6-HYDRAZINOADENOSINE COMPOUNDS WITH A2A ADENOSINE RECEPTOR AGONIST ACTIVITY

Abstract

The present disclosure provides 6-hydrazinoadenosine represented by the general Formula (I) and its derivatives with A.sub.2A adenosine receptor agonist activity, and pharmaceutical compositions containing them. The compound and composition can be used as A.sub.2A adenosine receptor agonists and used as medicament.

##STR00001##

Claims

1. A compound represented by the general Formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt of the compound or stereoisomer, or a pharmaceutically acceptable hydrate or solvate of the compound or stereoisomer, or a pharmaceutically acceptable ester of the compound or stereoisomer, wherein the compound has a structure represented by the general Formula (I): ##STR00032## wherein, R.sub.1 is selected from the group consisting of aryl, heteroaryl, cycloalkyl, C.sub.1-10 alkyl, heterocycloalkyl, C.sub.1-10 heteroalkyl or C.sub.2-10 alkenyl; R.sub.1 is optionally substituted with one or more R′, each R′ is independently selected from the group consisting of phenyl, halophenyl, amino-substituted phenyl, benzyloxy, halobenzyloxy, phenylamino, heteroaryl, cycloalkyl, heterocycloalkyl, C.sub.1-6 alkyl, halogenated C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthio, -—HC(O)R.sup.10, halogen or cyano, wherein R.sup.10 is C.sub.1-6 alkyl.

2. The compound, or the stereoisomer thereof, or the pharmaceutically acceptable salt of the compound or stereoisomer, or the pharmaceutically acceptable hydrate or solvate of the compound or stereoisomer, or the pharmaceutically acceptable ester of the compound or stereoisomer, according to claim 1, wherein: R.sub.1 is selected from C.sub.6-10 aryl, 5- to 7-membered heteroaryl, 5- to 6-membered cycloalkyl, 5- to 6-membered heterocycloalkyl, C.sub.1-10 alkyl, C.sub.1-10 heteroalkyl or C.sub.2-10 alkenyl; preferably, R.sub.1 is selected from the group consisting of phenyl, pyrrolyl, imidazolyl, thiazolyl, furyl, pyridyl, cyclopentyl, cyclohexyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentyloxy, n-hexyloxy, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, tert-butylthio, sec-butylthio, n-pentylthio, n-hexylthio or C.sub.2-10 alkenyl; preferably, R.sub.1 is selected from the group consisting of phenyl, pyrrolyl, furyl, imidazolyl, thiazolyl, cyclohexyl, alkylthio, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, tert-pentyl, neopentyl, hexyl, trifluoromethyl, difluoromethyl, fluoromethyl, vinyl, or decadienyl.

3. The compound, or the stereoisomer thereof, or the pharmaceutically acceptable salt of the compound or stereoisomer, or the pharmaceutically acceptable hydrate or solvate of the compound or stereoisomer, or the pharmaceutically acceptable ester of the compound or stereoisomer, according to claim 1, wherein: each R′ is independently selected from the group consisting of phenyl, halophenyl, amino-substituted phenyl, benzyloxy, halobenzyloxy, phenylamino, imidazolyl, pyridyl, 5- to 6-membered cycloalkyl, 5- to 6-membered heterocycloalkyl, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, —NHC(O)R.sup.10, halogen or cyano, wherein R.sup.10 is C.sub.1-4 alkyl; preferably, each R′ is independently selected from the group consisting of phenyl, halophenyl, dimethylamino-substituted phenyl, benzyloxy, halobenzyloxy, diphenylamino, 1H-imidazol-1-yl, pyridin-2-yl, 1H-imidazol-1-yl, pyrrolidin-1-yl, cyclopentyl, cyclohexyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentyloxy, n-hexyloxy, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, tert-butylthio, sec-butylthio, n-pentylthio, n-hexylthio, —NH(CO)CH.sub.3, F, Cl, Br or cyano.

4. The compound, or the stereoisomer thereof, or the pharmaceutically acceptable salt of the compound or stereoisomer, or the pharmaceutically acceptable hydrate or solvate of the compound or stereoisomer, or the pharmaceutically acceptable ester of the compound or stereoisomer, according to claim 1, wherein the compound has a structure represented by Formula I-1: ##STR00033## R.sub.2 represents a substituent attached to the benzene ring; n is 1, 2, 3, 4 or 5; each R.sub.2 is independently selected from the group consisting of phenyl, halophenyl, amino-substituted phenyl, benzyloxy, halobenzyloxy, phenylamino, heteroaryl, cycloalkyl, heterocycloalkyl, C.sub.1-6 alkyl, C.sub.1-6 heteroalkyl, C.sub.1-6 haloalkyl, C.sub.2-10 alkenyl (e.g., C.sub.2-6 alkenyl), C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, C.sub.1-6 alkylamino, acylamino, halogen, hydroxy, cyano or —NHC(O)R.sup.10, wherein R.sup.10 is C.sub.1-4 alkyl; preferably, each R.sub.2 is independently selected from the group consisting of phenyl, halophenyl, amino-substituted phenyl, benzyloxy, halobenzyloxy, phenylamino, heteroaryl, cycloalkyl, heterocycloalkyl, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-10 alkenyl (e.g., C.sub.2-6 alkenyl), C.sub.1-6 alkoxy, —NHC(O)R.sup.10, halogen or cyano, wherein R.sup.10 is C.sub.1-4 alkyl.

5. The compound, or the stereoisomer thereof, or the pharmaceutically acceptable salt of the compound or stereoisomer, or the pharmaceutically acceptable hydrate or solvate of the compound or stereoisomer, or the pharmaceutically acceptable ester of the compound or stereoisomer, according to claim 4, wherein, each R.sub.2 is independently selected from the group consisting of C.sub.1-6 alkyl, C.sub.1-6 heteroalkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, C.sub.1-6 alkylamino, acylamino, phenyl, benzyloxy, halobenzyloxy, phenylamino, 5- to 6-membered heterocycloalkyl, —NH(CO)CH.sub.3, halogen, hydroxy, or cyano.

6. The compound, or the stereoisomer thereof, or the pharmaceutically acceptable salt of the compound or stereoisomer, or the pharmaceutically acceptable hydrate or solvate of the compound or stereoisomer, or the pharmaceutically acceptable ester of the compound or stereoisomer, according to claim 4, wherein, each R.sub.2 is independently selected from the group consisting of methyl, trifluoromethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, C.sub.1-3 alkoxy, phenyl, diphenylamino, benzyloxy, halobenzyloxy, pyridin-2-yl, 1H-imidazol-1-yl, pyrrolidin-1-yl, —NH(CO)CH.sub.3, F, Cl, Br or cyano.

7. The compound, or the stereoisomer thereof, or the pharmaceutically acceptable salt of the compound or stereoisomer, or the pharmaceutically acceptable hydrate or solvate of the compound or stereoisomer, or the pharmaceutically acceptable ester of the compound or stereoisomer, according to claim 1, wherein the compound is selected from: ##STR00034## ##STR00035## ##STR00036## ##STR00037## ##STR00038## ##STR00039##

8. A method for preparing the compound, or the stereoisomer thereof, or the pharmaceutically acceptable salt of the compound or stereoisomer, or the pharmaceutically acceptable hydrate or solvate of the compound or stereoisomer, or the pharmaceutically acceptable ester of the compound or stereoisomer, according to any one of claims 1 to 7, comprising: ##STR00040## reacting a compound of Formula (vii) with a substituted formaldehyde represented by Formula (viii) to obtain the compound represented by general Formula (I), wherein the definition of R.sub.1 is the same as that described in any one of claims 1 to 3; preferably, the compound of Formula (vii) reacts with the substituted formaldehyde (viii) in a methanol solution under a microwave at 70˜90° C.; ##STR00041## preferably, the compound of Formula (vii) is produced from a compound of Formula (vi) by hydrazinolysis with hydrazine hydrate at 60˜80° C.

