WO2023231254A1 - Composés de phosphate d'avanafil, leur procédé de préparation et leur utilisation - Google Patents

Composés de phosphate d'avanafil, leur procédé de préparation et leur utilisation Download PDF

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WO2023231254A1
WO2023231254A1 PCT/CN2022/122414 CN2022122414W WO2023231254A1 WO 2023231254 A1 WO2023231254 A1 WO 2023231254A1 CN 2022122414 W CN2022122414 W CN 2022122414W WO 2023231254 A1 WO2023231254 A1 WO 2023231254A1
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avanafil
formula
reaction
compound
preparation
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PCT/CN2022/122414
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Chinese (zh)
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顾艳飞
冯飞
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苏州正永生物医药有限公司
苏州菲默斯生物医药技术有限公司
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Publication of WO2023231254A1 publication Critical patent/WO2023231254A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the technical field of pharmaceutical compounds of the present invention relates in particular to an avanafil phosphate compound and its preparation method and application.
  • Phosphodiesterase 5 belongs to a superfamily of enzymes that can catalyze the conversion of the second messenger cGMP into GMP.
  • PDE5 inhibitors are recommended as first-line drugs for the treatment of erectile dysfunction (ED).
  • PDE5 inhibitors can also be used to treat diseases such as hypertension, coronary heart disease, and prostatic hyperplasia [Chinese Journal of Medicinal Chemistry. 2017.27.400-07].
  • diseases such as hypertension, coronary heart disease, and prostatic hyperplasia
  • According to survey statistics about 15% of men aged 40 to 59 have ED, and 70% of men in their 60s and 70s have ED. Like many other chronic diseases, the incidence of ED is also Increases with age [Am J Med.2021.134.310-16].
  • Avanafil is a selective PDE5 inhibitor approved by the US FDA in April 2012 for the treatment of ED.
  • the PDE5 inhibitors on the market include sildenafil, vardenafil, tadenafil, udenafil and mironafil.
  • Clinical research data shows that many ED patients can successfully have sex within 30 minutes of using avanafil, sildenafil, vardenafil, and tadalafil take about 90 minutes to take effect, and tadalafil takes 2 hours [ Advances in Pharmacy.2012.36.135-36]. Therefore, the rapid-acting advantage of avanafil will be more favored by ED patients.
  • avanafil has the disadvantages of poor water solubility and short action time. Therefore, it is of great value to develop water-soluble avanafil and avanafil prodrugs to extend the action time of the drug.
  • the present invention provides an avanafil phosphate compound and its preparation method and application.
  • the avanafil phosphate compound provided by the invention has good water solubility and long acting time.
  • avanafil phosphate ester compound or a pharmaceutically acceptable salt thereof the structural formula of the avanafil phosphate ester compound is as shown in Formula I:
  • R is hydrogen, phenyl, substituted phenyl, benzyl, alkyl or substituted alkyl;
  • the substituted phenyl group is a mono-substituted or poly-substituted phenyl group at the ortho, meta or para position;
  • the substituent on the substituted phenyl group is halogen, nitro or alkyl
  • the substituent on the substituted alkyl group is halogen or cyano group.
  • R is an alkyl group or a substituted alkyl group
  • the number of carbon atoms in the alkyl group or substituted alkyl group is 1 to 18; when the substituent on the substituted alkyl group is halogen, the halogen is fluorine, Chlorine or bromine.
  • the substituted phenyl group is a monosubstituted phenyl group, a disubstituted phenyl group or a trisubstituted phenyl group.
  • the substituent on the substituted phenyl group is halogen
  • the halogen is preferably fluorine, chlorine or bromine.
  • the substituent on the substituted phenyl group is an alkyl group, the number of carbon atoms of the alkyl group is 1 to 18.
  • R in formula I is any one of the following groups:
  • the avanafil phosphate compound is any one of Formula II to Formula IV:
  • the present invention also provides a method for preparing avanafil phosphate compounds described in the above scheme, including method one, method two, method three or method four;
  • the method one includes the following steps:
  • Avanafil, a base, a solvent and a compound having the structure represented by formula a are mixed to perform a condensation reaction to obtain an avanafil phosphate ester compound having the structure represented by formula I;
  • R is phenyl, substituted phenyl, alkyl or substituted alkyl
  • the second method includes the following steps:
  • Avanafil, a base, a solvent and a compound having a structure represented by formula b are mixed to perform a condensation reaction to obtain an intermediate reaction liquid; the intermediate product in the intermediate reaction liquid has a structure represented by formula c;
  • the intermediate reaction solution and m-chloroperoxybenzoic acid solution are mixed to perform an oxidation reaction to obtain an avanafil phosphate ester compound having the structure shown in Formula I;
  • R is benzyl, phenyl, alkyl or substituted alkyl.
  • the third method includes the following steps:
  • the fourth method includes the following steps:
  • the solvents in Method One and Method Two are independently non-polar solvents or polar aprotic solvents.
  • the base in method one and method two is independently an organic base or an inorganic base;
  • the inorganic base includes an alkali metal carbonate or an alkali metal phosphate;
  • the organic base includes pyridine, 4-dimethylamino One or more of pyridine, triethylamine, trimethylamine and tetrazole.
  • the molar ratio of avanafil and alkali is 1:(1.1 ⁇ 1.3), and the molar ratio of avanafil and the compound having the structure shown in formula a is 1:(1.1 ⁇ 1.3 ).
  • the molar ratio of avanafil and alkali is 1:(1.1 ⁇ 1.3), and the molar ratio of avanafil and the compound having the structure shown in formula b is 1:(1.1 ⁇ 1.3 ).
  • the base in method one and method two is independently an organic base or an inorganic base.
  • the temperature of the condensation reaction in the first method is room temperature, and the reaction time is 12 to 24 hours;
  • the temperature of the condensation reaction in the second method is room temperature, and the reaction time is 12 to 24 hours;
  • the temperature of the oxidation reaction in the second method is preferably At room temperature, the time is 4 to 12 hours.
  • the mass ratio of m-chloroperbenzoic acid and avanafil is (0.7-0.8):1.
  • the temperature of the esterification reaction in the third method is 0°C to 25°C, and the reaction time is 1h to 8h; the temperature of the debenzylation reaction in the fourth method is room temperature, and the reaction time is 12 to 48h.
  • the present invention also provides the use of the avanafil phosphate compound or its pharmaceutically acceptable salt described in the above scheme in the preparation of drugs for treating phosphodiesterase 5-related diseases.
  • the phosphodiesterase 5-related diseases include erectile dysfunction-related diseases, hypertension, coronary heart disease or prostatic hyperplasia.
  • avanafil phosphate compound or its pharmaceutically acceptable salt is used alone or mixed with pharmaceutically acceptable excipients.
  • the dosage form of the drug for treating phosphodiesterase 5-related diseases is tablets, capsules, granules or syrups.
  • the present invention also provides the use of the avanafil phosphate compound or its pharmaceutically acceptable salt described in the above scheme in the treatment of phosphodiesterase 5-related diseases.
  • the invention provides an avanafil phosphate compound with a structural formula shown in Formula I.
  • the avanafil phosphate compound provided by the present invention has good water solubility due to its phosphate structure and increased polarity.
  • the sustained-release effect of the phosphate ester allows the drug to have a long action time and is useful in treating phosphodiesterase 5-related diseases. It has broad application prospects in medicines.
  • the present invention also provides a preparation method for the avanafil phosphate compound described in the above scheme.
  • the preparation method provided by the present invention has simple steps, is easy to operate, and is suitable for large-scale production.
  • Figure 1 is a comparison of the intragastric drug release effects of avanafil and compounds with structures shown in Formula II and Formula III;
  • Figure 2 is a comparison of the intragastric drug release effects of avanafil and the compound having the structure shown in Formula IV.
  • the invention provides an avanafil phosphate compound or a pharmaceutically acceptable salt thereof.
  • the structural formula of the avanafil phosphate compound is as shown in Formula I:
  • R is hydrogen, phenyl, substituted phenyl, alkyl or substituted alkyl;
  • the substituted phenyl group is a mono-substituted or poly-substituted phenyl group at the ortho, meta or para position;
  • the substituent on the substituted phenyl group is halogen, nitro or alkyl
  • the substituent on the substituted alkyl group is halogen or cyano group.
