Facially Amphiphilic Polymers and Oligomers and Uses Thereof

Abstract

The present invention discloses methods of use of facially amphiphilic polymers and oligomers, including pharmaceutical uses of the polymers and oligomers as antimicrobial agents and antidotes for hemorrhagic complications associated with heparin therapy. The present invention also discloses novel facially amphiphilic polymers and oligomers and their compositions, including pharmaceutical compositions. The present invention further discloses the design and synthesis of facially amphiphilic polymers and oligomers.

1 .- 54 . (canceled) 
     
     
         55 . A method of treating a microbial infection in an animal in need thereof, said method comprising administering to the animal an effective amount of a pharmaceutical composition comprising an oligomer of Formula IV:
   R 1 -[- x -A 1 - x - z - y -A 2 - y - z]   m -R 2   (IV)
   or an acceptable salt or solvate thereof,   wherein:   x is NR 8 , —NR 8 NR 8 —, C═O, or O; y is NR 8 , —NR 8 NR 8 —, C═O, S, or O; and R 8  is hydrogen or alkyl;   z is C═O, C═S, O═S═O, —NR 8 NR 8 —, or —C(═O)C(═O)—;   A 1  and A 2  are independently optionally substituted arylene or optionally substituted heteroarylene, wherein A 1  and A 2  are independently optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s);   R 1  is   (i) hydrogen, a polar group (PL), or a non-polar group (NPL), and R 2  is -x-A 1 -x-R 1 , wherein A 1  is as defined above and is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); or   (ii) hydrogen, a polar group (PL), or a non-polar group (NPL), and R 2  is -x-A 1 -x-z-y-A 2 -y-R 1 , wherein A 1  and A 2  are as defined above, and each of which is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); or   (iii) hydrogen, a polar group (PL), or a non-polar group (NPL), and R 2  is -x-A′-x-R 1 , wherein A′ is aryl or heteroaryl and is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); or   (iv) hydrogen, a polar group (PL), or a non-polar group (NPL), and R 2  is -x-A 1 -x-z-y-A′-y-R 1 , wherein A 1  is as defined above, A′ is aryl or heteroaryl, and each of A 1  and A′ is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); or   (v) -z-y-A′ and R 2  is hydrogen, a polar group (PL), or a non-polar group (NPL), wherein A′ is aryl or heteroaryl and is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); or   (vi) -z-y-A′, and R 2  is -x-A″, wherein A′ and A″ are independently aryl or heteroaryl, and each of A′ and A″ is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); or   (vii) R 1  and R 2  are independently a polar group (PL) or a non-polar group (NPL); or   (viii) R 1  and R 2  together form a single bond;   NPL is a nonpolar group independently selected from the group consisting of —B(OR 4 ) 2  and —(NR 3′ ) q1NPL —U NPL —(CH 2 ) pNPL —(NR 3″ ) q2NPL —R 4′ , wherein:   R 3 , R 3′ , and R 3″  are independently selected from the group consisting of hydrogen, alkyl, and alkoxy;   R 4  and R 4′  are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, any of which is optionally substituted with one or more alkyl or halo groups;   U NPL  is absent or selected from the group consisting of O, S, S(═O), S(═O) 2 , NR 3 , —C(═O)—, —C(═O)—N═N—NR 3 —, —C(═O)—NR 3 —N═N—, —N═N—NR 3 —, —C(═N—N(R 3 ) 2 )—, —C(═NR 3 )—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O) 2 O—, —R 3 O—, —R 3 S—, —S—C═N— and —C(═O)—NR 3 —O—, wherein groups with two chemically nonequivalent termini can adopt both possible orientations;   the —(CH 2 ) pNPL — alkylene chain is optionally substituted with one or more amino or hydroxy groups, or is unsaturated;   pNPL is 0 to 8;   q1NPL and q2NPL are independently 0, 1 or 2;   PL is a polar group selected from the group consisting of halo, hydroxyethoxymethyl, methoxyethoxymethyl, polyoxyethylene, and —(NR 5′ ) q1PL —U PL —(CH 2 ) pPL —(NR 5′ ) q2PL —V, wherein:   R 5 , R 5′ , and R 5″  are independently selected from the group consisting of hydrogen, alkyl, and alkoxy;   U PL  is absent or selected from the group consisting of O, S, S(═O), S(═O) 2 , NR 5 , —C(═O)—, —C(═O)—N═N—NR 5 —, —C(═O)—NR 5 —N═N—, —N═N—NR 5 —, —C(═N—N(R 5 ) 2 )—, —C(═NR 5 )—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O) 2 O—, —R 5 O—, —R 5 S—, —S—C═N— and —C(═O)—NR 5 —O—, wherein groups with two chemically nonequivalent termini can adopt both possible orientations;   V is selected from the group consisting of nitro, cyano, amino, hydroxy, alkoxy, alkylthio, alkylamino, dialkylamino, —NH(CH 2 ) p NH 2  wherein p is 1 to 4, —N(CH 2 CH 2 NH 2 ) 2 , diazamino, amidino, guanidino, guanyl, semicarbazone, aryl, heterocycle and heteroaryl, any of which is optionally substituted with one or more of amino, halo, cyano, nitro, hydroxy, —NH(CH 2 ) p NH 2  wherein p is 1 to 4, —N(CH 2 CH 2 NH 2 ) 2 , amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy, aminoalkythio, lower acylamino, or benzyloxycarbonyl;   the —(CH 2 ) pPL — alkylene chain is optionally substituted with one or more amino or hydroxy groups, or is unsaturated;
 pPL is 0 to 8; 
 q1PL and q2PL are independently 0, 1 or 2; and 
   m is 1 to about 20;   and a pharmaceutically acceptable carrier or diluent.   
     
