Heterocyclic 2-substituted ketoamides

Abstract

The present disclosure describes novel compounds and compositions which are particularly useful for treating hair loss in mammals, including arresting and/or reversing hair loss and promoting hair growth. The present compounds and compositions may also be useful against a variety of disorders including, for example, multi-drug resistance, human immunodeficiency virus (HIV), cardiac injury, and neurological disorders, and may be useful for controlling parasites and invoking immunosuppression.

What is claimed is:  
     
         1 . A compound having a structure:  
                   
       and pharmaceutically acceptable salts, hydrates, and biohydrolyzable amides, esters, and imides thereof, wherein: 
 (a) V is a heteroatom wherein the heteroatom is nitrogen;  
 (b) R 1  is selected from the group consisting of alkyl having at least 3 carbon atoms, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl;  
 (c) Z is a saturated or unsaturated 4-, 5-, 6-, 7-, 8-, or 9-membered heterocycle optionally containing one or more additional heteroatoms selected from the group consisting of O, N, S, S(O), S(O) 2 , and P((O)OK);  
 (d) K is selected from the group consisting of hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl;  
 (e) W is selected from the group consisting of nil, hydrogen, and lower alkyl;  
 (f) A is selected from the group consisting of nil and alkyl;  
 (g) X and Y are each, independently, selected from the group consisting of C(O), P(O), N, O, and S, wherein: 
 (i) when X is C(O) then R 3  is nil and Y is selected from the group consisting of N, O, and S;  
 (ii) when X is P(O) then R 3  is nil and Y is selected from the group consisting of N and O;  
 (iii) when X is N then R 3  is selected from hydrogen, alkyl, and arylalkyl, Y is selected from the group consisting of C(O) and P(O), and R 2  is nil;  
 (iv) when X is O then R 3  is nil, Y is selected from the group consisting of C(O) and P(O), and R 2  is nil; and  
 (v) when X is S then R 3  is nil, Y is C(O), and R 2  is nil;  
 
 (h) R 2  and R 3  are each independently, selected from the group consisting of nil, hydrogen, alkyl, and arylalkyl;  
 (i) R 4  is alkyl;  
 (j) R 5  and R 6  are each, independently, selected from the group consisting of nil, hydrogen, alkyl having at least three carbon atoms, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl, or wherein R 5  and R 6  are bonded together to form a carbocyclic or hetercyclic ring; wherein at least one of R 5  or R 6  is not nil or hydrogen; and wherein when A is nil and R 7  and R 8  are bonded together to form a 5- or 6-membered aromatic carbocyclic ring which is fused to Z, then R 4 , R 5 , and R 6  are not bonded together to form a substituted or unsubstituted tetrahydronapthalene moiety;  
 (k) R 7 , R 8 , and R 9 , and R 10  are each, independently, selected from the group consisting of nil hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, halo, cyano, hydroxy, oxo, imino, —R 14 SR 15 , —R 14 S(O 2 )R 15 , — R 14 S(O)R 15 , —R 14 C(O)R 15 , —R 14 C(O)NR 15 R 16 , —R 14 C(O)OR 15 , —R 14 OR 15 , — R 14 NR 15 R 16 , —R 14 P(O)NR 15 ,R 16 , —R 14 P(O)OR 15 R 16 , and a spiro moiety, and wherein R 7  and R 8  may be optionally bonded together to form an aromatic or saturated, carbocyclic or heterocyclic ring wherein the ring is fused to Z; wherein when A is nil and X is C(O) at least one of R 7 , R 8 , R 9 , and R 10  is not nil or hydrogen;  
 (l) R 14 , and R 15  are each, independently, selected from the group consisting of nil, hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl; and  
 (m) R 16  is selected from the group consisting of hydrogen and alkyl.  
 
     
     
         2 . A compound according to    claim 1    wherein Z is a 5-, 6-, or 7-membered heterocycle optionally containing one or more of the additional heteroatoms which are selected from the group consisting of O, N, S, S(O), and S(O) 2 , and wherein W is hydrogen.  
     
     
         3 . A compound according to    claim 2    wherein Z is a 5-membered heterocycle.  
     
     
         4 . A compound according to    claim 3    wherein A is nil, X is C(O), Y is N, and R 2  is hydrogen.  
     
     
         5 . A compound according to    claim 4    wherein R 8 , R 9  and R 10  are each, independently, selected from the group consisting of nil and hydrogen.  
     
