AZOLE DERIVATIVES AND FUSED BICYCLIC AZOLE DERIVATIVES AS THERAPEUTIC AGENTS
This invention provides certain compounds, methods of their preparation, pharmaceutical compositions comprising the compounds, and their use in treating human or animal disorders. The compounds of the invention are useful as modulators of the interaction between the receptor for advanced glycated end products (RAGE) and its ligands, such as advanced glycated end products (AGEs), S100/calgranulin/EN-RAGE, β-amyloid and amphoterin, and for the management, treatment, control, or as an adjunct treatment for diseases in humans caused by RAGE. Such diseases or disease states include acute and chronic inflammation, the development of diabetic late complications such as increased vascular permeability, nephropathy, atherosclerosis, and retinopathy, the development of Alzheimer's disease, erectile dysfunction, and tumor invasion and metastasis.
1 .- 7 . (canceled)
8 . A method for treating retinopathy in a subject having retinopathy comprising administering to the subject a therapeutically effective amount of a compound of Formula (Ib):
wherein
R 1 is -hydrogen, -alkyl, or -alkenyl,
R 3 is -hydrogen or -alkyl, and
R 102 and R 104 are independently selected from the group consisting of:
a) —H,
b) -alkyl,
c) -aryl,
d) -heteroaryl,
e) -alkylene-heteroaryl-aryl,
f) -alkylene-aryl,
g) -alkylene-W 2 —R 18 ,
h) —Y 4 —NR 23 R 24 ,
i) —Y 4 —NH—C(═NR 25 )NR 23 R 24 ,
j) —Y 4 —C(═NR 25 )NR 23 R 24 , and
k) —Y 4 —Y 5 -A 2 ;
wherein
W 2 is —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—S(O) 2 —, —O—CO—,
wherein R 19 and R 20 are independently selected from the group consisting of: -hydrogen, -aryl, -alkyl, -alkylene-aryl, -alkoxy, and
-alkylene-O-aryl;
R 18 is -aryl, -alkyl, -alkylene-aryl, -alkylene-heteroaryl, or -alkylene-O-aryl;
Y 5 is a direct bond, —CH 2 —, —O—, —N(H), —S—, SO 2 —, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —NHSO 2 NH—, —O—CO—,
wherein R 27 and R 26 are independently selected from the group consisting of -aryl, -alkyl, -alkylene-aryl, -alkoxy, and -alkyl-O-aryl;
Y 4 is
a) -alkylene,
b) -alkenylene,
c) -alkynylene,
d) -arylene,
e) -heteroarylene,
f) -cycloalkylene,
g) -heterocyclylene,
h) -alkylene-arylene,
i) -alkylene-heteroarylene,
j) -alkylene-cycloalkylene,
k) -alkylene-heterocyclylene,
l) -arylene-alkylene,
m) -heteroarylene-alkylene,
n) -cycloalkylene-alkylene,
o) -heterocyclylene-alkylene,
p) —O—,
q) —S—,
r) —S(O 2 )—, or
s) —S(O)—;
wherein said alkylene groups may optionally contain one or more O, S, S(O), or SO 2 atoms;
A 2 is
a) heterocyclyl, fused arylheterocyclyl, or fused heteroarylheterocyclyl, containing at least one basic nitrogen atom, or
b) -imidazolyl,
R 23 , R 24 , and R 25 are independently selected from the group consisting of: -hydrogen, -aryl, -heteroaryl, -alkylene-heteroaryl, -alkyl, -alkylene-aryl, -alkylene-O-aryl, and -alkylene-O-heteroaryl; and R 23 and R 24 may be taken together to form a five-membered ring having the formula —(CH 2 ) s —X 3 —(CH 2 ) t — bonded to the nitrogen atom to which R 23 and R 24 are attached
wherein
s and t are, independently, 1, 2, 3, or 4;
X 3 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 28 and R 29 are independently selected from the group consisting of: -hydrogen, -aryl, -heteroaryl, -alkyl, -alkylene-aryl, and -alkylene-heteroaryl;
wherein
the alkyl and/or aryl groups of R 102 and R 104 may be optionally substituted 1-4 times with a substituent group selected from the group consisting of:
a) halogen,
b) perhaloalkyl,
c) alkyl,
d) cyano,
e) alkyloxy,
f) aryl, and
g) aryloxy
wherein the ring or rings containing a heteroatom in the heteroaryl, heterarylene, heterocyclyl, heterocyclene, fused arylheterocyclyl, or fused heteroarylheterocyclyl groups in R 102 or R 104 or in a substituent of R 102 or R 104 is a five-membered nitrogen containing ring,
or a pharmaceutically acceptable salt thereof, and wherein a therapeutically effective amount comprises sufficient compound to at least partially inhibit the binding of a ligand to RAGE.
9 . The method according to claim 8 , wherein the compound is mixed with a pharmaceutically acceptable carrier.
10 . The method according to claim 8 , wherein the compound is administered parenterally, orally, topically, rectally or by inhalation as a spray.
11 . The method according to claim 8 , wherein the compound comprises a dosage ranging from 0.01 to 500 mg/kg/day.
12 . The method according to claim 8 , wherein the compound comprises a dosage ranging from 0.01 to 200 mg/kg/day.
13 . The method according to claim 8 , wherein the compound comprises a dosage ranging from 0.1 to 100 mg/kg/day.
14 . The method according to claim 8 , wherein the compound comprises a dosage ranging from 5 to 500 mg/kg/day.
15 . A method for treating retinopathy in a subject having retinopathy comprising administering to the subject a therapeutically effective amount of [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine or a pharmaceutically acceptable salt thereof, and wherein a therapeutically effective amount comprises sufficient [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine or a pharmaceutically acceptable salt thereof to at least partially inhibit the binding of a ligand to RAGE.
16 . The method according to claim 15 , wherein the [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine or a pharmaceutically acceptable salt thereof is mixed with a pharmaceutically acceptable carrier.
17 . The method according to claim 15 , wherein the [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine or a pharmaceutically acceptable salt thereof is administered parenterally, orally, topically, rectally or by inhalation as a spray.
18 . The method according to claim 15 , wherein the [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine or a pharmaceutically acceptable salt thereof comprises a dosage ranging from 0.01 to 500 mg/kg/day.
19 . The method according to claim 15 , wherein the [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine or a pharmaceutically acceptable salt thereof comprises a dosage ranging from 0.01 to 200 mg/kg/day.
20 . The method according to claim 15 , wherein the [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine or a pharmaceutically acceptable salt thereof comprises a dosage ranging from 0.01 to 100 mg/kg/day.
21 . The method according to claim 15 , wherein the [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine or a pharmaceutically acceptable salt thereof comprises a dosage ranging from 5 to 500 mg/kg/day.
22 . The method according to claim 8 , wherein the retinopathy is diabetic retinopathy.
23 . The method according to claim 15 , wherein the retinopathy is diabetic retinopathy.