IP Library Granted Patent US 7,456,211
Granted Patent B2
US 7,456,211 · App. 11/683,089 · Granted Nov 25, 2008

Peptide deformylase inhibitors

Assignee: SmithKline Beecham Corp
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 7,456,211
App. No.
11/683,089
Granted
Nov 25, 2008
Kind
B2
Abstract

The present invention involves novel anti-bacterial compounds represented by Formula (I), pharmaceutical compositions thereof, their use as PDF inhibitors, and their use in the treatment of bacterial infections.

Claims (70)

1. A compound according to formula (I):

wherein

R1 is selected from the group consisting of: C 1-6 alkyl, —C 1-2 alkylAr, and Ar;

R2 is selected ftrom the group consisting of hydrogen, C 1-6 alkyl, —(CH 2 ) m OH, —(CH 2 ) n Ar′, —SO 2 R3, —C(O)R3, —C(O)NHR3, —C(O)OR3, —CH(R4)CONR5R6, and —CH(R4)CO 2 R7;

R3 is selected from the group consisting of C 1-6 alkyl, —C 1-2 alkylAr′, and Ar′;

R4 is hydrogen or C 1-6 alkyl;

R5 and R6 are independently selected from the group consisting of hydrogen and C 1-6 alkyl;

R7 is selected from the group consisting of hydrogen and C 1-3 alkyl;

Ar is selected from the group consisting of phenyl, furyl, and thienyl, all of which may be optionally substituted by one or more Z 1 groups;

Ar′ is selected from the group consisting of phenyl, naphthyl, furyl, pyridyl, thienyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, benzofuranyl, indolyl, thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl, morpholinyl, piperidinyl, piperazinyl, pyrrolyl, and pyrimidyl, all of which may be optionally substituted by one or more Z 2 groups;

Z 1 is independently selected from the group consisting of hydrogen, C 1-3 alkyl, —CN, F, Cl, Br, and I;

Z 2 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkoxy, —(CH 2 ) n CO 2 R4, —C(O)NR5R6, —CN, —(CH 2 ) n OH, —NO 2 , F, Cl, Br, I, —NR5R6, and —NHC(O)R1;

m is 2 to 5; and

n is 0 to 5; or a pharmaceutically acceptable salt thereof.

2. A compound selected from the group consisting of:

N-[(3S,4R)-4-Butyl-1-(5-hydroxypentyl)-2-oxopyrrolidin-3-yl-methyl]-N-hydroxyformamide;

N-[(3R,4S)-4-Butyl-1-(5-hydroxypentyl)-2-oxopyrrolidin-3-yl-methyl]-N-hydroxyformamide;

(+/−)-(3RS,4SR)-N-[4-Butyl-2-oxo-1-(t-butylcarboxy)pyrrolidin-3-yl-methyl]-N-hydroxyformamide;

(+/−)-(3RS,4SR)-N-(4-Butyl-2-oxopyrrolidin-3-yl-methyl)-N-hydroxyformamide;

(+/−)-(3RS,4SR)-N-(4-Butyl-2-oxo-1-pentanoylpyrrolidin-3-yl-methyl)-N-hydroxyformamide;

(+/−)-(3RS,4SR)-N-[4-Butyl-2-oxo-1-(2-phenylethanoyl)pyrrolidin-3-yl-methyl]-N-hydroxyformamide;

(+/−)-(3RS,4SR)-N-[4-Butyl-2-oxo-1-(1-phenylmethanoyl)pyrrolidin-3-yl-methyl]-N-hydroxyformamide;

(+/−)-(3RS,4SR)-N-(1-Benzenesulfonyl-4-butyl-2-oxopyrrolidin-3-yl-methyl)-N-hydroxyformarnide;

(+/−)-(3RS,4SR)-N-[1-(Butane-1-sulfonyl)-4-butyl-2-oxopyrrolidin-3-yl-methyl]-N-hydroxyformamide;

(+/−)-(3RS,4SR)-N-[4-Butyl-1-(naphthalen-2-ylmethanoyl)-2-oxopyrrolidin-3-yl-methyl]-N-hydroxyformamide;