     
         6 . A compound according to    claim 5    which is selected from the group consisting of:  
                 
 
     
     
         7 . A compound according to    claim 4    wherein R 7  and R 8  are bonded together to form a 5-, 6-, or 7-membered carbocyclic or heterocyclic aromatic ring which is fused to Z.  
     
     
         8 . A compound according to    claim 7    which is selected from the group consisting of:  
                 
 
       wherein R 18 , R 19 , and R 20  are each, independently, selected from the group consisting of hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, halogen, hydroxy, oxo, alkoxy, aryloxy, —SR 21 , —S(O 2 )R 21 , —S(O)R 22 , —C(O)R 21 , —C(O)OR 21 , —C(O)NR 21 R 23 , — C(S)R 21 , —OR 21 , and —NR 21 ,R 22 , and wherein R 2 ,, R 22 , and R 23  are each, independently, selected from the group consisting of hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl.  
     
     
         9 . A compound according to    claim 8    which is selected from the group consisting of:  
                 
 
       wherein R 30  is selected from the group consisting of —OR 32  and —OCH 2 C(O)OR 32 , wherein R 32  is selected from the group consisting of hydrogen and alkyl.  
     
     
         10 . A compound according to    claim 9    wherein R 30  is —OCH 3 .  
     
     
         11 . A compound according to    claim 2    wherein Z is a 6-membered heterocycle and wherein A is nil, X is C(O), Y is N, and R 2  is hydrogen.  
     
     
         12 . A compound according to    claim 11    wherein R 8 , R 9 , and R 10  are each, independently, selected from the group consisting of hydrogen and nil.  
     
     
         13 . A compound according to    claim 12    which is:  
                 
 
       wherein R 24  is selected from the group consisting of nil, hydrogen, and alkyl, and R 25  and R 26  are each, independently, selected from the group consisting of nil, hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, halogen, hydroxy, oxo, alkoxy, aryloxy, — SR 27 , —SO 2 R 27 , —SOR 27 , —COR 27 , —C(O)OR 27 , —C(O)NR 29 R 27 , —CSR 27 , —OR 27 , and —NR 27 R 28 , wherein R 27 , R 28 , and R 29  are each, independently, selected from the group consisting of hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl.  
     
     
         14 . A compound according to    claim 13    which is selected from the group consisting of:  
                 
 
     
     
         15 . A compound according to    claim 11    wherein R 7  and R 8  are bonded together to form a carbocyclic or heterocyclic aromatic ring.  
     
     
         16 . A compound according to    claim 15    which is selected from the group consisting of:  
                 
 
       wherein R 18 , R 19 , and R 20  are each, independently, selected from the group consisting of nil, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, halogen, hydroxy, oxo, alkoxy, aryloxy, —SR 21 , —S(O 2 )R 21 , —S(O)R 21 , —C(O)R 21 , —C(O)OR 21 , —C(O)NR 21 R 23 , —C(S)R 21 , —OR 21 , and —NR 21 R 22 , and wherein R 18  and R 19  may be bonded together to form a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring; wherein R 21 , R 22 , and R 23  are each, independently, selected from the group consisting of hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl.  
     
     
         17 . A compound according to    claim 16    wherein R 18 , R 19 , and R 20  are each, independently, hydrogen.  
     
     
         18 . A compound according to    claim 16    which is selected from the group consisting of:  
                 
 
       wherein R 30  is selected from the group consisting of —OR 32  and —OCH 2 C(O)OR 32 , wherein R 32  is selected from the group consisting of hydrogen and alkyl, and wherein R 31 , is selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl.  
     
     
         19 . A compound according to    claim 18    wherein R 30  is —OCH 3 .  
     
     
         20 . A composition comprising a compound according to    claim 1    and a pharmaceutically-acceptable carrier.  
     
     
         21 . A method of treating hair loss comprising administering to a mammal a composition according to    claim 20   .  
     
     
         22 . A method according to    claim 21    wherein the administration is topical.  
     
     
         23 . A method according to    claim 21    wherein the administration is oral.  
     
     
         24 . A method of treating or preventing multi-drug resistance comprising administering to a mammal a composition according to    claim 20   .  
     
     
         25 . A composition according to    claim 20    additionally comprising a matrix metalloproteinase inhibitor.