[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

CN118206555A - 3, 8-Disubstituted adenine derivative, preparation method and application thereof - Google Patents

3, 8-Disubstituted adenine derivative, preparation method and application thereof Download PDF

Info

Publication number
CN118206555A
CN118206555A CN202410296480.4A CN202410296480A CN118206555A CN 118206555 A CN118206555 A CN 118206555A CN 202410296480 A CN202410296480 A CN 202410296480A CN 118206555 A CN118206555 A CN 118206555A
Authority
CN
China
Prior art keywords
compound
acid
formula
pharmaceutically acceptable
acceptable salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202410296480.4A
Other languages
Chinese (zh)
Inventor
罗海彬
吴德燕
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Haifu Pharmaceutical Hainan Co ltd
Original Assignee
Haifu Pharmaceutical Hainan Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Haifu Pharmaceutical Hainan Co ltd filed Critical Haifu Pharmaceutical Hainan Co ltd
Priority to CN202410296480.4A priority Critical patent/CN118206555A/en
Publication of CN118206555A publication Critical patent/CN118206555A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a3, 8-disubstituted adenine derivative, a preparation method and application thereof. The 3, 8-disubstituted adenine derivative provided by the invention has good inhibition effect on phosphodiesterase type 8, has good liver microsome stability and drug-like quality, can be applied to preparation of drugs for treating and/or preventing diseases related to the phosphodiesterase type 8, has good development potential, and increases the selectable range of drugs for treating diseases related to the phosphodiesterase type 8.

