Facially amphiphilic polymers and oligomers and uses thereof

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 IIa:

• R1-x-A1-x-y-A2-y-x-A1-x-R2 (IIa)
• or an acceptable salt or solvate thereof,
• wherein:
• x is NR8, O, S, or —N(R8)N(R8)—;
• and y is C═O, C═S, or O═S═O;
• wherein R8 is hydrogen or alkyl;
• A1 and A2 are independently optionally substituted arylene or optionally substituted heteroarylene, wherein A1 and A2 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);
• R1 is a polar group (PL) or a non-polar group (NPL);
• and R2 is R1;
• NPL is a nonpolar group independently selected from the group consisting of —B(OR4)2 and -(NR3′)q1NPL—UNPL—(CH2)pNPL—(NR3″)q2NPL—R4′, wherein:
• R3, R3′, and R3″ are independently selected from the group consisting of hydrogen, alkyl, and alkoxy;
• R4 and R4′ 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;
• UNPL is absent or selected from the group consisting of O, S, S(═O), S(═O)2, NR3, —C(═O)—, —C(═O)—N═N—NR3—, —C(═O)—NR3—N═N—, —N═N—NR3—, —C(═N—N(R3)2)—, —C(═NR3)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)2O—, —R30—, —R3S—, —S—C═N— and —C(═O)—NR3—, wherein groups with two chemically nonequivalent termini can adopt both possible orientations;
• the —(CH2)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
• —(NR5′)q1PL—UPL—(CH2)pPL—(NR5′)q2PL—V, wherein:
• R5, R5′, and R5″ are independently selected from the group consisting of hydrogen, alkyl, and alkoxy;
• UPL is absent or selected from the group consisting of O, S, S(═O), S(═O)2, NR5, —C(═O)—, —C(═O)—N═N—NR5—, —C(═O)—NR5—N═N—, —N═N—NR5—, —C(═N—N(R5)2)—, —C(═NR5)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)2O—, —R5O—, —R5S—, —S—C═N— and
• —C(═O)—NR5—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(CH2)pNH2 wherein p is 1 to 4, —N(CH2CH2NH2)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(CH2)pNH2 wherein p is 1 to 4, —N(CH2CH2NH2)2, amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy, aminoalkylhio, lower acylamino, or benzyloxycarbonyl;
• the —(CH2)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.

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:

• R1-[x-A1-x-z-y-A2-y-z]-R2 (IV)
• or an acceptable salt or solvate thereof,
• wherein:
• x is NR8, —NR8NR8—, C═O, or O;
• y is NR8, —NR8NR8—, C═O, S, or O;
• and R8 is hydrogen or alkyl;
• z is C═O, C═S, O═S═O, —NR8NR8—, or —C(═O)C(═O)—;
• A1 and A2 are independently optionally substituted arylene or optionally substituted heteroarylene, wherein A1 and A2 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);
• R1 is
• (i) hydrogen, a polar group (PL), or a non-polar group (NPL), and R2 is -x-A1-x-R1, wherein A1 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 R2 is -x-A1-x-z-y-A2-y-R1, wherein A1 and A2 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 R2 is -x-A′-x-R1, 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 R2 is -x-A1-x-z-y-A′-y-R1, wherein A1 is as defined above, A′ is aryl or heteroaryl, and each of A1 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 R2 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 R2 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) R1 and R2 are independently a polar group (PL) or a non-polar group (NPL);
• or
• (viii) R1 and R2 together form a single bond;
• NPL is a nonpolar group independently selected from the group consisting of —B(OR4)2 and (NR3′)q1NPL—UNPL—(CH2)pNPL—(NR3′)q2NPL—R4′, wherein:
• R3, R3′, and R3″ are independently selected from the group consisting of hydrogen, alkyl, and alkoxy;
• R4 and R4′ 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;
• UNPL is absent or selected from the group consisting of O, S, S(═O), S(═O)2, NR3, —C(═O)—, —C(═O)—N═N—NR3—, —C(═O)—NR3—N═N—, —N═N—NR3—, —C(═N—N(R3)2)—, —C(═NR3)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)2O—, —R30—, —R3S—, —S—C═N— and —C(═O)—NR3—_-, wherein groups with two chemically nonequivalent termini can adopt both possible orientations;
• the —(CH2)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
• —NR5″)q1PL—UPL-l -(CH2)pPL—(NR5)q2PL—V, wherein:
• R5, R5′, and R5″ are independently selected from the group consisting of hydrogen, alkyl, and alkoxy;
• UPL is absent or selected from the group consisting of O, S, S(═O), S(═O)2, NR5, —C(═O)—, —C(═O)—N═N—NR5—, —C(═O)—NR5—N═N—, —N═N—NR5—, —C(═N—N(R5)2)—, —C(═NR5)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)2O—, —R5O—, —R5S—, —S—C═N— and —C(═O)—NR5—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(CH2)pNH2 wherein p is 1 to 4, —N(CH2CH2NH2)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(CH2)pNH2 wherein p is 1 to 4, —N(CH2CH2NH2)2, amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy, aminoalkylhio, lower acylamino, or benzyloxycarbonyl;
• the —(CH2)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.

