IP Library › Granted Patent US 8,133,894

Granted Patent B2

US 8,133,894 · App. 12/845,061 · Granted Mar 13, 2012

N-benzyl-4-methyleneamino-3-hydroxy-2-pyridones

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Quick Facts

Patent No.: US 8,133,894
App. No.: 12/845,061
Granted: Mar 13, 2012
Kind: B2

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Abstract

Compounds of Formula (I) are effective in the treatment of a microbial infection.

Claims (130)

1. A compound of formula (I)

wherein:

each R 1 is independently:

i) hydrogen;

ii) halogen;

iii) cyano; or

iv) C 1 -C 3 alkoxy;

R 3 and R 4 are taken together to form a piperazin-1-yl ring, wherein said ring can be optionally substituted at the 4-position nitrogen atom by a unit chosen from:

i) C 1 -C 15 alkyl;

ii) C 3 -C 9 cycloalkyl;

iii) C 1 -C 12 haloalkyl;

iv) C 2 -C 15 alkenyl;

v) C 2 -C 15 alkynyl;

vi) acyl having the formula —C(═O)R, R is hydrogen or C 1 -C 3 alkyl;

vii) C 2 -C 15 heteroalkyl, optionally substituted with C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halogen, cyano, hydroxy, —C(═O)OH, —NH 2 ; —NHC(═O)R; —C(═O)NH 2 , phenyl, or combinations thereof;

viii) phenyl; optionally substituted with C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halogen, cyano, hydroxy, —C(═O)OH, —NH 2 ; —NHC(═O)R; —C(═O)NH 2 , phenyl, or combinations thereof; or

ix) benzyl; optionally substituted with C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halogen, cyano, hydroxy, —C(═O)OH, —NH 2 ; —NHC(═O)R; —C(═O)NH 2 , phenyl, or combinations thereof;

R 5 and R 6 are each independently:

i) C 1 -C 15 alkyl;

ii) C 3 -C 9 cycloalkyl;

iii) C 1 -C 12 haloalkyl;

iv) C 2 -C 15 alkenyl;

v) C 2 -C 15 alkynyl;

vi) halogen;

vii) cyano; or

viii) hydroxy; or

a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , wherein R 5 and R 6 are both hydrogen.

3. The compound according to claim 1 , wherein the piperazin-1-yl ring formed when R 3 and R 4 are taken together is substituted at the 4-position nitrogen atom with a unit chosen from:

i) phenyl; or

ii) benzyl;

wherein said units are optionally substituted with a unit chosen from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halogen, cyano, hydroxy, —C(═O)OH, —NH 2 ; —NHC(═O)R; —C(═O)NH 2 , phenyl, or combinations thereof.

4. The compound according to claim 1 , wherein the piperazin-1-yl ring formed when R 3 and R 4 are taken together is substituted at the 4-position nitrogen atom with an acyl having the formula —C(═O)R, R is hydrogen or C 1 -C 3 alkyl.

5. The compound according to claim 4 , wherein the acyl unit is a unit having the formula —C(═O)CH 3 .

6. The compound according to claim 1 , chosen from:

1-benzyl-3-hydroxy-4[(4-methylpiperazin-1-yl)methyl]pyridine-2(1H)-one;

1-(3-methoxybenzyl)-3-hydroxy-4[(4-methylpiperazin-1-yl)methyl]pyridine-2(1H)-one;

1-(3-methylbenzyl)-3-hydroxy-4[(4-methylpiperazin-1-yl)methyl]pyridine-2(1H)-one;

1-(3-chlorobenzyl)-3-hydroxy-4[(4-methylpiperazin-1-yl)methyl]pyridine-2(1H)-one;

1-benzyl-3-hydroxy-4[(4-ethylpiperazin-1-yl)methyl]pyridine-2(1H)-one;

1-benzyl-3-hydroxy-4[(4-trifluoromethylpiperazin-1-yl)methyl]pyridine-2(1H)-one;

1-benzyl-3-hydroxy-4[(4-phenylpiperazin-1-yl)methyl]pyridine-2(1H)-one;

1-(3-methoxybenzyl)-3-hydroxy-4[(4-phenylpiperazin-1-yl)methyl]pyridine-2(1H)-one;

1-benzyl-3-hydroxy-4[(4-phenylpiperazin-1-yl)methyl]pyridine-2(1H)-one;

1-benzyl-3-hydroxy-4{[(4-(2-methoxyphenyl)piperazin-1-yl]methyl}pyridine-2(1H)-one;

1-(3-methoxybenzyl)-3-hydroxy-4{[(4-(2-methoxyphenyl)piperazin-1-yl]methyl}pyridine-2(1H)-one;

1-(3-methylbenzyl)-3-hydroxy-4{[(4-(2-methoxyphenyl)piperazin-1-yl]methyl}pyridine-2(1H)-one; and

1-(3-chlorobenzyl)-3-hydroxy-4{[(4-(2-methoxyphenyl)piperazin-1-yl]methyl}pyridine-2(1H)-one.