Description

3, 8-Disubstituted adenine derivative, preparation method and application thereof
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a3, 8-disubstituted adenine derivative, a preparation method and application thereof.
Background
Phosphodiesterases (PDEs) are the only family of superases responsible for the specific hydrolysis of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) in the body, catalyzing the hydrolysis of 3' -phosphate bonds to produce 5' -AMP and 5' -GMP, respectively. cAMP and cGMP are important second messengers within cells that regulate a variety of signaling pathways, such as various intracellular physiological processes and neurobehavioral functions, through direct interactions with cAMP-dependent Protein Kinase A (PKA) and cGMP-dependent Protein Kinase G (PKG), respectively. To date, there have been almost twenty approved PDE inhibitors for marketing in various countries, such as the PDE5 inhibitor sildenafil and the PDE4 inhibitor aplastic. cAMP-specific PDE subtypes include PDE4, PDE7, and PDE8. Wherein, the affinity of PDE8 to cAMP substrate is highest in all PDEs, and the Km value is 40-150nM and is more than 40 times of PDE 4.
The biological function of PDE8 is not yet thoroughly studied, but from its expression level PDE8 is presumed to have important physiological roles in different life processes, in particular in brain and thyroid functions, and is thus likely to be a suitable therapeutic target for central nervous system diseases. Studies have shown that PDE8B knockout mice have enhanced spatial memory and motor coordination, and PDE8 levels in the brain of older rats are overexpressed, suggesting that inhibition of PDE8 may enhance cognitive function and prevent age-induced motor coordination decline, treating age-related diseases.
However, while the prior art has less research on PDE8, no inhibitors with better effects have been found for clinical use against PDE8, only less research on PDE8 inhibitors, such as the patent numbers: WO2011058478A1 discloses "a substituted triazolopyrimidine inhibitor of PDE8 enzyme", which has various degrees of inhibitory activity on PDE8 enzyme, but the clinical effect thereof is not known, and the physiological effect of PDE8 cannot be explored, so that PDE8 inhibitors having strong activity, high selectivity and excellent properties are urgently required to be discovered to explore the physiological effect of PDE 8.
Disclosure of Invention
The invention aims to solve the technical problem that the available PDE8 inhibitors in the prior art are few in variety, and therefore, the invention provides a3, 8-disubstituted adenine derivative which is a compound with novel structure and better inhibition on phosphodiesterase 8 type activity and can be used for preventing or treating diseases related to phosphodiesterase 8 type metabolism.
The above object of the present invention is achieved by the following technical scheme:
The invention provides a compound shown in a formula (I) or pharmaceutically acceptable salt thereof,
Wherein:
r 1、R2 and R 3 are each independently selected from one of hydrogen, halogen, substituted or unsubstituted C 1-6 alkoxy;
R 4 is selected from hydrogen, halogen or
R 5 is hydrogen, substituted or unsubstituted C 1-6 alkyl.
Further, R 1 and R 3 are each independently selected from hydrogen or halogen; r 2 is selected from one of halogen and substituted or unsubstituted C 1-6 alkoxy.
Further, the R 1、R2 or R 3 is C 1-6 alkoxy, and at least one H on the C 1-6 alkoxy is substituted with a halogen atom.
Further, the R 5 is C 1-6 alkyl and at least one H on the C 1-6 alkyl is substituted with a halogen atom, C 4-5 heteroaryl, halogenated C 4-5 heteroaryl, C 6 aryl, halogenated C 6 aryl, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl or tetrahydropyran.
Further, the substituted or unsubstituted C 1-6 alkoxy group is independently selected from one of -OCH3、-OCH2CH3、-OCH(CH3)2、-OCH2CH2CH3、-OCHF2、-OCH2CHF2、-OCH2CH2CF3.
Further, the substituted or unsubstituted C 1-6 alkyl is independently selected from -CH3、-CH2CH3、-CH(CH3)2、-CH2CH2CH3、-CH2CH(CH3)2、-CH2CHF2、 One of them.
Further, the pharmaceutically acceptable salt is a product salt obtained by reacting a compound of formula (I) with an acid, which acid comprises one or more of hydrochloric acid, hydrobromic acid, hydrofluoric acid, phosphoric acid, acetic acid, oxalic acid, sulfuric acid, methanesulfonic acid, salicylic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, maleic acid, fumaric acid, citric acid, tartaric acid, succinic acid, malic acid and glutamic acid.
Further, the structure of the compound shown in the formula (I) is shown as one of the following:
the present invention also provides a pharmaceutical composition comprising: the compound shown in the formula (I) or pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipient.
In addition, the invention also provides a preparation method of the compound shown in the formula (I) or pharmaceutically acceptable salt thereof, and the synthetic route of the compound shown in the formula (I) is as follows:
the method specifically comprises the following steps:
(one) when X in compound 1 is H:
(1) Dissolving the compound 1 in a solvent, reacting for 12-18 hours at 0-60 ℃ under the action of liquid bromine, and obtaining a compound 2 after the reaction is completed;
(2) Dissolving the compound 2 obtained in the step (1) in a solvent, reacting with halogenated hydrocarbon at 0-60 ℃ for 8-16h under the action of an alkaline reagent, and obtaining a compound 3 after the reaction is completed;
(3) Dissolving the compound 3 obtained in the step (2) in a solvent, reacting for 20-36 hours at 100-150 ℃ under the action of thiourea, and generating a compound 4 after the reaction is completed;
(4) Dissolving the compound 4 obtained in the step (3) in a solvent, reacting with halogenated hydrocarbon at 60-120 ℃ for 8-16 hours under the action of an alkaline reagent, and obtaining a compound shown in a formula (I) after the reaction is completed;
(II) when X in Compound 1 is SH:
(1) Dissolving the compound 1 in a solvent, reacting with halogenated hydrocarbon or p-toluenesulfonate derivative for 8-16h at 80-150 ℃ under the action of an alkaline reagent, and obtaining a compound 5 after the reaction is completed;