     
         56 . A method of treating a microbial infection in an animal in need thereof, said method comprising administering to the animal an effective amount of a pharmaceutical composition comprising an oligomer of Formula IVa, Formula IVb, or Formula IVc:
   R 1 - x -A 1 - x - z - y -A 2 - y -R 2   (IVa)
     R 1 - x -A 1 - x - z - y -A 2 - y - z - x -A 1 - x -R 2   (IVb)
     R 1 - x -A 1 - x - z - y -A 2 - y - z - x -A 1 - x - z - y -A 2 - y -R 2   (IVc)
   or an acceptable salt or solvate thereof,   wherein:   x is NR 8 , —NR 8 NR 8 —, C═O, or O; y is NR 8 , —NR 8 NR 8 —, C═O, S, or O; and R 8  is hydrogen or alkyl;   z is C═O, C═S, O═S═O, —NR 8 NR 8 —, or —C(═O)C(═O)—;   A 1  and A 2  are independently optionally substituted arylene or optionally substituted heteroarylene, wherein A 1  and A 2  are independently optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s);   R 1  is hydrogen, a polar group (PL), or a non-polar group (NPL), and R 2  is R 1 ;   NPL is a nonpolar group independently selected from the group consisting of —B(OR 4 ) 2  and —(NR 3′ ) q1NPL —U NPL —(CH 2 ) pNPL —(NR 3″ ) q2NPL —R 4′ , wherein:   R 3 , R 3′ , and R 3″  are independently selected from the group consisting of hydrogen, alkyl, and alkoxy;   R 4  and R 4′  are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, any of which is optionally substituted with one or more alkyl or halo groups;   U NPL  is absent or selected from the group consisting of O, S, S(═O), S(═O) 2 , NR 3 , —C(═O)—, —C(═O)—N═N—NR 3 —, —C(═O)—NR 3 —N═N—, —N═N—NR 3 —, —C(═N—N(R 3 ) 2 )—, —C(═NR 3 )—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O) 2 O—, —R 3 O—, —R 3 S—, —S—C═N— and —C(═O)—NR 3 —O—, wherein groups with two chemically nonequivalent termini can adopt both possible orientations;   the —(CH 2 ) pNPL — alkylene chain is optionally substituted with one or more amino or hydroxy groups, or is unsaturated;   pNPL is 0 to 8;   q1NPL and q2NPL are independently 0, 1 or 2;   PL is a polar group selected from the group consisting of halo, hydroxyethoxymethyl, methoxyethoxymethyl, polyoxyethylene, and —(NR 5′ ) q1PL —U PL —(CH 2 ) pPL —(NR 5′ ) q2PL —V, wherein:   R 5 , R 5′ , and R 5″  are independently selected from the group consisting of hydrogen, alkyl, and alkoxy;   U PL  is absent or selected from the group consisting of O, S, S(═O), S(═O) 2 , NR 5 , —C(═O)—, —C(═O)—N═N—NR 5 —, —C(═O)—NR 5 —N═N—, —N═N—NR 5 —, —C(═N—N(R 5 ) 2 )—, —C(═NR 5 )—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O) 2 O—, —R 5 O—, —R 5 S—, —S—C═N— and —C(═O)—NR 5 —O—, wherein groups with two chemically nonequivalent termini can adopt both possible orientations;   V is selected from the group consisting of nitro, cyano, amino, hydroxy, alkoxy, alkylthio, alkylamino, dialkylamino, —NH(CH 2 ) p NH 2  wherein p is 1 to 4, —N(CH 2 CH 2 NH 2 ) 2 , diazamino, amidino, guanidino, guanyl, semicarbazone, aryl, heterocycle and heteroaryl, any of which is optionally substituted with one or more of amino, halo, cyano, nitro, hydroxy, —NH(CH 2 ) p NH 2  wherein p is 1 to 4, —N(CH 2 CH 2 NH 2 ) 2 , amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy, aminoalkythio, lower acylamino, or benzyloxycarbonyl;   the —(CH 2 ) pPL — alkylene chain is optionally substituted with one or more amino or hydroxy groups, or is unsaturated;   pPL is 0 to 8;   q1PL and q2PL are independently 0, 1 or 2; and   a pharmaceutically acceptable carrier or diluent.   
     
     
         57 . The method of  claim 56 , wherein the pharmaceutical composition comprises an oligomer of Formula IV′b, wherein:
 x is NR 8 , y is NR 8 , z is C═O, and R 8  is hydrogen; 
 A 1  and A 2  are independently optionally substituted o-, m-, or p-phenylene; 
 NPL is —(NR 3′ ) q1NPL —U NPL —(CH 2 ) pNPL —(NR 3′ ) q2NPL —R 4′ , wherein: 
 R 4′  is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, any of which is optionally substituted with one or more alkyl or halo groups; 
 U NPL  is selected from the group consisting of O, S, NR 3 , —C(═O)—, —R 3 O—, and —R 3 S—, wherein groups with two chemically nonequivalent termini can adopt both possible orientations; 
 the —(CH 2 ) pNPL — alkylene chain is optionally substituted with one or more amino groups; 
 pNPL is 0 to 8; 
 q1NPL and q2NPL are 0; 
 PL is —(NR 5′ ) q1PL —U PL —(CH 2 ) pPL —(NR 5′ ) q2PL —V, wherein: 
 U PL  is selected from the group consisting of O, S, NR 5 , —C(═O), —R 5 O— and —R 5 S—, wherein groups with two chemically nonequivalent termini can adopt both possible orientations; 
 V is selected from the group consisting of amino, alkylamino, dialkylamino, —NH(CH 2 ) p NH 2  wherein p is 1 to 4, —N(CH 2 CH 2 NH 2 ) 2 , diazamino, amidino, guanidino, guanyl, aryl, heterocycle and heteroaryl; 
 the —(CH 2 ) pPL — alkylene chain is optionally substituted with one or more amino groups; 
 pPL is 0 to 8; and 
 q1PL and q2PL are 0. 
 
     
     
         58 . The method of  claim 56 , wherein the oligomer is one of 
       
         
           
           
               
               
           
         
       
     
     
         59 . The method of  claim 55 , wherein the microbial infection is a bacterial infection, a fungal infection, or a viral infection. 
     
     
         60 . A method of killing or inhibiting the growth of a microorganism, said method comprising contacting the microorganism with an effective amount of an oligomer of  claim 55 . 
     
     
         61 . The method of  claim 60 , wherein the microorganism is a bacterial cell, a fungus, or a virus. 
     
     
         62 . A method of providing an antidote to low molecular weight heparin overdose in an animal, said method comprising administering to the animal an effective amount of a pharmaceutical composition comprising an oligomer of  claim 55 . 
     
     
         63 .- 65 . (canceled) 
     
     
         66 . The method of  claim 56 , wherein the microbial infection is a bacterial infection, a fungal infection, or a viral infection. 
     
     
         67 . A method of killing or inhibiting the growth of a microorganism, said method comprising contacting the microorganism with an effective amount of an oligomer of  claim 56 . 
     
     
         68 . A method of providing an antidote to low molecular weight heparin overdose in an animal, said method comprising administering to the animal an effective amount of a pharmaceutical composition comprising an oligomer of  claim 56 .