# US 10,870,625 B2 · Zwitterionic propargyl-linked antifolates useful for treating bacterial infections

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- Number: US 10,870,625 B2
- Document ID: US10870625B2
- Status: Granted
- Kind: B2
- Application number: 16/068,262
- Filed: 2017-01-09
- Published: 2019-01-03
- Granted: 2020-12-22
- Earliest claimed: 2016-01-08
- Assignees: University of Connecticut
- Applicants: The University of Connecticut; United States of America as represented by the Department of Veterans Affairs
- Inventors: Dennis Wright; Amy C. Anderson; Eric Scocchera; Narendran Gummudipundi Dayanandan; Santosh Keshipeddy; Stephanie Reeve; Michael N. Lombardo; Michael Henry Cynamon
- Web page: https://patentgrep.com/patent/US10870625B2

## CPC

- C07D 239/49: with an aralkyl radical, or substituted aralkyl radical, attached in position 5, e.g. trimethoprim
- A61K 31/505: Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61P 31/04: Antibacterial agents
- A61P 31/06: for tuberculosis
- C07D 239/48: Two nitrogen atoms
- C07D 403/10: linked by a carbon chain containing aromatic rings
- C07D 405/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 405/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The disclosure provides compounds of the formula I and the pharmaceutically acceptable salts thereof. The variables, e.g. R1, R2, R3, R4, A, B, J, V, W, M, J and Ar are defined herein. The disclosure also provides pharmaceutical compositions comprising a compound or salt of formula I and a pharmaceutically acceptable carrier, methods of inhibiting dihydrofolate reductase (DHFR) in vitro or in vivo with a compound or salt of formula I, and methods of treating a bacterial infections, fungal infections, and protozoal infections with a compound or salt of formula I. A compound or salt of formula I can be the first and only active ingredient used in a pharmaceutical composition or method of this disclosure or may be combined with one or more additional active ingredients that are not compounds or salts of formula I.

## Claims

### Claim 1

A compound of the formula I
or a pharmaceutically acceptable salt thereof, wherein:
R is H, hydroxyl, C1-C6alkyl, or C1-C6alkoxy;
R1, R2, R3, and R4 are independently chosen from H, C1-C6alkyl, and cycloalkyl;
A and B are independently chosen from H, hydroxyl, C1-C6alkyl, and C1-C6alkoxy;
one of V and W is methoxy and the other is chosen from H, C1-C6alkyl, and C1-C6alkoxy;
J and M are independently selected from H, halogen, hydroxyl, nitro, cyano, —COOH, —CHO, —CONH2, cycloalkyl, or C1-C6alkyl in which any methylene (—CH2) is optionally replaced by O, NH, N(C1-C6alkyl), S, SO2, C(O)O, OC(O), or C(O), and which is optionally substituted with hydroxyl, amino, or halogen;
W and M may be joined to form a 5- or 6-membered carbocyclic ring or a 5- or 6-membered heterocyclic ring that contains 1, 2, or 3 heteroatoms independently chosen from N, O, and S; and
the Ar ring is a phenyl, pyridyl, or pyrimidinyl ring substituted with at least one —COOH, or —CH2COOH, group and optionally substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, C1-C6alkyl, C1-C6alkoxy, C1-C2haloalkyl, and C1-C2haloalkoxy.

### Claim 2 (depends on 1)

The compound or pharmaceutically acceptable salt of claim 1, wherein
R is methyl or ethyl;
A is hydrogen;
B is hydrogen or C1-C6alkyl; and
one of V and W is methoxy and the other is H.

### Claim 3 (depends on 1)

The compound or pharmaceutically acceptable salt of claim 1, wherein
R is methyl or ethyl;
A is hydrogen;
B is hydrogen or C1-C6alkyl; and
W and M are joined to form a 5-membered heterocyclic ring containing 2 oxygen atoms.

### Claim 4 (depends on 1)

The compound or pharmaceutically acceptable salt of claim 1, wherein
R1, R2, R3, and R4 are H.

### Claim 5 (depends on 2)

The compound or pharmaceutically acceptable salt claim 2, wherein
J and M are independently selected from H, halogen, hydroxyl, C1-C6alkyl, C1-C6alkoxy, C1-C2haloalkyl, and C1-C2haloalkoxy.

### Claim 6 (depends on 1)

The compound or pharmaceutically acceptable salt of claim 1, wherein A is H and B is methyl.

### Claim 7 (depends on 2)

The compound or pharmaceutically acceptable salt of any one of claim 2, wherein J and M are both H.

