Therapeutic compounds for inhibiting interleukin-12 signaling and methods for using same

Abstract

Novel heterocyclic compounds having a six membered ring structure fused to a five membered ring structure are found to be useful for the treatment and prevention of symptoms or manifestations associated with disorders affected by lnterleukin-12 (“IL-12”) intracellular signaling, such as, for example, Th1 cell-mediated disorders. The therapeutic compounds, pharmaceutically acceptable derivatives (e.g., resolved enantiomers, diastereomers, tautomers, salts and solvates thereof) or prodrugs thereof, have the following general formula: Each X, Y and Z are independently selected from a member of the group consisting of C(R 3 ), N, N(R 3 ) and S. Each R 1 , R 2 and R 3 is substituted or unsubstituted and is independently selected from a member of the group consisting of hydrogen, halo, oxo, C (1-20) alkyl, C (1-20) hydroxyalkyl, C (1-20) thioalkyl, C (1-20) alkylamino, C (1-20) alkylaminoalkyl, C (1-20) aminoalkyl, C (1-20) aminoalkoxyalkenyl, C (1-20) aminoalkoxyalkynyl, C (1-20) diaminoalkyl, C (1-20) triaminoalkyl, C (1-20) tetraaminoalkyl, C (5-15) aminotrialkoxyamino, C (1-20) alkylamido, C (1-20) alkylamidoalkyl, C (1-20) amidoalkyl, C (1-20) acetamidoalkyl, C (1-20) alkenyl, C (1-20) alkynyl, C (3-8) alkoxyl, C (1-11) alkoxyalkyl, and C (1-20) dialkoxyalkyl.

1 . A therapeutic compound, including resolved enantiomers, diastereomers, tautomers, salts and solvates thereof, having the following formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 X, Y and Z are independently selected from a member of the group consisting of C(R 3 ), N, N(R 3 ) and S;  
 R 1  is selected from a member of the group consisting of hydrogen, methyl, C (5-9) alkyl, C (5-9) alkenyl, C (5-9) alkynyl, C (5-9) hydroxyalkyl, C (3-8) alkoxyl, C (5-9) alkoxyalkyl, the R 1  being optionally substituted;  
 R 2  and R 3  are independently selected from a member of the group consisting of hydrogen, halo, oxo, C (1-20) alkyl, C (1-20) hydroxyalkyl, C (1-20) thioalkyl, C (1-20) alkylamino, C (1-20) alkylaminoalkyl, C (1-20) aminoalkyl, C (1-20) aminoalkoxyalkenyl, C (1-20) aminoalkoxyalkynyl, C (1-20) diaminoalkyl, C (1-20) triaminoalkyl, C (1-20) tetraaminoalkyl, C (5-15) aminotrialkoxyamino, C (1-20) alkylamido, C (1-20) alkylamidoalkyl, C (1-20) amidoalkyl, C (1-20) acetamidoalkyl, C (1-20) alkenyl, C (1-20) alkynyl, C (3-8) alkoxyl, C (1-11) alkoxyalkyl, and C (1-20) dialkoxyalkyl;  
 with the proviso that R 1  is not an ω-1 secondary alcohol substituted C (5-8)  alkyl when both X and Y are N(R 3 ), Z is C(R 3 ) and R 3  is H or C (1-3)  alkyl.  
 
     
     
         2 . The therapeutic compound of  claim 1 , wherein R 1  is substituted with a member of the group consisting of N—OH, acylamino, cyano group, sulfo, sulfonyl, sulfinyl, sulfhydryl (mercapto), sulfeno, sulfanilyl, sulfamyl, sulfamino, and phosphino, phosphinyl, phospho, phosphono and —NR a R b , wherein each of R a  and R b  may be the same or different and each is selected from the group consisting of hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic group.  
     
     
         3 . The therapeutic compound of  claim 1 , wherein R 2  and R 3  are selected from the group consisting of methyl, ethyl, oxo, isopropyl, n-propyl, isobutyl, n-butyl, t-butyl, 2-hydroxyethyl, 3-hydroxypropyl, 3-hydroxy-n-butyl, 2methoxyethyl, 4-methoxy-n-butyl, 5-hydroxyhexyl, 2-bromopropyl, 3-dimethylaminobutyl, 4-chloropentyl, methylamino, aminomethyl, and methylphenyl.  
     
