Prodrugs of 2,4-pyrimidinediamine compounds and their uses

Abstract

The present disclosure provides prodrugs of biologically active 2,4-pyrimidinediamine compounds, compositions comprising the prodrugs, intermediates and methods for synthesizing the prodrugs and methods of using the prodrugs in a variety of applications.

We claim: 
     
         1 . A compound, comprising a 2,4-pyrimidinediamine moiety and a means for delivering the 2,4-pyrimidinediamine moiety in vivo. 
     
     
         2 . The compound of  claim 1  wherein the 2,4-pyrimidinediamine moiety comprises the structural formula (I): 
       
         
           
           
               
               
           
         
       
       and salts thereof, wherein:
 Y is selected from CH 2 , NR 24 , O, S, S(O) and S(O) 2 ; 
 Z 1  and Z 2  are each, independently of one another, selected from CH and N; 
 R 2  is selected from (C1-C6) alkyl optionally substituted with one or more of the same or different R 8  groups, (C3-C8) cycloalkyl optionally substituted with one or more of the same or different R 8  groups, cyclohexyl optionally substituted with one or more of the same or different R 8  groups, 3-8 membered cycloheteroalkyl optionally substituted with one or more of the same or different R 8  groups, (C6-C14) aryl optionally substituted with one or more of the same or different R 8  groups, phenyl optionally substituted with one or more of the same or different R 8  groups and 5-15 membered heteroaryl optionally substituted with one or more of the same or different R 8  groups; 
 R 5  is selected from halo, fluoro, cyano, nitro, trihalomethyl and trifluoromethyl; 
 R 8  is selected from R a , R b , R a  substituted with one or more of the same or different R a  or R b , —OR a  substituted with one or more of the same or different R a  or R b , —B(OR a ) 2 , —B(NR c R c ) 2 , —(CH 2 ) m —R b , —(CHR a ) m —R b , —O—(CH 2 ) m —R b , —S—(CH 2 ) m —R b , —O—CHR a R b , —O—CR a (R b ) 2 , —O—(CHR a ) m —R b , —O— (CH 2 ) m —CH[(CH 2 ) m R b ]R b , —S—(CHR a ) m —R b , —C(O)NH—(CH 2 ) m —R b , —C(O)NH—(CHR a ) m —R b , —O—(CH 2 ) m —C(O)NH—(CH 2 ) m —R b , —S—(CH 2 ) m —C(O)NH—(CH 2 ) m —R b , —O—(CHR a ) m —C(O)NH(CHR a ) m —R b , —S—(CHR a ) m —C(O)NH—(CHR a ) m —R b , —NH—(CH 2 ) m —R b , —NH—(CHR a ) m —R b , —NH[(CH 2 ) m R b ], —N[(CH 2 ) m R b ] 2 , —NH—C(O)—NH—(CH 2 ) m —R b , —NH—C(O)—(CH 2 ) m —CHR b R b  and —NH—(CH 2 ) m —C(O)—NH—(CH 2 ) m —R b ; 
 R 17  is selected from hydrogen, halogen, fluoro, lower alkyl and methyl or, alternatively, R 17  may be taken together with R 18  to form an oxo (═O) group or, together with the carbon atom to which they are attached, a spirocycle containing from 3 to 7 carbon atoms; 
 R 18  is selected from hydrogen, halogen, fluoro, lower alkyl and methyl or, alternatively, R 18  may be taken together with R 17  to form an oxo (═O) group or, together with the carbon atom to which they are attached, a spirocycle containing from 3 to 7 carbon atoms; 
 R 19  is selected from hydrogen, lower alkyl, and methyl or, alternatively, R 19  may be taken together with R 20  to form an oxo (═O) group or, together with the carbon atom to which they are attached, a spirocycle containing from 3 to 7 carbon atoms; 
 R 20  is selected from hydrogen, lower alkyl and methyl or, alternatively, R 20  may be taken together with R 19  to form an oxo (═O) group or, together with the carbon atom to which they are attached, a spirocycle containing from 3 to 7 carbon atoms; 
 each R a  is, independently of the others, selected from hydrogen, lower alkyl, lower cycloalkyl, cyclohexyl, (C4-C11) cycloalkylalkyl, (C6-C10) aryl, phenyl, (C7-C16) arylalkyl, benzyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl; 
 each R b  is a suitable group independently selected from ═O, —OR a , (C1-C3) haloalkyloxy, ═S, —SR a , ═NR a , ═NOR a , —NR c R c , halogen, —CF 3 , —CN, —NC, —OCN, —SCN, —NO, —NO 2 , ═N 2 , —N 3 , —S(O)R a , —S(O) 2 R a , —S(O) 2 OR a , —S(O)NR c R c , —S(O) 2 NR c R c , —OS(O)R a , —OS(O) 2 R a , —OS(O) 2 OR a , —OS(O) 2 NR c R c , —C(O)R a , —C(O)OR a , —C(O)NR c R c , —C(NH)NR c R c , —C(NR a )NR c R c , —C(NOH)R a , —C(NOH)NR c R c , —OC(O)R a , —OC(O)OR a , —OC(O)NR c R c , —OC(NH)NR c R c , —OC(NR a )NR c R c , —[NHC(O)]R a , —[NR a C(O)], R a , —[NHC(O)] n OR a , —[NR a C(O)] n OR a , —[NHC(O)] n NR c R c , —[NR a C(O)] n NR c R c , —[NHC(NH)] n NR c R c  and —[NR a C(NR a )] n NR c R c ; 
 each R c  is, independently of the others, selected from a protecting group and R a , or, alternatively, the two R c  bonded to the same nitrogen atom are taken together with that nitrogen atom to form a 5 to 8-membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different R a  groups; 
 R 24  is selected from hydrogen and lower alkyl; 
 each m is, independently of the others, an integer from 1 to 3; and 
 each n is, independently of the others, an integer from 0 to 3. 
 
