US2008119534A1PendingUtilityA1
Benzimidazole Derivatives as Therapeutic Agents
Est. expiryMar 5, 2021(expired)· nominal 20-yr term from priority
A61P 3/10A61P 9/00A61P 35/04A61P 9/10A61P 43/00A61P 7/00A61P 35/00A61P 25/00A61P 25/28A61P 27/00A61P 31/00A61P 29/00A61P 27/02A61K 31/4188A61P 13/12C07D 235/16C07D 235/14A61P 15/10
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Claims
Abstract
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.
Claims
exact text as granted — not AI-modified1 . A method for the inhibition of the interaction of RAGE with its physiological ligands, which comprises administering to a subject in need thereof a pharmaceutical composition comprising the compound of Formula (II)
wherein
m is an integer of from 0 to 3;
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;
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-N—R 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 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, wherein o and p are, independently, 1, 2, 3, or 4; X is a direct bond, —CH 2 —, —O—, —S—, —SO 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 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 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 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—, —SO 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,
and a pharmaceutically acceptable carrier, excipient, diluent, or mixture thereof.
2 . The method of claim 1 , wherein the ligand(s) is (are) selected from advanced glycated end products (AGEs), S100/calgranulin/EN-RAGE, β-amyloid and amphoterin.
3 . A method for treating a disease state selected from the group consisting of acute and chronic inflammation, symptoms of diabetes, vascular permeability, nephropathy, atherosclerosis, retinopathy, Alzheimer's disease, erectile dysfunction, and tumor invasion and/or metastasis, which comprises administering to a subject in need thereof a pharmaceutical composition comprising the compound of Formula (II)
wherein
m is an integer of from 0 to 3;
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;
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-N—R 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 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, wherein o and p are, independently, 1, 2, 3, or 4; X is a direct bond, —CH 2 —, —O—, —S—, —SO 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 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 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 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—, —SO 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,
and a pharmaceutically acceptable carrier, excipient, diluent, or mixture thereof, wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound of Formula (II).
4 . A method of prevention and/or treatment of a RAGE mediated human disease comprising administering to a human in need thereof a pharmaceutical composition comprising the compound of Formula (II)
wherein
m is an integer of from 0 to 3;
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;
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-N—R 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 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, wherein o and p are, independently, 1, 2, 3, or 4; X is a direct bond, —CH 2 —, —O—, —S—, —SO 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 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 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 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—, —SO 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,
and a pharmaceutically acceptable carrier, excipient, diluent, or mixture thereof, wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound of Formula (II), and wherein a therapeutically effective amount comprises sufficient compound to at least partially inhibit the binding of a ligand to the RAGE receptor.
5 . The method of claim 4 , further comprising administering to a subject in need thereof at least one adjuvant and/or additional therapeutic agent(s).
6 . The method of claim 5 , wherein said therapeutic agents are 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.
7 . The method of claim 4 , wherein the RAGE mediated human disease is acute and/or chronic inflammation.
8 . The method of claim 4 , wherein the RAGE mediated human disease is abnormal vascular permeability.
9 . The method of claim 4 , wherein the RAGE mediated human disease is nephropathy.
10 . The method of claim 4 , wherein the RAGE mediated human disease is atherosclerosis.
11 . The method of claim 4 , wherein the RAGE mediated human disease is retinopathy.
12 . The method of claim 4 , wherein the RAGE mediated human disease is Alzheimer's disease.
13 . The method of claim 4 , wherein the RAGE mediated human disease is erectile dysfunction.
14 . The method of claim 4 , wherein the RAGE mediated human disease is tumor invasion and/or metastasis.Join the waitlist — get patent alerts
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