 Purine Derivatives
专利摘要:
The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and a process for its preparation, an intermediate used in the preparation, a complex comprising the same, and the use of these compounds as adenosine A2a receptor agonists. <Formula I> 公开号:KR20030036138A 申请号:KR1020027010481 申请日:2001-02-09 公开日:2003-05-09 发明作者:사이먼 존 맨텔；샌드라 마리나 모노간；피터 토마스 스티븐슨 申请人:화이자 인코포레이티드； IPC主号:
专利说明:
Purine Derivatives [1] The present invention relates to certain purine derivatives. More particularly, the present invention relates to purin-2-ylcarboxamide derivatives and methods for their preparation, compositions, uses, and intermediates used in their preparation. These derivatives are selective functional agents of the human adenosine A2a receptor and can be used as anti-inflammatory agents, especially in the treatment of diseases of the respiratory tract. [2] Adenosine is a ubiquitous molecule that has a central role in mammalian metabolism. Independently, adenosine acts on multiple surface receptors to produce a variety of responses. Adenosine receptor classification showed the presence of four or more subtypes: A1, A2a, A2b and A3. Stimulation of the surface of human neutrophils of adenosine A2 receptors has been reported to strongly inhibit a range of neutrophil function. Activated neutrophils can damage lung tissue by the release of reactive oxygen species such as superoxide anionic radicals (O 2 − ) and granular products such as human neutrophil elastase (HNE), among other inflammatory mediators. In addition, activated neutrophils perform both de novo synthesis and release of arachidonate products such as leukotriene B 4 (LTB 4 ). LTB 4 is a potent chemoattractant that supplements neutrophils with inflammatory lesions, whereas released O 2 − and HNE adversely affect pulmonary extracellular matrix. A2 receptor subtypes that mediate many of these responses (O 2 − and LTB 4 / HNE release and cell adhesion) have been defined as A2a. A2 subtypes (A2a or A2b) that mediate other effects have not yet been determined. [3] Selective agonist activity at the A2a receptor is believed to provide greater therapeutic benefit than non-selective adenosine receptor agonists because their interaction with other receptor subtypes is associated with deleterious effects on the lung in animal models or human tissue studies. For example, bronchial contraction occurs in asthma patients when attacked with inhaled adenosine, but not in non-asthmatic patients. This response is at least in part due to the activation of the A1 receptor subtype. Activation of the A1 receptor also promotes neutrophil chemotaxis and adhesion to endothelial cells, thereby promoting lung damage. In addition, many patients with respiratory disease will be co-prescribed with β 2 -agonists, a negative interaction in animal studies between adenosine receptors and isoprenins that are negatively bound to adenylate cyclase. Action appeared. Since degranulation of human mast cells is promoted by activation of the adenosine A2b receptor, selectivity to the A2b receptor is also advantageous. [4] The inventors have surprisingly found that the purine derivatives of the present invention inhibit neutrophil function and are selective agonists of the adenosine A2a receptor. [5] The compounds of the present invention can be used to treat any disease in which the use of adenosine A2a receptor agonists is required. They can be used to treat diseases associated with leukocytes (eg, neutrophils, eosinophils, basophils, lymphocytes, macrophages) -induced tissue damage. They are useful as anti-inflammatory agents in the treatment of respiratory tract diseases such as adult respiratory distress syndrome (ARDS), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, bronchiectasis, chronic sinusitis and rhinitis. Compounds of the present invention also include septic shock, male erectile dysfunction, hypertension, seizures, epilepsy, cerebral ischemia, peripheral vascular disease, post-ischaemic reperfusion injury, diabetes, rheumatoid arthritis, multiple sclerosis, psoriasis, allergic dermatitis , In the treatment of eczema, ulcerative colitis, Crohn's disease, inflammatory bowel disease, gastritis caused by Helicobacter pylori, gastritis not caused by Helicobacter pylori, nonsteroidal anti-inflammatory agents-induced damage to the gastrointestinal tract or psychotic disorders, or for wound healing May be used. [6] Accordingly, the present invention provides, in one aspect, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. [7] [8] Where [9] R 1 is optionally substituted by one or two substituents each independently selected from hydrogen, C 1 -C 6 alkyl or C 3 -C 7 cycloalkyl (each of hydroxyl, fluorenyl, phenyl and naphthyl, and Phenyl and naphthyl are optionally substituted by C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo or cyano); [10] A is a bond or C 1 -C 6 alkylene; [11] R 2 is (i) hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, phenyl or naphthyl (the C 3 -C 7 cycloalkyl, phenyl and naphthyl are C 1 -C 6 alkyl, phenyl , C 1 -C 6 alkoxy- (C 1 -C 6 ) -alkyl, amino- (C 1 -C 6 ) -alkyl, fluoro- (C 1 -C 6 ) -alkyl, fluoro- (C 1- C 6 ) -alkoxy, C 2 -C 5 alkanoyl, halo, -OR 3 , cyano, -COOR 3 , C 3 -C 7 cycloalkyl, -S (O) m R 4 , -NR 3 R 3 , Optionally substituted by -SO 2 NR 3 R 3 , -CONR 3 R 3 , -NR 3 COR 4 or -NR 3 SO 2 R 4 , provided that when A is a bond, R 2 is not hydrogen, or [12] (ii) when A is C 2 -C 6 alkylene, -NR 3 R 3 , -OR 3 , -COOR 3 , -OCOR 4 , -SO 2 R 4 , -CN, -SO 2 NR 3 R 3 ,- NR 3 SO 2 R 4 , -NR 3 COR 4 or -CONR 3 R 3, or [13] (iii) a C-linked 4 to 11 membered mono or bicyclic heterocycle (optionally oxo, having 1 to 4 ring nitrogen atom (s) or 1 or 2 nitrogen, and 1 oxygen or 1 sulfur ring atom COne-C6Alkoxy- (COne-C6) -Alkyl, amino- (COne-C6) -Alkyl, fluoro- (COne-C6) -Alkyl, fluoro- (COne-C6) -Alkoxy, fluoro- (C2-C5) -Alkane oil, halo, cyano, -OR5, R6, -COR5, -NR5R5, -COOR5, -S (O)mR6, -SO2NR5R5, -CONR5R5, -NR5SO2R6Or -NR5COR6C-substituted by, optionally COne-C6Alkoxy- (COne-C6) -Alkyl, amino- (C2-C6) -Alkyl, fluoro- (COne-C6) -Alkyl, fluoro- (C2-C5) -Alkane oil, R6, -COR5, -COOR6, -SO2R6, -SO2NR5R5Or -CONR5R5N-substituted by) or [14] (iv) when A is C 2 -C 6 alkylene, N-linked azetidinyl, pyrrolidinyl, morpholinyl, tetrahydroisoquinolinyl, piperidinyl or piperazinyl (each optionally C 1- ); C 6 alkyl, phenyl, C 1 -C 6 alkoxy- (C 1 -C 6 ) -alkyl, amino- (C 1 -C 6 ) -alkyl, fluoro- (C 1 -C 6 ) -alkyl, fluoro - (C 1 -C 6) - alkoxy, C 2 -C 5 - alkanoyl, halo, -OR 3, cyano, -COOR 3, C 3 -C 7 cycloalkyl, -S (O) m R 4 , C-substituted by -NR 3 R 3 , -SO 2 NR 3 R 3 , -CONR 3 R 3 , -NR 3 COR 4 or -NR 3 SO 2 R 4 , wherein the piperazinyl is optionally C 1 -C 6 alkyl, phenyl, C 1 -C 6 alkoxy- (C 1 -C 6 ) -alkyl, amino- (C 2 -C 6 ) -alkyl, fluoro- (C 1 -C 6 ) -alkyl, C 2- N 5 -substituted by C 5 -alkanoyl, -COOR 4 , C 3 -C 7 cycloalkyl, -SO 2 R 4 , -SO 2 NR 3 R 3 or -CONR 3 R 3 ; [15] Each R 3 is independently selected from H, C 1 -C 6 alkyl, phenyl or pyridinyl; [16] R 4 is C 1 -C 6 alkyl or phenyl; [17] R 5 is H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, phenyl, naphthyl or het; [18] R 6 is C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, phenyl, naphthyl or het; [19] m is 0, 1 or 2; [20] R 7 is hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, phenyl, naphthyl, azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl, piperi Din-4-yl or het, wherein the azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl and piperidin-4-yl are optionally substituted by C 1 -C 6 alkyl Become; [21] R 8 is H or C 1 -C 6 alkyl; [22] As used in the definitions of R 5 , R 6 and R 7 , “het” refers to C-linked pyrrolyl, imidazolyl, triazolyl, thienyl, furyl, thiazolyl, oxazolyl, thiadiazolyl, oxdiazolyl, Pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, quinazolinyl, phthalazinyl, benzoxazolyl or quinoxalinyl (each C 1 -C 6 alkyl, C 1 -C 6 alkoxy, cyano or halo. [23] Preferably, R 1 is cyclohexyl or optionally substituted C 1 -C 6 alkyl. More preferably, R 1 is optionally substituted C 1 -C 5 alkyl and most preferably R 1 is optionally substituted C 1 -C 2 alkyl. [24] Preferably, the C 1 -C 6 , C 1 -C 5 or C 1 -C 2 alkyl substituents are selected from benzyl, fluorenyl, phenyl and hydroxyl. [25] Preferably, R 1 is substituted by one or two phenyl group (s) when substituted by phenyl. [26] Preferably, R 1 is 2,2-diphenylethyl, cyclohexyl, 1-ethylpropyl, 1-benzyl-2-hydroxyethyl, 9H-fluorene-9-ylmethyl and 1-benzyl-2-phenyl Selected from ethyl. [27] Preferably, R 1 is 2,2-diphenylethyl. [28] Preferably, A is C 1 -C 6 alkylene. [29] Preferably, A is C 1 -C 4 alkylene. [30] Preferably, A is selected from methylene, 1,2-ethylene, 1,3-propylene and 1,4-butylene. [31] Preferably, A is 1,2-ethylene. [32] Preferably, R 2 is phenyl, pyrrolidinyl, pyridinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted imidazolyl, morpholinyl, tetrahydroisoquinolyl, C 1 − C 6 alkylamino, di-C 1 -C 6 alkylamino, pyridinylamino and —NR 3 SO 2 R 4 . [33] Preferably, R 2 is phenyl, 2-pyridinyl, 1-piperazinyl, 4-piperidinyl, 1-pyrrolidinyl, 4-morpholinyl, 3,4-tetrahydro-2 (1H)- Isoquinolinyl, C 1 -C 3 alkylamino, di-C 1 -C 3 alkylamino and substituted 1H-imidazol-4-yl. [34] Preferably, R 2 is isopropylamino, methylamino, dimethylamino, diethylamino, 1-methyl-1H-imidazol-4-yl, 5-methyl-1H-imidazol-4-yl, 4-methyl Piperazin-1-yl, 1- (2-propyl) piperidin-4-yl and 2-pyridylamino. [35] Preferably, R 2 is piperidinyl optionally substituted by C 1 -C 6 alkyl or methoxy. [36] Preferably, R 2 is piperidinyl optionally substituted at the 1-position or 4-position by C 1 -C 6 alkyl or methoxy. [37] Preferably, R 2 is N-linked piperidinyl optionally C-substituted by C 1 -C 6 alkyl or methoxy. [38] Preferably, R 2 is N-linked piperidinyl optionally C-substituted by C 1 -C 3 alkyl or methoxy. [39] Preferably, R 2 is N-linked piperidinyl optionally C-substituted by methyl, methoxy or propyl. [40] Preferably, R 2 is N-linked piperidinyl optionally substituted at the 4-position by methyl, methoxy or propyl. [41] Preferably, R 2 is piperidin-1-yl, 4- (methyl) piperidin-1-yl, 4- (methoxy) piperidin-1-yl or 4- (prop-2- I) piperidin-1-yl. [42] Preferably, R 3 is methyl. [43] Preferably, R 4 is methyl or phenyl. [44] Preferably, R 7 is C 1 -C 6 alkyl. [45] Preferably, R 7 is C 1 -C 4 alkyl. [46] Preferably, R 7 is ethyl or n-propyl. [47] Preferably, R 8 is H. [48] In another aspect of the invention, there is provided a compound of formula II, III, XI, XIII, XIV, XV, XVI, XIX, XIXb, XIXc or XIXd. [49] [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] [60] Where [61] R 1 to R 8 , A, “het” and where present m are as defined above, [62] P 1 , P 2 and P 3 are protecting groups, [63] Z is a leaving group. [64] In another aspect of the present invention, there is provided a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising reacting an ester of formula (II) with an amine of formula (X). [65] <Formula II> [66] [67] R 2 -A-NHR 8 [68] Where [69] R 1 to R 8 , A, "het" and, where present, m are as defined above. [70] In another aspect of the present invention, there is provided a process for preparing a compound of formula II, comprising the step of deprotecting a compound of formula III. [71] <Formula II> [72] [73] <Formula III> [74] [75] Where [76] P 1 and P 2 may be the same or different protecting groups, or may be part of the same protecting group, [77] R 1 to R 8 , A, "het" and, where present, m are as defined above. [78] In another aspect of the invention, reacting a compound of formula XI with trimethylsilyltrifluoromethanesulfonate and a compound of formula IV, wherein the compound of formula IV is N, O-bis (trimethylsilyl) acetamide And reacted with a compound of Formula XI) to provide a process for preparing a compound of Formula III. [79] <Formula III> [80] [81] <Formula XI> [82] [83] [84] Where [85] P 1 and P 2 are protecting groups, [86] R 1 to R 8 , A, "het" and, where present, m are as defined above. [87] In another aspect of the present invention, there is provided a process for preparing a compound of formula IV by performing alcoholic decomposition and then hydrolysis of the nitrile of formula V. [88] <Formula IV> [89] [90] [91] Where [92] R 1 to R 8 , A, "het" and, where present, m are as defined above. [93] In