IP Library › Granted Patent US 8,536,181

Granted Patent B2

US 8,536,181 · App. 12/940,891 · Granted Sep 17, 2013

Prolyl hydroxylase inhibitors

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Quick Facts

Patent No.: US 8,536,181
App. No.: 12/940,891
Granted: Sep 17, 2013
Kind: B2

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Abstract

Disclosed herein are prolyl hydroxylase inhibitors that can stabilize hypoxia inducible factor-1 alpha (HIF-1α), as well as hypoxia inducible factor-2 (HIF-2). Also disclosed herein are pharmaceutical compositions comprising one or more of the disclosed compounds. Yet further disclosed are methods for stimulating the cellular immune response in a mammal such as increasing phagocytosis, for example, prolonging the life of phagocytes, inter alia, kerotyiocytes, neutrophils. As such the disclosed compounds provide methods for treating diseases that relate to the body's immune response.

Claims (96)

1. A compound having the formula:

wherein Z is phenyl substituted with from 1 to 5 halogens chosen from fluorine and chlorine;

R 4 is C 1 -C 4 linear alkyl or C 3 -C 4 branched alkyl; or

a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , wherein R 4 is methyl.

3. The compound according to claim 1 , wherein R 4 is ethyl.

4. The compound according to claim 1 , wherein R 4 is tert-butyl.

5. The compound according to claim 1 , wherein Z is 4-chlorophenyl.

6. The compound according to claim 1 , wherein Z is chosen from 2-chlorophenyl, 3-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, or 4-fluorophenyl.

7. The compound according to claim 1 , wherein Z is chosen from 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, and 2,6-dichlorophenyl.

8. The compound tert-butyl 4-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate.

9. A compound chosen from:

Methyl 4-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate;

Methyl 4-{[1-(3-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate;

Methyl 4-{[1-(2-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate;

Ethyl 4-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate;

Ethyl 4-{[1-(3-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate;

Ethyl 4-{[1-(2-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate;

tert-Butyl 4-{[1-(3-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate;

tert-Butyl 4-{[1-(2-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate;

Methyl 4-{[1-(4-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate;

Methyl 4-{[1-(3-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate;

Methyl 4-{[1-(2-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate;

Ethyl 4-{[1-(4-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate;

Ethyl 4-{[1-(3-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate;

Ethyl 4-{[1-(2-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate;

tert-Butyl 4-{[1-(4-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate;

tert-Butyl 4-{[1-(3-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate;

tert-Butyl 4-{[1-(2-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate;

Methyl 4-{[1-(4-chlorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate;

Methyl 4-{[1-(3-chlorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate;

Methyl 4-{[1-(2-chlorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate;

Ethyl 4-{[1-(4-chlorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate;

Ethyl 4-{[1-(3-chlorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate;

Ethyl 4-{[1-(2-chlorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate;

tert-Butyl 4-{[1-(3-chlorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate;

tert-Butyl 4-{[1-(2-chlorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate;

Methyl 4-{[1-(4-fluorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate;

Methyl 4-{[1-(3-fluorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate;

Methyl 4-{[1-(2-fluorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate;

Ethyl 4-{[1-(4-fluorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate;

Ethyl 4-{[1-(3-fluorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate;

Ethyl 4-{[1-(2-fluorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate;

tert-Butyl 4-{[1-(4-fluorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate;

tert-Butyl 4-{[1-(3-fluorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; and

tert-Butyl 4-{[1-(2-fluorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate.

10. A compound according to claim 1 , wherein the compound is a pharmaceutically acceptable salt of an anion chosen from chloride, bromide, iodide, sulfate, bisulfate, carbonate, bicarbonate, phosphate, hydrogensulfonate, p-toluenesulfonate, methanesulfonate, formate, acetate, propionate, butyrate, pyruvate, lactate, oxalate, malonate, maleate, succinate, tartrate, fumarate, glycolate, or citrate.

11. A composition comprising:

a) one or more compounds having the formula:

wherein Z is phenyl substituted with from 1 to 5 halogens chosen from fluorine and chlorine;

R 4 is C 1 -C 4 linear alkyl or C 3 -C 4 branched alkyl;

or a pharmaceutically acceptable salt thereof; and

b) one or more pharmaceutically acceptable excipients.

12. The composition according to claim 11 , wherein R 4 is methyl.

13. The composition according to claim 11 , wherein R 4 is ethyl.

14. The composition according to claim 11 , wherein R 4 is tert-butyl.

15. The composition according to claim 11 , wherein Z is 4-chlorophenyl.

16. The composition according to claim 11 , wherein Z is chosen from 2-chlorophenyl, 3-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, or 4-fluorophenyl.

17. The composition according to claim 11 , wherein Z is chosen from 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, and 2,6-dichlorophenyl.

18. The composition according to claim 11 , comprising tert-butyl 4-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate.

19. The composition according to claim 11 , comprising one or more compounds chosen from:

Methyl 4-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate;

Methyl 4-{[1-(3-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate;

Methyl 4-{[1-(2-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate;

Ethyl 4-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate;

Ethyl 4-{[1-(3-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate;