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    • 专利摘要:
    Imidazopyridine compounds containing amine functionality substituted in the 1-position are useful as immune response modulators. The compounds and compositions of the present invention can induce the biosynthesis of various cytokines and are useful in the treatment of a variety of diseases, including viral and neoplastic diseases.
    公开号:KR20030070048A
    申请号:KR10-2003-7007533
    申请日:2001-12-06
    公开日:2003-08-27
    发明作者:카일제이. 린드스트롬
    申请人:쓰리엠 이노베이티브 프로퍼티즈 컴파니；
    IPC主号:
    专利说明:

    Substituted Imidazopyridines
    [2] Backman et al . , The first reliable report on the 1H-imidazo [4,5-c] quinoline ring system, see J. Org. Chem. 15, 1278-1284 (1950)] is described the synthesis of 1- (6-methoxy-8-quinolinyl) -2-methyl-1H-imidazo [4,5-c] quinoline that can be used as an antimalarial agent It is. Subsequently, the synthesis of various substituted 1H-imidazo [4,5-c] quinolines was reported. For example, Jain et al. Synthesized compound 1- [2- (4-piperidyl) ethyl] -1H-imidazo [4,5-c] quinoline that can be used as an anticonvulsant and cardiovascular agent [ J. Med. Chem. 11, pp. 87-92 (1968). In addition, Baranov et al. Reported several 2-oxoimidazo [4,5-c] quinolines [ Chem. Abs. 85, 94362 (1976), Berenyi et al. Reported 2-oxoimidazo [4,5-c] quinoline [ J. Heterocyclic Chem. 18, 1537-1540 (1981).
    [3] Certain 1H-imidazo [4,5-c] quinolin-4-amines and their 1- and 2-substituted derivatives were later found to be useful as antiviral agents, bronchodilators and immunomodulators. These are described in particular in US Pat. Nos. 4,689,338, 4,698,348, 4,929,624, 5,037,986, 5,268,376, 5,346,905 and 5,389,640, which are incorporated herein by reference.
    [4] Substituted 1H-imidazopyridin-4-amine compounds useful as immune response modulators are described in US Pat. Nos. 5,446,153, 5,494,916 and 5,644,063. The compounds described in this patent do not have amine containing substituents at the 1-position. Certain 1H-imidazo [4,5-c] quinolin-4-amines having amide, sulfonamide and urea functionality in the 1-position are described in PCT publications WO 00/76505, WO 00/76518 and WO 00/76519. It is.
    [5] Despite the recent discovery of compounds useful as immune response modulators, there is a continuing need for compounds that can modulate the immune response by inducing cytokine biosynthesis or other mechanisms.
    [1] The present invention relates to an imidazopyridine compound having an amine function substituted in the 1-position, and a pharmaceutical composition containing the compound. The present invention further relates to the use of said compounds as immunomodulators for inducing cytokine biosynthesis in animals and for the treatment of diseases including viral and neoplastic diseases.
    [6] Summary of the Invention
    [7] The inventors have discovered a new group of compounds useful for inducing cytokine biosynthesis in animals. Accordingly, the present invention provides an imidazopyridin-4-amine compound having an amine function substituted in the 1-position. Compounds that have been found to be useful inducers of cytokine biosynthesis are defined by Formula (I), described in more detail below. Formula (I) is as follows:
    [8]
    [9] Wherein X, Y, Z, R 1 , R 2 , R 3 , R 4 and R 5 are as defined herein.
    [10] Compounds of formula (I) are useful as immune response modulators when administered to animals because they can induce cytokine biosynthesis or otherwise modulate the immune response. Because of this, the compounds are useful for the treatment of various diseases such as tumors and viral diseases that are responsive to changes in the immune response.
    [11] The invention further provides a pharmaceutical composition containing an immune response modulating compound, and a method of inducing cytokine biosynthesis in an animal by administering a compound of formula (I) to the animal, a method for treating a viral infection in an animal, and / or) Provided are methods for treating neoplastic disease in an animal.
    [12] In addition, the present invention provides methods for synthesizing the compounds of the invention and intermediates useful for the synthesis of these compounds.
    [13] Detailed description of the invention
    [14] As mentioned above, the inventors have discovered that certain compounds induce cytokine biosynthesis in animals and modulate immune responses. The compound is represented by the formula (I) or a pharmaceutically acceptable salt thereof:
    [15] <Formula I>
    [16]
    [17] (Wherein
    [18] X is alkylene or alkenylene;
    [19] Y is -CO-, -CS- or -SO 2- ;
    [20] Z is a bond, -O-, -S- or -NR 5- ;
    [21] R 1 is unsubstituted or alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, substituted cycloalkyl, -O-alkyl, -O- (alkyl) 0-1 -aryl, -O- (alkyl) 0-1 -heteroaryl, -O- (alkyl) 0-1 -heterocyclyl, -COOH, -CO-O-alkyl, -CO-alkyl, -S (O) 0-2 alkyl, -S (O ) 0-2- (alkyl) 0-1 -aryl, -S (O) 0-2- (alkyl) 0-1 -heteroaryl, -S (O) 0-2- (alkyl) 0-1 -hetero Cyclyl,-(alkyl) 0-1 -N (R 5 ) 2 ,-(alkyl) 0-1 -NR 5 -CO-O-alkyl,-(alkyl) 0-1 -NR 5 -CO-alkyl, -(Alkyl) 0-1 -NR 5 -CO-aryl,-(alkyl) 0-1 -NR 5 -CO-heteroaryl, N 3 , halogen, haloalkyl, haloalkoxy, -CO-haloalkyl, -CO Aryl, heteroaryl, hetero substituted by one or more substituents independently selected from the group consisting of -haloalkoxy, -NO 2 , -CN, -OH, -SH and oxo (if alkyl, alkenyl and heterocyclyl) Cyclyl, C 1-20 alkyl or C 2-20 alkenyl;
    [22] R 2 is hydrogen, alkyl, alkenyl, -alkyl-O-alkyl, -alkyl-S-alkyl, -alkyl-O-aryl, -alkyl-S-aryl, -alkyl-O-alkenyl, -alkyl-S -Alkenyl, and -OH, halogen, -N (R 5 ) 2 , -CO-N (R 5 ) 2 , -CS-N (R 5 ) 2 , -SO 2 -N (R 5 ) 2 ,- NR 5 -CO-C 1-10 alkyl, -NR 5 -CS-C 1-10 alkyl, -NR 5 -SO 2 -C 1-10 alkyl, -CO-C 1-10 alkyl, -CO-OC 1 -10 alkyl, N 3 , aryl, heteroaryl, heterocyclyl, -CO-aryl and -CO-heteroaryl is selected from the group consisting of alkyl or alkenyl substituted by one or more substituents selected from the group consisting of;
    [23] R 3 and R 4 are independently selected from the group consisting of alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino and alkylthio;
    [24] Each R 5 is independently hydrogen or C 1-10 alkyl.
    [25] Preparation of the compound
    [26] Compounds of the invention can be prepared according to Scheme I, wherein R 1 , R 2 , R 3 , R 4 , R 5 , X, Y and Z are as defined above, Bn is benzyl and R 'is Alkyl having 1 to 4 carbon atoms, perfluoroalkyl having 1 to 4 carbon atoms, phenyl, or phenyl substituted by halogen or alkyl having 1 to 4 carbon atoms.
    [27] In step (1) of Scheme I, 3-nitropyridine-2,4-disulfonate of formula X is reacted with an amine of formula R 1 -ZYN (R 5 ) -X-NH 2 to obtain 3- Obtain nitro-4-aminopyridine-2-sulfonate. Since there are in principle two sulfonate groups which can be substituted, the reaction can provide a mixture of products which can be easily separated using conventional techniques such as column chromatography. Preferably, the reaction is carried out by adding the amine to a solution of the compound of formula X in a suitable solvent such as dichloromethane in the presence of a tertiary amine such as triethylamine. Since sulfonate groups are relatively easy leaving groups, the reaction can be carried out at low temperatures (0 ° C.) to reduce the amount of unwanted 2-aminoated and 2,4-diaminoated by-products. 3-nitropyridine-2,4-sulfonate is known and can be readily prepared using known synthetic methods. See, eg, US Pat. No. 5,446,153 to Lindstom et al. And the references cited therein.
    [28] In step (2) of Scheme I, 3-nitro-4-aminopyridine-2-sulfonate of formula (XI) is reacted with dibenzylamine to react 2-dibenzylamino-3-nitropyridin-4-amine of formula (XII) Get The reaction is carried out by mixing a compound of formula XI, a tertiary amine such as dibenzylamine, and triethylamine in an inert solvent such as benzene, toluene or xylene, and heating the resulting mixture.
    [29] In step (3) of Scheme I, the nitro group of 2-dibenzylamino-3-nitropyridin-4-amine of formula XII is reduced to an amino group. Preferably, the reduction is carried out using NiB 2 generated in situ from sodium borohydride and nickel chloride hydrate in methanol. Preferably, the reaction is carried out at ambient temperature.
    [30] In step (4) of Scheme I, 2-dibenzylaminopyridine-3,4-diamine of formula XIII is reacted with a carboxylic acid or an equivalent thereof to 4-dibenzylamino-1H-imidazo [4] , 5-c] pyridine. Suitable carboxylic acid equivalents include orthoesters and 1,1-dialkoxyalkyl alkanoates. Carboxylic acids or equivalents are chosen such that they provide the desired R 2 substituents in the formula XV compound. For example, triethyl orthoformate will provide compounds wherein R 2 is hydrogen, and triethyl orthoacetate will provide compounds where R 2 is methyl. The reaction can be carried out in the absence of solvent or in an inert solvent such as toluene. The reaction is carried out with sufficient heating to remove any alcohol or water formed as a byproduct of the reaction. Optionally, a catalyst such as pyridine hydrochloride may be included.