(2) Dissolving a compound 5 in a solvent, reacting with halogenated hydrocarbon at 0-60 ℃ for 8-16 hours under the action of an alkaline reagent, and obtaining a compound shown in a formula (I) after the reaction is completed;
Wherein the solvent involved in the steps is one or more of water, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, methanol, ethanol, isopropanol, acetonitrile, acetone, tetrahydrofuran, chloroform, ethyl acetate, dichloromethane, 1, 2-dichloroethane and 1, 4-dioxane;
The alkaline reagent involved in the above steps is one or more selected from diisopropylethylamine, triethylamine, 4-dimethylaminopyridine, piperidine, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium tert-butoxide, sodium hydride, sodium methoxide and sodium ethoxide.
The invention also provides application of the substance X in preparation of phosphodiesterase 8 type inhibitors, wherein the substance X is a compound shown in a formula (I) or pharmaceutically acceptable salt thereof or the pharmaceutical composition.
The invention also provides application of the substance X in preparing medicines, wherein the substance X is a compound shown in a formula (I) or pharmaceutically acceptable salt thereof or the medicine composition; the medicine is used for treating and/or preventing diseases related to phosphodiesterase type 8.
The invention has the following beneficial effects:
The 3, 8-disubstituted adenine derivative provided by the invention has good inhibition effect on phosphodiesterase type 8, high selectivity on other phosphodiesterase subtypes, and good stability of liver microsome and pharmacokinetic property of oral medicine, can be applied to preparing medicines for treating and/or preventing diseases related to the phosphodiesterase type 8, has good development potential, and increases the selectable range of medicines for treating diseases related to the phosphodiesterase type 8.
Detailed Description
The present invention is further illustrated below with reference to specific examples, which are not intended to limit the invention in any way. Unless specifically stated otherwise, the reagents, methods and apparatus employed in the present invention are those conventional in the art. Reagents and materials used in the following examples are commercially available unless otherwise specified.
The preparation method of the 3, 8-disubstituted adenine derivative (I) provided by the invention comprises the following steps:
the method specifically comprises the following steps:
(one) when X in compound 1 is H:
(1) Dissolving the compound 1 in N, N-dimethylformamide, and completely reacting under the action of liquid bromine to obtain a compound 2;
(2) Dissolving the compound 2 obtained in the step (1) in N, N-dimethylacetamide, and reacting with halogenated hydrocarbon under the action of diisopropylethylamine to obtain a compound 3;
(3) Dissolving the compound 3 obtained in the step (2) in N, N-dimethylformamide, and reacting completely under the action of thiourea to generate a compound 4;
(4) Dissolving the compound 4 obtained in the step (3) in methanol, and reacting with halogenated hydrocarbon under the action of triethylamine to obtain a compound shown in a formula (I);
(II) when X in Compound 1 is SH:
(1) The compound 1 is dissolved in water and reacts with halohydrocarbon or p-toluenesulfonate derivative completely under the action of 4-dimethylaminopyridine to obtain a compound 5;
(2) And (3) dissolving the compound 5 in acetonitrile, and reacting with halogenated hydrocarbon under the action of piperidine to obtain the compound shown in the formula (I). The synthesis process and effect verification of the 3, 8-disubstituted adenine derivative are described below.
Example 1: synthesis of Compounds 1a-n
(1) Synthesis of intermediate 8-bromo-9H-purin-6-amine (M1)
Adenine (16 mmol) was dissolved in water (200 mL), bromine (6 mL) was slowly added dropwise and reacted at room temperature for 16 hours. Filtering, washing off residual bromine water with water, and drying to obtain yellow solid. Yield rate 28％.1H NMR(400MHz,DMSO-d6)δ8.23(s,1H),8.06(s,2H).ESI:calculated for C5H4BrN5＝211.96,213.96.Observed m/z[M-H]-＝212.00,214.00.
(2) Synthesis of intermediate 3-benzol-8-bromo-3H-purin-6-amine (M2)
Intermediate M1 (10 mmol) was dissolved in N, N-dimethylformamide (15 mL), potassium carbonate (20 mmol) was added, benzyl bromide (10 mmol) was added dropwise, and the reaction was carried out at room temperature overnight. Water was added to the reaction system to dilute, and extraction was performed three times with ethyl acetate. The organic layer was collected, washed three times with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation under reduced pressure and purified by column chromatography to give a white solid. Yield rate 33％.1HNMR(400MHz,DMSO-d6)δ8.54(s,1H),8.20(s,1H),8.08(s,1H),7.42–7.28(m,5H),5.47(s,2H).
(3) Synthesis of intermediate 6-amino-3-benzol-3H-purine-8-thio (M3)
Intermediate M2 (3 mmol) was dissolved in n-butanol (15 mL), thiourea (24 mmol) was added and the reaction was refluxed for 24 hours. After the reaction is completed, water is added for dilution, suction filtration is carried out, and filter residues are washed by water. Drying gave a white solid. The yield was 86%. 1HNMR(400MHz,DMSO-d6 ) δ11.39 (s, 1H), 8.51 (s, 1H), 7.47-7.26 (m, 5H), 5.42 (s, 2H).
(4) Synthesis of end products 1a-n
Intermediate M3 (0.3 mmol) and potassium hydroxide (0.45 mmol) were dissolved in a mixed solution of ethanol and water (2:1, 3 mL), methyl iodide or alkyl bromide or arylmethyl bromide (0.36 mmol) was added and reacted overnight at 80 ℃. After the reaction was completed, water was added to dilute, and extraction was performed three times with ethyl acetate. The organic layers were combined, dried, solvent was distilled off and purified by column to give a white solid, see table 1 for the results.
TABLE 1
EXAMPLE 2 Synthesis of Compounds 2a-l
(1) Synthesis of intermediate 5-nitropyrimidine-4,6-diamine (M4)
4, 6-Dichloro-5-nitropyrimidine (26 mmol) was dissolved in aqueous ammonia (15 mL) and reacted at 60℃for 5 hours. Suction filtration, washing with water and drying filter residue to obtain white solid. The yield was 95%. 1H NMR(400MHz,DMSO-d6 ) Delta 8.49 (s, 2H), 8.41 (s, 2H), 7.88 (s, 1H).
(2) Synthesis of intermediate pyrimidine-4,5,6-triamine (M5)
Intermediate M4 (20 mmol) was dissolved in ethanol (400 mL), raney nickel (5 g) was added, and 80% hydrazine hydrate solution (8 mL) was added dropwise and reacted at room temperature for 40 hours. Suction filtration, rotary evaporation of the solvent and drying to obtain white solid. The yield thereof was found to be 93%. 1HNMR(400MHz,DMSO-d6 ) Delta 7.45 (s, 1H), 5.55 (s, 4H), 3.76 (s, 2H).
(3) Synthesis of intermediate 6-amino-9H-purine-8-thio (M6)
Intermediate M5 (10 mmol) was mixed with thiourea (35 mmol), warmed to 180℃and reacted for 1 hour. Water was added while hot, the solid was crushed and stirred overnight at room temperature. Suction filtration, washing with saturated saline and drying filter residue to obtain yellow solid. The yield thereof was found to be 73%. 1H NMR(400MHz,DMSO-d6 ) Delta 7.45 (s, 1H), 5.55 (s, 4H), 3.76 (s, 2H).
(4) Synthesis of intermediates M7a-e
Intermediate M6 (1 mmol) and potassium hydroxide (2 mmol) were dissolved in a mixed solution of ethanol and water (2:1, 3 mL), bromide or p-toluenesulfonate derivative (1.5 mmol) was added and reacted at room temperature overnight. After the reaction was completed, ethanol was removed by rotary evaporation, and the pH was adjusted to 5 with glacial acetic acid. Suction filtration, washing with water and drying filter residue to obtain yellow or white solid.
Yield of 8- (propylthio) -9H-purin-6-amine (M7 a) 74％.1H NMR(400MHz,DMSO-d6)δ12.95(s,1H),8.02(s,1H),6.96(s,2H),3.24–3.18(m,2H),1.73–1.64(m,2H),0.98(t,J＝7.3Hz,3H).
8- ((2- (Tetrahydro-2H-pyran-4-yl) ethyl) thio) -9H-purin-6-amine (M7 b) yield 54％.1H NMR(500MHz,DMSO-d6)δ12.98(s,1H),8.02(s,1H),7.00(s,2H),3.82(dd,J＝11.0,3.6Hz,2H),3.32–3.20(m,4H),1.68–1.55(m,5H),1.24–1.10(m,2H).
Yield of 8- (((4, 4-difluorocyclohexyl) methyl) thio) -9H-purin-6-amine (M7 c) 55％.1H NMR(400MHz,DMSO-d6)δ12.96(s,1H),8.05(s,1H),6.98(s,2H),3.25(d,J＝6.7Hz,2H),2.05–1.96(m,2H),1.92–1.87(m,2H),1.85–1.70(m,3H),1.33–1.23(m,2H).
8- (((Tetrahydro2H-pyran-4-yl) methyl) thio) -9H-purin-6-amine (M7 d) yield 49％.1H NMR(400MHz,DMSO-d6)δ12.88(s,1H),8.04(s,1H),6.94(s,2H),3.84(dd,J＝11.2,3.0Hz,2H),3.27–3.20(m,4H),1.88–1.77(m,1H),1.75–1.64(m,2H),1.34–1.17(m,2H).
Yield of 8- ((cyclohexylmethyl) thio) -9H-purin-6-amine (M7 e) 38％.1H NMR(400MHz,DMSO-d6)δ12.82(s,1H),8.04(s,1H),6.96(s,2H),3.18(d,J＝6.8Hz,2H),1.82(d,J＝11.3Hz,2H),1.73–1.64(m,2H),1.62–1.48(m,2H),1.27–1.09(m,3H),1.07–0.92(m,2H).
(5) Synthesis of end products 2a-l
Intermediate M7a-e (0.5 mmol) was dissolved in N, N-dimethylformamide (1 mL), cesium carbonate (1 mmol) was added, and benzyl bromide derivative (0.5 mmol) was added and reacted overnight at room temperature. After the reaction was completed, water was added to dilute, and extraction was performed three times with ethyl acetate. The organic layers were combined, washed three times with brine, dried, solvent was distilled off and purified by column to give a white or pale yellow solid, see table 2 for results.
TABLE 2
EXAMPLE 3 Synthesis of Compounds 3a-f
The synthesis of compounds 3a-f was carried out in accordance with the synthesis of compounds 2a-l of example 2 above, and the results are shown in Table 3.
TABLE 3 Table 3
Example 4: synthesis of Compound 3- (3, 5-dichloro-4- (2, 2-difluoroethoxy) benzyl) -3H-purin-6-amine (4 a)
(1) Synthesis of intermediate N- (2, 4-dimethoxybenzyl) -9H-purin-6-amine (M8)
6-Chloropurine (20 mmol), 2, 4-dimethoxybenzylamine (24 mmol) and N, N-diisopropylethylamine (40 mmol) were dissolved in N-butanol (16 mL) and reacted at 100℃for 3h. The white solid is separated out, cooled to room temperature, diluted by acetonitrile, filtered and washed to obtain the white solid. Yield rate 96％.1HNMR(400MHz,DMSO-d6)δ12.92(s,1H),8.12(d,J＝19.2Hz,2H),7.76(s,1H),7.07(s,1H),6.56(s,1H),6.42(d,J＝7.8Hz,1H),4.59(s,2H),3.82(s,3H),3.72(s,3H).
(2) Synthesis of intermediate 3- (3, 5-dichloro-4- (2, 2-difluoroethoxy) benzyl) -N- (2, 4-dimethyl-benzyl) -3H-purin-6-amine (M9)
Intermediate M8 (7 mmol) and 5-bromomethyl-1, 3-dichloro-2- (2, 2-difluoroethoxy) benzene (7 mmol) were dissolved in N, N-dimethylformamide (40 mL) and reacted overnight at 110 ℃. The solvent is dried by an oil pump, and the mixed solution of dichloromethane and methanol is pulped, filtered and washed to obtain white solid. Yield rate 74％.1H NMR(400MHz,CDCl3)δ8.07(s,1H),7.99(s,1H),7.38(s,2H),7.26–7.22(m,1H),6.47(d,J＝1.9Hz,1H),6.41(dd,J＝8.2,1.9Hz,1H),6.14(tt,J＝55.2,4.4Hz,1H),5.45(s,2H),4.80(s,2H),4.21(td,J＝12.9,4.2Hz,2H),3.85(s,3H),3.79(s,3H).
(5) Synthesis of end product 3- (3, 5-dichloro-4- (2, 2-difluoroethoxy) benzol) -3H-purin-6-amine (4 a)
Intermediate M9 (5 mmol) was dissolved in trifluoroacetic acid/dichloromethane (1:3, 20 mL) and reacted overnight at room temperature. The solvent was distilled off, diluted with methanol, adjusted to pH 8 with ammonia methanol, and purified by column to give a white solid. Yield rate 97％.1H NMR(400MHz,MeOD)δ8.56(s,1H),8.08(s,1H),7.53(s,2H),6.19(tt,J＝54.6,4.2Hz,1H),5.54(s,2H),4.23(td,J＝13.6,2.7Hz,2H).
Example 5: synthesis of Compound 8-bromo-3- (3, 5-dichloro-4- (2, 2-difluoroethoxy) benzol) -3H-purin-6-amine (4 b)
The compound 4a (1 mmol) in example 4 was dissolved in anhydrous N, N-dimethylformamide (2.5 mL), N-bromosuccinimide (1.2 mmol) was added, and the mixture was reacted overnight at room temperature. The solvent was dried by oil pump and purified by column to give a white solid. Yield rate 83％.1H NMR(500MHz,Acetone-d6)δ8.52(s,1H),7.69(s,2H),6.33(tt,J＝54.7,3.8Hz,1H),5.57(s,2H),4.33(td,J＝13.9,3.9Hz,2H).
Effect example 1: biological Activity assay
(1) Determination of PDE8A enzyme inhibitory Activity of Compounds
3 H-cAMP was diluted to 20,000-30,000cpm with test buffer (20 mM Tris-HCl (pH 7.5), 10mM MnCl 2 and 1mM DTT). The substrate, PDE8A protein and test compound were incubated at room temperature for 15 minutes, and then the reaction was stopped by the addition of 0.2M ZnSO 4 and 0.2M Ba (OH) 2. Unreacted 3 H-cAMP was measured in the supernatant using a Perkinelmer 2910 counter. Calculation of each test compound IC 50 was repeated 3 times using 8-10 different concentrations and the activity results are shown in table 4.
Inhibition of PDE8A enzyme by Compounds of Table 4
Compounds of formula (I) PDE8A，IC50(nM) Compounds of formula (I) PDE8A，IC50(nM) Compounds of formula (I) PDE8A，IC50(nM)
1a 18461±277 1m 1084±207 2k 452±87