  • the substituted phenyl group is preferably a monosubstituted phenyl group, a disubstituted phenyl group or a trisubstituted phenyl group.
  • the halogen is preferably fluorine or chlorine. Or bromine
  • the 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.
  • the alkyl group is preferably methyl Or isobutyl.
  • R is an alkyl group or a substituted alkyl group
  • the number of carbon atoms in the alkyl group or substituted alkyl group is preferably 1 to 18, more preferably 1 to 10;
  • the substituent is preferably halogen or cyano, and the halogen is preferably fluorine, chlorine or bromine.
  • R in formula I is preferably any one of the following groups:
  • the avanafil phosphate compound is preferably any one of Formula II to Formula IV:
  • the chemical name of the compound with the structure shown in formula II is: (S)-(1-(4-((3-chloro-4-methoxybenzyl)amino)5-((pyrimidine) -2-methylene)carbamoyl)-2-pyrimidinyl)-2-pyrrolidinyl)methyl phosphate dimethyl ester;
  • the chemical name of the compound with the structure shown in formula III is: (S)- (1-(4-((3-chloro-4-methoxybenzyl)amino)5-((pyrimidin-2-methylene)carbamoyl)-2-pyrimidinyl)-2-pyrrolidinyl) Methyl dibenzyl phosphate;
  • the chemical name of the compound with the structure shown in formula IV is: (S)-(1-(4-((3-chloro-4-methoxybenzyl)amino)5-( (pyrimidin-2-methylene)carbamoyl)-2-
  • the present invention also provides a method for preparing avanafil phosphate compounds described in the above scheme, including method one, method two, method three and method four, wherein method one is used to prepare R is phenyl, substituted phenyl, alkyl Avanafil phosphate ester compounds when R is a benzyl, phenyl, alkyl or substituted alkyl group, method two is used to prepare avanafil phosphate ester compounds when R is a benzyl, phenyl, alkyl or substituted alkyl group, method three and method Four is used to prepare avanafil phosphate ester compounds when R is hydrogen (i.e., avanafil phosphate ester compounds represented by formula IV). Detailed descriptions are given below:
  • the method one includes the following steps:
  • Avanafil, a base, a solvent and a compound having the structure shown in formula a are mixed to perform a condensation reaction to obtain an avanafil phosphate ester compound having a structure shown in formula I;
  • R is a phenyl group, a substituted phenyl group, an alkyl group or a substituted alkyl group.
  • the types of the substituted phenyl group and the substituted alkyl group are consistent with the above scheme and will not be described again here.
  • the solvent used in the method one is preferably a non-polar solvent or a polar aprotic solvent, and more preferably includes dichloromethane, 1,2-dichloroethane, dioxane, tetrahydrofuran, N , one or more of N-dimethylacetamide and dimethyl sulfoxide;
  • the base is preferably an inorganic base or an organic base, and the inorganic base 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 both of potassium phosphate and sodium phosphate;
  • the organic base Preferably, it includes one or more of pyridine, 4-dimethylaminopyridine, triethylamine, trimethylamine and tetrazole.
  • the molar ratio of avanafil and alkali is preferably 1:(1.1 ⁇ 1.3), more preferably 1:1.2; the avanafil and alkali have the structure shown in formula a
  • the molar ratio of the compound is preferably 1: (1.1 ⁇ 1.3), more preferably 1:1.2; the present invention has no special requirements on the source of the compound having the structure shown in formula a, and the above-mentioned compound on the market is used or the present invention is used. It can be synthesized by methods well known to those skilled in the art.
  • the present invention has no special requirements on the amount of the solvent, as long as it can ensure the smooth progress of the reaction.
  • the temperature of the condensation reaction in the method one is preferably room temperature, and the reaction time is preferably 12 to 24 hours; the condensation reaction is preferably carried out under nitrogen protection conditions; in specific embodiments of the present invention, it is preferred to first Dissolve avanafil in the solvent, then add a base, and then cool it in an ice-water bath for 15 minutes under nitrogen protection. Use a syringe to add a compound with the structure shown in formula a to the reaction solution, and then naturally warm it to room temperature for reaction.