    [31] Alternatively, the compound of formula XV can be prepared by (a) reacting an acyl halide of formula R 2 C (O) Cl or R 2 C (O) Br with a diamine of formula XIII to obtain a compound of formula XIV, and then (b) cyclization This can be produced in two steps. In step (4a), acyl halides are added to a solution of diamine in an inert solvent such as acetonitrile, pyridine or dichloromethane. The reaction can be carried out at ambient temperature. In step (4b), the product of step (4a) is heated in an alcoholic solvent in the presence of a base. Preferably, the product of step (4a) is refluxed in ethanol in the presence of excess triethylamine or heated with methanolic ammonia. Alternatively, step (4b) can be carried out by heating the product of step (4a) in pyridine. When step (4a) is carried out in pyridine, step (4b) can be carried out by heating the reaction mixture after confirming by analysis that step (4a) is complete.
    [32] In step (5) of Scheme I, 4-dibenzylamino-1H-imidazo [4,5-c] pyridine of formula (XV) is hydrolyzed to form 4-amino-1H-imidazo [4,5] of formula (I). -c] pyridine. Preferably, the compound of formula XV is heated in formic acid in the presence of palladium hydroxide on carbon. Conventional methods may be used to separate the product or a pharmaceutically acceptable salt thereof.
    [33]
    [34] Compounds of the invention can be prepared according to Scheme II, wherein R 1 , R 2 , R 3 , R 4 , R 5 and X are as defined above, Bn is benzyl and BOC is tert-butoxycar Carbonyl and W is O or S.
    [35] In step (1) of Scheme II, the amine protecting group of 1H-imidazo [4,5-c] pyridine of formula XVI is removed to give 1H-imidazo [4,5-c] pyridine of formula II. Preferably, a solution of the compound of formula XVI in a suitable solvent such as dichloromethane is treated with triflic acid at ambient temperature. Synthetic XVI compounds can be prepared using the synthetic methods described in Scheme I. In step (1), the 2,4-disulfonate of formula X is reacted with an amine of formula BOC-NR 5 -X-NH 2 . Subsequently, steps 2-4 are carried out as described above to give the compound of formula XVI which is a subgenus of formula XV.
    [36] In step (2a) of Scheme II, the 1H-imidazo [4,5-c] pyridine of Formula II is either an acid chloride of Formula R 1 -C (O) Cl or Formula R 1 -C (O) OC (O) Reaction with the acid anhydride of —R 1 gives the 1H-imidazo [4,5-c] pyridin-1-yl amide of formula XVII which is a subgenus of formula (I). Preferably, the reaction is carried out by adding acid chlorides or acid anhydrides to a solution of the compound of formula II in a suitable solvent such as dichloromethane or acetonitrile in the presence of a base such as triethylamine. The reaction can be carried out at low temperature (0 ° C.) or at ambient temperature. Conventional methods may be used to separate the product or a pharmaceutically acceptable salt thereof.
    [37] In step (2b) of Reaction Scheme II, the Formula II 1H- imidazo [4,5-c] pyridine formula R 1 -N = C = O in the formula or an isocyanate R 1 -N = C = S of the isothiocyanate Reaction with Nate yields 1H-imidazo [4,5-c] pyridin-1-yl urea or thiourea of formula XVIII, which is a subgenus of formula (I). Preferably, the reaction is carried out by adding isocyanate or isothiocyanate to a solution of the compound of formula II in a suitable solvent such as dichloromethane at low temperature (0 ° C.). Conventional methods may be used to separate the product or a pharmaceutically acceptable salt thereof.
    [38] In step (2c) of Scheme II, the 1H-imidazo [4,5-c] pyridine of Formula II is substituted with sulfonyl chloride of Formula R 1 -S (O) 2 Cl or Formula R 1 -S (O) 2 OS Reaction with (O) 2 -R 1 sulfonic anhydride yields 1H-imidazo [4,5-c] pyridin-1-yl sulfonamide of formula XIX, which is a subgenus of formula (I). Preferably, the reaction is carried out by adding sulfonyl chloride or sulfonic anhydride to a solution of the compound of formula II in a suitable solvent such as dichloromethane in the presence of a base such as triethylamine. The reaction can be carried out at low temperature (0 ° C.) or at ambient temperature. Conventional methods may be used to separate the product or a pharmaceutically acceptable salt thereof.
    [39]
    [40] Compounds of the invention can be prepared according to Scheme III, wherein R 1 , R 2 , R 3 , R 4 , R 5 and X are as defined above.
    [41] In step (1) of Scheme III, the 1H-imidazo [4,5-c] pyridine of Formula II is reacted with sulfamoyl chloride of Formula R 1 -N (R 5 ) S (O) 2 Cl to obtain Obtain 1H-imidazo [4,5-c] pyridin-1-yl sulfamide of Formula XXI as a subgen. Preferably, sulfamoyl chloride is added to a solution of the compound of formula II in a suitable solvent such as 1,2-dichloroethane in the presence of a base such as triethylamine. The reaction can be carried out at elevated temperature. Conventional methods may be used to separate the product or a pharmaceutically acceptable salt thereof.
    [42] Alternatively, (a) reacting 1H-imidazo [4,5-c] pyridine of Formula (II) with sulfuryl chloride to generate sulfamoyl chloride of Formula (XX) in situ, and (b) sulfamoyl chloride is represented by Formula R 1 The sulfamide of Formula XXI can be prepared in two steps by reacting with an amine of —N (R 5 ) H. In step (1a), the reaction can be carried out by adding a solution of sulfuryl chloride in dichloromethane to a solution of the compound of formula II in the presence of 1 equivalent of 4- (dimethylamino) pyridine. Preferably, the reaction is carried out at low temperature (-78 ° C). Optionally, after the addition is complete, the reaction mixture may be raised to ambient temperature. In step (1b), a solution containing 2 equivalents of R 1 -N (R 5 ) H and 2 equivalents of triethylamine in dichloromethane is added to the reaction mixture of step (1a). Preferably, the reaction is carried out at low temperature (-78 ° C). Conventional methods may be used to separate the product or a pharmaceutically acceptable salt thereof.
    [43]
    [44] Compounds of the invention can be prepared according to Scheme IV, wherein R 1 , R 2 , R 3 , R 4 , R 5 and X are as defined above and BOC is tert-butoxycarbonyl.
    [45] In step (1) of Scheme IV, 2,4-dihydroxy-3-nitropyridine of formula (XXII) is chlorinated using conventional chlorinating agent to give 2,4-dichloro-3-nitropyridine of formula (XXIII). Preferably, the compound of formula XXII is mixed with oxyphosphoric chloride and heated. Many 2,4-dihydroxy-3-nitropyridine of formula (XXII) are known, others can be easily prepared using known synthetic methods. See, eg, US Pat. No. 5,446,153 to Lindstorm et al. And the references cited therein.
    [46] In step (2) of Scheme IV, 2,4-dichloro-3-nitropyridine of formula XXIII is reacted with an amine of formula BOC-NR 5 -X-NH 2 to give 2-chloro-3-nitropyridine of formula XXIV. Get Preferably, the reaction is carried out by adding an amine to a solution of the compound of formula XXIII in a suitable solvent such as N, N-dimethylformamide in the presence of a tertiary amine such as triethylamine.
    [47] In step (3) of Scheme IV, 2-chloro-3-nitropyridine of formula XXIV is reacted with phenol to give 3-nitro-2-phenoxypyridine of formula XXV. The phenol is reacted with sodium hydride in a suitable solvent such as diglyme to form phenoxide. The phenoxide is then reacted with the compound of formula XXIV at elevated temperature.
    [48] In step (4) of Scheme IV, 3-nitro-2-phenoxypyridine of formula XXV is reduced to give 3-amino-2-phenoxypyridine of formula XXVI. Preferably, the reaction is carried out using conventional heterogenous hydrogenation catalysts such as platinum on carbon or palladium on carbon. The reaction can conveniently be carried out with a Parr device in a suitable solvent such as isopropyl alcohol or toluene.
    [49] In step (5) of Scheme IV, 3-amino-2-phenoxypyridine of formula XXVI is reacted with a carboxylic acid or an equivalent thereof to 4-phenoxy-1H-imidazo [4,5-c of formula IV] ] Quinoline is obtained. Suitable equivalents of carboxylic acids include orthoesters and 1,1-dialkoxyalkyl alkanoates. Carboxylic acids or equivalents are selected to provide the preferred R 2 substituents in the compound of formula IV. For example, triethyl orthoformate will provide compounds in which R 2 is hydrogen and trimethyl orthovalerate will provide compounds in which R 2 is butyl. The reaction can be carried out in the absence of solvent or in an inert solvent such as toluene. The reaction is carried out with sufficient heating to remove any alcohol or water formed as a byproduct of the reaction. Optionally, a catalyst such as pyridine hydrochloride may be included.
    [50] Alternatively, step (5) may be performed by (i) reacting an acyl halide of formula R 2 C (O) Cl or R 2 C (O) Br with a compound of formula XXVI, and then (ii) cyclization. . In part (i), acyl halides are added to a solution of the compound of formula XXV in an inert solvent such as acetonitrile, pyridine or dichloromethane. The reaction can be carried out at ambient temperature. In part (ii), the product of part (i) is heated in pyridine.
    [51] In step (6) of Scheme IV, the BOC group is removed from the compound of formula IV to give 4-phenoxy-1H-imidazo [4,5-c] quinoline of formula V. Preferably, a solution of the compound of formula IV in a suitable solvent such as dichloromethane is treated with trifluoroacetic acid or hydrochloric acid at low temperature.
    [52] In step (7) of Scheme IV, 4-phenoxy-1H-imidazo [4,5-c] quinoline of formula V is converted to 4-phenoxy- of formula VI using the method of step (2c) of scheme II. Convert to 1H-imidazo [4,5-c] quinolin-1-yl sulfonamide.
    [53] In step (8) of Scheme IV, the 4-phenoxy-1H-imidazo [4,5-c] quinolin-1-yl sulfonamide of Formula VI is a 4-amino-1H- of Formula XIX that is a subgenus of Formula I Amination with imidazo [4,5-c] quinolin-1-yl sulfonamide. The reaction may be carried out by mixing the compound of formula VI with ammonium acetate and heating (about 150 ° C.) in a sealed tube. Conventional methods may be used to separate the product or a pharmaceutically acceptable salt thereof.
    [54]
    [55] The present invention also provides novel compounds useful as intermediates in the synthesis of compounds of formula (I). The intermediate has the formulas (II) to (VI) described in more detail below.
    [56] One group of intermediate compounds has the formula (II) or a pharmaceutically acceptable salt thereof:
    [57]
    [58] (Wherein
    [59] X is alkylene or alkenylene;
    [60] R 2 is hydrogen, alkyl, alkenyl, -alkyl-O-alkyl, -alkyl-S-alkyl, -alkyl-O-aryl, -alkyl-S-aryl, -alkyl-O-alkenyl, -alkyl-S -Alkenyl, and -OH, halogen, -N (R 5 ) 2 , -CO-N (R 5 ) 2 , -CS-N (R 5 ) 2 , -SO 2 -N (R 5 ) 2 ,- NR 5 -CO-C 1-10 alkyl, -NR 5 -CS-C 1-10 alkyl, -NR 5 -SO 2 -C 1-10 alkyl, -CO-C 1-10 alkyl, -CO-OC 1 -10 alkyl, N 3 , aryl, heteroaryl, heterocyclyl, -CO-aryl and -CO-heteroaryl is selected from the group consisting of alkyl or alkenyl substituted by one or more substituents selected from the group consisting of;
    [61] R 3 and R 4 are independently selected from the group consisting of alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino and alkylthio;
    [62] Each R 5 is independently hydrogen or C 1-10 alkyl.
    [63] Another group of intermediate compounds have the formula (III) or a pharmaceutically acceptable salt thereof:
    [64]
    [65] (Wherein
    [66] Q is NO 2 or NH 2 ;
    [67] X is alkylene or alkenylene;
    [68] R 3 and R 4 are independently selected from the group consisting of alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino and alkylthio;
    [69] Each R 5 is independently hydrogen or C 1-10 alkyl.
    [70] Another group of intermediate compounds have the formula (IV) or a pharmaceutically acceptable salt thereof:
    [71]
    [72] (Wherein
    [73] X is alkylene or alkenylene;
    [74] R 2 is hydrogen, alkyl, alkenyl, -alkyl-O-alkyl, -alkyl-S-alkyl, -alkyl-O-aryl, -alkyl-S-aryl, -alkyl-O-alkenyl, -alkyl-S -Alkenyl, and -OH, halogen, -N (R 5 ) 2 , -CO-N (R 5 ) 2 , -CS-N (R 5 ) 2 , -SO 2 -N (R 5 ) 2 ,- NR 5 -CO-C 1-10 alkyl, -NR 5 -CS-C 1-10 alkyl, -NR 5 -SO 2 -C 1-10 alkyl, -CO-C 1-10 alkyl, -CO-OC 1 -10 alkyl, N 3 , aryl, heteroaryl, heterocyclyl, -CO-aryl and -CO-heteroaryl is selected from the group consisting of alkyl or alkenyl substituted by one or more substituents selected from the group consisting of;
    [75] R 3 and R 4 are independently selected from the group consisting of alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino and alkylthio;
    [76] Each R 5 is independently hydrogen or C 1-10 alkyl.
    [77] Another group of intermediate compounds have the formula (V) or a pharmaceutically acceptable salt thereof:
    [78]
    [79] (Wherein
    [80] X is alkylene or alkenylene;
    [81] R 2 is hydrogen, alkyl, alkenyl, -alkyl-O-alkyl, -alkyl-S-alkyl, -alkyl-O-aryl, -alkyl-S-aryl, -alkyl-O-alkenyl, -alkyl-S -Alkenyl, and -OH, halogen, -N (R 5 ) 2 , -CO-N (R 5 ) 2 , -CS-N (R 5 ) 2 , -SO 2 -N (R 5 ) 2 ,- NR 5 -CO-C 1-10 alkyl, -NR 5 -CS-C 1-10 alkyl, -NR 5 -SO 2 -C 1-10 alkyl, -CO-C 1-10 alkyl, -CO-OC 1 -10 alkyl, N 3 , aryl, heteroaryl, heterocyclyl, -CO-aryl and -CO-heteroaryl is selected from the group consisting of alkyl or alkenyl substituted by one or more substituents selected from the group consisting of;
    [82] R 3 and R 4 are independently selected from the group consisting of alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino and alkylthio;
    [83] Each R 5 is independently hydrogen or C 1-10 alkyl.
    [84] Another group of intermediate compounds have the general formula (VI) or a pharmaceutically acceptable salt thereof:
    [85]
    [86] (Wherein
    [87] X is alkylene or alkenylene;
    [88] R 1 is unsubstituted or alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, substituted cycloalkyl, -O-alkyl, -O- (alkyl) 0-1 -aryl, -O- (alkyl) 0-1 -heteroaryl, -O- (alkyl) 0-1 -heterocyclyl, -COOH, -CO-O-alkyl, -CO-alkyl, -S (O) 0-2 alkyl, -S (O ) 0-2- (alkyl) 0-1 -aryl, -S (O) 0-2- (alkyl) 0-1 -heteroaryl, -S (O) 0-2- (alkyl) 0-1 -hetero Cyclyl,-(alkyl) 0-1 -N (R 5 ) 2 ,-(alkyl) 0-1 -NR 5 -CO-O-alkyl,-(alkyl) 0-1 -NR 5 -CO-alkyl, -(Alkyl) 0-1 -NR 5 -CO-aryl,-(alkyl) 0-1 -NR 5 -CO-heteroaryl, N 3 , halogen, haloalkyl, haloalkoxy, -CO-haloalkyl, -CO Aryl, heteroaryl, hetero substituted by one or more substituents independently selected from the group consisting of -haloalkoxy, -NO 2 , -CN, -OH, -SH and oxo (if alkyl, alkenyl and heterocyclyl) Cyclyl, C 1-20 alkyl or C 2-20 alkenyl;
    [89] R 2 is hydrogen, alkyl, alkenyl, -alkyl-O-alkyl, -alkyl-S-alkyl, -alkyl-O-aryl, -alkyl-S-aryl, -alkyl-O-alkenyl, -alkyl-S -Alkenyl, and -OH, halogen, -N (R 5 ) 2 , -CO-N (R 5 ) 2 , -CS-N (R 5 ) 2 , -SO 2 -N (R 5 ) 2 ,- NR 5 -CO-C 1-10 alkyl, -NR 5 -CS-C 1-10 alkyl, -NR 5 -SO 2 -C 1-10 alkyl, -CO-C 1-10 alkyl, -CO-OC 1 -10 alkyl, N 3 , aryl, heteroaryl, heterocyclyl, -CO-aryl and -CO-heteroaryl is selected from the group consisting of alkyl or alkenyl substituted by one or more substituents selected from the group consisting of;
    [90] R 3 and R 4 are independently selected from the group consisting of alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino and alkylthio;
    [91] Each R 5 is independently hydrogen or C 1-10 alkyl.
    [92] As used herein, the terms "alkyl", "alkenyl" and the prefix "alk-" include both straight and branched chain and cyclic groups (ie, cycloalkyl and cycloalkenyl). Unless otherwise specified, these groups contain 1-20 carbon atoms and alkenyl groups contain 2-20 carbon atoms. Preferred groups have a total of up to 10 carbon atoms. The cyclic group may be monocyclic or polycyclic and preferably has 3 to 10 ring carbon atoms. Examples of cyclic groups include cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl and adamantyl.
    [93] The term "haloalkyl" includes groups substituted by one or more halogen atoms, including perfluorinated groups. This also applies to groups containing the prefix "halo-". Examples of suitable haloalkyl groups are chloromethyl, trifluoromethyl and the like.
    [94] As used herein, the term "aryl" includes carbocyclic aromatic rings or ring systems. Examples of aryl groups include phenyl, naphthyl, biphenyl, fluorenyl and indenyl. The term “heteroaryl” includes aromatic rings or ring systems containing one or more ring heteroatoms (eg, O, S, N). Examples of suitable heteroaryl groups include furyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, indolyl, isoindoleyl, triazolyl, pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, Thiazolyl, benzofuranyl, benzothiophenyl, carbazolyl, benzoxazolyl, pyrimidinyl, benzimidazolyl, quinoxalinyl, benzothiazolyl, naphthyridinyl, isoxazolyl, isothiazolyl, furinyl , Quinazolinyl and the like.
    [95] “Heterocyclyl” includes non-aromatic rings or ring systems containing one or more ring heteroatoms (eg, O, S, N) and includes both fully saturated and partially unsaturated derivatives of the aforementioned heteroaryl groups. . Examples of heterocyclyl groups include pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, thiazolidinyl, isothiazolidinyl and imidazolidinyl.
    [96] Aryl, heteroaryl and heterocyclyl groups are unsubstituted or alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, haloalkylthio, halogen, nitro, hydroxy, mercapto, cyano, carboxy, formyl, aryl , Aryloxy, arylthio, arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroarylalkoxy, heteroarylalkylthio, amino, alkylamino, dialkylamino, heterocyclyl, heterocycloalkyl , Alkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl, arylcarbonyl, heteroarylcarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aryl Thiocarbonyl, heteroarylthiocarbonyl, alkanoyloxy, alkanoylthio, alkanoylamino, arylcarbonyloxy, arylcarbonylthio, alkylaminosulfonyl, alkyl Sulfonyl, arylsulfonyl, heteroarylsulfonyl, aryldiazinyl, alkylsulfonylamino, arylsulfonylamino, arylalkylsulfonylamino, alkylcarbonylamino, alkenylcarbonylamino, arylcarbonylamino, arylalkyl Carbonylamino, heteroarylcarbonylamino, heteroarylalkylcarbonylamino, alkylsulfonylamino, alkenylsulfonylamino, arylsulfonylamino, arylalkylsulfonylamino, heteroarylsulfonylamino, heteroarylalkylsulfonylamino , Alkylaminocarbonylamino, alkenylaminocarbonylamino, arylaminocarbonylamino, arylalkylaminocarbonylamino, heteroarylaminocarbonylamino, heteroarylalkylaminocarbonylamino and oxo (for heterocyclyl) It may be substituted by one or more substituents independently selected from the group consisting of. When other groups are described as "substituted" or "optionally substituted", these groups may also be substituted by one or more of the substituents listed above.
