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 Interleukin-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) tetraminoalkyl, 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;  
         the   in Formula I represents a single or double bond;  
         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 (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) tetraminoalkyl, 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.  
       
     
     
         2 . The therapeutic compound of  claim 1 , wherein R 1  is substituted with a member of the group consisting of N—OH, cyano group, sulfo, sulfonyl, sulfinyl, sulfhydryl (mercapto), sulfeno, sulfanilyl, sulfamyl, sulfamino, and phosphino, phosphinyl, phospho, and phosphono.  
     
     
         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, pyrazolinyl, 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 - 9 . (CANCELED)  
     
     
         10 . A pharmaceutical composition comprising the compound of  claim 1 , in admixture with a pharmaceutically acceptable carrier, adjuvant or vehicle.  
     
     
         11 . 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 1;  and    (b) determining that the cellular process or activity mediated by IL-12 is inhibited.    
     
     
         12 . The method of  claim 11 , wherein step (a) is carried out in vitro.  
     
     
         13 . The method of  claim 11 , wherein said cellular process is the differentiation of naïve T cells into Th1 cells.  
     
     
         14 . The method of  claim 11 , wherein said activity is the secretion of proinflammatory cytokines.  
     
     
         15 . The method of  claim 14 , wherein said cytokines are secreted by Th1 cells.  
     
     
         16 . 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.    
     
     
         17 . The method of  claim 16 , 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.  
     
     
         18 . The method of  claim 17 , wherein the inflammatory response is associated with an autoimmune disorder.  
     
     
         19 . The method of  claim 18 , wherein said autoimmune disorder is selected from type-i IDDM, multiple sclerosis, rheumatoid arthritis, uveitis, inflammatory bowel disease, lupus disorders, and acute and chronic graft-versus-host disease.  
     
     
         20 . The method of  claim 16 , wherein said mammal is a human.