1b 7711±1065 1n 2259±81 2l 1527±304
1c 13674±361 2a >1000 3a 900±207
1d 2592±55 2b >1000 3b 459±30
1e 2967±16 2c >1000 3c 77±13
1f 4964±383 2d >1000 3d 102±17
1g 1868±150 2e >1000 3e 228±49
1h 473±70 2f >1000 3f 31±4
1i 1912±172 2g >1000 4a 634±173
1j 9615±1355 2h 2556±586 4b 17±3
1k 4833±1152 2i >1000
1l 5207±832 2j >1000
(2) Selective testing of Compound 4b for other PDE isoforms
As shown in Table 5, the compound 4b has better sub-selectivity to other PDEs, as shown in the data in Table 4b, and the selectivity index to PDEs family is tested by the same method as the measurement of PDE8A enzyme inhibition activity.
TABLE 5 Selectivity of Compound 4b for other PDE isoforms
PDE isoforms IC50(nM) Selectivity index
PDE8A 17±3 -
PDE1C >10000 >588
PDE2A >10000 >588
PDE3A ～10000 ～588
PDE4D ～10000 ～588
PDE9A >10000 >588
Effect example 2: compound 4b determination of the metabolic stability of rat liver microsomes
The experiment adopts a method for determining the percentage of the residual compound by using LC-MS/MS after in vitro incubation of the 4b compound and the liver microsome, and researches the metabolic stability of the 4b compound in the liver microsome, and comprises the following specific steps:
Solution preparation
(1) Tris/HCl (0.1M, pH 7.4) buffer: 12.12g TRIS (TRIS-hydroxymethyl aminomethane) was weighed, dissolved in 800mL of water, pH adjusted to 7.4 with HCl (2M) and then fixed to 1000mL with water.
(2) MgCl 2: mgCl 2 (100 mM) solution was prepared with 0.1M Tris/HCl buffer, and stored at-20℃after packaging.
(3) NADPH formulation: a solution of NADPH (10 mM) was prepared with 0.1M Tris/HCl buffer, and stored at-20℃after packaging.
(4) Preparing a compound to be tested: stock solutions at a concentration of 10mM were obtained by dissolving the compound in DMSO. After dilution to 1mM in DMSO, the solution was diluted with 0.1% BSA-water to give a working solution with a concentration of 2. Mu.M. In the incubation system, 2. Mu.M working solution was diluted 20-fold to a final concentration of 0.1. Mu.M. The DMSO concentration in the incubation system is less than or equal to 0.01 percent.
(5) Positive control compound formulation: 2mM VIVID stock was diluted 50-fold with 2. Mu.M of test object working solution. In the incubation system, the final VIVID concentration was 2. Mu.M.
(II) Experimental methods
The incubation of the liver microsomes was performed in 96-well plates with a volume of 450. Mu.L of each incubation system and 0.1M Tris buffer (pH 7.4) medium, including liver microsomes at a final concentration of 0.33mg/mL, 0.1. Mu.M of the drug tested, 5.0mM MgCl2,0.01%DMSO, 0.005% BSA and 1.0mM NADPH. The reaction was initiated by adding NADPH after 10min of pre-incubation at 37℃and terminated by adding 50. Mu.L of methanol of the same volume to the incubation system after 0, 7, 17, 30, 60min, respectively, as shown in Table 6 below.
Table 6 metabolic stability of compound 4b against rat liver microsomes
Compounds of formula (I) Liver microsome half-time of metabolism (min)
4b 169
Effect example 3: compound 4b in vivo pharmacokinetic assay
After compound 4b was administered by intragastric and intravenous injection to rats, the blood concentration was observed over time, and the corresponding pharmacokinetic parameters and absolute bioavailability were estimated, and the measurement procedures and results were as follows:
(1) Measurement procedure
Dividing 6 rats into two groups, respectively performing gastric lavage and tail intravenous injection for administration of the compound 4b, wherein the intravenous injection groups are 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h and 24h after administration; the blood samples were collected from jugular vein 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 24h, after administration. The LC-MS/MS method is adopted to measure the concentration of LWWX22194 in the rat plasma sample, the PK parameter (WinNonlin V5.2, pharsight) of each compound is calculated by statistical analysis, and the in vivo pharmacokinetics property of the compound of the invention is reflected.
(2) Measurement results
After single intravenous injection of 2.5mg/kg of 4b compound in rats, the main pharmacokinetic parameters of intravenous administration are: cmax is 1847ng/mL, tmax is 0.083h, T1/2 is 3.78h, AUC0-T is 4900hr ng/mL, AUC0- ≡is 5028hr ng/mL, vz is 2820mL/kg, cl is 512mL/hr/kg, MRT0-T is 3.104h, MRT0- ≡3.53h, and the results are shown in Table 7 below.
Table 7 in vivo pharmacokinetic parameters of intravenous 4b rats (n=3)
Parameter Units NO.1 NO.2 NO.3 Mean SD
T1/2 hr 2.12 5.11 4.12 3.78 1.52
Tmax hr 0.083 0.083 0.083 0.083 0.000
Cmax ng/ml 2170 1600 1770 1847 293
C0 ng/ml 2543 1615 1910 2023 474
AUC0-t hr*ng/ml 4480 4054 6167 4900 1117
AUC0-∞ hr*ng/ml 4712 4128 6245 5028 1094
Vz ml/kg 1620 4463 2378 2820 1472
Cl ml/hr/kg 531 606 400 512 104
MRT0-t hr 1.93 3.25 4.14 3.10 1.11
MRT0-∞ hr 2.38 3.75 4.46 3.53 1.06
After 10mg/kg of 4b is administered by lavage of rats, the main pharmacokinetic parameters of the administration by lavage are as follows: cmax is 1763ng/mL, tmax is 5.33h, T1/2 is 3.34h, AUC0-t is 22932hr ng/mL, AUC0- ≡is 233554 hr ng/mL, MRT0-t is 6.75h, MRT0- ≡is 7.10h, oral bioavailability is 116.1%, results are shown in Table 8 below.
Table 8 intragastric administration 4b pharmacokinetic parameters in rats (n=3)
Parameter Units NO.4 NO.5 NO.6 Mean SD
T1/2 hr 2.66 2.56 4.81 3.34 1.27
Tmax hr 4.00 6.00 6.00 5.33 1.15
Cmax ng/ml 1650 1460 2180 1763 373
AUC0-t hr*ng/ml 20275 19847 28674 22932 4977
AUC0-∞ hr*ng/ml 20337 19898 29826 23354 5610
MRT0-t hr 6.48 6.67 7.11 6.75 0.320
MRT0-∞ hr 6.55 6.72 8.03 7.10 0.808
F 101.1％ 98.9％ 148.3％ 116.1％ 0.279
From the contents in tables 4 to 8, it can be shown that the compounds provided by the invention have good PDE8 inhibition activity, PDE subtype selectivity, good liver microsome stability, good pharmacokinetic properties and other drug properties, and fully demonstrate that the 3, 8-disubstituted adenine derivative compounds provided by the invention have good drug properties. Therefore, the 3, 8-disubstituted adenine derivative disclosed by the invention has a wide application space as a phosphodiesterase type 8 (PDE 8) inhibitor, and can be used for further drug research and development.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.

Claims (11)

1. A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, characterized in that,
Wherein:
r 1、R2 and R 3 are each independently selected from one of hydrogen, halogen, substituted or unsubstituted C 1-6 alkoxy;
R 4 is selected from hydrogen, halogen or
R 5 is hydrogen, substituted or unsubstituted C 1-6 alkyl.
2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 and R 3 are each independently selected from hydrogen or halogen; r 2 is selected from one of halogen and substituted or unsubstituted C 1-6 alkoxy.
3. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1、R2 or R 3 is C 1-6 alkoxy and at least one H on the C 1-6 alkoxy is substituted by a halogen atom.
4. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 5 is C 1-6 alkyl and at least one H on C 1-6 alkyl is substituted with a halogen atom, C 4-5 heteroaryl, halogenated C 4-5 heteroaryl, C 6 aryl, halogenated C 6 aryl, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl or tetrahydropyran.
5. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the substituted or unsubstituted C 1-6 alkoxy is independently selected from -OCH3、-OCH2CH3、-OCH(CH3)2、-OCH2CH2CH3、-OCHF2、-OCH2CHF2、-OCH2CH2CF3.
6. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the substituted or unsubstituted C 1-6 alkyl is independently selected from the group consisting of -CH3、-CH2CH3、-CH(CH3)2、-CH2CH2CH3、-CH2CH(CH3)2、-CH2CHF2、 One of them.
7. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the pharmaceutically acceptable salt is a product salt of the reaction of the compound of formula (I) with an acid comprising one or more of hydrochloric acid, hydrobromic acid, hydrofluoric acid, phosphoric acid, acetic acid, oxalic acid, sulfuric acid, methanesulfonic acid, salicylic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, maleic acid, fumaric acid, citric acid, tartaric acid, succinic acid, malic acid and glutamic acid.
8. A method for preparing a compound shown in a formula (I) or pharmaceutically acceptable salt thereof, which is characterized in that the compound shown in the formula (I) has the following synthetic route:
the method specifically comprises the following steps:
(one) when X in compound 1 is H:
(1) Dissolving the compound 1 in a solvent, reacting for 12-18 hours at 0-60 ℃ under the action of liquid bromine, and obtaining a compound 2 after the reaction is completed;
(2) Dissolving the compound 2 obtained in the step (1) in a solvent, reacting with halogenated hydrocarbon at 0-60 ℃ for 8-16h under the action of an alkaline reagent, and obtaining a compound 3 after the reaction is completed;
(3) Dissolving the compound 3 obtained in the step (2) in a solvent, reacting for 20-36 hours at 100-150 ℃ under the action of thiourea, and generating a compound 4 after the reaction is completed;
(4) Dissolving the compound 4 obtained in the step (3) in a solvent, reacting with halogenated hydrocarbon at 60-120 ℃ for 8-16 hours under the action of an alkaline reagent, and obtaining a compound shown in a formula (I) after the reaction is completed;
(II) when X in Compound 1 is SH:
(1) Dissolving the compound 1 in a solvent, reacting with halogenated hydrocarbon or p-toluenesulfonate derivative for 8-16h at 80-150 ℃ under the action of an alkaline reagent, and obtaining a compound 5 after the reaction is completed;
(2) Dissolving a compound 5 in a solvent, reacting with halogenated hydrocarbon at 0-60 ℃ for 8-16 hours under the action of an alkaline reagent, and obtaining a compound shown in a formula (I) after the reaction is completed;
Wherein the solvent involved in the steps is one or more of water, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, methanol, ethanol, isopropanol, acetonitrile, acetone, tetrahydrofuran, chloroform, ethyl acetate, dichloromethane, 1, 2-dichloroethane and 1, 4-dioxane;
The alkaline reagent involved in the above steps is one or more selected from diisopropylethylamine, triethylamine, 4-dimethylaminopyridine, piperidine, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium tert-butoxide, sodium hydride, sodium methoxide and sodium ethoxide.
9. A pharmaceutical composition comprising: a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-7, and a pharmaceutically acceptable excipient.
10. Use of a substance X for the preparation of phosphodiesterase type 8 inhibitors, characterized in that said substance X is a compound of formula (I) according to any of claims 1 to 7 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 8.
11. Use of a substance X for the preparation of a medicament, wherein said substance X is a compound of formula (I) according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 8; the medicine is used for treating and/or preventing diseases related to phosphodiesterase type 8.
CN202410296480.4A 2024-03-15 2024-03-15 3, 8-Disubstituted adenine derivative, preparation method and application thereof Pending CN118206555A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202410296480.4A CN118206555A (en) 2024-03-15 2024-03-15 3, 8-Disubstituted adenine derivative, preparation method and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202410296480.4A CN118206555A (en) 2024-03-15 2024-03-15 3, 8-Disubstituted adenine derivative, preparation method and application thereof

Publications (1)

Publication Number Publication Date
CN118206555A true CN118206555A (en) 2024-06-18

Family

ID=91448376

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202410296480.4A Pending CN118206555A (en) 2024-03-15 2024-03-15 3, 8-Disubstituted adenine derivative, preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN118206555A (en)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1377353A (en) * 1999-04-02 2002-10-30 欧罗赛铁克股份有限公司 Purine derivatives having phosphodiesterase IN inhibition activity
US20030073834A1 (en) * 1997-11-03 2003-04-17 Cavalla David J. Purine compounds having PDE IV inhibitory activity and methods of synthesis
WO2011058478A1 (en) * 2009-11-16 2011-05-19 Pfizer Inc. Substituted triazolopyrimidines as pde8 inhibitors
WO2019136093A1 (en) * 2018-01-02 2019-07-11 Sanford Burnham Prebys Medical Discovery Institute Inhibitors of low molecular weight protein tyrosine phosphatase (lmptp) and uses thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030073834A1 (en) * 1997-11-03 2003-04-17 Cavalla David J. Purine compounds having PDE IV inhibitory activity and methods of synthesis
CN1377353A (en) * 1999-04-02 2002-10-30 欧罗赛铁克股份有限公司 Purine derivatives having phosphodiesterase IN inhibition activity
WO2011058478A1 (en) * 2009-11-16 2011-05-19 Pfizer Inc. Substituted triazolopyrimidines as pde8 inhibitors
WO2019136093A1 (en) * 2018-01-02 2019-07-11 Sanford Burnham Prebys Medical Discovery Institute Inhibitors of low molecular weight protein tyrosine phosphatase (lmptp) and uses thereof