    [97] Certain substituents are generally preferred. For example, preferred Y groups are -CO- and -SO 2- , Z is preferably a bond or -NR 5- , and R 1 is preferably C 1-4 alkyl, aryl or substituted aryl. Preferred R 2 groups are alkyl groups having 1 to 4 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl), methoxyethyl, ethoxymethyl and cyclo Propylmethyl. R 3 and R 4 are preferably methyl. One or more of the above preferred substituents, if any, may be present in the compounds of the present invention in any combination.
    [98] The invention includes all pharmaceutically acceptable forms of the compounds described herein, including isomers such as diastereomers and enantiomers, salts, solvates, polymorphs, and the like. In particular, when the compound is optically active, the present invention particularly encompasses each enantiomer and racemic mixture of the enantiomers of the compound.
    [99] Pharmaceutical Compositions and Biological Activities
    [100] The pharmaceutical composition of the present invention contains a therapeutically effective amount of a compound of the present invention together with a pharmaceutically acceptable carrier.
    [101] The term "therapeutically effective amount" means an amount of a compound sufficient to induce a therapeutic effect, such as cytokine induction, antitumor activity and / or antiviral activity. The exact amount of active compound used in the pharmaceutical composition of the present invention will depend on factors known to those skilled in the art, such as the physicochemical properties of the compound, the nature of the carrier and the desired dosing regimen, but the composition of the present invention is about 100 ng / It is expected to include enough active ingredient to provide to the subject a compound of kg to about 50 mg / kg, preferably about 10 μg / kg to about 5 mg / kg. Any conventional formulation can be used, such as tablets, lozenges, parenteral preparations, syrups, creams, ointments, aerosol preparations, transdermal patches, transmucosal patches, and the like.
    [102] The compounds of the present invention may be administered as a monotherapy in a therapeutic regime, or the compounds of the present invention may be mixed with one another or with other active agents, including additional immune response modulators, antiviral agents, antibiotics, and the like.
    [103] In experiments conducted according to the test methods described below, the compounds of the present invention were found to induce the production of certain cytokines. These results indicate that the compounds of the present invention are useful as immune response modulators that can modulate the immune response in a variety of ways, and thus, for the treatment of various diseases.
    [104] Cytokines from which synthesis can be induced by administration of a compound according to the invention generally include interferon-α (IFN-α) and / or tumor necrosis factor-α (TNF-α) as well as certain interleukins (IL). Included. Cytokines from which biosynthesis can be induced by compounds of the invention include IFN-α, TNF-α, IL-1, IL-6, IL-10 and IL-12, and various other cytokines. Among other effects, the compounds of the present invention are useful in the treatment of viral diseases and tumors, because these and other cytokines can inhibit virus production and tumor cell growth. Accordingly, the present invention provides a method for inducing cytokine biosynthesis in an animal comprising administering to the animal an effective amount of a compound or composition of the invention.
    [105] Certain compounds of the present invention preferentially induce the expression of IFN-α in hematopoietic cell populations such as PBMCs (peripheral blood mononuclear cells) containing pDC2 cells (progenitor dendritic cell-type 2), but do not induce significant levels of inflammatory cytokines. It was found not to be incidentally produced.
    [106] In addition to inducing cytokine production, the compounds of the present invention also affect other aspects of the innate immune response. For example, natural killer cell activity, which may be due to cytokine induction, may be stimulated. The compounds of the present invention can also activate macrophages, which in turn stimulate the release of nitric oxide and additional cytokine production. Furthermore, the compounds of the present invention can cause proliferation and differentiation of B-lymphocytes.
    [107] The compounds of the present invention also affect the acquired immune response. For example, it is not considered a direct effect on T cells or direct induction of T cell cytokines, but indirectly induces production of T helper cell type 1 (Th1) cytokine IFN-γ upon administration of a compound of the invention. Production of the T helper type 2 (Th2) cytokines IL-4, IL-5 and IL-13 is inhibited. Such activity means that the compounds of the present invention are useful for treating diseases in which upregulation of the Th1 response and / or downregulation of the Th2 response is required. In that the compounds of the present invention can inhibit the Th2 immune response, the compounds of the present invention may be used for atopic diseases such as atopic dermatitis, asthma, allergy, allergic rhinitis; Treatment of systemic lupus erythematosus; It is expected to be useful as a vaccine adjuvant for cell mediated immune responses and to be used in the treatment of recurrent fungal diseases and chlamydia.
    [108] The compounds of the present invention are useful for the treatment of various diseases due to their immune response modulating effects. Compounds of the invention are particularly useful for the treatment of viral diseases and tumors, as they can induce the production of cytokines such as IFN-α and / or TNF-α. Such immunomodulatory activity is characterized in that the compounds of the present invention are genital warts, vulgaris warts, plantar warts, hepatitis B, hepatitis C, herpes simplex virus type I and type II, infectious continuous species, stool, especially soybean, HIV, Viral diseases including CMV, VZV, rhinovirus, adenovirus, coronavirus, influenza, and parainfluenza; Intraepithelial neoplasms, such as uterine epithelial neoplasms; Human papillomavirus (HPV) and related tumors; Fungal diseases such as Candida, Aspergillus and Cryptococcus meningitis; Neoplastic diseases such as basal cell carcinoma, hairy cell leukemia, Kaposi's sarcoma, renal cell carcinoma, squamous cell carcinoma, myeloid leukemia, multiple myeloma, melanoma, non-Hodgkin's lymphoma, cutaneous T cell lymphoma and other cancers; Parasitic diseases such as pneumocystis carini, Cryptosporidium disease, histoplasmosis, toxoplasmosis, tripanosome infection and lischmaniasis; And bacterial infections such as but not limited to tuberculosis, mycobacterium avium. Other diseases or conditions that can be treated using the compounds of the present invention include actinic keratosis, eczema, eosinophilia, idiopathic thrombocytopenia, leprosy, multiple sclerosis, Omen syndrome, discoid lupus, Bowen disease, Bowen's papules, alopecia areata , Postoperative keloid formation and other forms of postoperative scar suppression. In addition, the compounds of the present invention may enhance or promote wound treatment, including chronic wounds. The compounds of the present invention may be useful for the treatment of opportunistic infections and tumors that occur after inhibition of cell mediated immunity, for example in transplant patients, cancer patients and HIV patients.
    [109] An effective amount of a compound for inducing cytokine biosynthesis is determined by one or more cells such as monocytes, macrophages, dendritic cells and B cells, for example IFN-α, TNF-α, IL-1, IL-6, IL-10. And an amount of at least one cytokine such as IL-12 is sufficient to produce above the usual level of the cytokine. The exact amount will vary depending on factors known in the art, but is expected to be about 100 ng / kg to about 50 mg / kg, preferably about 10 μg / kg to about 5 mg / kg. The invention also provides a method of treating viral infections and neoplastic diseases in an animal comprising administering to the animal an effective amount of a compound or composition of the invention. An effective amount for treating or inhibiting a viral infection is an amount that can cause a reduction in one or more of the signs of viral infection such as viral lesion, viral load, viral production rate and mortality as compared to untreated control animals. The exact amount will vary depending on factors known in the art, but is expected to be about 100 ng / kg to about 50 mg / kg, preferably about 10 μg / kg to about 5 mg / kg. An effective amount of a compound for treating neoplastic disease is an amount that can reduce tumor size or the number of tumor lesions. Again, the exact amount will depend on factors known in the art, but is expected to be about 100 ng / kg to about 50 mg / kg, preferably about 10 μg / kg to about 5 mg / kg.
    [110] The present invention will be further illustrated by the following examples, but these examples are only for illustrating the invention and should not be construed as limiting at all.
    [111] Example 1
    [112] N- [4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl] benzamide
    [113]
    [114] Part A
    [115] Triethylamine (16.8 ml, 123.8 mmol) was added to a suspension of 4-hydroxy-5,6-dimethyl-3-nitro-2 (1H) -pyridone (7.6 g, 41.2 mmol) in dichloromethane (200 ml). Added. The reaction mixture was cooled in an ice bath. Triflic anhydride (13.7 ml, 82.5 mmol) was added and the reaction mixture was stirred for 30 minutes. Mono-tert-butoxycarbonyl-1,4-butyldiamine (7.6 g, 41.2 mmol) was added in one portion and the reaction mixture was allowed to warm to ambient temperature. After 1 h, the reaction mixture was washed with 1% aqueous sodium carbonate solution (2 × 100 ml), dried over magnesium sulfate and then concentrated under reduced pressure to give the crude product. This material was dissolved in dichloromethane and loaded onto a silica gel layer. Silica gel was first eluted with dichloromethane to remove impurities and then eluted with 2-5% ethyl acetate in dichloromethane to afford the desired product. Fractions containing product were combined and then concentrated under reduced pressure to afford 4-({4-[(tert-butoxycarbonyl) amino] butyl} amino) -5,6-dimethyl-3-nitropyridin-2-yl trifluoro 12 g of romethanesulfonate was obtained as a pale yellow oil.
    [116] Part B
    [117] The material from Part A was mixed with triethylamine (2.5 g, 24.7 mmol), dibenzylamine (4.8 g, 24.7 mmol) and toluene (150 ml) and then heated at reflux for 4 hours. The reaction mixture was washed with 1% aqueous sodium carbonate solution and then concentrated under reduced pressure to give a crude product. This material was dissolved in dichloromethane and loaded onto silica gel. Silica gel eluted with 2-20% ethyl acetate in dichloromethane. The fractions containing the product were combined and concentrated under reduced pressure to give tert-butyl 4-{[2- (dibenzylamino) -5,6-dimethyl-3-nitropyridin-4-yl] amino} butylcarbamate g was obtained.
    [118] Part C
    [119] Sodium borohydride (1.4 g, 36 mmol) was added slowly to a solution of nickel chloride hydrate (2.9 g, 12.3 mmol) in methanol and the resulting mixture was stirred for 30 minutes. A solution of the material from Part B in methanol was added at one time. Sodium borohydride was added slowly until the foam became colorless. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The resulting residue was mixed with dichloromethane and the mixture was filtered to remove salts. The filtrate was concentrated under reduced pressure to obtain about 12 g of tert-butyl 4-{[3-amino-2- (dibenzylamino) -5,6-dimethylpyridin-4-yl] amino} butylcarbamate.
