A purine pde8 inhibitor and preparation method and application thereof
By preparing novel purine compounds, the problem of the limited variety of existing PDE8 inhibitors has been solved, providing highly selective and highly active PDE8 inhibitors for drug development to treat PDE8-related diseases.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- HAINAN UNIV
- Filing Date
- 2026-03-20
- Publication Date
- 2026-05-29
AI Technical Summary
There are currently a limited number of PDE8 inhibitors, and most of them lack selectivity, making it difficult to confirm the mechanism of action of PDE8 in specific physiological processes.
A class of novel purine compounds is provided, including compounds with structures of formula (I), formula (II), formula (III), formula (IV), formula (V) and formula (VI). Through the synthesis of intermediates G4-G10, purine compounds such as b4-b8, c4-c8, and e1-e12 are prepared for the preparation of PDE8 inhibitors.
The prepared purine compounds exhibit good inhibitory effects on PDE8, with low inhibitory activity concentrations, making them suitable for preparing drugs to treat PDE8-related diseases and expanding the range of drug options.
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of medicinal chemistry technology, and more specifically, relates to a purine PDE8 inhibitor, its preparation method, and its application. Background Technology
[0002] Phosphodiesterases (PDEs) are a superfamily of enzymes that hydrolyze the intracellular second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). They play a central role in cellular function, homeostasis, and stress response by finely regulating cyclic nucleotide-dependent signaling pathways. This family comprises 11 subtypes (PDE1-11), each exhibiting significant differences in tissue distribution, substrate selectivity, and subcellular localization. Selective inhibitors of PDEs have demonstrated important therapeutic value in cardiovascular, respiratory, and neurological diseases.
[0003] Within the PDE family, PDE4, PDE7, and PDE8 are subtypes that specifically hydrolyze cAMP. Among them, PDE8 has the highest affinity for cAMP and is widely expressed in brain regions closely related to learning and memory, such as the cerebral cortex and hippocampus. Recent studies have shown that PDE8 participates in regulating the cAMP / PKA / CREB signaling pathway, which plays a crucial role in neuronal survival, synaptic plasticity, and long-term potentiation (LTP) formation.
[0004] However, research on the biological functions of PDE8 remains relatively lagging, primarily due to the lack of highly selective and active PDE8 inhibitors. Existing PDE8 inhibitors are extremely limited, and most suffer from insufficient selectivity, making them unsuitable for confirming the mechanisms of action of PDE8 in specific physiological processes. Therefore, developing novel and highly active PDE8 inhibitors has significant research value and application prospects. Summary of the Invention
[0005] The purpose of this invention is to provide a novel class of purine compounds, aiming to solve the problem of the limited types of PDE8 inhibitors in the prior art, and to provide new tool molecules for the study of the biological function of PDE8.
[0006] The above-mentioned objective of this invention is achieved through the following technical solution: A first aspect of the present invention is to provide a purine compound, a pharmaceutically acceptable salt, solvate, or isomer thereof, said compound having the structure shown in formula (I), (II), or (III). ; ; ; in: R1 and R2 are each independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, amino, mercapto, methoxy, carboxyl, ester, C 1-3 Ester group, C 1-6 Alkyl or substituted C 1-6 Alkyl, C 3-6 Cycloalkyl or substituted C 3-6 cycloalkyl, C 1-6 Alkoxy or substituted C 1-6 Alkoxy, C 1-6 Alkyl or substituted C 1-6 Alkyl group, substituted C 1-6 Amide group, heterocyclic group or substituted heterocyclic group, aryl or substituted aryl group; X is selected from , , , , Any one of them.
[0007] Furthermore, the compound has the structure shown in formula (Ⅳ), formula (Ⅴ), or formula (Ⅵ). ; ; ; in: R1 and R2 are each independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, amino, mercapto, methoxy, carboxyl, ester, C 1-3 Ester group, C 1-6 Alkyl or substituted C 1-6 Alkyl, C 3-6 Cycloalkyl or substituted C 3-6 cycloalkyl, C 1-6 Alkoxy or substituted C 1-6 Alkoxy, C 1-6 Alkyl or substituted C 1-6 Alkyl group, substituted C 1-6 Amide group, heterocyclic group or substituted heterocyclic group, aryl or substituted aryl group; X is selected from , , , , Any one of them; R3 is a substituent that substituted at any position on the ring other than the X substituent, independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, amino, mercapto, methoxy, carboxyl, ester, C 1-3 Ester group, C 1-6 Alkyl or substituted C 1-6 Alkyl, C 3-6 Cycloalkyl or substituted C 3-6 cycloalkyl, C 1-6 Alkoxy or substituted C1-6 Alkoxy, C 1-6 Alkyl or substituted C 1-6 Alkyl group, substituted C 1-6 Amide group, heterocyclic group or substituted heterocyclic group, aryl or substituted aryl group.
[0008] Furthermore, R1 and R2 are each independently selected from hydrogen, halogen, amino, hydroxyl, methoxy, carboxyl, ester, C 1-6 Alkyl or substituted C 1-6 alkyl; X is selected from or .
[0009] Furthermore, R1 and R2 are each independently selected from hydrogen, halogen, amino, and hydroxyl groups; X is selected from .
[0010] Furthermore, replacing C 1-6 Alkyl, substituted C 3-6 cycloalkyl, substituted C 3-6 Epoxy groups, substituted C 1-6 Alkoxy, substituted C 1-6 Alkyl group, substituted C 1-6 The substituents of the amide group, substituted heterocyclic group, and substituted aryl group are halogens, hydroxyl groups, and C. 1-6 Alkyl, amino, nitro, cyano, mercapto, carbonyl, methyl ester, formamide, C 1-6 Alkoxy, C 1-6 One or more of the alkyl acyl groups.
[0011] Furthermore, any position of R3 can be replaced by any one position, any two positions, any three positions, or any four positions.
[0012] A third aspect of the present invention is to provide a pharmaceutical composition comprising the aforementioned purine compound, a pharmaceutically acceptable salt, solvate or isomer thereof, and a pharmaceutically acceptable excipient.
[0013] A fourth aspect of the present invention is to provide the use of substance X in the preparation of a phosphodiesterase type 8 inhibitor, said substance X being the aforementioned purine compound, its pharmaceutically acceptable salt, solvate, isomer, or pharmaceutical composition.
[0014] The present invention has the following beneficial effects: The purine compounds provided by this invention have good inhibitory effects on phosphodiesterase type 8 with low inhibitory activity concentrations. They can be used in the preparation of drugs for the treatment and / or prevention of diseases related to phosphodiesterase type 8, and have good development potential, increasing the range of drugs available for the treatment of phosphodiesterase type 8 related diseases. Detailed Implementation
[0015] The present invention will be further illustrated below with reference to specific embodiments, but these embodiments do not 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 this technical field. Unless otherwise specified, the reagents and materials used in the following embodiments are commercially available.
[0016] Example 1: Synthesis of compounds b4-b8 (1) Synthesis of intermediates G4-G7
[0017] The brominated derivative (0.5 mmol) and adenine (0.5 mmol) were dissolved in N,N-dimethylformamide (1.5 mL), and cesium carbonate (1 mmol) was added. The mixture was heated to 70 °C and reacted for 5 h. After the reaction was complete, the system was cooled to room temperature, diluted with water, and extracted three times with ethyl acetate. The organic layers were combined, washed three times with water, dried, and the solvent was evaporated by rotary evaporation. The mixture was then purified by column chromatography to give a white solid.
[0018] (2) Synthesis of intermediates G8-G10
[0019] The brominated derivative (0.5 mmol) and adenine (0.5 mmol) were dissolved in N,N-dimethylformamide (1.5 mL), and cesium carbonate (1 mmol) was added. The mixture was heated to 70 °C and reacted for 5 h. After the reaction was complete, the system was cooled to room temperature, diluted with water, and extracted three times with ethyl acetate. The organic layers were combined, washed three times with water, dried, and the solvent was evaporated by rotary evaporation. The mixture was then purified by column chromatography to give a white solid.