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:

• R1-x-A1-x-z-y-A2-y-R2 (IVa)
• R1-x-A1-x-z-y-A2-y-z-x-A1-x-R2 (IVb)
• R1-x-A1-x-z-y-A2-y-z-x-A1-x-z-y-A2-y-R2 (IVc)
• or an acceptable salt or solvate thereof,
• wherein:
• x is NR8, —NR8NR8—, C═O, or O;
• y is NR8, —NR8NR8—, C═O, S, or O;
• and R8 is hydrogen or alkyl;
• z is C═O, C═S, O═S═O, —NR8NR8—, or —C(═O)C(═O)—;
• A1 and A2 are independently optionally substituted arylene or optionally substituted heteroarylene, wherein A1 and A2 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);
• R1 is hydrogen, a polar group (PL), or a non-polar group (NPL), and R2 is R1;
• NPL is a nonpolar group independently selected from the group consisting of —B(OR4)2 and (NR3′)q1NPL—UNPL—(CH2)pNPL(NR3′)q2NPL—R4′, wherein:
• R3, R3′, and R3″ are independently selected from the group consisting of hydrogen, alkyl, and alkoxy;
• R4 and R4′ 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;
• UNPL is absent or selected from the group consisting of O, S, S(═O), S(═O)2, NR3, —C(═O)—, —C(═O)—N═N—NR3—, —C(═O)—NR3—N═N—, —N═N—NR3—, —C(═N—N(R3)2)—, —C(═NR3)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)2O—, —R30—, —R3S—, —S—C═N— and —C(═O)—NR3—O—, wherein groups with two chemically nonequivalent termini can adopt both possible orientations;
• the —(CH2)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
• NR5′)q1PL—UPL—(CH2)pPL—(NR5′)q2PL—V wherein:
• R5, R5′, and R5″ are independently selected from the group consisting of hydrogen, alkyl, and alkoxy;
• UPL is absent or selected from the group consisting of O, S, S(═O), S(═O)2, NR5, —C(═O)—, —C(═O)—N═N—NR5—, —C(═O)—NR5—N═N—, —N═N—NR5—, —C(═N—N(R5)2)—, —C(═NR5)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)2O—, —R5O—, —R5S—, —S—C═N— and
• —C(═O)—NR5—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(CH2)pNH2 wherein p is 1 to 4, —N(CH2CH2NH2)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(CH2)pNH2 wherein p is 1 to 4, —N(CH2CH2NH2)2, amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy, aminoalkylhio, lower acylamino, or benzyloxycarbonyl;
• the —(CH2)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.

