Granted Patent B2

US 7,501,538 · App. 10/913,882 · Granted Mar 10, 2009

Abstract

Claims (141)

1. The compound of Formula (I):

wherein

c is equal to 0;

G is: —CO 2 R 1 ;

wherein

R 1 is -hydrogen;

V is: —CH 2 —;

X is —N(R 8 )CO—,

wherein

R 8 is: -hydrogen;

Ar 1 is a mono-substituted phenyl group, wherein the substituent is selected from the group consisting of: -aryl, -arylene-alkyl, -D-aryl, -D-alkylene-arylene-alkyl, -arylene-D-alkyl, -arylene-D-R 10, and -D-alkylene-arylene-aryl,

wherein

R 10 is -aryl or -alkylene-aryl, and

D is —O—, or —N(R 11 )—,

wherein R 11 is: -hydrogen, -alkyl, or -aryl;

Ar 2 is a substituted phenyl having 2 to 5 substituents wherein the phenyl is substituted at an ortho and a meta position on Ar 2 , relative to X; and wherein the substituents are independently selected from the group consisting of: -fluoro, -chloro, -bromo, iodo, -cyano, -nitro, - perfluoroalkyl, -T 1 -R 14 , -alkyl, -aryl, -arylene-alkyl, -T 1 -alkyl, -T 1 -alkylene-aryl, -T 1 -alkylene-arylene-aryl, -T 1 -alkylene-arylene-alkyl, -arylene-T 1 -alkyl, -T 1 -arylene-aryl, -T 1 -arylene-alkyl, -T 1 -aryl, -T 1 -alkylene-T 2 -R 14 and -T 1 -arylene-T 2 -R 14 ;

wherein

T 1 and T 2 are independently selected from the group consisting of —CH 2 —, —O—, —N(R 15 )—, —CON(R 15 )—, —N(R 15 )C(O), —N(R 15 )SO 2 , and —C(O)—O—;

wherein

R 14 and R 15 are independently selected from the group consisting of: -hydrogen, -alkyl, and -aryl,

and wherein

the alkyl, aryl alkylene, and arylene groups in Ar 1 , Ar 2 , and R 10 , R 11 , R 14 , and R 15 , may be optionally substituted 1 to 4 times with a substituent, wherein the substituents are independently selected from the group consisting of:

a) -hydrogen;

b) -fluoro;

c) -chloro;

d) -bromo

e) -iodo;

f) -cyano;

g) -nitro;

h) -perfluoroalkyl;

i) -Q-R 18 ;

j) -Q-alkyl;

k) -Q-aryl;

I) -Q-alkylene-aryl;

m) -Q-alkylene-NR 19 R 20 ; and

n) -Q-alkyl-W—R 21 ;

wherein

Q and W are independently selected from the group consisting of: —CH 2 —, —O—, —N(R 22 )—, —C(O)—, —CON(R 22 )—, —N(R 22 )C(O)—, —N(R 22 )CON(R 23 )—, —N(R 22 )C(O)O—, —OC(O)N(R 22 )—, —N(R 22 )SO 2 —, —SO 2 N(R 22 )—, —C(O)—O—, —O—C(O)—, and —N(R 22 )SO 2 N(R 23 )—, wherein

R 18 , R 19 , R 20 , R 21 , R 22 , and R 23 are independently selected from the group consisting of: -hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, and -alkylene-arylene-alkyl,

or a pharmaceutically acceptable salt thereof.

2. The compound of Formula (I) in claim 1 , wherein

Ar 1 is: biphenyl-4-yl;

trifluoromethyl-biphenyl-4-yl;

(biphenyl-4-ylmethoxy)-phenyl;

(tert-butyl-benzyloxy)-phenyl; or

4′-phenoxy-biphenyl-4-yl,

or a pharmaceutically acceptable salt thereof.

3. The compound of Formula (I) in claim 1 , wherein

Ar 2 and X together form a group selected from:

[bromo-(tert-butyl-benzenesulfonylamino)]-benzoylamino;

(3′-chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino;

{chloro-[(naphthalen-1-yl-methyl)-amino]}-benzoylamino;

[(bistrifluoromethyl-benzoylamino)-bromo]-benzoylamino;

[chloro-(carboxyhexylamino)]-benzoylamino;

{chloro-[(dimethylamino-naphthalene)-sulfonylamino]}-benzoylamino;

[chloro-(2-methyl-pentylamino)]-benzoylamino;

[(biphenyl-sulfonylamino)-chloro]-benzoylamino;

[chloro-(2-methyl-butylamino)]-benzoylamino;

{chloro-[N-(carboxyhexyl)-N′-(bis-trifluoromethyl-benzoyl)-amino)]}-benzoylamino; and

{[N-(bis-trifluoromethyl-benzoyl)-N′-pentylamino]-chloro}-benzoylamino,

or a pharmaceutically acceptable salt thereof.

4. A compound of Formula (I) as in claim 1 selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition comprising a compound of Formula (I) wherein

c is equal to 0;

G is: —CO 2 R 1 ;

wherein

R 1 is -hydrogen;

V is: —CH 2 —;

X is —N(R 8 )CO—,

wherein

R 8 is: -hydrogen;

Ar 1 is a mono-substituted phenyl group, wherein the substituent is selected from the group consisting of: -aryl, -arylene-alkyl, -D-aryl, -D-alkylene-arylene-alkyl, -arylene-D-alkyl, -arylene-D-R 10, and -D-alkylene-arylene-aryl,

wherein

R 10 is -aryl or -alkylene-aryl, and

D is —O—, or —N(R 11 )—,

wherein R 11 is: -hydrogen, -alkyl, or -aryl;

Ar 2 is a substituted phenyl having 2 to 5 substituents wherein the phenyl is substituted at an ortho and a meta position on Ar 2 relative to X; and wherein the substituents are independently selected from the group consisting of: -fluoro, -chloro, -bromo, iodo, -cyano, -nitro, -perfluoroalkyl, -T 1 -R 14 , -alkyl, -aryl, -arylene-alkyl, -T 1 -alkyl, -T 1 -alkylene-aryl, -T 1 -alkylene-arylene-aryl, -T 1 -alkylene-arylene-alkyl, -arylene-T 1 -alkyl, -T 1 -arylene-aryl, -T 1 -arylene-alkyl, -T 1 aryl, -T 1 alkylene-T 2 -R 14, and -T 1 -arylene-T 2 -R 14 ;

wherein

T 1 and T 2 are independently selected from the group consisting of —CH 2 —, —O—, —N(R 15 —, —CON(R 15 )—, —N(R 15 )C(O), —N(R 15 )SO 2 , and —C(O)—O—;

wherein

R 14 and R 15 are independently selected from the group consisting of: -hydrogen, -alkyl, and -aryl,

and wherein

the alkyl, aryl, alkylene, and arylene groups in Ar 1 , Ar 2 , and R 10 , R 11 , R 14 , and R 15 , may be optionally substituted 1 to 4 times with a substituent, wherein the substituents are independently selected from the group consisting of:

a) -hydrogen;

b) -fluoro

c) -chloro;

d) -bromo

e) -iodo;

f) -cyano;

g) -nitro;

h) -perfluoroalkyl;

i) -Q-R 18 ;

j) -Q-alkyl;

k) -Q-aryl;

I) -Q-alkylene-aryl;

m) -Q-alkylene-NR 19 R 20 ; and

n) -Q-alkyl-W—R 21 ;

wherein

Q and W are independently selected from the group consisting of: —CH 2 —, —O—, —N(R 22 )—, —C(O)—, —CON(R 22 )—, —N(R 22 )C(O)—, —N(R 22 )CON(R 23 )—, —N(R 22 )C(O)O—, —OC(O)N(R 22 )—, —N(R 22 )SO 2 —, —SO 2 N(R 22 )—, —C(O)—O—, —O—C(O)—, and —N(R 22 )SO 2 N(R 23 )—, wherein

R 18 , R 19 , R 20 , R 21 , R 22 , and R 23 , are independently selected from the group consisting of: -hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, and -alkylene-arylene-alkyl,

or a pharmaceutically acceptable salt thereof.

6. The pharmaceutical composition of claim 5 , further comprising one or more pharmaceutically acceptable carriers, excipients, or diluents.

7. The pharmaceutical composition of claim 5 , comprising a therapeutically effective amount of the compound.

8. The pharmaceutical composition of claim 7 , wherein a therapeutically effective amount of the compound is an amount sufficient to treat a disease mediated at least in part by an erythropoietin receptor.

9. The pharmaceutical composition of claim 5 , wherein the compound binds to an erythropoietin receptor.

10. The pharmaceutical composition of claim 5 , wherein the compound activates erythropoietin receptor-mediated signal transduction.

11. The pharmaceutical composition of claim 5 , wherein the compound induces red blood cell production mediated by erythropoietin receptor activation.

12. The pharmaceutical composition of claim 5 , in the form of an oral dosage unit.

13. The pharmaceutical composition of claim 5 , in the form of or parenteral dosage unit.

14. The pharmaceutical composition of claim 5 , wherein said compound is a dose in a range from about 0.01 to 1,000 mg/kg of body weight per day.

15. The pharmaceutical composition of claim 5 , wherein said compound is a dose in a range from about 0.1 to 100 mg/kg of body weight per day.

16. The pharmaceutical composition of claim 5 , wherein said compound is a dose in a range from about 0.5 to 10 mg/kg of body weight per day.

17. The pharmaceutical composition of claim 8 , wherein the disease mediated by an erythropoietin receptor comprises anemia of renal failure.

18. The pharmaceutical composition of claim 8 , wherein the disease mediated by an erythropoietin receptor comprises anemia of end-stage renal disease.

19. The pharmaceutical composition of claim 8 , wherein the disease mediated by an erythropoietin receptor comprises anemia of chronic disorders.

20. The pharmaceutical composition of claim 8 , wherein the disease mediated by an erythropoietin receptor comprises anemia of chronic infection.

21. The pharmaceutical composition of claim 8 , wherein the disease mediated by an erythropoietin receptor comprises anemia of rheumatoid arthritis.

22. The pharmaceutical composition of claim 8 ,wherein the disease mediated by an erythropoietin receptor comprises anemia of autoimmune disease.

23. The pharmaceutical composition of claim 8 , wherein the disease mediated by an erythropoietin receptor comprises anemia of AIDS.

24. The pharmaceutical composition of claim 8 , wherein the disease mediated by an erythropoietin receptor comprises anemia of malignancy.

25. The pharmaceutical composition of claim 5 , further comprising one or more additional therapeutic agents.

26. The pharmaceutical composition of claim 5 , wherein Ar 1 is: biphenyl-4-yl;

trifluoromethyl-biphenyl-4-yl;

(biphenyl-4-ylmethoxy)-phenyl;

(tert-butyl-benzyloxy)-phenyl; or

4′-phenoxy-biphenyl-4-yl.

27. The pharmaceutical composition of claim 5 , wherein Ar 2 and X together form a group selected from:

[bromo-(tert-butyl-benzenesulfonylamino)]-benzoylamino;

(3′-chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino;

{chloro-[(naphthalen-1-yl-methyl)-amino]}-benzoylamino;

[(bistrifluoromethyl-benzoylamino)-bromo]-benzoylamino;

[chloro-(carboxyhexylamino)]-benzoylamino;

{chloro-[(dimethylamino-naphthalene)-sulfonylamino]}-benzoylamino;

[chloro-(2-methyl-pentylamino)]-benzoylamino;

[(biphenyl-sulfonylamino)-chloro]-benzoylamino;

[chloro-(2-methyl-butylamino)]-benzoylamino;

{chloro-[N-(carboxyhexyl)-N′-(bis-trifluoromethyl-benzoyl)-amino)]}-benzoylamino; and

{[N-(bis-trifluoromethyl-benzoyl)-N′-pentylamino]-chloro}-benzoylamino.

28. The pharmaceutical composition of claim 5 , wherein the compound of Formula (I) is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

Assignments (11)