Benzimidazole derivatives as therapeutic agents

1. A compound of Formula (I):

wherein

m is an integer of from 0 to 3;

n is an integer of from 0 to 3;

R 1 is aryl;

R 2 is

a group of the formula —N(R 9 R 10 ), —NHC(O)R 9 , or —NHC(O)OR 9 ;

wherein R 9 and R 10 are independently selected from the group consisting of

1) —H;

2) -Aryl;

3) —C 1-6 alkyl;

4) —C 1-6 alkylaryl; and

R 3 and R 4 are independently selected from the group consisting of

a) —H;

b) -aryl;

c) —C 1-6 alkyl;

d) —C 1-6 alkylaryl; and

e) —C 1-6 alkoxyaryl;

R 5 , R 6 , R 7 , and R 8 are independently selected from the group consisting of

a) —H;

b) —C 1-6 alkyl;

c) -aryl;

d) —C 1-6 alkylaryl;

e) —C(O)—O—C 1-6 alkyl;

f) —C(O)—O—C 1-6 alkylaryl;

g) —C(O)—NH—C 1-6 alkyl;

h) —C(O)—NH—C 1-6 alkylaryl;

i) —SO 2 —C 1-6 alkyl;

j) —SO 2 —C 1-6 alkylaryl;

k) —SO 2 -aryl;

l) —SO 2 —NH—C 1-6 alkyl;

m) —SO 2 —NH—C 1-6 alkylaryl;

n) —C(O)—C 1-6 alkyl;

o) —C(O)—C 1-6 alkylaryl;

p) —Y—C 1-6 alkyl;

q) —Y-aryl;

r) —Y—C- 1-6 alkylaryl;

s) —Y—C 1-6 alkylene-NR 13 R 14 ;

t) —Y—C 1-6 alkylene-W—R 15 ;

wherein Y and W independently selected from the group consisting of —CH 2 —, —O—, —N(H)—, —S—, SO 2 —, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —NHSO 2 NH—, —O—CO—,

 wherein R 16 and R 17 are independently selected from the group consisting of aryl, C 1 –C 6 alkyl, C 1 –C 6 alkylaryl, C 1 –C 6 alkoxy, and C 1 –C 6 alkoxyaryl;

R 15 is aryl, C 1 –C 6 alkyl, or C 1 –C 6 alkylaryl; and

u) halogen, hydroxyl, cyano, carbamoyl, and carboxyl;

wherein at least one of R 5 , R 6 , R 7 , and R 8 —Y—C 1-6 alkylene-NR 13 R 14 , and

R 11 , R 12 , R 13 , and R 14 are independently selected from the group consisting of hydrogen, aryl, C 1 –C 6 alkyl, C 1 –C 6 alkylaryl, C 1 –C 6 alkoxy, and C 1 –C 6 alkoxyaryl; or

R 13 and R 14 are taken together to form a ring having the formula —(CH 2 ) o —X—(CH 2 ) p — bonded to the nitrogen atom to which R 13 and R 14 are attached, and/or R 11 and R 12 are taken together to form a ring having the formula —(CH 2 ) o —X—(CH 2 ) p — bonded to the atoms to which R 11 and R 12 are connected, wherein o and p are, independently, 1, 2, 3, or 4; X is a direct bond, —CH 2 —, —O—, —S—, —S(O 2 )—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —O—C(O)—, —NHSO 2 NH—,

wherein R 18 and R 19 are alkyl or aryl; and

wherein the aryl and/or alkyl group(s) in R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 R 15 , R 16 , R 17 , R 18 , and R 19 may be optionally substituted 1–4 times with a substituent group, wherein said substituent group(s) or the term substituted refers to groups selected from the group consisting of:

a) —H;

b) -Z-C 1-6 alkyl;

-Z-aryl;

-Z-C- 1-6 alkylaryl;

-Z-C 1-6 -alkyl-NR 20 R 21 ;

-Z-C 1-6 -alkyl-W—R 22 ;

wherein Z and W are independently selected from the group consisting of —CH 2 —, —O—, —N(H), —S—, SO 2 —, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —NHSO 2 NH—, —O—CO—,

wherein;

R 22 , R 23 , and R 24 are independently selected from the group consisting of aryl, C 1 –C 6 alkyl, C 1 –C 6 alkylaryl, C 1 –C 6 alkoxy, and C 1 –C 6 alkoxyaryl;

c) halogen, hydroxyl, cyano, and carbamoyl; and

wherein R 20 R 21 are independently selected from the group consisting of hydrogen, aryl, C 1 –C 6 alkyl, C 1 –C 6 alkylaryl, C 1 –C 6 alkoxy, and C 1 –C 6 alkoxyaryl; or

R 20 and R 21 are taken together to form a ring having the formula —(CH 2 ) q —X—(CH 2 ) r — bonded to the nitrogen atom to which R 20 and R 21 are attached wherein q and r are, independently, 1, 2, 3, or 4; X comprises a direct bond, —CH 2 —, —O—, —S—, —S(O 2 )—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —O—C(O)—, —NHSO 2 NH—,

R 25 , R 26 and R 27 are independently selected from the group consisting of hydrogen, aryl, C 1 –C 6 alkyl, or C 1 –C 6 alkylaryl; or a pharmaceutically acceptable salt, solvate or prodrug thereof.

2. The compound of claim 1 , wherein m is an integer of from 0 to 3;

n is 0; R 3 is hydrogen as represented by the formula (II)

and wherein

R 1 is an aryl group;

R 2 is a group of the formula —N(R 9 R 10 ), —NHC(O)R 9 , or —NHC(O)OR 9 ;

wherein R 9 and R 10 are independently selected from the group consisting of

1) —H;

2) -Aryl; or

3) —C 1-6 alkyl; and

4) —C 1-6 alkylaryl;

R 4 is

a) H;

b) -aryl;

c) —C 1-6 alkyl;

d) —C 1-6 alkylaryl; or

e) —C 1-6 alkoxyaryl;

R 5 , R 6 , R 7 , and R 8 are independently selected from the group consisting of

a) —H;

b) —C 1-6 alkyl;

c) -aryl;

d) —C 1-6 alkylaryl;

e) —C(O)—O—C 1-6 alkyl;

f) —C(O)—O—C 1-6 alkylaryl;

g) —C(O)—NH—C 1-6 alkyl;

h) —C(O)—NH—C 1-6 alkylaryl;

i) —SO 2 —C 1-6 alkyl;

j) —SO 2 —C 1-6 alkylaryl;

k) —SO 2 -aryl;

l) —SO 2 —NH—C 1-6 alkyl;

m) —SO 2 —NH—C 1-6 alkylaryl

n) —C(O)—C 1-6 alkyl;

o) —C(O)—C 1-6 alkylaryl;

p) —Y—C 1-6 alkyl;

q) —Y-aryl;

r) —Y—C- 1-6 alkylaryl;

s) —Y—C 1-6 alkylene-NR 13 R 14 ;

t) —Y—C 1-6 alkylene-W—R 15 ;

wherein Y and W are independently selected from the group consisting of —CH 2 —, —O—, —N(H), —S—, SO 2 —, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —NHSO 2 NH—, —O—CO—,

wherein R 16 and R 17 are independently selected from the group consisting of aryl, C 1 –C 6 alkyl, C 1 –C 6 alkylaryl, C 1 –C 6 alkoxy, and C 1 –C 6 alkoxyaryl;

R 15 is aryl, C 1 –C 6 alkyl, or C 1 –C 6 alkylaryl, and

u) halogen, hydroxyl, cyano, carbamoyl, and carboxyl;

wherein at least one of R 5 , R 6 , R 7 , and R 8 is —Y—C 1-6 alkylene-NR 13 R 14 ,

R 13 , and R 14 are independently selected from the group consisting of hydrogen, aryl, C 1 –C 6 alkyl, C 1 –C 6 alkylaryl, C 1 –C 6 alkoxy, and C 1 –C 6 alkoxyaryl; or

R 13 and R 14 are together to form a ring having the formula —(CH 2 ) o —X—(CH 2 ) p — bonded to the nitrogen atom to which R 13 and R 14 are attached, wherein o and p are, independently, 1, 2, 3, or 4; X is a direct bond, —CH 2 —, —O—, —S—, —S(O 2 )—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —O—C(O)—, —NHSO 2 NH—,

wherein R 18 and R 19 are alkyl or aryl; and

and wherein the aryl and/or alkyl group(s) in R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 13 , R 14 R 15 , R 16 , R 17 , R 18 , and R 19 may be optionally substituted 1–4 times with a substituent group, wherein said substituent group(s) or the term substituted refers to groups selected from the group consisting of:

a) —H;

b) -Z-C 1-6 alkyl;

-Z-aryl;

-Z-C- 1-6 alkylaryl;

-Z-C 1-6 -alkyl-NR 20 R 21 ;

-Z-C 1-6 -alkyl-W—R 22 ;

wherein Z and W independently selected from the group consisting of —CH 2 —, —O—, —N(H), —S—, —SO 2 —, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —NHSO 2 NH—, —O—CO—,

wherein;

R 22 , R 23 , and R 24 are independently selected from the group consisting of aryl, C 1 –C 6 alkyl, C 1 –C 6 alkylaryl, C 1 –C 6 alkoxy, and C 1 –C 6 alkoxyaryl;

c) halogen, hydroxyl, cyano, and carbamoyl; and

wherein R 20 and R 21 are independently selected from the group consisting of hydrogen, aryl, C 1 –C 6 alkyl, C 1 –C 6 alkylaryl, C 1 –C 6 alkoxy, and C 1 –C 6 alkoxyaryl; or

R 20 and R 21 are taken together to form a ring having the formula —(CH 2 ) q —X—(CH 2 ) r — bonded to the nitrogen atom to which R 20 and R 21 are attached, wherein q and r are, independently, 1, 2, 3, or 4; X is a direct bond, —CH 2 —, —O—, —S—, —S(O 2 )—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —O—C(O)—, —NHSO 2 NH—,

R 25 and R 26 are independently selected from the group consisting of hydrogen, aryl, C 1 –C 6 alkyl, and C 1 –C 6 alkylaryl; or a pharmaceutically acceptable salt, solvate or prodrug thereof.

3. The compound of claim 1 , wherein the compound is 2-[(1R)-2-(4-Benzyloxyphenyl)-1-tert-butoxycarbonylamino-1-ethyl]-3-butyl-5-(3-diethylamino-1-propoxy)benzimidazole.

4. The compound of claim 1 , wherein the compound is 2-[(1R)-2-(4-Benzyloxyphenyl)-1-amino-1-ethyl]-3-butyl-5-(3-diethylamino-1-propoxy)benzimidazole Trihydrochloride.

5. The compound of claim 1 , wherein the compound is 2-[(1R)-2-(4-Benzyloxyphenyl)-1-tert-butoxycarbonylamino-1-ethyl]-3-butyl-6-(3-diethylamino-1-propoxy)benzimidazole.

6. The compound of claim 1 , wherein the compound is 2-[(1R)-2-(4-Benzyloxyphenyl)-1-amino-1-ethyl]-3-butyl-6-(3-diethylamino-1-propoxy)benzimidazole.

7. The compound of claim 1 , wherein the compound is 2-[(1R)-2-(4-Benzyloxyphenyl)-1-tert-butoxycarbonylamino-1-ethyl]-6-(3-diethylamino-1-propoxy)benzimidazole.

8. The compound of claim 1 , wherein the compound is 2-[(1R)-2-(4-Benzyloxyphenyl)-1-amino-1-ethyl]-6-(3-diethylamino-1-propoxy)benzimidazole.

9. The compound of claim 1 , wherein the compound is 2-[2-(3-Benzyloxyphenyl)-1-(tert-butoxycarbonylamino)-1-ethyl]-3-butyl-5-(3-diethylamino-1-propoxy)benzimidazole.

10. The compound of claim 1 , wherein the compound is 2-[(1R)-2-(4-Ethoxyphenyl)-1-(tert-butoxycarbonylamino)-1-ethyl]-3-butyl-5-(3-diethylamino-1-propoxy)benzimidazole.

11. The compound of claim 1 , wherein the compound is 2-[(1R)-2-(4-(4-Chloro)phenethoxy)phenyl)-1-(tert-butoxycarbonylamino)-1-ethyl]-3-butyl-5-(3-diethylamino-1-propoxy)benzimidazole.

12. The compound of claim 1 , wherein the compound is 2-[(1R)-2-(4-Benzyloxyphenyl)-1-(tert-butoxycarbonylamino)-1-ethyl]-3-(3-diethylamino-1-propyl)-5-(3-diethylamino-1-propoxy)benzimidazole.

13. The compound of claim 1 , wherein the compound is 2-[(1R)-2-(4-Benzyloxyphenyl)-1-(tert-butoxycarbonylamino)-1-ethyl]-3-ethyl-5-(3-diethylamino-1-propoxy)benzimidazole.

14. The compound of claim 1 , wherein the compound is 2-[(1R)-2-(4-Benzyloxyphenyl)-1-amino-1-ethyl]-3-(3-diethylamino-1-propyl)-5-(3-diethylamino-1-propoxy)benzimidazole.

15. The compound of claim 1 , wherein the compound is 2-[(1R)-2-(4-Benzyloxyphenyl)-1-(tert-butoxycarbonylamino)-1-ethyl]-3-benzyl-5-(3-diethylamino-1-propoxy)benzimidazole.

16. The compound of claim 1 , wherein the compound is 2-[(1R)-2-(4-Benzyloxyphenyl)-1-amino-1-ethyl]-3-benzyl-5-(3-diethylamino-1-propoxy)benzimidazole.

17. The compound of claim 1 , wherein the compound is 2-[(1R)-2-(4-Benzyloxyphenyl)-1-(tert-butoxycarbonylamino)-1-ethyl]-3-propyl-5-(3-diethylamino-1-propoxy)benzimidazole.

18. The compound of claim 1 , wherein the compound is 2-[(1R)-2-(4-Benzyloxyphenyl)-1-amino-1-ethyl]-3-propyl-5-(3-diethylamino-1-propoxy)benzimidazole.

19. A pharmaceutical composition comprising the compound of Formula (I) as claimed in claim 1 , and one or more pharmaceutically acceptable carriers, excipients, or diluents.

20. The pharmaceutical composition of claim 19 , in the form of an oral dosage or parenteral dosage unit.

21. The pharmaceutical composition of claim 19 , wherein said compound is administered as a dose in a range from about 0.01 to 500 mg/kg of body weight per day.

22. The pharmaceutical composition of claim 19 , wherein said compound is administered as a dose in a range from about 0.1 to 200 mg/kg of body weight per day.

23. The pharmaceutical composition of claim 19 , wherein said compound is administered as a dose in a range from about 0.1 to 100 mg/kg of body weight per day.

24. The pharmaceutical composition of claim 19 , further comprising one or more therapeutic agents selected from the group consisting of alkylating agents, antimetabolites, plant alkaloids, antibiotics, hormones, biologic response modifiers, analgesics, NSAIDs, DMARDs, glucocorticoids, sulfonylureas, biguanides, insulin, cholinesterase inhibitors, antipsychotics, antidepressants, and anticonvulsants.

25. A method of treating RAGE mediated human diseases comprising administration to a human in need thereof a therapeutically effective amount of a compound of Formula (I) as claimed in claim 1 , wherein a therapeutically effective amount comprises sufficient compound to at least partially inhibit the binding of a physiological ligand to the RAGE receptor, and wherein the RAGE mediated human disease is acute and/or chronic inflammation.

26. A method of treating RAGE mediated human diseases comprising administering to a human in need thereof a therapeutically effective amount of a compound of Formula (I) as claimed in claim 1 , wherein a therapeutically effective amount is sufficient compound to at least partially inhibit the binding of a physiological ligand to the RAGE receptor, and wherein the RAGE mediated human disease is abnormal vascular permeability.

27. A method of treating RAGE mediated human diseases comprising administering to a human in need thereof a therapeutically effective amount of a compound of Formula (I) as claimed in claim 1 , wherein a therapeutically effective amount is sufficient compound to at least partially inhibit the binding of a physiological ligand to the RAGE receptor, and wherein the RAGE mediated human disease is nephropathy.

28. A method of treating RAGE mediated human diseases comprising administering to a human in need thereof a therapeutically effective amount of a compound of Formula (I) as claimed in claim 1 , wherein a therapeutically effective amount is sufficient compound to at least partially inhibit the binding of a physiological ligand to the RAGE receptor, and wherein the RAGE mediated human disease is atherosclerosis.

29. A method of treating RAGE mediated human diseases comprising administering to a human in need thereof a therapeutically effective amount of a compound of Formula (I) as claimed in claim 1 , wherein a therapeutically effective amount is sufficient compound to at least partially inhibit the binding of a physiological ligand to the RAGE receptor, and wherein the RAGE mediated human disease is retinopathy.

30. A method of treating RAGE mediated human diseases comprising administering to a human in need thereof a therapeutically effective amount of a compound of Formula (I) as claimed in claim 1 , wherein a therapeutically effective amount is sufficient compound to at least partially inhibit the binding of a physiological ligand to the RAGE receptor, and wherein the RAGE mediated human disease is Alzheimer's disease.

31. A method of treating RAGE mediated human diseases comprising administering to a human in need thereof a therapeutically effective amount of a compound of Formula (I) as claimed in claim 1 , wherein a therapeutically effective amount is sufficient compound to at least partially inhibit the binding of a physiological ligand to the RAGE receptor, and wherein the RAGE mediated human disease is erectile dysfunction.

32. The compound of claim 1 , wherein R 4 is

a) -aryl;

b) —C 1-6 alkyl;

c) —C 1-6 alkylaryl; or

d) —C 1-6 alkoxyaryl.