[0020] (3) Synthesis of compounds b4-b8
[0021]
[0022] Mixtures of intermediates G4-G8 (0.2 mmol) were prepared separately in a THF / H2O solvent system (3:1, v / v, 4.0 mL), to which LiOH (3.0 mmol) was added respectively. The resulting mixtures were stirred at room temperature for 3 hours, and the process was monitored by TLC until complete conversion. Subsequently, the solvent was removed under vacuum, and the precipitate was dissolved in water (2.0 mL). Then, a 10% HCl aqueous solution (5.0 mL) was added to adjust the pH to 2. The resulting solid was filtered, washed with water, and dried in an oven to obtain the desired white solid compounds. Each intermediate corresponds to one compound, and the four compounds are as follows:
[0023]
[0024]
[0025]
[0026]
[0027] Example 2: Synthesis of compounds c4-c8, e1, and e2
[0028]
[0029] Solutions containing a mixture of intermediates G4-G10 (0.1 mmol) dissolved in a CH2Cl2 / CH3OH solvent system (1:2, v / v, 3.0 mL) were prepared separately, and commercially available reagent NH2OH (50% aqueous solution) (2.0 mmol) was added to each solution. The resulting mixtures were stirred at room temperature for 1 hour, and then NaOH (0.4 mmol) was added. Stirring was continued for 3 hours, and the reaction progress was monitored by TLC until complete conversion. Subsequently, the solvent was removed under vacuum, and the precipitate was dissolved in water (2.0 mL). Then, 10% HCl aqueous solution (2.0 mL) was added to adjust the pH to 6. The resulting solid was filtered, thoroughly washed with water, and dried in an oven to obtain the desired yellow or white solid compound. Each intermediate corresponds to one compound, and the seven compounds are as follows:
[0030]
[0031]
[0032]
[0033]
[0034]
[0035]
[0036] Example 3: Synthesis of compound e3
[0037] 3-Bromomethylphenylboronic acid and adenine (0.5 mmol) were dissolved in N,N-dimethylformamide (1.5 mL), and cesium carbonate (1 mmol) was added. The mixture was heated to 70 °C and reacted for 40 min. After the reaction was complete, the system was cooled to room temperature, diluted with water, and extracted three times with ethyl acetate. The organic layers were combined, washed three times with water, dried, and the solvent was rotary evaporated. The mixture was purified by column chromatography to give a white solid (yield 45%, purity 98%).
[0038]
[0039] Example 4: Synthesis of compound e5
[0040] 3-Bromomethylphenylboronic acid and 2-chloro-6-aminopurine (0.5 mmol) were dissolved in N,N-dimethylformamide (1.5 mL), and cesium carbonate (1 mmol) was added. The mixture was heated to 70 °C and reacted for 1 h. After the reaction was complete, the system was cooled to room temperature, diluted with water, and extracted three times with ethyl acetate. The organic layers were combined, washed three times with water, dried, and the solvent was rotary evaporated. The mixture was then slurried with a mixture of dichloromethane and methanol, filtered, and a white solid was obtained (78% yield, 98% purity).
[0041]
[0042] Example 5: Synthesis of compound e7
[0043] 3-Bromomethylphenylboronic acid and 2-fluoro-6-aminopurine (0.5 mmol) were dissolved in N,N-dimethylformamide (1.5 mL), and cesium carbonate (1 mmol) was added. The mixture was heated to 70 °C and reacted for 30 min. After the reaction was complete, the system was cooled to room temperature, diluted with water, and extracted three times with ethyl acetate. The organic layers were combined, washed three times with water, dried, and the solvent was rotary evaporated to give a white solid (yield 88%, purity 96%).
[0044]
[0045] Example 6: Synthesis of compound e11
[0046] 3-Bromomethylphenylboronic acid and 2-methyl-6-aminopurine (0.5 mmol) were dissolved in N,N-dimethylformamide (1.5 mL), and cesium carbonate (1 mmol) was added. The reaction was carried out at room temperature for 1.5 h. After the reaction was complete, the mixture was diluted with water and extracted three times with ethyl acetate. The organic layers were combined, washed three times with water, dried, and the solvent was evaporated by rotary evaporation. The mixture was then purified by column chromatography to give a white or gray solid (yield 34%, purity 96%).
[0047]
[0048] Example 7: Synthesis of compounds e4, e6, and e12
[0049] 0.5 mmol of ortho- or para-bromomethylphenylboronic acid and 0.5 mmol of adenine were dissolved in 1.5 mL of N,N-dimethylformamide, and 1 mmol of cesium carbonate was added. The mixture was heated to 70 °C and reacted for 40 min–1 h. After the reaction was complete, the system was cooled to room temperature, diluted with water, and extracted three times with ethyl acetate. The organic layers were combined, washed three times with water, dried, and the solvent was rotary evaporated. The mixture was then purified by column chromatography to give a yellow or white solid.
[0050]
[0051]
[0052]
[0053] 4-Bromomethylphenylboronic acid (0.5 mmol) and 2-chloro-1H-benzo[d]imidazol-4-amine (0.5 mmol) were dissolved in N,N-dimethylformamide (1.5 mL), and cesium carbonate (1 mmol) was added. The mixture was heated to 70 °C and reacted for 2 h. After the reaction was complete, the system was cooled to room temperature, diluted with water, and extracted three times with ethyl acetate. The organic layers were combined, washed three times with water, dried, and the solvent was rotary evaporated. The mixture was purified by column chromatography to give a yellow or white solid.
[0054]
[0055] The structures of the compounds obtained in Examples 1-7 above are shown in Table 1 below: Table 1. Structures of compounds in Examples 1-7
[0056]
[0057]
[0058]
[0059]
[0060] Example of efficacy verification: Study on the inhibitory activity of purine compounds on phosphodiesterase type 8 (PDE8) enzyme. (1) Determination of required enzyme concentration: A series of PDE8A enzyme solutions with gradient concentrations were prepared using test buffer (20 mM Tris-HCl pH 7.5, 10 mM MnCl2, 1 mM DTT). 40 μL of each solution was added to 60 μL of diluted ³H-cAMP substrate (approximately 20,000 cpm). For the negative control, 40 μL of test buffer was used instead of the enzyme solution. The reaction was carried out at 25°C for 15 minutes. 200 μL of 0.2 M zinc sulfate solution and 200 μL of 0.2 M barium hydroxide solution were added to terminate the reaction. The mixture was centrifuged at 14,000 rpm for 5 minutes. 430 μL of the supernatant was transferred to a scintillation tube containing 2.5 mL of scintillation fluid, vortexed to mix thoroughly, and tested using a PerkinElmer 2910 liquid scintillation counter. The enzyme concentration with a ³H-cAMP hydrolysis rate between 40% and 70% was taken as the required enzyme concentration for the assay.
[0061] (2) Determination of the inhibitory activity of the test compound on the enzyme: Take 2.0 μL of the DMSO solution of the test compound and add it to 58 μL of diluted ³H-cAMP substrate, mix well; add 2.0 μL of DMSO solution of a known PDE8 inhibitor to the positive control. Then add 40 μL of enzyme solution with a suitable hydrolysis range, and add 40 μL of test buffer instead of enzyme solution to the negative control. React at 25℃ for 15 minutes. The reaction is terminated as above. Take 430 μL of supernatant and transfer it to a scintillation tube containing 2.5 mL of scintillation fluid, mix well, and then measure it using a liquid scintillation counter. The inhibitory activity of the compound on the enzyme is expressed as inhibition rate or half-maximal inhibitory concentration (IC50). 50 This indicates that each sample was tested three times, and at least eight different concentration points were used to calculate the IC through nonlinear regression fitting. 50 Values are given, and results are expressed as mean ± standard deviation. The inhibitory activity of the compounds against PDE8A enzyme is shown in Table 2 below.
[0062] Table 2. Inhibitory activity of purine compounds against PDE8A enzyme
[0063] As shown in the table, compounds e3, e5, e7, and e11 all exhibited good inhibitory effects on PDE8 enzyme, with IC50 values of 100%. 50All compounds were below 10 nM and showed better inhibitory effects on PDE8 enzyme than the positive control clofarabine; however, compound e5 exhibited the best inhibitory effect on PDE8 enzyme, with an IC50 value of [missing value]. 50 With a value less than 1.0 nM, it is a potent PDE8 inhibitor.