     
     
         3 . The compound of  claim 2  in which R 5  is fluoro. 
     
     
         4 . The compound of  claim 2  in which R 2  is a phenyl optionally substituted with one or more of the same or different R 8  groups. 
     
     
         5 . The compound of  claim 4  in which R 2  is 3,4,5-tri(loweralkoxy)phenyl. 
     
     
         6 . The compound of  claim 5  in which R 2  is 3,4,5-(trimethoxy)phenyl. 
     
     
         7 . The compound of  claim 2  in which Y is O, Z 1  is CH, Z 2  is N, R 17  and R 18  are each methyl, and R 19  and R 20  are taken together to form an oxo group. 
     
     
         8 . The compound of  claim 7  in which R 2  is a phenyl optionally substituted with one or more of the same or different R 8  groups. 
     
     
         9 . The compound of  claim 8  in which R 2  is 3,4,5-tri(loweralkoxy)phenyl. 
     
     
         10 . The compound of  claim 9  in which R 2  is 3,4,5-(trimethoxy)phenyl. 
     
     
         11 . The compound of  claim 1  in which the means for delivering the 2,4-pyrimidinediamine moiety in vivo comprises a water solubilizing means. 
     
     
         12 . The compound of  claim 1  in which the means for delivering the 2,4-pyrimidinediamine moiety in vivo is cleaved by an esterase. 
     
     
         13 . The compound of  claim 1  in which the means for delivering the 2,4-pyrimidinediamine moiety in vivo cleaves chemically in the stomach. 
     
     
         14 . The compound of  claim 1  in which the means for delivering the 2,4-pyrimidinediamine moiety in vivo can be cleaved in the presence of a phosphatase. 
     
     
         15 . The compound of  claim 2  wherein the 2,4-pyrimidinediamine moiety has the structure (III): 
       
         
           
           
               
               
           
         
         including salts thereof, wherein each R 30 , R 31  and R 32  are each, independently of one another, selected from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, (C6-C14) aryl, phenyl, 5-14 membered heteroaryl, (C7-C20) arylalkyl, benzyl, 7-20 membered heteroarylalkyl, —OR, chloro, fluoro, bromo, cyano, nitro, —C(O)R, —C(O)OR, —NRR, —S(O) 2 NRR, —C(O)NRR, —N(R)S(O) 2 R and —NC(O)OR, where each R is, independently of the others, selected from hydrogen and lower alkyl. 
       
     
     
         16 . The compound of  claim 15  in which each R 30 , R 31  and R 32  are each methoxy. 
     
     
         17 . A pharmaceutical composition comprising a means for delivering a therapeutic agent effective to inhibit Syk in vivo, and a pharmaceutically acceptable carrier. 
     
     
         18 . The pharmaceutical composition of  claim 17  wherein the therapeutic agent comprises a 2,4-diaminopyrimidine moiety. 
     
     
         19 . A method of administering to a subject a 2,4-pyrimidinediamine compound according to structural formula (IV): 
       
         
           
           
               
               
           
         
         including salts thereof, wherein Z 1 , Z 2 , R 2 , R 5 , R 17 , R 18 , R 19  and R 20  are as defined in  claim 2  and Y 2  is selected from CH 2 , NH, O and S, comprising administering to the subject a compound according to  claim 2 . 
       
     
     
         20 . A method of inhibiting cell degranulation in a subject, comprising administering to the subject an amount of a compound according to  claim 2  sufficient to deliver an amount of the 2,4-pyrimidinediamine moiety effective to inhibit degranulation. 
     
     
         21 . The method of  claim 20  in which the amount is sufficient to inhibit a disease selected from an allergic disease, low grade scarring, a disease associated with tissue destruction, a disease associated with tissue inflammation, inflammation and scarring. 
     
     
         22 . A method of inhibiting an activity of a Syk kinase in a subject, comprising administering to the subject an amount of a compound according to  claim 2  sufficient to deliver an amount of the 2,4-pyrimidinediamine moiety effective to inhibit the Syk kinase activity. 
     
     
         23 . A method of treating or preventing an autoimmune disease in a subject, and/or one or more symptoms associated therewith, comprising administering to the subject an amount of a compound according to  claim 1  to deliver sufficient 2,4-pyrimidinediamine moiety effective to treat or prevent the autoimmune disease. 
     
     
         24 . The method of  claim 23  in which the autoimmune disease is selected from Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis of pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture's disease, autoimmune thrombocytopenia, sympathetic ophthalmia, myasthenia gravis, Graves' disease, primary biliary cirrhosis, chronic aggressive hepatitis, ulcerative colitis, membranous glomerulopathy, systemic lupus erythematosis, rheumatoid arthritis, Sjogren's syndrome, Reiter's syndrome, polymyositis-dermatomyositis, systemic sclerosis, polyarteritis nodosa, multiple sclerosis and bullous pemphigoid. 
     
     
         25 . The method of  claim 24  in which the amount of compound administered is effective to achieve a serum concentration of the 2,4-pyrimidinediamine moiety that is at or above the IC 50  of Syk inhibition of the 2,4-pyrimidinediamine moiety, as measured in an in vitro assay.