  • the present invention preferably uses TLC to monitor the reaction, and stops the reaction after the raw material reaction is complete;
  • 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%, recorded as 5 %MeOH/DCM.
  • the present invention preferably evaporates the solvent in the obtained reaction liquid to dryness to obtain a crude product, which is then purified by silica gel column chromatography to obtain avanafil phosphates having the structure shown in Formula I.
  • Compound; in the present invention, the elution reagent used for the silica gel column chromatography purification 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 ).
  • the second method includes the following steps:
  • Avanafil, a base, a solvent and a compound having a structure represented by formula b are mixed to perform a condensation reaction to obtain an intermediate reaction liquid; the intermediate product in the intermediate reaction liquid has a structure represented by formula c;
  • the intermediate reaction solution and the m-CPBA solution are mixed to perform an oxidation reaction to obtain an avanafil phosphate compound having the structure shown in Formula I;
  • R is benzyl, phenyl, alkyl or substituted alkyl.
  • avanafil, a base, a solvent and a compound having the structure shown in formula b are first mixed to perform a condensation reaction to obtain an intermediate reaction liquid.
  • the solvent used in the second method is preferably a non-polar solvent or a polar aprotic solvent, and more preferably includes dichloromethane, 1,2-dichloroethane, dioxane, tetrahydrofuran, N , one or more of N-dimethylacetamide and dimethyl sulfoxide;
  • the base is preferably an inorganic base or an organic base, and the inorganic base 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 both of potassium phosphate and sodium phosphate;
  • the organic base Preferably, it includes one or more of pyridine, 4-dimethylamino
  • the molar ratio of avanafil and alkali is preferably 1:(1.1 ⁇ 1.3), more preferably 1:1.2; the avanafil and alkali have the structure shown in formula b
  • the molar ratio of the compound is preferably 1: (1.1 ⁇ 1.3), more preferably 1:1.2; the present invention has no special requirements on the source of the compound having the structure shown in formula b.
  • the above-mentioned compound on the market is used or the present invention is used. It can be synthesized by methods well known to those skilled in the art.
  • the present invention has no special requirements on the amount of the solvent, as long as it can ensure the smooth progress of the reaction.
  • the temperature of the condensation reaction in the second method is preferably room temperature
  • the reaction time is preferably 12 to 24 hours
  • the condensation reaction is preferably carried out under nitrogen protection conditions.
  • the present invention mixes the intermediate reaction liquid and m-CPBA (meta-chloroperoxybenzoic acid) solution to perform an oxidation reaction to obtain avanafil phosphate ester compounds having the structure shown in Formula I.
  • the solvent used in the m-CPBA solution is preferably consistent with the solvent used in the condensation reaction step, which will not be described in detail here;
  • the concentration of the m-CPBA solution is preferably 0.143g/mL;
  • the m- The mass ratio of CPBA and avanafil is preferably (0.7-0.8):1, more preferably 0.715:1.
  • the temperature of the oxidation reaction is preferably room temperature, and the reaction time is preferably 4 to 12 hours; in specific embodiments of the present invention, it is preferred to first transfer the intermediate reaction solution to a -78°C cold trap, cool and stir for 15 minutes, Then use a constant pressure dropping funnel to add the m-CPBA solution, and after the addition is completed, the temperature is naturally raised to room temperature to perform the oxidation reaction; the present invention preferably uses TLC to monitor the reaction, and stops the reaction after the raw material reaction is complete; the reagent used in the TLC monitoring is methanol and dichloromethane, the volume fraction of methanol in the mixed solvent is preferably 5%, recorded as 5% MeOH/DCM.
  • the present invention preferably mixes the obtained product liquid and water and then separates the layers.
  • the aqueous layer is extracted with an organic solvent.
  • the obtained organic layer is washed with saturated sodium chloride, dried with anhydrous sodium sulfate and evaporated to dryness in order to obtain a crude product.
  • product, and the obtained crude product is purified by silica gel column chromatography to obtain avanafil phosphate ester compounds having the structure shown in Formula I.
  • the organic solvent for extraction is preferably dichloromethane, and the number of extractions is preferably 2 times;
  • the elution reagent used for the silica gel column chromatography purification is a mixed solvent of methanol and dichloromethane, so The volume ratio of methanol and methylene chloride in the mixed solvent is preferably 1: (20-30).
  • the third method includes the following steps:
  • the dosage ratio of (CH 3 O) 3 PO, POCl 3 and avanafil is preferably 6 mL: 6 mL: 1 mol; the temperature of the esterification reaction is preferably 0 to 25°C, and the reaction time is preferably It is 1 to 8 hours; in the specific embodiment of the present invention, preferably at 5°C, avanafil is added to the mixture of (CH 3 O) 3 PO and POCl 3 , and then stirred rapidly until the reaction is complete.
  • the present invention preferably quenches the reaction with ice water, adjusts the pH value of the obtained aqueous solution to 4 to 6 with NaOH, and then uses a C 18 column to purify the avanafil phosphate ester compound; the C 18 column
  • the eluent used for purification is preferably a mixed solvent of methanol and water.
  • the volume ratio of methanol and water in the mixed solvent is preferably 1: (1-10).
  • the elution method used is preferably gradient elution, preferably in a volume ratio of methanol and water of 1:10, 2:8:3:7, 4:6:5:5, and 6:4. Collect the components eluted when the volume ratio is 6:4.
  • the fourth method includes the following steps:
  • the compound having the structure represented by Formula III, BCl 3 and a solvent are mixed to perform a debenzylation reaction to obtain an avanafil phosphate ester compound having the structure represented by Formula IV.
  • the solvent used in the method four is preferably a non-polar solvent or a polar aprotic solvent, and more preferably includes dichloromethane, 1,2-dichloroethane, dioxane, tetrahydrofuran, N, One or more of N-dimethylacetamide and dimethyl sulfoxide; the molar ratio of the compound having the structure shown in formula II and BCl 3 is preferably 1:12.5; the debenzylation reaction The temperature is preferably room temperature, and the reaction time is preferably 12 to 48 hours.
  • the compound having the structure shown in Formula II it is preferred to first dissolve the compound having the structure shown in Formula II in a solvent, then add BCl 3 solution at 0°C, and then warm to room temperature to carry out the reaction. LC-MS monitors until the reaction is completed. ;
  • the concentration of the BCl 3 solution is preferably 1 mol/L, and the solvent used in the BCl 3 solution is preferably consistent with the solvent used in the debenzylation reaction, which will not be described again here.
  • the present invention preferably adds a saturated sodium bicarbonate solution to the obtained product liquid for neutralization, and then freeze-dries the obtained neutralized liquid to obtain a crude product, which is purified using a C 18 column to obtain Avanafil phosphate compound;
  • the eluent used for the C 18 column purification is preferably a mixed solvent of methanol and water, and the volume ratio of methanol and water in the mixed solvent is preferably 1: (1-10).
  • the present invention also provides the use of the avanafil phosphate compound or its pharmaceutically acceptable salt described in the above scheme in the preparation of drugs for treating phosphodiesterase 5-related diseases;
  • the phosphoric acid Diesterase 5-related diseases preferably include erectile dysfunction-related diseases, hypertension, coronary heart disease or prostatic hyperplasia; when used, avanafil phosphate compounds or pharmaceutically acceptable salts thereof are preferably used alone or together with Medicinal auxiliary materials are mixed and used; the present invention has no special requirements for the specific types of the auxiliary materials, and auxiliary materials well known to those skilled in the art can be used, such as excipients, diluents, etc., in specific embodiments of the present invention,
  • the above-mentioned avanafil phosphate ester compound or its pharmaceutically acceptable salt is prepared into tablets, capsules, granules or syrups for oral administration using excipients.
  • reaction was monitored by TLC (5% MeOH/DCM), and the reaction was stopped after the reaction was complete for 6 hours at room temperature. Add 100 mL of water, separate the layers, extract the water layer with DCM 50 mL Product 1.7g, yield 55.4%.
  • UV model SHIMADZU UV-2550 UV-visible spectrophotometer
  • Compound of formula II absorbance: 0.476, solubility: 18.44 ⁇ g/mL, multiplied by the dilution factor of 100, solubility: 1.872 mg/mL.
  • Compound of formula III absorbance: 0.481, solubility: 18.65 ⁇ g/mL, multiplied by the dilution factor of 100, solubility: 1.840 mg/mL.
  • Compound of formula IV absorbance: 0.869, solubility: 34.29 ⁇ g/mL, multiplied by the dilution factor of 100, solubility: 3.392 mg/mL.
  • the activity of the compounds of the invention was evaluated by testing the rate of release of avanafil in rats.
  • Liquid sample preparation After reviewing the pharmacokinetics literature of avanafil, it was found that it is difficult to detect the prototype drug of avanafil after 6 hours, so this experiment chose to detect blood samples within 1 hour of intraperitoneal administration. Using the liquid-liquid extraction method, place 300 ⁇ L of serum and 300 ⁇ L of ethyl acetate into a clean EP tube, vortex to mix, and then aspirate the supernatant, repeat three times, and combine the supernatants.
  • the residue was redissolved by adding 200 ⁇ L of 75% acetonitrile, centrifuged at low temperature and high speed (18000g, 4 degrees Celsius) for 20 min, and 150 ⁇ L was pipetted and placed in a sampling bottle for analysis.
  • Chromatographic conditions The chromatographic column is AgilentZORBAX Eclipse Plus C 18 column (2.1 ⁇ 100mm, 1.8 ⁇ m), mobile phase A is 0.1% formic acid aqueous solution, mobile phase B is acetonitrile, gradient elution is performed as specified in Table 1, and the flow rate is 0.4 mL/min, column temperature is 25°C, injection volume: 2 ⁇ L.
  • Mass spectrometry conditions Apply ESI + positive mode for detection, gas temperature (Gas temp.) is 325°C, drying gas (Drying Gas) is 8L/min, nebulizer (Nebulizer) is 35psi, sheath gas temperature (Sheath Gas temp. .) is 350°C, the sheath gas flow rate (Aux Gas Flow) is 11L/min, the capillary voltage (VCap) is 4000V, the fragmentation voltage (Fragment) is 150V, the skimmer (Skimmer) is 65V, and Oct 1 RF Vpp is 750V .
  • Use ESI-L Low Concentration tuning Mix (G1969-8500) to correct the accurate mass.
  • the first-level mass spectrometry scanning range m/z 50 ⁇ 1100; the second-level mass spectrometry selects the top three based on the first-level scan to perform induced collision dissociation (CID) to obtain the second-level mass spectrometry data.
  • CID induced collision dissociation
  • Figures 1 and 2 The comparative results of the drug release effects of avanafil phosphate esters and avanafil administered by intragastric administration are shown in Figures 1 and 2.
  • Figure 1 shows the intragastric administration of avanafil and compounds with structures shown in Formula II and Formula III. Comparison of drug release effects.
  • Figure 2 shows the comparison of intragastric drug release effects of avanafil and the compound with the structure shown in formula IV.
  • AV represents the original drug of avanafil
  • II, III, and IV represent Compounds with structures represented by formulas II, III, and IV are subsequently represented as compound (II), compound (III), and compound (IV).

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Abstract

La présente invention relève du domaine technique des composés pharmaceutiques. L'invention concerne des composés de phosphate d'avanafil, leur formule développée étant représentée par la formule I, R dans la formule I est hydrogène, phényle, phényle substitué, alkyle ou alkyle substitué. Les composés de phosphate d'avanafil selon la présente invention ont une bonne solubilité dans l'eau, un long temps d'action de médicament, et un bon effet de libération lente, ayant ainsi de larges perspectives d'application dans la préparation de médicaments pour le traitement de maladies liées à la phosphodiestérase 5. La présente invention concerne également un procédé de préparation de composés de phosphate d'avanafil dans la solution ci-dessus, et le procédé de préparation selon la présente invention implique des étapes simples et un fonctionnement facile, étant ainsi approprié pour une production à grande échelle.
PCT/CN2022/122414 2022-05-30 2022-09-29 Composés de phosphate d'avanafil, leur procédé de préparation et leur utilisation WO2023231254A1 (fr)

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