# US 5,707,990 A · 2-substituted amino and thio alkyl benzoxazine antimicrobial agents

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 5,707,990 A
- Document ID: US5707990A
- Status: Granted
- Kind: A
- Application number: 08/594,020
- Filed: 1996-01-30
- Granted: 1998-01-13
- Earliest claimed: 1996-01-30
- Assignees: Ortho Pharmaceutical Corporation
- Inventors: Roger Frechette; Michael Beach
- Web page: https://patentgrep.com/patent/US5707990A

## CPC

- C07D 413/12: linked by a chain containing hetero atoms as chain links
- A61K 31/538: ortho- or peri-condensed with carbocyclic ring systems
- A61P 31/04: Antibacterial agents
- C07D 265/36: condensed with one six-membered ring
- 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 invention relates to benzoxazine and pyrido-oxazine antibacterial compounds of the general formula: ##STR1## wherein the moiety Q is a fused phenyl or fused pyridyl moiety and R is a substituted amine or substituted thio moiety as herein described, pharmaceutical compositions containing the compounds, methods for their production and their use in treating bacterial infections.

## Claims

### Claim 1

A method of treating bacterial infections in mammals by administering to a mammal suffering from such infection a therapeutically effective amount of a compound selected from those of Formula 1: ##STR48## wherein the moiety Q is a fused phenyl moiety; Z.sub.1 is hydrogen, halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, phenyl, hydroxy, amino, nitro, sulfonylamino or trifluoromethyl;
Z.sub.2 is hydrogen or a halogen;
X is hydrogen or oxygen;
A is --C.sub.1 -C.sub.6 alkyl, --C.sub.1 -C.sub.6 alkylaryl or --C.sub.1 -C.sub.6 alkylheterocyclyl where in each case the A moiety is bonded to the nitrogen through the alkyl group;
wherein aryl is biphenyl, naphthyl or phenyl; and heterocyclyl is a 5 or 6 membered saturated or unsaturated heterocyclic group containing 1-4 nitrogen atoms and/or an oxygen or a sulfur atom;
wherein said aryl or heterocyclyl group is optionally substituted with (C.sub.1 -C.sub.6)alkyl, benzyl, oxybenzyl, phenoxy, hydroxy, alkoxy, halogen, dihalogen, nitro, amino, carboxyl, carbo(C.sub.1 -C.sub.4)alkoxy or methylsulfonylamino;
R is a moiety selected from: ##STR49## wherein R.sub.1, R.sub.2 and R.sub.3 are independently hydrogen, C.sub.1 -C.sub.6 alkyl, t-butoxycarbonyl, or carboxyethylpiperidine;
R.sub.4 and R.sub.5 are independently t-butoxycarbonyl or hydrogen or R.sub.4 and R.sub.5 may be joined together to form an imidazoline, imidazolyl or pyrimidine ring;
and the pharmaceutically acceptable salts, esters and pro-drug forms thereof.

### Claim 2 (depends on 1)

A method according to claim 1 wherein the moiety A is selected from C.sub.1 -C.sub.5 alkyl, CH.sub.2 phenyl, CH.sub.2 thienyl, CH.sub.2 pyridyl, CH.sub.2 furyl, and ethyl piperidine.

### Claim 3 (depends on 1)

A method according to claim 1 wherein:
the moiety Q is fused phenyl;
Z.sub.1 is hydrogen, halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, phenyl, hydroxy, amino, nitro, sulfonylamino or trifluoromethyl;
Z.sub.2 is hydrogen or, where Z.sub.1 is a halogen, Z.sub.2 is also a halogen;
X is oxygen;
A is C.sub.1 -C.sub.5 alkyl, --CH.sub.2 phenyl, --CH.sub.2 thienyl, --CH.sub.2 pyridyl, --CH.sub.2 furyl, or -ethyl piperidine; wherein said phenyl, thienyl, pyridyl, furyl or piperidine moiety is optionally substituted with (C.sub.1 -C.sub.6)alkyl, benzyl, oxybenzyl, phenoxy, hydroxy, alkoxy, halogen, dihalogen, nitro, amino, carboxyl or carbomethoxy;
R is the moiety: ##STR50## wherein R.sub.4 and R.sub.5 are independently t-butoxycarbonyl or hydrogen or R.sub.4 and R.sub.5 may be joined together to form an imidazoline, imidazolyl or pyrimidine ring;
and the pharmaceutically acceptable salts, esters and pro-drug forms thereof.

