Compositions and Methods For The Treatment and Prevention of Disease

Abstract

The present invention relates to various novel substituted dipeptide derived nitrogen-containing heterocyclic compounds, their pharmaceutically acceptable salt derivatives, and their methods of use. In one aspect the present invention relates to compositions and methods for the treatment and prevention of disease in a mammal comprising administering the compounds of the invention in a pharmaceutically acceptable form to a mammal. In particular, the invention relates to medicaments comprising various novel substituted dipeptide derived nitrogen-containing heterocyclic compounds and pharmaceutically acceptable salt derivatives and methods for administration to a mammal for the treatment and prevention of malarial diseases. The compounds of the invention may optionally be administered with at least one pharmaceutically acceptable excipient, another biologically active agent or a combination thereof.

1 . A therapeutic composition for treating or preventing a disease or condition in an individual comprising an effective amount of a compound of formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein,
 W is a member selected from the group consisting of —C(R 5 )(R 5a )—; —C(R 6 )(R 6a )—C(R 7 )(R 7a )—; —C(R 8 )═C(R 9 )—; and —N(R 10 ); 
 X is a member selected from the group consisting of —N(R 1a )C(═Y)N(R 4 )—; —OC(═Y)N(R 4 )—; —N(R 1a )C(═Y)O—; —N(R 1a )S(═O)N(R 4 )—; —N(R 1a )S(═O) 2 N(R 4 )—; and —C(R 1 a )(R 3a )C(═Y)N(R 4 )—; 
 Y and Z represent, each independent from the other, a member selected from the group consisting of oxygen (“O”) or sulfur (“S”); and 
 R 1 , R 1a , R 2 , R 3 , R 3a , R 4 , R 5 , R 5a , R 6 , R 6a , R 7 , R 7a , R 8 , R 9 , and R 10  represent, each independent from the other, a member selected from the group consisting of: a hydrogen atom; an amino acid side chain; a (C1-C10) alkyl; (C1-C10) alkenyl; (C1-C10) alkynyl; (C5-C12) monocyclic or bicyclic aryl; (C5-C14) monocyclic or bicyclic aralkyl; monocyclic or bicyclic (C5-C14) heteroaralkyl; and (C1-C10) monocyclic or bicyclic heteroaryl group having up to 5 heteroatoms selected from N, O, S, and P said groups being able to be non-substituted or substituted by 1 to 6 substituents further selected from the group consisting of: a halogen atom, an NO 2 , OH, amidine, benzamidine, imidazole, 1,2,3-triazole, alkoxy, (C1-C4), amino, piperazine, piperidine, dialkylamino, guanidine group, bis alkylated or bis acylated guanido group, carboxylic acid, carboxamide, ester, hydroxamic acid, phosphinic acid, phosphonate, phosphonamidate, sulfhydryl and any combination thereof. 
 
     
     
         2 . The therapeutic composition of  claim 1 , wherein the disease or condition comprises malaria. 
     
     
         3 . The therapeutic composition of  claim 1 , wherein the composition further comprises at least one of a pharmaceutically acceptable carrier or vehicle, excipient, adjuvant, an additional biologically active agent or combination thereof. 
     
     
         4 . The therapeutic composition of  claim 1 , wherein the composition comprises from about 1% to about 50% by weight of the compound of formula I. 
     
     
         5 . The therapeutic composition of  claim 3 , wherein the biologically active agent comprises chloroquine, a chloroquine derivative, an HIV protease inhibitor, an antiviral or a combination thereof. 
     
     
         6 . The therapeutic composition of  claim 3 , wherein the composition is present in a pharmaceutically acceptable form. 
     
     
         7 . The therapeutic composition of  claim 6 , wherein the pharmaceutically acceptable form comprises a tablet or capsule having an enteric coating. 
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . A kit for treating or preventing a physiological condition associated with HIV infection, malaria or both, said kit comprising a plurality of containers, wherein at least one of said containers contains the compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         14 . A method for the treatment or prevention of AIDS comprising;
 administering to an individual in need thereof, a therapeutic composition comprising an effective amount the compound of  claim 1 , in a pharmaceutically acceptable form.   
     
     
         15 . The method of  claim 14 , wherein the therapeutic composition is administered as a single daily dose. 
     
     
         16 . The method of  claim 14 , wherein the therapeutic composition is administered in two or more unitary dosage units. 
     
     
         17 . The method of  claim 14 , wherein the therapeutic composition further comprises at least one of a pharmaceutically acceptable carrier or vehicle, excipient, adjuvant, an additional biologically active agent or combination thereof. 
     
     
         18 . The method of  claim 17 , wherein the biologically active agent comprises chloroquine, a chloroquine derivative, an HIV protease inhibitor, an antiviral or a combination thereof. 
     
     
         19 . The method of  claim 14 , wherein the composition comprises from about 1% to about 50% by weight of the compound of formula I.