another aspect of the invention, there is provided a process for preparing a compound of formula V by deprotecting a compound of formula VI. [94] <Formula V> [95] [96] [97] Where [98] P 3 is a protecting group, [99] R 1 to R 8 , A, "het" and, where present, m are as defined above. [100] In another aspect of the present invention, there is provided a method of preparing a compound of formula VI by replacing the chloro group of the compound of formula VII with a cyano group. [101] <Formula VI> [102] [103] [104] Where [105] R 1 to R 8 , A, "het" and, where present, m are as defined above. [106] In another aspect of the invention, there is provided a process for preparing a compound of formula VII by reacting a compound of formula VIII with an amino of formula XII. [107] <Formula VII> [108] [109] [110] R 1 NH 2 [111] Where [112] R 1 to R 8 , A, "het" and, where present, m are as defined above. [113] In another aspect of the present invention, there is provided a process for preparing a compound of formula VIII by protecting 2,6-dichloro-9H-purine of formula IX. [114] <Formula VIII> [115] [116] [117] In the above definition, halo means fluoro, chloro, bromo or iodo, and alkyl, alkylene, alkanoyl and alkoxy groups having the required number of carbon atoms can be unbranched or branched. The heterocycle of definition (iii) of R 2 may be aromatic or completely or partially saturated. The expression "C-linked" as used in the definitions of R 2 and het means that the group is linked to an adjacent atom by a ring carbon. The expression "N-linked" as used in the definition of R 2 means that the group is connected to an adjacent atom by a ring nitrogen. Examples of alkyl are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl. Examples of alkoxy are methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy and t-butoxy. Examples of alkylene are methylene, 1,1-ethylene, 1,2-ethylene, 1,3-propylene and 1,2-propylene. Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. [118] Pharmaceutically acceptable salts of compounds of formula I include acid addition salts and base salts thereof. [119] Suitable acid addition salts are formed from acids which form non-toxic salts, for example hydrochloride, hydrobromide, hydroiodide, sulfates, bisulfates, nitrates, phosphates, hydrogen phosphates, acetates, maleates, fumarates , Lactate, tartrate, citrate, gluconate, succinate, saccharide, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate salts. [120] Suitable base salts are formed from bases which form non-toxic salts, for example sodium, potassium, aluminum, calcium, magnesium, zinc and diethanolamine salts. [121] For references for suitable salts, see Berge et al., J. Pharm. Sci., 1977, 66, 1-19. [122] Pharmaceutically acceptable solvates of compounds of formula (I) include hydrates thereof. [123] Within the scope of the compounds of formula (I) are also included polymorphs thereof. [124] Compounds of formula (I) may contain one or more additional asymmetric carbon atoms and may therefore exist in two or more stereoisomeric forms. The present invention encompasses the individual stereoisomers of the compounds of formula (I) and mixtures thereof, if desired, the individual tautomers of compounds of formula (I) and mixtures thereof. [125] Separation of diastereomers can be carried out by conventional techniques, for example by fractional crystallization, chromatography or H.P.L.C. of stereoisomer mixtures of the compounds of formula (I) or suitable salts or derivatives thereof. Individual enantiomers of the compounds of formula (I) are also prepared by HPLC of the corresponding racemate using a suitable chiral support, or by fractionation of diastereomeric salts formed by reaction of the corresponding racemate with a suitable optically active acid or base. It can be prepared by the same separation method or from a corresponding optically pure intermediate. [126] All compounds of formula (I) may be prepared by conventional routes, such as the procedures described in the general methods provided below, or by the specific methods described in the Examples section, or by analogous methods. The present invention also encompasses any one or more of these methods of preparing compounds of Formula (I) in addition to any novel intermediates used herein. In the general methods described, R 1 , R 2 , R 7 , R 8 and A are as defined for compounds of formula I above, unless otherwise noted. [127] All compounds of formula I are prepared according to the route shown in Scheme 1, wherein R 9 is C 1 -C 4 alkyl, preferably methyl or ethyl, and P 1 , P 2 and P 3 represent protecting groups can do. [128] [129] In Scheme 1, a compound of formula I can be prepared by reacting an ester of formula II with an amine of formula X: [130] <Formula X> [131] R 2 -A-NHR 8 [132] The reaction can be carried out at elevated temperature, preferably from 100 to 150 ° C., optionally in the presence of a suitable solvent such as ethanol. In one typical method, the compound of formula II and the amine of formula X are heated together at about 120 ° C. Compounds of formula (II) may be prepared by deprotecting compounds of formula (III), wherein the protecting groups P 1 and P 2 may be the same or different and may optionally form part of the same protecting group. Examples of suitable protecting groups will be apparent to the skilled person (see, e.g., Protecting Groups in Organic Synthesis (Second Edition), Theodora W. Green and Peter GM Wuts, John Wiley and Sons, 1991). Preferred individual protecting groups are alkanoils and aroyls. P 1 and P 2 is a preferred protecting group to form part of the same protecting group is when the P 1 and P 2 C 1 -C 6 alkylene forming a together. Particularly preferred individual protecting groups are acetyl and benzoyl. P 1 and P 2 group is particularly preferred protecting group to form part of the same protecting group is when the P 1 and P 2 together form a dimethylmethylene. Conditions suitable for deprotection are well known in the art (see, eg, Protecting Groups in Organic Synthesis (Second Edition), Theodora W. Green and Peter GM Wuts, John Wiley and Sons, 1991). In one typical method, when P 1 and P 2 are each benzoyl, the protecting groups can be removed by treating a solution of the compound of formula III in a suitable solvent such as methanol with a base such as potassium carbonate at room temperature. Compounds of formula III can be prepared by reacting a compound of formula XI with trimethylsilyltrifluoromethanesulfonate and a compound of formula IV (derived from N, O-bis (trimethylsilyl) acetamide). [133] <Formula XI> [134] [135] Wherein P 1 and P 2 are as defined above. [136] In one typical method the compound of formula IV is heated at elevated temperature, preferably at reflux, in the presence of a suitable solvent such as 1,1,1-trichloroethane and N, O-bis (trimethylsilyl) acetamide. Thereafter, the mixture is cooled and the solvent is removed. The residue is treated with a solution of the compound of formula XI in a suitable solvent such as toluene and then with trimethylsilyl trifluoromethanesulfonate and the mixture is heated under reflux at room temperature to the reflux temperature of the selected solvent to Obtain the compound. In the case of toluene, for example, a temperature of 110 ° C is preferred. Compounds of formula IV can be prepared by subjecting the nitrile of formula V to hydroalcolysis followed by hydrolysis. In one typical method a solution of nitrile of formula V in alcoholic solvent R 9 OH is treated with sodium alkoxide of formula R 9 ONa and heated under reflux, where R 9 is as defined above. The resulting mixture is cooled, evaporated, dissolved in a suitable solvent such as tetrahydrofuran and treated with an acid such as hydrochloric acid, preferably 2N hydrochloric acid to give a compound of formula IV. Compounds of formula (V) can be prepared by deprotecting compounds of formula (VI), wherein P 3 is a suitable protecting group. Examples of suitable protecting groups will be apparent to the skilled person (see, e.g., Protecting Groups in Organic Synthesis (Second Edition), Theodora W. Green and Peter GM Wuts, John Wiley and Sons, 1991). Preferred protecting groups are groups in which P 3 represents tetrahydropyran-2-yl. Conditions suitable for deprotection are well known in the art (see, eg, Protecting Groups in Organic Synthesis (Second Edition), Theodora W. Green and Peter GM Wuts, John Wiley and Sons, 1991). In one typical method, when P 3 is tetrahydropyran-2-yl, the protecting group can be removed by treating a solution of the compound of formula VI in a suitable solvent such as ethanol with an acid such as hydrochloric acid. Compounds of formula VI can be prepared by substituting cyano groups for chloro groups of compounds of formula VII. In one typical method a solution of the compound of formula VII in a suitable solvent such as N, N-dimethylformamide is treated with acid acceptors such as zinc cyanide, tetrakis (triphenylphosphine) -palladium (0) and triethylamine In the atmosphere of nitrogen, it heats to 80-120 degreeC, Preferably it is 100 degreeC. The product of the reaction is usually contaminated with the amount of the corresponding compound of formula V, which can be separated by conventional chromatography. [137] Compounds of formula (VII) can be prepared by reacting a compound of formula (VIII) with an amine of formula (XII). [138] <Formula XII> [139] R 1 NH 2 [140] In one typical method, a solution of a compound of formula VIII in a suitable solvent, such as isopropyl alcohol, is treated with a compound of formula XII and optionally at an reflux temperature of an acid acceptor, such as N-ethyl-N-isopropyl-2-propylamine. Heat in presence Compounds of formula (VIII) may be prepared by protecting 2,6-dichloro-9H-purine of formula (IX). Examples of suitable protecting groups P 3 will be apparent to the skilled person (see, e.g., Protecting Groups in Organic Synthesis (Second Edition), Theodora W. Green and Peter GM Wuts, John Wiley and Sons, 1991). Preferred protecting groups are where P 3 represents tetrahydropyran-2-yl. Conditions suitable for protection are well known in the art (see, eg, Protecting Groups in Organic Synthesis (Second Edition), Theodora W. Green and Peter GM Wuts, John Wiley and Sons, 1991). In one typical method, a solution of an acid catalyst such as 2,6-dichloro-9H-purine and 4-toluenesulfonic acid monohydrate in a suitable solvent such as ethyl acetate when P 3 is tetrahydropyran-2-yl Heated to 30-70 ° C., preferably 50 ° C. and treated with a solution of 2,3-dihydropyran in a suitable solvent such as ethyl acetate. [141] All compounds of formula (I) can be prepared according to the route shown in Scheme 2, wherein R 9 , P 1 , P 2 and P 3 are as defined above. [142] [143] In Scheme 2, the compound of formula (I) can be prepared by deprotecting the compound of formula (XIII). Conditions suitable for deprotection are well known in the art (see, eg, Protecting Groups in Organic Synthesis (Second Edition), Theodora W. Green and Peter GM Wuts, John Wiley and Sons, 1991). In one typical method, when P 1 and P 2 are each benzoyl, a solution of the compound of formula XIII in a suitable solvent such as methanol may be treated with a base such as potassium carbonate at room temperature, to remove the protecting groups. Compounds of formula (XIII) can be prepared by reacting compounds of formula (XI) with trimethylsilyltrifluoromethanesulfonate and compounds of formula (XIV) (derived from N, O-bis (trimethylsilyl) acetamide). [144] <Formula XI> [145] [146] Wherein P 1 and P 2 are as defined above. [147] In one typical method, the compound of formula XIV is heated at elevated temperature, preferably at reflux, in the presence of a suitable solvent such as 1,1,1-trichloroethane and N, O-bis (trimethylsilyl) acetamide. Thereafter, the mixture is cooled and the solvent is removed. The residue is treated with a solution of the compound of formula XI in a suitable solvent such as toluene and then with trimethylsilyl trifluoromethanesulfonate and the mixture is heated at room temperature to the reflux temperature of the selected solvent to give Obtain the compound. In the case of toluene, for example, a temperature of 90 ° C is preferred. Compounds of formula (XIV) may be prepared by deprotecting compounds of formula (XV). Conditions suitable for deprotection are well known in the art (see, eg, Protecting Groups in Organic Synthesis (Second Edition), Theodora W. Green and Peter GM Wuts, John Wiley and Sons, 1991). In one typical method, when P 3 is tetrahydropyran-2-yl, the protecting group can be removed by treating a solution of the compound of formula XV in a suitable solvent such as ethanol with an acid such as hydrochloric acid. Compounds of formula (XV) may be prepared by reacting an ester of formula (XVI) with an amine of formula (X) at elevated temperature, preferably from 100 to 150 ° C. [148] <Formula X> [149] R 2 -A-NHR 8 [150] In one typical method, the compound of formula XVI and the amine of formula X are heated together at 130 ° C. Compounds of formula (XVI) can be prepared by subjecting the nitrile of formula (VI) to alcoholic decomposition and then hydrolysis. In one typical method a solution of nitrile of formula VI in alcoholic solvent R 9 OH is treated with sodium alkoxide of formula R 9 ONa and heated under reflux. The resulting mixture is cooled, evaporated, dissolved in a suitable solvent such as a mixture of tetrahydrofuran and water (preferably by volume 3: 1) and treated with an acid such as acetic acid. The resulting mixture is heated to elevated temperature, preferably at reflux, to afford the compound of formula XVI. [151] Compounds of formula (XI) used in Schemes 1 and 2 can be prepared as shown in Scheme 3, wherein P 1 and P 2 are as defined above. [152] [153] Compounds of formula (XI) can be prepared by treating compounds of formula (XVII) with cooling (typically at -10 ° C) with a mixture of acetic acid, acetic anhydride and a strong acid such as hydrochloric acid or sulfuric acid. Compounds of formula (XVII) can be prepared from acids of formula (XVIII) by activating an acid with, for example, acid chloride and treating this activated intermediate with an amine of formula (XIXa). [154] R 7 NH 2 [155] In one typical method, the compound of formula XVIII is dissolved in a suitable inert solvent (eg dichloromethane) and treated with oxalyl chloride and a catalytic amount of N, N-dimethylformamide. After excess solvent and reagent are removed by evaporation under reduced pressure, the residue is dissolved in anhydrous dichloromethane and treated with an amine of formula XIXa. With regard to the conditions used in the subsequent steps, it may be desirable to exchange protecting groups P 1 and P 2 in the compound of formula XVII. Alternatively, suitable protecting groups are well known to the skilled person (see, eg, Protecting Groups in Organic Synthesis (Second Edition), Theodora W. Green and Peter GM Wuts, John Wiley and Sons, 1991). In one typical case, a solution of a compound of formula (XVII) in which P 1 and P 2 together in a suitable solvent, such as methanol, together form dimethylmethylene, can be treated with an acid such as pyridinium paratoluenesulfonate to be subsequently reprotected with other functional groups. H may provide a compound of formula XVII in which both P 1 and P 2 are substituted. For example, compounds of formula (XVII) in which both P 1 and P 2 are substituted by H are dissolved in a suitable solvent such as dichloromethane, and the resulting solution is treated with acid acceptors such as pyridine and benzoyl chloride to give P 1 and It is possible to provide compounds of formula (XVII) wherein each P 2 is benzoyl. Compounds of formula (XVIII) are known in the art (see, eg, J. Amer. Chem. Soc., 1958, 80 , 5168) (P 1 and P 2 together form dimethylmethylene). [156] Amines of formula R 7 NH 2 (XIXa), R 1 NH 2 (XII) and R 2 -A-NHR 8 (X) are commercially available or can be prepared by standard techniques well known to those skilled in the art. [157] All compounds of formula I can also be prepared by condensing an acid of formula XIX with an amine of formula X, as shown in Scheme 4 below. [158] [159] Condensation is typically performed under conventional peptide-coupling conditions. For example, a solution of the acid of formula XIX in a suitable solvent, such as dichloromethane, may first be treated with a suitable coupling agent such as carbonyl diimidazole and then with a compound of formula X. Acids of formula (XIX) may be prepared by hydrolysis of the compound of formula (II). To carry out the hydrolysis, the compound of formula II is typically dissolved in a suitable solvent such as ethanol and treated with a suitable base such as aqueous sodium hydroxide. [160] Compounds of formula (I) can be prepared by aminocarbonylation of compounds of formula (XIXb) with compounds of formula (X) in the presence of carbon monoxide and a suitable coupling catalyst. [161] <Formula X> [162] R 2 -A-NHR 8 [163] <Formula XIXb> [164] [165] Wherein Z is a suitable leaving group such as bromo, iodo, Sn (C 1 -C 12 alkyl) 3 or CF 3 SO 2 O—, preferably iodo. [166] The catalyst is preferably a palladium (II) catalyst, more preferably 1,1'-bis (diphenylphosphino) ferrocenedichloropalladium (II) (optionally 1: 1 complex with dichloromethane). Alternatively, palladium acetate (II) may contain 1,1'-bis (diphenylphosphino) ferrocene, triphenylphosphine, tri (o-tolyl) phosphine or (R)-, (S)-or racemic 2 It may be used in the presence of a suitable ligand, such as, 2'-bis (diphenylphosphino) -1,1'-binafyl. [167] In one typical method the reaction is carried out in a suitable solvent, for example tetrahydrofuran, methanol or ethanol at elevated pressure, eg at about 60 ° C., at elevated pressure, eg at about 345 kPa (50 psi) in the presence of carbon monoxide in a sealed vessel. Perform. Optionally, suitable organic bases may be present, such as tertiary amines such as triethylamine, N-ethyldiisopropylamine or 4-methylmorpholine. [168] Intermediates of Formula (XIXc) can be prepared as shown in Scheme 5 below. [169] [170] Where [171] Z is as defined for the compound of formula XIXb, [172] Ac is acetyl. [173] In one typical method, the compound of formula XIXd is reacted with an amine of formula R 1 NH 2 (XII) at elevated temperature if necessary in a suitable solvent such as acetonitrile in the presence of a suitable acid acceptor such as triethylamine. The product of formula XIXc obtained is in a suitable solvent such as methanol, ethanol, isopropanol, 1,2-dimethoxyethane, tetrahydrofuran, dimethylformamide, acetone, 2-butanone or 4-methyl-2-pentanone By conventional methods such as using a suitable inorganic base such as sodium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate or cesium carbonate, optionally at 0 ° C. to a reflux temperature of the solvent, for example at room temperature under aqueous conditions. Deprotection by hydrolysis can provide the compound of formula XIXb. Alternatively, deprotection may be achieved by using triethylamine, diisopropylethylamine, 4-methylmorpholine at 0 ° C. to the reflux temperature of the solvent in a suitable solvent such as methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran or dichloromethane. , And suitable amines such as ammonia, methylamine, ethylamine or dimethylamine. Compounds of formula (XIXd) can be prepared by conventional methods. [174] Pharmaceutically acceptable salts of the compounds of formula (I) can be readily prepared by mixing together a solution of the compound of formula (I) and the appropriate desired acid or base. The salt may precipitate out of solution and be collected by filtration or may be recovered by evaporation of the solvent. [175] The anti-inflammatory properties of the compounds of formula (I) are evidenced by their ability to inhibit neutrophil function exhibiting A2a receptor agonist activity. This is assessed by measuring the compound profile in the assay in which superoxide production is determined from neutrophils activated by fMLP. Neutrophils were isolated from human peripheral blood by the use of centrifugation via dextran sediment followed by Ficoll-Hypaque solution. Any contaminating red blood cells in the granulocyte pellets were removed by hemolysis with ice cold distilled water. Superoxide production from neutrophils was induced by fMLP in the presence of priming concentrates of cytochalasin B. Adenosine deaminoases were included in the assay to remove any endogenous adenosine that may inhibit superoxide production. The effect of the compound on the fMLP-induced response was monitored by colorometric from reduction of cytochrome C in assay buffer. The efficacy of the compounds was assessed by concentrations (IC 50 ) that provide 50% inhibition compared to the control response to fMLP. [176] In this assay, the compounds of the present invention have an IC 50 value of 200 nM or less. The compounds of Examples 7, 10, 12, 16, 20, 21, 27 and 31 are the most effective and they have IC 50 values of 40 nM or less. [177] Therefore, the present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as defined above together with a pharmaceutically acceptable excipient, diluent or carrier. [178] The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof as defined above for use as a medicament. [179] The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof as defined above for use as a medicament for the treatment of a disease in which the use of an A2a receptor agonist is required. [180] The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof as defined above for the manufacture of a medicament for the treatment of a disease requiring the use of an A2a receptor agonist. [181] The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof as defined above for use as an anti-inflammatory agent. [182] The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof as defined above for the preparation of anti-inflammatory agents. [183] The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof as defined above for the manufacture of a medicament for the treatment of respiratory diseases. The present invention also relates to the above-mentioned disease, wherein the disease is selected from the group consisting of adult respiratory distress syndrome (ARDS), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, bronchiectasis, chronic sinusitis and rhinitis It provides a use as such. [184] In addition, the present invention is septic shock, male erectile dysfunction, hypertension, seizures, epilepsy, cerebral ischemia, peripheral vascular disease, post-ischaemic reperfusion injury, diabetes, rheumatoid arthritis, multiple sclerosis, psoriasis, allergic dermatitis, Medicinal products for the treatment of eczema, ulcerative colitis, Crohn's disease, inflammatory bowel disease, gastritis caused by Helicobacter pylori, gastritis not caused by Helicobacter pylori, nonsteroidal anti-inflammatory drugs-induced damage to the gastrointestinal tract, or psychological disorders, or for wound healing Provided is the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof as defined above for the preparation. [185] The invention also provides for the treatment of a disease requiring the use of an A2a receptor agonist comprising treating a mammal, including a human, with an effective amount of a compound of Formula I as defined above or a pharmaceutically acceptable salt, solvate or composition thereof. Provided is a method of treating said mammal. [186] In addition, the present invention comprises treating a mammal, including a human, with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof as defined above, the treatment of said mammal for treating an inflammatory disease. Provide a method. [187] In addition, the present invention comprises treating a mammal, including a human, with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof as defined above, the treatment of said mammal for treating respiratory disease. Provide a method. The present invention also relates to the above-mentioned disease, wherein the disease is selected from the group consisting of adult respiratory distress syndrome (ARDS), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, bronchiectasis, chronic sinusitis and rhinitis It provides a method as described above. [188] The invention also includes treating mammals, including humans, with an effective amount of a compound of Formula (I) as defined above or a pharmaceutically acceptable salt, solvate or composition thereof, septic shock, male impotence, hypertension, seizures , Epilepsy, cerebral ischemia, peripheral vascular disease, post-ischemic reperfusion injury, diabetes, rheumatoid arthritis, multiple sclerosis, psoriasis, allergic dermatitis, eczema, ulcerative colitis, Crohn's disease, inflammatory bowel disease, gastritis caused by Helicobacter pylori, Helicobacter pylori A method of treating said mammal for treating gastritis, non-steroidal anti-inflammatory agents-induced damage to the gastrointestinal tract or psychiatric disorders or for wound healing. [189] The compounds of formula (I) may be administered alone, but will generally be administered in a mixture with a suitable pharmaceutically acceptable excipient, diluent or carrier selected with respect to the intended route of administration and standard pharmaceutical practice. [190] For example, the compounds of formula (I) may be used immediately orally, buccally or sublingually in the form of tablets, capsules, obules, elixir, solutions or suspensions, which may include spices or colorants. It may be administered for delayed-, sustained-, pulsed- or controlled-release applications. [191] The tablets include excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, starch (preferably corn, potato or tapioca starch), sodium starch glycolate, croscarmellose sodium and certain combinations. Disintegrants such as silicates and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. In addition, lubricants such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included. [192] Solid compositions of a similar form can also be used as fillers in gelatin capsules. Preferred excipients in this regard are lactose, starch, cellulose, lactose or high molecular weight polyethylene glycols. In the case of aqueous suspensions and / or elixirs, the compounds of formula (I) are combined with various sweeteners or spices, pigments or dyes, emulsifiers and / or suspending agents and diluents such as water, ethanol, propylene glycol or glycerin. It can be combined with these combinations. [193] The compounds of formula (I) may also be administered parenterally, eg, intravenously, intraarterally, intraperitoneally, intramenorrally, intraventricularly, intrasternally, intracranially, intramuscularly or subcutaneously, or by infusion techniques. Can be. They are best used in the form of sterile aqueous solutions which may contain enough substances or glucose to make the solution into blood and isotonic, for example. The aqueous solution should be suitably buffered (preferably pH 3-9), if necessary. Preparation of suitable parenteral formulations under sterile conditions can be readily accomplished by standard pharmaceutical techniques well known to those skilled in the art. [194] When administered orally and parenterally to human patients, the daily dosage level of the compound of formula (I) is generally (in single or divided doses) from 0.01 to 100 mg / kg (weight of the subject to be treated), preferably from 0.1 to Will be 100 mg / kg. [195] Thus, tablets or capsules of the compound of formula (I) may contain from 5 to 500 mg of the active compound, if appropriate, for administration once or more than once at a time. In any case, doctors will determine the actual dosage that will be best suited for any individual patient, which will vary depending on the age, weight and response of the particular patient. The dosage is an example of an average case. Of course, there may be individual examples where the higher or lower dosage ranges have advantages, and such cases are within the scope of the present invention. [196] The compounds of formula (I) may also be administered intranasally or by inhalation and are conveniently administered with suitable propellants, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, 1, Hydrofluoroalkanes such as 1,1,2-tetrafluoroethane (HFA 134A ™) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA ™), It is provided in the form of a dry powder inhaler or aerosol spray product provided from pressurized containers, pumps, sprays, atomizers or medical nebulizers using carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve for delivering a metered amount. The pressurized vessel, pump, spray, nebulizer or medical nebulizer is a solution of the active compound with, for example, a mixture of propellants as ethanol and a solvent, which may further comprise a lubricant, for example sorbitan trioleate. Or suspensions. Capsules and cartridges (eg, made of gelatin) for use in an inhaler or insufflator may be formulated to contain a compound of formula I and a powder mixture based on a suitable powder such as lactose or starch. [197] Aerosol or dry powder formulations are preferably configured to contain 20 to 4000 μg of compound of formula (I) for each metered dose or “puff” to be delivered to a patient. For aerosols the total daily dose will be in the range of 20 μg to 20 mg, which may be administered in a single dose, or more usually in divided doses, throughout the day. [198] Alternatively, the compounds of formula I may be administered in the form of suppositories or pessaries, or may be lotions, solutions, creams, ointments, gels, suspensions, dusting powders, sprays or drug-containing dressings (eg , Wet dressings, white soft paraffin or polyethylene glycol gauze dressings, or hydrogels, hydrochloride, alginate or film dressings). The compounds of formula (I) can also be administered transdermally, for example using skin patches. [199] For topical application to the skin, compounds of formula (I) are suspended or dissolved in, for example, a mixture of one or more of mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. It may be formulated as a suitable ointment containing the active compound. Alternatively, they may be, for example, one or more of mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water It may be formulated as a suitable lotion or cream suspended or dissolved in the mixture. They can also be formulated as hydrogels with cellulose or polyacrylate derivatives or other viscosity modifiers. [200] It will be appreciated that all references to treatment herein include curative, palliative and prophylactic treatments. [201] The following examples illustrate the preparation of compounds of formula (I). 1 H nuclear magnetic resonance (NMR) spectra were consistent with the structures shown in all cases. Characterized by low field percentages from tetramethylsilane using abbreviations indicating major peaks (e.g., s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad) Chemical shifts δ are provided. Mass spectra (m / z) were recorded in thermal spray ionization mode. The following abbreviations were used for conventional solvents: CDCl 3 (chloroform in deuterium), DMSO (dimethylsulfoxide, THF (tetrahydrofuran)). When thin layer chromatography (TLC) was used, this refers to silica gel TLC using silica gel 60 F 254 plates, where R f is the distance traveled by the compound divided by the distance traveled by the solvent in front of the TLC plate. [202] Example 1 [203] 6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2 -Furanyl} -N- [2- (1-piperidinyl) ethyl] -9H-purine-2-carboxamide [204] [205] (2R, 3R, 4R, 5S) -4- (benzoyloxy) -2- [6-[(2,2-diphenylethyl) amino] -2-({[2- (1) in methanol (3 mL) -Piperidinyl) -ethyl] amino} carbonyl) -9H-purin-9-yl] -5-[(ethylamino) carbonyl] tetrahydro-3-furanyl benzoate (Preparation 7) (104 mg , 0.12 mmol) was treated with potassium carbonate (100 mg, 0.72 mmol). The mixture was stirred at rt for 30 min. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol (90:10 volume ratio) to give the title compound as a white solid (44 mg). [206] [207] Example 2 [208] 6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2 -Furanyl} -N- [2- (4-isopropyl-1-piperidinyl) ethyl] -9H-purine-2-carboxamide [209] [210] Methyl 6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetra-hydro -2-furanyl} -9H-purine-2-carboxylate (Preparation 11) (100 mg, 0.18 mmol) and 2- (4-isopropyl-1-piperidinyl) ethylamine (Preparation 17) (300 mg, 1.76 mmol) was heated at 120 ° C. under nitrogen atmosphere for 3 hours. The reaction mixture was cooled to room temperature and purified by column chromatography on silica gel eluting with dichloromethane: methanol: concentrated aqueous ammonia (90: 10: 1 volume ratio) to give the title compound as a white solid (76 mg, 62%). . [211] [212] Examples 3 to 34 [213] Examples 3 to 33 were prepared by methods analogous to those used in Example 2 or Example 34 (for Examples 10, 11, 20 and 28). Mass spectral data were obtained by electrospray method. [214] Example 3 [215] 6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2 -Furanyl} -N- (2-pyridinylmethyl) -9H-purine-2-carboxamide [216] [217] [218] Example 4 [219] N-benzyl-6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxy Tetrahydro-2-furanyl} -9H-purine-2-carboxamide [220] [221] [222] Example 5 [223] 6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2 -Furanyl} -N- (2-phenylethyl) -9H-purine-2-carboxamide [224] [225] [226] Example 6 [227] N- [2- (dimethylamino) ethyl] -6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} -9H-purine-2-carboxamide [228] [229] [230] Example 7 [231] 6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2 -Furanyl} -N- [3- (1-pyrrolidinyl) propyl] -9H-purine-2-carboxamide [232] [233] [234] Example 8 [235] 6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2 -Furanyl} -N- [2- (2-pyridinyl) ethyl] -9H-purine-2-carboxamide [236] [237] [238] Example 9 [239] 6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2 -Furanyl} -N- [2- (4-morpholinyl) ethyl] -9H-purine-2-carboxamide [240] [241] [242] Example 10 [243] 9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} -6-[(1-ethylpropyl) amino ] -N- [2- (1-piperidinyl) ethyl] -9H-purine-2-carboxamide [244] [245] [246] Example 11 [247] 6-{[(1S) -1-benzyl-2-hydroxyethyl] amino} -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-di Hydroxytetrahydro-2-furanyl] -N- [2- (1-piperidinyl) ethyl] -9H-purine-2-carboxamide [248] [249] [250] Example 12 [251] 6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2 -Furanyl} -N- [2- (4-isopropyl-1-piperidinyl) ethyl] -9H-purine-2-carboxamide [252] [253] [254] Example 13 [255] N- [2- (3,4-dihydro-2 (1H) -isoquinolinyl) ethyl] -6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S , 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} -9H-purine-2-carboxamide [256] [257] [258] Example 14 [259] 6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2 -Furanyl} -N- (4-piperidinylmethyl) -9H-purine-2-carboxamide [260] [261] [262] Example 15 [263] 6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2 -Furanyl} -N- [4- (1-piperidinyl) butyl] -9H-purine-2-carboxamide [264] [265] [266] Example 16 [267] 6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2 -Furanyl} -N- [3- (isopropylamino) propyl] -9H-purine-2-carboxamide [268] [269] [270] Example 17 [271] 6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2 -Furanyl} -N- [3- (2-pyridinylamino) propyl] -9H-purine-2-carboxamide [272] [273] [274] Example 18 [275] 6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2 -Furanyl} -N- {3- [methyl (phenylsulfonyl) amino] propyl} -9H-purine-2-carboxamide [276] [277] [278] Example 19 [279] 6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2 -Furanyl} -N- {3- [methyl (methylsulfonyl) amino] propyl} -9H-purine-2-carboxamide [280] [281] [282] Example 20 [283] 9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} -6-[(9H-fluorene-9 -Ylmethyl) amino] -N- [2- (1-piperidinyl) ethyl] -9H-purine-2-carboxamide [284] [285] [286] Example 21 [287] N- [3- (diethylamino) propyl] -6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl ] -3,4-dihydroxytetrahydro-2-furanyl} -9H-purine-2-carboxamide [288] [289] [290] Example 22 [291] 6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2 -Furanyl} -N- [3- (4-morpholinyl) propyl] -9H-purine-2-carboxamide [292] [293] [294] Example 23 [295] 6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2 -Furanyl} -N- [3- (methylamino) propyl] -9H-purine-2-carboxamide [296] [297] [298] Example 24 [299] 6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2 -Furanyl} -N- [2- (5-methyl-1H-imidazol-4-yl) ethyl] -9H-purine-2-carboxamide [300] [301] [302] Example 25 [303] N- [4- (dimethylamino) butyl] -6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} -9H-purine-2-carboxamide [304] [305] [306] Example 26 [307] 6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2 -Furanyl} -N- [3- (4-methyl-1-piperazinyl) propyl] -9H-purine-2-carboxamide [308] [309] [310] Example 27 [311] N- [3- (dimethylamino) propyl] -6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} -9H-purine-2-carboxamide [312] [313] [314] Example 28 [315] 6-[(1-benzyl-2-phenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro- 2-furanyl} -N- [2- (1-piperidinyl) ethyl] -9H-purine-2-carboxamide [316] [317] [318] Example 29 [319] 9-{(2R, 3R, 4S, 5S) -3,4-dihydroxy-5-[(propylamino) carbonyl] tetrahydro-2-furanyl} -6-[(2,2-diphenyl Ethyl) amino] -N- [2- (1-piperidinyl) ethyl] -9H-purine-2-carboxamide [320] [321] [322] Example 30 [323] 6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2 -Furanyl} -N- [2- (1-isopropyl-4-piperidinyl) ethyl] -9H-purine-2-carboxamide [324] [325] [326] Example 31 [327] 6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2 -Furanyl} -N- [2- (4-methyl-1-piperidinyl) ethyl] -9H-purine-2-carboxamide [328] [329] [330] Example 32 [331] 6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2 -Furanyl} -N- [2- (4-methoxy-1-piperidinyl) ethyl] -9H-purine-2-carboxamide [332] [333] [334] Example 33 [335] 6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S} -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2 -Furanyl} -N-[(1-methyl-1H-imidazol-4-yl) methyl] -9H-purine-2-carboxamide [336] [337] [338] Example 34 [339] 6- (cyclohexylamino) -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} -N- [2- (1-piperidinyl) ethyl] -9H-purine-2-carboxamide [340] [341] (2S, 3S, 4R, 5R) -5- [6- (cyclohexylamino) -2-iodo-9H-purin-9-yl] -N-ethyl-3,4-di in THF (5 mL) Hydroxytetrahydro-2-furancarboxamide (Preparation 31) (125 mg, 0.24 mmol), 2- (1-piperidinyl) ethylamine (0.14 mL, 0.96 mmol) and tetrakis (triphenylphosphine) A solution of palladium (0) (20 mg, 0.024 mmol) was carbonylated at 345 KPa carbon monoxide at 60 ° C. for 18 hours. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol: concentrated aqueous ammonia (95: 5: 1 volume ratio). After evaporation of the appropriate fractions, the residue was triturated with diethyl ether, filtered and dried to give the target compound as a beige powder (77 mg, 58%). [342] [343] The following preparations describe the preparation of the specific intermediates used in the above examples. [344] Preparation Example 1 [345] 2,6-dichloro-9-tetrahydro-2H-pyran-2-yl-9H-purine [346] [347] 2,6-dichloro-9H-purine (20 g, 0.11 mol) and 4-toluenesulfonic acid monohydrate (0.2 g) are dissolved in ethyl acetate (300 mL), the mixture is heated to 50 ° C. and ethyl acetate (50 Ml) of 2,3-dihydropyran (12.6 ml, 0.14 mol) was added slowly over 30 minutes. The reaction mixture was then cooled to room temperature, water (100 mL) was added, and saturated aqueous sodium hydrogen carbonate solution was added to adjust the pH of the solution to 7. The organic layer was separated, washed with water then brine, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was (x 2) azeotropic distilled from pentane to give the title compound as a slightly impure white solid (30.9 g). [348] [349] Preparation Example 2 [350] 2-Chloro-N- (2,2-diphenylethyl) -9-tetrahydro-2H-pyran-2-yl-9H-purin-6-amine [351] [352] A solution of 2,6-dichloro-9-tetrahydro-2H-pyran-2-yl-9H-purine (Preparation Example 1) (30.9 g, 0.11 mol) in isopropyl alcohol (600 mL) was added with N-ethyl-N Treat with isopropyl-2-propanamine (47.5 mL, 0.27 mol) and 2,2-diphenylethylamine (24.8 g, 0.13 mol) and heat the resulting mixture at reflux for 3 hours. The solvent was removed under reduced pressure and the residue was azeotropically distilled from ethyl acetate. The residue is then purified by column chromatography on silica gel eluting with a gradient system which gradually changes from ethyl acetate: hexane (40:60 volume ratio) to ethyl acetate: hexane (60:40 volume ratio) to give the title compound as a foam. Obtained (49.7 g). [353] [354] Preparation Example 3 [355] 6-[(2,2-diphenylethyl) amino] -9-tetrahydro-2H-pyran-2-yl-9H-purin-2-carbonitrile [356] [357] 2-Chloro-N- (2,2-diphenylethyl) -9-tetrahydro-2H-pyran-2-yl-9H-purin-6-amine in N, N-dimethylformamide (3 mL) (Preparation Example 2) (1.0 g, 2.31 mmol), zinc cyanide (0.162 g, 1.38 mmol), triethylamine (0.28 g, 2.77 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.133 g, 0.12 mmol ) Was heated at 100 ° C. for 6 hours under a nitrogen atmosphere. The reaction mixture was cooled down and partitioned between ethyl acetate (100 mL) and 2M sodium hydroxide solution (100 mL). The organic layer was separated, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Resulting 6-[(2,2-diphenylethyl) amino] -9-tetrahydro-2H-pyran-2-yl-9H-purin-2-carbonitrile and 6-[(2,2-diphenylethyl Gradient system wherein a 1: 1 mixture of) amino] -9H-purine-2-carbonitrile (Preparation Example 8) is gradually changed from ethyl acetate: hexane (40:60 volume ratio) to ethyl acetate: hexane (60:40 volume ratio) Eluting with column chromatography on silica gel gave the title compound as a white solid (0.4 g). [358] [359] Preparation Example 4 [360] Methyl 6-[(2,2-diphenylethyl) amino] -9-tetrahydro-2H-pyran-2-yl-9H-purin-2-carboxylate [361] [362] 6-[(2,2-diphenylethyl) amino] -9-tetrahydro-2H-pyran-2-yl-9H-purin-2-carbonitrile (Preparation 3) in methanol (20 mL) (1.00 g) , 2.36 mmol), were treated with sodium methoxide (0.14 g, 2.59 mmol) and the resulting mixture was heated at reflux for 20 hours under nitrogen atmosphere. TLC analysis indicated that some starting material was still left, so additional sodium methoxide (64 mg, 1.18 mmol) was added and the mixture was heated at reflux for 1 additional hour under nitrogen atmosphere. Thereafter, the mixture was cooled to room temperature and the solvent was removed under reduced pressure. Tetrahydrofuran (30 mL) and water (10 mL) were added to the residue and acetic acid (1 mL) was added to adjust the pH to 4. This mixture was heated at reflux for 1 hour. TLC analysis indicated that some starting material was still left, so additional acetic acid (0.5 mL) was added and heating continued at reflux for 18 h. The reaction was cooled to room temperature and partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The organic phase was separated, washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol (98.5: 1.5 volume ratio) to give the title compound (521 mg). [363] [364] Preparation Example 5 [365] 6-[(2,2-diphenylethyl) amino] -N- [2- (1-piperidinyl) ethyl] -9-tetrahydro-2H-pyran-2-yl-9H-purin-2-car Voxamide [366] [367] Methyl 6-[(2,2-diphenylethyl) amino] -9-tetrahydro-2H-pyran-2-yl-9H-purin-2-carboxylate (Preparation 4) (100 mg, 0.22 mmol) And 1- (2-aminoethyl) piperidine (0.31 mL, 2.19 mmol) were heated together at 130 ° C. for 2 hours. Excess amine was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol (95: 5 volume ratio) to give the title compound as a yellow foam (104 mg). [368] [369] Preparation Example 6 [370] 6-[(2,2-diphenylethyl) amino] -N- [2- (1-piperidinyl) ethyl] -9H-purine-2-carboxamide [371] [372] 6-[(2,2-diphenylethyl) amino] -N- [2- (1-piperidinyl) ethyl] -9-tetrahydro-2H-pyran-2-yl-9H in ethanol (20 mL) A solution of Purine-2-carboxamide (Preparation 5) (420 mg, 0.76 mmol) was treated with hydrochloric acid (2M, 0.9 mL). After the white precipitate formed, the mixture was heated at reflux for 30 minutes. The mixture was cooled to rt and the solvent was removed under reduced pressure. The residue was partitioned between dichloromethane and 10% weight / volume aqueous ammonia. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give the title compound as a white solid (319 mg). [373] [374] Preparation Example 7 [375] (2R, 3R, 4R, 5S) -4- (benzoyloxy) -2- [6-[(2,2-diphenylethyl) amino] -2-({[2- (1-piperidinyl)- Ethyl] amino} carbonyl) -9H-purin-9-yl] -5-[(ethylamino) carbonyl] tetrahydro-3-furanyl benzoate [376] [377] 6-[(2,2-diphenylethyl) amino] -N- [2- (1-piperidinyl) ethyl] -9H-purin-2- in 1,1,1-trichloroethane (2 mL) A suspension of carboxamide (Preparation 6) (100 mg, 0.21 mmol) was treated with N, O-bis (trimethylsilyl) acetamide (0.21 mL, 0.85 mmol). The mixture was heated at reflux for 90 minutes. The solution was cooled to rt and the solvent was removed under reduced pressure. The residue was taken up in (2S, 3R, 4R, 5R)-and (2S, 3R, 4R, 5S) -5- (in anhydrous toluene (2 mL) and trimethylsilyl trifluoromethanesulfonate (0.05 mL, 0.30 mmol). Treatment with acetyloxy) -4- (benzoyloxy) -2-[(ethylamino) carbonyl] tetrahydro-3-furanyl benzoate (Preparation 15) (111 mg, 0.25 mmol). The resulting solution was then heated at 90 ° C. under nitrogen atmosphere for 1 hour. TLC analysis indicated that some starting material was still left, so further trimethylsilyl trifluoromethanesulfonate (0.05 mL, 0.30 mmol) was added and heating continued for 2 h. Again, TLC analysis indicated that some starting material was still left, so additional trimethylsilyl trifluoromethanesulfonate (0.025 mL, 0.15 mmol) was added and heating continued for an additional hour. The mixture was cooled to rt, diluted with ethyl acetate (20 mL) and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol (90:10 volume ratio) to give the title compound as a foam (109 mg). [378] [379] Preparation Example 8 [380] 6-[(2,2-diphenylethyl) amino] -9H-purine-2-carbonitrile [381] [382] 6-[(2,2-diphenylethyl) amino] -9-tetrahydro-2H-pyran-2-yl-9H-purin-2-carbonitrile (Preparation 3) in ethanol (850 mL) (17 g , 40.1 mmol) was treated with 2M aqueous hydrochloric acid (50 mL) and the mixture was stirred at rt for 24 h. The solvent is removed under reduced pressure, the residue is dissolved in ethanol and the solvent is removed again under reduced pressure. The residue is triturated with diethyl ether, filtered, washed with diethyl ether and pentane and dried to give the title compound solid. Obtained as (13.6 g). [383] [384] Preparation Example 9 [385] Methyl 6-[(2,2-diphenylethyl) amino] -9H-purine-2-carboxylate [386] [387] 6-[(2,2-diphenylethyl) amino] -9H-purine-2-carbonitrile (Preparation 8) (5.0 g, 14.7 mmol) and sodium methoxide (4.0 g, 74.1) in methanol (300 mL) mmol) was heated at reflux for 24 h. Then additional sodium methoxide (2.0 g, 37 mmol) and methanol (100 mL) were added and heating continued for an additional 24 hours. The reaction mixture was cooled down and the solvent was removed under reduced pressure. The residue was dissolved in THF (375 mL), 2M hydrochloric acid (125 mL) was added and the mixture was stirred at rt for 24 h. THF was removed under reduced pressure and the pH of the suspension was adjusted to 7 with saturated aqueous sodium bicarbonate solution. Ethyl acetate (100 mL) was then added and the white solid based on the desired product was filtered off, washed with a small amount of water and ethyl acetate and dried. Purification by column chromatography on silica gel eluting with a gradient system which gradually changed from dichloromethane: methanol (90:10 volume ratio) to dichloromethane: methanol (75:25 volume ratio) gave the title compound as a white solid (1.25 g). . Ethyl acetate filtrate was evaporated to recover 2.6 g of starting material. [388] [389] Preparation Example 10 [390] Methyl 9-{(2R, 3R, 4R, 5S) -3,4-bis (benzoyloxy) -5-[(ethylamino) carbonyl] -tetrahydro-2-furanyl} -6-[(2, 2-diphenylethyl) amino] -9H-purine-2-carboxylate [391] [392] Methyl 6-[(2,2-diphenylethyl) amino] -9H-purin-2-carboxylate (Preparation 9) in 1,1,1-trichloroethane (25 mL) (440 mg, 1.18 mmol ) Suspension was treated with N, O-bis (trimethylsilyl) acetamide (1.7 mL, 6.95 mmol). The mixture was heated at reflux for 1 h. The solution was cooled to rt and the solvent was removed under reduced pressure. The residue was taken up in (2S, 3R, 4R, 5R)-and (2S, 3R, 4R, 5S) -5- (in anhydrous toluene (25 mL) and trimethylsilyl trifluoromethanesulfonate (0.26 mL, 1.42 mmol). Treated with a solution of acetyloxy) -4- (benzoyloxy) -2-[(ethylamino) carbonyl] tetrahydro-3-furanyl benzoate (Preparation 15) (620 mg, 1.4 mmol). Thereafter, the resulting solution was heated at 110 ° C. under a nitrogen atmosphere for 2.5 hours. The mixture was cooled to rt, diluted with ethyl acetate (200 mL) and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane: ethyl acetate (5: 1 volume ratio) followed by dichloromethane: ethyl acetate (1: 1 volume ratio) to give the title compound as a foam (540 