Oxazolidinone thioamides with piperazine amide substituents

• US 6,642,238 B2
• Filed: 01/09/2002
• Issued: 11/04/2003
• Est. Priority Date: 02/10/2000
• Status: Expired due to Fees

• Current Assignee: Pharmacia & Upjohn Company (Pfizer Inc.)
• Original Assignee: Pharmacia & Upjohn Company (Pfizer Inc.)
• Inventors: Hester, Jackson B. Jr.
• Primary Examiner(s): BERNHARDT, EMILY B
• Application Number:
  US10/042,916
• Publication Number:
  US 20020137754A1
• Time in Patent Office: 664 Days
• Field of Search: 544/369, 514/254.02
• US Class Current: 514/254.02
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: C07D 263/20 attached in position 2

Abstract

The present invention provides a compound of formula I

which have potent activities against gram-positive and gram-negative bacteria.

Claims

1. A compound of formula I

or a pharmaceutically acceptable salt thereof wherein:

W is NHC(═

S)R₁,

R¹ is

(a) H,

(b) NH₂,

(c) NHC_1-4 alkyl,

(d) C_2-4 alkenyl,

(e) OC_1-4 alkyl,

(f) SC_1-4 alkyl,

(g) (CH₂)_n-C_3-6 cycloalkyl, or

(h) C_1-4 alkyl, optionally substituted with 1-3 F, 1-2 Cl or CN;

R₂ and R₃ are independently H, F, Cl or C_1-2 alkyl;

R₄ is

(a) —

C(═

O)—

CH₂S(O)_n—

CH₃,

(b) —

C(═

S)C_1-4 alkyl,

(c) —

C(═

O)—

(CH₂)_m—

C(═

O)—

CH₃,

(d) —

C(═

O)—

CH₂—

O—

R₁₀, or

(e) —

CN;

R₁₀ is —

CO₂—

(CH₂)₂—

OCH₃, or —

C(═

O)—

NHC_1-4alkyl;

n is 0, 1 or 2; and

m is 0 or 1.

2. A compound of formula I according to claim 1 which is an optical configuration of formula Ia,

3. A compound of formula I according to claim 1 wherein R₁ is C_1-4 alkyl.

4. A compound of formula I according to claim 1 wherein R₁ is ethyl.

5. A compound of formula I according to claim 1 wherein R₂ and R₃ are independently H or F.

6. A compound of formula I according to claim 1 wherein R₂ is H, R₃ is F.

7. A compound of claim 1 which is

(a) N{](5S)-3-(3-fluoro-4-{4-[2-(methylsulfinyl)acetyl]-1-piperazinyl}phenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}propanethioamide,

(b) N-{[(5S)-3-(3-fluoro-4-{4-[2-(methylsulfanyl)acetyl]-1-piperazinyl}phenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}propanethioamide, or

(c) N-{[(5S)-3-(3-fluoro-4-{4-[2-(methylsulfonyl)acetyl]-1-piperazinyl}phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl}propanethioamide.

8. A compound of claim 1 which is N-({(5S)-3-[4-(4-cyano-1-piperazinyl)-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)propanethioamide.

9. A compound of claim 1 which is

(a) N-({(5S)-3-(3-fluoro-4-{4-[2-(methylaminocarbonyloxy)acetyl]-1-piperazinyl}phenyl)-2-oxo-1,3-oxazolidin-5-yl}methyl)propanethioamide,

(b) N-({(5S)-3-(3-fluoro-4-{4-[2-[(2-methoxyethoxy)carbonyloxy]acetyl]-1-piperazinyl}phenyl)-2-oxo-1,3-oxazolidin-5-yl}methyl)propanethioamide or

(c) N-({(5S)-3-[3-fluoro-4-(4-acetoacetyl-1-piperazinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)propanethioamide.

10. A compound of claim 1 which is N-({(5S)-3-[3-fluoro-4-(4-pyruvoyl-1-piperazinyl) phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)propanethioamide.

11. A compound of claim 1 which is a structure Ib

12. A method for treating microbial infections in mammals comprising administration of an effective amount of a compound of claim 1 to said mammal.

13. The method of claim 12 wherein said compound is administered to the mammal orally, parenterally, transdermally, or topically in a pharmaceutical composition.

14. The method of claim 12 wherein said compound is administered in an amount of from about 0.1 to about 100 mg/kg of body weight/day.

15. The method of claim 12 wherein said compound is administered in an amount of from about 1 to about 50 mg/kg of body weight/day.

16. The method of claim 12 wherein the infection is skin infection.

17. The method of claim 12 wherein the infection is eye infection.

18. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

19. N-[((5S)-3-{3-fluoro-4-[4-((2S)-2-acetoxy-2-phenylacetyl)-1-piperazinyl]phenyl}1,3-oxazolidin-5-yl)methyl]propanethioamide.