NUCLEOSIDE DERIVATIVE FOR PREVENTING AND TREATING INFLAMMATION AND APPLICATION THEREOF

Abstract

The present invention provides a nucleoside derivative for preventing and treating inflammation and an application thereof in the preparation of a drug for preventing and treating inflammatory diseases. The nucleoside derivative for preventing and treating inflammation provided by the present invention can significantly ameliorate conditions of pancreatitis, hepatitis, arthritis and the like, ameliorate organ injury and inflammatory indexes, and have better effects than positive control drug, indometacin. Compared with the conventional anti-inflammatory drugs, aspirin, ibuprofen, indomethacin, phenylbutazone, diclofenac, piroxicam and glucocorticoids, the nucleoside derivative for preventing and treating inflammation provided by the present invention has the advantage of significantly fewer side effects.

Claims

1. A nucleoside derivative for preventing and treating inflammation, wherein the structure formula of the derivative is represented by formula (I)˜formula (IV), or the derivative is a pharmaceutically acceptable salt of a compound of formula (I)˜formula (IV), ##STR00006## in formula (I)˜formula (IV), R.sub.1 is H, alkyl, heterocyclyl, alkyl substituted with an oxygen atom, a sulfur atom, a nitrogen atom or halogen, an ester group, amido or amino; R.sub.3 and R.sub.4 are alkyl, heterocyclyl, alkyl substituted with an oxygen atom, a sulfur atom, a nitrogen atom or halogen; R.sub.2 and R.sub.5 are O or S, X and Y are N or C, and Z is halogen.

2. The nucleoside derivative for preventing and treating inflammation according to claim 1, wherein in formula (I)˜formula (IV), R.sub.1 is H, (C.sub.1-C.sub.18) alkyl, (C.sub.3-C.sub.12) heterocyclyl, (C.sub.1-C.sub.18) alkyl substituted with an oxygen atom, a sulfur atom, a nitrogen atom or halogen, an ester group, amido or amino; R.sub.3 and R.sub.4 are (C.sub.1-C.sub.3) alkyl.

3. The nucleoside derivative for preventing and treating inflammation according to claim 2, wherein in formula (I)˜formula (IV) , R.sub.1 is H, (C.sub.1-C.sub.3) alkyl, (C.sub.3-C.sub.12) heterocyclyl, (C.sub.1-C.sub.3) alkyl substituted with an oxygen atom, a sulfur atom, a nitrogen atom or halogen, or is a group equivalent to -A.sub.1OC(O)A.sub.2, -A.sub.1NHA.sub.2 and -A.sub.1NHCOA.sub.2, wherein A.sub.1 and A.sub.2 are (C.sub.1-C.sub.3) alkyl and (C.sub.1-C.sub.3) alkyl substituted with an oxygen atom, a sulfur atom, a nitrogen atom or halogen.

4. The nucleoside derivative for preventing and treating inflammation according to claim 3, wherein in formula (I)˜formula (IV), R.sub.1 is H or (C.sub.1-C.sub.3) alkyl, or is a group equivalent to -A.sub.1OC(O)A.sub.2, -A.sub.1NHA.sub.2 and -A.sub.1NHCOA.sub.2, wherein A.sub.1 and A.sub.2 are (C.sub.1-C.sub.3) alkyl.

5. The nucleoside derivative for preventing and treating inflammation according to claim 4, wherein in formula (I)˜formula (IV), R.sub.1 is (C.sub.1-C.sub.3) alkyl, or is a group equivalent to -A.sub.1OC(O)A.sub.2, -A.sub.1NHA.sub.2 and -A.sub.1NHCOA.sub.2, wherein A.sub.1 and A.sub.2 are (C.sub.1-C.sub.3) alkyl; in formula (I)˜formula (IV), R.sub.1 is H.

6. The nucleoside derivative for preventing and treating inflammation according to claim 5, wherein the nucleoside derivative is any one of the following compounds 1˜19, or is a pharmaceutically acceptable salt of any one of the following compounds 1˜19: ##STR00007## ##STR00008## ##STR00009## ##STR00010##

7. The nucleoside derivatives for preventing and treating inflammation according to claim 1, wherein pharmaceutically acceptable salts of compounds of formula (I)˜formula (IV) and a pharmaceutically acceptable salt of any one of compounds 1˜19 are addition salts formed by compounds of formula (I)˜formula (IV) and any one of compounds 1˜19 in combination with hydrochloric acid, hydrobromic acid, sulfuric acid, carbonic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-methylbenzenesulfonic acid or ferulic acid.

8. Application of the nucleoside derivative according to claim 1 in preparation of a drug for preventing and treating inflammatory diseases.

9. The application according to claim 8, wherein the inflammatory diseases comprise pancreatitis, hepatitis, arthritis and related complications of pancreatitis, hepatitis and arthritis.

Description

EXAMPLE 1

[0021] In this example, compounds 1˜19 were synthesized.

1. Synthesis of Compound 1: 1-ethyl-3-7-dimethylxanthine

[0022] 540 mg (3 mmol) of theobromine and 720 mg (30 mmol) of NaH were dissolved into 80 ml of DMF, 2 mL (24.7 mmol) of ethane iodide was dropwise added under the stirring, the reaction was quenched with water after 4 hours of reaction, and the reaction product was subjected to spin drying under reduced pressure, and then loaded to a silica gel column with petroleum ether: CH.sub.3CH.sub.2OCOCH.sub.3=3:1 (V/V) as a mobile phase to obtain 495 mg (2.5 mmol) of compound 1 with a yield of 85%.

[0023] The compound 1 was detected via nuclear magnetic hydrogen spectroscopy, nuclear magnetic carbon spectroscopy and mass spectrometry. The results are as follows: .sup.1H NMR (400 MHz, DMSO) δ8.00 (s, 1H), 3.92-3.85 (m, 5H), 3.40 (s, 3H), 1.11 (t, J=7.0 Hz, 3H).

[0024] .sup.13C NMR (101 MHz, DMSO) δ154.09 (s), 150.54 (s), 148.08 (s), 142.75 (s), 106.56 (s), 35.44 (s), 33.05 (s), 29.20 (s), 13.02 (s).

[0025] HRMS (TOF MS ES+) for C.sub.9H.sub.12N.sub.4O.sub.2Na.sup.+ (M+Na.sup.+) calcd 231.0858, found 231.0856.

2. Synthesis of Compound 2: 1-isopropyl-3,7-dimethylxanthine

[0026] 1.08 g (6 mmol) of theophylline and 1.8 mg (75 mmol) of NaH were dissolved into 100 ml of DMF, 10 mL (100 mmol) of isopropane iodide was dropwise added under the stirring, the reaction was quenched with water after 4 hours of reaction, and the reaction product was subjected to spin drying under reduced pressure, and then loaded to a silica gel column with petroleum ether: CH.sub.3CH.sub.2OCOCH.sub.3=3:1 (V/V) as a mobile phase to obtain 1.83 g (5.3 mmol) of compound 2 with a yield of 88%.

[0027] The compound 2 was detected via nuclear magnetic hydrogen spectroscopy, nuclear magnetic carbon spectroscopy and mass spectrometry. The results are as follows: .sup.1H NMR (600 MHz, DMSO) δ8.19 (s, 1H), 4.91 (hept, J=6.5 Hz, 1H), 3.42 (s, 3H), 3.23 (s, 3H), 1.50 (d, J=6.7 Hz, 6H).

[0028] .sup.13C NMR (151 MHz, DMSO) δ154.69 (s), 151.36 (s), 149.16 (s), 140.57 (s), 106.14 (s), 49.88 (s), 29.85 (s), 28.13 (s), 22.90 (s).

[0029] HRMS (TOF MS ES+) for C.sub.10H.sub.14N.sub.4O.sub.2Na.sup.+ (M+Na.sup.+) calcd 245.1009, found 245.1013.

3. Synthesis of Compound 3: 1-ethyl-3,9-dimethylxanthine

[0030] 3 mmol of 3, 9-dimethylxanthine and 720 mg (30 mmol) of NaH were dissolved into 80 ml of DMF, 2 mL (24.7 mmol) of ethane iodide was dropwise added under the stirring, the reaction was quenched with water after 4 hours of reaction, and the reaction product was subjected to spin drying under reduced pressure, and then loaded to a silica gel column with petroleum ether: CH.sub.3CH.sub.2OCOCH.sub.3=3:1 (V/V) as a mobile phase to obtain the compound 3 with a yield of 89%.

[0031] The compound 3 was detected via nuclear magnetic hydrogen spectroscopy. The results are as follows: .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ7.88(s, 1H), 3.92(q, 2H), 3.72(s, 3H), 3.28(s, 3H), 1.14(t, 3H).

4. Synthesis of Compound 4: 1,3-dimethyl-7-ethylxanthine

[0032] 3 mmol of 1,3-dimethylxanthine and 720 mg (30 mmol) of NaH were dissolved into 80 ml of DMF, 2 mL (24.7 mmol) of ethane iodide was dropwise added under the stirring, the reaction was quenched with water after 4 hours of reaction, and the reaction product was subjected to spin drying under reduced pressure, and then loaded to a silica gel column with petroleum ether: CH.sub.3CH.sub.2OCOCH.sub.3=3:1 (V/V) as a mobile phase to obtain the compound 4 with a yield of 86%.

[0033] The compound 4 was detected via nuclear magnetic hydrogen spectroscopy, nuclear magnetic carbon spectroscopy and mass spectrometry. The results are as follows: .sup.1H NMR (400 MHz, DMSO) δ8.08 (s, 1H), 4.26 (q, J=7.2 Hz, 2H), 3.41 (s, 3H), 3.22 (s, 3H), 1.39 (t, J =7.2 Hz, 3H).

[0034] .sup.13C NMR (101 MHz, DMSO) δ154.17, 150.94, 148.37, 141.78, 105.75, 41.44, 29.32, 27.47, 16.24.

[0035] HRMS (TOF MS ES+) for C.sub.9H.sub.12N.sub.4O.sub.2Na.sup.+ (M+Na.sup.+) calcd 231.0858, found 231.0858.

5. Synthesis of Compound 5: 1,7-diethyl-3-methylxanthine

[0036] 3 mmol of 3-methylxanthine and 720 mg (30 mmol) of NaH were dissolved into 80 ml of DMF, 4 mL (49.4 mmol) of ethane iodide was dropwise added under the stirring, the reaction was quenched with water after 4 hours of reaction, and the reaction product was subjected to spin drying under reduced pressure, and then loaded to a silica gel column with petroleum ether: CH.sub.3CH.sub.2OCOCH.sub.3=3:1 (V/V) as a mobile phase to obtain the compound 5 with a yield of 92%.

[0037] The compound 5 was detected via nuclear magnetic hydrogen spectroscopy, nuclear magnetic carbon spectroscopy and mass spectrometry. The results are as follows: .sup.1H NMR (400 MHz, DMSO) δ8.09 (s, 1H), 4.28 (q, J=7.2 Hz, 2H), 3.91 (q, J=7.0 Hz, 2H), 3.42 (s, 3H), 1.41 (t, J=7.2 Hz, 3H), 1.13 (t, J=7.0 Hz, 3H) ppm.

[0038] .sup.13C NMR (101 MHz, DMSO) δ153.80 (s), 150.52 (s), 148.42 (s), 141.79 (s), 105.83 (s), 41.43 (s), 35.51 (s), 29.22 (s), 16.19 (s), 13.01 (s) ppm.

[0039] HRMS (TOF MS ES+) for C.sub.10H.sub.14N.sub.4O.sub.2Na.sup.+ (M+Na.sup.+) calcd 245.1014,found 245.1016.

6. Synthesis of Compound 6: 9-isopropyl Hypoxanthine

[0040] 6 mmol of hypoxanthine and 1.8 g (75 mmol) of NaH were dissolved into 100 ml of DMF, 10 mL (100 mmol) of isopropane iodide was dropwise added under the stirring, the reaction was quenched with water after 4 hours of reaction, and the reaction product was subjected to spin drying under reduced pressure, and then loaded to a silica gel column with petroleum ether: CH.sub.3CH.sub.2OCOCH.sub.3=3:1 (V/V) as a mobile phase to obtain the compound 6 with a yield of 75%.

