A pyridodihydrofuranone derivative, and a preparation method and application thereof

Abstract

The present application belongs to the technical field of biological medicine, and particularly relates to a pyridodihydrofuranone derivative, a preparation method and application thereof. The derivative shows good inhibitory effect on phosphodiesterase type 1 (PDE1), and can be applied as a phosphodiesterase type 1 inhibitor. According to the research on phosphodiesterase type 1 related diseases in the prior art, the pyridodihydrofuranone derivative can be further applied in the treatment of pulmonary arterial hypertension, idiopathic pulmonary fibrosis, liver fibrosis, vascular dementia, intestinal inflammation and other diseases related to phosphodiesterase type 1, more optional drugs are provided, and the pyridodihydrofuranone derivative has important medicinal value and clinical application prospect. Moreover, the pyridodihydrofuranone derivative has novel structure, the preparation method is simple, and is very suitable for large-scale industrial production and application.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine technology and more specifically relates to a pyridodihydrofuranone derivative and a preparation method and application thereof. Background Art

[0002] Phosphodiesterases (PDEs) hydrolyze intracellular second messengers (cyclic adenosine monophosphate (cAMP) or cyclic guanosine monophosphate (cGMP)). By degrading intracellular cAMP or cGMP, they terminate the biochemical effects transmitted by these second messengers. Research has demonstrated that cAMP and cGMP play important regulatory roles in cellular activity. They serve as second messengers for substances such as neurotransmitters, hormones, light, and odors, acting on a wide range of intracellular target organs. The regulation of intracellular cAMP and cGMP concentrations is primarily determined by the balance between synthesis by nucleotide cyclases and hydrolysis by phosphodiesterases (PDEs).

[0003] PDEs are widely distributed in the body and are divided into 11 isoenzyme families (PDE1 to PDE11) based on their protein sequence similarity, enzyme kinetics, regulatory properties, cell tissue distribution, and pharmacological properties. Among them, PDE1 was identified as Ca 2+ Calmodulin-dependent phosphodiesterase (CaM-pde), which is activated by Ca 2+Calmodulin activates and mediates calcium and cyclic nucleotide signaling pathways. Studies have found that changes in the signaling pathways regulated by PDE1 are associated with the central nervous system and can be used to regulate mental disorders, movement disorders, cognitive function and Alzheimer's disease; some studies have also shown that PDE1 is related to cardiac insufficiency and can be used to regulate heart failure, cardiac remodeling and dysfunction; some studies have also shown that PDE1 is associated with lung, kidney, hematology, gastrointestinal tract, liver, fertility, cancer and metabolic disorders ([1] Ren, L.; Yang, C.; Dou, Y.; Zhan, R.; Sun, Y.; Yu, Y., MiR-541-5p Regulates Lung Fibrosis by Targeting Cyclic NucleotidePhosphodiesterase 1A. Exp Lung Res 2017, 43(6-7), 249-258. [2] Xin, W.; Li, N.; Fernandes, VS; Chen, B.; Rovner, ES; Petkov, GV, BK Channel Regulation byPhosphodiesterase Type 1:A Novel Signaling Pathway Controlling Human DetrusorSmooth Muscle Function.Am J Physiol Renal Physiol 2016,310(10),F994-9.). It can be seen that PDE1 inhibitors play an important role in the field of disease treatment.

[0004] Currently, PDE1 inhibitors have been reported as drugs for treating pulmonary arterial hypertension (PAH), but the development and research of PDE1 inhibitors is still relatively limited. There is still a need to provide more PDE1 inhibitors to expand the range of drug options for research and clinical applications. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to overcome the defects and shortcomings of the limited types of existing PDE1 inhibitors and provide a pyridodihydrofuranone derivative with significant inhibitory effect on PDE1.

[0006] The purpose of the present invention is to provide a method for preparing the pyridodihydrofuranone derivatives.

[0007] Another object of the present invention is to provide the use of the pyridodihydrofuranone derivatives in the preparation of phosphodiesterase type I inhibitors.

[0008] Another object of the present invention is to provide a phosphodiesterase type I inhibitor and its use in preparing a drug for treating phosphodiesterase type I related diseases.

[0009] The above-mentioned purpose of the present invention is achieved through the following technical solutions:

[0010] A pyridodihydrofuranone derivative having a structure of formula (I) or formula (II), or a pharmaceutically acceptable salt or solvate of the structure of formula (I) or formula (II):

[0011]

[0012] Wherein, R1 is selected from indolyl, C 1～6 Alkyl or substituted C 1～6 Alkyl, five-membered or six-membered heterocyclic ring, One of, R3, R4 are each independently selected from hydrogen, C 1～6 Alkoxy, halogen, -O-R5-R6, wherein R5 is C 1～6 Alkyl or O is directly connected to R6, and R6 is C 3～8 Cycloalkyl, morpholinyl, dimethylamino, pyrrolidinyl, halogenated pyrrolidinyl, C 1～6 alkoxy;

[0013] R2 is selected from C 1～6 Alkyl or substituted C 1～6 Alkyl, phenyl or substituted phenyl, benzyl or substituted benzyl, C 3～8 One of cycloalkyl and furyl;

[0014] The substituted substituent is one or more, and the substituent is selected from C 1～6 One or more of alkoxy, phenyl, and halogen.

[0015] Preferably, R1 is selected from tetrahydropyranyl, indolyl, C 1～3 Alkyl or substituted C 1～3 Alkyl, five-membered or six-membered heteroaromatic ring, One of, R3, R4 are each independently selected from hydrogen, C 1～3 Alkoxy, halogen, -O-R5-R6, wherein R5 is C 1～3 Alkyl or O is directly connected to R6, and R6 is C 3～6 Cycloalkyl, morpholinyl, dimethylamino, pyrrolidinyl, halogenated pyrrolidinyl, C 1～3 alkoxy;

[0016] R2 is selected from C 1～3 Alkyl or substituted C 1～3 One of alkyl, phenyl or substituted phenyl, benzyl or substituted benzyl;

[0017] The substituted substituent is one or more, and the substituent is selected from C 1～3 One or more of alkoxy, phenyl, and halogen.

[0018] More preferably, R1 is selected from phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-isopropoxyphenyl, 3-isopropoxyphenyl, 4-isopropoxyphenyl, 2-chlorophenyl, 2-trifluoromethoxyphenyl, 2-ethoxyphenyl, 2-propoxyphenyl, 2-cyclopentyloxyphenyl, 4-bromo-2-isopropoxyphenyl, 4-fluoro-2-isopropoxyphenyl, 2,5-diisopropoxyphenyl, 2,5-diethoxyphenyl, 5-bromo-2-isopropoxyphenyl, 5-fluoro-2-isopropoxyphenyl, 5-iodo-2-isopropoxyphenyl, 5-chloro-2-isopropoxyphenyl,

[0019]

[0020] One of; R2 is selected from methyl, propyl, isopropyl, phenyl, One of them.

[0021] In addition, the present invention also provides a method for preparing the pyridodihydrofuranone derivatives, and the synthetic route is as follows:

[0022]

[0023] The specific steps include:

[0024] S1. Suspend the reducing agent in an organic solvent, protect with inert gas, add ethyl 2-ethoxyacetate and compound a under ice bath conditions and react to completion (preferably at 0°C for 3 hours, then at room temperature for 1-5 hours), quench with acid (preferably 2M hydrochloric acid), extract, remove impurities and purify to obtain compound b;

[0025] S2. 2-cyanoacetamide is suspended in an organic solvent, compound b and an alkaline reagent are added, the temperature is raised (preferably to 75° C.) and stirred until the reaction is complete, the mixture is cooled and crystallized, and the mixture is filtered and then treated to obtain compound c;

[0026] S3. Dissolve compound c in concentrated hydrochloric acid, heat at 90-130°C until the reaction is complete (preferably at 120°C for 10 h), quench with ice water, crystallize, filter, and then process to obtain compound d;

[0027] S4, suspending compound d in an organic solvent, adding an alkaline reagent and compound e, reacting at 75-100° C. for completion, and post-processing (preferably by suction filtration or column purification) to obtain a compound of formula (I);

[0028] S5, dissolving the compound of formula (I) in an organic solvent, reacting completely under the conditions of a reducing agent and hydrogen at room temperature, and post-treating (preferably column purification) to obtain a compound of formula (II);

[0029] Wherein, R1 and R2 are consistent with any of the above definitions.