7. A composition comprising:

a) one or more compounds having the formula:

wherein:

each R 1 is independently:

i) hydrogen;

ii) halogen;

iii) cyano; or

iv) C 1 -C 3 alkoxy;

R 3 and R 4 are taken together to form a piperazin-1-yl ring, wherein said ring can be optionally substituted at the 4-position nitrogen atom by a unit chosen from:

i) C 1 -C 15 alkyl;

ii) C 3 -C 9 cycloalkyl;

iii) C 1 -C 12 haloalkyl;

iv) C 2 -C 15 alkenyl;

v) C 2 -C 15 alkynyl;

vi) acyl having the formula —C(═O)R, R is hydrogen or C 1 -C 3 alkyl;

viii) phenyl; optionally substituted with C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halogen, cyano, hydroxy, —C(═O)OH, —NH 2 ; —NHC(═O)R; —C(═O)NH 2 , phenyl, or combinations thereof; or

ix) benzyl; optionally substituted with C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halogen, cyano, hydroxy, —C(═O)OH, —NH 2 ; —NHC(═O)R; —C(═O)NH 2 , phenyl, or combinations thereof;

R 5 and R 6 are each independently:

i) C 1 -C 15 alkyl;

ii) C 3 -C 9 cycloalkyl;

iii) C 1 -C 12 haloalkyl;

iv) C 2 -C 15 alkenyl;

v) C 2 -C 15 alkynyl;

vi) halogen;

vii) cyano; or

viii) hydroxy; or

a pharmaceutically acceptable salt thereof; and

b) one or more pharmaceutically acceptable excipients.

8. The composition according to claim 7 , wherein R 5 and R 6 are both hydrogen.

9. The composition according to claim 7 , wherein the piperazin-1-yl ring formed when R 3 and R 4 are taken together is substituted at the 4-position nitrogen atom with a unit chosen from:

i) phenyl; or

ii) benzyl;

10. The composition according to claim 7 , wherein the piperazin-1-yl ring formed when R 3 and R 4 are taken together is substituted at the 4-position nitrogen atom with an acyl having the formula —C(═O)R, R is hydrogen or C 1 -C 3 alkyl.

11. The composition according to claim 10 , wherein the acyl unit is a unit having the formula —C(═O)CH 3 .

12. A method of treating a microbial infection, comprising administering a safe and effective of amount of a compound having the formula:

wherein:

each R 1 is independently:

i) hydrogen;

ii) halogen;

iii) cyano; or

iv) C 1 -C 3 alkoxy;

R 3 and R 4 are taken together to form a piperazin-1-yl ring, wherein said ring can be optionally substituted at the 4-position nitrogen atom by a unit chosen from:

i) C 1 -C 15 alkyl;

ii) C 3 -C 9 cycloalkyl;

iii) C 1 -C 12 haloalkyl;

iv) C 2 -C 15 alkenyl;

v) C 2 -C 15 alkynyl;

vi) acyl having the formula —C(═O)R, R is hydrogen or C 1 -C 3 alkyl;

viii) phenyl; optionally substituted with C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halogen, cyano, hydroxy, —C(═O)OH, —NH 2 ; —NHC(═O)R; —C(═O)NH 2 , phenyl, or combinations thereof; or

ix) benzyl; optionally substituted with C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halogen, cyano, hydroxy, —C(═O)OH, —NH 2 ; —NHC(═O)R; —C(═O)NH 2 , phenyl, or combinations thereof;

R 5 and R 6 are each independently:

i) C 1 -C 15 alkyl;

ii) C 3 -C 9 cycloalkyl;

iii) C 1 -C 12 haloalkyl;

iv) C 2 -C 15 alkenyl;

v) C 2 -C 15 alkynyl;

vi) halogen;

vii) cyano; or

viii) hydroxy; or

a pharmaceutically acceptable salt thereof.

13. The method according to claim 12 , wherein R 5 and R 6 are both hydrogen.

14. The method according to claim 12 , wherein the piperazin-1-yl ring formed when R 3 and R 4 are taken together is substituted at the 4-position nitrogen atom with a unit chosen from:

i) phenyl; or

ii) benzyl;

15. The method according to claim 12 , wherein the compound is chosen from: