then C 18 Column purification is used to obtain an avanafil phosphate ester compound, 18The eluent used in the column purification is preferably a mixed solvent of methanol and water, and the volume ratio of methanol to water in the mixed solvent is preferably 1:(1-10). In a specific embodiment of the present invention, the elution method used in the C18 column purification is preferably gradient elution, and gradient elution is preferably performed at a volume ratio of methanol to water of 1:10, 2:8:3:7, 4:6:5:5, or 6:4, and the components eluted when the volume ratio is 6:4 are collected.

[0052] In the present invention, the method 4 comprises: The method includes the step of mixing a compound having the structure shown in formula III, BCl3 and a solvent to carry out a debenzylation reaction to obtain an avanafil phosphate ester compound having the structure shown in formula IV.

[0053] In the present invention, the synthetic route of the method 4 is as shown in the following formula: JPEG2025511592000021.jpg50150 In the present invention, the solvent used in the method 4 is preferably a non-polar solvent or a polar aprotic solvent, more preferably one or more of dichloromethane, 1,2-dichloroethane, dioxane, tetrahydrofuran, N,N-dimethylacetamide and dimethylsulfoxide, the molar ratio of the compound having the structure shown in formula II and BCl3 is preferably 1:12.5, the temperature of the debenzylation reaction is preferably room temperature, and the reaction time is preferably 12-48h. In a specific embodiment of the present invention, preferably, the compound having the structure shown in formula II is first dissolved in a solvent, and then the BCl3 solution is added under 0°C conditions, and then the reaction is carried out by raising the temperature to room temperature, and the reaction is monitored by LC-MS until the reaction is completed, the concentration of the BCl3 solution is preferably 1mol / L, and the solvent used in the BCl3 solution is preferably the same as the solvent used in the debenzylation reaction, and will not be further described here.

[0054] After the debenzylation reaction is completed, the present invention preferably neutralizes the obtained product sample solution by adding saturated sodium bicarbonate solution, and then freeze-drying the obtained neutralized solution to obtain a crude product, and the crude product is then subjected to the process described below.18 The avanafil phosphate compound is obtained by purifying the compound in a column. 18 The eluent used in column purification is preferably a mixed solvent of methanol and water, and the volume ratio of methanol to water in the mixed solvent is preferably 1:(1 to 10).

[0055] The present invention also provides the application of the avanafil phosphate compound or its pharma- ceutically acceptable salt as described in the above-mentioned solution in the preparation of medicine for the treatment of phosphodiesterase-5 related diseases. In the present invention, the phosphodiesterase-5 related diseases preferably include erectile dysfunction related diseases, hypertension, coronary heart disease or prostatic hyperplasia. In the above application, the avanafil phosphate compound or its pharma-ceutically acceptable salt is preferably used alone or mixed with medicinal auxiliary materials. The present invention does not have any special requirements for the specific type of the auxiliary materials, and it is sufficient to use auxiliary materials well known to those skilled in the art, specifically excipients, diluents, etc. In the specific embodiment of the present invention, the above avanafil phosphate compound or its pharma-ceutically acceptable salt is preferably used to prepare oral tablets, capsules, granules or syrups.

[0056] The following describes the technical solutions of the present invention clearly and completely with reference to the embodiments of the present invention, but they cannot be understood as limitations on the protection scope of the present invention.

[0057] In the following examples: 1 H-NMR was recorded on a JEOL JNM-ECZS 400 nuclear magnetic resonance spectrometer, and chemical shifts are shown in δ (ppm). Separation and purification were performed using silica gel, which was 200-300 mesh unless otherwise specified. The blending ratios of the eluents were all by volume. The reagents used were all commercially available analytically pure unless otherwise specified.

[0058] Example 1 For the preparation of (S)-(1-(4-((3-chloro-4-methoxybenzyl)amino)5-((pyrimidine-2-methylene)carbamoyl)-2-pyrimidinyl)-2-pyrrolidinyl)dimethylmethylphosphonate (formula II), the reaction scheme is JPEG2025511592000022.jpg48150, Avanafil (2.0g, 4.13mmol) was dissolved in DCM (50mL), Py (400mg, 4.96mmol) was added, the mixture was protected with nitrogen gas, cooled in an ice-water bath for 15min, dimethyl chlorophosphate (720mg, 4.96mmol) was added by syringe, the mixture was allowed to warm to room temperature, and stirred overnight. The reaction was monitored by TLC (5% MeOH / DCM), and the reaction was stopped after the raw materials had completely reacted. The solvent was directly evaporated to dryness, and the mixture was eluted by column chromatography with 4-5% MeOH / DCM to obtain 1.64g of a yellow oily substance, with a yield of 67.2%. 1 H NMR (400 MHz, Chloroform-d) δ 9.02 (t, J = 5.9 Hz, 1H), 8.69 (d, J = 4.9 Hz, 2H), 8.39 (d, J = 11.5 Hz, 1H), 7.44 - 7.28 (m, 2H), 7.23 - 7.12 (m, 2H), 6.83 (d, J = 7.8 Hz, 1H), 4.75 (d, J = 4.5 Hz, 2H), 4.66 - 4.45 (m, 2H), 4.38 - 4.22 (m, 2H), 3.83 (s, 3H), 3.76 - 3.44 (m, 9H), 2.16 - 1.87 (m, 4H). HPLC-MS (ESI + ): [M+H] + : 593.0

[0059] Example 2 For the preparation of (S)-(1-(4-((3-chloro-4-methoxybenzyl)amino)5-((pyrimidine-2-methylene)carbamoyl)-2-pyrimidinyl)-2-pyrrolidinyl)dibenzylmethylphosphonate (formula III), the reaction scheme is JPEG2025511592000023.jpg84150, Avanafil (2.0 g, 4.13 mmol) was dissolved in DCM (50 mL), tetrazole (350 mg, 4.96 mmol) was added, and the mixture was protected with nitrogen gas and stirred at room temperature for 5 min. Diphenyl N,N'-diisopropyl phosphoramidite (1.72 g, 4.96 mmol) was added with a syringe and stirred overnight. The reaction solution was transferred to a cooling trap at -78 ° C and stirred while cooling for 15 min. A methylene chloride solution of m-CPBA (1.43 g, 10 mL DCM) was added with a constant pressure dropping funnel, m-CPBA was added dropwise to the reaction solution, and after the addition was completed, the temperature was naturally raised to room temperature. The reaction was monitored by TLC (5% MeOH / DCM), and the reaction was stopped after completion at room temperature for 6 h. Add 100mL of water, separate, extract the aqueous layer with 50mL×2 of DCM, combine with the dichloromethane layer, wash with 50mL×1 of saturated sodium chloride, dry with anhydrous sodium sulfate, evaporate to dryness, and purify by 3% MeOH / DCM column chromatography to give 1.7g of yellow oily product, yield 55.4%. 1 H NMR (400 MHz,Chloroform-d)δ9.28-9.11(m,1H),8.69(d,J=5.0Hz,2H),8.59(s,1H),7.95(t,J=1.9Hz,1H),7.87(dd,J=7.7,1.5Hz, 1H),7.84-7.74(m,1H),7.45-7.39(m,1H),7.31(d,J=11.4Hz,2H),7.25(d,J=7.7Hz,3H),7.19(t,J=5.0Hz,2H),7.07(td,J =9.1,3.5Hz,1H),6.76(d,J=8.8Hz,1H),5.25(s,1H),4.98(td,J=9.0,3.2Hz,4H),4.79(d,J=4.9Hz,2H),4.52(p,J=7.4,6. 6Hz,1H),4.32-4.18(m,2H),4.07-3.89(m,1H),3.79(d,J=13.2Hz,3H),3.72-3.41(m,2H),2.03-1.82(m,4H).HPLC-MS(ESI + ):[M+H] + :745.1

[0060] Example 3 Preparation of (S)-(1-(4-((3-chloro-4-methoxybenzyl)amino)5-((pyrimidine-2-methylene)carbamoyl)-2-pyrimidinyl)-2-pyrrolidinyl)methylphosphonic acid (compound III). It was prepared using route 1 and route 2, respectively. The reaction scheme of route 1 is The file is TIFF2025511592000024.tif33106. To a solution of (CH3O)3PO (6 mL) and POCl3 (6 mL, 40 mmol) at 5 °C, avanafil (1.0 g, 2.0 mmol) was added and stirred rapidly. After the reaction was complete, the reaction was quenched with ice water, and the resulting aqueous solution was adjusted to pH 4-6 (yellow pH paper) with NaOH and directly added to C. 18 The column was loaded and eluted with 400 mL water, 200 mL methanol to give the product, which was rotary evaporated to 50 mL with methanol and allowed to crystallize on standing to give 1.4 g of product, a yield of 62%.

[0061] The reaction equation for route 2 is The file is TIFF2025511592000025.tif37123. Compound II (1.0 g, 1.3 mmol) was dissolved in DCM (20 mL), and 1 mol / L BCl3 solution (16.25 mL) was added at 0° C. and stirred at room temperature for 2 days. The reaction was monitored by LC-MS. After the reaction was complete, saturated sodium bicarbonate was added to adjust the pH to 7, the reaction solution was lyophilized, and the mixture was subjected to HPLC. 18 Purification by gradient elution using a column MeOH:H2O=1:10 to 3:2 gave 300 mg of white solid product, with a yield of 40.8%. 1H NMR(400MHz,DMSO-d6)δ9.14(dt,J=11.6,6.0Hz,1H),8.82(dt,J=11.8,5.8Hz, 1H),8.75(d,J=4.9Hz,2H),8.54(d,J=4.2Hz,1H),7.37(dd,J=8.6,3.7Hz,2H), 7.34-7.23(m,1H),7.07(t,J=7.5Hz,1H),4.57(d,J=5.9Hz,3H),4.29-3.89(m, 5H),3.80(s,3H),3.65-3.37(m,3H),2.11-1.71(m,4H).HPLC-MS(ESI+):[M+H] + :564.1.

[0062] Test Example 1 Water Solubility Test 1. Standard curve layout 500 mg of sample was weighed out and ground in a mortar for 5 min, 24.57 mg was weighed out into a 50 mL volumetric flask, diluted to the mark with methanol, and dissolved by ultrasonication for 5 min. The solubility of the obtained mother liquor was 0.4914 mg / mL, and the mother liquor was diluted according to the ratio in Table 1 to obtain a linear solution.

[0063] [Table 1]

[0064] 2. Measurement of standard curve using UV equipment UV model: SHIMADZU UV-2550 UV-visible spectrophotometer Detection wavelength: 260nm The measured standard curve is y=0.0248x+0.0185, R 2 = 0.9984, r = 0.9992, where y is the solubility and x is the absorbance. 3. Accurately weigh the test sample (about 20 mg), add pure water to make the volume 2 mL, and vortex to dissolve for 20 seconds. Filter the sample through a 0.22 μm filter membrane, then dilute the filtrate 100 times with water and wait for measurement (pipette 100 μL into a 10 mL volumetric flask and make the volume constant). Measure the absorbance at a wavelength of 260 nm, and substitute the test results into the standard curve to calculate the solubility. The test results are as follows: Compound of formula II: absorbance: 0.476, solubility: 18.44 μg / mL, multiplied by dilution factor 100, solubility: 1.872 mg / mL. Compound of formula III: absorbance: 0.481, solubility: 18.65 μg / mL, multiplied by dilution factor 100, solubility: 1.840 mg / mL. Compound of formula IV: absorbance: 0.869, solubility: 34.29 μg / mL, multiplied by dilution factor 100, solubility: 3.392 mg / mL.

[0065] Test Example 2 Biological activity test The activity of the compounds of the present invention was evaluated by measuring the rate of avanafil release in rats. Experimental principle and method: Based on ultra-performance liquid chromatography-mass spectrometry-mass spectrometry combined (LC-MS-MS), the blood concentrations of avanafil and avanafil phosphate-derived compounds in rats were compared after intraperitoneal administration. Testing Method: (1) Preparation of liquid samples: By examining the avanafil pharmacokinetic literature, it was found that it was very difficult to detect the prototype drug, avanafil, after 6 h, so in this experiment, we chose to detect blood samples within 1 h of intraperitoneal administration. Using the liquid-liquid extraction method, 300 μL of serum and 300 μL of ethyl acetate were placed in a clean EP tube, vortexed, and then the supernatant was aspirated, and the process was repeated three times to combine the supernatants. After the supernatant was vacuum dried, 200 μL of 75% acetonitrile was added to the residue to redissolve it, and it was centrifuged at high speed (18000 g, 4 °C) at low temperature for 20 min, 150 μL was aspirated, and placed in a vial to wait for analysis. (2) Liquid phase analysis conditions: Chromatography conditions: The chromatography column was Agilent ZORBAX Eclipse Plus C 18 The column was (2.1 x 100 mm, 1.8 μm), mobile phase A was 0.1% formic acid aqueous solution, and mobile phase B was acetonitrile. Gradient elution was performed as specified in Table 1 below, with a flow rate of 0.4 mL / min, column temperature of 25°C, and sampling volume of 2 μL.

[0066] [Table 2]

[0067] (3) Mass spectrometry conditions: ESI + Detected in positive mode, gas temperature (Gas temp.) was 325°C, drying gas (Drying Gas) was 8L / min, nebulizer (Nebulizer) was 35psi, sheath gas temperature (Sheath Gas temp.) was 350°C, sheath gas flow rate (Aux Gas Flow) was 11L / min, capillary voltage (VCap) was 4000V, fragmentor voltage (Fragment) was 150V, skimmer (Skimmer) was 65V, and Oct 1 RF Vpp was 750V. The exact mass number was corrected using ESI-L Low Concentration tuning Mix (G1969-8500). Scanning range of primary mass analysis: m / z 50-1100. For secondary mass analysis, the strongest of the previous three was selected based on the primary scan, and induced collision dissociation (CID) was performed to obtain secondary mass analysis data.

[0068] Test Results: Optimization of chromatography-mass spectrometry: Avanafil belongs to the nitrogen-containing heterocyclic compound (the structural formula is shown in Formula V), and its molecular formula is C 23 H 27 ClN7O3, the exact molecular weight is 483.1858 Da, ESI + The chromatographic peak response at the ESI - Therefore, avanafil was monitored at [M+H]. +A chromatographic peak at =484.1858 was selected, and a peak appeared at 7.88 min in the chromatography. There was no other heterogeneous interference near this retention time, indicating high chromatographic specificity. TIFF2025511592000028.tif3346 formula V.

[0069] The comparative results of the drug release effect of intragastric injection of avanafil phosphate ester compounds and avanafil are shown in Figures 1 and 2. Figure 1 shows the comparative drug release effect of intragastric injection of avanafil and compounds having structures shown in formulas II and III. Figure 2 shows the comparative drug release effect of intragastric injection of avanafil and compounds having structures shown in formula IV. In Figures 1 and 2, AV represents avanafil drug substance, II, III, and IV represent compounds having structures shown in formulas II, III, and IVIII, and are subsequently shown as compound (II), compound (III), and compound (IV).

[0070] According to FIG. 1, avanafil 1h shows that avanafil is in the excretion phase when the avanafil blood concentration starts to decrease, compared with avanafil 0.5h. Compound (II) 1h shows that avanafil is in the absorption phase when the avanafil blood concentration starts to increase, compared with compound (II) 0.5h. Therefore, it is explained that compound (II) may have a certain sustained release effect, and compound (III) 1h shows that compound (III) is in the excretion phase when the avanafil blood concentration starts to decrease, compared with compound (III) 0.5h, and has no sustained release effect. Compound (IV) 1h shows that avanafil is in the absorption phase when the avanafil blood concentration starts to increase, compared with compound (IV) 0.5h, and the blood concentration of avanafil 1h reaches 80% of that of avanafil, therefore, it is explained that derivative compound (IV) has a very good sustained release effect.

[0071] It should be understood that the above is merely a preferred embodiment of the present invention, and that those skilled in the art can make a number of further improvements and modifications without departing from the principles of the present invention, and these improvements and modifications should also fall within the scope of protection of the present invention.

Claims

1. An avanafil phosphate compound or a pharma- ceutically acceptable salt thereof, the structural formula of the avanafil phosphate compound is as shown in Formula I: Formula I, In formula I, R is hydrogen, a phenyl group, a substituted phenyl group, a benzyl group, an alkyl group or a substituted alkyl group, the substituted phenyl group being a mono- or poly-substituted phenyl group at the ortho, meta or para position, the substituents on the substituted phenyl group being a halogen, a nitro group or an alkyl group, and the substituents on the substituted alkyl group being a halogen or a cyano group, a stendral phosphate compound or a pharma- ceutically acceptable salt thereof.

2. The avanafil phosphate compound or its pharma- ceutical acceptable salt according to claim 1, characterized in that, when R is an alkyl group or a substituted alkyl group, the alkyl group or the substituted alkyl group has 1 to 18 carbon atoms, and when the substituent of the substituted alkyl group is a halogen, the halogen is fluorine, chlorine or bromine.

3. The avanafil phosphate compound or its pharma- ceutically acceptable salt according to claim 1, characterized in that the substituted phenyl group is a mono-, di- or tri-substituted phenyl group, and if the substituent in the substituted phenyl group is a halogen, the halogen is fluorine, chlorine or bromine, and if the substituent in the substituted phenyl group is an alkyl group, the alkyl group has 1 to 18 carbon atoms.

4. R in the formula I is H. The avanafil phosphate compound or its pharma- ceutically acceptable salt according to claim 1, which is any one of the following:

5. The avanafil phosphate compound or its pharma- ceutical acceptable salt according to any one of claims 1 to 4, wherein the avanafil phosphate compound is any one of formulas II to IV. Formula II Formula III Formula IV

6. A method for producing the avanafil phosphate ester compound according to any one of claims 1 to 5, comprising the steps of: The method 1 includes the steps of mixing avanafil, an alkali, a solvent and a compound having the structure shown in formula a to carry out a condensation reaction to obtain an avanafil phosphate compound having the structure shown in formula I, Formula a, In formula (a), R is a phenyl group, a substituted phenyl group, an alkyl group, or a substituted alkyl group; The method 2 includes the steps of: mixing avanafil, an alkali, a solvent and a compound having a structure shown in formula b to carry out a condensation reaction to obtain an intermediate reaction solution (the intermediate product in the intermediate reaction solution has a structure shown in formula c); and mixing the intermediate reaction solution with a metachloroperbenzoic acid solution to carry out an oxidation reaction to obtain an avanafil phosphate compound having a structure shown in formula I; formula b formula c In formula (b) and formula (c), R is a benzyl group, a phenyl group, an alkyl group or a substituted alkyl group; The method 3 is (CH ３ O) ３ PO, POCl ３ and avanafil to carry out an esterification reaction to obtain an avanafil phosphate compound having the structure shown in formula I, wherein R is hydrogen; Method 4 comprises preparing a compound having the structure shown in Formula III, BCl ３ and a solvent to perform a debenzylation reaction to obtain an avanafil phosphate compound having the structure shown in formula I, wherein R is hydrogen. Formula III

7. The method according to claim 6, wherein the solvent in the method 1 and the method 2 is independently a non-polar solvent or a polar aprotic solvent.

8. 7. The method according to claim 6, wherein the alkali in the method 1 and the method 2 is independently an organic alkali or an inorganic alkali, the inorganic alkali includes an alkali metal carbonate or an alkali metal phosphate, and the organic alkali includes one or more of pyridine, 4-dimethylaminopyridine, triethylamine, trimethylamine, and tetrazole.

9. The preparation method according to claim 6 or 8, characterized in that in the method 1, the molar ratio of avanafil to alkali is 1: (1.1-1.3), and the molar ratio of avanafil to the compound having the structure shown in formula a is 1: (1.1-1.3).

10. The method according to claim 6 or 8, characterized in that in the method 2, the molar ratio of avanafil to alkali is 1: (1.1-1.3), and the molar ratio of avanafil to the compound having the structure shown in formula b is 1: (1.1-1.3).

11. The method according to claim 6, wherein the condensation reaction in the method 1 is carried out at room temperature for 12 to 24 hours.

12. The method according to claim 6, wherein the condensation reaction in the method 2 is carried out at room temperature for 12 to 24 hours, and the oxidation reaction in the method 2 is carried out at room temperature for 4 to 12 hours.

13. The method according to claim 6 or 12, characterized in that in the method 2, the mass ratio of metachloroperbenzoic acid to avanafil is (0.7-0.8):

1.

14. The method according to claim 6, wherein the esterification reaction temperature in the method 3 is 0°C to 25°C, and the reaction time is 1 hour to 8 hours.

15. The method according to claim 6, wherein the debenzylation reaction in the method 4 is carried out at room temperature for 12 to 48 hours.

16. Application of the avanafil phosphate compound or its pharma- ceutically acceptable salt according to any one of claims 1 to 5 in the preparation of a drug for the treatment of phosphodiesterase 5-related diseases.

17. The use according to claim 15, characterized in that the phosphodiesterase 5 related disease comprises erectile dysfunction related disease, hypertension, coronary heart disease or prostatic hyperplasia.

18. The application according to claim 15, characterized in that, in said application, the avanafil phosphate compound or its pharma- ceutical acceptable salt is used alone or in combination with medicinal auxiliary materials.

19. The application according to claim 16, characterized in that the dosage form of the drug for treating phosphodiesterase 5-related diseases is tablets, capsules, granules or syrup.

20. Use of the avanafil phosphate compound or its pharma- ceutically acceptable salt according to any one of claims 1 to 5 in the treatment of phosphodiesterase 5-related diseases.

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