Bicyclic oxazine and thiazine oxazolidinone antibacterials

• US 5,952,324 A
• Filed: 05/14/1997
• Issued: 09/14/1999
• Est. Priority Date: 11/15/1994
• Status: Expired due to Fees

• Current Assignee: Pharmacia & Upjohn Company (Pfizer Inc.)
• Original Assignee: Pharmacia & Upjohn Company (Pfizer Inc.)
• Inventors: Thomasco, Lisa M., Cleek, Gary L., Barbachyn, Michael R., Thomas, Richard C., Gadwood, Robert C.
• Primary Examiner(s): Raymond, Richard L.
• Assistant Examiner(s): Kifle, Bruck
• Application Number:
  US09/051,466
• Time in Patent Office: 853 Days
• Field of Search: 514/211, 514/215, 514/224.2, 514/230.5, 514/301, 514/302, 514/324, 546/114, 546/115, 540/593, 540/582, 540/477
• US Class Current: 514/214.03
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: C07D 491/04 Ortho-condensed systems
• CPC Class Codes: C07D 491/08 Bridged systems
• CPC Class Codes: C07D 495/04 Ortho-condensed systems
• CPC Class Codes: C07D 495/08 Bridged systems

Abstract

Phenyloxazolidinone compound of formula (I)or a pharmaceutically acceptable salt thereof characterized by a bicyclic thiazine or oxazine substituent. The compounds are useful antimicrobial agents, effective against a number of human and veterinary pathogens, including gram-positive aerobic bacteria such as multiply-resistant staphylococci, streptococci and enterococci as well as anaerobic organisms such as Bacteroides spp. and Clostridia spp. species, and acid-fast organisms such as Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium spp.

Claims

1. A compound of structural Formula I:

or a pharmaceutically acceptable Salt thereof wherein;

X is (a) O,

(b) S,

(c) SO,

(d) SO₂ ;

R¹ is independently H, F, Cl or OMe;

R² is (a) hydrogen,

(b) C₁ -C₈ alkyl optionally substituted with one or more of the following;

F, Cl, hydroxy, C₁ -C₈ alkoxy, C₁ -C₈ acyloxy,

(c) C₃ -C₆ cycloalkyl,

(d) amino,

(e) C₁ -C₈ alkylamino,

(f) C₁ -C₈ dialkylamino,

(g) C₁ -C₈ alkoxy;

a is 0 to 3;

b is 0 to 2;

c is 0 to 2 (provided b and c cannot both be

     0);

d is 0 to 2;

and e is 0 to 2 (provided d and e cannot both be

     0).

2. The compound of claim 1 wherein X is S.

3. The compound of claim 1 wherein each R¹ is independently H or F.

4. The compound of claim 3 wherein each R¹ is F.

5. The compound of claim 1 wherein R² is hydrogen, a C₁ -C₈ alkoxy, or a C₁ -C₈ alkyl optionally substituted with one or more Cl or OH.

6. The compound of claim 1 wherein R² is methyl, dichloromethyl, hydroxymethyl, or methyl.

7. The compound of claim 1 which is:

a) (S)-N- 3- 3-fluoro-4- (1S,4S)-2-oxa-5-azabicylo 2.2.1!heptan-5-yl!phenyl!-2-oxo-5-oxazolidinyl!methyl!acetamide;

b) (S)-N- 3- 3-fluoro-4- (1S,4S)-2-thia-5-azabicyclo 2.2.1!heptan-5-yl!phenyl!-2-oxo-5-oxazolidinyl!methyl!acetamide;

or

c) (S)-N- 3- 3-fluoro-4- (1S,4S)-2-thia-2,2-dioxo-5-azabicyclo- 2.2.1!heptan-5-yl!phenyl!-2-oxo-5-oxalidinyl!methyl!acetamide.

8. The compound of claim 1 which is the S-enantiomer form.

9. The compound of claim 1 wherein c and b are both 1.

10. The compound of claim 9 wherein d and e are both 1.

11. The compound of claim 10 wherein a is 0.

12. A method for treating microbial infections in a patient in need thereof by administering an effective amount of a compound of Formula I.

13. A compound of structural Formula II:

##STR5## or pharmaceutically acceptable salts thereof wherein;

X is (a) O,

(b) S,

(c) SO,

(d) SO₂ ;

R¹ is independently H, F, Cl or OMe; and

R² is (a) hydrogen,

(b) C₁ -C₈ alkyl optionally substituted with one or more of the following;

F, Cl, hydroxy, C₁ -C₈ alkoxy, C₁ -C₈ acyloxy,

(c) C₃ -C₆ cycloalkyl,

(d) amino,

(e) C₁ -C₈ alkylamino,

(f) C₁ -C₈ dialkylamino,

(g) C₁ -C₈ alkoxy.

14. The compound of claim 13 which is the S-enantiomer form.

15. A method for treating microbial infections in warm-blooded animals by administering to a patient in need thereof an effective amount of a compound of Formula II.