[0041] The compound 6 was detected via nuclear magnetic hydrogen spectroscopy. The results are as follows: .sup.1H NMR (500 MHz, Chloroform-d) δ8.28 (d, J=7.6 Hz, 1H), 7.64 (s, 1H), 4.73 (p, J=6.3 Hz, 1H), 1.52 (d, J=6.8 Hz, 6H).

7. Synthesis of Compound 7: 1,7-diisopropyl-3-methylxanthine

[0042] 6 mmol of 3-methylxanthine and 1.8 g (75 mmol) of NaH were dissolved into 100 ml of DMF, 10 mL (100 mmol) of isopropane iodide was dropwise added under the stirring, the reaction was quenched with water after 4 hours of reaction, and the reaction product was subjected to spin drying under reduced pressure, and then loaded to a silica gel column with petroleum ether: CH.sub.3CH.sub.2OCOCH.sub.3=3:1 (V/V) as a mobile phase to obtain the compound 7 with a yield of 87%.

[0043] The compound 7 was detected via nuclear magnetic hydrogen spectroscopy. The results are as follows: .sup.1H NMR (500 MHz, Chloroform-d) δ8.33 (s, 1H), 4.92 (hept, J=6.2 Hz, 1H), 4.32 (hept, J=6.2 Hz, 1H), 3.21 (s, 2H), 1.51 (d, J=6.1 Hz, 5H), 1.31 (d, J=6.1 Hz, 5H).

8. Synthesis of Compound 8: 1-(acetic acid-2-ethyl)-3,7-dimethylxanthine

[0044] 540 mg (3 mmol) of theobromine and 720 mg (30 mmol) of NaH were dissolved into 80 ml of DMF, 4 mmol of 2-iodoethanol was dropwise added under the stirring, the reaction was quenched with water after 4 hours of reaction, and the reaction product was subjected to spin drying under reduced pressure, and then loaded to a silica gel column with petroleum ether: CH.sub.3CH.sub.2OCOCH.sub.3=3:1 (V/V) as a mobile phase to obtain compound 1-ethylhydroxy-3-7-dimethylxanthine with a yield of 94%.

[0045] 3 mmol of 1-ethylhydroxy-3-7-dimethylxanthine, 3 mmol of acetic anhydride and 0.3 mmol of NaOH were dissolved into 80 ml of DMF, the reaction was quenched with water after 4 hours of reaction, and the reaction product was subjected to spin drying under reduced pressure, and then loaded to a silica gel column with petroleum ether: CH.sub.3CH.sub.2OCOCH.sub.3=3:1 (V/V) as a mobile phase to obtain the compound 8 with a yield of 82%.

[0046] The compound 8 was detected via nuclear magnetic hydrogen spectroscopy. The results are as follows: .sup.1H NMR (400 MHz, DMSO) δ8.02 (s, 1H), 4.20 (t, J=5.5 Hz, 2H), 4.11 (t, J=5.6 Hz, 2H), 3.88 (s, 3H), 3.41 (s, 3H), 1.95 (s, 3H)..sup.13C NMR (101 MHz, DMSO) δ170.74 (s), 154.86 (s), 151.39 (s), 148.82 (s), 143.52 (s), 107.01 (s), 61.34 (s), 33.63 (s), 29.83 (s), 21.09 (s).

9. Synthesis of Compound 9: 1-(propionic acid -2-ethyl)-3,7-dimethylxanthine

[0047] 540 mg (3 mmol) of theobromine and 720 mg (30 mmol) of NaH were dissolved into 80 ml of DMF, 4 mmol of 2-iodoethanol was dropwise added under the stirring, the reaction was quenched with water after 4 hours of reaction, and the reaction product was subjected to spin drying under reduced pressure, and then loaded to a silica gel column with petroleum ether: CH.sub.3CH.sub.2OCOCH.sub.3=3:1 (V/V) as a mobile phase to obtain compound 1-ethylhydroxy-3-7-dimethylxanthine with a yield of 94%.

[0048] 3 mmol of 1-ethylhydroxy-3-7-dimethylxanthine, 3 mmol of propionic anhydride and 0.3 mmol of NaOH were dissolved into 80 ml of DMF, the reaction was quenched with water after 4 hours of reaction, and the reaction product was subjected to spin drying under reduced pressure, and then loaded to a silica gel column with petroleum ether: CH.sub.3CH.sub.2OCOCH.sub.3=3:1 (V/V) as a mobile phase to obtain the compound 9 with a yield of 80%.

[0049] The compound 9 was detected via nuclear magnetic hydrogen spectroscopy. The results are as follows: .sup.1H NMR (500 MHz, Chloroform-d) δ7.54 (s, 1H), 4.34 (t, J=6.3 Hz, 1H), 3.76 (s, 1H), 3.54 (t, J=6.32 Hz, 1H), 3.54 (s, 1H), 2.34 (q, J=7.4 Hz, 1H), 1.43 (t, J=7.9 Hz, 1H).

10. Synthesis of Compound 10: 1-(isopropyl acid-2-ethyl)-3,7-dimethylxanthine

[0050] 540 mg (3 mmol) of theobromine and 720 mg (30 mmol) of NaH were dissolved into 80 ml of DMF, 4 mmol of 2-iodoethanol was dropwise added under the stirring, the reaction was quenched with water after 4 hours of reaction, and the reaction product was subjected to spin drying under reduced pressure, and then loaded to a silica gel column with petroleum ether: CH.sub.3CH.sub.2OCOCH.sub.3=3:1 (V/V) as a mobile phase to obtain compound 1-ethylhydroxy-3-7-dimethylxanthine with a yield of 94%.

[0051] 3 mmol of 1-ethylhydroxy-3-7-dimethylxanthine, 3 mmol of isopropyl anhydride and 0.3 mmol of NaOH were dissolved into 80 ml of DMF, the reaction was quenched with water after 4 hours of reaction, and the reaction product was subjected to spin drying under reduced pressure, and then loaded to a silica gel column with petroleum ether: CH.sub.3CH.sub.2OCOCH.sub.3=3:1 (V/V) as a mobile phase to obtain the compound 10 with a yield of 81%.

[0052] The compound 10 was detected via nuclear magnetic hydrogen spectroscopy. The results are as follows: .sup.1H NMR (500 MHz, Chloroform-d) δ7.62 (s, OH), 4.43 (t, J=6.2 Hz, 1H), 3.46 (s, 1H), 3.48 (t, J=6.5 Hz, 1H), 3.43 (s, 1H), 2.53 (hept, J=7.2 Hz, OH), 1.25 (d, J=7.4 Hz, 3H).

11. Synthesis of Compound 11: 1-(2-methylaminoethyl)-3,7-dimethylxanthine

[0053] 540 mg (3 mmol) of theobromine and 720 mg (30 mmol) of NaH were dissolved into 80 ml of DMF, 4 mmol of 1,2-diiodoethane was dropwise added under the stirring, the reaction was quenched with water after 4 hours of reaction, and the reaction product was subjected to spin drying under reduced pressure, and then loaded to a silica gel column with petroleum ether: CH.sub.3CH.sub.2OCOCH.sub.3=3:1 (V/V) as a mobile phase to obtain compound 1-(2-iodoethyl)-3-7-dimethylxanthine with a yield of 89%.

[0054] 3 mmol of 1-(2-iodoethyl)-3-7-dimethylxanthine, 3 mmol of methylamine and 0.3 mmol of NaH were dissolved into 80 ml of DMF, the reaction was quenched with water after 4 hours of reaction, and the reaction product was subjected to spin drying under reduced pressure, and then loaded to a silica gel column with petroleum ether: CH.sub.3CH.sub.2OCOCH.sub.3=3:1 (V/V) as a mobile phase to obtain the compound 11 with a yield of 80%.

[0055] The compound 11 was detected via nuclear magnetic hydrogen spectroscopy. The results are as follows: .sup.1H NMR (500 MHz, Chloroform-d) δ7.54 (s, 1H), 4.33 (t, J=5.1 Hz, 2H), 3.77 (s, 2H), 3.32 (s, 2H), 2.84 (td, J=5.4, 3.5 Hz, 2H), 2.56 (d, J=4.8 Hz, 3H), 2.34 (qt, J=4.3, 3.5 Hz, 1H).

12. Synthesis of Compound 12: 1-(2-ethylaminoethyl)-3,7-dimethylxanthine

[0056] 540 mg (3 mmol) of theobromine and 720 mg (30 mmol) of NaH were dissolved into 80 ml of DMF, 4 mmol of 1,2-diiodoethane was dropwise added under the stirring, the reaction was quenched with water after 4 hours of reaction, and the reaction product was subjected to spin drying under reduced pressure, and then loaded to a silica gel column with petroleum ether: CH.sub.3CH.sub.2OCOCH.sub.3=3:1 (V/V) as a mobile phase to obtain compound 1-(2-iodoethyl)-3-7-dimethylxanthine with a yield of 89%.

[0057] 3 mmol of 1-(2-iodoethyl)-3-7-dimethylxanthine, 3 mmol of ethylamine and 0.3 mmol of NaH were dissolved into 80 ml of DMF, the reaction was quenched with water after 4 hours of reaction, and the reaction product was subjected to spin drying under reduced pressure, and then loaded to a silica gel column with petroleum ether: CH.sub.3CH.sub.2OCOCH.sub.3=3:1 (V/V) as a mobile phase to obtain the compound 12 with a yield of 78%.

[0058] The compound 12 was detected via nuclear magnetic hydrogen spectroscopy. The results are as follows: .sup.1H NMR (500 MHz, Chloroform-d) δ7.54 (s, 1H), 4.01 — 3.72 (m, 4H), 3.41 (s, 2H), 2.83 (td, J=5.2, 4.0 Hz, 2H), 2.76 (p, J=4.3 Hz, 1H), 2.62 (qd, J=7.2, 4.2 Hz, 2H), 1.32 (t, J=7.3 Hz, 3H).

13. Synthesis of Compound 13: 1-(2-isopropylaminoethyl)-3,7-dimethylxanthine

[0059] 540 mg (3 mmol) of theobromine and 720 mg (30 mmol) of NaH were dissolved into 80 ml of DMF, 4 mmol of 1,2-diiodoethane was dropwise added under the stirring, the reaction was quenched with water after 4 hours of reaction, and the reaction product was subjected to spin drying under reduced pressure, and then loaded to a silica gel column with petroleum ether: CH.sub.3CH.sub.2OCOCH.sub.3=3:1 (V/V) as a mobile phase to obtain the compound 1-(2-iodoethyl)-3-7-dimethylxanthine with a yield of 89%.

[0060] 3 mmol of 1-(2-iodoethyl)-3-7-dimethylxanthine, 3 mmol of isopropylamine and 0.3 mmol of NaH were dissolved into 80 ml of DMF, the reaction was quenched with water after 4 hours of reaction, and the reaction product was subjected to spin drying under reduced pressure, and then loaded to a silica gel column with petroleum ether: CH.sub.3CH.sub.2OCOCH.sub.3=3:1 (V/V) as a mobile phase to obtain the compound 13 with a yield of 79%.

[0061] The compound 13 was detected via nuclear magnetic hydrogen spectroscopy. The results are as follows: .sup.1H NMR (500 MHz, Chloroform-d) δ7.52 (s, 1H), 4.23 (t, J=5.3 Hz, 2H), 3.84 (s, 2H), 3.41 (s, 2H), 3.03 (td, J=5.5, 3.5 Hz, 2H), 2.81 (dp, J=7.4, 6.4 Hz, 1H), 2.35 (dt, J=7.3, 3.7 Hz, 1H), 1.13 (d, J=6.1 Hz, 6H).

14. Synthesis of Compound 14: 1-(2-propylaminoethyl)-3,7-dimethylxanthine

[0062] 540 mg (3 mmol) of theobromine and 720 mg (30 mmol) of NaH were dissolved into 80 ml of DMF, 4 mmol of 1,2-diiodoethane was dropwise added under the stirring, the reaction was quenched with water after 4 hours of reaction, and the reaction product was subjected to spin drying under reduced pressure, and then loaded to a silica gel column with petroleum ether: CH.sub.3CH.sub.2OCOCH.sub.3=3:1 (V/V) as a mobile phase to obtain the compound 1-(2-iodoethyl)-3-7-dimethylxanthine with a yield of 89%.