9. A pharmaceutical composition, which comprises at least one of the compound, or the stereoisomer thereof, or the pharmaceutically acceptable salt of the compound or stereoisomer, or the pharmaceutically acceptable hydrate or solvate of the compound or stereoisomer, or the pharmaceutically acceptable ester of the compound or stereoisomer, according to any one of claims 1 to 7, and one or more pharmaceutically acceptable carriers or excipients.

10. The pharmaceutical composition according to claim 9, which further comprises: a drug for crossing the blood-brain barrier, which is selected from the group consisting of a drug for treating a disease or disorder of the central nervous system, a neurotoxin antidote, and a drug for treating a brain glioma.

11. Use of the compound, or the stereoisomer thereof, or the pharmaceutically acceptable salt of the compound or stereoisomer, or the pharmaceutically acceptable hydrate or solvate of the compound or stereoisomer, or the pharmaceutically acceptable ester of the compound or stereoisomer, according to any one of claims 1 to 7, or the pharmaceutical composition according to claim 9 or 10 in the manufacture of a medicament as an A.sub.2A adenosine receptor agonist, or in the manufacture of a medicament for the prevention and/or treatment of a human pathological condition or symptom, wherein the prevention or treatment of a human pathological condition or symptom is related to the activity of A.sub.2A adenosine receptor, and the prevention and/or treatment of a human pathological condition or symptom requires agonizing of the A.sub.2A adenosine receptor.

12. Use according to claim 11, wherein the human pathological condition or symptom is selected from the group consisting of: autoimmune irritation, inflammation, allergic disease, skin disease, infectious disease, wasting disease, neuropathic pain, open trauma, adverse reaction caused by drug therapy, cardiovascular disease, ischemia-reperfusion injury, gout, chemical trauma, thermal trauma, diabetic nephropathy, sickle cell disease, laminitis, founder's disease, glaucoma, ocular hypertension, spinal cord injury, myocardial infarction, and acute myocardial infarction.

13. Use of the compound, or the stereoisomer thereof, or the pharmaceutically acceptable salt of the compound or stereoisomer, or the pharmaceutically acceptable hydrate or solvate of the compound or stereoisomer, or the pharmaceutically acceptable ester of the compound or stereoisomer, according to any one of claims 1 to 7, or the pharmaceutical composition according to claim 9 or 10 in the manufacture of a medicament for diagnosing a human myocardial perfusion abnormality.

14. Use of the compound, or the stereoisomer thereof, or the pharmaceutically acceptable salt of the compound or stereoisomer, or the pharmaceutically acceptable hydrate or solvate of the compound or stereoisomer, or the pharmaceutically acceptable ester of the compound or stereoisomer, according to any one of claims 1 to 7, or the pharmaceutical composition according to claim 9 or 10 in the manufacture of a medicament for increasing a blood-brain barrier permeability of a subject receiving a therapeutic drug, wherein the subject is benefited from the increased blood-brain barrier permeability for delivering the therapeutic drug across the blood-brain barrier.

15. Use according to claim 14, wherein the therapeutic drug is selected from the group consisting of: a drug that is effective in treating a disease or disorder of the central nervous system, a neurotoxin antidote, and a drug for treating a brain glioma.

16. A method for prevention and/or treatment of a human pathological condition or symptom, comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one of the compound, or the stereoisomer thereof, or the pharmaceutically acceptable salt of the compound or stereoisomer, or the pharmaceutically acceptable hydrate or solvate of the compound or stereoisomer, or the pharmaceutically acceptable ester of the compound or stereoisomer, according to any one of claims 1 to 7, or the pharmaceutical composition according to claim 9 or 10, wherein the human pathological condition or symptom is related to the activity of A.sub.2A adenosine receptor, and the prevention or treatment of the pathological condition or symptom of the patient requires agonizing of the A.sub.2A adenosine receptor; preferably, the human pathological condition or symptom is selected from the group consisting of: autoimmune irritation, inflammation, allergic disease, skin disease, infectious disease, wasting disease, neuropathic pain, open trauma, adverse reaction caused by drug therapy, cardiovascular disease, ischemia-reperfusion injury, gout, chemical trauma, thermal trauma, diabetic nephropathy, sickle cell disease, laminitis, founder's disease, glaucoma, ocular hypertension, spinal cord injury, myocardial infarction, and acute myocardial infarction.

17. The compound represented by the general Formula (I), or the stereoisomer thereof, or the pharmaceutically acceptable salt of the compound or stereoisomer, or the pharmaceutically acceptable hydrate or solvate of the compound or stereoisomer, or the pharmaceutically acceptable ester of the compound or stereoisomer, according to any one of claims 1 to 7, for use in prevention and/or treatment of a human pathological condition or symptom, the human pathological condition or symptom is related to the activity of A.sub.2A adenosine receptor, and the prevention or treatment of the human pathological condition or symptom requires agonizing of the A.sub.2A adenosine receptor; preferably, the human pathological condition or symptom is selected from the group consisting of: autoimmune irritation, inflammation, allergic disease, skin disease, infectious disease, wasting disease, neuropathic pain, open trauma, adverse reaction caused by drug therapy, cardiovascular disease, ischemia-reperfusion injury, gout, chemical trauma, thermal trauma, diabetic nephropathy, sickle cell disease, laminitis, founder's disease, glaucoma, ocular hypertension, spinal cord injury, myocardial infarction, and acute myocardial infarction.

18. The compound represented by the general Formula (I), or the stereoisomer thereof, or the pharmaceutically acceptable salt of the compound or stereoisomer, or the pharmaceutically acceptable hydrate or solvate of the compound or stereoisomer, or the pharmaceutically acceptable ester of the compound or stereoisomer, according to any one of claims 1 to 7, for use in agonizing A.sub.2A adenosine receptor or vasodilating a coronary artery, or for use in diagnosing a human myocardial perfusion abnormality, or for use in increasing a blood-brain barrier permeability of a subject receiving a therapeutic drug, in which the subject benefits from the increased blood-brain barrier permeability for delivering the therapeutic drug across the blood-brain barrier, preferably, the therapeutic drug is selected from the group consisting of: a drug for treating a disease or disorder of the central nervous system, a neurotoxin antidote, and a drug for treating a brain glioma.

19. A method for diagnosing a human myocardial perfusion abnormality, comprising administering to a patient in need of such diagnosis a diagnostically effective amount of the compound, or the stereoisomer thereof, or the pharmaceutically acceptable salt of the compound or stereoisomer, or the pharmaceutically acceptable hydrate or solvate of the compound or stereoisomer, or the pharmaceutically acceptable ester of the compound or stereoisomer, according to any one of claims 1 to 7, or the pharmaceutical composition according to claim 9 or 10.

20. A method for increasing a blood-brain barrier permeability of a subject receiving a therapeutic drug, the method comprising administering to the subject an effective amount of the compound, or the stereoisomer thereof, or the pharmaceutically acceptable salt of the compound or stereoisomer, or the pharmaceutically acceptable hydrate or solvate of the compound or stereoisomer, or the pharmaceutically acceptable ester of the compound or stereoisomer, according to any one of claims 1 to 7, or the pharmaceutical composition according to claim 9 or 10, wherein the subject benefits from the increased blood-brain barrier permeability for delivering the therapeutic drug across the blood-brain barrier; preferably, the therapeutic drug is selected from the group consisting of: a drug for treating a disease or disorder of the central nervous system, a neurotoxin antidote, and a drug for treating a brain glioma.

Description

SPECIFIC MODELS FOR CARRYING OUT THE INVENTION

[0101] The present disclosure can be further described through the following examples and test examples. However, the scope of the present disclosure is not limited to the following examples or test examples. Those skilled in the art can understand that various changes and modifications can be made to the present disclosure without departing from the spirit and scope of the present disclosure. This disclosure provides a general and/or specific description of the materials and methods used herein. Although many materials and operating methods used to achieve the purpose of the present disclosure are well-known in the art, the present disclosure is still described herein as much detail as possible.

[0102] For all the following examples, standard operations and purification methods known to those skilled in the art can be used. Unless otherwise stated, all temperatures were expressed in ° C. (Celsius). The structure of compound was determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). The melting point m.p. of compound was determined by RY-1 melting point instrument. The thermometer had not been corrected. The m.p. was given in ° C. .sup.1H NMR was measured by JNM-ECA-400 nuclear magnetic resonance instrument of JEOL. The mass spectrum was measured by API3000 (ESI) instrument. All reaction solvents that were not specified were subject to standardized pretreatment.

Example 1: Synthesis of (2R,3R,4S,5R)-2-{6-{2-[(E)-(1H-pyrrol-2-yl)methylene]hydrazino}-9H-purin-9-yl}-5- (hydroxymethyl)tetrahydrofuran-3,4-diol (Compound 1)

[0103] ##STR00010##

1.1 Synthesis of (2R,3R,45S,5R)-2-(6-hydrazino-9H-purin-9-yl)-5-(hydroxymethyl) tetrahydrofuran-3,4-diol (II)

[0104] To 10 ml of hydrazine hydrate (65 wt % aqueous solution), 5 g (0.018 mol) of (2R,3R,4S,5R)-2-(6-chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (vi) was added, heated to 70° C. while stirring, continued heating for 2 hours until the reactant (I) disappeared, the reaction progress was monitored by TLC (CH.sub.2Cl.sub.2:MeOH=3:1 (v/v)). Then, the reaction mixture was heated to 25° C., diluted with 2-propanol (50 ml) and stirred overnight. The separated precipitate was filtered to obtain 4.8 g of (2R,3R,4S,5R)-2-(6-hydrazino-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (vii) as white solid, which was directly used in the next reaction.

1.2 Synthesis of (2R,3R,4S,5R)-2-{6-{2-[(E)-(1H-pyrrol-2-yl)methylene]hydrazino}-9H-purin-9-yl}-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (Compound 1)

[0105] 0.5 g (0.0018 mol) of (2R,3R,4S,5R)-2-(6-hydrazino-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (II) and 0.19 g (0.002 mol) of pyrrole-2-carbaldehyde (1H-pyrrole-2-carbaldehyde, 1.1 equivalent) were mixed in methanol (20 ml) and heated by microwave at 70° C. for 30 minutes.

[0106] The crude product was precipitated from methanol. After filtration, the crude product was further purified by medium pressure preparative chromatography using C18 reverse phase column, and 323 mg of white solid (Compound 1) was obtained. m.p. 160° C.; .sup.1H NMR (DMSO-d.sub.6): δ (ppm) 11.52(s, 1H), 11.44(s, 1H), 8.50(s, 1H), 8.34(s, 1H), 8.28(s, 1H), 6.90(s, 1H), 6.43(s, 1H), 6.14(s, 1H), 5.95(d, 1H, J=6.0 Hz), 5.54(d, 1H, J=6.0 Hz), 5.40(dd, 1H, J=2.0 Hz, 4.8 Hz), 5.26(d, 1H, J=4.4 Hz), 4.65(dd, 1H, J=5.6 Hz, 5.6 Hz), 4.18(d, 1H, J=3.6 Hz), 3.99(d, 1H, J=2.8 Hz), 3.73-3.55(m, 2H); HRMS (ESI+) m/z [M+H].sup.+ calculated for C.sub.15H.sub.17N.sub.7O.sub.4: 360.1415; found: 360.1415.

[0107] The following compounds could be prepared by referring to the method of Example 1, using different reactants (such as the above-mentioned compound of Formula viii, various substituted formaldehydes) in place of pyrrole-2-carboxaldehyde in step 1.2.

Example 2: Synthesis of (2R,3S,4R,5R)-2-(hydroxymethyl)-5-{6-{2-[(E)-3-(methylthio)propylene]hydrazino}-9H-purin-9-yl}tetrahydrofuran-3,4-diol (Compound 2)

[0108] ##STR00011##

[0109] The method of step 1.2 in Example 1 was adopted, in which 3-(methylsulfanyl)propanal was used in place of pyrrole-2-carboxaldehyde to prepare Compound 2, and 424 mg of white solid (Compound 2) was obtained. m.p. 94° C.; .sup.1H NMR (DMSO-d.sub.6): δ (ppm) 11.42(s, 1H), 8.47(s, 1H), 8.31(s, 1H), 7.72(t, 1H, J=5.2 Hz), 5.93(d, 1H, J=6.0 Hz), 5.5-(d, 1H, J=6.0 Hz), 5.34(t, 1H, J=6.0 Hz), 5.23(d, 1H, J=4.8 Hz), 4.61(dd, 1H, J=5.2 Hz, 6.0 Hz), 4.16(d, 1H, J=3.6 Hz), 3.97(d, 1H, J=3.6 Hz), 3.71-3.54(m, 2H), 2.71(t, 2H, J=7.2 Hz), 2.58(t, 2H, J=6.2 Hz), 2.10(s, 3H); HRMS (ESI+) m/z [M+H].sup.+ calculated for C.sub.14H.sub.20N.sub.6O.sub.4S: 369.1340; found: 369.1340.

Example 3: Synthesis of N-{4-{(E)-{2-{9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-9H-purin-6-yl}hydrazino}methyl}phenyl}acetamide (Compound 3)

[0110] ##STR00012##

[0111] The method of step 1.2 in Example 1 was adopted, and 4-acetamidobenzaldehyde (N-(4-formylphenyl)acetamide) was used in place of pyrrole-2-carbaldehyde to prepare Compound 3, and 331 mg of white solid (Compound 3) was obtained.

[0112] m.p. 170° C.; .sup.1H NMR (DMSO-d.sub.6): δ (ppm) 11.72(s, 1H), 10.13(s, 1H), 8.53(s, 1H), 8.38(s, 1H), 7.67(s, 4H), 5.96(d, 1H, J=5.6 Hz), 5.51(d, 1H, J=6.0 Hz), 5.33(t, 1H, J=5.6 Hz), 5.24(d, 1H, J=4.8 Hz), 4.63(d, 1H, J=5.6 Hz), 4.17(s, 1H), 3.98(s, 1H), 3.72-3.55(m, 2H), 2.07(s, 3H); HRMS (ESI+) m/z [M+H].sup.+ calculated for C.sub.19H.sub.21N.sub.7O.sub.5: 428.1677; found: 428.1677.

Example 4: Synthesis of (2R,3R,4S,5R)-2-{6-{2-[(E)-3,4-bis(benzyloxy)benzylidene]hydrazino}-9H-purin-9-yl}-5hydroxymethyl)tetrahydrofuran-3,4-diol (Compound 4)

[0113] ##STR00013##

[0114] The method of step 1.2 in Example 1 was adopted, in which 3,4-bis(benzyloxy)benzaldehyde was used in place of pyrrole-2-carbaldehyde to prepare Compound 4, and 880 mg of white solid (Compound 4) was obtained. m.p. 186° C.; .sup.1H NMR (DMSO-d.sub.6): δ (ppm) 11.71(s, 1H), 8.54(s, 1H), 8.39(s, 1H), 8.27(s, 1H), 7.53-7.14(m, 13H), 5.95(s, 1H), 5.51(s, 1H), 5.34(s, 1H), 5.25(s, 1H), 5.21(s, 4H), 4.63(s, 1H), 4.17(s, 1H), 3.99(s, 1H), 3.72-3.58(m, 2H); HRMS (ESI+) m/z [M+H].sup.+ calculated for C.sub.31H.sub.30N.sub.6O.sub.6: 583.2300; found: 583.2298.