     
         4 . The therapeutic compound of  claim 1 , wherein each R 2  and R 3  is substituted with one or more members of the group consisting of hydroxyl, methyl, carboxyl, furyl, furfuryl, biotinyl, phenyl, naphthyl, amino group, amido group, carbamoyl group, cyano group, sulfo, sulfonyl, sulfinyl., sulfhydryl, sulfeno, sulfanilyl, sulfamyl, sulfamino, phosphino, phosphinyl, phospho, phosphono, N—OH, —Si(CH 3 ) 3 , C (1-3) alkyl, C (1-3) hydroxyalkyl, C (1-3) thioalkyl, C (1-3) alkylamino, benzyldihydrocinnamoyl group, benzoyldihydrocinnamido group, optionally substituted heterocyclic group and optionally substituted carbocyclic group.  
     
     
         5 . The therapeutic compound of  claim 4 , wherein the heterocyclic group or carbocyclic group is substituted with one or more members of the group consisting of halo, hydroxyl, nitro, SO 2 NH 2 , C (1-6) alkyl, C (1-6) haloalkyl, C (1-8) alkoxyl, C (1-11) alkoxyalkyl, C (1-6) alkylamino, and C (1-6) aminoalkyl.  
     
     
         6 . The therapeutic compound of  claim 4 , wherein the heterocyclic group is a member selected from the group consisting of acridinyl, aziridinyl, azocinyl, azepinyl, benzimidazolyl, benzodioxolanyl, benzofuranyl, benzothiophenyl, carbazole, 4a H-carbazole, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, dioxoindolyl, furazanyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthalenyl, naphthyridinyl, norbornanyl, norpinanyl, octahydroisoquinolinyl, oxazolidinyl, oxazolyl, oxiranyl, perimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phenyl, phthalazinyl, piperazinyl, piperidinyl, 4-piperidonyl, piperidyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazoliny), pyrazolyl, pyrenyl, pyridazinyl, pyridinyl, pyridyl, pyridyl, pyrimidinyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolonyl, pyrrolyl, 2H-pyrrolyl, quinazolinyl, 4H-quinolizinyl, quinolinyl, quinoxalinyl, quinuclidinyl, β-carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 2H-,6H-1,5,2-dithiazinyl, thianthrenyl, thiazolyl, thienyl, thiophenyl, triazinyl, xanthenyl and xanthinyl.  
     
     
         7 . The therapeutic compound of  claim 4 , wherein the carbocyclic group is a member selected from the group consisting of adamantyl, anthracenyl, benzamidyl, benzyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]hexanyl, bicyclo[2.2.2]octanyl, bicyclo[3.2.0]heptanyl, bicyclo[4.3.0]nonanyl, bicyclo[4.4.0]decanyl, biphenyl, biscyclooctyl, cyclobutyl, cyclobutenyl, cycloheptyl, cycloheptenyl, cyclohexanedionyl, cyclohexenyl, cyclohexyl, cyclooctanyl, cyclopentadienyl, cyclopentanedionyl, cyclopentenyl, cyclopentyl, cyclopropyl, decalinyl, 1,2-diphenylethanyl, indanyl, 1-indanonyl, indenyl, naphthyl, napthlalenyl, phenyl, resorcinolyl, stilbenyl, tetrahydronaphthyl, tetralinyl, tetralonyl, and tricyclododecanyl.  
     
     
         8 . A compound having the formula  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof.  
       
     
     
         9 . A compound having the formula  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof.  
       
     
     
         10 . A compound having the formula  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof.  
       
     
     
         11 . A compound having the formula  
       
         
           
           
               
               
           
         
       
     
     
         12 - 15 . (CANCELED)  
     
     
         16 . A compound, or pharmaceutically acceptable sat thereof, selected from the group consisting of:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         17 . A compound, or pharmaceutically acceptable salt thereof, selected from the group consisting of the compounds defined in Table 1.  
     
     
         18 . A pharmaceutical composition comprising the compound of  claim 1  in admixture with a pharmaceutically acceptable carrier, adjuvant or vehicle.  
     
     
         19 . A method for inhibiting a cellular process or activity mediated by IL-12, the method comprising: 
 (a) contacting L12 responsive cells with a compound as defined in  claim 1;  and    (b) determining that the cellular process or activity mediated by IL-12 is inhibited.    
     
     
         20 . The method of  claim 19 , wherein step (a) is carried out in vitro.  
     
     
         21 . The method of  claim 19 , wherein said cellular process is the differentiation of naive T cells into Th1 cells.  
     
     
         22 . The method of  claim 19 , wherein said activity is the secretion of proinflammatory cytokines.  
     
