Inhibitors of Cdc25 phosphatases

Abstract

A method of inhibiting cdc25 phosphatases in warm-blooded animals comprising administering to warm-blooded animals in need thereof an effective amount of a compound of the formula wherein the substituents are defined as in the specification.

1 - 17 . (canceled)  
     
     
         18 . A method of inhibiting cdc 25 phosphatases in warm-blooded animals comprising administering to warm-blooded animals in need thereof an amount of a compound of the formula  
       
         
           
           
               
               
           
         
       
       wherein A is  
       
         
           
           
               
               
           
         
       
       wherein two of R 1 , R 2 , R 3 , R 4 , and R 5  are hydrogen and the other three are independently selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy, alkylcarbonyloxy, alkylthio and —NR 6 R 7 , it being understood that: 
 either R 1  and one of R 2  and R 4  are independently selected from the group consisting of hydroxy, alkylcarbonyloxy and —NR 6 R 7 ,  
 or R 2  and one of R 3  and R 5  are independently selected from the group consisting of hydroxy, alkylcarbonyloxy and —NR 6 R 7 ,  
 or R 4  and one of R 3  and R 5  are independently selected from the group consisting of hydroxy, alkylcarbonyloxy and —NR 6 R 7 ,  
 or also one of R 1 , R 3  and R 5  is selected from the group consisting of hydroxy, alkylcarbonyloxy and —NR 6 R 7 , and B—N(W)—X—Y remainder is attached to A by nitrogen, R 6  and R 7  are independently each time that they occur a hydrogen or alkyl or R 6  and R 7  together with the nitrogen atom form a heterocycle of 4 to 7 ring members comprising 1 to 2 heteroatoms, the members necessary to complete the heterocycle being independently selected from the group consisting of —CR 8 R 9 —, —O—, —S— and —NR 10 —, R 8  and R 9  independently are each time that they occur selected from the group consisting of hydrogen, alkyl, alkoxy, benzyloxycarbonylamino and dialkylamino, and R 10  independently is each time that it occurs hydrogen or alkyl,  
 wherein either R 11  and one of R 13 , R 14  and R 15  are hydroxy while R 13 , R 14  and R 15  as well as R 16  are hydrogen,  
 or R 12  and R 16  are hydroxy while R 11 , R 13 , R 14  and R 15  are hydrogen;  
 B is —(CH 2 ) p —, p is an integer from 0 to 1;  
 W is hydrogen or alkyl;  
 X is selected from the group consisting of 4CH 2 ) q —, —(CH 2 ) q —NH and —CO—(CH 2 ) r —, q is an integer from 1 to 6 and r is an integer from 0 to 6;  
 or B—N(W)—X—Y is  
                     
 wherein B is as defined above, t is an integer from 0 to 2, s is an integer from 0 to 1 and R 17  and R 18  are independently hydrogen or alkyl;  
 and:  
 when X is —CH 2 ) q — or —CO—(CH 2 ) r —, then Y is  
                     
 wherein R 19  is selected from the group consisting of hydrogen, halogen, nitro, alkyl, alkylthio, —NR 21 R 22 , —SO 2 —NR 22 R 24 , —NH—SO 2 —R 25  and —O—P(O)(OR 26 )(OR) 27 , R 21  and R 22  independently are hydrogen or alkyl,  
 R 23  and R 24  independently are hydrogen or alkyl, or R 23  and R 24  representing together with the nitrogen atom which carries them a heterocycle with 5 to 7 ring members, the additional members are independently selected from the group consisting of —CHR 28 —, —NR 29 —, —O— and —S—, R 28 — and R 29  are independently each time that they occur, hydrogen or alkyl,  
 R 25  is selected from the group consisting of alkyl, haloalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl, the aryl or heteroaryl nucleus of which is optionally substituted by at least one member independently selected from the group consisting of halogen, alkyl, haloalkyl, hydroxy, alkoxy and nitro, except for the optional nitrogen atoms of the heteroaryl nucleus for which the optional substituents are alkyl,  
 R 26  and R 27  are independently alkyl,  
 and R 20  is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy and alkylthio,  
 when X is 4CH 2 ) q —NH— or when B—N(W)—X—Y is  
                     
 then Y exclusively is —SO 2 —R 30  wherein R 30  is selected from the group consisting of alkyl, haloalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl, the aryl or heteroaryl nucleus of which is optionally substituted by at least one member independently selected from the group consisting of halogen, alkyl, haloalkyl, hydroxy, alkoxy and nitro, except for the optional nitrogen atoms of the heteroaryl nucleus for which the optional substituents are alkyl;  
 it being understood that when B—N(W)—X—Y is  
                     
 then B is —CH 2 )—;  
 or a pharmaceutically acceptable salt thereof sufficient to inhibit cdc25 phosphatases.  
 
