Substituted pyrrolo[2,3-d]pyrimidines for selectively targeting tumor cells with fr-alpha and fr-beta type receptors

Abstract

Pyrrolo[2,3-d]pyrimidine derivatives, and pharmaceutical acceptable salts thereof, useful in therapeutically treating patients with cancer are disclosed. These compounds selectively target folate receptors (FR) of cancerous tumor cells and inhibit purine synthesis and hence, DNA synthesis.

We claim: 
     
         1 . A compound, or pharmaceutically acceptable salt thereof, having a general formula 1: 
       
         
           
           
               
               
           
         
         wherein,
 R 1  is selected from the group consisting of hydrogen, hydroxyl, methyl and NHR wherein R is selected from the group consisting of hydrogen, lower alkyl, and a tautomer of the hydroxyl or the NHR; 
 R 2  is selected from the group consisting of hydrogen, hydroxyl, methyl and NHR wherein R is selected from the group consisting of hydrogen and lower alkyl, and when R 1  is hydrogen, R is not hydrogen; 
 A is selected from the group consisting of sulfur, oxygen, CR′R″ and NR′, wherein R′ and R″ are the same or different and each is selected from the group consisting of hydrogen and lower alkyl, and when R 1  is hydrogen, R′ is not hydrogen; 
 B is selected from the group consisting of sulfur, oxygen, CR′R″ and NR′, wherein R′ and R″ are the same or different and each is selected from the group consisting of H and lower alkyl, and when R 1  is hydrogen, both R′ and R″ are not hydrogen; 
 A and B are the same or different; 
 the chemical bond between positions 5 and 6 is selected from the group consisting of a single bond and a double bond; 
 the position of the side chain on the five-membered ring is selected from the group consisting of position 5, 6 and 7; 
 when the side chain is at position 7, A is selected from the group consisting of CR′ and N, and optionally, carbon atoms at positions 5 and 6, independently, have attached thereto a substituent selected from the group consisting of two hydrogen atoms when the bond between the carbon atoms 5 and 6 is a single bond and a hydrogen atom when the bond between the carbon atoms 5 and 6 is a double bone, and a lower alkyl group and a hydrogen atom when the bond between the carbon atoms at positions 5 and 6 is a single bond or a lower alkyl when the bond between the carbon atoms 5 and 6 is a double bond; 
 each of X, Y, Z and Q is selected from the group consisting of carbonyl, sulfonyl, oxygen, (CR′R″) n  and NR′, wherein n is 0 to 6, R′ and R″ are the same or different, and 
 each of R′ and R″ is selected from the group consisting of hydrogen, straight or branched lower alkyl, partially to fully fluoro substituted alkyl, benzyl, formyl, methylketone, trifluoromethyl ketone; 
 X, Y, Z and Q are different or two of X, Y, Z and Q are the same; 
 Ar is selected from the group consisting of phenyl, thiophene, pyridine, naphthyl, indole, benzothiophene, substituted and unsubstituted aromatic, substituted and unsubstituted heteroaromatic and, partially and completely reduced aromatic and heteroaromatic; 
 when Ar is a six-membered ring and one of X, Y and Z is carbonyl, the Q and carbonyl substituents are meta or para; and 
 when Ar is a five-membered ring and one of X, Y and Z is carbonyl, the Q and carbonyl substituents are in positions selected from the group consisting of 2,4 and 2,5 and 3,5. 
 
       
     
     
         2 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, selected from a formula 1a, 1b, 1c and 1d: 
       
         
           
           
               
               
           
         
       
     
     
         3 . A method of therapeutically treating a patient for cancer, comprising the steps of:
 a) employing a compound, or pharmaceutically acceptable salt thereof, having a formula 1:   
       
         
           
           
               
               
           
         
       
       wherein,
 R 1  is selected from the group consisting of hydrogen, hydroxyl, methyl and NHR wherein R is selected from the group consisting of H, lower alkyl, and a tautomer of the hydroxyl or the NHR; 
 R 2  is selected from the group consisting of hydrogen, hydroxyl, methyl and NHR wherein R is selected from the group consisting of H and lower alkyl; 
 A is selected from the group consisting of sulfur, oxygen, CR′R″ and NR′, wherein R′ and R″ are the same or different and each is selected from the group consisting of H and lower alkyl; 
 B is selected from the group consisting of sulfur, oxygen, CR′R″ and NR′, wherein R′ and R″ are the same or different and each is selected from the group consisting of H and lower alkyl; 
 A and B are the same or different; 
 the chemical bond between positions 5 and 6 is selected from the group consisting of a single bond and a double bond; 
 the position of the side chain on the five-membered ring is selected from the group consisting of position 5, 6 and 7; 
 when the side chain is at position 7, A is selected from the group consisting of CR′ and N, and optionally, carbon atoms at positions 5 and 6, independently, have attached thereto a substituent selected from the group consisting of two hydrogen atoms when the bond between the carbon atoms 5 and 6 is a single bond and a hydrogen atom when the bond between the carbon atoms 5 and 6 is a double bone, and a lower alkyl group and a hydrogen atom when the bond between the carbon atoms at positions 5 and 6 is a single bond or a lower alkyl when the bond between the carbon atoms 5 and 6 is a double bond; 
 each of X, Y, Z and Q is selected from the group consisting of carbonyl, sulfonyl, oxygen, (CR′R″) n  and NR′, wherein n is 0 to 6, R′ and R″ are the same or different, and 
 each of R′ and R″ is selected from the group consisting of hydrogen, straight or branched C 1 -C 6  alkyl, partially to fully fluoro substituted alkyl, benzyl, formyl, methylketone, trifluoromethyl ketone; 
 X, Y, Z and Q are different or two of X, Y, Z and Q are the same; 
 Ar is selected from the group consisting of phenyl, thiophene, pyridine, naphthyl, indole, benzothiophene, substituted and unsubstituted aromatic, substituted and unsubstituted heteroaromatic and, partially and completely reduced aromatic and heteroaromatic; 
 when Ar is a six-membered ring and one of X, Y and Z is carbonyl, the Q and carbonyl substituents are meta or para; and 
 when Ar is a five-membered ring and one of X, Y and Z is carbonyl, the Q and carbonyl substituents are in positions selected from the group consisting of 2,4 and 2,5 and 3,5; 
 b) incorporating said compound in a suitable pharmaceutical carrier; and 
 c) administering a therapeutically effective amount of said compound incorporated in said carrier to a patient.