mg). [393] [394] Preparation Example 11 [395] Methyl 6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro- 2-furanyl} -9H-purine-2-carboxylate [396] [397] Methyl 9-{(2R, 3R, 4R, 5S) -3,4-bis (benzoyloxy) -5-[(ethylamino) carbonyl] -tetrahydro-2-furanyl} in dry methanol (60 mL) A solution of -6-[(2,2-diphenylethyl) amino] -9H-purine-2-carboxylate (Preparation 10) (3.4 g, 4.5 mmol) and sodium carbonate (50 mg) was added at room temperature for 4 hours. Was stirred. The solvent was removed under reduced pressure and the residue was taken up in a mixture of dichloromethane: methanol (95: 5 vol. Ratio, 60 mL). The inorganic salts were filtered off and the filtrate was evaporated under reduced pressure. The residue was triturated with ether, filtered and dried to give the target compound as a white solid (2.4 g). [398] [399] Preparation Example 12 [400] (3aS, 4S, 6R, 6aR) -N-ethyl-6-methoxy-2,2-dimethyltetrahydrofuro [3,4-d] [1,3] dioxol-4-carboxamide [401] [402] Oxalyl chloride (14.0 mL, 160 mmol) was added (3aR, 4S, 6R, 6aR) -6-methoxy-2,2- in anhydrous dichloromethane (120 mL) and N, N-dimethylformamide (2 drops). Stirred solution of dimethyltetrahydrofuro [3,4-d] [1,3] dioxol-4-carboxylic acid (J. Am. Chem. Soc., 1958, 80, 5168) (23.30 g, 107 mmol) Was added dropwise and the mixture was stirred at room temperature for 3 hours until gas evolution ceased. TLC analysis indicated that some starting material was still left, so additional N, N-dimethylformamide (2 drops) was added and stirring continued for 1 hour. The solvent was removed under reduced pressure and the residue was azeotropic distilled with anhydrous dichloromethane (x 2). The residue was then dissolved in anhydrous dichloromethane (200 mL) and the solution was treated dropwise with ethylamine (2M in tetrahydrofuran, 140 mL, 280 mmol). This solution was left at room temperature for 48 hours. Diethyl ether (250 mL) was added and the mixture was stirred for 15 minutes. The mixture is filtered and the solvent is removed from the filtrate under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system gradually changing from dichloromethane: ethyl acetate (100: 0 volume ratio) to dichloromethane: ethyl acetate (44:66 volume ratio) to afford the title compound as a yellow solid. Obtained (24.70 g). [403] [404] Preparation Example 13 [405] (2S, 3S, 4R, 5R)-and (2S, 3S, 4R, 5S) -N-ethyl-3,4-dihydroxy-5-methoxytetrahydro-2-furancarboxamide [406] [407] (3aS, 4S, 6R, 6aR) -N-ethyl-6-methoxy-2,2-dimethyltetrahydrofuro [3,4-d] [1,3] dioxol-4- in methanol (500 mL) A solution of carboxamide (Preparation 12) (24.60 g, 100 mmol) and pyridinium p-toluenesulfonate (2.50 g, 10 mmol) was heated at reflux for 18 h. NMR analysis indicated that some starting material remained. The solvent was removed under reduced pressure. The residue was dissolved in methanol (500 mL) and heated at reflux for 8 h. NMR analysis indicated that some starting material was still left, so that the solvent was removed one or more times under reduced pressure. The residue was dissolved in methanol (500 mL) and the resulting solution was heated to reflux for 24 h. The solvent was then removed under reduced pressure and the residue was azeotropic distilled with dichloromethane (x 3) to afford the title compound as an oil (20.50 g). [408] [409] Preparation Example 14 [410] (2S, 3R, 4R, 5S)-and (2R, 3R, 4R, 5S) -4- (benzoyloxy) -5-[(ethylamino) carbonyl] -2-methoxytetrahydro-3-furanyl Benzoate [411] [412] A solution of benzoyl chloride (30.0 mL, 259 mmol) in dichloromethane (100 mL) was added to (2S, 3S, 4R, 5R)-and (2S, 3S, 4R, 5S) -N-ethyl in dichloromethane (400 mL). Slowly added to a solution of -3,4-dihydroxy-5-methoxytetrahydro-2-furancarboxamide (Preparation Example 13) (20.50 g, 100 mmol) and pyridine (33.0 mL, 409 mmol), The resulting mixture was stirred at rt for 18 h. The solvent was removed under reduced pressure and the residue was partitioned between diethyl ether and hydrochloric acid (1M, 300 mL). The layers were separated and the aqueous layer was reextracted with diethyl ether. The organic layers were combined, washed sequentially with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system which gradually changed from dichloromethane: diethyl ether (95: 5 volume ratio) to dichloromethane: diethyl ether (80:20 volume ratio) to give the title compound as an oil. And as a mixture of α and β anomers (37.0 g). [413] [414] Preparation Example 15 [415] (2S, 3R, 4R, 5R)-and (2S, 3R, 4R, 5S) -5- (acetyloxy) -4- (benzoyloxy) -2-[(ethylamino) carbonyl] tetrahydro-3- Furanyl benzoate [416] [417] (2S, 3R, 4R, 5S)-and (2R, 3R, 4R, 5S) -4- (benzoyloxy) -5 in a mixture of acetic acid (330 mL, 5.77 mol) and acetic anhydride (67 mL, 709 mmol) A solution of-[(ethylamino) carbonyl] -2-methoxytetrahydro-3-furanyl benzoate (Preparation 14) (37.0 g, 89.6 mmol) was cooled to -10 ° C and hydrochloric acid (12N, 7.0 132 mmol) was added dropwise. The mixture was stirred for 18 hours, during which time it was warmed to room temperature. The mixture was cooled to 0 ° C., then diluted with water (1000 mL) and then extracted with ethyl acetate (3 × 500 mL). The organic layers were combined, washed sequentially with water, saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system that gradually changed from diethyl ether: pentane (66:44 volume ratio) to diethyl ether: pentane (100: 0 volume ratio). The residue was further purified by column chromatography on silica gel, eluting with a gradient system which gradually changed from dichloromethane: diethyl ether (95: 5 volume ratio) to dichloromethane: diethyl ether (90:10 volume ratio) to give the title compound. Was obtained as a mixture of α and β anomers (15.40 g). [418] [419] (2S, 3R, 4R, 5R)-and (2S, 3R, 4R, 5S) -5- (acetyloxy) -4- (benzoyloxy) -2-[(propylamino) carbonyl] tetrahydro-3- Furanyl benzoate was prepared in a similar manner. [420] Preparation Example 16 [421] 2- [2- (4-isopropyl-1-piperidinyl) ethyl] -1 H-isoindole-1,3 (2H) -dione [422] [423] A solution of 4-isopropylpiperidine (3.3 g, 20.2 mmol) and 2-bromoethylphthalimide (5.4 g, 21.3 mmol) in acetonitrile (100 mL) with potassium carbonate (5.9 g, 45.4 mmol) The treatment was heated at reflux for 2.5 h and then stirred at rt overnight. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was separated and the aqueous layer was extracted with additional ethyl acetate (100 mL). The combined organic extracts were dried over sodium sulfate and the solvent was removed under reduced pressure. The resulting oil was purified by column chromatography on silica gel eluting with a gradient system changing from dichloromethane: diethyl ether (50:50 volume ratio) to pure diethyl ether to give the title compound (3.3 g). [424] [425] Preparation Example 17 [426] 2- (4-isopropyl-1-piperidinyl) ethylamine [427] [428] (2- [2- (4-isopropyl-1-piperidinyl) ethyl] -1H-isoindole-1,3 (2H) -dione in 33% methylamine solution in ethanol (60 mL) (Preparation 16 ) (3.2 g, 10.6 mmol) was heated at reflux for 3 h The solvent was removed under reduced pressure, additional ethanol (60 mL) was added and the solvent was removed again under reduced pressure. Suspended in methane (100 mL), the solid was filtered off and washed with additional dichloromethane (100 mL) The filtrate was evaporated under reduced pressure and diluted with dichloromethane: methanol: concentrated aqueous ammonia (90: 10: 1 volume ratio). Elution and purification by column chromatography on silica gel yielded a colorless oil, which was subjected to bulb to bulb distillation (150-160 ° C., 30 mm Hg) to give the title compound (1.0 g). [429] [430] Preparation Example 18 [431] (2R, 3R, 4S, 5S) -2- (2-amino-6-chloro-9H-purin-9-yl) -4- (benzoyloxy) -5-[(ethylamino) carbonyl] -tetrahydro 3-furanyl benzoate [432] [433] A suspension of 2-amino-6-chloropurine (4.60 g, 27.13 mmol) in 1,1,1-trichloroethane (230 mL) was charged with N, O-bis (trimethylsilyl) acetamide (20 mL, 81.4 mmol). Treated with. The mixture was heated at reflux for 6 hours. The solution was cooled to rt and the solvent was removed under reduced pressure. The residue was taken up in (2S, 3R, 4R, 5R)-and (2S, 3R, 4R, 5S) -5- (in anhydrous toluene (230 mL) and trimethylsilyl trifluoromethanesulfonate (20 mL, 108.5 mmol). Treatment with a solution of acetyloxy) -4- (benzoyloxy) -2-[(ethylamino) carbonyl] tetrahydro-3-furanyl benzoate (Preparation 15) (14.39 g, 32.6 mmol). The resulting solution was then heated at 90 ° C. under nitrogen atmosphere for 90 minutes. The mixture was cooled to rt, diluted with ethyl acetate (250 mL), washed with saturated aqueous sodium hydrogen carbonate solution (350 mL) and then brine (350 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol (98: 2 volume ratio) to give the title compound as a white foam (8.1 g). [434] [435] Preparation Example 19 [436] (2R, 3R, 4S, 5S) -4- (benzoyloxy) -2- (6-chloro-2-iodo-9H-purin-9-yl) -5-[(ethylamino) carbonyl] -tetra Hydro-3-furanyl benzoate [437] [438] n-butyl nitrite (4.65 mL, 39.7 mmol) was added (2R, 3R, 4S, 5S) -2- (2-amino-6-chloro-9H-purin-9-yl) -4 in THF (100 mL). -(Benzoyloxy) -5-[(ethylamino) carbonyl] -tetrahydro-3-furanyl benzoate (Preparation 18) (8.10 g, 14.7 mmol), iodine (3.73 g, 14.7 mmol), copper iodide (I) to a suspension of (6.16 g, 32.3 mmol) and diiodomethane (12.55 mL, 155.8 mmol) and the mixture was heated at reflux for 2.5 h. The solution was cooled to rt and the solvent was removed under reduced pressure. The residue was partitioned between aqueous sodium metabisulfite solution (5%, 100 mL) and dichloromethane (100 mL). The organic layer was separated, filtered through arbacel, dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol (99: 1 volume ratio) to give the title compound as a yellow foam (7.55 g, 78%). [439] [440] Preparation Example 20 [441] (2R, 3R, 4S, 5S) -4- (benzoyloxy) -2- {6-[(2-benzyl-3-phenylpropyl) amino] -2-iodo-9H-purin-9-yl}- 5-[(ethylamino) carbonyl] tetrahydro-3-furanyl benzoate [442] [443] ((2R, 3R, 4S, 5S) -4- (benzoyloxy) -2- (6-chloro-2-iodo-9H-purin-9-yl) -5-[(ethyl in isopropanol (10 mL) A solution of amino) carbonyl] -tetrahydro-3-furanyl benzoate (Preparation 19) (0.25 g, 0.38 mmol) and 2-benzyl-3-phenylpropylamine (0.16 g, 0.76 mmol) was added at room temperature to 48 The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol (99: 1 volume ratio) to give the title compound as a yellow foam (0.26 g, 83%). ). [444] [445] Preparation Example 21 [446] (2R, 3R, 4S, 5S) -4- (benzoyloxy) -2- (6-{[2,2-bis (3-phenyl) ethyl] amino} -2-iodo-9H-purine-9- Yl) -5-[(ethylamino) carbonyl] tetrahydro-3-furanyl benzoate [447] [448] ((2R, 3R, 4S, 5S) -4- (benzoyloxy) -2- (6-chloro-2-iodo-9H-purin-9-yl) -5- [ Prepared from (ethylamino) carbonyl] -tetrahydro-3-furanyl benzoate (Preparation 19) and 2,2-bis (phenyl) ethylamine The title compound was obtained as a yellow foam. [449] [450] Preparation Example 22 [451] (2R, 3R, 4S, 5S) -4- (benzoyloxy) -5-[(ethylamino) carbonyl] -2- {6-[(1-ethylpropyl) amino] -2-iodo-9H- Purin-9-yl} tetrahydro-3-furanyl benzoate [452] [453] ((2R, 3R, 4S, 5S) -4- (benzoyloxy) -2- (6-chloro-2-iodo-9H-purin-9-yl) -5- [ Prepared from (ethylamino) carbonyl] -tetrahydro-3-furanyl benzoate (Preparation 19) and 1-ethylpropylamine The title compound was obtained as a yellow foam. [454] [455] Preparation Example 23 [456] (2R, 3R, 4S, 5S) -4- (benzoyloxy) -2- (6-{[(1S) -1-benzyl-2-hydroxyethyl] amino} -2-iodo-9H-purine- 9-yl) -5-[(ethylamino) carbonyl] tetrahydro-3-furanyl benzoate [457] [458] ((2R, 3R, 4S, 5S) -4- (benzoyloxy) -2- (6-chloro-2-iodo-9H-purin-9-yl) -5- [ Prepared from (ethylamino) carbonyl] -tetrahydro-3-furanyl benzoate (Preparation 19) and (2S) -2-amino-3-phenyl-1-propanol The title compound was obtained as a yellow foam. [459] [460] Preparation Example 24 [461] (2R, 3R, 4S, 5S) -4- (benzoyloxy) -5-[(ethylamino) carbonyl] -2- {6-[(9H-fluorene-9-ylmethyl) amino] -2- Iodo-9H-purin-9-yl} tetrahydro-3-furanyl benzoate [462] [463] ((2R, 3R, 4S, 5S) -4- (benzoyloxy) -2- (6-chloro-2-iodo-9H-purin-9-yl) -5- [ Prepared from (ethylamino) carbonyl] -tetrahydro-3-furanyl benzoate (Preparation 19) and 9H-fluorene-9-ylmethylamine The title compound was obtained as a yellow foam. [464] [465] Preparation Example 25 [466] (2R, 3R, 4S, 5S) -4- (benzoyloxy) -2- [6- (cyclohexylamino) -2-iodo-9H-purin-9-yl] -5-[(ethylamino) car Carbonyl] tetrahydro-3-furanyl benzoate [467] [468] ((2R, 3R, 4S, 5S) -4- (benzoyloxy) -2- (6-chloro-2-iodo-9H-purin-9-yl) -5- [ Prepared from (ethylamino) carbonyl] -tetrahydro-3-furanyl benzoate (Preparation 19) and cyclohexylamine The title compound was obtained as a yellow foam. [469] [470] Preparation Example 26 [471] (2S, 3S, 4R, 5R) -5- {6-[(2-benzyl-3-phenylpropyl) amino] -2-iodo-9H-purin-9-yl} -N-ethyl-3,4 -Dihydroxytetrahydro-2-furancarboxamide [472] [473] (2R, 3R, 4S, 5S) -4- (benzoyloxy) -2- {6-[(2-benzyl-3-phenylpropyl) amino] -2-iodo-9H-purine in methanol (5 mL) A solution of -9-yl} -5-[(ethylamino) carbonyl] tetrahydro-3-furanyl benzoate (Preparation 20) (0.26 g, 0.31 mmol) and sodium carbonate (33 mg, 0.3 mmol) was room temperature Stirred for 14 h. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane: methanol (99: 1 volume ratio; 5 mL) and filtered. The solvent was again evaporated under reduced pressure and the residue was triturated with diethyl ether to give the title compound as a beige powder (0.17 g, 86%). [474] [475] Preparation Example 27 [476] (2S, 3S, 4R, 5R) -5- {6-[(2,2-diphenylethyl) amino] -2-iodo-9H-purin-9-yl} -N-ethyl-3,4- Dihydroxytetrahydro-2-furancarboxamide [477] [478] (2R, 3R, 4S, 5S) -4- (benzoyloxy) -2- (6-{[2,2-bis (3-phenyl) ethyl] amino} -2-iodo by the same method as in Preparation Example 26 Fig. 9H-Purin-9-yl) -5-[(ethylamino) carbonyl] tetrahydro-3-furanyl benzoate (Preparation 21). The title compound was obtained as a yellow powder. [479] [480] Preparation Example 28 [481] (2S, 3S, 4R, 5R) -N-ethyl-5- {6-[(1-ethylpropyl) amino] -2-iodo-9H-purin-9-yl} -3,4-dihydroxy Tetrahydro-2-furancarboxamide [482] [483] (2R, 3R, 4S, 5S) -4- (benzoyloxy) -5-[(ethylamino) carbonyl] -2- {6-[(1-ethylpropyl) amino] by the same method as in Production Example 26 2-iodo-9H-purin-9-yl} tetrahydro-3-furanyl benzoate (Preparation 22). The title compound was obtained as a yellow powder. [484] [485] Preparation Example 29 [486] (2S, 3S, 4R, 5R) -5- (6-{[(1S) -1-benzyl-2-hydroxyethyl] amino} -2-iodo-9H-purin-9-yl) -N- Ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide [487] [488] (2R, 3R, 4S, 5S) -4- (benzoyloxy) -2- (6-{[(1S) -1-benzyl-2-hydroxyethyl] amino} -2 by the same method as in Preparation Example 26 -Iodo-9H-purin-9-yl) -5-[(ethylamino) carbonyl] tetrahydro-3-furanyl benzoate (Preparation 23). The title compound was obtained as a yellow powder. [489] [490] Preparation Example 30 [491] (2S, 3S, 4R, 5R) -N-ethyl-5- {6-[(9H-fluorene-9-ylmethyl) amino] -2-iodo-9H-purin-9-yl} -3, 4-dihydroxytetrahydro-2-furancarboxamide [492] [493] By (2R, 3R, 4S, 5S) -4- (benzoyloxy) -5-[(ethylamino) carbonyl] -2- {6-[(9H-fluorene-9- Ilmethyl) amino] -2-iodo-9H-purin-9-yl} tetrahydro-3-furanyl benzoate (Preparation 24). The title compound was obtained as a yellow powder. [494] [495] Preparation Example 31 [496] (2S, 3S, 4R, 5R) -5- [6- (cyclohexylamino) -2-iodo-9H-purin-9-yl] -N-ethyl-3,4-dihydroxytetrahydro-2 Furancarboxamide [497] [498] (2R, 3R, 4S, 5S) -4- (benzoyloxy) -2- [6- (cyclohexylamino) -2-iodo-9H-purin-9-yl]-in the same manner as in Production Example 26- Prepared from 5-[(ethylamino) carbonyl] tetrahydro-3-furanyl benzoate (Preparation 25). The title compound was obtained as a yellow powder. [499]
权利要求:
Claims (55) [1" claim-type="Currently amended] A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. <Formula I> Where R 1 is optionally substituted by one or two substituents each independently selected from hydrogen, C 1 -C 6 alkyl or C 3 -C 7 cycloalkyl (each of hydroxyl, fluorenyl, phenyl and naphthyl, and Phenyl and naphthyl are optionally substituted by C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo or cyano); A is a bond or C 1 -C 6 alkylene; R 2 is (i) hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, phenyl or naphthyl (the C 3 -C 7 cycloalkyl, phenyl and naphthyl are C 1 -C 6 alkyl, phenyl , C 1 -C 6 alkoxy- (C 1 -C 6 ) -alkyl, amino- (C 1 -C 6 ) -alkyl, fluoro- (C 1 -C 6 ) -alkyl, fluoro- (C 1- C 6 ) -alkoxy, C 2 -C 5 alkanoyl, halo, -OR 3 , cyano, -COOR 3 , C 3 -C 7 cycloalkyl, -S (O) m R 4 , -NR 3 R 3 , Optionally substituted by -SO 2 NR 3 R 3 , -CONR 3 R 3 , -NR 3 COR 4 or -NR 3 SO 2 R 4 , provided that when A is a bond, R 2 is not hydrogen, or (ii) when A is C 2 -C 6 alkylene, -NR 3 R 3 , -OR 3 , -COOR 3 , -OCOR 4 , -SO 2 R 4 , -CN, -SO 2 NR 3 R 4 ,- NR 3 SO 2 R 4 , -NR 3 COR 4 or -CONR 3 R 3, or (iii) C-linked 4 to 11 membered mono or bicyclic heterocycle (optionally oxo, having 1 to 4 ring nitrogen atom (s) or 1 or 2 nitrogen, and 1 oxygen or 1 sulfur ring atom COne-C6Alkoxy- (COne-C6) -Alkyl, amino- (COne-C6) -Alkyl, fluoro- (COne-C6) -Alkyl, fluoro- (COne-C6) -Alkoxy, fluoro- (C2-C5) -Alkane oil, halo, cyano, -OR5, R6, -COR5, -NR5R5, -COOR5, -S (O)mR6, -SO2NR5R5, -CONR5R5, -NR5SO2R6Or -NR5COR6C-substituted by, optionally COne-C6Alkoxy- (COne-C6) -Alkyl, amino- (C2-C6) -Alkyl, fluoro- (COne-C6) -Alkyl, fluoro- (C2-C5) -Alkane oil, R6, -COR5, -COOR6, -SO2R6, -SO2NR5R5Or -CONR5R5N-substituted by) or (iv) when A is C 2 -C 6 alkylene, N-linked azetidinyl, pyrrolidinyl, morpholinyl, tetrahydroisoquinolinyl, piperidinyl or piperazinyl (each optionally C 1- ); C 6 alkyl, phenyl, C 1 -C 6 alkoxy- (C 1 -C 6 ) -alkyl, amino- (C 1 -C 6 ) -alkyl, fluoro- (C 1 -C 6 ) -alkyl, fluoro - (C 1 -C 6) - alkoxy, C 2 -C 5 - alkanoyl, halo, -OR 3, cyano, -COOR 3, C 3 -C 7 cycloalkyl, -S (O) m R 4 , C-substituted by -NR 3 R 3 , -SO 2 NR 3 R 3 , -CONR 3 R 3 , -NR 3 COR 4 or -NR 3 SO 2 R 4 , wherein the piperazinyl is optionally C 1 -C 6 alkyl, phenyl, C 1 -C 6 alkoxy- (C 1 -C 6 ) -alkyl, amino- (C 2 -C 6 ) -alkyl, fluoro- (C 1 -C 6 ) -alkyl, C 2- N 5 -substituted by C 5 -alkanoyl, -COOR 4 , C 3 -C 7 cycloalkyl, -SO 2 R 4 , -SO 2 NR 3 R 3 or -CONR 3 R 3 ; Each R 3 is independently selected from H, C 1 -C 6 alkyl, phenyl or pyridinyl; R 4 is C 1 -C 6 alkyl or phenyl; R 5 is H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, phenyl, naphthyl or het; R 6 is C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, phenyl, naphthyl or het; m is 0, 1 or 2; R 7 is hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, phenyl, naphthyl, azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl, piperi Din-4-yl or het, wherein the azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl and piperidin-4-yl are optionally substituted by C 1 -C 6 alkyl Become; R 8 is H or C 1 -C 6 alkyl; As used in the definitions of R 5 , R 6 and R 7 , “het” refers to C-linked pyrrolyl, imidazolyl, triazolyl, thienyl, furyl, thiazolyl, oxazolyl, thiadiazolyl, oxdiazolyl, Pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, quinazolinyl, phthalazinyl, benzoxazolyl or quinoxalinyl (each C 1 -C 6 alkyl, C 1 -C 6 alkoxy, cyano or halo. [2" claim-type="Currently amended] The compound of claim 1, wherein R 1 is cyclohexyl or optionally substituted C 1 -C 6 alkyl. [3" claim-type="Currently amended] The compound of claim 2, wherein R 1 is optionally substituted C 1 -C 5 alkyl. [4" claim-type="Currently amended] The compound of claim 3, wherein R 1 is optionally substituted C 1 -C 2 alkyl. [5" claim-type="Currently amended] 5. The compound of claim 2, wherein the C 1 -C 6 , C 1 -C 5 or C 1 -C 2 alkyl substituent is selected from benzyl, fluorenyl, phenyl and hydroxyl. [6" claim-type="Currently amended] 6. A compound according to claim 5, wherein R 1 is substituted by one or two phenyl groups when substituted by phenyl. [7" claim-type="Currently amended] 6. The compound of claim 2, wherein R 1 is 2,2-diphenylethyl, cyclohexyl, 1-ethylpropyl, 1-benzyl-2-hydroxyethyl, 9H-fluorene-9- Compound selected from monomethyl and 1-benzyl-2-phenylethyl. [8" claim-type="Currently amended] 8. A compound according to claim 7, wherein R 1 is diphenylethyl. [9" claim-type="Currently amended] The compound of claim 8, wherein R 1 is 2,2-diphenylethyl. [10" claim-type="Currently amended] The compound of any one of claims 1-9, wherein A is C 1 -C 6 alkylene. [11" claim-type="Currently amended] The compound of claim 10, wherein A is C 1 -C 4 alkylene. [12" claim-type="Currently amended] 12. A compound according to claim 11, wherein A is selected from methylene, 1,2-ethylene, 1,3-propylene and 1,4-butylene. [13" claim-type="Currently amended] 13. The compound of claim 12, wherein A is 1,2-ethylene. [14" claim-type="Currently amended] 14. The compound of claim 1, wherein R 2 is phenyl, pyrrolidinyl, pyridinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted imidazolyl, morpholinyl , Tetrahydroisoquinolyl, C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, pyridinylamino and —NR 3 SO 2 R 4 . [15" claim-type="Currently amended] The compound of claim 14, wherein R 2 is phenyl, 2-pyridinyl, 1-piperidinyl, 4-piperazinyl, 1-pyrrolidinyl, 4-morpholinyl, 3,4-tetrahydro-2 (1H ) -Isoquinolinyl, C 1 -C 3 alkylamino, di-C 1 -C 3 alkylamino and substituted 1H-imidazol-4-yl. [16" claim-type="Currently amended] The compound of claim 15, wherein R 2 is 3-isopropylamino, methylamino, dimethylamino, diethylamino, 1-methyl-1H-imidazol-4-yl, 5-methyl-1H-imidazol-4-yl , 4-methylpiperazin-1-yl, 1- (2-propyl) piperidin-4-yl and 2-pyridylamino. [17" claim-type="Currently amended] The compound of claim 15, wherein R 2 is piperidinyl optionally substituted by C 1 -C 6 alkyl or methoxy. [18" claim-type="Currently amended] 18. The compound of claim 17, wherein R 2 is piperidinyl optionally substituted at the 1-position or 4-position by C 1 -C 6 alkyl or methoxy. [19" claim-type="Currently amended] 19. The compound of claim 18, wherein R 2 is N-linked piperidinyl optionally C-substituted with C 1 -C 6 alkyl or methoxy. [20" claim-type="Currently amended] The compound of claim 19, wherein R 2 is N-linked piperidinyl optionally C-substituted with C 1 -C 3 alkyl or methoxy. [21" claim-type="Currently amended] The compound of claim 20, wherein R 2 is N-linked piperidinyl optionally C-substituted by methyl, methoxy or propyl. [22" claim-type="Currently amended] The compound of claim 21, wherein R 2 is N-linked piperidinyl optionally substituted at the 4-position by methyl, methoxy or propyl. [23" claim-type="Currently amended] The method of claim 22, wherein R 2 is piperidin-1-yl, 4- (methyl) piperidin-1-yl, 4- (methoxy) piperidin-1-yl or 4- (prop- 2-yl) piperidin-1-yl. [24" claim-type="Currently amended] The compound of any one of claims 1-23 wherein R 3 is methyl. [25" claim-type="Currently amended] The compound of any one of claims 1-24, wherein R 4 is methyl or phenyl. [26" claim-type="Currently amended] The compound of any one of claims 1-25, wherein R 7 is C 1 -C 6 alkyl. [27" claim-type="Currently amended] The compound of claim 26, wherein R 7 is C 1 -C 4 alkyl. [28" claim-type="Currently amended] The compound of claim 27, wherein R 7 is ethyl or n-propyl. [29" claim-type="Currently amended] 29. The compound of any one of claims 1-28, wherein R 8 is H. [30" claim-type="Currently amended] The method of claim 1, 6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2 -Furanyl} -N- (2-pyridinylmethyl) -9H-purine-2-carboxamide; N-benzyl-6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5- (ethylamino) carbonyl] -3,4-dihydroxytetra Hydro-2-furanyl} -9H-purine-2-carboxamide; 6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2 -Furanyl} -N- (2-phenylethyl) -9H-purine-2-carboxamide; N- [2- (dimethylamino) ethyl] -6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} -9H-purine-2-carboxamide; 6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2 -Furanyl} -N- [3- (1-pyrrolidinyl) propyl] -9H-purine-2-carboxamide; 6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2 -Furanyl} -N- [2- (2-pyridinyl) ethyl] -9H-purine-2-carboxamide; 6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2 -Furanyl} -N- [2- (4-morpholinyl) ethyl] -9H-purine-2-carboxamide; 9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} -6-[(1-ethylpropyl) amino ] -N- [2- (1-piperidinyl) ethyl] -9H-purine-2-carboxamide; 6-{[(1S) -1-benzyl-2-hydroxyethyl] amino} -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-di Hydroxytetrahydro-2-furanyl} -N- [2- (1-piperidinyl) ethyl] -9H-purine-2-carboxamide; 6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2 -Furanyl} -N- [2- (4-isopropyl-1-piperidinyl) ethyl] -9H-purine-2-carboxamide; N- [2- (3,4-dihydro-2 (1H) -isoquinolinyl) ethyl] -6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S , 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} -9H-purine-2-carboxamide; 6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2 -Furanyl} -N- (4-piperidinylmethyl) -9H-purine-2-carboxamide; 6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2 -Furanyl] -N- [4- (1-piperidinyl) butyl] -9H-purine-2-carboxamide; 6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2 -Furanyl} -N- [3- (isopropylamino) propyl] -9H-purine-2-carboxamide; 6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2 -Furanyl} -N- [3- (2-pyridinylamino) propyl] -9H-purine-2-carboxamide; 6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2 -Furanyl} -N- {3- [methyl (phenylsulfonyl) amino] propyl} -9H-purine-2-carboxamide; 6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2 -Furanyl} -N- {3- [methyl (methylsulfonyl) amino] propyl} -9H-purine-2-carboxamide; 9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} -6-[(9H-fluorene-9 -Ylmethyl) amino] -N- [2- (1-piperidinyl) ethyl] -9H-purine-2-carboxamide; N- [3- (diethylamino) propyl] -6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl ] -3,4-dihydroxytetrahydro-2-furanyl} -9H-purine-2-carboxamide; 6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2 -Furanyl} -N- [3- (4-morpholinyl) propyl] -9H-purine-2-carboxamide; 6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2 -Furanyl} -N- [3- (methylamino) propyl] -9H-purine-2-carboxamide; 6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2 -Furanyl} -N- [2- (5-methyl-1H-imidazol-4-yl) ethyl] -9H-purine-2-carboxamide; N- [4- (dimethylamino) butyl] -6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} -9H-purine-2-carboxamide; 6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2 -Furanyl} -N- [3- (4-methyl-1-piperazinyl) propyl] -9H-purine-2-carboxamide; N- [3- (dimethylamino) propyl] -6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} -9H-purine-2-carboxamide; 6-[(1-benzyl-2-phenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro- 2-furanyl} -N- [2- (1-piperidinyl) ethyl] -9H-purine-2-carboxamide; 9-{(2R, 3R, 4S, 5S) -3,4-dihydroxy-5-[(propylamino) carbonyl] tetrahydro-2-furanyl} -6-[(2,2-diphenyl Ethyl) amino] -N- [2- (1-piperidinyl) ethyl] -9H-purine-2-carboxamide; 6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2 -Furanyl} -N- [2- (1-isopropyl-4-piperidinyl) ethyl] -9H-purine-2-carboxamide; 6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2 -Furanyl} -N- [2- (4-methyl-1-piperidinyl) ethyl] -9H-purine-2-carboxamide; 6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2 -Furanyl} -N- [2- (4-methoxy-1-piperidinyl) ethyl] -9H-purine-2-carboxamide; 6-[(2,2-diphenylethyl) amino] -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2 -Furanyl} -N-[(1-methyl-1H-imidazol-4-yl) methyl] -9H-purin-2-carboxamide; And 6- (cyclohexylamino) -9-{(2R, 3R, 4S, 5S) -5-[(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} -N- A compound selected from the group comprising [2- (1-piperidinyl) ethyl] -9H-purine-2-carboxamide, or a pharmaceutically acceptable salt or solvate thereof. [31" claim-type="Currently amended] 31. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof of any one of claims 1 to 30 together with a pharmaceutically acceptable excipient, diluent or carrier. [32" claim-type="Currently amended] 31. A compound of formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof of any one of claims 1 to 30 for use as a medicament. [33" claim-type="Currently amended] 31. Use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or composition of any one of claims 1 to 30 for the manufacture of a medicament for the treatment of a disease in which the use of an A2a receptor agonist is required. [34" claim-type="Currently amended] Use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof of any one of claims 1 to 30 for the preparation of an anti-inflammatory agent. [35" claim-type="Currently amended] Use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof according to any one of claims 1 to 30 for the manufacture of a medicament for the treatment of respiratory diseases. [36" claim-type="Currently amended] 36. The use of claim 35, wherein the disease is selected from the group consisting of adult respiratory distress syndrome (ARDS), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, bronchial dilatation, chronic sinusitis and rhinitis. [37" claim-type="Currently amended] Septic shock, male erectile dysfunction, hypertension, seizures, epilepsy, cerebral ischemia, peripheral vascular disease, post-ischaemic reperfusion injury, diabetes, rheumatoid arthritis, multiple sclerosis, psoriasis, allergic dermatitis, eczema, ulcerative colitis , Crohn's disease, inflammatory bowel disease, gastritis caused by Helicobacter pylori, gastritis not caused by Helicobacter pylori, nonsteroidal anti-inflammatory agents-induced damage to the gastrointestinal tract, or for treating psychotic disorders, or for the manufacture of a medicament for wound healing Use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof of any one of claims 30-30. [38" claim-type="Currently amended] Use of an A2a receptor agonist, comprising treating a mammal, including a human, with an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof according to any one of claims 1-30. A method of treating said mammal for treating a disease. [39" claim-type="Currently amended] A mammal for treating an inflammatory disease comprising treating a mammal, including a human, with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof according to any one of claims 1 to 30. Method of treatment of animals. [40" claim-type="Currently amended] The mammal for treating a respiratory disease comprising treating a mammal, including a human, with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof according to any one of claims 1 to 30. Method of treatment of animals. [41" claim-type="Currently amended] 41. The method of claim 40, wherein said disease is selected from the group consisting of adult respiratory distress syndrome (ARDS), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, bronchial dilatation, chronic sinusitis and rhinitis. [42" claim-type="Currently amended] Septic shock, male erectile dysfunction, comprising treating a mammal, including a human, with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof according to any one of claims 1 to 30, Hypertension, seizures, epilepsy, cerebral ischemia, peripheral vascular disease, post-ischemic reperfusion injury, diabetes, rheumatoid arthritis, multiple sclerosis, psoriasis, allergic dermatitis, eczema, ulcerative colitis, Crohn's disease, inflammatory bowel disease, gastritis caused by Helicobacter pylori And a method of treating said mammal for treating gastritis not caused by Helicobacter pylori, nonsteroidal anti-inflammatory agent-induced damage to the gastrointestinal tract, or psychotic disorders or for wound healing. [43" claim-type="Currently amended] A compound of formula II, III, XI, XIII, XIV, XV, XVI, XIX, XIXb, XIXc or XIXd. <Formula II> <Formula III> <Formula XI> <Formula XIII> <Formula XIV> <Formula XV> <Formula XVI> <Formula XIX> <Formula XIXb> <Formula XIXc> <Formula XIXd> Where R 1 to R 8 , A, “het” and where present m are as defined above, P 1 , P 2 and P 3 are protecting groups, Z is a leaving group. [44" claim-type="Currently amended] A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising reacting an ester of formula (II) with an amine of formula (X). <Formula II> <Formula X> R 2 -A-NHR 8 Where R 1 to R 8 , A, “het” and, where present, m are as defined in claim 1. [45" claim-type="Currently amended] A process for preparing a compound of formula II, comprising the step of deprotecting a compound of formula III. <Formula II> <Formula III> Where P 1 and P 2 may be the same or different protecting groups, or may be part of the same protecting group, R 1 to R 8 , A, “het” and, where present, m are as defined in claim 1. [46" claim-type="Currently amended] Reacting a compound of formula XI with trimethylsilyltrifluoromethanesulfonate and a compound of formula IV, wherein the compound of formula IV is induced with N, O-bis (trimethylsilyl) acetamide, Reacting with a compound of formula (II). <Formula III> <Formula XI> <Formula IV> Where R 1 to R 8 , A, “het” and, where present, m are as defined in claim 1. [47" claim-type="Currently amended] A process for preparing a compound of formula (IV) by performing alcoholic decomposition and then hydrolysis of a nitrile of formula (V). <Formula IV> <Formula V> Where R 1 to R 8 , A, “het” and, where present, m are as defined in claim 1. [48" claim-type="Currently amended] A process for preparing a compound of formula V by deprotecting a compound of formula VI: <Formula V> <Formula VI> Where P 3 is a protecting group, R 1 to R 8 , A, “het” and, where present, m are as defined in claim 1. [49" claim-type="Currently amended] A process for preparing the compound of formula VI by replacing the chloro group of the compound of formula VII with a cyano group. <Formula VI> <Formula VII> Where R 1 to R 8 , A, “het” and, where present, m are as defined in claim 1. [50" claim-type="Currently amended] A process for preparing a compound of formula VII by reacting a compound of formula VIII with an amino of formula XII. <Formula VII> <Formula VIII> <Formula XII> R 1 NH 2 Where R 1 to R 8 , A, “het” and, where present, m are as defined in claim 1. [51" claim-type="Currently amended] A process for preparing a compound of formula VIII by protecting 2,6-dichloro-9H-purine of formula IX: <Formula VIII> <Formula IX> [52" claim-type="Currently amended] A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising deprotecting a compound of formula (XIII): <Formula XIII> Where P 1 and P 2 are protecting groups, R 1 to R 8 , A, “het” and, where present, m are as defined in claim 1. [53" claim-type="Currently amended] Formula XIII comprising reacting a compound of Formula XI with trimethylsilyl trifluoromethanesulfonate and a compound of Formula XIV as defined in claim 43 (derived from N, O-bis (trimethylsilyl) acetamide) Process for preparing a compound of the present invention or a pharmaceutically acceptable salt thereof. <Formula XI> Where R 1 to R 8 , A, “het” and, where present, m are as defined in claim 1. [54" claim-type="Currently amended] A process for preparing the compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising condensing an acid of formula (XIX) with an amine of formula (X). <Formula X> R 2 -A-NHR 8 <Formula XIX> [55" claim-type="Currently amended] A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising the step of aminocarbonylating a compound of formula (XIXb) with a compound of formula (X) in the presence of carbon monoxide. <Formula X> R 2 -A-NHR 8 <Formula XIXb> Wherein Z is a suitable leaving group.
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同族专利:
公开号 | 公开日 DE60119492T2|2006-11-09| EA004987B1|2004-10-28| HRP20020676A2|2004-12-31| EP1255764A1|2002-11-13| US20010020089A1|2001-09-06| MA26873A1|2004-12-20| SV2002000317A|2002-07-16| ES2260199T3|2006-11-01| PL357220A1|2004-07-26| DE60119492D1|2006-06-14| EA200200770A1|2002-12-26| NO20023894D0|2002-08-16| TNSN01028A1|2005-11-10| SK11692002A3|2003-11-04| EP1255764B1|2006-05-10| GB0003960D0|2000-04-12| BG106906A|2003-04-30| EE200200452A|2003-12-15| PA8511801A1|2002-02-21| CA2400619A1|2001-08-23| HN2001000027A|2001-09-11| MXPA02008068A|2004-04-05| PE20011122A1|2001-11-06| IS6458A|2002-07-05| WO2001060835A1|2001-08-23| BR0108408A|2002-11-26| CZ20022703A3|2003-09-17| AR027437A1|2003-03-26| CN1400975A|2003-03-05| GT200100027A|2001-12-19| HU0301055A2|2003-08-28| US6525032B2|2003-02-25| WO2001060835A8|2001-11-29| OA12177A|2006-05-09| JP2004508284A|2004-03-18| CO5271668A1|2003-04-30| AU3044001A|2001-08-27| CR6722A|2003-11-25| NO20023894L|2002-10-01| NZ519971A|2004-04-30| IL150543D0|2003-02-12| AT325807T|2006-06-15| AP200202598A0|2002-09-30| ZA200206526B|2003-10-16| EP1255764B8|2006-06-28|
引用文献:
公开号 | 申请日 | 公开日 | 申请人 | 专利标题
法律状态:
2000-02-18|Priority to GB0003960.2 2000-02-18|Priority to GBGB0003960.2A 2001-02-09|Application filed by 화이자 인코포레이티드 2003-05-09|Publication of KR20030036138A
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申请号 | 申请日 | 专利标题 GB0003960.2|2000-02-18| GBGB0003960.2A|GB0003960D0|2000-02-18|2000-02-18|Purine derivatives| 相关专利
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