Example 5: Synthesis of (2R,3R,4S,5R)-2-{6-{2-{(E)-[5-(4-bromophenyl)furan-2-yl]methylene}hydrazino}-9H-purin-9-yl}-5- (hydroxymethyl)tetrahydrofuran-3,4-diol (Compound 5)

[0115] ##STR00014##

[0116] The method of step 1.2 in Example 1 was adopted, in which 5-(4-bromophenyl)furan-2-carbaldehyde was used in place of pyrrole-2-carbaldehyde to prepare Compound 5, and 712 mg of yellow solid (Compound 5) was obtained. m.p. 162° C.; .sup.1H NMR (DMSO-d.sub.6): δ (ppm) 11.99(br, 1H), 8.58(s, 1H), 8.44(s, 1H), 8.35(s, 1H), 7.76(d, 2H, J=8.4 Hz), 7.68(d, 2H, J=8.4 Hz), 7.22(d, 1H, J=3.6 Hz), 7.02(d, 1H, J=3.6 Hz), 5.98(d, 1H, J=6.0 Hz), 5.55-5.28(br, 3H), 4.65(s, 1H), 4.19(s, 1H), 4.01(s, 1H), 3.73-3.57(m, 2H); HRMS (ESI+) m/z [M +H].sup.+ calculated for C.sub.21H.sub.19BrN.sub.6O.sub.5: 515.0673; found: 515.0673.

Example 6: Synthesis of (2R,3R,4S,5R)-2-{6-{2-[(E)-2,4-bis(trifluoromethyl)benzylidene]hydrazino}-9H-purin-9-yl}-5- (hydroxymethyl)tetrahydrofuran-3,4-diol (Compound 6)

[0117] ##STR00015##

[0118] The method of step 1.2 in Example 1 was adopted, in which 2,4-bis(trifluoromethyl)benzaldehyde was used in place of pyrrole-2-carbaldehyde to prepare Compound 6, and 592 mg of white solid (Compound 6) was obtained. m.p. 200° C.; .sup.1H NMR (DMSO-d.sub.6): δ (ppm) 12.42(s, 1H), 8.78(s, 1H), 8.65(s, 1H), 8.62(d, 1H, J=8.4 Hz), 8.50(s, 1H), 8.19(d, 1H, J=8.4 Hz), 8.08(s, 1H), 6.01(d, 1H, J=6.0 Hz), 5.57(d, 1H, J=6.0 Hz), 5.31-5.28(m, 2H), 4.65(dd, 1H, J=4.8 Hz, 6.0 Hz), 4.20(d, 1H, J=3.6 Hz), 4.01(d, 1H, J=3.2 Hz), 3.75-3.57(m, 2H); HRMS (ESI+) m/z [M+H].sup.+ calculated for C.sub.19H.sub.16F.sub.6N.sub.6O.sub.4: 507.1210; found: 507.1209.

Example 7: Synthesis of (2R,3R,4S,5R)-2-{6-{2-{(E)-4-[(4-fluorobenzyl)oxy]benzylidene}hydrazino}9H-purin-9-yl}-5- (hydroxymethyl)tetrahydrofuran-3,4-diol (Compound 7)

[0119] ##STR00016##

[0120] The method of step 1.2 in Example 1 was adopted, in which 4-(4-fluorobenzyloxy)benzaldehyde (4-[(4-fluorophenyl)methoxy]benzaldehyde) was used in place of pyrrole-2-carboxaldehyde to prepare Compound 7, and 859 mg of white Solid (Compound 7) was obtained. m.p. 206° C.; .sup.1H NMR (DMSO-d.sub.6): δ (ppm) 11.69(s, 1H), 8.54(s, 1H), 8.38(s, 1H), 8.31(s, 1H), 7.70(d, 2H, J=8.8 Hz), 7.53(t, 2H, J=5.6 Hz), 7.24(t, 2H, J=8.8 Hz), 7.11(d, 2H, J=8.4 Hz), 5.97(d, 1H, J=6.0 Hz), 5.52(d, 1H,J=6.4 Hz), 5.34(t, 1H, J=5.20 Hz), 5.24(d, 1H, J=4.4 Hz), 5.14(s, 2H), 4.63(d, 1H, J=5.6 Hz), 4.18(s, 1H), 3.99(s, 1H), 3.72-3.56(m, 2H); HRMS (ESI+) m/z [M+H].sup.+ calculated for C.sub.24H.sub.23FN.sub.6O.sub.5: 495.1787; found: 495.1787.

Example 8: Synthesis of (2R,3R,4S,5R)-2-{6-{2-[(E)-3-(benzyloxy)benzylidene]hydrazino}-9H-purin-9-yl}-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (Compound 8)

[0121] ##STR00017##

[0122] The method of step 1.2 in Example 1 was adopted, in which 3-(benzyloxy)benzaldehyde was used in place of pyrrole-2-carbaldehyde to prepare Compound 8, and 568 mg of white solid (Compound 8) was obtained. m.p. 140° C.; .sup.1H NMR (DMSO-d.sub.6): δ (ppm) 11.80(s, 1H), 8.57(s, 1H), 8.40(s, 1H), 8.32(s, 1H), 7.51-7.32(m, 8H), 7.07-7.04(m, 1H), 5.97(d, 1H, J=5.6 Hz), 5.49(d, 1H, J=6.4 Hz), 5.29(t, 1H, J=5.20 Hz), 5.21(d, 1H, J=4.8 Hz), 5.17(s, 2H), 4.63(dd, 1H, J=5.6 Hz, 5.6 Hz), 4.18(dd, 1H, J=3.6 Hz, 4.8 Hz), 3.99(d, 1H, J=3.2 Hz), 3.73-3.55(m, 2H); HRMS (ESI+) m/z [M+H].sup.+ calculated for C.sub.24H.sub.24N.sub.6O.sub.5: 477.1881; found: 477.1883.

Example 9: Synthesis of (2R,3S,4R,5R)-2-(hydroxymethyl)-5-{6-{2-[(E)-4-(pyridin-2-yl) benzylidene]hydrazino}-9H-purin-9-yl}tetrahydrofuran-3,4-diol (Compound 9)

[0123] ##STR00018##

[0124] The method in step 1.2 of Example 1 was adopted, in which 4-(pyridin-2-yl)benzaldehyde was used in place of pyrrole-2-carbaldehyde to prepare Compound 9, and 652 mg of white solid (Compound 9) was obtained. m.p. 236° C.; .sup.1H NMR (DMSO-d.sub.6): δ (ppm) 11.88(s, 1H), 8.70(d, 1H, J=5.6 Hz), 8.58(s, 1H), 8.43(s, 2H), 8.20(d, 2H, J=8.4 Hz), 8.03(d, 1H,J=8.0 Hz), 7.92(d, 1H, J=9.2 Hz), 7.88(d, 2H, J=8.4 Hz), 7.40-7.37(m, 1H), 5.99(d, 1H, J=6.0 Hz), 5.51(d, 1H,J=6.4 Hz), 5.30(t, 1H, J=6.4 Hz), 5.22(d, 1H, J=4.8 Hz), 4.64(dd, 1H, J=5.6 Hz, 5.6 Hz), 4.19(dd, 1H, J=3.6 Hz, 4.4 Hz), 4.00(d, 1H, J=3.2 Hz), 3.73-3.57(m, 2H); HRMS (ESI+) m/z [M+H].sup.+ calculated for C.sub.22H.sub.21N.sub.7O.sub.4: 448.1728; found: 448.1729.