[0063] 3 mmol of 1-(2-iodoethyl)-3-7-dimethylxanthine, 3 mmol of propylamine and 0.3 mmol of NaH were dissolved into 80 ml of DMF, the reaction was quenched with water after 4 hours of reaction, and the reaction product was subjected to spin drying under reduced pressure, and then loaded to a silica gel column with petroleum ether: CH.sub.3CH.sub.2OCOCH.sub.3=3:1 (V/V) as a mobile phase to obtain the compound 14 with a yield of 78%.

[0064] The compound 14 was detected via nuclear magnetic hydrogen spectroscopy. The results are as follows: .sup.1H NMR (500 MHz, Chloroform-d) δ7.63 (s, 1H), 4.03 (t, J=5.4 Hz, 2H), 3.92 (s, 2H), 3.48 (s, 2H), 2.82 (td, J=5.4, 4.2 Hz, 2H), 2.76 (.sub.p, J=4.3 Hz, 1H), 2.86 (td, J=6.2, 4.2 Hz, 2H), 1.54 (qt, J=7.4, 6.1 Hz, 2H), 0.92 (t, J=7.4 Hz, 3H).

15. Synthesis of Compound 15: 1-(2-acetylethyl)-3,7-dimethylxanthine

[0065] 540 mg (3 mmol) of theobromine and 720 mg (30 mmol) of NaH were dissolved into 80 ml of DMF, 4 mmol of 1,2-diiodoethane was dropwise added under the stirring, the reaction was quenched with water after 4 hours of reaction, and the reaction product was subjected to spin drying under reduced pressure, and then loaded to a silica gel column with petroleum ether: CH.sub.3CH.sub.2OCOCH.sub.3=3:1 (V/V) as a mobile phase to obtain the compound 1-(2-iodoethyl)-3-7-dimethylxanthine with a yield of 89%.

[0066] 3 mmol of 1-(2-iodoethyl)-3-7-dimethylxanthine, 3 mmol of acetamide and 0.3 mmol of NaH were dissolved into 80 ml of DMF, the reaction was quenched with water after 4 hours of reaction, and the reaction product was subjected to spin drying under reduced pressure, and then loaded to a silica gel column with petroleum ether: CH.sub.3CH.sub.2OCOCH.sub.3=3:1 (V/V) as a mobile phase to obtain the compound 15 with a yield of 79%.

[0067] The compound 15 was detected via nuclear magnetic hydrogen spectroscopy. The results are as follows: .sup.1H NMR (500 MHz, Chloroform-d) δ7.54 — 7.65 (m, 1H), 4.12 (t, J=5.4 Hz, 1H), 3.65 (s, 1H), 3.65 (td, J=5.4, 4.4 Hz, 1H), 3.48 (s, 1H), 1.87 (s, 1H).

16. Synthesis of Compound 16: 1-(2-propionyl ethyl)-3,7-dimethylxanthine

[0068] 540 mg (3 mmol) of theobromine and 720 mg (30 mmol) of NaH were dissolved into 80 ml of DMF, 4 mmol of 1,2-diiodoethane was dropwise added under the stirring, the reaction was quenched with water after 4 hours of reaction, and the reaction product was subjected to spin drying under reduced pressure, and then loaded to a silica gel column with petroleum ether: CH.sub.3CH.sub.2OCOCH.sub.3=3:1 (V/V) as a mobile phase to obtain the compound 1-(2-iodoethyl)-3-7-dimethylxanthine with a yield of 89%.

[0069] 3 mmol of 1-(2-iodoethyl)-3-7-dimethylxanthine, 3 mmol of propanamide and 0.3 mmol of NaH were dissolved into 80 ml of DMF, the reaction was quenched with water after 4 hours of reaction, and the reaction product was subjected to spin drying under reduced pressure, and then loaded to a silica gel column with petroleum ether: CH.sub.3CH.sub.2OCOCH.sub.3=3:1 (V/V) as a mobile phase to obtain the compound 16 with a yield of 76%.

[0070] The compound 16 was detected via nuclear magnetic hydrogen spectroscopy. The results are as follows: .sup.1H NMR (500 MHz, Chloroform-d) δ7.54 (t, J=4.1 Hz, 1H), 7.65 (s, 1H), 4.21 (t, J=5.3 Hz, 2H), 3.76 (s, 2H), 3.65 (td, J=5.4, 4.4 Hz, 2H), 3.54 (s, 2H), 2.24 (q, J =7.9 Hz, 2H), 1.25 (t, J=7.9 Hz, 3H).

17. Synthesis of Compound 17: 1-(2-isopropionyl ethyl)-3,7-dimethylxanthine

[0071] 540 mg (3 mmol) of theobromine and 720 mg (30 mmol) of NaH were dissolved into 80 ml of DMF, 4 mmol of 1,2-diiodoethane was dropwise added under the stirring, the reaction was quenched with water after 4 hours of reaction, and the reaction product was subjected to spin drying under reduced pressure, and then loaded to a silica gel column with petroleum ether: CH.sub.3CH.sub.2OCOCH.sub.3=3:1 (V/V) as a mobile phase to obtain compound 1-(2-iodoethyl)-3-7-dimethylxanthine with a yield of 89%.

[0072] 3 mmol of 1-(2-iodoethyl)-3-7-dimethylxanthine, 3 mmol of isopropanamide and 0.3 mmol of NaH were dissolved into 80 ml of DMF, the reaction was quenched with water after 4 hours of reaction, and the reaction product was subjected to spin drying under reduced pressure, and then loaded to a silica gel column with petroleum ether: CH.sub.3CH.sub.2OCOCH.sub.3=3:1 (V/V) as a mobile phase to obtain the compound 17 with a yield of 79%.

[0073] The compound 17 was detected via nuclear magnetic hydrogen spectroscopy. The results are as follows: .sup.1H NMR (500 MHz, Chloroform-d) δ7.45 (s, 1H), 7.65 (t, J=4.4 Hz, 1H), 4.43 (t, J=5.3 Hz, 2H), 3.65 (s, 2H), 3.65 (td, J=5.5, 4.1 Hz, 2H), 3.43 (s, 2H), 2.35 (hept, J=7.2 Hz, 1H), 1.32 (d, J=7.3 Hz, 5H).

18. Synthesis of Compound 18: 1-(2-butyrylethyl)-3,7-dimethylxanthine

[0074] 540 mg (3 mmol) of theobromine and 720 mg (30 mmol) of NaH were dissolved into 80 ml of DMF, 4 mmol of 1,2-diiodoethane was dropwise added under the stirring, the reaction was quenched with water after 4 hours of reaction, and the reaction product was subjected to spin drying under reduced pressure, and then loaded to a silica gel column with petroleum ether: CH.sub.3CH.sub.2OCOCH.sub.3=3:1 (V/V) as a mobile phase to obtain compound 1-(2-iodoethyl)-3-7-dimethylxanthine with a yield of 89%.

[0075] 3 mmol of 1-(2-iodoethyl)-3-7-dimethylxanthine, 3 mmol of butyrylamide and 0.3 mmol of NaH were dissolved into 80 ml of DMF, the reaction was quenched with water after 4 hours of reaction, and the reaction product was subjected to spin drying under reduced pressure, and then loaded to a silica gel column with petroleum ether: CH.sub.3CH.sub.2OCOCH.sub.3=3:1 (V/V) as a mobile phase to obtain the compound 18 with a yield of 79%.

[0076] The compound 18 was detected via nuclear magnetic hydrogen spectroscopy. The results are as follows: .sup.1H NMR (500 MHz, Chloroform-d) δ7.73-7.62 (m, 1H), 4.13 (t, J=5.5 Hz, 1H), 3.76 (s, 1H), 3.46 (td, J=5.4, 4.2 Hz, 1H), 3.43 (s, 1H), 2.43-2.13 (m, 1H), 1.54 (h, J =7.4 Hz, 1H), 0.98 (t, J=7.4 Hz, 1H).

19. Synthesis of Compound 19: 3-isopropyl-5-fluorouracil

[0077] 6 mmol of 5-fluorouracil and 1.8 g (75 mmol) of NaH were dissolved into 100 ml of DMF, 1 mL (10 mmol) of iodoisopropane was dropwise added under the stirring, the reaction was quenched with water after 4 hours of reaction, and the reaction product was subjected to spin drying under reduced pressure, and then loaded to a silica gel column with petroleum ether: CH.sub.3CH.sub.2OCOCH.sub.3=3:1 (V/V) as a mobile phase to obtain the compound 19 with a yield of 87%.

[0078] The compound 19 was detected via nuclear magnetic hydrogen spectroscopy. The results are as follows: .sup.1H NMR (400 MHz, DMSO) δ11.72 (s, 1H), 8.13 (d, J=7.3 Hz, 1H), 4.64 (dt, J=13.6, 6.8 Hz, 1H), 1.24 (d, J=6.8 Hz, 6H).

EXAMPLE 2

[0079] In this example, the improvement effect of compounds 1˜19 prepared in example 1 on pancreatits was measured.

1. Test Method

[0080] (1) Animals: adult and healthy male Blab/c mice, 25˜30 g.

(2) Grouping

[0081] Blab/c mice were divided into blank control group, model control group, caffeine treatment group, and compound 1˜compound 19 treatment group, 10 mice/group.

(3) Construction of Pancreatits Model

[0082] A model was made with sodium taurocholate. Prior to the experiment, the mice were fasted for 12 hours with water, then operated in a sterile environment, and subsequently underwent intraperitoneal injection with 3.5% sodium pentobarbital. After anesthesia, the surgical site was sterilized with an alcohol cotton ball. The sterile gauze was placed on the surgical site. A laparotomy was made at the width of two fingers under the xiphoid process. After seeing the liver, an incision was made, the cotton swab soaked in normal saline was stretched into the enterocoelia, the duodenum was sought on the back of the liver, turned out and placed on the sterile gauze, the pancreaticobiliary duct and duodenal papilla were sought, and the needle of 1 mL syringe was used to pierce a hole on the along the direction of the nipple, a 24G indwelling needle tube was inserted into the pancreatic duct along the nipple, and the common bile duct below the liver was closed with an arterial vascular clip, with a dose of 0.1 mL/100 g and 0.1 mL/min inject sodium taurocholate with a concentration of 3.8% at a flow rate. During this process, pay attention to adding saline to the exposed pancreas and duodenum to keep it moist. After the injection, the tube was slowly taken out and the bile duct was continued to be closed. The main tube was removed from the vascular artery clip 3 minutes later, the duodenum was also accommodated, and the abdominal cavity was sutured in double layers. The blank control group was injected with equal volume of isotonic saline.

(4) Administration

[0083] For caffeine treatment group and compound 1˜compound 19 treatment group, caffeine and compound 1˜compound 19 were injected into caudal vein at the dose of 17.5 mg/kg 1 h, 3 h and 6 h after pancreatitis models were respectively constructed.

[0084] The blank control group and the model control group were given equal volume of isotonic saline.

(5) Index Measurement

[0085] After 24 hours, pancreatic tissue and blood samples were taken, and the pancreatic histopathological injury score and the level of pancreatic amylase in serum were evaluated.

2. Results

[0086] The pancreatic histopathological injury score and pancreatic amylase level of mice in each group are shown in Table 1. It can be seen from Table 1 that compounds 1˜19 provided by the present invention can effectively reduce the pancreatic amylase level of sodium taurocholate-induced pancreatitis model so as to alleviate the injury of pancreas.