[0030] Furthermore, in step S1, the reducing agent is selected from one or more of sodium hydride, potassium tert-butoxide, sodium ethoxide, sodium methoxide, and sodium.

[0031] Furthermore, in steps S2 and S4, the alkaline reagent is selected from one or more of piperidine, pyridine, sodium hydroxide, sodium carbonate, potassium fluoride, and diammonium hydrogen phosphate.

[0032] Furthermore, in step S5, the reducing agent is selected from one or more of palladium carbon, palladium chloride, palladium hydroxide, nickel, sodium borohydride, and lithium aluminum hydride. Preferably, the reducing agent is 20% palladium carbon.

[0033] Furthermore, in steps S1, S2, S4, and S5, the organic solvent is selected from one or more of diethyl ether, ethanol, tetrahydrofuran, dimethylformamide, toluene, and benzene. Preferably, in step S5, the organic solvent is an alcohol solution such as tetrahydrofuran or ethanol.

[0034] In addition, the present invention also claims the use of the pyridodihydrofuranone derivatives in the preparation of phosphodiesterase type I inhibitors.

[0035] Based on this, the present invention provides a phosphodiesterase type I inhibitor comprising any of the above-mentioned pyridodihydrofuranone derivatives.

[0036] In addition, the present invention also claims protection for the use of the phosphodiesterase type I inhibitor in the preparation of drugs for treating phosphodiesterase type I related diseases.

[0037] Furthermore, the phosphodiesterase type I related diseases include pulmonary hypertension, idiopathic pulmonary fibrosis, liver fibrosis, pneumonia, vascular dementia, enteritis, and Alzheimer's disease.

[0038] The present invention has the following beneficial effects:

[0039] The present invention provides a pyridodihydrofuranone derivative that exhibits a good inhibitory effect on phosphodiesterase type 1 (PDE1) and can be used as a phosphodiesterase type 1 inhibitor. Based on prior art research on phosphodiesterase type 1-related diseases, the pyridodihydrofuranone derivative can also be further used in the treatment of phosphodiesterase type 1-related diseases such as pulmonary hypertension, idiopathic pulmonary fibrosis, vascular dementia, and enteritis, providing more optional drugs and having important medicinal value and clinical application prospects. In addition, the pyridodihydrofuranone derivative of the present invention has a novel structure and a simple preparation method, making it very suitable for large-scale industrial production and application. DETAILED DESCRIPTION

[0040] The present invention is further described below with reference to specific examples, which, however, are not intended to limit the present invention in any way. Unless otherwise specified, the reagents, methods, and equipment used in the present invention are conventional reagents, methods, and equipment in the art.

[0041] Unless otherwise specified, all reagents and materials used in the following examples were commercially available.

[0042] Example 1 Preparation of Pyridodihydrofuranone Derivative Compound 8

[0043] The synthetic route of the pyridodihydrofuranone derivative compound 8 is as follows:

[0044]

[0045] The specific steps include:

[0046] S1. Sodium hydride (3.5 g, 88 mmol, wt. = 60%, containing mineral oil) was weighed into a two-necked flask and rinsed with n-hexane (50 mL × 2). Ether was added to form a suspension, which was protected by argon and stirred at -5°C. The starting material, ethyl 2-ethoxyacetate (10 mL, 74 mmol) and an acetone solution diluted with ether (78 mL, 81 mmol) were added and stirred at -5°C for 3 hours. The mixture was transferred to room temperature and stirred for 1 hour. After the reaction was completed, 4.0 M dilute hydrochloric acid was slowly added to the solution in an ice bath to quench the reaction. The solution was then extracted with ethyl acetate (100 mL × 3). The organic layer was washed with saturated sodium chloride solution (100 mL × 3), dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether:ethyl acetate = 40:1). The mixture was collected by rotary evaporation to obtain a light yellow oily liquid, compound 8-1 (7.0 g), with a yield of 66%.

