Facially amphiphilic polymers and oligomers and uses thereof

1. 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 a facially amphiphilic oligomer of Formula IIa:

R 1 - x -A 1 - x - y -A 2 - y - x -A 1 - x -R 2   (IIa)

or an acceptable salt or solvate thereof,

wherein:

x is NR 8 , O, S, or —N(R 8 )N(R 8 )—; and y is C═O, C═S, or O═S═O; wherein R 8 is hydrogen;

A 1 and A 2 are independently arylene or heteroarylene, wherein A 1 is substituted with one or more polar (PL) groups and is optionally substituted with one or more non-polar (NPL) groups and A 2 is 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 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 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, aminoalkylthio, 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; and

q1PL and q2PL are independently 0, 1 or 2;

and a pharmaceutically acceptable carrier or diluent.

2. The method of claim 1 , wherein the facially amphiphilic oligomer is selected from the group consisting of:

3. The method of claim 1 , wherein the microbial infection is a bacterial infection, a fungal infection, or a viral infection.

4. A method of killing or inhibiting the growth of a microorganism, said method comprising contacting the microorganism with an effective amount of a facially amphiphilic oligomer of Formula IIa:

R 1 - x -A 1 - x - y -A 2 - y - x -A 1 - x -R 2   (IIa)

or an acceptable salt or solvate thereof,

wherein:

x is NR 8 , O, S, or —N(R 8 )N(R 8 )—; and y is C═O, C═S, or O═S═O; wherein R 8 is hydrogen;

A 1 and A 2 are independently arylene or heteroarylene, wherein A 1 is substituted with one or more polar (PL) groups and is optionally substituted with one or more non-polar (NPL) groups and A 2 is 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 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 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, aminoalkylthio, 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; and

q1PL and q2PL are independently 0, 1 or 2;

and a pharmaceutically acceptable carrier or diluent.

5. The method of claim 4 , wherein the microorganism is a bacterial cell, a fungus, or a virus.

6. The method of claim 1 , said method comprising administering to the animal an effective amount of a pharmaceutical composition comprising a facially amphiphilic oligomer of Formula IIa, wherein x is NR 8 , y is C═O, and R 8 is hydrogen.

7. The method of claim 6 , said method comprising administering to the animal an effective amount of a pharmaceutical composition comprising a facially amphiphilic oligomer of Formula IIa, wherein A 1 is o-, m-, or p-phenylene and A 2 is optionally substituted heteroarylene.

8. The method of claim 7 , said method comprising administering to the animal an effective amount of a pharmaceutical composition comprising a facially amphiphilic oligomer of Formula IIa, wherein A 1 is m-phenylene and A 2 is optionally substituted pyrimidinylene.

9. The method of claim 8 , said method comprising administering to the animal an effective amount of a pharmaceutical composition comprising a facially amphiphilic oligomer of Formula IIa, wherein A 1 is substituted with one polar group (PL) and one nonpolar group (NPL).

10. The method of claim 8 , said method comprising administering to the animal an effective amount of a pharmaceutical composition comprising a facially amphiphilic oligomer of Formula IIa, wherein A 2 is unsubstituted.

11. The method of claim 1 , said method comprising administering to the animal an effective amount of a pharmaceutical composition comprising a facially amphiphilic oligomer of Formula IIa, wherein R 1 is a polar (PL) group and R 2 is R 1 .

12. The method of claim 11 , said method comprising administering to the animal an effective amount of a pharmaceutical composition comprising a facially amphiphilic oligomer of Formula IIa, wherein R 1 is a polar (PL) group and R 2 is R 1 , wherein:

PL is —(NR 5′ ) q1pL —U PL —(CH 2 ) pPL —(NR 5′ ) q2PL —V; wherein

q1PL is 0;

U PL is —C(═O)—;

pPL is 2 to 4;

q2PL is 0; and

V is guanidino; and

R 5′ is as defined in claim 1 .

13. The method of claim 1 , said method comprising administering to the animal an effective amount of a pharmaceutical composition comprising a facially amphiphilic oligomer of Formula IIa, wherein:

NPL is —(NR 3′ ) q1NPL —U NPL —(CH 2 ) pNPL —(NR 3″ ) q2NPL —R 4′ , wherein:

q1NPL is 0;

U NPL is absent;

pNPL is 0, 1, or 2;

q2NPL is 0; and

R 4′ is C 1 -C 10 alkyl or C 3 -C 18 branched alkyl, any of which are optionally substituted with one or more halo groups.

14. The method of claim 13 , said method comprising administering to the animal an effective amount of a pharmaceutical composition comprising a facially amphiphilic oligomer of Formula IIa, wherein NPL is —(NR 3′ ) q1NPL —U NPL —(CH 2 ) pNPL —(NR 3″ ) q2NPL —R 4′ , wherein:

q1NPL is 0;

U NPL is absent;

pNPL is 0;

q2NPL is 0;

and R 4′ is C 1 -C 10 alkyl or C 3 -C 18 branched alkyl, any of which are optionally substituted with one or more halo groups.

15. The method of claim 14 , said method comprising administering to the animal an effective amount of a pharmaceutical composition comprising a facially amphiphilic oligomer of Formula IIa, wherein NPL is tert-butyl.

16. The method of claim 1 , said method comprising administering to the animal an effective amount of a pharmaceutical composition comprising a facially amphiphilic oligomer of Formula IIa, wherein:

PL is —(NR 5′ ) q1PL —U PL —(CH 2 ) pPL —(NR 5′ ) q2pL —V, wherein:

q1PL is 0;

U PL is O or S;

pPL is 0 to 4;

q2PL is 0; and

V is amino, guanidino, or heterocycle.

17. 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 a facially amphiphilic oligomer of Formula IIa:

R 1 - x -A 1 - x - y -A 2 - y - x -A 1 - x -R 2   (IIa)

or an acceptable salt or solvate thereof,

wherein:

x is NR 8 ; y is C═O; R 8 is hydrogen;

A 1 is m-phenylene and A 2 is pyrimidinylene, wherein A 1 is substituted with one polar (PL) group and one non-polar (NPL) group and A 2 is unsubstituted; wherein

PL is —(NR 5′ ) q1pL —U PL —(CH 2 ) pPL —(NR 5′ ) q2PL —V, wherein:

q1PL is 0;

U PL is O or S;

pPL is 0 to 4;

q2PL is 0; and

V is amino, guanidino, or heterocycle;

NPL is —(NR 3′ ) q1PL —U NPL —(CH 2 ) pNPL —(NR 3″ ) q2NPL —R 4′ , wherein:

q1NPL is 0;

U NPL is absent;

pNPL is 0;

q2NPL is 0; and

R 4′ is C 1 -C 10 alkyl or C 3 -C 18 branched alkyl, any of which are optionally substituted with one or more halo groups;

R 1 is —(NR 5′ ) q1PL —U PL —(CH 2 ) pPL —(NR 5′ ) q2PL —V, wherein q1PL is 0; U PL is —C(═O)—; pPL is 2 to 4; q2PL is 0; and V is guanidino;

and R 2 is R 1 .

18. The method of claim 1 , said method comprising administering to the animal an effective amount of a pharmaceutical composition comprising a facially amphiphilic oligomer of Formula IIa, wherein said pharmaceutical composition is administered by a route chosen from systemic, topical or oral.

19. The method of claim 18 , said method comprising administering to the animal an effective amount of a pharmaceutical composition comprising a facially amphiphilic oligomer of Formula IIa, wherein said pharmaceutical composition is administered by a route chosen from parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, buccal, ocular, intravaginally, inhalation, depot injection, and implant.