TABLE-US-00001 TABLE 1 Pancreatic histopathological injury score and pancreatic amylase level of mice in each group (n = 10) Pancreatic histopathological Amylopsin Group injury score (KU/L) Blank 0.3 ± 0.2 2 ± 3 control group Model 3.8 ± 0.3 24 ± 3  control group Caffeine 2.6 ± 0.4 16 ± 2  treatment group Compound 1 0.4 ± 0.3 3 ± 1 treatment group Compound 2 0.6 ± 0.2 4 ± 2 treatment group Compound 3 0.5 ± 0.2 3 ± 2 treatment group Compound 4 1.4 ± 0.4 11 ± 2  treatment group Compound 5 0.4 ± 0.2 3 ± 1 treatment group Compound 6 0.4 ± 0.1 2 ± 1 treatment group Compound 7 0.5 ± 0.2 4 ± 2 treatment group Compound 8 0.8 ± 0.4 5 ± 2 treatment group Compound 9 0.5 ± 0.4 5 ± 3 treatment group Compound 10 0.6 ± 0.4 7 ± 5 treatment group Compound 11 0.5 ± 0.2 5 ± 3 treatment group Compound 12 0.4 ± 0.5 4 ± 2 treatment group Compound 13 1.8 ± 0.2 6 ± 2 treatment group Compound 14 1.9 ± 0.4 5 ± 3 treatment group Compound 15 1.6 ± 0.4 5 ± 4 treatment group Compound 16 1.8 ± 0.3 5 ± 2 treatment group Compound 17 1.5 ± 0.4 10 ± 3  treatment group Compound 18 1.3 ± 0.4 9 ± 2 treatment group Compound 19 1.0 ± 0.3 8 ± 2 treatment group

EXAMPLE 3

[0087] In this example, the improvement effect of compounds 1˜19 prepared in example 1 on arthritic was measured.

1. Test Method

[0088] (1) Animals: SD rats, four rates in one cage, were fed under the conditions of constant temperature (25±2° C.) and illumination control (12 h day/night circulation). The animals were fed with standard feed, and fed for at least 7 days to adapt environment before the experiment.

(2) Grouping

[0089] SD rates were divided into blank control group, model control group, caffeine treatment group, indometacin treatment group and compound 1—compound 19 treatment group, 10 mice/group.

[0090] (3) SD rats were fasted for 12 hours before operation, and weighed and recorded prior to operation. The blank control group was not treated any more.

[0091] SD rats in model control group, caffeine treatment group, indomethacin treatment group and compound 1˜compound 19 treatment group were intraperitoneally injected with 10% chloral hydrate solution at the dose of 3.5 ml/kg. After anesthesia, they were fixed in the supine position. 0.1 ml of 1 g/L sodium iodoacetate solution was injected into the knee joint. From the fifth day, the animals were driven to run for 30 minutes every day, and they were allowed to move freely in the cage the rest of the time. After modeling, indomethacin and compounds 1˜19 were given by gavage every day at the dose of 100 mg/kg/d. The blank control group and the model control group were given equal volume of isotonic saline.

(4) Index Measurement

[0092] At the 4th week after operation, the articular fluid of rats in each group was extracted to measure the content of MMP-13. The rats were killed, and the subchondral bone plate of the inner condyle of the tibia of the right knee was cut and processed into specimens, and pathological scores were made.

2. Results

[0093] The content of MMP-13 measured in the joint fluid and the score of joint pathological tissue of rats in each group are shown in Table 2. It can be seen from Table 2 that compared with the model control group, compound 1˜compound 19 treatment group can effectively reduce the level of MMP-13 in the arthritis model and reduce joint injury. Meanwhile, compared with the positive control drug indomethacin treatment group, the compound 1˜compound 19 treatment group has a significantly better improvement effect on arthritis.

TABLE-US-00002 TABLE 2 MMP-13 contents and joint pathological tissue scores in joint fluid of rats in each group (n = 10) MMP-13 Pathological content Group tissue score (mg/L) Blank 0.1 ± 0.2 81 ± 7 control group Model 3.2 ± 0.3 256 ± 24 control group Caffeine 2.6 ± 0.4 59 ± 8 treatment group Indometacin 2.1 ± 0.3 195 ± 8  treatment group Compound 1 0.2 ± 0.3 86 ± 4 treatment group Compound 2 0.3 ± 0.4 92 ± 8 treatment group Compound 3 0.6 ± 0.3 97 ± 4 treatment group Compound 4 0.6 ± 0.4 102 ± 8  treatment group Compound 5 0.7 ± 0.3 99 ± 5 treatment group Compound 6 0.3 ± 0.4 90 ± 8 treatment group Compound 7 0.3 ± 0.3 84 ± 5 treatment group Compound 8 0.4 ± 0.5 92 ± 8 treatment group Compound 9 0.6 ± 0.2 97 ± 7 treatment group Compound 10 0.7 ± 0.4 91 ± 8 treatment group Compound 11 0.3 ± 0.3 86 ± 5 treatment group Compound 12 0.3 ± 0.4 83 ± 8 treatment group Compound 13 0.3 ± 0.5 98 ± 5 treatment group Compound 14 0.7 ± 0.3 93 ± 7 treatment group Compound 15 0.6 ± 0.5 91 ± 7 treatment group Compound 16 0.4 ± 0.3 93 ± 9 treatment group Compound 17 0.5 ± 0.5 99 ± 6 treatment group Compound 18 0.5 ± 0.3 91 ± 8 treatment group Compound 19 0.3 ± 0.2 89 ± 6 treatment group

EXAMPLE 4

[0094] In this example, the improvement effect of compounds 1˜19 prepared in example 1 on pepatitis was measured.

1. Test Method

[0095] (1) Animals: adult and healthy male Blab/c mice, 25˜30 g.

(2) Grouping

[0096] Blab/c mice were adaptively fed for one week and then divided into blank control group, model control group, caffeine treatment group, and compound 1˜compound 19 treatment group at random, 10 mice/group.

[0097] (3) Blab/c mice in model control group, caffeine treatment group, indomethacin treatment group and compound 1˜compound 19 treatment group were injected with concanavalin A (ConA) solution through caudal vein to form a mouse hepatitis model. The blank control group was injected with equal volume of isotonic saline.

[0098] After modeling, indomethacin and compounds 1˜19 were given by gavage every day at the dose of 50 mg/kg. The blank control group and the model control group were given equal volume of isotonic saline.

(4) Index Measurement

[0099] Eyeball blood and liver tissue were taken at 6 h, 12 h, 24 h and 48 h after administration. The levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured.

2. Results

(1) Serum alanine aminotransferase and aspartate aminotransferase levels

[0100] After 6 h, 12 h, 24 h and 48 h of administration, the levels of serum alanine aminotransferase and aspartate aminotransferase of mice in each group are shown in Table 3. It can be seen from Table 3 that compared with the model control group, the compound 1˜19 treatment group can significantly reduce the levels of serum alanine aminotransferase and aspartate aminotransferase and reduce liver injury. Meanwhile, compared with the positive control drug indomethacin treatment group, the compound 1˜compound 19 treatment group has a significantly better improvement effect on hepatitis.

TABLE-US-00003 TABLE 3 Serum alanine aminotransferase and aspartate aminotransferase levels of mice in each group (n = 10) Serum alanine aminotransferase (ALT, U/L) Aspartate aminotransferase (AST, U/L) Group 6 (h) 12 (h) 24 (h) 48 (h) 6 (h) 12 (h) 24 (h) 48 (h) Blank control 12 ± 3 11 ± 3 13 ± 2 12 ± 3 25 ± 4 22 ± 4 25 ± 5 23 ± 4 group Model control 890 ± 73 1832 ± 173 3565 ± 363 1987 ± 193 320 ± 72 1035 ± 123 1534 ± 143 1243 ± 121 group Caffeine 590 ± 54 1456 ± 132 2632 ± 321 1432 ± 152 260 ± 31 860 ± 91 1234 ± 133 943 ± 91 treatment group Indometacin 465 ± 43 1232 ± 113 2165 ± 203 1287 ± 133 220 ± 19 780 ± 82 1021 ± 103 870 ± 91 treatment group Compound 1 56 ± 8 97 ± 8 132 ± 12 100 ± 12 43 ± 7 82 ± 8 104 ± 8  89 ± 9 treatment group Compound 2 59 ± 8 98 ± 6 142 ± 12 112 ± 13 53 ± 7 89 ± 8 112 ± 10 99 ± 9 treatment group Compound 3 67 ± 8 102 ± 8  152 ± 14 113 ± 12 59 ± 7 96 ± 8 114 ± 11 103 ± 9  treatment group Compound 4 79 ± 8 118 ± 9  142 ± 12 105 ± 13 65 ± 7 91 ± 8 103 ± 9  96 ± 9 treatment group Compound 5 73 ± 8 109 ± 8  136 ± 12 105 ± 12 71 ± 7 93 ± 8 101 ± 8  91 ± 9 treatment group Compound 6 56 ± 5 85 ± 6 136 ± 16 103 ± 13 49 ± 7 86 ± 8 103 ± 9  84 ± 8 treatment group Compound 7 51 ± 8 93 ± 8 131 ± 12  95 ± 12 41 ± 7 78 ± 8 101 ± 8  84 ± 7 treatment group Compound 8 67 ± 8 110 ± 13 172 ± 16 132 ± 13 68 ± 7 95 ± 8 122 ± 12 98 ± 9 treatment group Compound 9 78 ± 8 110 ± 13 175 ± 18 123 ± 12 78 ± 7 123 ± 8  142 ± 13 131 ± 14 treatment group Compound 10 83 ± 8 132 ± 13 186 ± 19 154 ± 17 87 ± 9 167 ± 19 189 ± 15 176 ± 17 treatment group Compound 11 54 ± 6 92 ± 9 142 ± 14 110 ± 13 48 ± 7 89 ± 8 112 ± 12 95 ± 9 treatment group Compound 12 76 ± 8 113 ± 12 162 ± 16 121 ± 13 58 ± 7 93 ± 9 121 ± 19 102 ± 9  treatment group Compound 13 87 ± 9 121 ± 13 172 ± 17 143 ± 12 63 ± 7 102 ± 12 132 ± 13 93 ± 9 treatment group Compound 14 56 ± 8 134 ± 15 193 ± 12 132 ± 13 65 ± 7  93 ± 12 152 ± 15 119 ± 12 treatment group Compound 15 65 ± 8 171 ± 15 218 ± 26 132 ± 12 65 ± 7 118 ± 18 198 ± 18 129 ± 9  treatment group Compound 16 61 ± 8 101 ± 16 132 ± 12 104 ± 13 59 ± 7  93 ± 11 121 ± 12 103 ± 9  treatment group Compound 17 79 ± 8 145 ± 13 163 ± 16 142 ± 15 65 ± 5 102 ± 12 119 ± 12 107 ± 11 treatment group Compound 18 67 ± 8 106 ± 11 157 ± 15 121 ± 13 54 ± 7 98 ± 8 131 ± 8  117 ± 9  treatment group Compound 19 55 ± 6 87 ± 6 139 ± 12 111 ± 13 57 ± 7 92 ± 8 117 ± 9  101 ± 9  treatment group

EXAMPLE 5

[0101] In this example, the toxicities of compounds 1-19 prepared in example 1 were analyzed.

[0102] C57 mice were given compounds 1-19 at a dose of 100 mg/kg/D for 180 consecutive days by gavage. One hour after the last administration of the drug, the mice were anesthetized by intraperitoneal injection of sodium pentobarbital (40 mg/kg), placed on a constant temperature hot plate at 37±1° C., blood was taken by cardiac puncture or pathological sections were made to detect the side effects (gastrointestinal reaction, nervous system toxicity, hematological toxicity, allergic reaction, nephrotoxicity, hepatotoxicity, rash and asthma) The side effects of aspirin, ibuprofen, indomethacin, phenylbutazone, diclofenac, piroxicam and glucocorticoid groups were investigated according to the same administration method as compounds 1-19. The results are shown in Table 4. Compared with the traditional anti-inflammatory drugs aspirin, ibuprofen, indomethacin, phenylbutazone, diclofenac, piroxicam and glucocorticoid, the compounds 1-19 provided by the invention have the advantage of significantly less side effects.

TABLE-US-00004 TABLE 4 Toxicity test results Occurrence rate Side effects of side effects Aspirin Gastrointestinal tract, 20%  Ibuprofen nervous system, blood Indometacin system, allergic reaction, Baotaisong nephrotoxicity, Diclofenac hepatotoxicity, Piroxicam hepatonephrotoxicity, rash and asthma Glucocorticoid Intestinal tract, 35%  cardiovascular system, immune function, nervous system Compounds 1, 3-6, 12 Gastrointestinal tract, 1% Compounds 2, 7-9 nervous system, blood 1.5%.sup.  Compounds 10, 11, 13-15 system, allergic reaction, 3% Compounds 16-19 nephrotoxicity, 2% hepatotoxicity, rash and asthma