Diaminopyrroloquinazolines compounds as protein tyrosine phosphatase inhibitors

Abstract

The invention relates to pyrimido[5,4-e][1,2,4]triazine-5,7-diamine compounds which are useful for inhibiting protein tyrosine phosphatases, particularly PTP1B, and are useful for lowering blood glucose concentrations in mammals.

1 . A compound of the formula:  
     
       
         
         
             
             
         
       
       wherein  
       {circle around (P)} is a 5 or 6 membered heteroaromatic ring containing from 1 to 2 hetero atoms selected from the group consisting of oxygen, sulfur, and nitrogen;  
       R 1  is selected from hydrogen and lower alkyl;  
       R 2  is selected from the group consisting of hydrogen,  
       
         
           
           
               
               
           
         
       
       R 3  and R 4  are independently selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkoxy, hydroxy lower alkyl, perfluoroloweralklyl, nitro, halo, lower alkanoyl, —N R 5 R 6 , R 7 S—,  
       
         
           
           
               
               
           
         
         phenyl, hydroxy, perfluoroloweralkoxy, and phenoxy, or  
       
       R 3  and R 4  when present on adjacent carbon atoms on the heteroaromatic ring can be taken together to form a lower alkylene bridge or taken together with their adjacent carbon atoms to form an aromatic ring system fused to the heteroaromatic ring, said aromatic ring system containing one or two aromatic rings with one of said rings being either an aromatic or heteroaromatic ring;  
       R 5  and R 6  are selected from hydrogen and lower alkyl;  
       R 2  is selected from the group consisting of hydrogen, benzyl, phenyl and lower alkyl;  
       R 7  is lower alkyl;  
       R 13  is selected from the group consisting of hydrogen, lower alkyl, benzyl and phenyl;  
       R 10 , R 11  and R 12  are independently selected from hydrogen and lower alkyl; and  
       m, n, o and v are independent integers selected from 0 to 4, or pharmaceutically acceptable salts thereof,  
     
   
   
       2 . The compound of  claim 1  wherein {circle around (P)} is a heteroaromatic ring containing sulfur as the only hetero atom.  
   
   
       3 . The compound of  claim 2  wherein R 3  and R 4  are independently selected from hydrogen, halogen and lower alkyl.  
   
   
       4 . The compound of  claim 3  wherein said compound is 7-methanesulfonyl-6-thiophen-2-yl-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine trifluoro-acetic acid salt.  
   
   
       5 . The compound of  claim 3  wherein said compound is 7-methyl-6-thiophen-2-yl-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine.  
   
   
       6 . The compound of  claim 3  wherein said compound is 6-(5-chloro-thiophen-2-yl)-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine trifluoro-acetic acid salt.  
   
   
       7 . The compound of  claim 2  wherein 
 R 3  and R 4  is selected from hydrogen and                          R 12  is selected from hydrogen and lower alkyl; and    R 3  and R 4  are other than hydrogen.    
   
   
       8 . The compound of  claim 7  wherein said compound is 1-[5-(1,3-diamino-7H-pyrrolo[3,2-f]quinazolin-6-yl)-thiophen-2-yl]-ethanone trifluoro-acetic acid salt.  
   
   
       9 . The compound of  claim 7  wherein said compound is 1-[5-(1,3-diamino-7-methyl-7H-pyrrolo[3,2-f]quinazolin-6-yl)-thiophen-2-yl]-ethanone trifluoro-acetic acid salt.  
   
   
       10 . The compound of  claim 1  wherein R 3  and R 4  are attached to the hetero atom ring on adjacent carbon atoms and taken together with their attached carbon atoms a fused phenyl ring.  
   
   
       11 . The compound of  claim 10  wherein said compound is 6-benzo[b]thiophen-2-yl-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine trifluoro-acetic acid salt.  
   
   
       12 . The compound of  claim 10  wherein said compound is 6-benzo[b]thiophen-2-yl-7-methyl-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine trifluoro-acetic acid salt.  
   
   
       13 . The compound of  claim 7  wherein said compound is 6-benzofuran-2-yl-7-methyl-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine.  
   
   
       14 . The compound of  claim 1  wherein {circle around (P)} is a heteroaromatic ring containing an oxygen atom as the only hetero atom.  
   
   
       15 . The compound of  claim 14  wherein said compound is 6-furan-2-yl-7-methyl-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine trifluoro-acetic acid salt.  
   
   
       16 . The compound of  claim 14  wherein said compound is 6-benzofuran-2-yl-7-methyl-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine  
   
   
       17 . The compound of  claim 1  wherein {circle around (P)} is a heteroaromatic ring containing a nitrogen hetero atom.  
   
   
       18 . The compound of  claim 17  wherein said compound is 6-(3,5-dimethyl-isoxazol-4-yl)-7-methyl-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine trifluoro-acetic acid salt.  
   
   
       19 . A pharmaceutical composition comprising one or more compounds of the formula  
     
       
         
         
             
             
         
       
       and one or more pharamceutically acceptable excipients wherein  
       {circle around (P)} is a 5 or 6 membered heteroaromatic ring containing from 1 to 2 hetero atoms selected from the group consisting of oxygen, sulfur, and nitrogen;  
       R 1  is selected from hydrogen and lower alkyl;  
       R 2  is selected from the group consisting of hydrogen,  
       
         
           
           
               
               
           
         
       
       R 3  and R 4  are independently selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkoxy, hydroxy lower alky, perfluoroloweralklyl, nitro, halo, lower alkanoyl, —N R 5 R 6 , R 7 S—,  
       
         
           
           
               
               
           
         
         phenyl, hydroxy, perfluoroloweralkoxy, and phenoxy, or  
       
       R 3  and R 4  when present on adjacent carbon atoms on the heteroaromatic ring can be taken together with their adjacent carbon atoms to form a lower alkylenedioxy bridge or an aromatic ring system fused to the phenyl ring, said aromatic ring system containing one or two aromatic rings with one of said rings being either an aromatic or heteroaromatic ring;  
       R 5  and R 6  are selected from hydrogen and lower alkyl;  
       R 2  is selected from the group consisting of hydrogen, benzyl, phenyl and lower alkyl;  
       R 7  is lower alkyl;  
       R 13  is selected from the group consisting of hydrogen, lower alkyl, benzyl and phenyl;  
       R 10 , R 11  and R 12  are independently selected from hydrogen and lower alkyl; and  
       m, n, o and v are independent integers selected from 0 to 4 or pharmaceutically acceptable salts thereof.  
     
   
   
       20 . A method of treating a disease based on high blood glucose concentration comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one compound of the formula:  
     
       
         
         
             
             
         
       
       wherein,  
       {circle around (P)} is a 5 or 6 membered heteroaromatic ring containing from 1 to 2 hetero atoms selected from the group consisting of oxygen, sulfur, and nitrogen;  
       R 1  is selected from hydrogen and lower alkyl;  
       R 2  is selected from the group consisting of hydrogen,  
       
         
           
           
               
               
           
         
       
       R 3  and R 4  are independently selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkoxy, hydroxy lower alkyl, perfluoroloweralklyl, nitro, halo, lower alkanoyl, —N R 5 R 6 , R 7 S—,  
       
         
           
           
               
               
           
         
       
       phenyl, hydroxy, perfluoroloweralkoxy, and phenoxy, or  
       R 3  and R 4  when present on adjacent carbon atoms on the heteroaromatic ring can be taken together with their adjacent carbon atoms to form a lower alkylenedioxy bridge or an aromatic ring system fused to the phenyl ring, said aromatic ring system containing one or two aromatic rings with one of said rings being either an aromatic or heteroaromatic ring;  
       R 5  and R 6  are selected from hydrogen and lower alkyl;  
       R 2  is selected from the group consisting of hydrogen, benzyl, phenyl and lower alkyl;  
       R 7  is lower alkyl;  
       R 13  is selected from the group consisting of hydrogen, lower alkyl, benzyl and phenyl;  
       R 10 , R 11  and R 12  are independently selected from hydrogen and lower alkyl; and  
       m, n, o and v are independent integers selected from 0 to 4 or pharmaceutically acceptable salts thereof.