An oligomer of Formula IIa:

• R1-x-A1-x-y-A2-y-x-A1-x-R2 (IIa)
• or an acceptable salt or solvate thereof,
• wherein:
• x is NR8, O, S, or —N(R8)N(R8)—;
• and y is C═O, C═S, or O═S═O;
• wherein R8 is hydrogen or alkyl;
• A1 and A2 are independently optionally substituted arylene or optionally substituted heteroarylene, wherein A1 and A2 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);
• R1 is a polar group (PL) or a non-polar group (NPL);
• and R2 is R1;
• NPL is a nonpolar group independently selected from the group consisting of —B(OR4)2 and —(NR3′)q1NPL—U (CH2)pNPL—(NR2″)q2NPL—R4, wherein:
• R3, R3′, and R3″ are independently selected from the group consisting of hydrogen, alkyl, and alkoxy;
• R4 and R4′ 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;
• UNPL is absent or selected from the group consisting of O, S, S(═O), S(═O)2, NR3, —C(═O)—, —C(═O)—N═N—NR3—, —C(═O)—NR3—N═N—, —N═N—NR3, —C(═N—N(R3)2)—, —C(═NR3)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)2O—, —R30—, —R3S—, —S—C═N— and —C(═O)—NR3—O—, wherein groups with two chemically nonequivalent termini can adopt both possible orientations;
• the —(CH2)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
• —(NR5′)q1PL—UPL—(CH2)pPL—(NR5′)q2PL—V, wherein:
• R5, R5′, and R5″ are independently selected from the group consisting of hydrogen, alkyl, and alkoxy;
• UPL is absent or selected from the group consisting of O, S, S(═O), S(═O)2, NR5, —C(═O)—, —C(═O)—N═N—NR5—, —C(═O)—NR5—N═N—, —N═N—NR5—,
• —C(═N—N(R5)2)—, —C(═NR5)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)2O—, —R5O—, —R5S—, —S—C═N— and
• —C(═O)—NR5—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(CH2)pNH2 wherein p is 1 to 4, —N(CH2CH2NH2)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(CH2)pNH2 wherein p is 1 to 4, —N(CH2CH2NH2)2, amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy, aminoalkylhio, lower acylamino, or benzyloxycarbonyl;
• the —(CH2)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.

An oligomer of Formula I:

• R1—[-x-A1-y-x-A2-y-]m—R2 (I)
• or an acceptable salt or solvate thereof,
• wherein:
• x is NR8, y is C═O, and R8 is hydrogen;
• A1 is optionally substituted o-, m-, or p-phenylene and A2 is —(CH2)q—, wherein q is 1, wherein one of A1 and A2 is substituted with one or two polar (PL) group(s), and the other of A1 and A2 is substituted with one or two non-polar (NPL) group(s);
• or
• A2 is optionally substituted o-, m-, or p-phenylene and A1 is —(CH2)q—, wherein q is 1, wherein one of A1 and A2 is substituted with one or two polar (PL) group(s), and the other of A1 and A2 is substituted with one or two non-polar (NPL) group(s);
• R1 and R2 are independently hydrogen, a polar (PL) group, or a non-polar (NPL) group;
• NPL is -13 (NR3′)q1NPL—UNPL—(CH2)pNPL—(NR3″)q2NPL—R4′, wherein:
• R4 is selected from the group consisting of C1-C10 alkyl, C3-C18 branched alkyl, C2-C10 alkenyl, C2-C10 alkynyl, and C6-C10 aryl, any of which is optionally substituted with one or more alkyl or halo groups;
• UNPL is absent or selected from the group consisting of NH, —C(═O)—, O and S;
• the —(CH2)pNPL-alkylene chain is optionally substituted with one or more amino groups;
• pNPL is 0 to 8;
• q1NPL and q2NPL are 0;
• PL is -(NR5′)q1PL—UPL—(CH2)pPL—(NR5′)q2PL—V, wherein:
• UPL is absent or selected from the group consisting of O, S, NH, and —C(═O);
• V is selected from the group consisting of amino, C1-C6 alkylamino, —NH(CH2)pNH2 wherein p is 1 to 4, —N(CH2CH2NH2)2, diazamino, amidino, and guanidino, any of which is optionally substituted with one or more of amino, halo, cyano, nitro, hydroxy, —NH(CH2)pNH2 wherein p is 1 to 4, —N(CH2CH2NH2)2, amidino, guanyl, guanidino, or aminoalkoxy;
• the —(CH2)pPL-alkylene chain is optionally substituted with one or more amino groups;
• pPL is 0 to 8;
• q1PL and q2PL are 0;
• and
• m is 4 or 5.