     
         23 . The method of  claim 22 , wherein said cytokines are secreted by Th1 cells.  
     
     
         24 . A method for treating a Th1 cell-mediated inflammatory response in a mammal in need of such treatment, the method comprising: 
 administering to the mammal a therapeutically effective amount of the compound defined in  claim 1 , wherein said compound is capable of inhibiting an IL-12 mediated cellular process or activity, thereby inhibiting the inflammatory response.    
     
     
         25 . The method of  claim 24 , wherein the inflammatory response is associated with a disease or condition selected from the group consisting of chronic inflammatory disease, chronic intestinal inflammation, arthritis, psoriasis, asthma and autoimmune disorders.  
     
     
         26 . The method of  claim 25 , wherein the inflammatory response is associated with an autoimmune disorder.  
     
     
         27 . The method of  claim 26 , wherein said autoimmune disorder is selected from type-1 IDDM, multiple sclerosis, rheumatoid arthritis, uveitis, inflammatory bowel disease, lupus disorders, and acute and chronic graft-versus-host disease.  
     
     
         28 . The method of  claim 24 , wherein said mammal is a human.  
     
     
         29 . A therapeutic compound, including resolved enantiomers, diastereomers, tautomers, salts and solvates thereof, having the following formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 X, Y and Z are independently selected from a member of the group consisting of C(R 3 ), N, N(R 3 ) and S;  
 R 1  is selected from a member of the group consisting of hydrogen, methyl, substituted alkyl, C (5-9) alkenyl, C (5-9) alkynyl, C (5-9) hydroxyalkyl, C (3-8) alkoxyl, C (5-9) alkoxyalkyl, the R 1  being optionally substituted;  
 R 2  and R 3  are independently selected from a member of the group consisting of hydrogen, halo, oxo, C (1-20) alkyl, C (1-20) hydroxyalkyl, C (1-20) thioalkyl, C (1-20) alkylamino, C (1-20) alkylaminoalkyl, C (1-20) aminoalkyl, C (1-20) aminoalkoxyalkenyl, C (1-20) aminoalkoxyalkynyl, C (1-20) diaminoalkyl, C (1-20) triaminoalkyl, C (1-20) tetraaminoalkyl, C (5-15) aminotrialkoxyamino, C (1-20) alkylamido, C (1-20) alkylamidoalkyl, C (1-20) amidoalkyl, C (1-20) acetamidoalkyl, C (1-20) alkenyl, C (1-20) alkynyl, C (3-8) alkoxyl, C (1-11) alkoxyalkyl, and C (1-20) dialkoxyalkyl;  
 with the proviso that R 1  is not an ω-1 secondary alcohol substituted C (5-8)  alkyl when both X and Y are N(R 3 ), Z is C(R 3 ) and R 3  is H or C (1-3)  alkyl.  
 
     
     
         30 . The therapeutic compound of  claim 29 , wherein R 1  is substituted with a member of the group consisting of N—OH, acylamino, cyano group, sulfo, sulfonyl, sulfinyl, sulfhydryl (mercapto), sulfeno, sulfanilyl, sulfamyl, sulfamino, and phosphino, phosphinyl, phospho, phosphono and —NR a N b , wherein each of R a  and R b  may be the same or different and each is selected from the group consisting of hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic group.  
     
     
         31 . The therapeutic compound of  claim 29 , wherein R 2  and R 3  are selected from the group consisting of methyl, ethyl, oxo, isopropyl, n-propyl, isobutyl, n-butyl, t-butyl, 2-hydroxyethyl, 3-hydroxypropyl, 3-hydroxy-n-butyl, 2methoxyethyl, 4-methoxy-n-butyl, 5-hydroxyhexyl, 2-bromopropyl, 3-dimethylaminobutyl, 4-chloropentyl, methylamino, aminomethyl, and methylphenyl.  
     
     
         32 . The therapeutic compound of  claim 29 , wherein each R 2  and R 3  is substituted with one or more members of the group consisting of hydroxyl, methyl, carboxyl, furyl, furfuryl, biotinyl, phenyl, naphthyl, amino group, amido group, carbamoyl group, cyano group, sulfo, sulfonyl, sulfinyl, sulfhydryl, sulfeno, sulfanilyl, sulfamyl, sulfamino, phosphino, phosphinyl, phospho, phosphono, N—OH, —Si(CH 3 ) 3 , C (1-3) alkyl, C (1-3) hydroxyalkyl, C (1-3) thioalkyl, C (1-3) alkylamino, benzyldihydrocinnamoyl group, benzoyldihydrocinnamido group, optionally substituted heterocyclic group and optionally substituted carbocyclic group.  
     