    [120] Part D
    [121] Valeryl chloride (3 ml, 24.7 mmol) was added to a solution (200 ml) of material from Part C in acetonitrile. The reaction mixture was stirred at ambient temperature. The reaction mixture was concentrated under reduced pressure. The residue was mixed with ethanol and triethylamine (5 g, 49 mmol). The reaction mixture was heated at reflux overnight and then concentrated under reduced pressure. The resulting residue was partitioned between dichloromethane and water. The dichloromethane layer was separated and then loaded onto a silica gel column. The column was eluted with 9: 90: 1 ethyl acetate: dichloromethane: methanol. Fractions containing product were combined and concentrated under reduced pressure to afford tert-butyl 4- [2-butyl-4- (dibenzylamino) -6,7-dimethyl-1H-imidazo [4,5-c] pyridine-1 6.5 g of butylcarbamate was obtained as an oil.
    [122] Part E
    [123] Triflic acid (16 g, 107 mmol) was added to a solution of the substance from Part D (6.5 g, 11.4 mmol) in dichloromethane (250 ml). The resulting mixture was stirred overnight. Ammonium hydroxide (50 ml) and water (100 ml) were added and the resulting mixture was stirred for 30 minutes. The layers were separated and the aqueous fraction was extracted with dichloromethane (100 ml). The organic fractions were combined, washed sequentially with 1% aqueous sodium carbonate solution and brine, and concentrated under reduced pressure. The residue was mixed with methanol (30 ml), stirred for 30 minutes and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was mixed with an aqueous 1% sodium carbonate solution and stirred. The mixture was extracted with hexane to remove organic impurities. The aqueous layer contained an insoluble oil, which was extracted with dichloromethane. The organic layer was mixed with magnesium sulfate, stirred for 5 minutes and filtered. The filtrate was concentrated under reduced pressure to give a solid, which was recrystallized from toluene to give 1- (4-aminobutyl) -2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-4-amine 1 g was obtained.
    [124] Part F
    [125] Triethylamine (0.07 ml, 0.5 mmol) was added 1- (4-aminobutyl) -2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridine- in dichloromethane (150 ml). To a solution of 4-amine (150 mg, 0.5 mmol) was added. The reaction mixture was cooled in an ice bath. Benzoyl chloride (0.07 ml, 0.5 mmol) was added and the reaction mixture was recovered from an ice bath. The reaction mixture was washed twice with water and then concentrated under reduced pressure. The resulting residue was purified by flash chromatography using 10% methanol in dichloromethane as eluent to obtain an oily brown substance. This material was dissolved in a minimum amount of isopropanol and then ethanesulfonic acid (55 mg, 0.5 mmol) was added with stirring. The reaction mixture was stirred at ambient temperature for about 1 hour and then heated briefly in a sand bath until homogeneous. The solution was cooled to ambient temperature and then cooled in an ice bath. The resulting precipitate was isolated by filtration to give N- [4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl] benzamide 111 mg were obtained as crystalline solid. mp 127.8-128.8 ° C. Anal: calcd for C 23 H 31 N 5 O:% C, 70.20; % H, 7.94; % N, 17.80; Found:% C, 69.82; % H, 7.70; % N, 17.68.
    [126] Example 2
    [127] N- [4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl] methanesulfonamide
    [128]
    [129] Triethylamine (0.07 ml, 0.5 mmol) was added 1- (4-aminobutyl) -2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridine- in dichloromethane (160 ml). To a solution of 4-amine (150 mg, 0.5 mmol) was added. The reaction mixture was cooled in an ice bath. Methanesulfonic anhydride (90 mg, 0.5 mmol) was added and the reaction mixture was recovered from an ice bath. The reaction mixture was stirred for 35 minutes. The reaction mixture was washed three times with water, concentrated under reduced pressure and triturated with minimal amount of methyl acetate. The resulting crystalline solid is isolated by filtration and then dried in an Abderhalden drying apparatus to form N- [4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4]. 94 mg of, 5-c] pyridin-1-yl) butyl] methanesulfonamide was obtained. mp 130-130.5 ° C. Anal: calcd for C 17 H 29 N 5 O 2 S:% C, 55.56; % H, 7.95; % N, 19.06; Found:% C, 55.37; % H, 7.89; % N, 18.03.
    [130] Example 3
    [131] N- [4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl] -4-fluorobenzenesulfonamide hydrate
    [132]
    [133] Triethylamine (0.07 ml, 0.5 mmol) was added 1- (4-aminobutyl) -2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridine- in dichloromethane (150 ml). To a solution of 4-amine (150 mg, 0.5 mmol) was added. The reaction mixture was cooled in an ice bath. 4-fluorobenzenesulfonyl chloride (113 mg, 0.5 mmol) was added and the reaction mixture was recovered from an ice bath. The reaction mixture was stirred at ambient temperature for 48 hours. The reaction mixture was washed with water (2 x 150 ml) and then concentrated under reduced pressure. The resulting residue was recrystallized from methyl acetate and then dried in an Abderhaldene drying apparatus to give N- [4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5-c 50 mg of] pyridin-1-yl) butyl] -4-fluorobenzenesulfonamide hydrate was obtained as a white crystalline solid. mp 133.1-133.7 ° C. Anal: C 22 H 30 FN 5 O 2 S Calcd for H 2 O:% C, 56.75; % H, 6.93; % N, 15.04; Found:% C, 56.99; % H, 6.58; % N, 15.24.
    [134] Example 4
    [135] N- [4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl] -N'-phenylurea
    [136]
    [137] Phenyl isocyanate (0.056 ml, 0.5 mmol) was added 1- (4-aminobutyl) -2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridine-4 in dichloromethane (150 ml). -To a cooled solution of amine (150 mg, 0.5 mmol). The ice bath was removed. After 5 minutes a white precipitate formed. The reaction mixture was stirred for 30 minutes and then concentrated under reduced pressure to yield a greyish white crystalline solid. The material was transferred to a filter using a small amount of diethyl ether and isolated by filtration, and then dried in an Abderhaldene drying apparatus, followed by N- [4- (4-amino-2-butyl-6,7-dimethyl-1H-imide. 185 mg of polyzo [4,5-c] pyridin-1-yl) butyl] -N'-phenylurea were obtained. mp 195.8-196.8 ° C. Anal: calcd for C 23 H 32 N 6 O:% C, 67.62; % H, 7.89; % N, 20.57; Found:% C, 66.84; % H, 7.71; % N, 20.54.
    [138] Example 5
    [139] N- [4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl] -N'-phenylthiourea hydrate
    [140]
    [141] Using the method of Example 4, 1- (4-aminobutyl) -2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-4-amine (100 mg, 0.35 mmol ) Is reacted with phenylisothiocyanate (0.041 ml, 0.35 mmol) to give N- [4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridine- 97 mg of 1-yl) butyl] -N'-phenylthiourea hydrate was obtained as a white crystalline solid. mp 160.0-160.8 ° C. Anal: calcd for C 23 H 32 N 6 SH 2 O:% C, 62.41; % H, 7.74; % N, 18.99; Found:% C, 62.39; % H, 7.47; % N, 18.52.
    [142] Example 6
    [143] N '-[4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl] -N, N-dimethylsulfamide
    [144]
    [145] Triethylamine (0.031 ml, 0.23 mmol) was diluted with 1- (4-aminobutyl) -2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridine- in dichloromethane (45 ml). To a solution of 4-amine (67 mg, 0.23 mmol). The reaction mixture was cooled in an ice bath. Dimethylsulfamoyl chloride (0.025 ml, 0.23 mmol) was added. The reaction mixture was recovered from the ice bath. The reaction mixture was stirred at ambient temperature for about 113 hours. HPLC analysis showed that the reaction was terminated. Dichloromethane was removed under reduced pressure. 1,2-dichloroethane (50 ml) was added and the reaction mixture was heated to 60 ° C. After 3 hours, additional dimethylsulfamoyl chloride (2.5 μl) was added and heating continued. After 22 hours, the reaction temperature was raised to reflux and the reaction mixture was refluxed for 100 hours. The reaction mixture was extracted twice with water. The aqueous fractions were combined and concentrated under reduced pressure. The resulting residue was recrystallized from methyl acetate to give N '-[4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl] 10 mg of -N, N-dimethylsulfamide were obtained as a greyish-white crystalline solid. mp 129.5-131 ° C. M / Z = 397.1 (M + H) + .
    [146] Example 7
    [147] N- [4- (4-amino-2,6,7-trimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl] methanesulfonamide
    [148]
    [149] Part A
    [150] A mixture of 5,6-dimethyl-3-nitropyridine-2,4-diol (60.0 g, 326 mmol) and oxyphosphoric chloride (600 ml) was heated at reflux for 2 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was mixed with ethyl acetate (300 ml) and then filtered. The filtrate was washed with aqueous sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, dried over magnesium sulfate and concentrated under reduced pressure to give a brown solid. This material was purified by chromatography (silica gel, eluting with 60/40 ethyl acetate / hexanes) to give 55 g of 2,4-dichloro-5,6-dimethyl-3-nitropyridine.
    [151] Part B
    [152] To a mixture of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (50 g, 226 mmol), anhydrous N, N-dimethylformamide (500 ml) and triethylamine (50 ml, 339 mmol) tert-butyl 4-aminobutylcarbamate (60 g, 339 mmol) was added slowly. The reaction mixture was stirred overnight and then concentrated under reduced pressure to give an oil. The oil was dissolved in ethyl acetate and then washed with water. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure to give a dark oil. This material was purified by column chromatography (eluting the silica gel with 40/60 ethyl acetate / hexanes) to tert-butyl 4- (2-chloro-5,6-dimethyl-3-nitropyridine-4 which solidified on standing. 64.5 g of -yl) butylcarbamate were obtained as a bright orange oil.
