U.S. patent application number 11/331256 was filed with the patent office on 2006-08-24 for method for the synthesis of compounds of formula i and their uses thereof.
This patent application is currently assigned to TransTech Pharma. Invention is credited to Kwasi S. Avor, Ramesh Gopalaswamy, Adnan M.M. Mjalli, Andrew Patron, Christopher L. Wysong.
Application Number | 20060189578 11/331256 |
Document ID | / |
Family ID | 26902168 |
Filed Date | 2006-08-24 |
United States Patent
Application |
20060189578 |
Kind Code |
A1 |
Mjalli; Adnan M.M. ; et
al. |
August 24, 2006 |
Method for the synthesis of compounds of formula I and their uses
thereof
Abstract
This invention provides certain compounds, methods of their
preparation, pharmaceutical compositions comprising the compounds,
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, .beta.-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.
Inventors: |
Mjalli; Adnan M.M.; (Oak
Ridge, NC) ; Gopalaswamy; Ramesh; (High Point,
NC) ; Avor; Kwasi S.; (High Point, NC) ;
Wysong; Christopher L.; (Ashland, KY) ; Patron;
Andrew; (Encinitas, CA) |
Correspondence
Address: |
KILPATRICK STOCKTON LLP - 41305;CHARLES CALKINS
1001 WEST FOURTH STREET
WINSTON-SALEM
NC
27101
US
|
Assignee: |
TransTech Pharma
High Point
NC
|
Family ID: |
26902168 |
Appl. No.: |
11/331256 |
Filed: |
January 12, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10611741 |
Jul 1, 2003 |
7067554 |
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11331256 |
Jan 12, 2006 |
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09799317 |
Mar 5, 2001 |
6613801 |
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10611741 |
Jul 1, 2003 |
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60207343 |
May 30, 2000 |
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Current U.S.
Class: |
514/63 ; 514/480;
514/575; 514/616 |
Current CPC
Class: |
C07C 311/19 20130101;
C07D 307/42 20130101; A61K 31/16 20130101; C07C 279/14 20130101;
C07C 275/24 20130101; A61P 43/00 20180101; A61P 25/28 20180101;
A61P 15/10 20180101; A61P 9/10 20180101; C07C 311/06 20130101; A61P
3/10 20180101; A61P 35/00 20180101; C07C 237/22 20130101; C07C
271/22 20130101; C07C 237/20 20130101; A61P 13/12 20180101; Y10S
977/915 20130101; A61P 35/04 20180101; A61P 29/00 20180101; A61P
27/02 20180101 |
Class at
Publication: |
514/063 ;
514/616; 514/575; 514/480 |
International
Class: |
A61K 31/695 20060101
A61K031/695; A61K 31/16 20060101 A61K031/16; A61K 31/325 20060101
A61K031/325; A61K 31/19 20060101 A61K031/19 |
Claims
1. A method for the inhibition of the interaction of RAGE with its
physiological ligands, which comprises administering to a subject
in need thereof, at least one compound comprising at least one
moiety of the formula ##STR42## wherein L.sub.1 is a
C.sub.1-C.sub.4 alkyl group and L.sub.2 is a direct bond, and
Aryl.sub.1 and Aryl.sub.2 are aryl, wherein each of Aryl.sub.1 and
Aryl.sub.2 are substituted by at least one lipophilic group
selected from the group consisting of a) --Y--C.sub.1-6 alkyl; b)
--Y-aryl; c) --Y--C-.sub.1-6 alkylaryl; d)
--Y--C.sub.1-6-alkyl-NR.sub.7R.sub.8; e)
--Y--C.sub.1-6-alkyl-W--R.sub.20; wherein Y and W are,
independently selected from the group consisting of --CH.sub.2--,
--O--, --N(H), --S--, SO.sub.2--, --CON(H)--, --NHC(O)--,
--NHCON(H)--, --NHSO.sub.2--, --SO.sub.2N(H)--, --C(O)--O--,
--NHSO.sub.2NH--, --O--CO--, ##STR43## and f) halogen, hydroxyl,
cyano, carbamoyl, and carboxyl; wherein R.sub.18 and R.sub.19 are
independently selected from the group consisting of aryl,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkylaryl, C.sub.1-C.sub.6
alkoxy, and C.sub.1-C.sub.6 alkoxyaryl; R.sub.20 is selected from
the group consisting of aryl, C.sub.1-C.sub.6 alkyl, and
C.sub.1-C.sub.6 alkylaryl; R.sub.7, R.sub.8, R.sub.9 and R.sub.10
are independently selected from the group consisting of hydrogen,
aryl, C.sub.1-C.sub.6 alkyl, and C.sub.1-C.sub.6 alkylaryl; and
wherein R.sub.7 and R.sub.8 may be taken together to form a ring
having the formula --(CH.sub.2).sub.m-X-(CH.sub.2).sub.n-- bonded
to the nitrogen atom to which R.sub.7 and R.sub.8 are attached,
wherein m and n are, independently, 1, 2, 3, or 4; X is selected
from the group consisting of --CH.sub.2--, --O--, --S--,
--S(O.sub.2)--, --C(O)--, --CON(H)--, --NHC(O)--, --NHCON(H)--,
--NHSO.sub.2--, --SO.sub.2N(H)--, --C(O)--O--, --O--C(O)--,
--NHSO.sub.2NH--, ##STR44## or a pharmaceutically acceptable salt
thereof, wherein at least one of Aryl.sub.1 and Aryl.sub.2 is
substituted with a lipophilic group of the formula
--Y--C.sub.1-6-alkyl-NR.sub.7R.sub.8.
2. The method of claim 1, wherein the ligand(s) is(are) selected
from advanced glycated end products (AGEs),
S100/calgranulin/EN-RAGE, .beta.-amyloid and amphoterin.
3. The method of claim 1, wherein at least on of Aryl.sub.1 or
Aryl.sub.2 is further substituted with a lipophilic group selected
from the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.6 alkylaryl, and C.sub.1-C.sub.6
alkoxyaryl.
4. A method for treating acute and/or chronic inflammation, which
comprises administering to a subject in need thereof a
therapeutically effective amount of at least one compound
comprising at least one moiety of the formula ##STR45## wherein
L.sub.1 is a C.sub.1-C.sub.4 alkyl group and L.sub.2 is a direct
bond, and Aryl.sub.1 and Aryl.sub.2 are aryl, wherein each of
Aryl.sub.1 and Aryl.sub.2 are substituted by at least one
lipophilic group selected from the group consisting of a)
--Y--C.sub.1-6 alkyl; b) --Y-aryl; c) --Y--C-.sub.1-6 alkylaryl; d)
--Y--C.sub.1-6-alkyl-NR.sub.7R.sub.8; e)
--Y--C.sub.1-6-alkyl-W--R.sub.20; wherein Y and W are,
independently selected from the group consisting of --CH.sub.2--,
--O--, --N(H), --S--, SO.sub.2--, --CON(H)--, --NHC(O)--,
--NHCON(H)--, --NHSO.sub.2--, --SO.sub.2N(H)--, --C(O)--O--,
--NHSO.sub.2NH--, --O--CO--, ##STR46## and f) halogen, hydroxyl,
cyano, carbamoyl, and carboxyl; wherein R.sub.18 and R.sub.19 are
independently selected from the group consisting of aryl,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkylaryl, C.sub.1-C.sub.6
alkoxy, and C.sub.1-C.sub.6 alkoxyaryl; R.sub.20 is selected from
the group consisting of aryl, C.sub.1-C.sub.6 alkyl, and
C.sub.1-C.sub.6 alkylaryl; R.sub.7, R.sub.8, R.sub.9 and R.sub.10
are independently selected from the group consisting of hydrogen,
aryl, C.sub.1-C.sub.6 alkyl, and C.sub.1-C.sub.6 alkylaryl; and
wherein R.sub.7 and R.sub.8 may be taken together to form a ring
having the formula --(CH.sub.2).sub.m-X-(CH.sub.2).sub.n-- bonded
to the nitrogen atom to which R.sub.7 and R.sub.8 are attached,
wherein m and n are, independently, 1, 2, 3, or 4; X is selected
from the group consisting of --CH.sub.2--, --O--, --S--,
--S(O.sub.2)--, --C(O)--, --CON(H)--, --NHC(O)--, --NHCON(H)--,
--NHSO.sub.2--, --SO.sub.2N(H)--, --C(O)--O--, --O--C(O)--,
--NHSO.sub.2NH--, ##STR47## or a pharmaceutically acceptable salt
thereof, wherein at least one of Aryl.sub.1 and Aryl.sub.2 is
substituted with a lipophilic group of the formula
--Y--C.sub.1-6-alkyl-NR.sub.7R.sub.8.
5. A method for treating vascular permeability, which comprises
administering to a subject in need thereof a therapeutically
effective amount of at least one compound comprising at least one
moiety of the formula ##STR48## wherein L.sub.1 is a
C.sub.1-C.sub.4 alkyl group and L.sub.2 is a direct bond, and
Aryl.sub.1 and Aryl.sub.2 are aryl, wherein each of Aryl.sub.1 and
Aryl.sub.2 are substituted by at least one lipophilic group
selected from the group consisting of a) --Y--C.sub.1-6 alkyl; b)
--Y-aryl; c) --Y--C-.sub.1-6 alkylaryl; d)
--Y--C.sub.1-6-alkyl-NR.sub.7R.sub.8; e)
--Y--C.sub.1-6-alkyl-W--R.sub.20; wherein Y and W are,
independently selected from the group consisting of --CH.sub.2--,
--O--, --N(H), --S--, SO.sub.2--, --CON(H)--, --NHC(O)--,
--NHCON(H)--, --NHSO.sub.2--, --SO.sub.2N(H)--, --C(O)--O--,
--NHSO.sub.2NH--, --O--CO--, ##STR49## and f) halogen, hydroxyl,
cyano, carbamoyl, and carboxyl; wherein R.sub.18 and R.sub.19 are
independently selected from the group consisting of aryl,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkylaryl, C.sub.1-C.sub.6
alkoxy, and C.sub.1-C.sub.6 alkoxyaryl; R.sub.20 is selected from
the group consisting of aryl, C.sub.1-C.sub.6 alkyl, and
C.sub.1-C.sub.6 alkylaryl; R.sub.7, R.sub.8, R.sub.9 and R.sub.10
are independently selected from the group consisting of hydrogen,
aryl, C.sub.1-C.sub.6 alkyl, and C.sub.1-C.sub.6 alkylaryl; and
wherein R.sub.7 and R.sub.8 may be taken together to form a ring
having the formula --(CH.sub.2).sub.m-X-(CH.sub.2).sub.n-- bonded
to the nitrogen atom to which R.sub.7 and R.sub.8 are attached,
wherein m and n are, independently, 1, 2, 3, or 4; X is selected
from the group consisting of --CH.sub.2--, --O--, --S--,
--S(O.sub.2)--, --C(O)--, --CON(H)--, --NHC(O)--, --NHCON(H)--,
--NHSO.sub.2--, --SO.sub.2N(H)--, --C(O)--O--, --O--C(O)--,
--NHSO.sub.2NH--, ##STR50## or a pharmaceutically acceptable salt
thereof, wherein at least one of Aryl.sub.1 and Aryl.sub.2 is
substituted with a lipophilic group of the formula
--Y--C.sub.1-6-alkyl-NR.sub.7R.sub.8.
6. A method for treating nephropathy, which comprises administering
to a subject in need thereof a therapeutically effective amount of
a compound of at least one compound comprising at least one moiety
of the formula ##STR51## wherein L.sub.1 is a C.sub.1-C.sub.4 alkyl
group and L.sub.2 is a direct bond, and Aryl.sub.1 and Aryl.sub.2
are aryl, wherein each of Aryl.sub.1 and Aryl.sub.2 are substituted
by at least one lipophilic group selected from the group consisting
of a) --Y--C.sub.1-6 alkyl; b) --Y-aryl; c) --Y--C-.sub.1-6
alkylaryl; d) --Y--C.sub.1-6-alkyl-NR.sub.7R.sub.8; e)
--Y--C.sub.1-6-alkyl-W--R.sub.20; wherein Y and W are,
independently selected from the group consisting of --CH.sub.2--,
--O--, --N(H), --S--, SO.sub.2--, --CON(H)--, --NHC(O)--,
--NHCON(H)--, --NHSO.sub.2--, --SO.sub.2N(H)--, --C(O)--O--,
--NHSO.sub.2NH--, --O--CO--, ##STR52## and f) halogen, hydroxyl,
cyano, carbamoyl, and carboxyl; wherein R.sub.18 and R.sub.19 are
independently selected from the group consisting of aryl,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkylaryl, C.sub.1-C.sub.6
alkoxy, and C.sub.1-C.sub.6 alkoxyaryl; R.sub.20 is selected from
the group consisting of aryl, C.sub.1-C.sub.6 alkyl, and
C.sub.1-C.sub.6 alkylaryl; R.sub.7, R.sub.8, R.sub.9 and R.sub.10
are independently selected from the group consisting of hydrogen,
aryl, C.sub.1-C.sub.6 alkyl, and C.sub.1-C.sub.6 alkylaryl; and
wherein R.sub.7 and R.sub.8 may be taken together to form a ring
having the formula --(CH.sub.2).sub.m-X-(CH.sub.2).sub.n-- bonded
to the nitrogen atom to which R.sub.7 and R.sub.8 are attached,
wherein m and n are, independently, 1, 2, 3, or 4; X is selected
from the group consisting of --CH.sub.2--, --O--, --S--,
--S(O.sub.2)--, --C(O)--, --CON(H)--, --NHC(O)--, --NHCON(H)--,
--NHSO.sub.2--, --SO.sub.2N(H)--, --C(O)--O--, --O--C(O)--,
--NHSO.sub.2NH--, ##STR53## or a pharmaceutically acceptable salt
thereof, wherein at least one of Aryl.sub.1 and Aryl.sub.2 is
substituted with a lipophilic group of the formula
--Y--C.sub.1-6-alkyl-NR.sub.7R.sub.8.
7. A method for treating atherosclerosis, which comprises
administering to a subject in need thereof a therapeutically
effective amount of a compound of at least one compound comprising
at least one moiety of the formula ##STR54## wherein L.sub.1 is a
C.sub.1-C.sub.4 alkyl group and L.sub.2 is a direct bond, and
Aryl.sub.1 and Aryl.sub.2 are aryl, wherein each of Aryl.sub.1 and
Aryl.sub.2 are substituted by at least one lipophilic group
selected from the group consisting of a) --Y--C.sub.1-6 alkyl; b)
--Y-aryl; c) --Y--C-.sub.1-6 alkylaryl; d)
--Y--C.sub.1-6-alkyl-NR.sub.7R.sub.8; e)
--Y--C.sub.1-6-alkyl-W--R.sub.20; wherein Y and W are,
independently selected from the group consisting of --CH.sub.2--,
--O--, --N(H), --S--, SO.sub.2--, --CON(H)--, --NHC(O)--,
--NHCON(H)--, --NHSO.sub.2--, --SO.sub.2N(H)--, --C(O)--O--,
--NHSO.sub.2NH--, --O--CO--, ##STR55## and f) halogen, hydroxyl,
cyano, carbamoyl, and carboxyl; wherein R.sub.18 and R.sub.19 are
independently selected from the group consisting of aryl,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkylaryl, C.sub.1-C.sub.6
alkoxy, and C.sub.1-C.sub.6 alkoxyaryl; R.sub.20 is selected from
the group consisting of aryl, C.sub.1-C.sub.6 alkyl, and
C.sub.1-C.sub.6 alkylaryl; R.sub.7, R.sub.8, R.sub.9 and R.sub.10
are independently selected from the group consisting of hydrogen,
aryl, C.sub.1-C.sub.6 alkyl, and C.sub.1-C.sub.6 alkylaryl; and
wherein R.sub.7 and R.sub.8 may be taken together to form a ring
having the formula --(CH.sub.2).sub.m-X-(CH.sub.2).sub.n-- bonded
to the nitrogen atom to which R.sub.7 and R.sub.8 are attached,
wherein m and n are, independently, 1, 2, 3, or 4; X is selected
from the group consisting of --CH.sub.2--, --O--, --S--,
--S(O.sub.2)--, --C(O)--, --CON(H)--, --NHC(O)--, --NHCON(H)--,
--NHSO.sub.2--, --SO.sub.2N(H)--, --C(O)--O--, --O--C(O)--,
--NHSO.sub.2NH--, ##STR56## or a pharmaceutically acceptable salt
thereof, wherein at least one of Aryl.sub.1 and Aryl.sub.2 is
substituted with a lipophilic group of the formula
--Y--C.sub.1-6-alkyl-NR.sub.7R.sub.8.
8. A method for treating retinopathy, which comprises administering
to a subject in need thereof a therapeutically effective amount of
compound of at least one compound comprising at least one moiety of
the formula ##STR57## wherein L.sub.1 is a C.sub.1-C.sub.4 alkyl
group and L.sub.2 is a direct bond, and Aryl.sub.1 and Aryl.sub.2
are aryl, wherein each of Aryl.sub.1 and Aryl.sub.2 are substituted
by at least one lipophilic group selected from the group consisting
of a) --Y--C.sub.1-6 alkyl; b) --Y-aryl; c) --Y--C-.sub.1-6
alkylaryl; d) --Y--C.sub.1-6-alkyl-NR.sub.7R.sub.8; e)
--Y--C.sub.1-6-alkyl-W--R.sub.20; wherein Y and W are,
independently selected from the group consisting of --CH.sub.2--,
--O--, --N(H), --S--, SO.sub.2--, --CON(H)--, --NHC(O)--,
--NHCON(H)--, --NHSO.sub.2--, --SO.sub.2N(H)--, --C(O)--O--,
--NHSO.sub.2NH--, --O--CO--, ##STR58## and f) halogen, hydroxyl,
cyano, carbamoyl, and carboxyl; wherein R.sub.18 and R.sub.19 are
independently selected from the group consisting of aryl,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkylaryl, C.sub.1-C.sub.6
alkoxy, and C.sub.1-C.sub.6 alkoxyaryl; R.sub.20 is selected from
the group consisting of aryl, C.sub.1-C.sub.6 alkyl, and
C.sub.1-C.sub.6 alkylaryl; R.sub.7, R.sub.8, R.sub.9 and R.sub.10
are independently selected from the group consisting of hydrogen,
aryl, C.sub.1-C.sub.6 alkyl, and C.sub.1-C.sub.6 alkylaryl; and
wherein R.sub.7 and R.sub.8 may be taken together to form a ring
having the formula --(CH.sub.2).sub.m-X-(CH.sub.2).sub.n-- bonded
to the nitrogen atom to which R.sub.7 and R.sub.8 are attached,
wherein m and n are, independently, 1, 2, 3, or 4; X is selected
from the group consisting of --CH.sub.2--, --O--, --S--,
--S(O.sub.2)--, --C(O)--, --CON(H)--, --NHC(O)--, --NHCON(H)--,
--NHSO.sub.2--, --SO.sub.2N(H)--, --C(O)--O--, --O--C(O)--,
--NHSO.sub.2NH--, ##STR59## or a pharmaceutically acceptable salt
thereof, wherein at least one of Aryl.sub.1 and Aryl.sub.2 is
substituted with a lipophilic group of the formula
--Y--C.sub.1-6-alkyl-NR.sub.7R.sub.8.
9. A method for treating Alzheimer's disease, which comprises
administering to a subject in need thereof a therapeutically
effective amount of at least one compound comprising at least one
moiety of the formula ##STR60## wherein L.sub.1 is a
C.sub.1-C.sub.4 alkyl group and L.sub.2 is a direct bond, and
Aryl.sub.1 and Aryl.sub.2 are aryl, wherein each of Aryl.sub.1 and
Aryl.sub.2 are substituted by at least one lipophilic group
selected from the group consisting of a) --Y--C.sub.1-6 alkyl; b)
--Y-aryl; c) --Y--C-.sub.1-6 alkylaryl; d)
--Y--C.sub.1-6-alkyl-NR.sub.7R.sub.8; e)
--Y--C.sub.1-6-alkyl-W--R.sub.20; wherein Y and W are,
independently selected from the group consisting of --CH.sub.2--,
--O--, --N(H), --S--, SO.sub.2--, --CON(H)--, --NHC(O)--,
--NHCON(H)--, --NHSO.sub.2--, --SO.sub.2N(H)--, --C(O)--O--,
--NHSO.sub.2NH--, --O--CO--, ##STR61## and f) halogen, hydroxyl,
cyano, carbamoyl, and carboxyl; wherein R.sub.18 and R.sub.19 are
independently selected from the group consisting of aryl,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkylaryl, C.sub.1-C.sub.6
alkoxy, and C.sub.1-C.sub.6 alkoxyaryl; R.sub.20 is selected from
the group consisting of aryl, C.sub.1-C.sub.6 alkyl, and
C.sub.1-C.sub.6 alkylaryl; R.sub.7, R.sub.8, R.sub.9 and R.sub.10
are independently selected from the group consisting of hydrogen,
aryl, C.sub.1-C.sub.6 alkyl, and C.sub.1-C.sub.6 alkylaryl; and
wherein R.sub.7 and R.sub.8 may be taken together to form a ring
having the formula --(CH.sub.2).sub.m-X-(CH.sub.2).sub.n-- bonded
to the nitrogen atom to which R.sub.7 and R.sub.8 are attached,
wherein m and n are, independently, 1, 2, 3, or 4; X is selected
from the group consisting of --CH.sub.2--, --O--, --S--,
--S(O.sub.2)--, --C(O)--, --CON(H)--, --NHC(O)--, --NHCON(H)--,
--NHSO.sub.2--, --SO.sub.2N(H)--, --C(O)--O--, --O--C(O)--,
--NHSO.sub.2NH--, ##STR62## or a pharmaceutically acceptable salt
thereof, wherein at least one of Aryl.sub.1 and Aryl.sub.2 is
substituted with a lipophilic group of the formula
--Y--C.sub.1-6-alkyl-NR.sub.7R.sub.8.
10. A method for treating erectile dysfunction, which comprises
administering to a subject in need thereof a therapeutically
effective amount of a compound of at least one compound comprising
at least one moiety of the formula ##STR63## wherein L.sub.1 is a
C.sub.1-C.sub.4 alkyl group and L.sub.2 is a direct bond, and
Aryl.sub.1 and Aryl.sub.2 are aryl, wherein each of Aryl.sub.1 and
Aryl.sub.2 are substituted by at least one lipophilic group
selected from the group consisting of a) --Y--C.sub.1-6 alkyl; b)
--Y-aryl; c) --Y--C-.sub.1-6 alkylaryl; d)
--Y--C.sub.1-6-alkyl-NR.sub.7R.sub.8; e)
--Y--C.sub.1-6-alkyl-W--R.sub.20; wherein Y and W are,
independently selected from the group consisting of --CH.sub.2--,
--O--, --N(H), --S--, SO.sub.2--, --CON(H)--, --NHC(O)--,
--NHCON(H)--, --NHSO.sub.2--, --SO.sub.2N(H)--, --C(O)--O--,
--NHSO.sub.2NH--, --O--CO--, ##STR64## and f) halogen, hydroxyl,
cyano, carbamoyl, and carboxyl; wherein R.sub.18 and R.sub.19 are
independently selected from the group consisting of aryl,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkylaryl, C.sub.1-C.sub.6
alkoxy, and C.sub.1-C.sub.6 alkoxyaryl; R.sub.20 is selected from
the group consisting of aryl, C.sub.1-C.sub.6 alkyl, and
C.sub.1-C.sub.6 alkylaryl; R.sub.7, R.sub.8, R.sub.9 and R.sub.10
are independently selected from the group consisting of hydrogen,
aryl, C.sub.1-C.sub.6 alkyl, and C.sub.1-C.sub.6 alkylaryl; and
wherein R.sub.7 and R.sub.8 may be taken together to form a ring
having the formula --(CH.sub.2).sub.m-X-(CH.sub.2).sub.n-- bonded
to the nitrogen atom to which R.sub.7 and R.sub.8 are attached,
wherein m and n are, independently, 1, 2, 3, or 4; X is selected
from the group consisting of --CH.sub.2--, --O--, --S--,
--S(O.sub.2)--, --C(O)--, --CON(H)--, --NHC(O)--, --NHCON(H)--,
--NHSO.sub.2--, --SO.sub.2N(H)--, --C(O)--O--, --O--C(O)--,
--NHSO.sub.2NH--, ##STR65## or a pharmaceutically acceptable salt
thereof, wherein at least one of Aryl.sub.1 and Aryl.sub.2 is
substituted with a lipophilic group of the formula
--Y--C.sub.1-6-alkyl-NR.sub.7R.sub.8.
11. A method for treating tumor invasion and/or metastasis, which
comprises administering to a subject in need thereof a
therapeutically effective amount of at least one compound
comprising at least one moiety of the formula ##STR66## wherein
L.sub.1 is a C.sub.1-C.sub.4 alkyl group and L.sub.2 is a direct
bond, and Aryl.sub.1 and Aryl.sub.2 are aryl, wherein each of
Aryl.sub.1 and Aryl.sub.2 are substituted by at least one
lipophilic group selected from the group consisting of a)
--Y--C.sub.1-6 alkyl; b) --Y-aryl; c) --Y--C-.sub.1-6 alkylaryl; d)
--Y--C.sub.1-6-alkyl-NR.sub.7R.sub.8; e)
--Y--C.sub.1-6-alkyl-W--R.sub.20; wherein Y and W are,
independently selected from the group consisting of --CH.sub.2--,
--O--, --N(H), --S--, SO.sub.2--, --CON(H)--, --NHC(O)--,
--NHCON(H)--, --NHSO.sub.2--, --SO.sub.2N(H)--, --C(O)--O--,
--NHSO.sub.2NH--, --O--CO--, ##STR67## and f) halogen, hydroxyl,
cyano, carbamoyl, and carboxyl; wherein R.sub.18 and R.sub.19 are
independently selected from the group consisting of aryl,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkylaryl, C.sub.1-C.sub.6
alkoxy, and C.sub.1-C.sub.6 alkoxyaryl; R.sub.20 is selected from
the group consisting of aryl, C.sub.1-C.sub.6 alkyl, and
C.sub.1-C.sub.6 alkylaryl; R.sub.7, R.sub.8, R.sub.9 and R.sub.10
are independently selected from the group consisting of hydrogen,
aryl, C.sub.1-C.sub.6 alkyl, and C.sub.1-C.sub.6 alkylaryl; and
wherein R.sub.7 and R.sub.8 may be taken together to form a ring
having the formula --(CH.sub.2).sub.m-X-(CH.sub.2)n-- bonded to the
nitrogen atom to which R.sub.7 and R.sub.8 are attached, wherein m
and n are, independently, 1, 2, 3, or 4; X is selected from the
group consisting of --CH.sub.2--, --O--, --S--, --S(O.sub.2)--,
--C(O)--, --CON(H)--, --NHC(O)--, --NHCON(H)--, --NHSO.sub.2--,
--SO.sub.2N(H)--, --C(O)--O--, --O--C(O)--, --NHSO.sub.2NH--,
##STR68## or a pharmaceutically acceptable salt thereof, wherein at
least one of Aryl.sub.1 and Aryl.sub.2 is substituted with a
lipophilic group of the formula
--Y--C.sub.1-6-alkyl-NR.sub.7R.sub.8.
12. A method of treating RAGE mediated diseases, the method
comprising administering to a subject in need thereof, a
therapeutically effective amount of at least one compound
comprising at least one moiety of the formula ##STR69## wherein
L.sub.1 is a C.sub.1-C.sub.4 alkyl group and L.sub.2 is a direct
bond, and Aryl.sub.1 and Aryl.sub.2 are aryl, wherein each of
Aryl.sub.1 and Aryl.sub.2 are substituted by at least one
lipophilic group selected from the group consisting of a)
--Y--C.sub.1-6 alkyl; b) --Y-aryl; c) --Y--C.sub.1-6 alkylaryl; d)
--Y--C.sub.1-6-alkyl-NR.sub.7R.sub.8; e)
--Y--C.sub.1-6-alkyl-W--R.sub.20; wherein Y and W are,
independently selected from the group consisting of --CH.sub.2--,
--O--, --N(H), --S--, SO.sub.2--, --CON(H)--, --NHC(O)--,
--NHCON(H)--, --NHSO.sub.2--, --SO.sub.2N(H)--, --C(O)--O--,
--NHSO.sub.2NH--, --O--CO--, ##STR70## and f) halogen, hydroxyl,
cyano, carbamoyl, and carboxyl; wherein R.sub.18 and R.sub.19 are
independently selected from the group consisting of aryl,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkylaryl, C.sub.1-C.sub.6
alkoxy, and C.sub.1-C.sub.6 alkoxyaryl; R.sub.20 is selected from
the group consisting of aryl, C.sub.1-C.sub.6 alkyl, and
C.sub.1-C.sub.6 alkylaryl; R.sub.7, R.sub.8, R.sub.9 and R.sub.10
are independently selected from the group consisting of hydrogen,
aryl, C.sub.1-C.sub.6 alkyl, and C.sub.1-C.sub.6 alkylaryl; and
wherein R.sub.7 and R.sub.8 may be taken together to form a ring
having the formula --(CH.sub.2).sub.m-X-(CH.sub.2).sub.n-- bonded
to the nitrogen atom to which R.sub.7 and R.sub.8 are attached,
wherein m and n are, independently, 1, 2, 3, or 4; X is selected
from the group consisting of --CH.sub.2--, --O--, --S--,
--S(O.sub.2)--, --C(O)--, --CON(H)--, --NHC(O)--, --NHCON(H)--,
--NHSO.sub.2--, --SO.sub.2N(H)--, --C(O)--O--, --O--C(O)--,
--NHSO.sub.2NH--, ##STR71## or a pharmaceutically acceptable salt
thereof, wherein at least one of Aryl.sub.1 and Aryl.sub.2 is
substituted with a lipophilic group of the formula
--Y--C.sub.1-6-alkyl-NR.sub.7R.sub.8; in combination with 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.
Description
[0001] This application is a continuation application of U.S.
application Ser. No. 10/611,741, filed Jul. 1, 2003, which is a
divisional application of application Ser. No. 09/799,317, filed
Mar. 5, 2001, now U.S. Pat. No. 6,613,801, which claims the benefit
of U.S. Provisional Application No. 60/207,343, filed May 30,
2000.
FIELD OF THE INVENTION
[0002] This invention relates to compounds which are modulators of
the receptor for advanced glycated end products (RAGE) and
interaction with its ligands such as advanced glycated end products
(AGEs), S100/calgranulin/EN-RAGE, .beta.-amyloid and amphoterin,
for the management, treatment, control, or as an adjunct treatment
of diseases caused by RAGE.
BACKGROUND OF THE INVENTION
[0003] Incubation of proteins or lipids with aldose sugars results
in nonenzymatic glycation and oxidation of amino groups on proteins
to form Amadori adducts. Over time, the adducts undergo additional
rearrangements, dehydrations, and cross-linking with other proteins
to form complexes known as Advanced Glycosylation End Products
(AGEs). Factors which promote formation of AGEs included delayed
protein turnover (e.g. as in amyloidoses), accumulation of
macromolecules having high lysine content, and high blood glucose
levels (e.g. as in diabetes) (Hori et al., J. Biol. Chem. 270:
25752-761, (1995)). AGEs have implicated in a variety of disorders
including complications associated with diabetes and normal
aging.
[0004] AGEs display specific and saturable binding to cell surface
receptors on endothelial cells of the microvasculature, monocytes
and macrophages, smooth muscle cells, mesengial cells, and neurons.
The Receptor for Advanced Glycated Endproducts (RAGE) is a member
of the immunoglobulin super family of cell surface molecules. The
extracellular (N-terminal) domain of RAGE includes three
immunoglobulin-type regions, one V (variable) type domain followed
by two C-type (constant) domains (Neeper et al., J. Biol. Chem.
267:14998-15004 (1992). A single transmembrane spanning domain and
a short, highly charged cytosolic tail follow the extracellular
domain. The N-terminal, extracellular domain can be isolated by
proteolysis of RAGE to generate soluble RAGE (sRAGE) comprised of
the V and C domains.
[0005] RAGE is expressed in most tissues, and in particular, is
found in cortical neurons during embryogenesis (Hori et al., J.
Biol. Chem. 270:25752-761 (1995)). Increased levels of RAGE are
also found in aging tissues (Schleicher et al., J. Clin. Invest. 99
(3): 457-468 (1997)), and the diabetic retina, vasculature and
kidney (Schmidt et al., Nature Med. 1: 1002-1004 (1995)).
Activation of RAGE in different tissues and organs leads to a
number of pathophysiological consequences. RAGE has been implicated
in a variety of conditions including: acute and chronic
inflammation (Hofmann et al., Cell 97:889-901 (1999)), the
development of diabetic late complications such as increased
vascular permeability (Wautier et al., J. Clin. Invest. 97:238-243
(1995)), nephropathy (Teillet et al., J. Am. Soc. Nephrol.
11:1488-1497 (2000)), atherosclerosis (Vlassara et. al., The
Finnish Medical Society DUODECIM, Ann. Med. 28:419-426 (1996)), and
retinopathy (Hammes et al., Diabetologia 42:603-607 (1999)). RAGE
has also been implicated in Alzheimer's disease (Yan et al., Nature
382: 685-691, (1996)), erectile dysfunction, and in tumor invasion
and metastasis (Taguchi et al., Nature 405: 354-357, (2000)).
[0006] In addition to AGEs, other compounds can bind to, and
modulate RAGE. In normal development, RAGE interacts with
amphoterin, a polypeptide which mediates neurite outgrowth in
cultured embryonic neurons (Hori et al., 1995). RAGE has also been
shown to interact with EN-RAGE, a protein having substantial
similarity to calgranulin (Hofmann et al., Cell 97:889-901 (1999)).
RAGE has also been shown to interact with .beta.-amyloid (Yan et
al., Nature 389:589-595, (1997); Yan et al., Nature 382:685-691
(1996); Yan et al., Proc. Natl. Acad. Sci., 94:5296-5301
(1997)).
[0007] Binding of ligands such as AGEs, S100/calgranulin/EN-RAGE,
.beta.-amyloid, CML (N.sup..epsilon.-Carboxymethyl lysine), and
amphoterin to RAGE has been shown to modify expression of a variety
of genes. For example, in many cell types interaction between RAGE
and its ligands generates oxidative stress, which thereby results
in activation of the free radical sensitive transcription factor
NF-.kappa.B, and the activation of NF-.kappa.B regulated genes,
such as the cytokines IL-1.beta., TNF-.alpha., and the like. In
addition, several other regulatory pathways, such as those
involving p21 ras, MAP kinases, ERK1 and ERK2, have been shown to
be activated by binding of AGEs and other ligands to RAGE. In fact,
transcription of RAGE itself is regulated at least in part by
NF-.kappa.B. Thus, an ascending, and often detrimental, spiral is
fueled by a positive feedback loop initiated by ligand binding.
Antagonizing binding of physiological ligands to RAGE, therefore,
is our target for down-regulation of the pathophysiological changes
brought about by excessive concentrations of AGEs and other ligands
for RAGE.
[0008] Thus, there is a need for the development of compounds that
antagonize binding of physiological ligands to the RAGE
receptor.