### Claim 4

A compound for treating bacterial infections in mammals selected from those of Formula 1: ##STR51## wherein the moiety Q is fused phenyl;
Z.sub.1 is hydrogen, halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, phenyl, hydroxy, amino, nitro, sulfonylamino or trifluoromethyl;
Z.sub.2 is hydrogen or, where Z.sub.1 is a halogen, Z.sub.2 is also a halogen;
X is oxygen;
A is C.sub.1 -C.sub.5 alkyl, --CH.sub.2 phenyl, --CH.sub.2 thienyl, --CH.sub.2 pyridyl, --CH.sub.2 furyl, or -ethyl piperidine; wherein said phenyl, thienyl, pyridyl, furyl or piperidine moiety is optionally substituted with (C.sub.1 -C.sub.6)alkyl, benzyl, oxybenzyl, phenoxy, hydroxy, alkoxy, halogen, dihalogen, nitro, amino, carboxyl or carbomethoxy;
R is the moiety: ##STR52## wherein R.sub.4 and R.sub.5 are independently t-butoxycarbonyl or hydrogen or R.sub.4 and R.sub.5 may be joined together to form an imidazoline, imidazolyl or pyrimidine ring;
and the pharmaceutically acceptable salts, esters and pro-drug forms thereof.

### Claim 5 (depends on 4)

The compound according to claim 4 wherein:
Q is a fused phenyl moiety; Z.sub.1 is 6-trifluoromethyl; Z.sub.2 is hydrogen; X is oxygen; A is 3-chlorobenzyl; and R is guanidino.

### Claim 6 (depends on 4)

The compound according to claim 4 wherein:
Q is a fused phenyl moiety; Z.sub.1 is 6-methyl; Z.sub.2 is hydrogen; X is oxygen; A is 3-chlorobenzyl; and R is guanidino.

### Claim 7 (depends on 4)

The compound according to claim 4 wherein:
Q is a fused phenyl moiety; Z.sub.1 is hydrogen; Z.sub.2 is hydrogen; X is oxygen; A is 3-nitrobenzyl; and R is guanidino.

### Claim 8 (depends on 4)

The compound according to claim 4 wherein:
Q is a fused phenyl moiety; Z.sub.1 is hydrogen; Z.sub.2 is hydrogen; X is oxygen; A is 2-chlorobenzyl; and R is guanidino.

### Claim 9 (depends on 4)

The compound according to claim 4 wherein:
Q is a fused phenyl moiety; Z.sub.1 is 7-nitro; Z.sub.2 is hydrogen; X is oxygen; A is 3-chlorobenzyl; and R is guanidino.

### Claim 10 (depends on 4)

A pharmaceutical composition for treating bacterial infections comprising an effective amount of a compound selected from claim 4 in association with a pharmaceutically acceptable carrier.

### Claim 11 (depends on 4)

A method of potentiating the activity of an antibacterial agent in mammals by administering said antibacterial agent in combination with a compound selected from claim 4.

### Claim 12 (depends on 4)

A pharmaceutical composition for treating bacterial infections comprising an antibacterial agent and a compound selected from claim 4 in therapeutically effective amounts in association with a pharmaceutically acceptable carrier.

### Claim 13

A method of preparing a compound selected from those of Formula 1: ##STR53## wherein the moiety Q is a fused phenyl moiety; Z.sub.1 is hydrogen, halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, phenyl, hydroxy, amino, nitro, sulfonylamino or trifluoromethyl;
Z.sub.2 is hydrogen or, where Z.sub.1 is a halogen, Z.sub.2 is also a halogen;
X is oxygen;
A is C.sub.1 -C.sub.5 alkyl, --CH.sub.2 phenyl, --CH.sub.2 thienyl, --CH.sub.2 pyridyl, --CH.sub.2 furyl, or -ethyl piperidine; wherein said phenyl, thienyl, pyridyl, furyl or piperidine moiety is optionally substituted with (C.sub.1 -C.sub.6)alkyl, benzyl, oxybenzyl, phenoxy, hydroxy, alkoxy, halogen, dihalogen, nitro, amino, carboxyl or carbomethoxy;
R' is a moiety; ##STR54## wherein R.sub.4 and R.sub.5 are independently t-butoxycarbonyl or hydrogen or R.sub.4 and R.sub.5 may be joined together to form an imidazoline, imidazolyl or pyrimidine ring; and
the pharmaceutically acceptable salts, esters and pro-drug forms thereof, which comprises reacting a compound of the formula: ##STR55## with a halogenating agent to form a halogenated compound of the formula: ##STR56## wherein the moiety Y is a halogen, in a suitable solvent followed by reacting said halogenated compound with compound of the formula HR' wherein R' is as hereinbefore defined and recovering the compound of formula 1.