     
     
         19 . The method of  claim 18 , wherein: 
 A is                          wherein two of R 1 , R 2 , R 3 , R 4  and R 5  are hydrogen and the other three are independently selected from the group consisting of hydrogen, halogen, alkyl, alkylcarbonyloxy, hydroxy, alkoxy and NR 6 R 7 , it being understood that:    either R 1  and one of R 2  and R 4  are independently selected from the group consisting of hydroxy, alkylcarbonyloxy and —NR 6 R 7 ,    or R 2  and one of R 3  and R 5  are independently selected from the group consisting of hydroxy, alkylcarbonyloxy and —NR 6 R 7 ,    or R 4  and one of R 3  and R 5  are independently selected from the group consisting of hydroxy, alkylcarbonyloxy and —NR 6 R 7 ,    or one of R 1 , R 3  and R 5  is independently selected from the group consisting of hydroxy, alkylcarbonyloxy and —NR 6 R 7 , and B—N(W)—X—Y remainder is attached to A by nitrogen,    R 6  and R 7  are independently each time that they occur, hydrogen or alkyl or R 6  and R 7  together with the nitrogen atom form a heterocycle with 5 to 7 ring members comprising 1 to 2 heteroatoms, the members necessary to complete the heterocycle being independently selected from the group consisting of CR 8 R 9 —, —O—, —S—, and —NR 10 —[radical], R 8  and R 9  independently each time that they occur hydrogen or alkyl or alkoxy, and R 10  independently is each time that it occurs hydrogen or alkyl,    or A is                          wherein    either R 11  and one of R 13 , R 14  and R 15  is hydroxy while the other R 13 , R 14  and R 15  as well as R 16  are hydrogen,    or R 12  and R 16  are hydroxy while R 11 , R 13 , R 14  and R 15  are hydrogen; 
 B is —CH 2 ) p , p is an integer from 0 to 1;  
 W is hydrogen or alkyl;  
 X is selected from the group consisting of —(CH 2 ) q —, —(CH 2 ) q —NH— and —CO—(CH 2 ) r , q is an integer from 1 to 4 and r is an integer from 0 to 5;  
   or B—N(W—X—Y is                          wherein B is as defined in  claim 18 , t is an integer from 0 to 2, s is an integer from 0 to 1, R 17  and R 18  are independently hydrogen or alkyl;    when X is —CH 2 ) q — or —CO—(CH 2 ) r —, Y is                          wherein R 19  is hydrogen, halogen, nitro, alkyl, alkylthio, —NR 21 R 22 , —SO 2 —NR 23 R 24 , —NH—SO 2 — —R 25  and —O—P(O)(OR 26 )(OR 27 ),    R 21  and R 22  independently are hydrogen or alkyl, R 23  and R 24  independently are hydrogen or alkyl, or R 23  and R 24  together with the nitrogen atom which carries them form a heterocycle with 5 to 6 ring members, the additional members of which are independently selected from the group consisting of —CHR 28 —, —NR 29 —, —O— and    —S—, R 28  and R 29  are independently each time that they occur, hydrogen or alkyl,    R 25  is alkyl or aryl optionally substituted by at least one member selected from the groups consisting of halogen, alkyl, haloalkyl, alkoxy and nitro, except for the optional nitrogen atoms of the heteroaryl nucleus for which the optional substituents are alkyl,    R 26  and R 27  are independently alkyl,    and R 20  is hydrogen or alkyl or akoxy, 
 when X is a —CH 2 ) q —NH— or B—N(W)—X—Y is  
                     
 then Y is —SO 2 —R 30 , R 30  is selected from the group consisting of alkyl haloalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl the aryl or heteroaryl nucleus of which is optionally substituted by at least one member independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy and nitro, except for the optional nitrogen atoms of the heteroaryl nucleus for which the optional substituents are alkyl.  
   
     
     
         20 . The method of  claim 18 , wherein the compound is selected from the group consisting of: 
 -4-(dimethylamino)-2-methoxy-6-({methyl[2-(4-nitrophenyl)ethyl]amino}methyl)-phenol;    -4-(dimethylamino)-2-({methyl[2-(4-nitrophenyl)ethyl]amino}methyl)phenol;    -4-(dimethylamino)-2-methoxy-6-({[2-(4-nitrophenyl)ethyl]amino}methyl)phenol;    -4-(dimethylamino)-2-({[2-(4-nitrophenyl)ethyl]amino}methyl)phenol;    -2-(dimethylamino)-6-methoxy-4-({methyl[2-(4-nitrophenyl)ethyl]amino}-methyl)phenol;    -2-({methyl[2-(4-nitrophenyl)ethyl]amino}methyl)-1,4-benzenediol;    -4-(dimethyl amino)-2-methoxy-6-({methyl[2-(4-nitrophenyl)ethyl]amino}-methyl)phenyl acetate;    or a pharmaceutically acceptable salt thereof.    
     
     
         21 . The method of  claim 18  wherein Y is not (T) and the condition to be treated is selected from the group consisting of prostate cancer, pancreatic cancer, breast cancer, lymphoma and head and neck cancer.  
     
     
         22 . The method of  claim 18  wherein Y is (T), and the condition being treated is spontaneous alopecia, alopecia induced by exogenous products, or radiation-induced alopecia.