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
A. ER-FTHAIMINI等: "The photosolvolysis of N-arylmethyladenines. Photoremovable N-arylmethyl protective groups for N-containing compounds", TETRAHEDRON LETTERS, vol. 31, no. 40, 31 December 1990 (1990-12-31), pages 5757 - 5760 *
COLUMBUS, OHIO, US: "REGISTRY[online]", STN检索报告 US REGISTRY, 6 December 2015 (2015-12-06), pages 1 - 7 *
DORON PAPPO等: "Synthesis of 9-substituted tetrahydrodiazepinopurines-asmarine A analogues", TETRAHEDRON, vol. 59, 31 December 2003 (2003-12-31), pages 6493 - 6501, XP004444226, DOI: 10.1016/S0040-4020(03)01058-5 *
DUNG TIEN LE等: "Virtual Screening of Tubercular Acetohydroxy Acid Synthase Inhibitors through Analysis of Structural Models", BULL. KOREAN CHEM. SOC., vol. 28, no. 6, 31 December 2007 (2007-12-31), pages 947 - 952 *
HUEY-SAN MELANIE SIAH 等: "NMR and X-ray Structural Studies on 3-Benzyl-8-bromoadenine", J. HETEROCYCLIC CHEM., vol. 48, 30 June 2011 (2011-06-30), pages 1375 - 1378 *
JIYUN SUN等: "Advances in Cyclic Nucleotide Phosphodiesterase-Targeted PET Imaging and Drug Discovery", J. MED. CHEM, vol. 64, 27 May 2021 (2021-05-27), pages 7083 - 7109 *
KOSAKU HIROTA等: "Synthesis and Biological Evaluation of 2, 8-Disubstituted 9-Benzyladenines: Discovery of 8-Mercaptoadenines as Potent Interferon-Inducers", BIOORGANIC & MEDICINALCHEMISTRY, vol. 11, 31 December 2003 (2003-12-31), pages 2715 - 2722, XP085050407, DOI: 10.1016/S0968-0896(03)00234-7 *
TOZO FUJII等: "3-Substituted Adenines. In Vitro Enzyme Inhibition and Antiviral Activity", JOURNAL OF MEDICINAL CHEMISTRY, vol. 22, no. 2, 31 December 1979 (1979-12-31), pages 125 - 129, XP002917146, DOI: 10.1021/jm00188a003 *
XINGNAN LI等: "Synthesis and biological evaluation of purine derivatives incorporating metal chelating ligands as HIV integrase inhibitors", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 14, 5 June 2006 (2006-06-05), pages 5742 - 5755 *
张猛: "PDE8与各系统疾病关系的研究进展", 老年医学研究, vol. 4, no. 1, 31 December 2023 (2023-12-31), pages 50 - 54 *

Similar Documents

Publication Publication Date Title
JP5597391B2 (en) Kinase antagonist
US8093383B2 (en) P70 S6 kinase inhibitors
US8314234B2 (en) Bicyclic pyrimidine kinase inhibitors
RU2258705C2 (en) DERIVATIVES OF 8-PHENYL-6,9=DIHYDRO[1,24]TRIAZOLO[3,4-i]PURINE-5-ONE, METHODS FOR THEIR PREPARING, INTERMEDIATE COMPOUNDS, PHARMACEUTICAL COMPOSITION AND TREATMENT METHOD
JP2009532476A5 (en)
EP3212201B1 (en) Nucleoside kinase inhibitors
CA2650661A1 (en) Pyrazolo [3, 4-d] pyrimidine derivatives useful to treat respiratory disorders
JP2009529541A (en) 8-heteroarylpurine MNK2 inhibitors for the treatment of metabolic disorders
EP2239261A1 (en) Pyrrolopyrimidin derivative for use as pi3k inhibitor, and use thereof
US20030232838A1 (en) 6-phenylpyrrolopyrimidinedione derivatives
US6166016A (en) Amide derivatives
EP1492793B1 (en) New-4-(pyrrolopyrimidin-6-yl)benzenesulphonamide derivatives
CN118206555A (en) 3, 8-Disubstituted adenine derivative, preparation method and application thereof
WO2021038540A1 (en) Cycloalkylidene carboxylic acids and derivatives as btk inhibitors
EP3133072B1 (en) Novel 6,7-dihydro-3h-oxazolo[3,4-a]pyrazine-5,8-dione derivative compounds
EP1307458B1 (en) Pyrrolotriazolopyrimidinone derivatives
CN113493459A (en) PDE5 inhibitor compound, preparation method and application thereof
CN116836162A (en) Pyrazolo [4,3-c ] pyridine compound or pharmaceutically acceptable salt thereof and application thereof
NZ751261A (en) Bicyclic nitrogenated heterocyclic compound
NZ751261B2 (en) Bicyclic nitrogenated heterocyclic compound

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination