Purine derivative, synthesis method and application thereof

Abstract

The present invention belongs to the field of biomedicine and specifically relates to a purine derivative, its synthesis method, and application. The structure of the purine derivative is shown in Formula I, wherein R1 is a saturated hydrocarbon group, alkenyl group, alkynyl group, cycloalkyl group, aryl group, heterocyclic group, or alkoxycarbonyl group; R2 is hydrogen, halogen, alkyl group, aryl group, amino group, hydrocarbon amino group, or alkoxy group; R3 is hydrogen, alkyl group, amino group, hydrocarbon amino group, alkoxy group, aminosulfonyl group, sulfanyl group, aryl group, heterocyclic group, or carboxyl group; and n is 1, 2, 3, 4, 5, or 6. The purine derivative has excellent inhibitory activity against 5-lipoxygenase and 5-lipoxygenase, can be used to prepare lipoxygenase inhibitors, and can also be used to prepare drugs for treating lipoxygenase-mediated diseases, and has good clinical application prospects.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine, and specifically relates to a purine derivative, a synthesis method and an application thereof. Background Art

[0002] Arachidonic acid in the human body undergoes oxidative metabolism via pathways such as cyclooxygenase and lipoxygenase. Lipoxygenase (LOX) is a non-heme, iron-containing dioxygenase that catalyzes the oxidation of polyunsaturated fatty acids and their esters. It catalyzes the conversion of polyunsaturated fatty acids with a Z,Z-1,4-pentadiene structure into hydroperoxy derivatives, which are then reduced to hydroxy fatty acids and other substances. There are at least four lipoxygenase subtypes: 5-lipoxygenase, 8-lipoxygenase, 12-lipoxygenase, and 15-lipoxygenase. 5-Lipoxygenase is the most intensively studied and important lipoxygenase, acting as a key enzyme in the conversion of arachidonic acid to leukotrienes (LT) and 5-hydroxyarachidonic acid (5-HETE).

[0003] 5-LOX inserts an oxygen molecule at the C-5 position of arachidonic acid to generate 5-hydroperoxyeicosatetraenoic acid (HPETE). This molecule then undergoes a series of enzymatic reactions to generate inflammatory substances (LTs), such as leukotriene B4 (LTB4) and cysteine ​​leukotrienes (Cys LTs). LTB4 is a highly potent lipid-based inflammatory cell chemokine that attracts, recruits, and activates leukocytes, inducing a strong inflammatory response. Therefore, 5-LOX plays a crucial role in the proinflammatory cascade, including the development and progression of diseases such as asthma and atherosclerosis. The search for a lipoxygenase inhibitor would be of great significance. Summary of the Invention

[0004] The purpose of the present invention is to provide a purine derivative, the structure of which is shown in Formula I:

[0005] Formula I;

[0006] Wherein, R1 is a saturated hydrocarbon group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, a heterocyclic group or an alkoxycarbonyl group;

[0007] R2 is hydrogen, halogen, alkyl, aryl, amino, hydrocarbon amino or alkoxy;

[0008] R3 is hydrogen, alkyl, amino, alkylamino, alkoxy, aminosulfonyl, sulfanyl, aryl, heterocyclic or carboxyl;

[0009] n is 1, 2, 3, 4, 5 or 6.

[0010] The purine derivatives first proposed by the inventors can be used to prepare lipoxygenase inhibitors and drugs for treating lipoxygenase-mediated diseases. These diseases include: diseases associated with inflammation (diabetes, arteritis, Crohn's disease, inflammatory bowel disease, kidney disease, asthma, allergic rhinitis, gout, rheumatoid arthritis, osteoarthritis, and skin inflammation) and diseases associated with hypoxia or hypoxia (atherosclerosis, myocardial infarction, cerebral ischemia, myocardial ischemia).

[0011] Preferably, the structure of the purine derivative is as shown in Formula II, Formula III, Formula IV, Formula V or Formula VI:

[0012] .

[0013] The present invention also provides a method for synthesizing the purine derivative, and the synthesis route thereof is as follows:

[0014] .

[0015] The present invention also provides a pharmaceutical composition comprising the purine derivative and a pharmaceutically acceptable excipient or carrier.

[0016] The beneficial effects of the present invention are as follows: the present invention provides a purine derivative, which has a positive effect on 5-lipoxygenase (IC 50 It has good inhibitory activity (less than 3 µM) and can be used to prepare lipoxygenase inhibitors and drugs for treating lipoxygenase-mediated diseases, with good clinical application prospects. DETAILED DESCRIPTION

[0017] The following will clearly and completely describe the concept and technical effects of the present invention in conjunction with the embodiments to fully understand the purpose, scheme and effects of the present invention.

[0018] Example 1:

[0019] Synthesis of 3-(6-methoxy-9H-purin-9-yl)-N-hydroxypropionamide:

[0020] Its structural formula is shown in Formula II:

[0021] Formula II.

[0022] The specific synthesis steps include:

[0023] (1) 3.5 g of sodium metal was added to 50 mL of anhydrous methanol to prepare sodium methoxide solution, 15.5 g of 6-chloropurine was added, and the mixture was stirred and refluxed for 7 hours, and then distilled under reduced pressure; washed with water and ethanol to obtain 12.1 g of 6-methoxy-9-hydrogen-purine; Mp194-196 ℃, IR: (KBr, cm -1 ) 3446, 3132, 2396, 1635, 1542, 1396;

[0024] (2) Dissolve 7.5 g of 6-methoxy-9-hydrogen-purine in 150 mL of DMF solution, add 10.3 g of K2CO3, and slowly dropwise add 9.6 mL of ethyl 3-bromopropionate. After stirring at room temperature for 14 hours, add 1 M hydrochloric acid solution to adjust the pH to neutral. Extract with ethyl acetate (3×100 mL), combine the extracts, and spin dry them through a column. Purify by silica gel column chromatography with a gradient elution of ethyl acetate: petroleum ether = 1:10 (volume ratio) and ethyl acetate: petroleum ether = 1:1 (volume ratio) to obtain the product as a colorless, transparent oil with a yield of 69%; 1 HNMR (601 MHz, DMSO) δ 8.53 (s, 1H), 8.37 (s, 1H), 4.54–4.42 (m, 2H), 4.14–4.06 (m, 3H), 4.06–3.97 (m, 2H), 3.03–2.95 (m, 2H), 1.17–1.07 (m, 3H);

[0025] (3) 3.5 g of metallic sodium was added to 150 mL of anhydrous methanol to prepare a sodium methoxide solution. 3.5 g of hydroxylamine hydrochloride was added to react at room temperature to remove hydrochloric acid. The solid was removed by filtration. 6.3 mL of 3-(6-(methoxy)-9-purinyl)propionic acid was added to the filtrate. The temperature was raised to 55 °C. After reacting for 6 hours, 4.7 g of a white solid was obtained by purification by column chromatography (eluent: methanol: ethyl acetate = 1:10, volume ratio). 1 H NMR (601 MHz, DMSO)δ 10.45 (s, 1H), 8.80 (s, 1H), 8.54 (s, 1H), 8.26 (s, 1H), 4.50–4.37 (m, 2H), 4.06 (d, J=32.1 Hz, 3H), 2.66–2.56(m, 2H). 13 C NMR (151 MHz, DMSO) δ 166.61, 160.69, 152.41, 151.88, 144.38,121.05, 54.34, 32.50, 31.42.HRMS (ESI) m / z calcd for C9H11 N5O3[M+H] + 238.0935,found:238.1050.

[0026] Example 2:

[0027] Synthesis of 3-(6-isopropoxy-9H-purin-9-yl)-N-hydroxypropionamide:

[0028] Its structural formula is shown in Formula III:

[0029] Formula III.

[0030] 3.5 g of sodium metal was added to 50 mL of anhydrous isopropanol to prepare a sodium isopropoxide solution. 15.5 g of 6-chloropurine was added, and the mixture was stirred and refluxed for 7 hours, followed by distillation under reduced pressure. The solution was washed with water and ethanol to obtain 15.3 g of 6-isopropoxy-9H-purine, Mp 156-158 °C. 6-isopropoxy-9H-purine was synthesized using the same method as in Example 1 to obtain 3-(6-isopropoxy-9H-purin-9-yl)-N-hydroxypropionamide, which was purified by column chromatography (eluent: ethyl acetate:petroleum ether = 1:5, methanol:ethyl acetate = 1:10, volume ratio) to obtain 4.2 g of a white solid. Mp 182-184 °C. IR: (KBr, cm -1 )3433, 3109, 2977, 1651, 1465, 1315, 713,648. 1 H NMR (601 MHz, DMSO) δ 10.43(s, 1H), 8.78 (s, 1H), 8.52 (d, J=23.9 Hz, 1H), 8.22 (d, J=5.4 Hz, 1H), 5.59(dt, J=12.4, 6.2 Hz, 1H), 4.44 (t, J=6.7 Hz, 2H), 2.60 (t, J=6.7 Hz, 2H), 1.39 (d, J=6.2 Hz, 6H). 13 C NMR (151 MHz, DMSO) δ 172.49, 160.03,152.56,151.90,144.17,121.10,69.94,34.24,33.93, 22.28, 19.02.HRMS(ESI) m / z calcd forC 11 H 15 N5O3[M+H] + 266.1248, found:266.1370.

[0031] Example 3:

[0032] Synthesis of 5-(2-chloro-6-propoxy-9H-purin-9-yl)-N-hydroxypentanamide:

[0033] Its structural formula is shown in Formula IV:

[0034] Formula IV.

[0035] 3.5 g of sodium metal was added to 50 mL of anhydrous n-propanol to prepare a sodium propoxide solution. 18.8 g of 2,6-dichloropurine was added and the mixture was stirred and refluxed for 7 hours, followed by distillation under reduced pressure. The solution was washed with water and ethanol to obtain 13.3 g of 2-chloro-6-propoxy-9H-purine (MP: 172-174 °C). 2-Chloro-6-propoxy-9H-purine and ethyl 5-bromovalerate were reacted by the same synthetic method as in Example 1 to obtain 5-(2-chloro-6-propoxy-9H-purin-9-yl)-N-hydroxypentanamide. The solution was purified by column chromatography (eluent: methanol:ethyl acetate = 1:20, volume ratio) to obtain 3.9 g of a white solid (MP: 198-199 °C). 1 H NMR (601 MHz, DMSO) δ 10.36 (s, 1H), 8.65 (s, 1H), 8.27 (s, 1H), 4.09 (t, J=6.9 Hz, 2H), 3.39 (m, J=19.1, 9.4 Hz, 2H), 2.01–1.93 (t, 2H), 1.82–1.66 (m, 2H), 1.65–1.52(m, 2H), 1.48–1.39 (m, 2H), 0.87 (t, J=6.9 Hz, 3H). 13 C NMR (151 MHz, DMSO) δ169.21, 155.55, 153.61, 150.13, 141.58, 118.56, 43.31, 42.23, 32.17, 29.42,22.72, 22.51, 11.80.HRMS (ESI) m / z calcd for C 13 H 18 ClN5O3[M+H] + 328.7770, found:328.7766.

[0036] Example 4:

[0037] Synthesis of 5-(2-chloro-6-(4-methylphenyl)oxy-9H-purin-9-yl)-N-hydroxypentanamide:

[0038] Its structural formula is shown in Formula V:

[0039] Formula V.

[0040] 3.5 g of sodium metal was added to 50 mL of anhydrous 4-methylphenol to prepare a sodium 4-methylphenol solution. 18.8 g of 2,6-dichloropurine was added, and the mixture was stirred and refluxed for 7 hours before distillation under reduced pressure. The solution was washed with water and ethanol to obtain 18.1 g of 2-chloro-6-(4-methylphenoxy)-9H-purine (MP:181-182 °C). 2-Chloro-6-(4-methylphenoxy)-9H-purine and ethyl 5-bromopentanoate were reacted by the same synthetic method as in Example 1 to prepare 5-(2-chloro-6-(4-methylphenyl)oxy-9H-purin-9-yl)-N-hydroxypentanamide. The solution was purified by column chromatography (eluent: methanol:ethyl acetate = 1:20, volume ratio) to obtain 5.2 g of a white solid (MP:198-199 °C). 1 H NMR (601 MHz, DMSO) δ 10.35 (d, J=17.4 Hz, 1H), 8.69 (d,J=16.0 Hz, 1H), 8.31 (d, J=8.1 Hz, 1H), 7.70 (d, J=8.3 Hz, 2H), 7.21–7.12 (m,2H), 4.19–4.12 (m, 2H), 2.33–2.22 (m, 3H), 1.98 (dd, J=8.4, 6.3 Hz, 2H), 1.85–1.73 (m, 2H), 1.55–1.40 (m, 2H). 13 C NMR (151 MHz, DMSO) δ 169.21, 152.94,152.81, 151.16, 142.60, 136.66, 133.03, 129.38, 121.99, 119.16, 43.49, 32.17,29.37, 22.74, 20.95.HRMS (ESI) m / z calcd for C 17 H 18 ClN5O3[M+H] + 376.1176, found:376.1169.

[0041] Example 5:

[0042] Synthesis of 5-(6-methoxy-8-benzyl-9H-purin-9-yl)-N-hydroxypentanamide:

[0043] Its structural formula is shown in Formula VI:

[0044] Formula VI.

[0045] (1) Dissolve 6.3 g of 4,5,6-triaminopyrimidine in 140 mL of N, N-dimethylformamide (DMF), add 8.3 g of K2CO3, 0.5 g of 4-dimethylaminopyridine, and 6.5 mL of phenylacetyl chloride, and stir at 120 °C for 2 hours. After cooling, filter, wash with methanol, and evaporate the solvent under reduced pressure to obtain 8.5 g of N-(4,6-diaminopyrimidin-5-yl)-phenylacetamide; Mp 192-193 °C, MS m / z 244.1 [M+H] + ;

[0046] (2) 8.5 g of N-(4,6-diaminopyrimidin-5-yl)-phenylacetamide was dissolved in 25 mL of isobutanol. 2.7 g of sodium metal was added to 25 mL of anhydrous methanol to prepare a sodium methoxide solution. The solution was added to the isobutanol solution and stirred at 105 °C for 5 hours. The solution was cooled and the pH of the solution was adjusted to 7 with concentrated hydrochloric acid. The solution was evaporated under reduced pressure and purified by silica gel column chromatography to obtain 6-amino-8-benzyl-9H-purine; Mp 154-157 °C, MS m / z 225.9 [M+H] + ;

[0047] (3) Add 7.9 g of 6-chloro-8-benzyl-9H-purine to 70 mL of HCl under ice bath, add 3.8 g of cuprous chloride, stir to form salt, dissolve 2.7 g of sodium nitrite in 9 mL of water, slowly add sodium nitrite solution dropwise to the reaction mixture at a temperature below 5 °C, stir for 2 hours, remove the ice bath, add 1 g of urea to decompose the unreacted sodium nitrite, stir at room temperature for 4 hours, adjust the pH to 4 with 50% NaOH solution, precipitate solid, filter, dissolve the filter residue with 30% NaOH solution, purify by silica gel column chromatography, adjust the solution pH to 7 with hydrochloric acid, filter and dry to obtain 7.3 g of 6-chloro-8-benzyl-9H-purine; Mp 181-185 °C, MS m / z 245.5 [M+H] + ;

[0048] (4) 5-(6-methoxy-8-benzyl-9H-purin-9-yl)-N-hydroxypentanamide was prepared from 6-chloro-8-benzyl-9H-purine by the same synthetic method as in Example 1. The product was purified by column chromatography (eluent: methanol:ethyl acetate = 1:20, volume ratio) to obtain 4.6 g of a white solid. Mp:192-193°C. 1 H NMR (601 MHz, DMSO) δ 10.44(s, 1H), 8.54(s, 1H), 8.26 (s, 1H), 7.28 (m, 2H), 7.24 (d,J =7.7 Hz, 2H), 7.07 (d, J =7.3 Hz, 1H), 4.43 (t, J=6.7 Hz, 2H), 4.10 (s, 2H), 4.06 (d, J=32.1 Hz, 3H), 2.62 (t, J=6.7 Hz, 2H). 13 HRMS (ESI) m / zcalcd for C 16 H 17 N5O3[M+H] + 328.1410 found:328.1401.

[0049] Example 6:

[0050] (1) 5-lipoxygenase inhibitory activity assay

[0051] 5-Lipoxygenase was diluted with 50 mM Tris-HCl buffer (pH = 7.4), and arachidonic acid (AA) was diluted to 70 µM with Tris-HCl buffer (pH = 7.4). 0.5 µL of the diluted enzyme was added to each well of a 96-well plate. The test compound was added, and AA was added. The plates were incubated at room temperature for 10 minutes. FOX reagent (25 mM sulfuric acid, 100 µM xylenol orange, 100 µM iron (II) sulfate, methanol: water = 9:1, volume ratio) was added to terminate the reaction. The plates were incubated at room temperature for 60 minutes, and the absorbance at 620 nm was measured. The inhibition rate of the test compound and the IC were calculated by measuring the absorbance at 620 nm of the test compound. 50 value.

[0052] The test compounds are: the compounds prepared in Examples 1-5, 3-(6-pentyloxy-9H-purin-9-yl)-N-hydroxypropionamide, and 5-(2-chloro-6-pentyloxy-9H-purin-9-yl)-N-hydroxypentanamide.

[0053] The synthesis process of 3-(6-pentyloxy-9H-purin-9-yl)-N-hydroxypropionamide is as follows: 6-pentyloxy-9H-purin-9-yl)-N-hydroxypropionamide is prepared from 6-chloropurine and amyl alcohol using the same synthesis method as in Example 1. 3-(6-pentyloxy-9H-purin-9-yl)-N-hydroxypropionamide is then obtained. Purification by column chromatography yields 3.4 g of a white solid. Mp 122-124 °C. 1 H NMR (601 MHz, DMSO) δ 10.43 (s, 1H), 8.77 (s, 1H), 8.20 (s, 1H), 7.97 (s, 1H), 4.41–4.28 (m, 2H), 3.45 (s, 2H), 2.60–2.53 (m, 2H), 1.65–1.51 (m, 2H), 1.39–1.22 (m, 4H), 0.86 (t, J=7.0 Hz, 3H). 13 C NMR (151 MHz, DMSO) δ 172.69,166.71,155.01,152.86,141.09,140.83,119.42,35.16,34.27,32.67,29.09,22.39,14.41.HRMS(ESI)m / zcalcdforC 13 H 19 N5O3[M+H] + 294.1566,found:294.1571.

[0054] The synthesis process of 5-(2-chloro-6-pentyloxy-9H-purin-9-yl)-N-hydroxypentanamide is as follows: 2-chloro-6-pentyloxy-9H-purin-9-yl)-N-hydroxypentanamide is prepared from 2,6-dichloropurine and amyl alcohol using the same synthesis method as in Example 1. 5-(2-chloro-6-pentyloxy-9H-purin-9-yl)-N-hydroxypentanamide is then obtained. Purification by column chromatography yields 5.2 g of a white solid. Mp: 146-148 °C. 1H NMR (601 MHz, DMSO) δ 10.35 (s, 1H), 8.67 (d, J=12.5 Hz, 1H), 8.25 (d, J=5.6 Hz, 1H), 4.09 (t, J=6.9 Hz, 2H), 3.39 (dt, J=19.1, 9.4Hz, 2H), 1.98 (dd, J=12.8, 5.4 Hz, 2H), 1.77–1.69 (m, 2H), 1.62–1.53 (m, 2H), 1.44 (dd, J=15.2, 7.5 Hz, 2H), 1.31 (d, J=12.8 Hz, 4H), 0.87 (t, J=6.9 Hz,3H). 13 C NMR (151 MHz, DMSO) δ 169.22, 155.50, 153.62, 150.11, 141.53, 118.57,56.52, 43.31, 32.16, 29.42, 28.89, 22.73, 22.29, 19.01, 14.35.HRMS (ESI) m / zcalcdfor C 15 H 22 ClN5O3[M+H] + 356.1489, found:356.1481.

[0055] The results are shown in Table 1 (IC 50 Mean ± SD, n = 3), as shown in Table 1, the IC values ​​of the compounds prepared in Examples 1-5 of the present invention against 5-lipoxygenase are 50 were all below 3 μM, thus showing good 5-lipoxygenase inhibitory activity; while the IC 50 The concentrations of the two compounds were all above 30 μM, and they had almost no 5-lipoxygenase inhibitory activity.

[0056] Table 1 Results of 5-lipoxygenase inhibition activity test

[0057]

[0058] (2) 12 / 15-lipoxygenase inhibitory activity assay

[0059] 12 / 15-lipoxygenase was diluted with 50 mM Tris-HCl buffer (pH = 7.4), and arachidonic acid (AA) was diluted to 70 µM with Tris-HCl buffer (pH = 7.4). 1.3 µL of the diluted enzyme was added to each well of a 96-well plate. The test compound was added, and AA was added. The plates were incubated at room temperature for 10 minutes. FOX reagent (25 mM sulfuric acid, 100 µM xylenol orange, 100 µM iron (II) sulfate, methanol: water = 9:1, volume ratio) was added to terminate the reaction. The plates were incubated at room temperature for 60 minutes, and the absorbance at 620 nm was measured. By measuring the absorbance at 620 nm of the test compound, the inhibition rate of the test compound and the IC were calculated. 50 value.

[0060] The test compounds are: the compounds prepared in Examples 1-5, 3-(6-pentyloxy-9H-purin-9-yl)-N-hydroxypropionamide, and 5-(2-chloro-6-pentyloxy-9H-purin-9-yl)-N-hydroxypentanamide.

[0061] The results are shown in Table 2 (IC 50 Mean ± SD, n = 3), as shown in Table 2, the IC values ​​of the compounds prepared in Examples 1-5 of the present invention against 12 / 15-lipoxygenase are 50 were all below 5 μM, thus showing good 12 / 15-lipoxygenase inhibitory activity; while the IC 50 The concentrations of the two compounds were all above 30 μM, and they had almost no 12 / 15-lipoxygenase inhibitory activity.

[0062] Table 2 Results of 12 / 15-lipoxygenase inhibition activity test

[0063]

[0064] Example 7:

[0065] Inflammation test - Carrageenan-induced mouse foot swelling test:

[0066] Kunming mice were randomly divided into three groups: a blank control group, a model group, and a drug-treated group, with five mice in each group. After one week of adaptive feeding with free access to water and food, the mice were administered daily for seven consecutive days (blank control and model groups: an equal volume of 0.5% sodium carboxymethylcellulose was administered by gavage; drug-treated groups: each test substance was prepared in 0.5% sodium carboxymethylcellulose and administered by gavage at a rate of 60 mg / kg). Thirty minutes after the last dose, 0.03 mL of 1% carrageenan was subcutaneously injected into the right hind paw of each mouse, except for the blank control group. All animals were sacrificed four hours later, and both hind paws of each mouse were cut at the ankle joint and weighed separately. The difference in weight between the two hind paws was used to represent the degree of swelling.

[0067] The experimental results are shown in Table 3. The results showed that compared with the blank control group, the paw swelling in the model group was significantly increased (P < 0.01), indicating that the model was successfully established; after administration of the five compounds 3-(6-methoxy-9H-purin-9-yl)-N-hydroxypropionamide, 3-(6-isopropoxy-9H-purin-9-yl)-N-hydroxypropionamide, 5-(2-chloro-6-propoxy-9H-purin-9-yl)-N-hydroxypentanamide, 5-(2-chloro-6-(4-methylphenyl)oxy-9H-purin-9-yl)-N-hydroxypentanamide, and 5-(6-methoxy-8-benzyl-9H-purin-9-yl)-N-hydroxypentanamide, the paw swelling induced by carrageenan was reduced by 31.0%-54.3%, indicating that these five compounds can effectively inhibit the paw swelling of mice.

[0068] Table 3 Results of carrageenan-induced foot swelling experiment in mice

[0069]

[0070] The above description is merely a preferred embodiment of the present invention. The present invention is not limited to the above-described embodiments. As long as the technical effects of the present invention are achieved by the same means, they shall fall within the scope of protection of the present invention. Within the scope of protection of the present invention, various modifications and variations of the technical solutions and / or implementation methods may be made.

Claims

1. A purine derivative, characterized in that Its structure is shown in Formula V or Formula VI: Formula V, Formula VI.

2. A method for synthesizing the purine derivative according to claim 1, characterized in that: Its synthetic route is as follows: 。 3. Use of the purine derivative according to claim 1 in the preparation of lipoxygenase inhibitors.

4. Use of the purine derivative according to claim 1 in the preparation of a medicament for treating lipoxygenase-mediated diseases.

5. The use according to claim 4, characterized in that The diseases include: diseases associated with inflammation, and diseases associated with hypoxia or anoxia.

6. The use according to claim 5, characterized in that Diseases associated with inflammation include: diabetes, arteritis, Crohn's disease, inflammatory bowel disease, kidney disease, asthma, allergic rhinitis, gout, rheumatoid arthritis, osteoarthritis, and skin inflammation.

7. The use according to claim 5, characterized in that Diseases associated with low oxygen or anoxia include: atherosclerosis, myocardial infarction, cerebral ischemia, and myocardial ischemia.

8. A pharmaceutical composition, characterized in that Including the purine derivative according to claim 1.

9. The pharmaceutical composition according to claim 8, characterized in that Pharmaceutically acceptable excipients or carriers are also included.

Images