Example 10: Synthesis of (2R,3R,4S,5R)-2-{6-{2-[(E)[1,1′-biphenyl]-4-ylmethylene]hydrazino}-9H-purin-9-yl}-5- hydroxymethyl)tetrahydrofuran-3,4-diol (Compound 10)

[0125] ##STR00019##

[0126] The method of step 1.2 in Example 1 was adopted, in which 4-phenylbenzaldehyde was used in place of pyrrole-2-carboxaldehyde to prepare Compound 10, and 698 mg of white solid (Compound 10) was obtained. m.p. 170° C.; .sup.1H NMR (DMSO-d.sub.6): δ (ppm) 11.87(s, 1H), 8.59(s, 1H), 8.43(s, 2H), 7.86 (d, 2H, J=8.0 Hz), 7.78(d, 2H, J=8.4 Hz), 7.74(d, 2H, J=7.2 Hz), 7.51(t, 2H, J=7.2 Hz), 7.41(t, 1H, J=7.6 Hz), 5.99(d, 1H, J=5.6 Hz), 5.54(d, 1H, J=6.4 Hz), 5.34(t, 1H, J=5.6 Hz), 5.26(d, 1H, J=4.8 Hz), 4.64(dd, 1H, J=5.2 Hz, 5.6 Hz), 4.19(dd, 1H, J=3.6 Hz, 4.4 Hz), 4.00(d, 1H, J=4.0 Hz), 3.74-3.57(m, 2H); HRMS (ESI+) m/z [M+H].sup.+ calculated for C.sub.23H.sub.22N.sub.6O.sub.4: 447.1775; found: 447.1775.

Example 11: Synthesis of (2R,3S,4R,5R)-2-(hydroxymethyl)-5-{6-{2-[(E)-4-(pyrrolidin-1-yl) benzylidene]hydrazino}-9H-purin-9-yl}tetrahydrofuran-3,4-diol (Compound 11)

[0127] ##STR00020##

[0128] The method of step 1.2 in Example 1 was adopted, in which 4-(1-pyrrolidin-1-yl)benzaldehyde was used in place of pyrrolidin-2-carbaldehyde to prepare Compound 11, and 664 mg of white solid (Compound 11) was obtained. m.p. 202° C.; .sup.1H NMR (DMSO-d.sub.6): δ (ppm) 11.43(s, 1H), 8.48(s, 1H), 8.33(s, 1H), 8.24(s, 1H), 7.54 (d, 2H, J=8.4 Hz), 6.59(d, 2H, J=8.4 Hz), 5.95(d, 1H, J=6.4 Hz), 5.48(d, 1H, J=6.0 Hz), 5.36(t, 1H, J=4.8 Hz), 5.20(d, 1H, J=4.8 Hz), 4.63(d, 1H, J=5.2 Hz), 4.17(d, 1H, J=2.8 Hz), 3.98(d, 1H, J=4.0 Hz), 3.72-3.55(m, 2H), 3.3(t, 4H, J=6.6 Hz), 1.97(s, 4H); HRMS (ESI+) m/z [M+H].sup.+ calculated for C.sub.21H.sub.25N.sub.7O.sub.4: 440.2041; found: 440.2039.

Example 12: Synthesis of (2R,3R,4S,5R)-2-{6-{2-[(E)-4-(1H-imidazol-1-yl)benzylidene]hydrazino}-9H-purin-9-yl}-5(hydroxymethyl)tetrahydrofuran-3,4-diol (Compound 12)

[0129] ##STR00021##

[0130] The method of step 1.2 in Example 1 was adopted, in which 4-(1H-imidazol-1-yl)benzaldehyde was used in place of pyrrole-2-carboxaldehyde to prepare Compound 12, and 683 mg white solid (Compound 12) was obtained. m.p. 222° C.; .sup.1H NMR (DMSO-d.sub.6): δ (ppm) 11.87(s, 1H), 8.57(s, 1H), 8.41(s, 1H), 8.38(s, 1H), 8.35(s, 1H), 7.90 (d, 2H, J=8.4 Hz), 7.83(s, 1H), 7.76(d, 2H, J=8.8 Hz), 7.14(s, 1H), 5.98(d, 1H, J=6.0 Hz), 5.50(d, 1H, J=6.0 Hz), 5.29(t, 1H, J=6.0 Hz), 5.22(d, 1H, J=4.8 Hz), 4.63(dd, 1H, J=5.2 Hz, 5.6 Hz), 4.19(dd, 1H, J=3.6 Hz, 4.4 Hz), 3.99(d, 1H, J=3.6 Hz), 3.74-3.56(m, 2H); HRMS (ESI+) m/z [M+H].sup.+ calculated for C.sub.20H.sub.20N.sub.8O.sub.4: 437.1680; found: 437.1714.

Example 13: Synthesis of (2R,3S,4R,5R)-2-(hydroxymethyl)-5-{6-{2-[(E)-4-propoxybenzylidene]hydrazino}-9H-purin-9-yl}tetrahydrofuran-3,4-diol (Compound 13)

[0131] ##STR00022##

[0132] The method of step 1.2 in Example 1 was adopted, in which 4-propoxybenzaldehyde was used in place of pyrrole-2-carboxaldehyde to prepare Compound 13, and 686 mg of white solid (Compound 13) was obtained. m.p. 202° C.; .sup.1H NMR (DMSO-d.sub.6): δ (ppm) 11.67(s, 1H), 8.54(s, 1H), 8.38(s, 1H), 8.31(s, 1H), 7.68 (d, 2H, J=8.4 Hz), 7.01(d, 2H, J=8.8 Hz), 5.97(d, 1H, J=5.6 Hz), 5.52(d, 1H,J=6.0 Hz), 5.35(s, 1H), 5.24(d, 1H, J=4.8 Hz), 4.63(d, 1H, J=4.8 Hz), 4.18(d, 1H, J=3.2 Hz), 3.99(s, 2H), 3.96(s, 1H), 3.72-3.57(m, 2H), 1.75(sext, 2H, J=7.2 Hz, 6.8 Hz, 6.4 Hz), 1.00(t, 3H, J=7.6 Hz); HRMS (ESI+) m/z [M+H].sup.+ calculated for C.sub.20H.sub.24N.sub.6O.sub.5: 429.1881; found: 429.1881.

Example 14: Synthesis of (2R,3S,4R,5R)-2-(hydroxymethyl)-5-{6-{2-[(E)-4-(trifluoromethyl) benzylidene]hydrazino}-9H-purin-9-yl}tetrahydrofuran-3,4-diol (Compound 14)

[0133] ##STR00023##

[0134] The method of step 1.2 in Example 1 was adopted, in which 4-(trifluoromethyl)benzaldehyde was used in place of pyrrole-2-carboxaldehyde to prepare Compound 14, and 639 mg of white solid was obtained. m.p. 182° C.; .sup.1H NMR (DMSO-d6): δ (ppm) 12.06(s, 1H), 8.60(s, 1H), 8.45(s, 1H), 8.42(s, 1H), 7.97 (d, 2H, J=8.4 Hz), 7.82(d, 2H, J=8.8 Hz), 5.99(d, 1H, J=5.6 Hz), 5.54(d, 1H,J=5.6 Hz), 5.31(t, 1H, J=5.2 Hz), 5.26(d, 1H, J=4.8 Hz), 4.63(dd, 1H, J=5.2 Hz, 5.6 Hz), 4.19(dd, 1H, J=3.6 Hz, 4.4 Hz), 3.96(d, 1H, J=3.6 Hz), 3.73-3.59(m, 2H); HRMS (ESI+) m/z [M+H].sup.+ calculated for C.sub.18H.sub.17F.sub.3N.sub.6O.sub.4: 439.1336; found: 439.1336.