    [153] Part C
    [154] A solution of phenol (18.50 g, 196 mmol) in diglyme (50 ml) was slowly added dropwise to a cooled suspension of sodium hydride (60% 8.28 g in mineral oil, 207 mmol) in diglyme (50 ml). After one hour the gas generation stopped. A solution of tert-butyl 4- (2-chloro-5,6-dimethyl-3-nitropyridin-4-yl) butylcarbamate (68.95 g, 185 mmol) in diglyme (200 ml) was slowly added to the reaction mixture. Added dropwise. After completion of the dropwise addition, the reaction mixture was heated at reflux for 4 hours. The reaction mixture was concentrated under reduced pressure to give a black oil. The oil was dissolved in ethyl acetate and then extracted with 1 N sodium hydroxide to remove excess phenol. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography (silica gel eluted with 30/70 ethyl acetate / hexanes) to give tert-butyl 4-[(2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl) amino ] 40.67 g of butylcarbamate were obtained as an orange oil.
    [155] Part D
    [156] tert-butyl 4-[(2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl) amino] butylcarbamate (9.17 g, 21.3 mmol), toluene (50 ml), isopropanol (5 ml) and 5% platinum on carbon (7.0 g) were mixed and placed under hydrogen pressure (50 psi, 3.5 Kg / cm 2 ) with Parr overnight. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The resulting brown oil was dried under high vacuum to yield 7.47 g of tert-butyl 4-[(3-amino-5,6-dimethyl-2-phenoxypyridin-4-yl) amino] butylcarbamate.
    [157] Part E
    [158] A mixture of the material from Part D, triethyl orthoacetate (3.59 ml, 19.58 mmol), anhydrous toluene (75 ml) and pyridine hydrochloride (0.75 g) was heated at reflux for 1 hour and then concentrated under reduced pressure to give a brown oil. Got it. The oil was dissolved in ethyl acetate and then washed sequentially with water (x 2) and brine, dried over magnesium sulfate, and then concentrated under reduced pressure to tert-butyl 4- (2,6,7-trimethyl-4-phenoxy 6.74 g of -1H-imidazo [4,5-c] pyridin-1-yl) butylcarbamate was obtained as a brown oil.
    [159] Part F
    [160] Tert-butyl 4- (2,6,7-trimethyl-4-phenoxy-1H-imidazo [4,5-c] pyridin-1-yl) butylcarbamate (6.70 g, in dichloromethane (50 ml) 15.8 mmol) was added slowly to a cooled (0 ° C.) mixture of trifluoroacetic acid (60 ml) and dichloromethane (100 ml). The reaction mixture was warmed to ambient temperature and left overnight. The reaction mixture was concentrated under reduced pressure to give a brown oil. The oil was dissolved in dichloromethane and the solution was made basic (pH 14) with 5% aqueous sodium hydroxide solution. The layers were separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over magnesium sulfate, and then concentrated under reduced pressure to give 4- (2,6,7-trimethyl-4-phenoxy-1H-imidazo [4,5-c] pyridin-1-yl) butylamine 4.50 g was obtained as a brown oil.
    [161] Part G
    [162] A mixture of the material from Part F, triethylamine (2.0 ml, 14.6 mmol) and anhydrous acetonitrile (450 ml) was heated until a homogeneous solution was obtained. Methanesulfonic anhydride (2.54 g, 14.6 mmol) was added slowly to the reaction mixture. After 10 minutes the reaction was assessed to be complete. The reaction mixture was concentrated under reduced pressure to give a brown oil. The oil was dissolved in dichloromethane and washed with 5% aqueous sodium hydroxide solution. The aqueous layer was separated and then extracted with dichloromethane. The organic layers were combined, dried over magnesium sulfate and concentrated under reduced pressure to give a brown solid. This material was purified by column chromatography (silica gel eluting with 95/5 dichloromethane / methanol) to give N- [4- (2,6,7-trimethyl-4-phenoxy-1H-imidazo [4,5]. 4.49 g of -c] pyridin-1-yl) butyl] methanesulfonamide were obtained as a light brown solid.
    [163] Part H
    [164] N- [4- (2,6,7-trimethyl-4-phenoxy-1H-imidazo [4,5-c] pyridin-1-yl) butyl] methanesulfonamide (4.20 g, 10.4 mmol) and ammonium Acetate (42 g) was combined and then heated in a sealed tube at 150 ° C. for 36 hours. The reaction mixture was cooled down and then dissolved in chloroform. The solution was extracted with 10% aqueous sodium hydroxide solution. The aqueous layer was separated and then extracted several times with chloroform. The organic layers were combined, dried over magnesium sulfate and concentrated under reduced pressure to give a yellow oil. The oil was dissolved in methanol and mixed with 1M hydrochloric acid (10.4 ml) in diethyl ether. The resulting white precipitate was isolated by filtration and dried. The solid was dissolved in water and the solution was adjusted to pH 10 with solid sodium carbonate. The resulting white precipitate was isolated by filtration, washed with diethyl ether and dried at 80 ° C. in a vacuum oven to give N- [4- (4-amino-2,6,7-trimethyl-1H-imidazo [4 2.00 g of, 5-c] pyridin-1-yl) butyl] methanesulfonamide was obtained. mp 228-230 ° C. Anal: calcd for C 14 H 23 N 5 0 2 S:% C, 51.67; % H, 7.12;% N, 21.52; Found:% C, 51.48; % H, 6.95; % N, 21.51.
    [165] Example 8
    [166] N- {4- [4-amino-2- (ethoxymethyl) -6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl] butyl} methanesulfonamide
    [167]
    [168] Part A
    [169] Triethylamine (3.3 ml, 23.7 mmol) was added tert-butyl 4-[(3-amino-5,6-dimethyl-2-phenoxypyridin-4-yl) amino] butylcarbamate (8.60 g, 21.5 mmol ) And a cooled (0 ° C) mixture of anhydrous dichloromethane (200 ml). Ethoxyacetyl chloride (2.76 g, 22.5 mmol) was added. After 1 hour, the reaction mixture was warmed to ambient temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure to afford tert-butyl 4-({3-[(ethoxyacetyl) amino] -5,6-dimethyl-2-phenoxypyridin-4-yl} amino) butylcarbamate as brown oil. Got it. The oil was mixed with pyridine (130 ml) and heated at reflux overnight. The reaction mixture was concentrated under reduced pressure to give a brown oil. The oil was dissolved in dichloromethane and washed with water. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was dissolved in diethyl ether and then concentrated under reduced pressure to afford tert-butyl 4- [2- (ethoxymethyl) -6,7-dimethyl-4-phenoxy-1H-imidazo [4,5-c] pyridine -1-yl] 8.21 g of butylcarbamate was obtained.
    [170] Part B
    [171] Using the method of Part F of Example 7, the material from Part A was hydrolyzed to yield 4- [2- (ethoxymethyl) -6,7-dimethyl-4-phenoxy-1H-imidazo [4, 5.76 g of 5-c] pyridin-1-yl] butan-1-amine were obtained as a brown oil.
    [172] Part C
    [173] 4- [2- (ethoxymethyl) -6,7-dimethyl-4-phenoxy-1H-imidazo [4,5-c] pyridin-1-yl, using the method of Part G of Example 7 ] Butane-1-amine (5.52 g, 15.0 mmol) is reacted with methanesulfonic anhydride (2.74 g, 15.7 mmol) to give N- {4- [2- (ethoxymethyl) -6,7-dimethyl-4-phenoxy 6.26 g of ci-1H-imidazo [4,5-c] pyridin-1-yl] butyl} methanesulfonamide were obtained as a brown solid.
    [174] Part D
    [175] Using the method of Part H of Example 7, N- {4- [2- (ethoxymethyl) -6,7-dimethyl-4-phenoxy-1H-imidazo [4,5-c] pyridine- N- {4- [4-amino-2- (ethoxymethyl) -6,7-dimethyl-1H-imidazo [4] by amination of 1-yl] butyl} methanesulfonamide (5.86 g, 13.1 mmol) 1.58 g of, 5-c] pyridin-1-yl] butyl} methanesulfonamide was obtained as a white solid. mp 165-167 ° C. Anal: calcd for C 16 H 27 N 5 0 3 S:% C, 52.01; % H, 7.37; % N, 18.95; Found:% C, 51.83; % H, 7.39; % N, 18.88.
    [176] Example 9
    [177] N- [4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl] -4-[[2- (dimethylamino) Ethoxy] (phenyl) methyl] benzamide
    [178]
    [179] Part A
    [180] Under nitrogen atmosphere, 4- (2-butyl-6,7-dimethyl-4-phenoxy-1H-imidazo [4,5-c] pyridin-1-yl) butan-1-amine (122 mg, 0.33 mmol ) Was dissolved in dichloromethane and triethylamine (0.093 ml, 0.67 mmol). The solution is cooled in an ice water bath, 4-[[2- (dimethylamino) ethoxy] (phenyl) methyl] benzoyl chloride (106 mg, 0.33 mmol) is dissolved and / or slurried in dichloromethane and added dropwise It was. The ice bath was removed and the reaction stirred for 16 hours. The reaction was quenched with 10% aqueous sodium carbonate solution. The phases were separated and the aqueous fraction was extracted with dichloromethane. The organic fractions were combined, washed sequentially with water and brine, dried (Na 2 SO 4 ), decanted and evaporated to give a yellow oil. Purified by flash column chromatography (silica gel, 92: 8 dichloromethane / methanol gradient to 95: 5 dichloromethane / methanol) to N- [4- (2-butyl-6,7-dimethyl-4-phenoxy-1H 101 mg of imidazo [4,5-c] pyridin-1-yl) butyl] -4-[[2- (dimethylamino) ethoxy] (phenyl) methyl] benzamide was obtained as a pale yellow solid. The product was 97 +% pure by HPLC measurement. MS (CI): 648 (M + H).