### Claim 8 (depends on 1)

The compound or pharmaceutically acceptable salt of claim 1, where the Ar ring is substituted with one —COOH substituent in the para position and optionally substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, C1-C6alkyl, C1-C6alkoxy, C1-C2haloalkyl, and C1-C2haloalkoxy.

### Claim 9 (depends on 1)

The compound or pharmaceutically acceptable salt of claim 1, where the Ar ring is substituted with one —COOH substituent in the meta position and optionally substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, C1-C6alkyl, C1-C6alkoxy, C1-C2haloalkyl, and C1-C2haloalkoxy.

### Claim 10 (depends on 1)

The compound or pharmaceutically acceptable salt of claim 1, where the Ar ring is substituted with one —COOH substituent in the ortho position and optionally substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, C1-C6alkyl, C1-C6alkoxy, C1-C2haloalkyl, and C1-C2haloalkoxy.

### Claim 11 (depends on 1)

The compound or pharmaceutically acceptable salt of claim 1, wherein the Ar ring is a substituted phenyl ring.

### Claim 12

A compound or pharmaceutically acceptable salt of of the formula I-A
(I-A) wherein the compound is selected from the compounds listed in
TABLE I
TABLE 1
Cpd
A
V
W
M
Ar
13
H
OCH3
H
H
o-COOH phenyl
14
H
OCH3
H
H
m-COOH phenyl
15
H
OCH3
H
H
p-COOH phenyl
16
H
H
OCH3
H
p-COOH phenyl
29
S—CH3
OCH3
H
H
p-COOH phenyl
30
R—CH3
OCH3
H
H
p-COOH phenyl
31
R—CH3
H
OCH3
H
p-COOH phenyl
32
S—CH3
H
OCH3
H
p-COOH phenyl
33
S—CH3
OCH3
H
H
p-COOCH3 phenyl
34
R—CH3
OCH3
H
H
p-COOCH3 phenyl
35
CH3
H
—O—CH2—O—
36
CH3
H
—O—CH2—O—
p-OH-phenyl
37
H
H
—O—CH2—O—
p-OH-phenyl
38
H
H
—O—CH2—O—
3-F,4-OH-phenyl
39
H
H
—O—CH2—O—
3,5-di-F,4-OH-phenyl
40
H
H
—O—CH2—O—
3,5-di-F,4-OCH3-phenyl
41
S—CH3
H
—O—CH2—O—
p-COOH-phenyl
42
R—CH3
H
—O—CH2—O—
p-COOH-phenyl
43
CH3
H
—O—CH2—O—
2,3,5-tri-F,4-OH-phenyl
44
CH3
H
—O—CH2—O—
2,3,5,6-tetra-F, 4-OH-
phenyl
45
CH3
H
—O—CH2—O—
3-CN, 4-OH-phenyl
46
CH3
H
—O—CH2—O—
4-CH3SO2HN-phenyl
47
CH3
H
—O—CH2—O—
4-CH3HNSO2-phenyl
48
CH3
H
—O—CH2—O—
49
CH3
H
—O—CH2—O—
50
CH3
H
—O—CH2—O—
3,4,-di-OH-phenyl
51
CH3
H
—O—CH2—O—
52
H
H
OMe
H
53
H
H
OMe
H
54
CH
H
—O—CH2—O—
55
R—CH3
H
—O—CH2—O—
pyrid-4-yl
56
H
OCH3
H
H
57
R—CH3
OCH3
H
H
pyrid-4-yl
58
R—CH3
H
OCH3
H
p-COOH phenyl
59
H
H
OCH3
H
p-COOH phenyl
60
H
H
OCH3
OCH3
4-Pyridyl

### Claim 13 (depends on 12)

The compound or pharmaceutically acceptable salt of claim 12, wherein the compound is

### Claim 14 (depends on 1)

A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof of claim 1, and a pharmaceutically acceptable carrier.

### Claim 15 (depends on 1)

A method of treating a bacterial infection or a fungal infection in a patient comprising administering a therapeutically effective amount of a compound or salt of claim 1 to the patient.

### Claim 16 (depends on 15)

The method of claim 15, additionally comprising administering an additional antibacterial compound that is not a compound of formula I or salt thereof to the patient.

### Claim 17 (depends on 15)

The method of claim 15, wherein the bacterial infection is a Gram negative bacterial infection.

### Claim 18 (depends on 15)

The method of claim 15, wherein the bacterial infection is a S. aureus infection.