# US 8,569,264 B2 · Antibacterial 4,5-substituted aminoglycoside analogs having multiple substituents

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- Number: US 8,569,264 B2
- Document ID: US8569264B2
- Status: Granted
- Kind: B2
- Application number: 13/344,247
- Filed: 2012-01-05
- Published: 2013-01-03
- Granted: 2013-10-29
- Earliest claimed: 2005-12-02
- Assignees: Isis Pharmaceuticals, Inc.
- Applicants: Eric E. Swayze; Stephen Hanessian; Janek Szychowski; Susanta Sekhar Adhikari; Kandasamy Pachamuthu; Xiaojing Wang; Michael T. Migawa; Richard H. Griffey
- Inventors: Eric E. Swayze; Stephen Hanessian; Janek Szychowski; Susanta Sekhar Adhikari; Kandasamy Pachamuthu; Xiaojing Wang; Michael T. Migawa; Richard H. Griffey
- Web page: https://patentgrep.com/patent/US8569264B2

## CPC

- C07H 15/23: with only two saccharide radicals in the molecule, e.g. ambutyrosin, butyrosin, xylostatin, ribostamycin
- A61P 31/04: Antibacterial agents
- C07H 15/232: with at least three saccharide radicals in the molecule, e.g. lividomycin, neomycin, paromomycin
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention is directed to analogs of aminoglycoside compounds as well as their preparation and use as prophylactic or therapeutics against microbial infection.

## Claims

### Claim 1

A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound having the following formula VI:
or a prodrug or pharmaceutically acceptable salt thereof,
wherein:
Q1 is —NR10R11;
Q2 is
each Q3 and Q4 is —OR7,
Q5 is —OR8;
each of R1, R6, R7 and R8 is, in each instance, H;
each R2 and R10 is, independently, H, C1-C12 alkyl or substituted C1-C12 alkyl;
R11 is cyano, C1-C12 alkyl, substituted C1-C12 alkyl, C2-C12 alkenyl, substituted C2-C12 alkenyl, C2-C12 alkynyl, substituted C2-C12 alkynyl or —(CH2)n-(L1)m—(CH2)nn-E1;
L1 is S, O or NJ1;
n is an integer from 1 to 8;
m is 0 or 1;
nn is 0 or an integer from 1 to 8;
mm is 1 or 2;
E1 is H, hydroxyl, halogen, cyano, —NJ1J2, C2-C12 alkenyl, substituted C2-C12 alkenyl, C2-C12 alkynyl, substituted C2-C12 alkynyl, C5-C20 aryl, substituted C5-C20 aryl, heteroaryl, substituted heteroaryl, a heterocyclic radical, a substituted heterocyclic radical or a substituted or unsubstituted mono or poly cyclic structure that is unsaturated, partially saturated or fully saturated and optionally includes one or more heteroatoms selected from O, N and S;
each J1 and J2 is, independently, H, C1-C12 alkyl, substituted C1-C12 alkyl, C2-C12 alkenyl, substituted C2-C12 alkenyl, C2-C12 alkynyl, substituted C2-C12 alkynyl, C5-C20 aryl, substituted C5-C20 aryl, —C(═O)—X, a heterocyclic radical or a substituted heterocyclic radical;
each X is, independently, H, C1-C12 alkyl or substituted C1-C12 alkyl; and
Z1 and Z2 are each, independently, H or —OH.

### Claim 2 (depends on 1)

A pharmaceutical composition according to claim 1, wherein mm is 1.

### Claim 3 (depends on 1)

A pharmaceutical composition according to claim 1, wherein mm is 2.

### Claim 4 (depends on 1)

A pharmaceutical composition according to claim 1, wherein each R2 is H.

### Claim 5 (depends on 1)

A pharmaceutical composition according to claim 1, wherein Z1 is —OH.

### Claim 6 (depends on 1)

A pharmaceutical composition according to claim 1, wherein R10 is H.

### Claim 7 (depends on 6)

A pharmaceutical composition according to claim 6, wherein R11 is substituted C1-C12 alkyl.

### Claim 8 (depends on 1)

A pharmaceutical composition according to claim 1, wherein:
R10 is H;
R11 is substituted C1-C12 alkyl;
each R2 is H; and
Z1 is —OH.

### Claim 9 (depends on 1)

A pharmaceutical composition according to claim 1, wherein said compound of formula VI has the configuration:

### Claim 10 (depends on 9)

A pharmaceutical composition according to claim 9, wherein mm is 1.

### Claim 11 (depends on 9)

A pharmaceutical composition according to claim 9, wherein mm is 2.

### Claim 12 (depends on 9)

A pharmaceutical composition according to claim 9, wherein each R2 is H.

### Claim 13 (depends on 9)

A pharmaceutical composition according to claim 9, wherein Z1 is —OH.

### Claim 14 (depends on 9)

A pharmaceutical composition according to claim 9, wherein R10 is H.

### Claim 15 (depends on 14)

A pharmaceutical composition according to claim 14, wherein R11 is substituted C1-C12 alkyl.

### Claim 16 (depends on 9)

A pharmaceutical composition according to claim 9, wherein:
R10 is H;
R11 is substituted C1-C12 alkyl;
each R2 is H; and
Z1 is —OH.

### Claim 17 (depends on 16)

A pharmaceutical composition according to claim 16, wherein mm is 1.

### Claim 18 (depends on 16)

A pharmaceutical composition according to claim 16, wherein mm is 2.

### Claim 19

A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound having the following formula I:
or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof,
wherein:
Q1 is azido or —NR10R1l;
Q2 is —NR10R12,
each Q3 and Q4 is —OR7,
Q5 is H, halogen, cyano, azido, —OR8, —NR2R3, a protected amino group or a nitrogen containing heterocyclic radical which optionally includes one or more additional heteroatoms selected from N, O and S wherein the heterocyclic radical is covalently linked through said nitrogen atom;
each R1 is, independently, H or a hydroxyl protecting group;
each R2 is, independently, H, an amino protecting group, C1-C12 alkyl or substituted C1-C12 alkyl;
each R3 is, independently, H, an amino protecting group, cyano, C1-C12 alkyl, substituted C1-C12 alkyl, C2-C12 alkenyl, substituted C2-C12 alkenyl, C2-C12 alkynyl, substituted C2-C12 alkynyl or —(CH2)n-(L1)m—(CH2)nn-E1;
each R6 is, independently, H or an amino protecting group;
each R7 is, independently, H, a hydroxyl protecting group or —(CH2)n-(L1)m-(CH2)nn-E1;
R8 is H, a hydroxyl protecting group, C1-C12 alkyl, substituted C1-C12 alkyl, C2-C12 alkenyl, substituted C2-C12 alkenyl, C2-C12 alkynyl, substituted C2-C12 alkynyl or —(CH2)n-(L1)m—(CH2)nn-E1;
each R10 is, independently, H, C1-C12 alkyl or substituted C1-C12 alkyl;
each R11 is, independently, cyano, C1-C12 alkyl, substituted C1-C12 alkyl, C2-C12 alkenyl, substituted C2-C12 alkenyl, C2-C12 alkynyl, substituted C2-C12 alkynyl or —(CH2)n-(L1)m—(CH2)nn-E1; and
R12 is a group having the following formula III:
each L1 is, independently, S, O or NJ1;
L2 is CH or N;
each n is, independently, an integer from 1 to 8;
each m is, independently, 0 or 1;
each nn is, independently, 0 or an integer from 1 to 8;
mm is 1 or 2;
each E1 is, independently, H, hydroxyl, halogen, cyano, —NJ1J2, C2-C12 alkenyl, substituted C2-C12 alkenyl, C2-C12 alkynyl, substituted C2-C12 alkynyl, C5-C20 aryl, substituted C5-C20 aryl, heteroaryl, substituted heteroaryl, a heterocyclic radical, a substituted heterocyclic radical or a substituted or unsubstituted mono or poly cyclic structure that is unsaturated, partially saturated or fully saturated and optionally includes one or more heteroatoms selected from O, N and S;
each J1 and J2 is, independently, H, C1-C12 alkyl, substituted C1-C12 alkyl, C2-C12 alkenyl, substituted C2-C12 alkenyl, C2-C12 alkynyl, substituted C2-C12 alkynyl, C5-C20 aryl, substituted C5-C20 aryl, —C(═O)—X, a heterocyclic radical or a substituted heterocyclic radical;
each X is, independently, H, C1-C12 alkyl or substituted C1-C12 alkyl;
each Z1 and Z2 is, independently, H, hydroxyl or a protected hydroxyl; and
Z3 is a group having the following formula IV:
and
wherein when Q2 is —N(H)C(═O)C(H)(OH)CH2CH2NH2 then Q1 is other than —N(H)CH3 or —N(H)CH2CH3 and Q5 is other than —N(H)C(═NH)NH2 or —N(H)CH═NH2.

### Claim 20 (depends on 19)

A pharmaceutical composition according to claim 19, wherein one of Z1 and Z2 is H.

### Claim 21 (depends on 19)

A pharmaceutical composition according to claim 19, wherein:
each of said substituted groups, is, independently, mono or poly substituted with optionally protected substituent groups independently selected from C1-C12 alkyl, substituted C1-C12 alkyl, C2-C12 alkenyl, substituted C2-C12 alkenyl, C2-C12 alkynyl, substituted C2-C12 alkynyl, C5-C20 aryl or substituted C5-C20 aryl, heterocyclic radical, substituted heterocyclic radical, heteroaryl, substituted heteroaryl, C5-C7 alicyclic radical, substituted C5-C7 alicyclic radical, halogen, —OJ3, —NJ1J2, —SJ3, —N3, —COOH, —C(═O)—X, —CN, —S(═O)2—X, —S(═O)—X, —C(═O)—NJ1J2, —N(H)C(═O)-J1, —N(J1)—(CH2)nm—OJ3 and —N(J1)-(CH2)nm—NJ1J2 and a substituted or unsubstituted mono or poly cyclic structure that is unsaturated, partially saturated or fully saturated and optionally includes one or more heteroatoms selected from O, N and S;
each J3 is, independently, H, C1-C12 alkyl, substituted C1-C12 alkyl, C2-C12 alkenyl, substituted C2-C12 alkenyl, C2-C12 alkynyl, substituted C2-C12 alkynyl, C1-C12 aminoalkyl, substituted C1-C12 aminoalkyl or a hydroxyl protecting group; and
nm is an integer from 1 to 20.

### Claim 22 (depends on 19)

A pharmaceutical composition according to claim 19, wherein said compound of formula I has the configuration:

### Claim 23 (depends on 19)

A pharmaceutical composition according to claim 19, wherein said compound of formula I has the configuration:

### Claim 24 (depends on 8)

A pharmaceutical composition according to claim 8, wherein mm is 1.

### Claim 25 (depends on 8)

A pharmaceutical composition according to claim 8, wherein mm is 2.