    [181] Part B
    [182] N- [4- (2-butyl-6,7-dimethyl-4-phenoxy-1H-imidazo [4,5-c] pyridin-1-yl) butyl] -4-[[2- (dimethylamino ) Ethoxy] (phenyl) methyl] benzamide (101 mg, 0.16 mmol) and ammonium acetate (1.1 g) were placed in a pressurized tube with a stir bar. The tube was sealed and heated at 150 ° C. for 16 hours. The reaction was cooled to rt and diluted with water. The resulting cloudy aqueous mixture was basified with 10% aqueous sodium hydroxide solution and extracted with chloroform (3 × 25 ml). The combined organic fractions were washed sequentially with water and brine, dried (Na 2 SO 4 ), decanted and evaporated to give a yellow oil. Purification by flash column chromatography (silica gel, 95: 5 dichloromethane / methanol gradient to 9: 1 dichloromethane / methanol and finally 94: 5: 1 dichloromethane / methanol / triethylamine) gave N- [4- ( 4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl] -4-[[2- (dimethylamino) ethoxy] (phenyl) 14 mg of methyl] benzamide was obtained as a yellow oil. 1 H-NMR (500 MHz, DMSO-d 6 ) δ 8.41 (t, J = 5.5 Hz, 1H), 7.76 (d, J = 8.3 Hz, 2H), 7.43 (d, J = 8.3 Hz, 2H) , 7.37-7.31 (m, 4H), 7.26-7.22 (m, 1H), 5.84 (bs, 2H), 5.52 (s, 1H), 4.22 (t, J = 7.7 Hz, 2H), 3.49 (t, J = 5.8 Hz, 2H), 3.29 (dd, J = 6.4, 12.4 Hz, 2H), 2.76 (t, J = 7.7 Hz, 2H), 2.58 (t, J = 5.7 Hz, 2H), 2.32 (s, 3H ), 2.27 (s, 3H), 2.22 (s, 6H), 1.73-1.65 (m, 4H), 1.61-1.55 (m, 2H), 1.35 (sextet, J = 7.4 Hz, 2H), 0.86 (t, J = 7.4 Hz, 3H); 13 C-NMR (125 MHz, DMSO-d 6 ) δ 165.9, 153.0, 148.1, 145.4, 142.0, 138.6, 133.5, 128.23, 127.4, 127.3, 127.1, 126.4, 126.1, 124.5, 103.0, 82.0, 66.3, 58.0 , 45.2, 43.6, 38.4, 29.3, 28.8, 26.1, 26.0, 21.7, 21.0, 13.6, 12.2. HRMS (CI) m / e 571.3763 (M + H), (calculated for C 34 H 47 N 6 O 2 571.3761, M + H).
    [183] Cytokine Induction in Human Cells
    [184] Cytokine induction was assessed using an in vitro human blood cell system. Activity is secreted into the medium, as described by Testerman et al., "Cytokine Induction by the Immunomodulators Imiquimod and S-27609," Journal of Leukocyte Biology, 58, 365-372 (1995, 9). Based on the measurement of interferon (α) and tumor necrosis factor (α) (IFN and TNF, respectively).
    [185] Preparation of Blood Cells for Culture
    [186] Whole blood from healthy human donors was collected into EDTA vacuum vessels by venipuncture. Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood by density gradient centrifugation using Histopaque®-1077. PBMCs were washed twice with Hank's balanced salt solution and then suspended in RPMI complete medium at 3-4 × 10 6 cells / ml. PBMC suspensions were prepared using 48-well flat bottom sterile tissue culture plates (Costar, Cambridge, Mass., Or Beckton Dickinson Labware, Lincoln, N.), containing copper volumes of RPMI complete medium containing test compounds. (Becton Dickinson Labware).
    [187] Compound manufacture
    [188] The compound was dissolved in dimethyl sulfoxide (DMSO). DMSO concentration should not exceed 1% final concentration when added to the culture wells. Compounds were generally tested at concentrations ranging from 0.12 to 30 μM.
    [189] culture
    [190] Test compound solutions were added at 60 μΜ to the first well containing RPMI complete medium and 3-fold serial dilutions were made. An equal volume of PBMC suspension was added to the wells to bring the concentration of test compound to the desired range (0.12-30 μΜ). The final concentration of PBMC suspension was 1.5-2 × 10 6 cells / ml. The plates were covered with sterile plastic lids, mixed gently and incubated at 37 ° C. for 18-24 hours under a 5% carbon dioxide atmosphere.
    [191] detach
    [192] After incubation, the plates were centrifuged for 5-10 minutes at 4 ° C. at 1000 rpm (˜200 × g). Cell-free culture supernatants were recovered in sterile polypropylene pipettes and transferred to sterile polypropylene tubes. Samples were kept between -30 and -70 ° C until analysis. Samples were analyzed for interferon (α) and tumor necrosis factor (α) by ELISA.
    [193] Interferon (α) and Tumor Necrosis Factor (α) Analysis by ELISA
    [194] Interferon (α) concentrations were measured by ELISA using a human multiple species kit (obtained from PBL Biomedical Laboratories, New Brunswick, NJ).
    [195] Using an ELISA kit (Genzyme, Cambridge, Mass., USA, available from R & D Systems, Minneapolis, Minn., USA, or Pharmingen, San Diego, Calif.) The concentration of tumor necrosis factor (α) was measured. The results are shown in pg / ml.
    [196] The lowest concentrations observed to induce interferon and the lowest concentrations observed to induce tumor necrosis factor for each compound are listed in the table below. "*" Indicates that no induction was observed at any of the concentrations tested.
    [197]
    [198] The invention has been described with reference to several embodiments. The foregoing detailed description and examples have been provided for clarity of understanding only, and no unnecessary limitations shall be construed therefrom. It will be apparent to those skilled in the art that numerous changes can be made in the described embodiments without departing from the spirit and scope of the invention. Accordingly, the scope of the invention should be defined by the following claims, rather than by the elaborate details of the compositions and structures described herein.
    权利要求:
    Claims (34)
    [1" claim-type="Currently amended] A compound of formula (I) or a pharmaceutically acceptable salt thereof.
    <Formula I>

    (Wherein
    X is alkylene or alkenylene;
    Y is -CO-, -CS- or -SO 2- ;
    Z is a bond, -O-, -S- or -NR 5- ;
    R 1 is unsubstituted or alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, substituted cycloalkyl, -O-alkyl, -O- (alkyl) 0-1 -aryl, -O- (alkyl) 0-1 -heteroaryl, -O- (alkyl) 0-1 -heterocyclyl, -COOH, -CO-O-alkyl, -CO-alkyl, -S (O) 0-2 alkyl, -S (O ) 0-2- (alkyl) 0-1 -aryl, -S (O) 0-2- (alkyl) 0-1 -heteroaryl, -S (O) 0-2- (alkyl) 0-1 -hetero Cyclyl,-(alkyl) 0-1 -N (R 5 ) 2 ,-(alkyl) 0-1 -NR 5 -CO-O-alkyl,-(alkyl) 0-1 -NR 5 -CO-alkyl, -(Alkyl) 0-1 -NR 5 -CO-aryl,-(alkyl) 0-1 -NR 5 -CO-heteroaryl, N 3 , halogen, haloalkyl, haloalkoxy, -CO-haloalkyl, -CO Aryl, heteroaryl, hetero substituted by one or more substituents independently selected from the group consisting of -haloalkoxy, -NO 2 , -CN, -OH, -SH and oxo (if alkyl, alkenyl and heterocyclyl) Cyclyl, C 1-20 alkyl or C 2-20 alkenyl;
    R 2 is hydrogen, alkyl, alkenyl, -alkyl-O-alkyl, -alkyl-S-alkyl, -alkyl-O-aryl, -alkyl-S-aryl, -alkyl-O-alkenyl, -alkyl-S -Alkenyl, and -OH, halogen, -N (R 5 ) 2 , -CO-N (R 5 ) 2 , -CS-N (R 5 ) 2 , -SO 2 -N (R 5 ) 2 ,- NR 5 -CO-C 1-10 alkyl, -NR 5 -CS-C 1-10 alkyl, -NR 5 -SO 2 -C 1-10 alkyl, -CO-C 1-10 alkyl, -CO-OC 1 -10 alkyl, N 3 , aryl, heteroaryl, heterocyclyl, -CO-aryl and -CO-heteroaryl is selected from the group consisting of alkyl or alkenyl substituted by one or more substituents selected from the group consisting of;
    R 3 and R 4 are independently selected from the group consisting of alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino and alkylthio;
    Each R 5 is independently hydrogen or C 1-10 alkyl.
    [2" claim-type="Currently amended] The compound or salt according to claim 1, wherein Y is -CO-.
    [3" claim-type="Currently amended] The compound or salt according to claim 1, wherein Y is -CO- and Z is a bond.
    [4" claim-type="Currently amended] The compound or salt according to claim 3, wherein R 1 is alkyl, aryl or substituted aryl.
    [5" claim-type="Currently amended] The compound or salt according to claim 1, wherein Y is -CS-.
    [6" claim-type="Currently amended] The compound or salt according to claim 1, wherein Y is -CS- and Z is -NR 5- .
    [7" claim-type="Currently amended] The compound or salt according to claim 6, wherein R 5 is H and R 1 is aryl or substituted aryl.
    [8" claim-type="Currently amended] The compound or salt according to claim 1, wherein Y is —SO 2 —.
    [9" claim-type="Currently amended] The compound or salt according to claim 1, wherein Y is —SO 2 — and Z is a bond.
    [10" claim-type="Currently amended] The compound or salt according to claim 9, wherein R 1 is alkyl, aryl or substituted aryl.
    [11" claim-type="Currently amended] The compound or salt according to claim 10, wherein R 1 is alkyl.
    [12" claim-type="Currently amended] The compound or salt according to claim 1, wherein Y is -SO 2 -and Z is -NR 5- .
    [13" claim-type="Currently amended] The compound or salt according to claim 12, wherein R 5 is alkyl and R 1 is alkyl.
    [14" claim-type="Currently amended] The compound or salt according to claim 1, wherein R 2 is H, alkyl or alkyl-O-alkyl.
    [15" claim-type="Currently amended] The compound or salt according to claim 1, wherein X is — (CH 2 ) 2-4 —.
    [16" claim-type="Currently amended] The compound or salt according to claim 1, wherein R 3 and R 4 are independently H or alkyl.
    [17" claim-type="Currently amended] A compound selected from the group consisting of:
    N- [4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl] benzamide,
    N- [4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl] methanesulfonamide,
    N- [4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl] -4-fluorobenzenesulfonamide monohydrate,
    N- [4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl] -N'-phenylthiourea monohydrate,
    N '-[4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl] -N, N-dimethylsulfamide,
    N- [4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl] -N'-phenylurea,
    N- [4- (4-amino-2,6,7-trimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl] methanesulfonamide,
    N- [4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl] -4-[[2- (dimethylamino) Ethoxy] (phenyl) methyl] benzamide, and
    N- {4- [4-amino-2- (ethoxymethyl) -6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl] butyl} methanesulfonamide.