[0047] S2, 2-cyanoacetamide (1.6g, 19mmol) is suspended in ethanol (17mL), and is warmed to 75 ℃, then compound 8-1 (2.5g, 17.3mmol) and piperidine (0.21mL, 2.3mmol) are added, and the reaction is stirred vigorously at 75 ℃ for 2 hours. The reaction system is cooled to room temperature and stored overnight in a 4 ℃ refrigerator. The obtained solid is collected by filtration and rinsed with ethanol (10mL×3). The vacuum rotary evaporation gives a white powder, which is compound 8-2 (2.2g), with a yield of 66%.

[0048] S3. Compound 8-2 (1.0 g, 5.2 mmol) was dissolved in concentrated hydrochloric acid (9 mL) and stirred at 120° C. for 10 hours, then cooled to room temperature. A mixture of ice and water (20 mL) was added to the system mixture to quench the reaction, and a solid was precipitated. The precipitate was collected by filtration, washed with water (5 mL×3), and evaporated under reduced pressure to give a white powder, compound 8-3 (0.60 g), with a yield of 70%.

[0049] S4. Compound 8-3 was added to ethanol (0.070 mmol / mL) to form a suspension, and the temperature was raised to 60°C. A solution of piperidine (0.12 eq) and 2-isopropoxybenzaldehyde (1.2 eq) in ethanol (0.30 mmol / mL) was added, and the temperature was raised to 80°C for reaction. The reaction was monitored by TLC and stopped when the starting material compound 8-3 disappeared. The system was cooled to room temperature, filtered, and the filter cake was washed with 2 mL of ethanol. The mixture was collected and evaporated under reduced pressure to obtain a high-yield yellow solid, which was compound 8, with a yield of 81%.

[0050] Example 2 Preparation of Pyridodihydrofuranone Derivative Compound 34

[0051] The synthetic route of the pyridodihydrofuranone derivative compound 34 is as follows:

[0052]

[0053] The specific steps include:

[0054] S5. Compound 8 (156 mg, 0.5 mmol) was dissolved in tetrahydrofuran (5 mL, 10 v), and 20% palladium carbon was added to react at room temperature under hydrogen conditions for 8 hours. After the reaction, the filtrate was filtered and purified by silica gel column using ethyl acetate as eluent. The white solid was dried to obtain compound 34 (130 mg) with a yield of 83%.

[0055] Example 3 Preparation, Molecular Structure and NMR Data of Pyridodihydrofuranone Derivatives

[0056] The synthetic route of the pyridodihydrofuranone derivatives is as follows:

[0057]

[0058] With reference to the preparation methods of Examples 1 to 2 and the above-mentioned synthetic route, pyridodihydrofuranone derivative compounds 1 to 55 were prepared. The specific structures are as follows:

[0059]

[0060] The NMR data of pyridodihydrofuranone derivatives compounds 1 to 54 are shown in Table 1.

[0061] Table 1 NMR data of pyridodihydrofuranone derivatives compounds 1 to 54

[0062]

[0063]

[0064]

[0065]

[0066]

[0067]

[0068]

[0069]

[0070] Example 4 Activity Test of Pyridodihydrofuranone Derivatives

[0071] Compounds 1 to 54 prepared in the Examples were tested to determine their inhibitory activity against phosphodiesterase type 1 at a test concentration of 1000 nM or 100 nM. The inhibition rate of the test compound against PDE1C at these two concentrations refers to the inhibition rate of the PDE1C enzyme obtained at a compound concentration of 1000 nanomolar or 100 nanomolar.

[0072] Compounds 1 to 54 prepared in the examples were used as test objects to determine their IC values ​​for phosphodiesterase type 1. 50 , that is, the half-maximal inhibitory concentration. IC 50 The concentration below 50000 nM indicates that the compound exhibits an inhibitory effect on PDE1.

[0073] The measured results are shown in Table 2.

[0074] Table 2 Inhibitory activity of pyridodihydrofuranone derivatives against PDE1C

[0075]

[0076] Wherein, “nd” means “not measured”; * indicates that the inhibition rate of PDE1C enzyme obtained by compound 53 at a concentration of 10 nM is 79%.

[0077] As can be seen from the table, most of the compounds showed significant inhibitory effects on phosphodiesterase type 1, among which compounds 13-18, 26, 29-33, 35-38, 40-46, 48-54 had particularly significant inhibitory effects on phosphodiesterase type 1, IC 50 Less than 200 nM; especially compounds 43, 44, 48, 49, 50, 51, 52, 53, IC 50 Less than 20 nM, showing significant inhibition of phosphodiesterase type 1.

[0078] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be considered as equivalent replacement methods and are included in the scope of protection of the present invention.

Claims

1. Use of a pyridodihydrofuranone derivative in the preparation of a phosphodiesterase type I inhibitor, characterized in that: The pyridodihydrofuranone derivatives have the structure of formula (I), formula (II), or pharmaceutically acceptable salts of the structure of formula (I) or formula (II): Wherein, R1 is selected from indole, , tetrahydropyranyl, One of, R3, R4 are each independently selected from hydrogen, C 1~6 Alkoxy, halogen, -O-R5-R6, wherein R5 is C 1~6 Alkyl or O is directly connected to R6, and R6 is C 3~8 Cycloalkyl, morpholinyl, dimethylamino, pyrrolidinyl, halogenated pyrrolidinyl, C 1~6 alkoxy; R2 is selected from C 1~6 Alkyl or substituted C 1~6 One of alkyl, phenyl or substituted phenyl, benzyl or substituted benzyl; The substituted substituent is one or more, and the substituent is selected from C 1~6 One or more of alkoxy, phenyl, and halogen.

2. The application according to claim 1, characterized in that R1 is selected from tetrahydropyranyl, indolyl, One of, R3, R4 are each independently selected from hydrogen, C 1~3 Alkoxy, halogen, -O-R5-R6, wherein R5 is C 1~3 Alkyl or O is directly connected to R6, and R6 is C 3~6 Cycloalkyl, morpholinyl, dimethylamino, pyrrolidinyl, halogenated pyrrolidinyl, C 1~3 alkoxy; R2 is selected from C 1~3 Alkyl or substituted C 1~3 One of alkyl, phenyl or substituted phenyl, benzyl or substituted benzyl; The substituted substituent is one or more, and the substituent is selected from C 1~3 One or more of alkoxy, phenyl, and halogen.

3. The application according to claim 2, characterized in that: R1 is selected from phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-isopropoxyphenyl, 3-isopropoxyphenyl, 4-isopropoxyphenyl, 2-chlorophenyl, 2-trifluoromethoxyphenyl, 2-ethoxyphenyl, 2-propoxyphenyl, 2-cyclopentyloxyphenyl, 4-bromo-2-isopropoxyphenyl, 4-fluoro-2-isopropoxyphenyl, 2,5-diisopropoxyphenyl, 2,5-diethoxyphenyl, 5-bromo-2-isopropoxyphenyl, 5-fluoro-2-isopropoxyphenyl, 5-iodo-2-isopropoxyphenyl, 5-chloro-2-isopropoxyphenyl, One of: R2 is selected from methyl, propyl, isopropyl, phenyl, 、 、 、 、 、 、 One of them.

4. A pyridodihydrofuranone derivative, characterized in that: The pyridodihydrofuranone derivatives have the structure of formula (I), formula (II), or pharmaceutically acceptable salts of the structure of formula (I) or formula (II): Wherein, R1 is selected from indole, , tetrahydropyranyl, One of, R3, R4 are each independently selected from hydrogen, C 1~6 Alkoxy, halogen, -O-R5-R6, wherein R5 is C 1~6 Alkyl or O is directly connected to R6, and R6 is C 3~8 Cycloalkyl, morpholinyl, dimethylamino, pyrrolidinyl, halogenated pyrrolidinyl, C 1~6 alkoxy; R2 is selected from C 1~6 Alkyl or substituted C 1~6 One of alkyl, phenyl or substituted phenyl, benzyl or substituted benzyl; The substituted substituent is one or more, and the substituent is selected from C 1~6 One or more of alkoxy, phenyl, and halogen; Wherein, the pyridodihydrofuranone derivatives do not include compounds with any of the following structures: 。 5. The pyridodihydrofuranone derivative according to claim 4, characterized in that: R1 is selected from tetrahydropyranyl, indolyl, One of, R3, R4 are each independently selected from hydrogen, C 1~3 Alkoxy, halogen, -O-R5-R6, wherein R5 is C 1~3 Alkyl or O is directly connected to R6, and R6 is C 3~6 Cycloalkyl, morpholinyl, dimethylamino, pyrrolidinyl, halogenated pyrrolidinyl, C 1~3 alkoxy; R2 is selected from C 1~3 Alkyl or substituted C 1~3 One of alkyl, phenyl or substituted phenyl, benzyl or substituted benzyl; The substituted substituent is one or more, and the substituent is selected from C 1~3 One or more of alkoxy, phenyl, and halogen.

6. The pyridodihydrofuranone derivative according to claim 5, characterized in that: R1 is selected from phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-isopropoxyphenyl, 3-isopropoxyphenyl, 4-isopropoxyphenyl, 2-chlorophenyl, 2-trifluoromethoxyphenyl, 2-ethoxyphenyl, 2-propoxyphenyl, 2-cyclopentyloxyphenyl, 4-bromo-2-isopropoxyphenyl, 4-fluoro-2-isopropoxyphenyl, 2,5-diisopropoxyphenyl, 2,5-diethoxyphenyl, 5-bromo-2-isopropoxyphenyl, 5-fluoro-2-isopropoxyphenyl, 5-iodo-2-isopropoxyphenyl, 5-chloro-2-isopropoxyphenyl, One of: R2 is selected from methyl, propyl, isopropyl, phenyl, 、 、 、 、 、 、 One of them.

7. The method for preparing the pyridodihydrofuranone derivatives according to any one of claims 4 to 6, characterized in that: The synthetic route is as follows: The specific steps include: S1. Suspending the reducing agent in an organic solvent, under inert gas protection, adding ethyl 2-ethoxyacetate and compound a in an ice bath and reacting them to completion, quenching with acid, extracting, removing impurities and purifying to obtain compound b; S2, suspending 2-cyanoacetamide in an organic solvent, adding compound b and an alkaline reagent, heating and stirring to react until complete, cooling and crystallizing, filtering and post-processing to obtain compound c; S3. Dissolve compound c in concentrated hydrochloric acid, heat at 90-130°C until the reaction is complete, quench with ice water, crystallize, and filter to obtain compound d. S4, suspending compound d in an organic solvent, adding an alkaline reagent and compound e, reacting at 75-100°C for completion, and post-treating to obtain a compound of formula (I); S5, dissolving the compound of formula (I) in an organic solvent, reacting completely under the conditions of a reducing agent and hydrogen at room temperature, and post-treating to obtain a compound of formula (II); Wherein, R1 and R2 are consistent with any definition of claims 4 to 6.

8. The preparation method according to claim 7, characterized in that: In step S1, the reducing agent is selected from one or more of sodium hydride, potassium tert-butoxide, sodium ethoxide, sodium methoxide, and sodium.

9. The preparation method according to claim 7, characterized in that: In step S5, the reducing agent is selected from one or more of palladium carbon, palladium chloride, palladium hydroxide, nickel, sodium borohydride, and lithium aluminum hydride.

10. A phosphodiesterase type 1 inhibitor, characterized in that Contains the pyridodihydrofuranone derivative according to any one of claims 4 to 6.

11. Use of the phosphodiesterase type 1 inhibitor according to claim 10 in the preparation of a drug for treating phosphodiesterase type 1 related diseases.

12. The application according to claim 11, characterized in that: The phosphodiesterase type I-related disease is selected from pulmonary hypertension, idiopathic pulmonary fibrosis, liver fibrosis, pneumonia, vascular dementia, enteritis, and Alzheimer's disease.

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