SUMMARY OF THE INVENTION
[0009] This invention provides compounds which are useful as RAGE
modulators. In a preferred embodiment, the present invention
provides compounds of Formula (I) as depicted below, to methods of
their preparation, pharmaceutical compositions comprising the
compounds and to their use in treating human or animal disorders.
The compounds of the invention are useful as modulators of the
interaction of the receptor for advanced glycated end products
(RAGE) with its ligands such as advanced glycated end products
(AGEs), S100/calgranulin/EN-RAGE, .beta.-amyloid and amphoterin,
and thus are useful for the management, treatment, control, and/or
as an adjunct treatment of 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.
DETAILED DESCRIPTION OF THE INVENTION
[0010] In a first aspect, the present invention provides a compound
comprising at least one moiety of the formula ##STR1## [0011]
wherein L.sub.1 and L.sub.2 are each a hydrocarbon group of from 1
to 6 carbons or a direct bond, and Aryl.sub.1 and Aryl.sub.2 are
aryl, wherein each of Aryl.sub.1 and Aryl.sub.2 are substituted by
at least one lipophilic group. In a preferred embodiment, the
lipophilic group is selected from C.sub.1-6 alkyl, C.sub.1-6
alkoxy, C.sub.1-6 alkylaryl, or C.sub.1-6 alkoxyaryl. We have found
such compounds to be useful in the modulation, preferably in the
inhibition of the interaction of RAGE with its physiological
ligands, as will be discussed in more detail below.
[0012] In a second aspect, the present invention provides compounds
of Formula (I): ##STR2## [0013] wherein [0014] R.sub.1 and R.sub.2
are independently selected from
[0015] a) --H;
[0016] b) -C.sub.1-6 alkyl;
[0017] c) -aryl;
[0018] d) -C.sub.1-6 alkylaryl;
[0019] e) --C(O)--O--C.sub.1-6 alkyl;
[0020] f) --C(O)--O--C.sub.1-6 alkylaryl;
[0021] g) --C(O)--NH--C.sub.1-6 alkyl;
[0022] h) --C(O)--NH--C.sub.1-6 alkylaryl;
[0023] i) --SO.sub.2--C.sub.1-6 alkyl;
[0024] j) --SO.sub.2--C.sub.1-6 alkylaryl;
[0025] k) --SO.sub.2-aryl;
[0026] l) --SO.sub.2--NH--C.sub.1-6 alkyl;
[0027] m) --SO.sub.2--NH--C.sub.1-6 alkylaryl;
[0028] n) ##STR3##
[0029] o) --C(O)--C.sub.1-6 alkyl; and
[0030] p) --C(O)--C.sub.1-6 alkylaryl; [0031] R.sub.3 is selected
from
[0032] a) -C.sub.1-6 alkyl;
[0033] b) -aryl; and
[0034] c) -C.sub.1-6 alkylaryl; [0035] R.sub.4 is selected from
[0036] a) -C.sub.1-6 alkylaryl;
[0037] b) -C.sub.1-6 alkoxyaryl; and
[0038] c) -aryl; [0039] R.sub.5 and R.sub.6 are independently
selected from the group consisting of hydrogen, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkylaryl, and aryl; and wherein [0040] the
aryl and/or alkyl group(s) in R.sub.1, R.sub.2, R.sub.3, R.sub.4,
R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.18,
R.sub.19, and R.sub.20 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:
[0041] a) --H;
[0042] b) --Y--C.sub.1-6 alkyl;
[0043] --Y-aryl;
[0044] --Y--C-.sub.1-6 alkylaryl;
[0045] --Y--C.sub.1-6-alkyl-NR.sub.7R.sub.8; and
[0046] --Y--C.sub.1-6-alkyl-W--R.sub.20; [0047] wherein Y and W
are, independently selected from the group consisting of
--CH.sub.2--, --O--, --N(H), --S--, SO.sub.2--, --CON(H)--,
--NHC(O)--, --NHCON(H)--, --NHSO.sub.2--, --SO.sub.2N(H)--,
--C(O)--O--, --NHSO.sub.2NH--, --O--CO--, ##STR4##
[0048] c) halogen, hydroxyl, cyano, carbamoyl, or carboxyl; and
[0049] R.sub.18 and R.sub.19 are independently selected from the
group consisting of aryl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkylaryl, C.sub.1-C.sub.6 alkoxy, and C.sub.1-C.sub.6 alkoxyaryl;
[0050] R.sub.20 is selected from the group consisting of aryl,
C.sub.1-C.sub.6 alkyl, and C.sub.1-C.sub.6 alkylaryl; [0051]
R.sub.7, R.sub.8, R.sub.9 and R.sub.10 are independently selected
from the group consisting of hydrogen, aryl, C.sub.1-C.sub.6 alkyl,
and C.sub.1-C.sub.6 alkylaryl; and wherein [0052] R.sub.7 and
R.sub.8 may be taken together to form a ring having the formula
--(CH.sub.2).sub.m-X-(CH.sub.2).sub.n-- bonded to the nitrogen atom
to which R.sub.7 and R.sub.8 are attached, and/or R.sub.5 and
R.sub.6 may, independently, be taken together to form a ring having
the formula --(CH.sub.2).sub.m-X-(CH.sub.2).sub.n-- bonded to the
nitrogen atoms to which R.sub.5 and R.sub.6 are attached, wherein m
and n are, independently, 1, 2, 3, or 4; X is selected from the
group consisting of --CH.sub.2--, --O--, --S--, --S(O.sub.2)--,
--C(O)--, --CON(H)--, --NHC(O)--, --NHCON(H)--, --NHSO.sub.2--,
--SO.sub.2N(H)--, --C(O)--O--, --O--C(O)--, --NHSO.sub.2NH--,
##STR5## or a pharmaceutically acceptable salt, solvate or prodrug
thereof.
[0053] In the compounds of Formula (I), the various functional
groups represented should be understood to have a point of
attachment at the functional group having the hyphen. In other
words, in the case of -C.sub.1-6 alkylaryl, it should be understood
that the point of attachment is the alkyl group; an example would
be benzyl. In the case of a group such as --C(O)--NH--C.sub.1-6
alkylaryl, the point of attachment is the carbonyl carbon.
[0054] In a preferred embodiment of this aspect of the invention,
the compounds of Formula (I) include those wherein: [0055] R.sub.1
is hydrogen; [0056] R.sub.2 is selected from [0057] a) --H; [0058]
b) -C.sub.1-6 alkyl; [0059] c) -C.sub.1-6 alkylaryl; [0060] d)
--C(O)--O--C.sub.1-6 alkyl; [0061] e) --C(O)--NH--C.sub.1-6 alkyl;
[0062] f) --C(O)--NH--C.sub.1-6 alkylaryl; [0063] g)
--SO.sub.2--C.sub.1-6 alkyl; [0064] h) --SO.sub.2--C.sub.1-6
alkylaryl; [0065] i) --SO.sub.2--NH--C.sub.1-6 alkyl; and [0066] j)
##STR6## [0067] k) --C(O)--C.sub.1-6 alkyl; [0068] l)
--C(O)--C.sub.1-6 alkylaryl; [0069] R.sub.3 is selected from [0070]
a) -C.sub.1-4 alkylaryl; and [0071] R.sub.4 is selected from [0072]
a) -C.sub.1-6 alkylaryl; and [0073] b) -aryl; [0074] and wherein
the aryl group in R.sub.1, R.sub.2, R.sub.3 and R.sub.4 is
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: [0075] a) --H; [0076] b)
--Y--C.sub.1-6 alkyl; [0077] --Y-aryl; [0078] --Y--C-.sub.1-6
alkylaryl; [0079] --Y--C.sub.1-6-alkyl-NR.sub.7R.sub.8; and [0080]
--Y--C.sub.1-6--W--R.sub.20; [0081] wherein Y and W are,
independently selected from the group consisting of --CH.sub.2--,
--O--, --N(H), --S--, SO.sub.2--, --CON(H)--, --NHC(O)--,
--NHCON(H)--, --NHSO.sub.2--, --SO.sub.2N(H)--, --C(O)--O--,
--NHSO.sub.2NH--, --O--CO--, ##STR7## [0082] c) halogen, hydroxyl,
carbamoyl, and carboxyl; [0083] R.sub.18 and R.sub.19 are selected
from the group consisting of aryl, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkylaryl, C.sub.1-C.sub.6 alkoxy, and
C.sub.1-C.sub.6 alkoxyaryl; [0084] R.sub.20 is selected from the
group consisting of aryl, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6
alkylaryl, and wherein [0085] R.sub.7 and R.sub.8 are selected from
the group consisting of hydrogen, aryl, C.sub.1-C.sub.6 alkyl, or
C.sub.1-C.sub.6 alkylaryl; and wherein [0086] R.sub.7 and R.sub.8
may be taken together to form a ring having the formula
--(CH.sub.2).sub.m-X-(CH.sub.2).sub.n-- bonded to the nitrogen atom
to which R.sub.7 and R.sub.8 are attached, and/or R.sub.5 and
R.sub.6 may, independently, be taken together to form a ring having
the formula --(CH.sub.2).sub.m-X-(CH.sub.2).sub.n-- bonded to the
nitrogen atoms to which R.sub.5 and R.sub.6 are attached, wherein
m, n, and X are as defined above.
[0087] In a further preferred embodiment, the R.sub.3 groups above
include C.sub.1-3 alkylaryl, said aryl optionally substituted by
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: [0088] --Y--C.sub.1-6 alkyl;
[0089] --Y-aryl; [0090] --Y--C-.sub.1-6 alkylaryl; [0091]
--Y--C.sub.1-6-alkyl-NR.sub.7R.sub.8; and [0092]
--Y--C.sub.1-6-alkyl-W--R.sub.20; [0093] wherein Y and W are,
independently selected from the group consisting of --CH.sub.2--,
--O--, --N(H), --S--, SO.sub.2--, --CON(H)--, --NHC(O)--,
--NHCON(H)--, --NHSO.sub.2--, --SO.sub.2N(H)--, --C(O)--O--,
--NHSO2NH--, --O--CO--, ##STR8##
[0094] A further preferred embodiment is the embodiment referred to
above, wherein wherein aryl is phenyl or napthyl, optionally
substituted by C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6
alkylaryl, or C.sub.1-6 alkoxyaryl.
[0095] Also included within the scope of the invention are the
individual enantiomers of the compounds represented by Formula (I)
above as well as any wholly or partially racemic mixtures thereof.
The present invention also covers the individual enantiomers of the
compounds represented by formula above as mixtures with
diastereoisomers thereof in which one or more stereocenters are
inverted.
[0096] Compounds of the present invention which are preferred for
their high biological activity are listed by name below in Table 1.
TABLE-US-00001 TABLE 1 Ex- am- ple Chemical Name 1
(R)-3-(2-Naphthyl)-2-aminopropionic Acid 4-
Diethylaminoethoxycarbonyl-2-butoxyaniline Amide Dihydrochloride 2
(R)-3-(2-Naphthyl)-2-aminopropionic Acid 4-Methoxycarbonyl-2-
butoxyaniline Amide Hydrochloride 3
(R)-3-(4-Benzyloxyphenyl)-2-tert-butoxycarbonylaminopropionic Acid
4-Diethylaminoethoxycarbonyl-2-butoxyaniline Amide 4
(R)-3-(4-Benzyloxyphenyl)-2-aminopropionic Acid 4-
Diethylaminoethoxycarbonyl-2-butoxyaniline Amide Dihydrochloride 5
(R)-3-(2-Naphthyl)-2-methylaminopropionic Acid 4-
Diethylaminoethoxycarbonyl-2-butoxyaniline Amide Dihydrochloride 6
(R)-3-(4-Benzyloxyphenyl)-2-tert-butoxycarbonylaminopropionic Acid
4-Methoxycarbonyl-2-hydroxyaniline Amide 7
(R)-3-(4-Benzyloxyphenyl)-2-tert-butoxycarbonylaminopropionic Acid
4-tert-Butoxycarbonyl-2-tert-butoxyaniline Amide 8
(R)-3-(4-Benzyloxyphenyl)-2-tert-butoxycarbonylaminopropionic Acid
4-Diethylaminoethoxycarbonyl-2-isobutoxyaniline Amide 9
(R)-3-(4-Benzyloxyphenyl)-2-aminopropionic Acid 4-
Diethylaminoethoxycarbonyl-2-isobutoxyaniline Amide Dihydrochloride
10 (R)-3-Phenyl-2-tert-butoxycarbonylaminopropionic Acid 4-
Diethylaminoethoxycarbonyl-2-butoxyaniline Amide 11
(R)-3-Phenyl-2-aminopropionic Acid 4-
Diethylaminoethoxycarbonyl-2-butoxyaniline Amide Dihydrochloride 12
(R)-3-(2-Naphthyl)-2-guanidinylpropionic Acid 4-
Diethylaminoethoxycarbonyl-2-butoxyaniline Amide Dihydrochloride 13
(R)-3-(4-Benzyloxyphenyl)-2-isopropylaminopropionic Acid 4-
Diethylaminoethoxycarbonyl-2-butoxyaniline Amide 14
(R)-3-(4-Benzyloxyphenyl)-2-benzylaminopropionic Acid 4-
Diethylaminoethoxycarbonyl-2-butoxyaniline Amide 15
(R)-3-(4-Benzyloxyphenyl)-2-methanesulfonylaminopropionic Acid
4-Diethylaminoethoxycarbonyl-2-butoxyaniline Amide 16
(R)-3-(4-Benzyloxyphenyl)-2-phenylsulfonylaminopropionic Acid
4-Diethylaminoethoxycarbonyl-2-butoxyaniline Amide 17
(R)-3-(4-Benzyloxyphenyl)-2-ethylcarbamoylaminopropionic Acid
4-Diethylaminoethoxycarbonyl-2-butoxyaniline Amide 18
(R)-3-(4-Benzyloxyphenyl)-2-tert-butylcarbamoylaminopropionic Acid
4-Diethylaminoethoxycarbonyl-2-butoxyaniline Amide 19
(R)-3-(4-Benzyloxyphenyl)-2-tert-butoxycarbonylaminopropionic Acid
4-Diethylaminoethoxy-2-diethylaminoethoxyaniline Amide 20
(R)-3-(4-Benzyloxyphenyl)-2-aminopropionic Acid 4-
Diethylaminoethoxy-2-diethylaminoethoxyaniline Amide
Trihydrochloride 21
(R)-3-(4-Benzyloxyphenyl)-2-tert-butoxycarbonylaminopropionic Acid
4-(3-Diethylamino-1-propoxy)-2-(3-diethylamino-1- propoxy)aniline
Amide 22 (R)-3-(4-Benzyloxyphenyl)-2-aminopropionic Acid 4-(3-
Diethylamino-1-propoxy)-2-(3-diethylamino-1-propoxyaniline Amide
Trihydrochloride 23
(R)-3-(4-Benzyloxyphenyl)-2-tert-butoxycarbonylaminopropionic Acid
4-Diethylaminoethoxycarbonyl-2-(2-furylmethoxy)aniline Amide 24
(R)-3-(4-Benzyloxyphenyl)-2-aminopropionic Acid 4-
Diethylaminoethoxycarbonyl)-2-(2-furylmethoxy)aniline Amide
Dihydrochloride 25 (R)-3-(2-Naphthyl)-2-acetylaminopropionic Acid
4- Diethylaminoethoxycarbonyl-2-butoxyaniline Amide 26
(R)-3-(4-Benzyloxyphenyl)-2-acetylaminopropionic Acid 4-
Diethylaminoethoxycarbonyl-2-butoxyaniline Amide
[0097] Accordingly, in a further embodiment of the invention, there
is provided the above compounds, or the free amine, free acid,
solvate, prodrug, or pharmaceutically acceptable salt thereof.
[0098] As used herein, the term "alkyl" refers to a straight or
branched chain hydrocarbon having the number of specified carbon
atoms. Examples of "alkyl" as used herein include, but are not
limited to, methyl, n-butyl, n-pentyl, isobutyl, and isopropyl, and
the like.
[0099] As used herein, the term "alkylene" refers to a straight or
branched chain divalent hydrocarbon radical having from one to ten
carbon atoms, optionally substituted with substituents selected
from the group consisting of lower alkyl, lower alkoxy, lower
alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo,
hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,
carbamoyl optionally substituted by alkyl, aminosulfonyl optionally
substituted by alkyl, nitro, cyano, halogen, or lower
perfluoroalkyl, multiple degrees of substitution being allowed.
Examples of "alkylene" as used herein include, but are not limited
to, methylene, ethylene, and the like.
[0100] As used herein, the term "aryl" refers to a five- to
seven-membered aromatic ring, or to an optionally substituted
benzene ring system, optionally containing one or more nitrogen,
oxygen, or sulfur heteroatoms, where N-oxides and sulfur monoxides
and sulfur dioxides are permissible substitutions. Such a ring may
be fused to one or more five- to seven-membered aromatic rings
optionally containing one or more nitrogen, oxygen, or sulfur
heteroatoms. Preferred aryl groups include phenyl, biphenyl,
2-naphthyl, 1-naphthyl, phenanthryl, 1-anthracenyl, pyridyl, furyl,
furanyl, thiophenyl, indolyl, isothiazolyl, imidazolyl,
benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl,
isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, benzindoyl,
pyrazolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl,
oxazolyl, benzothiazolyl, benzoxazolyl, and the like. In this
regard, especially preferred aryl groups include phenyl,
2-naphthyl, 1-naphthyl, biphenyl, and like ring systems optionally
substituted by tert-butyloxy, benzyloxy, n-butyloxy, ispropyloxy,
and phenoxy.
[0101] As used herein, the term "optionally" means that the
subsequently described event(s) may or may not occur, and includes
both event(s) which occur and events that do not occur.
[0102] As used herein, the term "substituted" refers to
substitution with the named substituent or substituents, multiple
degrees of substitution being allowed unless otherwise stated.
[0103] As used herein, the chemical structure terms "contain" or
"containing" refer to in-line substitutions at any position along
the above defined substituent at one or more of any of O, S, SO,
SO.sub.2, N, or N-alkyl, including, for example,
--CH.sub.2--O--CH.sub.2--, --CH.sub.2--SO.sub.2--CH.sub.2--,
--CH.sub.2--NH--CH.sub.3 and so forth.
[0104] As used herein, the term "solvate" is a complex of variable
stoichiometry formed by a solute (in this invention, a compound of
Formula (I)) and a solvent. Such solvents for the purpose of the
invention may not interfere with the biological activity of the
solute. Solvents may be, by way of example, water, ethanol, or
acetic acid.
[0105] As used herein, the term "biohydrolyzable ester" is an ester
of a drug substance (in this invention, a compound of formula (I) )
which either a) does not interfere with the biological activity of
the parent substance but confers on that substance advantageous
properties in vivo such as duration of action, onset of action, and
the like, or b) is biologically inactive but is readily converted
in vivo by the subject to the biologically active principle. The
advantage is that, for example, the biohydrolyzable ester is orally
absorbed from the gut and is transformed to (I) in plasma. Many
examples of such are known in the art and include by way of example
lower alkyl esters (e.g., C.sub.1-C.sub.4), lower acyloxyalkyl
esters, lower alkoxyacyloxyalkyl esters, alkoxyacyloxy esters,
alkyl acylamino alkyl esters, and choline esters.
[0106] As used herein, the term "biohydrolyzable amide" is an amide
of a drug substance (in this invention, a compound of general
formula (I)) which either a) does not interfere with the biological
activity of the parent substance but confers on that substance
advantageous properties in vivo such as duration of action, onset
of action, and the like, or b) is biologically inactive but is
readily converted in vivo by the subject to the biologically active
principle. The advantage is that, for example, the biohydrolyzable
amide is orally absorbed from the gut and is transformed to (I) in
plasma. Many examples of such are known in the art and include by
way of example lower alkyl amides, .alpha.-amino acid amides,
alkoxyacyl amides, and alkylaminoalkylcarbonyl amides.
[0107] As used herein, the term "prodrug" includes biohydrolyzable
amides and biohydrolyzable esters and also encompasses a) compounds
in which the biohydrolyzable functionality in such a prodrug is
encompassed in the compound of formula (I): for example, the lactam
formed by a carboxylic group in R.sub.2 and an amine in R.sub.4,
and b) compounds which may be oxidized or reduced biologically at a
given functional group to yield drug substances of formula (I).
Examples of these functional groups include, but are not limited
to, 1,4-dihydropyridine, N-alkylcarbonyl-1,4-dihydropyridine,
1,4-cyclohexadiene, tert-butyl, and the like. The term
"pharmacologically effective amount" shall mean that amount of a
drug or pharmaceutical agent that will elicit the biological or
medical response of a tissue, animal or human that is being sought
by a researcher or clinician. This amount can be a therapeutically
effective amount.
[0108] Whenever the terms "alkyl" or "aryl" or either of their
prefix roots appear in a name of a substituent (e.g.
arylalkoxyaryloxy) they shall be interpreted as including those
limitations given above for "alkyl" and "aryl". Alkyl substituents
shall be recognized as being functionally equivalent to those
having one or more degrees of unsaturation. Designated numbers of
carbon atoms (e.g. C.sub.1-6) shall refer independently to the
number of carbon atoms in an alkyl moiety or to the alkyl portion
of a larger substituent in which the term "alkyl" appears as its
prefix root. Similarly, the term "C.sub.2-C.sub.8 alkenyl" and
C.sub.2-C.sub.8 alkynyl" refer to groups having from 2 to 8 carbon
atoms and at least one carbon-carbon double bond or carbon-carbon
triple bond, respectively. The term "lower", for example in
relation to "lower alkyl" refers to a C.sub.1-6 alkyl group.
[0109] As used herein, the term "oxo" shall refer to the
substituent .dbd.O.
[0110] As used herein, the term "halogen" or "halo" shall include
iodine, bromine, chlorine and fluorine.
[0111] As used herein, the term "mercapto" shall refer to the
substituent --SH.
[0112] As used herein, the term "carboxy" shall refer to the
substituent --COOH.
[0113] As used herein, the term "cyano" shall refer to the
substituent --CN.
[0114] As used herein, the term "aminosulfonyl" shall refer to the
substituent --SO.sub.2NH.sub.2.
[0115] As used herein, the term "carbamoyl" shall refer to the
substituent --C(O)NH.sub.2.
[0116] The present invention also provides a method for the
synthesis of compounds useful as intermediates in the preparation
of compounds of Formula (I) along with methods for the preparation
of compounds of Formula (I).
[0117] A suitably protected alpha-amino acid (1), where PG is an
amine protecting group such as tert-butoxycarbonyl, is treated with
an amine in the presence of a coupling reagent such as but not
limited to diisopropyl carbodiimide (DIC) to form the amide (2).
The .alpha.-amino group in (2) is then deprotected, employing a
strong acid such as hydrogen chloride for the case where PG is
tert-butoxycarbonyl, to afford the free amine (3) either as the
free base or as a salt (Scheme 1). A suitably protected alpha-amino
acid (1), where PG is an amine protecting group such as
tert-butoxycarbonyl, is treated with an amine in the presence of a
coupling reagent such as but not limited to diisopropyl
carbodiimide (DIC) to form the amide (2). The .alpha.-amino group
in (2) is then deprotected, employing a strong acid such as
hydrogen chloride for the case where PG is tert-butoxycarbonyl, to
afford the free amine (3) either as the free base or as a salt
(Scheme 1). ##STR9##
[0118] To further derivatize the amino group of compound (3), the
free amino compound, or the suitable salt thereof may be treated
with an aldehyde or ketone R.sub.12C(O)R.sub.11 in the presence of
a reducing agent such as sodium cyanoborohydride or sodium
triacetoxyborohydride to afford compound (4), where R.sub.12 and
R.sub.11 are defined such that R.sub.2 in (4) conforms to the
specifications for Formula (I). Alternately, the amine compound (3)
may be treated with tertiary amine base such as DIEA and a molar
equvalent amount (or slight excess) of an alkylating agent of
general structure R.sub.2-Z, where Z is is a nucleofugal group such
as bromine, to form the secondary amine compound (4) (Scheme 2).
Amine (3) may be treated with a tertiary amine base such as DIEA
and 2 molar equivalents (or slight excess) of an alkylating agent
of general structure R.sub.2-Z, where Z is is a nucleofugal group
such as bromine, to form the amine compound (5). Alternately, the
amine compound (3) may be treated with an electron deficient
olefinic compound such as but not limited to ethyl acrylate, to
afford the adduct intermediate (6). Compound (6) may be
manipulated, employing methods known in the art such as hydride
reduction, in transforming such an adduct to compounds of general
structure (4). ##STR10##
[0119] To further derivatize the amino group of compound (3), the
free amino compound, or the suitable salt thereof may be treated
with a sulfonyl chloride such as benzenesulfonyl chloride to form
the sulfonamide (7) (Scheme 3), where R.sub.14 is C.sub.1-6 alkyl,
C.sub.1-6 alkylaryl, or aryl. Alternately, an amine
R.sub.15--NH.sub.2 may be treated with sulfuryl chloride and the
intermediate then treated with (2) to afford the sulfonylurea (7)
where R.sub.14 is --NH--C.sub.1-6 alkyl or --NH--C.sub.1-6
alkylaryl. ##STR11##
[0120] To further derivatize the amino group of compound (3), the
free amino compound, or the suitable salt thereof may be treated
with an isocyanate R.sub.15NCO in the presence or absence of a
tertiary amine base such as TEA to form the urea (8) (Scheme 4),
where R.sub.15 is -C.sub.1-6 alkyl or -C.sub.1-6 alkylaryl and Q is
NH. Alternately, compound (3) may be treated with R.sub.15O--C(O)Cl
and a tertiary amine base such as TEA to afford compound (8) where
R.sub.15 is -C.sub.1-6 alkyl or -C.sub.1-6 alkylaryl and Q is O.
##STR12##
[0121] Compound (9) may be treated with triphenyl phosphine, either
diisopropyl azodicarboxylate (DIAD) or diethyl azodicarboxylate
(DEAD) and an alcohol R.sub.16--OH to form the compound (10)
(Scheme 5), after removal of the protecting group PG. R.sub.16 is
-C.sub.1-6 alkyl, -C.sub.1-6 alkylaryl, -C.sub.1-6
alkyl-OSi(C.sub.1-6 alkyl).sub.3, -C.sub.1-6 alkyl-OSi(C.sub.1-6
alkylaryl).sub.3, or -C.sub.1-4 alkyl-NR.sub.8R.sub.9 (provided
that neither R.sub.8 nor R.sub.9 are hydrogen). PG may be, for
example, tert-butoxycarbonyl, benzyloxycarbonyl, and the like.
##STR13##
[0122] Compound (3) or a suitable salt thereof may be treated with
a acid anhydride (R.sub.17--CO).sub.2O and a base such as TEA in
the presence or absence of pyridine or DMAP to afford compound (11)
(Scheme 6). The substituent R.sub.17 may be chosen such that the
group R.sub.17--C(O)-- is as specified for R.sub.2 in Formula (I).
Alternately, compound (3) may be treated with the acid chloride
R.sub.17--COCl and an tertiary amine base such as TEA in the
presence or absence of pyridine or DMAP to afford compound (11).
Alternately, compound (3) may be treated with the carboxylic acid
R.sub.17--CO.sub.2H and a carbodiimide reagent (i.e., a "coupling
reagent") such as EDC, DIC, or DCC in the presence or absence of
HOBt to provide compound (11). ##STR14##
[0123] Compound (3) or a suitable salt thereof may be treated
(Scheme 7) with an activated amidine reagent such as
N,N'-bis-BOC-1-guanylpyrazole or
3,5-dimethylpyrazole-1-carboxamidine nitrate in the presence of a
tertiary organic base such as TEA to generate the guanidine
compound. Guanidine substituent protecting groups may be removed.
For example, where N,N'-bis-BOC-1-guanylpyrazole is employed, the
BOC groups of the adduct may be removed with a strong acid such as
hydrogen chloride to afford the free guanidine compound (12), where
R.sub.5 and R.sub.6 are as defined for Formula (I). ##STR15##
General Experimental
[0124] LC-MS data was obtained using gradient elution on a Waters
600 controller equipped with a 2487 dual wavelength detector and a
Leap Technologies HTS PAL Autosampler using an YMC Combiscreen
ODS-A 50.times.4.6 mm column. A three minute gradient was run from
25% B (97.5% acetonitrile, 2.5% water, 0.05% TFA) and 75% A (97.5%
water, 2.5% acetonitrile, 0.05% TFA) to 100% B. The MS was a
Micromass ZMD instrument. All data was obtained in the positive
mode unless otherwise noted. .sup.1H NMR data was obtained on a
Varian 300 MHz spectrometer.
[0125] Abbreviations used in the Examples are as follows: [0126]
APCI=atmospheric pressure chemical ionization [0127]
BOC=tert-butoxycarbonyl [0128]
BOP=(1-benzotriazolyloxy)tris(dimethylamino)phosphonium
hexafluorophosphate [0129] d=day [0130] DIAD=diisopropyl
azodicarboxylate [0131] DCC=dicyclohexylcarbodiimide [0132]
DCM=dichloromethane [0133] DIEA=diisopropylethylamine [0134]
DMF=N,N-dimethylformamide [0135] DMPU=1,3-dimethypropylene urea
[0136] DMSO=dimethylsulfoxide [0137]
EDC=1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride
[0138] EDTA=ethylenediamine tetraacetic acid [0139]
ELISA=enzyme-linked immunosorbent assay [0140] ESI=electrospray
ionization [0141] ether=diethyl ether [0142] EtOAc=ethyl acetate
[0143] FBS=fetal bovine serum [0144] g=gram [0145] h=hour [0146]
HBTU=O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium
hexafluorophosphate [0147] HMPA=hexamethylphosphoric triamide
[0148] HOBt=1-hydroxybenzotriazole [0149] Hz=hertz [0150]
i.v.=intravenous [0151] kD=kiloDalton [0152] L=liter [0153]
LAH=lithium aluminum hydride [0154] LDA=lithium diisopropylamide
[0155] LPS=lipopolysaccharide [0156] M=molar [0157] m/z=mass to
charge ratio [0158] mbar=millibar [0159] MeOH=methanol [0160]
mg=milligram [0161] min=minute [0162] mL=milliliter [0163]
mM=millimolar [0164] mmol=millimole [0165] mol=mole [0166]
mp=melting point [0167] MS=mass spectrometry [0168] N=normal [0169]
NMM=N-methylmorpholine, 4-methylmorpholine [0170] NMR=nuclear
magnetic resonance spectroscopy [0171] p.o.=per oral [0172]
PBS=phosphate buffered saline solution [0173] PMA=phorbol myristate
acetate [0174] ppm=parts per million [0175] psi=pounds per square
inch [0176] R.sub.f=relative TLC mobility [0177] rt=room
temperature [0178] s.c.=subcutaneous [0179] SPA=scintillation
proximity assay [0180] TEA=triethylamine [0181] TFA=trifluoroacetic
acid [0182] THF=tetrahydrofuran [0183] THP=tetrahydropyranyl [0184]
TLC=thin layer chromatography [0185] T.sub.r=retention time The
following compounds are synthesized according to the Schemes.
EXAMPLE 1
[0186] ##STR16##
[0187] To a solution of BOC-2-naphthyl-(D)-alanine (3.15 g) in
CH.sub.2Cl.sub.2 (40 mL), HOBt (1.35 g) and DCC (2.2 g) were added
at rt under nitrogen atmosphere. After 2 h NEt.sub.3 (2.79 mL) and
4-diethylaminoethoxycarbonyl-2-butoxyaniline hydrochloride (3.8 g)
were added followed by DMAP (122 mg). The reaction mixture is then
stirred at rt for 3 d and filtered to remove dicyclohexylurea. The
filtrate is concentrated and purified by silica gel column
chromatography to afford 4.8 g of the amide Intermediate 1A. 1H NMR
(CDCl3): 8.50 (d, 1H), 8.27 (br s, 1H), 7.55 -7.85 (m, 5H),
7.25-7.45 (m, 5H), 5.15 (br s, 1H), 4.60 (br s, 1H), 4.38 (t, 2H),
3.6-3.9 (m, 2H), 3.30 (d, 2H), 2.82 (t, 2H), 2.60 (q, 4H), 1.2-1.8
(m, 10H), 1.10 (t, 6H).
MS: m/z 606 (M+H).sup.+
[0188] 120 mg of Intermediate 1A obtained above is stirred in 4 M
HCl in dioxane (2 mL) for 3 h. Solvent is then removed in vacuo and
the residue obtained is treated with ether and stirred. The ether
is decanted off and the ether wash is repeated twice more. The
product is then dried under vacuum to afford a pale yellow solid
(90 mg), Example 1.
LC: T.sub.r 1.53; MS: 506 (M+H).sup.+
EXAMPLE 2
[0189] ##STR17##
[0190] Example 1 (115 mg) is dissolved in anhydrous methanol (5 mL)
and treated with 1M KOH in methanol (25 .mu.L). The reaction
mixture is stirred overnight at rt and added with 2 drops of acetic
acid and stirred. Solvent is then removed in vacuo and the residue
obtained is purified by silica gel column chromatography to yield
the methyl ester Intermediate 2A (65 mg).
NMR (acetone-d6): 9.10 (br s, 1H), 8.42 (d, 2H), 7.20-7.80 (m, 7H),
6.78 (br d, 1 h), 4.50 (br m, 1H), 4.0 (br m, 2H), 3.76 (s, 3H),
3.20 (dd, 1H), 2.9-3.2 (m, 4H), 1.22 (q, 2H), 1.20 (s, 9H), 0.90
(t, 3H).
MS: m/z 521 (M+H).sup.+
[0191] Intermediate 2A is dissolved in 4M HCl in dioxane (2 mL) and
stirred at rt for 3 h. Product is isolated as for Example 1 to
afford Example 2 as a fluffy white solid (50 mg).
MS: m/z 421 (M+H).sup.+
EXAMPLE 3
[0192] ##STR18##
[0193] To a solution of BOC-D-Tyr(Bzl)-OH (1.11 g) in
CH.sub.2Cl.sub.2 (15 mL), HOBT (406 mg) and DCC (681 mg) were added
at rt. After 2 h TEA (840 .mu.L) and
4-diethylaminoethoxycarbonyl-2-butoxyaniline hydrochloride (1.04 g)
were added followed by DMAP (36 mg). The reaction mixture is then
stirred at rt for 3 d and filtered to remove dicyclohexylurea. The
filtrate is concentrated and purified on a silica gel column
chromatography to afford 1.2 g of Example 3.
LC: T.sub.r 2.18; MS: m/z 662 (M+H).sup.+
EXAMPLE 4
[0194] ##STR19##
[0195] 165 mg of Example 3 is stirred in 4M HCl in dioxane (2 mL)
for 3 h. Product is isolated as for Example 1 to afford Example 4
as a pale yellow solid (105 mg).
LC: T.sub.r 1.75; MS: m/z 562(M+H).sup.+
EXAMPLE 5
[0196] ##STR20##
[0197] BOC-(2-naphthyl)-D-alanine (946 mg) is dissolved in
anhydrous THF at rt, added with methyl iodide (1.5 mL) and cooled
to 0.degree. C. Solid NaH (400 mg; 60% dispersion in oil) is slowly
added to it and the reaction is allowed to proceed overnight with
gradual warming up to rt. After 24 h the reaction mixture is
diluted with a mixture of EtOAc and cold water and stirred. The
contents were then shaken a separatory funnel and the layers were
separated. The aqueous layer is then extracted with EtOAc. The
organic extracts were combined, ished with water and brine and
dried over anhydrous sodium sulfate. Solvent is removed in vacuo
and the residue obtained is purified by silica gel solumn
chromatography to afford the acid Intermediate 5A (630 mg).
MS: m/z 230 (M+H).sup.+
[0198] To a solution of Intermediate 5A obtained as above (616 mg)
in CH.sub.2Cl.sub.2 (10 mL), HOBt (303 mg) and DCC (463 mg) were
added at rt under nitrogen atmosphere. After 2 h triethylamine (651
.mu.L) and 4-diethylaminoethoxycarbonyl-2-butoxyaniline
hydrochloride (645 mg) were added followed by DMAP (36 mg). The
reaction mixture is then stirred at rt for 4 d and filtered to
remove dicyclohexylurea. The filtrate is concentrated and purified
on a silica gel column chromatography to afford Intermediate 5B
(220 mg).
LC: T.sub.r 2.45 min; MS: m/z 620 (M+H).sup.+
[0199] Intermediate 5B is then dissolved in 4M HCl in dioxane (4
mL) for 3 h. Product is isolated as for Example 1 to afford Example
5 (160 mg).
MS: m/z 520 (M+H).sup.+
EXAMPLE 6
[0200] ##STR21##
[0201] BOC-D-Tyr(Bzl)-OH (4.46g, 12.0 mmol) is suspended in 50 mL
of DCM and to this is added DCC (2.72 g, 13.20 mmol) and HOBt (1.62
g, 12.01 mmol) and the mixture stirred under nitrogen for 2 h.
Triethylamine (3.3 mL) is added followed by 4-amino-3-hydroxy
benzoic acid methyl ester (2.67 g, 13.20 mmol). The mixture is
stirred for 4 d. The reaction mixture is filtered and the solid
residue washed with DCM. The filtrate is then washed with 5%
Na.sub.2CO.sub.3 solution (2.times.50 mL) followed by brine
solution. The organic extract is dried over Na.sub.2SO.sub.4,
filtered and concentrated and purified by flash chromatography on
silica gel eluted with EtOAc/hexanes (50:50) to obtain Example 6 as
a solid (5.0 g).
MS: m/z 521 (M+H).sup.+
EXAMPLE 7
[0202] ##STR22##
[0203] The compound of Example 6 is saponified to afford the
carboxylic acid by the general method employed in preparation of
Intermediate 2A, to afford Intermediate 7A.
[0204] Intermediate 7A (0.050 g, 0.099 mM) in 3 mL of DCM is added
2 drops each of BF.sub.3 Et.sub.2O and H.sub.3PO.sub.4. The
solution is then transferred to -78.degree. C. and isobutylene gas
bubbled through for 3 min and then allowed to warm to rt and
stirred for 12 h. The solution is extracted with saturated
NaHCO.sub.3 (2.times.10 mL), dried over Na.sub.2SO.sub.4 and
concentrated to an oil which is purified on silica gel eluted with
EtOAc/hexanes (30:70) to obtain Example 7 as a white solid (0.055
g).
MS: m/z 619 (M+H).sup.+
EXAMPLE 8
[0205] ##STR23##
[0206] To Example 6 (0.05 g, 0.096 mmol) in lmL of THF is added 6
uL of isobutyl alcohol and triphenylphosphine (0.025 g, 0.096 mmol)
followed by dropwise addition of diisopropyl azodicarboxylate
(0.019 g, 0.096 mmol) at 0.degree. C. The reaction is allowed to
warm to rt and stirred for 18 h. The solvent is removed under
reduced pressure and the oil obtained purified by flash
chromatography on silica gel eluting with EtOAc/hexane (30:70) to
yield Intermediate 8A as an oil (43.6 mg, 79%). Intermediate 8A is
hydrolyzed to with 1M KOH solution in dioxane at 80.degree. C. to
provide the acid Intermediate 8B (0.015 g).
[0207] Intermediate 8B (0.015 g, 0.026 mmol) is dissolved in 1 mL
of DCM and HBTU (0.020 g, 0.054 mmol) added. The mixture is stirred
for 1 h and 100 uL of TEA is added followed by
N,N-diethylethanolamine (0.021 g, 0.180 mmol). The resulting
solution is stirred for 18 h. After concentrating under reduced
pressure, the crude product is purified on silica gel eluted with
EtOAc/hexane (50/50) to provide Example 8 as a solid (0.014 g).
LC: T.sub.r 2.20 min; MS:m/z 662 (M+H).sup.+
EXAMPLE 9
[0208] ##STR24##
[0209] Example 8 (7 mg) is treated with 4N HCl/dioxane as described
or Intermediate 1A. The product (5 mg) is isolated as for Example 1
to afford Example 9.
MS: m/z 552 (M+H).sup.+
EXAMPLE 10
[0210] ##STR25##
[0211] To a solution of BOC-D-phenylalanine (1.33 g) in DCM (15
mL), HOBT (743 mg) and DCC (1.24 g) were added at rt. After 2 h TEA
(1.2 mL) and 4-diethylaminoethoxycarbonyl-2-butoxyaniline
hydrochloride (1.73 g) were added followed by DMAP (60 mg). The
reaction mixture is then stirred at rt for 3 d and filtered to
remove dicyclohexylurea. The filtrate is concentrated and purified
on a silica gel column chromatography to afford 1.9 g of Example
10.
LC: T.sub.r 2.05 min; MS: m/z 556 (M+H).sup.+
EXAMPLE 11
[0212] ##STR26##
[0213] Example 10 (47 mg) is stirred in 4M HCl in dioxane (2 mL)
for 3 h. Product is isolated as for Example 1 to afford Example 11
as a pale yellow solid (38 mg).
C: T.sub.r 0.83 min; MS: m/z 456 (M+H).sup.+
EXAMPLE 12
[0214] ##STR27##
[0215] Example 1 (80 mg) is dissolved in anhydrous acetonitrile (3
mL) and treated with DIEA (60 .mu.L) and
N,N'-bis-BOC-1-guanylpyrazole (60 mg). The resulting mixture is
then refluxed overnight. The reaction mixture is then cooled to rt
and diluted with EtOAc (5 mL). The mixture is washed with water and
brine and dried over anhydrous sodium sulfate. Solvent is removed
in vacuo and the residue obtained is purified by silica gel column
chromatography to afford the BOC-protected guanadino product
Intermediate 12A (12 mg).
NMR: (acetone-d6) 8.8 (br s, 1H), 8.20 (d, 1H), 7.2-7.8 (m, 9H),
4.95 (dd, 1H), 4.2 (br s, 2H), 3.65-3.85 (m, 4H), 3.0-3.3 (m, 4H),
1.25 (s, 9H), 1.20 (m, 4H), 1.15 (s, 9H), 0.95 (3, 3H)
MS: m/z 748 (M+H).sup.+
[0216] Intermediate 12A (12 mg) is treated with 4M HCI/dioxane (0.5
mL) to remove the BOC group as described for Intermediate 1A,
affording Example 12 (4 mg).
MS: m/z 549 (M+H).sup.+
EXAMPLE 13
[0217] ##STR28##
[0218] 53 mg (0.084 mmole) of Example 4 is dissolved in 5 mL
methanol. To this is added 10 .mu.L of acetone. After 40 min, 0.10
mL of 1 M sodium cyanoborohydride in THF is added. The reaction is
stirred overnight, the solvent removed in vacuo, and the crude
compound purified by flash chromatography on silica gel (4:1
hexane: EtOAc, 10% TEA) to yield 22 mg of Example 14.
LC: T.sub.r 1.77 min; MS: m/z 603 (M+H).sup.+
EXAMPLE 14
[0219] ##STR29##
[0220] 106 mg (0.168 mmol) of Example 4 is dissolved in 5 mL
methanol. To this is added 60 .mu.L of benzaldehyde, with stirring.
After 12 h, 0.50 mL of 1 M sodium cyanoborohydride in THF is added.
The reaction is stirred overnight, the solvent removed in vacuo,
and the crude compound purified by flash chromatography on silica
gel (4:1 hexane: EtOAc, 10% TEA) to yield 48.3 mg of Example
14.
LC: T.sub.r 1.83 min; MS: m/z 653 (M+H).sup.+
EXAMPLE 15
[0221] ##STR30##
[0222] 12 mg (0.019 mmole) of Example 4 is suspended in 3.5 mL dry
DCM. To this is added 10 .mu.L of methanesulfonyl chloride (0.13
mmole). The reaction is stirred overnight, then an additional 10
.mu.L of methanesulfonyl chloride is added and the reaction allowed
to stir for an additional 24 h. The solvent is removed in vacuo to
yield 12.2 mg of Example 15.
LC: T.sub.r 1.99 min; MS: m/z 640 (M+H).sup.+
EXAMPLE 16
[0223] ##STR31##
[0224] 15 mg (0.024 mmole) of Example 4 is suspended in 4.0 mL dry
DCM. To this is added 10 .mu.L (0.078 mmole) of benzenesulfonyl
chloride. The reaction is stirred overnight, then an additional 10
.mu.L of benzenesulfonyl chloride is added and the reaction allowed
to stir for an additional 24 h. The solvent is removed in vacuo to
yield 16.8 mg of Example 16.
LC: T.sub.r 2.05 min; MS: m/z 702 (M+H).sup.+
EXAMPLE 17
[0225] ##STR32##
[0226] 25 mg (0.040 mmole) of Example 4 is suspended in 5 mL dry
DCM. To this is added 50 .mu.L of ethyl isocyanate (0.63 mmole).
The reaction is stirred overnight, and the solvent is removed in
vacuo to yield 25.2 mg of Example 17.
LC: T.sup.r 1.99 min; MS: m/z 633 (M+H).sup.+
EXAMPLE 18
[0227] ##STR33##
[0228] 20 mg (0.032 mmole) of Example 4 is suspended in 5 mL dry
DCM. To this is added 50 .mu.L of tert-butyl isocyanate (0.44
mmole, 13.7 eq.). The reaction is stirred overnight, then an
additional 50 .mu.L of tert-butyl isocyanate is added and the
reaction allowed to stir for an additional 24 h. The solvent is
removed in vacuo to yield 21.1 mg of Example 18.
LC: T.sub.r 1.97min; MS: m/z 661 (M+H).sup.+
EXAMPLE 19
[0229] ##STR34##
[0230] To a solution of BOC-D-Tyr(Bzl)-OH (279 mg) and
4-aminoresorcinol hydrochloride (135 mg) in acetonitrile (2 mL) at
rt, HBTU (285 mg) and pyridine (145 .mu.L) were added in
succession. The resulting mixture is stirred overnight. The deep
reddish reaction mixture is diluted with EtOAc/water (5 mL/3 mL)
and the layers were separated. The aqueous layer is further
extracted with EtOAC (5 mL). The organic layers were combined and
washed with water and brine and dried over Na.sub.2SO.sub.4. The
solution is filtered and the solvent is removed in vacuo. The
resulting crude product is purified by silica gel column
chromatography using methanol/CHCl.sub.3/hexane (1:20:20) as eluent
to afford 300 mg of the amide Intermediate 19A.
LC:T.sub.r 2.17 min; MS:m/z 479 (M+H).sup.+
[0231] 120 mg of Intermediate 19A is dissolved in THF (2 mL) at rt
and added with triphenyl phosphine (197 mg), and
N,N-diethylaminoethanol (100 .mu.L). The resulting solution is
cooled to 0.degree. C. and treated with diisopropyl
azodicarboxylate (DIAD) (152 mg). The reaction is allowed to
proceed overnight with gradual warming up to rt. The reaction
mixture is diluted with EtOAc/water (5 mL/3 mL) and the layers were
separated. The aqueous layer is further extracted with EtOAc (5
mL). The organic layers were combined and washed with water and
brine and dried over Na.sub.2SO.sub.4. The solution is filtered and
the solvent is removed in vacuo. The resulting crude product is
purified by silica gel column chromatography using
NEt.sub.3/methanol/CHCl.sub.3/hexane (1:2:40:40) as eluent to
afford 100 mg of Example 19.