     
         33 . The therapeutic compound of  claim 32 , wherein the heterocyclic group or carbocyclic group is substituted with one or more members of the group consisting of halo, hydroxyl, nitro, SO 2 NH 2 , C (1-6) alkyl, C (1-6) haloalkyl, C (1-8) alkoxyl, C (1-11) alkoxyalkyl, C (1-6) alkylamino, and C (1-6) aminoalkyl.  
     
     
         34 . The therapeutic compound of  claim 32 , wherein the heterocyclic group is a member selected from the group consisting of acridinyl, aziridinyl, azocinyl, azepinyl, benzimidazolyl, benzodioxolanyl, benzofuranyl, benzothiophenyl, carbazole, 4a H-carbazole, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, dioxoindolyl, furazanyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthalenyl, naphthyridinyl, norbornanyl, norpinanyl, octahydroisoquinolinyl, oxazolidinyl, oxazolyl, oxiranyl, perimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phenyl, phthalazinyl, piperazinyl, piperidinyl, 4-piperidonyl, piperidyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyrenyl, pyridazinyl, pyridinyl, pyridyl, pyridyl, pyrimidinyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolonyl, pyrrolyl, 2H-pyrrolyl, quinazolinyl, 4H-quinolizinyl, quinolinyl, quinoxalinyl, quinuclidinyl, B-carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 2H-,6H-1,5,2-dithiazinyl, thianthrenyl, thiazolyl, thienyl, thiophenyl, triazinyl, xanthenyl and xanthinyl.  
     
     
         35 . The therapeutic compound of  claim 32 , wherein the carbocyclic group is a member selected from the group consisting of adamantyl, anthracenyl, benzamidyl, benzyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]hexanyl, bicyclo[2.2.2]octanyl, bicyclo[3.2.0]heptanyl, bicyclo[4.3.0]nonanyl, bicyclo[4.4.0]decanyl, biphenyl, biscyclooctyl, cyclobutyl, cyclobutenyl, cycloheptyl, cycloheptenyl, cyclohexanedionyl, cyclohexenyl, cyclohexyl, cyclooctanyl, cyclopentadienyl, cyclopentanedionyl, cyclopentenyl, cyclopentyl, cyclopropyl, decalinyl, 1,2-diphenylethanyl, indanyl, 1-indanonyl, indenyl, naphthyl, napthlalenyl, phenyl, resorcinolyl, stilbenyl, tetrahydronaphthyl, tetralinyl, tetralonyl, and tricyclododecanyl.  
     
     
         36 . A pharmaceutical composition comprising the compound of  claim 29  in admixture with a pharmaceutically acceptable carrier, adjuvant or vehicle.  
     
     
         37 . A method for inhibiting a cellular process or activity mediated by IL-12, the method comprising: 
 (a) contacting, IL-12 responsive cells with a compound as defined in  claim 29;  and    (b) determining that the cellular process or activity mediated by IL-12 is inhibited.    
     
     
         38 . The method of  claim 37 , wherein step (a) is carried out in vitro.  
     
     
         39 . The method of  claim 37 , wherein said cellular process is the differentiation of naive T cells into Th1 cells.  
     
     
         40 . The method of  claim 37 , wherein said activity is the secretion of proinflammatory cytokines.  
     
     
         41 . The method of  claim 40 , wherein said cytokines are secreted by Th1 cells.  
     
     
         42 . A method for treating a Th1 cell-mediated inflammatory response in a mammal in need of such treatment, the method comprising: 
 administering to the mammal a therapeutically effective amount of the compound defined in  claim 29 , wherein said compound is capable of inhibiting an EL-12 mediated cellular process or activity, thereby inhibiting the inflammatory response.    
     
     
         43 . The method of  claim 42 , wherein the inflammatory response is associated with a disease or condition selected from the group consisting of chronic inflammatory disease, chronic intestinal inflammation, arthritis, psoriasis, asthma and autoimmune disorders.  
     
     
         44 . The method of  claim 43 , wherein the inflammatory response is associated with an autoimmune disorder.  
     
     
         45 . The method of  claim 44 , wherein said autoimmune disorder is selected from type-1 IDDM, multiple sclerosis, rheumatoid arthritis, uveitis, inflammatory bowel disease, lupus disorders, and acute and chronic graft-versus-host disease.  
     
     
         46 . The method of  claim 42 , wherein said mammal is a human.