(+/−)-(3RS,4SR)-N-(1-Benzyl-4-butyl-2-oxopyrrolidin-3-yl-methyl)-N-hydroxyformnamide;

(+/−)-(3RS,4SR)-N-{4-Butyl-1-[1-(4-ethoxyphenyl)methanoyl]-2-oxopyrrolidin-3-yl-methyl}-N-hydroxyformamide;

(+/−)-(3RS,4SR)-N-{4-Butyl-1-[1-(3-ethoxyphenyl)methanoyl]-2-oxopyrrolidin-3-yl-methyl}-N-hydroxyformamide;

(+/−)-(3RS,4SR)-N-{4-Butyl-1-[1-(2-ethoxyphenyl)methanoyl]-2-oxopyrrolidin-3-yl-methyl}-N-hydroxyformamide;

(+/−)-(3RS,4SR)-N-(4-Butyl-2-oxo-1-pyridin-3-ylmethylpyrrolidin-3-yl-methyl)-N-hydroxyformamide;

N-((3S,4R)-4-Butyl-1-{(S)-1-[1-((S)-2-methoxymethyl-pyrrolidin-1-yl)methanoyl]-3-methylbutyl}-2-oxopyrrolidin-3-yl-methyl)-N-hydroxyformamide;

N-((3R,4S)-4-Butyl-1-{(S)-1-[1-((S)2-methoxymethyl-pyrrolidin-1-yl)-methanoyl]-3-methylbutyl}-2-oxopyrrolidin-3-yl-methyl)-N-hydroxyformamide;

N-((3S,4R)-4-Butyl-1-{(S)-1-[1-(dimethylamino)methanoyl]-3,3-dimethylbutyl}-2-oxopyrrolidin-3-yl-methyl)-N-hydroxyformamide;

(+/−)-(3RS,4SR)-N-[4-Butyl-1-(4-ethoxybenzyl)-2-oxopyrrolidin-3-yl-methyl]-N-hydroxyformamide;

(+/−)-(3RS,4SR)-N-[4-Butyl-1-(4-hydroxybenzyl)-2-oxopyrrolidin-3-yl-methyl]-N-hydroxyformamide;

(+/−)-(3RS,4SR)-N-{4-Butyl-1-[4-(2-morpholin-4-yl-2-oxoethoxy)benzyl]-2-oxopyrrolidin-3-yl-methyl}-N-hydroxyformamide;

(+/−)-(3RS,4SR)-N-{4-Butyl-1-[4-(4-carboxy-1-butoxy)benzyl]-2-oxopyrrolidin-3-yl-methyl}-N-hydroxyformamide;

(+/−)-(3RS,4SR)-N-{4-Butyl-1-[4-(3-hydroxybenzoxy)benzyl]-2-oxopyrrolidin-3-yl-methyl}-N-hydroxyformamide;

(+/−)-(3RS,4SR)-N-{4-Butyl-2-oxo-1-[4-(tetrahydrofuran-2-ylmethoxy)benzyl]pyrrolidin-3-yl-methyl}-N-hydroxyformamide;

(+/−)-(3RS,4SR)-N-{4-Butyl-1-[4-(furan-2-ylmethoxy)benzyl]-2-oxopyrrolidin-3-yl-methyl}-N-hydroxyformamide;

(+/−)-(3RS,4SR)-N-{4-Butyl-1-[4-(3-hydroxypropoxy)benzyl]-2-oxopyrrolidin-3-yl-methyl}-N-hydroxyformamide;

(+/−)-(3RS,4SR)-N-{4-Butyl-2-oxo-1-[4-(piperidin-3-ylmethoxy)benzyl]pyrrolidin-3-yl-methyl}-N-hydroxyformamide;

(+/−)-(3RS,4SR)-N-{4-Butyl-2-oxo-1-[4-(pyridin-3-ylmethoxy)benzyl]pyrrolidin-3-yl-methyl}-N-hydroxyformamide;

(+/−)-(3RS,4SR)-N-{4-Butyl-1-[4-(5-hydroxypentoxy)benzyl]-2-oxopyrrolidin-3-yl-methyl}-N-hydroxyformamide;

(+/−)-(3RS,4SR)-N-[4-Butyl-1-(2,3-dichlorobenzyl)-2-oxopyrrolidin-3-yl-methyl]-N-hydroxyformamide;

(+/−)-(3RS,4SR)-N-[4-Butyl-1-(3,4-dichlorobenzyl)-2-oxopyrrolidin-3-yl-methyl]-N-hydroxyformamide;

(+/−)-(3RS,4SR)-N-(4-Butyl-2-oxo-1-phenylpyrrolidin-3-yl-methyl]-N-hydroxyformamide;

(+/−)-(3RS,4SR)-N-{4-Butyl-1-[2-(2-hydroxyphenyl)-2-oxoethyl]-2-oxopyrrolidin-3-yl-methyl}-N-hydroxyformamide;

(+/−)-(3RS,4SR)-N-[4-Butyl-1-(3,5-dimethylisoxazol-4-ylmethyl)-2-oxopyrrolidin-3-yl-methyl]-N-hydroxyformamide; and

(+/−)-(3RS,4SR)-N-[4-Butyl-1-(2-methylthiazol-4-ylmethyl)-2-oxopyrrolidin-3-yl-methyl]-N-hydroxyformamide; or a pharmaceutically acceptable salt thereof.

3. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

4. A compound according to claim 1 wherein:

R1 is C 1-6 alkyl;

R2 is selected from the group consisting of hydrogen, —(CH 2 ) m OH, —(CH 2 ) n Ar′, —SO 2 R3, —C(O)R3, —C(O)OR3, and —CH(R4)CONR5R6;

R3 is selected from the group consisting of C 1-6 alkyl, —C 1-2 alkylAr′, and Ar′;

R4 is hydrogen or C 1-6 alkyl;

R5 and R6 are C 1-6 alkyl;

Ar′ is selected from the group consisting of phenyl, naphthyl, pyridyl, thiazolidinyl, and isoxazolyl, all of which may be optionally substituted by one or more Z 2 groups;

Z 2 is independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, —C(O)NR5R6, —(CH 2 ) n OH, and Cl;

m is 5; and

n is 0 or 1; or a pharmaceutically acceptable salt thereof.

5. A compound according to claim 4 wherein R1 is butyl; or a pharmaceutically acceptable salt thereof.

6. A method of treating a bacterial respiratory tract infection comprising administering to a subject in need of treatment a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

7. A method of treating a bacterial respiratory tract infection comprising administering to a subject in need of treatment a compound according to claim 4 or a pharmaceutically acceptable salt thereof.

8. A method of treating a bacterial respiratory tract infection comprising administering to a subject in need of treatment a compound according to claim 5 or a pharmaceutically acceptable salt thereof.

9. A method of treating a Haemophilus influenzae, Moraxella catarrhalis , or Streptococcus pneumoniae infection comprising administering to a subject in need of treatment a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

10. A method of treating a Haemophilus influenzae, Moraxella catarrhalis , or Streptococcus pneumoniae infection comprising administering to a subject in need of treatment a compound according to claim 4 or a pharmaceutically acceptable salt thereof.

11. A method of treating a Haemophilus influenzae, Moraxella catarrhalis , or Streptococcus pneumoniae infection comprising administering to a subject in need of treatment a compound according to claim 5 or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a compound according to claim 4 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

13. A pharmaceutical composition comprising a compound according to claim 5 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Assignments (1)
CHANGE OF NAME Recorded Jan 8, 2010
From: SMITHKLINE BEECHAM CORPORATION
To: GLAXOSMITHKLINE LLC
Reel/Frame 023750/0387 →
Continuity (4)
Continuation 1117882300 · Oct 14, 2005
Continuation 1046943400
Provisional Application 6027244600 · Mar 1, 2001
Related Publication 20070155792A1 · Jul 5, 2007