Example 15: Synthesis of (2R,3R,4S,5R)-2-{6-{2-[(E)-(5-bromopyridin-2-yl)methylene]hydrazino}-9H-purin-9-yl}-5- hydroxymethyl)tetrahydrofuran-3,4-diol (Compound 15)

[0135] ##STR00024##

[0136] The method in step 1.2 of Example 1 was adopted, in which 5-bromo-2-pyridinaldehyde (5-bromopyridine-2-carbaldehyde) was used in place of pyrrole-2-carbaldehyde to prepare Compound 15, and 590 mg of yellow solid (Compound 15) was obtained. m.p. 211° C.; .sup.1H NMR (DMSO-d.sub.6): δ (ppm) 12.14(s, 1H), 8.72(s, 1H), 8.61(s, 1H), 8.45(s, 1H), 8.36(s, 1H), 8.15 (d, 1H, J=8.0 Hz), 8.03(d, 1H, J=8.8 Hz), 5.99(d, 1H, J=6.0 Hz), 5.50(d, 1H,J=6.0 Hz), 5.25(t, 1H, J=6.0 Hz), 5.22(d, 1H, J=4.8 Hz), 4.62(dd, 1H, J=5.2 Hz, 5.6 Hz), 4.19(dd, 1H, J=3.6 Hz, 4.8 Hz), 3.99(d, 1H, J=3.2 Hz), 3.73-3.56(m, 2H); HRMS (ESI+) m/z [M+H].sup.+ calculated for C.sub.16H.sub.16BrN.sub.7O.sub.4: 450.0520; found: 450.0520.

Example 16: Synthesis of (2R,3S,4R,5R)-2-(hydroxymethyl)-5-{6-{2-[(E)-thiazol-5-yl-methylene]hydrazino}-9H-purin-9-yl}tetrahydrofuran-3,4-diol (Compound 16)

[0137] ##STR00025##

[0138] The method in step 1.2 of Example 1 was obtained, in which thiazole-5-formaldehyde (1,3-thiazole-5-carbaldehyde) was used in place of pyrrole-2-carbaldehyde to prepare Compound 16, and 440 mg of white solid (Compound 16) was obtained. m.p. 224° C.; .sup.1H NMR (DMSO-d.sub.6): δ (ppm) 12.00(s, 1H), 9.13(s, 1H), 8.65(s, 1H), 8.56(s, 1H), 8.42(s, 1H), 8.20 (s, 1H), 5.96(d, 1H, J=6.0 Hz), 5.52(d, 1H ,J=6.0 Hz), 5.30(s, 1H), 5.24(d, 1H, J=4.8 Hz), 4.62(dd, 1H, J=5.2 Hz, 5.6 Hz), 4.17(dd, 1H, J=3.6 Hz), 3.98(d, 1H, J=3.6 Hz), 3.72-3.55(m, 2H); HRMS (ESI+) m/z [M+H].sup.+ calculated for C.sub.14H.sub.15N.sub.7O.sub.4S: 378.0979; found: 378.0978.

Example 17: Synthesis of (2R,3R,4S,5R)-2-{6-{2-{(1E,2E)-3-[4-(dimethylamino)phenyl]allylidene}hydrazino}-9H-purin-9-yl}-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (Compound 17)

[0139] ##STR00026##

[0140] The method in step 1.2 of Example 1 was adopted, in which 4-dimethylamino-cinnamaldehyde ((2E)-3-[4-(dimethylamino)phenyl]prop-2-enal) was used in place of pyrrole-2-carboxaldehyde to prepare Compound 17, and 490 mg of yellow solid (Compound 17) was obtained. m.p. 172° C.; .sup.1H NMR (DMSO-d.sub.6): δ (ppm) 11.57(br, 1H), 8.51(d, 1H, J=3.6 Hz), 8.37(d, 1H, J=6.0 Hz), 8.16(br, 1H), 7.44(d, 1H, J=8.4 Hz), 7.31(d, 1H, J=8.8 Hz), 6.83-6.70(m, 4H), 5.95(d, 1H, J=5.6 Hz), 5.52(d, 1H, J=6.0 Hz), 5.35(dd, 1H, J=5.2 Hz, 6.0 Hz), 5.24(d, 1H, J=4.4 Hz), 4.63(dd, 1H, J=4.8 Hz, 6.0 Hz), 4.17(d, 1H, J=3.6 Hz), 3.98(d, 1H, J=3.2 Hz), 3.71-3.56(m, 2H), 2.95(s, 6H); HRMS (ESI+) m/z [M+H].sup.+ calculated for C.sub.21H.sub.25N.sub.7O.sub.4: 440.2041; found: 440.2044.

Example 18: Synthesis of (2R,3R,4S,5R)-2-{6-{2-[(E)-4-chloro-3-(trifluoromethyl)benzylidene]hydrazino}-9H-purin-9-yl}-5- hydroxymethyl)tetrahydrofuran-3,4-diol (Compound 18)

[0141] ##STR00027##

[0142] The method of step 1.2 in Example 1 was adopted, in which 4-chloro-3-(trifluoromethyl)benzaldehyde was used in place of pyrrole-2-carboxaldehyde to prepare Compound 18, and 600 mg of white solid was obtained. m.p. 196° C.; .sup.1H NMR (DMSO-d.sub.6): δ (ppm) 12.10(s, 1H), 8.60(s, 1H), 8.45(s, 1H), 8.40(s, 1H), 8.22 (s, 1H), 8.06(d, 1H, J=8.4 Hz), 7.82(d, 1H, J=8.4 Hz), 5.99(d, 1H, J=6.0 Hz), 5.53(d, 1H,J=5.6 Hz), 5.29(t, 1H, J=5.6 Hz), 5.25(d, 1H, J=4.8 Hz), 4.63(dd, 1H, J=5.2 Hz, 6.0 Hz), 4.19(dd, 1H, J=3.6 Hz, 4.8 Hz), 3.99(d, 1H, J=3.6 Hz), 3.73-3.56(m, 2H); HRMS (ESI+) m/z [M+H].sup.+ calculated for C.sub.18H.sub.16ClF.sub.3N.sub.6O.sub.4: 473.0946; found: 473.0945.

Example 19: Synthesis of (2R,3R,4S,5R)-2-{6-{2-[(E)-4-(diphenylamino)benzylidene]hydrazino}-9H-purin-9-yl}-5- hydroxymethyl)tetrahydrofuran-3,4-diol (Compound 19)

[0143] ##STR00028##

[0144] The method of step 1.2 in Example 1 was obtained, in which 4-(N,N-diphenylamino)benzaldehyde (4-(diphenylamino)benzaldehyde) was used in place of pyrrole-2-carbaldehyde to prepare Compound 19, and 460 mg of white solid (Compound 19) was obtained. m.p. 160° C.; .sup.1H NMR (DMSO-d.sub.6): δ (ppm) 11.66(s, 1H), 8.51(s, 1H), 8.37(s, 1H), 8.31(s, 1H), 7.63(d, 2H, J=8.4 Hz), 7.35(t, 4H, J=8.0 Hz), 7.13-7.07(m, 6H), 6.99(d, 2H, J=8.8 Hz), 5.96(d, 1H, J=6.0 Hz), 5.48(d, 1H,J=6.0 Hz), 5.31(t, 1H, J=6.0 Hz), 5.20(d, 1H, J=4.4 Hz), 4.62(dd, 1H, J=5.2 Hz, 5.6 Hz), 4.17(dd, 1H, J=3.6 Hz, 4.8 Hz), 3.98(d, 1H, J=3.2 Hz), 3.72-3.55(m, 2H); HRMS (ESI+) m/z [M+H].sup.+ calculated for C.sub.29H.sub.27N.sub.7O.sub.4: 538.2197; found: 538.2198.

Example 20: Synthesis of (2R,3R,4S,5R)-2-{6-{2-[(E)-(2-butyl-5-chloro-1H-imidazol-4-yl)methylene]hydrazino}-9H-purin-9-yl}-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (Compound 20)

[0145] ##STR00029##

[0146] The method in step 1.2 of Example 1 was adopted, in which 2-butyl-5-chloro-1H-imidazole-4-carbaldehyde was used in place of pyrrole-2-carbaldehyde to prepare Compound 20, and 640 mg of white solid (Compound 20) was obtained. m.p. 178° C.; .sup.1H NMR (DMSO-d.sub.6): δ (ppm) 12.79(s, 1H), 11.78(s, 1H), 8.53(s, 1H), 8.38(s, 1H), 8.36(s, 1H), 5.96(d, 1H, J=6.0 Hz), 5.53(d, 1H, J=6.4 Hz), 5.36(s, 1H), 5.26(d, 1H, J=4.4 Hz), 4.64(dd, 1H, J=5.2 Hz, 5.6 Hz), 4.17(d, 1H, J=3.6 Hz), 3.99(d, 1H, J=2.8 Hz), 3.71-3.56(m, 2H), 2.66(t, 2H, J=7.6 Hz), 1.62(quint, 2H, J=7.6 Hz,7.2 Hz), 1.29(sext, 2H, J=7.6 Hz, 7.6 Hz, 7.2 Hz), 0.891(t, 3H, J=7.2 Hz); HRMS (ESI+) m/z [M+H].sup.+ calculated for C.sub.18H.sub.23ClN.sub.8O.sub.4: 451.1604; found: 451.1606.

Example 21: Synthesis of (2R,3R,4S,5R)-2-{6-{2-[(1E,2E,4E)-deca-2,4-dien-1-ylidene]hydrazino}-9H-purin-9-yl}-5(hydroxymethyl)tetrahydrofuran-3,4-diol (Compound 21)

[0147] ##STR00030##

[0148] The method of step 1.2 in Example 1 was adopted, in which (2E,4E)-deca-2,4-dienal was used in place of pyrrole-2-carboxaldehyde to prepare Compound 21, and 112 mg of white solid (Compound 21) was obtained. m.p. 178° C.; .sup.1H NMR (DMSO-d.sub.6): δ (ppm) 11.59(s, 1H), 8.50(s, 1H), 8.33(s, 1H), 8.04(d, 1H, J=9.6 Hz), 6.61-6.00(m, 3H), 5.93(d, 1H, J=5.6 Hz), 5.50(d, 1H, J=6.4 Hz), 5.32(t, 1H, J=4.8 Hz), 5.23(d, 1H, J=4.8 Hz), 4.61(dd, 1H, J=5.2 Hz, 6.0 Hz), 4.16(d, 1H, J=3.6 Hz), 3.97(d, 1H, J=3.2 Hz), 3.71-3.54(m, 2H), 2.13(dd, 1H, J=6.8 Hz, 7.2 Hz), 1.43-1.23(m, 8H), 0.88(t, 3H, J=6.8 Hz); HRMS (ESI+) m/z [M+H].sup.+ calculated for C.sub.20H.sub.28N.sub.6O.sub.4: 417.2245; found: 417.2245.

Example 22: Synthesis of (2R,3R,4S,5R)-2-{6-{2-[(E)-cyclohexylmethylene]hydrazino}-9H-purin-9-yl}-5-(hydroxylmethyl)tetrahydrofuran-3,4diol (Compound 22)

[0149] ##STR00031##

[0150] The method of step 1.2 in Example 1 was adopted, in which cyclohexanecarbaldehyde was used in place of pyrrole-2-carbaldehyde to prepare Compound 22, and 300 mg of white solid (Compound 22) was obtained. m.p. 132° C.; .sup.1H NMR (DMSO-d.sub.6): δ (ppm) 11.25(s, 1H), 8.46(s, 1H), 8.30(s, 1H), 7.60(d, 1H, J=4.8 Hz), 5.93(d, 1H, J=6.4 Hz), 5.50(d, 1H, J=6.0 Hz), 5.35(s, 1H), 5.23(d, 1H, J=4.4 Hz), 4.61(dd, 1H, J=5.6 Hz, 5.6 Hz), 4.16(d, 1H, J=3.2 Hz, 4.4 Hz), 3.97(dd, 1H, J=3.2 Hz, 3.6 Hz), 3.70-3.54(m, 2H), 2.27(d, 1H, J=4.8 Hz), 1.80-1.62(m, 5H), 1.35-1.18(m, 5H); HRMS (ESI+) m/z [M+H].sup.+ calculated for C.sub.17H.sub.24N.sub.6O.sub.4: 377.1932; found: 377.1934.

Example 23: Radioligand Binding Test

1) Experimental Materials

[0151] [3H]CGS21680 (2-[p-(2-carboxyethyl)phenylethylamino]-5′-N-ethylformamidoadenosine, [carboxy-1-ethyl-3H(N)]; 250 μCi) was purchased from PerkinElmer Research Products (Boston, Mass.).

[0152] Cell membrane stably transfected with (human) A.sub.2A adenosine receptor was prepared in HEK-293 cells. The cell membrane was obtained from PerkinElmer Research Products (Boston, Mass.).

[0153] CGS21680 (2-[p-(2-carboxyethyl)phenylethylamino]-5′-N-ethylformamidoadenosine) was purchased from Selleck (Shanghai, CN).

[0154] All other reagents were of analytical grade and obtained from commercial sources.

2) Experimental Method

[0155] The A.sub.2A adenosine receptors used were all expressed in the cell membrane. The compound was diluted 3 times serially with DMSO (Solarbio, D8371-250 ml) so as to generate a compound source plate with 10 different concentrations (10 μM, 3.3 μM, 1.1 μM, 0.0412 μM, 0.0137 μM, 0.0046 μM, 0.0015 μM, 0.0005 μM); 250 nL of the compound was added to a 384-well Opti-plate, sealed with parafilm; to 1 mL of detection buffer (50 mM Tris-HCl pH 7.4, 10 mM MgCl.sub.2, 1 mM EDTA, 1 μg/mL adenosine deaminase), 20 U of hA.sub.2A HEK-293 cell membrane was added for dilution; to the diluted cell membrane, 0.75 μCi [3H]CGS 21680 (final 25 nM) was added and mixed well; 50 μL of the prepared cell membrane diluent was transferred to a 384-well Opti-plate containing a new compound, and incubated at 25° C. for 90 minutes; to a UNIFILTER-96 GF/B filter plate, 100 μL of 0.5% polyethyleneimine solution (PEI) was added to soak at 4° C. for 90 min; then Cell Harvester was used to transfer 500 μL of washing buffer/well (50 mM Tris-HCl pH 7.4, 154 mM NaCl), and the UNIFILTER-96 GF/B filter plate was washed twice; the mixture system in the Opti-plate was transferred to the washed UNIFILTER-96 GF/B filter plate; 500 μL of washing buffer/well (50 mM Tris-HCl pH 7.4, 154 mM NaCl) was used to wash the UNIFILTER-96 GF/B filter plate 9 times; incubation was performed in a 37° C. incubator for 3 min; 40 μL of ULTIMA GOLD scintillation solution (Perkin Elmer, Cat #77-16061) was added to each well, and MicroBeta liquid scintillation counter (PerkinElmer) was used to read CPM (count per minute) value. The specific binding percentage of [3H]CGS21680 was calculated according to the CPM value, % specific binding of [3H]CGS21680=(CPM.sub.sample−CPM.sub.Low Control)/(CPM.sub.High Control−CPM.sub.Low Control)*100, in which

[0156] High Control was 0.5% DMSO, Low Control was 100 μM CGS21680. The IC.sub.50 value was calculated based on the compound concentration and the specific binding percentage of [3H]CGS21680 by curve fitting.

3) Experimental Results

[0157] The inhibition constant (K.sub.i) value was calculated from the IC.sub.50 value according to the Cheng and Prusoff equation, K.sub.i=IC.sub.50/(1+[S]/K.sub.m), in which [S] was the concentration of the radioligand (25 nM), and K.sub.m was the human A.sub.2AAR dissociation constant (22 nM) of [3H]CGS21680. The inhibition constant K.sub.i values for Compounds 1 to 20 of the present invention binding to A.sub.2A adenosine receptor were shown in Table 1.

TABLE-US-00001 TABLE 1 Binding test results of compounds and A.sub.2A adenosine receptor Compound K.sub.i (nM) Compound 1 945.1 Compound 2 2147 Compound 3 3.6 Compound 4 >10,000 Compound 5 353 Compound 6 1.2 Compound 7 13.8 Compound 8 236 Compound 9 4593 Compound 10 1903 Compound 11 2.0 Compound 12 15.4 Compound 13 4470 Compound 14 520 Compound 15 3.4 Compound 16 15.8 Compound 17 1.4 Compound 18 1466 Compound 19 5581 Compound 20 998.4 Compound 21 1.2 Compound 22 86.6

Example 24: Adenosine Receptor A.SUB.2A .cAMP Test

1) Experimental Materials

[0158] Experimental reagents and consumables: DMEM/F12, G418, Penicillin-Streptomycin, Versene Solution, HEPES, Hank's Buffered Saline Solution, PBS (pH 7.4, 1×, sterile), FBS, BSA Stabilizer 7.5%, Rolipram, NECA, were purchased from Gibico, Hyclone and Sigma, respectively. LANCE® Ultra cAMP kit (Eu-cAMP tracer, Ulight-anti-cAMP reagent, cAMP detection buffer) and hADORA.sub.2A-HEK293 cells were purchased from PerkinElmer Research Products (Boston, Mass.). All other reagents were of analytical grade and obtained from commercial sources. 384-well polypropylene microplate and 384-well white solid plate were purchased from Labcyte and Corning, respectively.

[0159] Experimental instruments: TECAN automated pipetting workstation, Echo ultrasonic pipetting system, and EnVison microplate reader were purchased from TECAN, Labcyte and Envision, respectively.

2) Experimental Method

[0160] Cells stably expressing human adenosine receptor A.sub.2A (hADORA.sub.2A-HEK293 cells) were cultured in DMEM/F12 medium containing 10% FBS, 1× Penicillin-Streptomycin and 400 μg/ml G418 in a 37° C., 5% CO.sub.2 environment. Before the experiment, the cells were digested with Versene solution, and the cells were collected by centrifugation at 200 g at room temperature for 5 minutes, and finally resuspended with detection buffer (Hank's buffered saline solution, containing 5 mM HEPES, 0.1% BSA stabilizer and 10 μM Rolipram, pH 7.4). TECAN automated pipetting workstation was used to prepare a compound source plate by 3-fold diluting the compound in a 384-well polypropylene microplate with DMSO to form 11 concentration points, in which the 11 concentration points of the compound were 10 mM, 3.33 mM, 1.11 mM, 0.37 mM, 0.12 mM, 0.041 mM, 0.013 mM, 4.57×10.sup.−3 mM, 1.52×10.sup.−3 mM, 5×10.sup.−4 mM and 1.7×10.sup.−4 mM, respectively. Echo ultrasonic pipetting system (Labcyte) was used to transfer the test compound from the compound source plate to the detection plate, in which the volume of the compound transferred was 10 nl/well. The hADORA.sub.2A-HEK293 cell suspension was diluted with detection buffer to 30,000 cells/ml, and the cell suspension was transferred to the detection plate at a volume of 10 μl/well (300 cells/well). The detection plate was centrifuged at 150 g for 1 minute and pre-incubated at room temperature for 30 minutes. Eu-cAMP tracer working solution (40 μl of Eu-cAMP tracer, 1.96 ml of cAMP detection buffer) was added to the detection plate (5 μl/well), and then Ulight-anti-cAMP working solution (13 μl of Ulight-anti-cAMP reagent, and 1.95 ml of cAMP detection buffer) was added to the detection plate (5 μl/well). The detection plate was rotated at 150 g for 30 seconds, and incubated at room temperature for 30 minutes. EnVison microplate reader (EnVision multimode plate reader, PerkinElmer) was used to test the level of cyclic adenosine monophosphate in the final solution (λ.sub.ex=320 nm, λ.sub.em=665 nm & 615 nm). The EC.sub.50 (nM) value of the compound interacting with A.sub.2A adenosine receptor to stimulate the production of a level of cyclic adenosine monophosphate was calculated. The compound A.sub.2A receptor agonist titer was expressed as the EC.sub.50 (nM) value of the compound interacting with the A.sub.2A adenosine receptor to stimulate the production of a level of cyclic adenosine monophosphate.

3) Experimental Results

[0161] The EC.sub.50 (nM) values of the test compounds interacting with A.sub.2AAR to stimulate AMP level were shown in Table 2. The results showed that Compounds 7, 15 and 16 prepared by the present invention were all hA.sub.2AAR agonists. When Compounds 7, 15 and 16 interacted with A.sub.2AAR, their inhibition constant K.sub.i values and EC.sub.50 values of stimulating cAMP were basically in the same nanomolar range.

TABLE-US-00002 TABLE 2 Results of EC.sub.50 values of A.sub.2A agonist function determination of compounds Compound cAMP EC.sub.50 (nM) Compound 7 18.6 Compound 15 7.3 Compound 16 43.5

Example 25: Animal Experiment of Blood-Brain Barrier Opening Method

1) Experimental Materials

[0162] Fluorescein-labeled dextran FITC-Dextran (CAS: 60842-46-8) with a molecular weight of 10,000 MW was purchased from Tixiai (Shanghai) Chemical Industry Development Co., Ltd.; PBS solution and experimental animal SD rats were obtained from commercial sources.

2) Experimental Method

[0163] FITC-Dextran solution was prepared with PBS to obtain six concentration gradients (0.001, 0.01, 0.1, 1, 0.5, 10 μg/ml), and a FITC-Dextran concentration standard curve was prepared by using microplate reader (λ.sub.ex=490 nm, λ.sub.em=520 nm); 10 mg/ml FITC-Dextran solution was separately prepared, Compound 5 was added to PBS solution to make 1 mg/ml solution, 1 ml of 10 mg/ml FITC-Dextran solution and 1 ml of 1 mg/ml Compound 5 PBS solution were taken to make an administration solution; 1 ml of 10 mg/ml FITC-Dextran solution and 1 ml of PBS solution taken to make a blank control solution; 6 SD rats were injected with 2 ml of the administration solution respectively in the tail vein, while another 6 SD rats were injected with 2 ml of the blank control solution in the tail vein; after 30 minutes, the brain tissues of all SD rats were taken out, homogenized and centrifuged at 10,000 rpm for 15 minutes, and the supernatants were taken for testing; and a microplate reader (λ.sub.ex=490 nm, λ.sub.em=520 nm) was used for the fluorescence detection of the solutions to be tested.

3) Experimental Results

[0164] The fluorescence values measured by the microplate reader were converted into the corresponding FITC-Dextran average concentrations according to the obtained FITC-Dextran concentration standard curve. The results were shown in Table 3. The results showed that the macromolecule FITC-Dextran itself could pass through the blood-brain barrier, while the FITC-Dextran added with Compound 5 could enter the brain through the BBB, indicating that Compound 5 could open the blood-brain barrier.

TABLE-US-00003 TABLE 3 Results of FITC-Dextran concentration detection in the brain of SD rats PBS solution containing Compound 7 Blank control solution FITC-Dextran 0.057 0.021 concentration (μg/ml)

[0165] Although the specific embodiments of the present disclosure have been described in details, those skilled in the art will understand that according to all the teachings that have been disclosed, various modifications and substitutions can be made to those details, and these changes are within the protection scope of the present disclosure. The full scope of the disclosure is given by the appended claims and any equivalents thereof. The publications and patent documents cited in this disclosure are incorporated herein by reference.