[0064] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.
Claims
1. A purine compound, its pharmaceutically acceptable salt, solvate, or isomer, characterized in that, The compound has the structure shown in formula (I), formula (II), or formula (III). ； ； ； in: R1 and R2 are each independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, amino, mercapto, methoxy, carboxyl, ester, C 1-3 Ester group, C 1-6 Alkyl or substituted C 1-6 Alkyl, C 3-6 Cycloalkyl or substituted C 3-6 cycloalkyl, C 1-6 Alkyl or substituted C 1-6 Alkoxy, C 1-6 Alkyl or substituted C 1-6 Alkyl group, substituted C 1-6 Amide group, heterocyclic group or substituted heterocyclic group, aryl group or substituted aryl group; X is selected from , , , , Any one of them.
2. The purine compound, its pharmaceutically acceptable salt, solvate, or isomer according to claim 1, characterized in that, The compound has the structure shown in formula (Ⅳ), (Ⅴ), or (Ⅵ). ; ； ； in: R1 and R2 are each independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, amino, mercapto, methoxy, carboxyl, ester, C 1-3 Ester group, C 1-6 Alkyl or substituted C 1-6 Alkyl, C 3-6 Cycloalkyl or substituted C 3-6 cycloalkyl, C 1-6 Alkyl or substituted C 1-6 Alkoxy, C 1-6 Alkyl or substituted C 1-6 Alkyl group, substituted C 1-6 Amide group, heterocyclic group or substituted heterocyclic group, aryl or substituted aryl group; X is selected from , , , , Any one of them; R3 is a substituent that substituted at any position on the ring other than the substituent position of X, independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, amino, mercapto, methoxy, carboxyl, ester, C 1-3 Ester group, C 1-6 Alkyl or substituted C 1-6 Alkyl, C 3-6 Cycloalkyl or substituted C 3-6 cycloalkyl, C 1-6 Alkyl or substituted C 1-6 Alkoxy, C 1-6 Alkyl or substituted C 1-6 Alkyl group, substituted C 1-6 Amide group, heterocyclic group or substituted heterocyclic group, aryl or substituted aryl group.
3. The purine compound, its pharmaceutically acceptable salt, solvate, or isomer according to claim 1 or 2, characterized in that, R1 and R2 are each independently selected from hydrogen, halogen, amino, hydroxyl, methoxy, carboxyl, ester, C 1-6 Alkyl or substituted C 1-6 alkyl; X is selected from or .
4. The purine compound, its pharmaceutically acceptable salt, solvate, or isomer according to claim 3, characterized in that, R1 and R2 are each independently selected from hydrogen, halogen, amino, and hydroxyl groups; X is selected from .
5. The purine compound, its pharmaceutically acceptable salt, solvate, or isomer according to claim 1 or 2, characterized in that, Replace C 1-6 Alkyl, substituted C 3-6 cycloalkyl, substituted C 3-6 Epoxy groups, substituted C 1-6 Alkoxy, substituted C 1-6 Alkyl group, substituted C 1-6 The substituents of the amide group, substituted heterocyclic group, and substituted aryl group are halogens, hydroxyl groups, and C. 1-6 Alkyl, amino, nitro, cyano, mercapto, carbonyl, methyl ester, formamide, C 1-6 Alkoxy, C 1-6 One or more of the alkyl acyl groups.
6. The purine compound, its pharmaceutically acceptable salt, solvate, or isomer according to claim 2, characterized in that, The arbitrary substitution of R3 can be an arbitrary substitution of one position, an arbitrary substitution of two positions, an arbitrary substitution of three positions, or an arbitrary substitution of four positions.
7. A pharmaceutical composition comprising: a purine compound as described in any one of claims 1-6, a pharmaceutically acceptable salt, solvate or isomer thereof, and a pharmaceutically acceptable excipient.
8. The application of substance X in the preparation of phosphodiesterase type 8 inhibitors, characterized in that, The substance X is a purine compound as described in any one of claims 1-6, a pharmaceutically acceptable salt, solvate, or isomer thereof, or a pharmaceutical composition as described in claim 7.