    [18" claim-type="Currently amended] A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 together with a pharmaceutically acceptable carrier.
    [19" claim-type="Currently amended] A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 9 in combination with a pharmaceutically acceptable carrier.
    [20" claim-type="Currently amended] A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 17 in association with a pharmaceutically acceptable carrier.
    [21" claim-type="Currently amended] A method of inducing cytokine biosynthesis in an animal comprising administering to the animal a therapeutically effective amount of the compound of claim 1.
    [22" claim-type="Currently amended] A method of treating a viral disease in an animal comprising administering to the animal a therapeutically effective amount of the compound of claim 1.
    [23" claim-type="Currently amended] A method of treating neoplastic disease in an animal comprising administering to the animal a therapeutically effective amount of the compound of claim 1.
    [24" claim-type="Currently amended] A method of inducing cytokine biosynthesis in an animal comprising administering to the animal a therapeutically effective amount of the compound of claim 9.
    [25" claim-type="Currently amended] A method of treating a viral disease in an animal comprising administering to the animal a therapeutically effective amount of the compound of claim 9.
    [26" claim-type="Currently amended] A method of treating a neoplastic disease in an animal comprising administering to the animal a therapeutically effective amount of the compound of claim 9.
    [27" claim-type="Currently amended] A method of inducing cytokine biosynthesis in an animal comprising administering to the animal a therapeutically effective amount of the compound of claim 17.
    [28" claim-type="Currently amended] A method of treating a viral disease in an animal comprising administering to the animal a therapeutically effective amount of the compound of claim 17.
    [29" claim-type="Currently amended] A method of treating a neoplastic disease in an animal comprising administering to the animal a therapeutically effective amount of the compound of claim 17.
    [30" claim-type="Currently amended] A compound of formula (II): or a pharmaceutically acceptable salt thereof.
    <Formula II>

    (Wherein
    X is alkylene or alkenylene;
    R 2 is hydrogen, alkyl, alkenyl, -alkyl-O-alkyl, -alkyl-S-alkyl, -alkyl-O-aryl, -alkyl-S-aryl, -alkyl-O-alkenyl, -alkyl-S -Alkenyl, and -OH, halogen, -N (R 5 ) 2 , -CO-N (R 5 ) 2 , -CS-N (R 5 ) 2 , -SO 2 -N (R 5 ) 2 ,- NR 5 -CO-C 1-10 alkyl, -NR 5 -CS-C 1-10 alkyl, -NR 5 -SO 2 -C 1-10 alkyl, -CO-C 1-10 alkyl, -CO-OC 1 -10 alkyl, N 3 , aryl, heteroaryl, heterocyclyl, -CO-aryl and -CO-heteroaryl is selected from the group consisting of alkyl or alkenyl substituted by one or more substituents selected from the group consisting of;
    R 3 and R 4 are independently selected from the group consisting of alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino and alkylthio;
    Each R 5 is independently hydrogen or C 1-10 alkyl.
    [31" claim-type="Currently amended] A compound of formula (III): or a pharmaceutically acceptable salt thereof.
    <Formula III>

    (Wherein
    Q is NO 2 or NH 2 ;
    X is alkylene or alkenylene;
    R 3 and R 4 are independently selected from the group consisting of alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino and alkylthio;
    Each R 5 is independently hydrogen or C 1-10 alkyl.
    [32" claim-type="Currently amended] A compound of formula (IV): or a pharmaceutically acceptable salt thereof.
    <Formula IV>

    Where
    X is alkylene or alkenylene;
    R 2 is hydrogen, alkyl, alkenyl, -alkyl-O-alkyl, -alkyl-S-alkyl, -alkyl-O-aryl, -alkyl-S-aryl, -alkyl-O-alkenyl, -alkyl-S -Alkenyl, and -OH, halogen, -N (R 5 ) 2 , -CO-N (R 5 ) 2 , -CS-N (R 5 ) 2 , -SO 2 -N (R 5 ) 2 ,- NR 5 -CO-C 1-10 alkyl, -NR 5 -CS-C 1-10 alkyl, -NR 5 -SO 2 -C 1-10 alkyl, -CO-C 1-10 alkyl, -CO-OC 1 -10 alkyl, N 3 , aryl, heteroaryl, heterocyclyl, -CO-aryl and -CO-heteroaryl is selected from the group consisting of alkyl or alkenyl substituted by one or more substituents selected from the group consisting of;
    R 3 and R 4 are independently selected from the group consisting of alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino and alkylthio;
    Each R 5 is independently hydrogen or C 1-10 alkyl.
    [33" claim-type="Currently amended] A compound of formula (V): or a pharmaceutically acceptable salt thereof.
    <Formula V>

    (Wherein
    X is alkylene or alkenylene;
    R 2 is hydrogen, alkyl, alkenyl, -alkyl-O-alkyl, -alkyl-S-alkyl, -alkyl-O-aryl, -alkyl-S-aryl, -alkyl-O-alkenyl, -alkyl-S -Alkenyl, and -OH, halogen, -N (R 5 ) 2 , -CO-N (R 5 ) 2 , -CS-N (R 5 ) 2 , -SO 2 -N (R 5 ) 2 ,- NR 5 -CO-C 1-10 alkyl, -NR 5 -CS-C 1-10 alkyl, -NR 5 -SO 2 -C 1-10 alkyl, -CO-C 1-10 alkyl, -CO-OC 1 -10 alkyl, N 3 , aryl, heteroaryl, heterocyclyl, -CO-aryl and -CO-heteroaryl is selected from the group consisting of alkyl or alkenyl substituted by one or more substituents selected from the group consisting of;
    R 3 and R 4 are independently selected from the group consisting of alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino and alkylthio;
    Each R 5 is independently hydrogen or C 1-10 alkyl.
    [34" claim-type="Currently amended] A compound of formula (VI): or a pharmaceutically acceptable salt thereof.
    <Formula VI>

    (Wherein
    X is alkylene or alkenylene;
    R 1 is unsubstituted or alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, substituted cycloalkyl, -O-alkyl, -O- (alkyl) 0-1 -aryl, -O- (alkyl) 0-1 -heteroaryl, -O- (alkyl) 0-1 -heterocyclyl, -COOH, -CO-O-alkyl, -CO-alkyl, -S (O) 0-2 alkyl, -S (O ) 0-2- (alkyl) 0-1 -aryl, -S (O) 0-2- (alkyl) 0-1 -heteroaryl, -S (O) 0-2- (alkyl) 0-1 -hetero Cyclyl,-(alkyl) 0-1 -N (R 5 ) 2 ,-(alkyl) 0-1 -NR 5 -CO-O-alkyl,-(alkyl) 0-1 -NR 5 -CO-alkyl, -(Alkyl) 0-1 -NR 5 -CO-aryl,-(alkyl) 0-1 -NR 5 -CO-heteroaryl, N 3 , halogen, haloalkyl, haloalkoxy, -CO-haloalkyl, -CO Aryl, heteroaryl, hetero substituted by one or more substituents independently selected from the group consisting of -haloalkoxy, -NO 2 , -CN, -OH, -SH and oxo (if alkyl, alkenyl and heterocyclyl) Cyclyl, C 1-20 alkyl or C 2-20 alkenyl;
    R 2 is hydrogen, alkyl, alkenyl, -alkyl-O-alkyl, -alkyl-S-alkyl, -alkyl-O-aryl, -alkyl-S-aryl, -alkyl-O-alkenyl, -alkyl-S -Alkenyl, and -OH, halogen, -N (R 5 ) 2 , -CO-N (R 5 ) 2 , -CS-N (R 5 ) 2 , -SO 2 -N (R 5 ) 2 ,- NR 5 -CO-C 1-10 alkyl, -NR 5 -CS-C 1-10 alkyl, -NR 5 -SO 2 -C 1-10 alkyl, -CO-C 1-10 alkyl, -CO-OC 1 -10 alkyl, N 3 , aryl, heteroaryl, heterocyclyl, -CO-aryl and -CO-heteroaryl is selected from the group consisting of alkyl or alkenyl substituted by one or more substituents selected from the group consisting of;
    R 3 and R 4 are independently selected from the group consisting of alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino and alkylthio;
    Each R 5 is independently hydrogen or C 1-10 alkyl.
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    同族专利:
    公开号 | 公开日
    TWI243819B|2005-11-21|
    WO2002046194A2|2002-06-13|
    ZA200305238B|2004-08-27|
    RU2294934C2|2007-03-10|
    CN1478090A|2004-02-25|
    NO20032453D0|2003-05-28|
    IL155885D0|2003-12-23|
    CA2431040A1|2002-06-13|
    BR0116034A|2004-08-03|
    HK1063466A1|2006-09-01|
    PL365739A1|2005-01-10|
    JP2004525868A|2004-08-26|
    AU3954702A|2002-06-18|
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    NZ526085A|2004-12-24|
    RU2003116648A|2005-02-10|
    NO20032453L|2003-07-16|
    WO2002046194A3|2003-02-06|
    UA74593C2|2003-11-17|
    AU2002239547B2|2006-11-30|
    CZ20031593A3|2004-01-14|
    SK7142003A3|2003-10-07|
    HRP20030465A2|2004-06-30|
    MXPA03005013A|2003-09-05|
    CN1249062C|2006-04-05|
    HU0600592A2|2006-11-28|
    EE200300273A|2004-02-16|
    EP1343783A2|2003-09-17|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2000-12-08|Priority to US25422800P
    2000-12-08|Priority to US60/254,228
    2001-12-06|Application filed by 쓰리엠 이노베이티브 프로퍼티즈 컴파니
    2001-12-06|Priority to PCT/US2001/046915
    2003-08-27|Publication of KR20030070048A
    优先权:
    申请号 | 申请日 | 专利标题
    US25422800P| true| 2000-12-08|2000-12-08|
    US60/254,228|2000-12-08|
    PCT/US2001/046915|WO2002046194A2|2000-12-08|2001-12-06|Substituted imidazopyridines|
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