LC: T.sub.r 1.80 min; MS: m/z 677 (M+H).sup.+
EXAMPLE 20
[0232] ##STR35##
[0233] 50 mg of Example 19 is stirred in 4M HCl in dioxane (1 mL)
for 3 h. Product is isolated as for Example 1 to afford Example 21
as a pale yellow solid (35 mg).
MS: m/z 576 (M+H).sup.+
EXAMPLE 21
[0234] ##STR36##
[0235] 120 mg of Example 19 is dissolved in THF (2 mL) at rt and
added with triphenyl phosphine (197 mg), and
N,N-diethylaminopropanol (115 .mu.L). The resulting solution is
cooled to 0.degree. C. and added with diisopropyl azodicarboxylate
(DIAD) (152 mg). The reaction is allowed to proceed overnight with
gradual warming up to rt. The reaction mixture is diluted with
EtOAc/water (5 mL/3 mL) and the layers were separated. The aqueous
layer is further extracted with EtOAc (5 mL). The organic layers
were combined and washed with water and brine and dried over
Na.sub.2SO.sub.4. The solution is filtered and the solvent is
removed in vacuo. The resulting crude product is purified by silica
gel column chromatography using
triethylamine/methanol/CHCl.sub.3/hexane (1:2:40:40) as eluent to
afford 50 mg of Example 21.
LC: T.sub.r 1.84 min; MS: m/z 705 (M+H).sup.+
EXAMPLE 22
[0236] ##STR37##
[0237] 30 mg of Example 21 is stirred in 4M HCl in dioxane (1 mL)
for 3 h. Product is isolated as for Example 1 to afford Example 22
as a pale yellow solid (20 mg).
MS: m/z 604 (M+H).sup.+
EXAMPLE 23
[0238] ##STR38##
[0239] To example 6 (0.05g, 0.096 mmol ) in 1 mL of THF is added 6
uL of furfuryl alcohol and triphenylphosphine (0.025 g, 0.096 mmol)
followed by dropwise addition of diisopropyl azodicarboxylate
(0.019 g, 0.096 mmol) at 0.degree. C. The reaction is allowed to
warm to rt and stirred for 18 h. The solvent is removed under
reduced pressure and the oil obtained purified by flash
chromatography on silica gel eluting with EtOAc/hexane (30:70) to
yield the aryl ether Intermediate 23A as an oil (43.0 mg).
Intermediate 23A is hydrolyzed to the carboxylic acid using 1M KOH
solution in dioxane at 80.degree. C. The acid obtained (0.02 g,
0.036 mmmol) is dissolved in lmL of DCM and HBTU (0.015 g, 0.039
mmol) added. The mixture is stirred for 1 h and 36 uL of TEA is
added followed by N,N-diethylethanolamine (0.015 g, 0.130 mmol).
The resulting solution is stirred for 18 h. After concentrating
under reduced pressure, the crude product is purified on silica gel
eluting with EtOAc/hexane (1:1) to obtain Example 23 as a solid
(0.015 g).
MS: m/z 686 (M+H).sup.+
EXAMPLE 24
[0240] ##STR39##
[0241] Example 23 (7 mg) is treated with 4N HCl/dioxane as
described for Intermediate 1A, and the product is isolated as for
Example 1 to obtain Example 24 (4 mg).
LC: T.sub.r 1.87 min; MS: m/z 586 (M+H).sup.+
EXAMPLE 25
[0242] ##STR40##
[0243] 20 mg of Example 1 is dissolved in pyridine (100 .mu.L) and
treated with acetic anhydride (100 .mu.L) at rt and stirred for 1
h. The reaction mixture is added with ice/water mixture and
extracted with EtOAc. The organic layers were combined and washed
with 5% aqueous CuSO.sub.4, water and brine and dried over
Na.sub.2SO.sub.4. The solution is filtered and the solvent is
removed in vacuo to provide Example 25 as a pale white solid (15
mg).
LC: T.sub.r 1.90 min; MS:m/z 548 (M+H).sup.+
EXAMPLE 26
[0244] ##STR41##
[0245] 30 mg of Example 4 is dissolved in pyridine (200 .mu.L) and
treated with acetic anhydride (150 .mu.L) at rt and stirred for 1
h. The reaction mixture is treated with ice/water mixture and
extracted with EtOAC. The organic. layers were combined and washed
with 5% aqueous CuSO.sub.4, water and brine and dried over
Na.sub.2SO.sub.4. The solvent is removed in vacuo to provide
Example 26 as a pale white solid (25 mg).
LC: T.sub.r 1.97 min; MS: m/z 604 (M+H).sup.+
[0246] In the above schemes, "PG" represents an amino protecting
group. The term "amino protecting group" as used herein refers to
substituents of the amino group commonly employed to block or
protect the amino functionality while reacting other functional
groups on the compound. Examples of such amino-protecting groups
include the formyl group, the trityl group, the phthalimido group,
the trichloroacetyl group, the chloroacetyl, bromoacetyl and
iodoacetyl groups, urethane-type blocking groups such as
benzyloxycarbonyl, 4-phenylbenzyloxycarbonyl,
2-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,
4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl,
3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl,
2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,
3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,
4-cyanobenzyloxy-carbonyl, 2-(4-xenyl)iso-propoxycarbonyl,
1,1-diphenyleth- 1-yloxycarbonyl, 1,1-diphenylprop-1-yloxycarbonyl,
2-phenylprop-2-yloxycarbonyl, 2-(p-toluyl)prop-2-yloxycarbonyl,
cyclopentanyloxycarbonyl, 1-methylcyclopentanyloxycarbonyl,
cyclohexanyloxycarbonyl, 1-methylcyclohexanyloxycarbonyl,
2-methylcyclohexanyloxycarbonyl,
2-(4-toluylsulfonyl)ethoxycarbonyl,
2(methylsulfonyl)ethoxycarbonyl,
2-(triphenylphosphino)ethoxycarbonyl, 9-fluorenylmethoxycarbonyl
("FMOC"), t-butoxycarbonyl ("BOC"),
2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl,
1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl,
5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl,
2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl,
cyclopropylmethoxycarbonyl, 4-(decyloxy)benzyloxycarbonyl,
isobornyloxycarbonyl, 1-piperidyloxycarbonyl and the like; the
benzoylmethylsulfonyl group, the 2-(nitro)phenylsulfenyl group, the
diphenylphosphine oxide group and like amino-protecting groups. The
species of amino-protecting group employed is not critical so long
as the derivatized amino group is stable to the condition of
subsequent reaction(s) on other positions of the compound of
Formula (I) and can be removed at the desired point without
disrupting the remainder of the molecule. Preferred
amino-protecting groups are the allyloxycarbonyl, the
t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, and the trityl
groups. Similar amino-protecting groups used in the cephalosporin,
penicillin and peptide art are also embraced by the above terms.
Further examples of groups referred to by the above terms are
described by J. W. Barton, "Protective Groups In Organic
Chemistry", J. G. W. McOmie, Ed., Plenum Press, New York, N.Y.,
1973, Chapter 2, and T. W. Greene, "Protective Groups in Organic
Synthesis", John Wiley and Sons, New York, N.Y., 1981, Chapter 7.
The related term "protected amino" defines an amino group
substituted with an amino-protecting group discussed above.
[0247] In Scheme 1, other methods of coupling or acylating the
protected amino acid to the compound of formula R.sup.4NH.sub.2 can
be utilized, for example DCC/HBT, HBTU, and BOP and other methods,
including but not limited to those listed in: Fernando Albericio
and Louis A. Carpino "Coupling Reagents and Activation" in Methods
in Enzymology vol. 289 (Gregg B. Fields ed), pp 104-126, Academic
Press, San Diego, 1997.
I. Biological Assay
[0248] The following assay method is utilized to identify compounds
of Formula (I) which are effective in binding with RAGE, and hence
useful as modulators, preferably antagonists of RAGE. This method
is also described in U.S. Pat. No. 6,908,741.
GENERAL ASSAY PROCEDURE
[0249] S100b, .beta.-amyloid and CML (500 ng/100 .mu.L/well) in 100
mM sodium bicarbonate/sodium carbonate buffer (pH 9.8) is loaded
onto the wells of a NUNC Maxisorp flat bottom 96-well microtitre
plate. The plate is incubated at 4.degree. C. overnight. The wells
are aspirated and treated with 50 mM imidazole buffer saline (pH
7.2) (with 1 mM CaCl.sub.2/MgCl.sub.2) containing 1% bovine serum
albumin (BSA) (300 .mu.L/well) for two h at 37.degree. C. The wells
are aspirated and washed 3 times (400 .mu.L/well) with 155 mM NaCl
pH 7.2 buffer saline and soaked 10 seconds between each wash.
[0250] Test compounds are dissolved in nanopure water
(concentration: 10-100 .mu.M). DMSO may be used as co-solvent. 25
.mu.L of test compound solution in 2% DMSO is added, along with 75
.mu.L sRAGE (4.0.times.10.sup.-4 mg/mL FAC) to each well and
samples are incubated for 1 h at 37.degree. C. The wells are washed
3 times with 155 mM NaCl pH 7.2 buffer saline and are soaked 10
seconds between each wash. Non-radioactive binding is performed by
adding:
[0251] 10 .mu.L Biotinylated goat F(ab')2 Anti-mouse IgG.
(8.0.times.10.sup.-4 mg/mL, FAC)
[0252] 10 .mu.L Alk-phos-Sterptavidin (3.times.10.sup.-3 mg/mL
FAC)
[0253] 10 .mu.L Polyclonal antibody for sRAGE (FAC
6.0.times.10.sup.-3 mg/mL) to 5 mL 50 mM imidazole buffer saline
(pH 7.2) containing 0.2% bovine serum albumin and 1 mM CaCl.sub.2.
The mixture is incubated for 30 minutes at 37.degree. C. 100 .mu.L
complex is added to each well and incubation is allowed to proceed
at rt for 1 h. Wells are washed 3 times with wash buffer and soaked
10 s between each wash. 100 .mu.L 1 mg/mL (PNPP) in 1 M
diethanolamine (pH adjusted to 9.8 with HCl) is added. Color is
allowed to develop in the dark for 1 to 2 h at rt. The reaction is
quenched with 10 .mu.L of stop solution (0.5 N NaOH in 50% ethanol)
and the absorbance is measured spectrophotometrically with a
microplate reader at 405 nm.
[0254] The following compounds of Formula 1 were synthesized
according to the Schemes and tested according to the assay method
described above.
[0255] IC.sub.50 (.mu.M) of ELISA assay represents the
concentration of compound at which 50% signal has been
inhibited.
[0256] Compound inhibition of S-100b/RAGE interaction in Glioma
cells by Example 1 had an IC50 of 3.3 .mu.M. Thus, the cell based
assay demonstrated effective correlation with the binding of ELISA
IC.sub.50 value (1.75 .mu.M). TABLE-US-00002 Functional Assay
IC.sub.50 (.mu.M) Inhibition of NF-.kappa.B Example No. in Glioma
Cells ELISA Assay (S-100b) 1 3.3 1.75
[0257] TABLE-US-00003 ELISA Assay IC.sub.50 (.mu.M) Carboxymethyl
Lysine Example No. S-100b Amyloid-.beta. (CML) 1 1.75 3.4 2.29 2
5.1 -- 3.16 3 1.32 1.5 1.5 4 0.82 2.2 1.12 5 2.88 1.81 1.27 6 6.3
NA NA 7 1-3 -- 8 8 2.0 NA NA 9 1.6 NA NA 10 0.95 NA NA 11 10-30 NA
NA 12 0.3-1.0 5 0.7 13 1 1 0.7 14 2.8 NA NA 15 10-30 NA NA 16 20-30
NA NA 17 10 NA NA 18 2.3 2 0.84 19 1.14 0.80 0.80 20 0.84 1 1 21
0.64 1.23 0.46 22 0.92 1.73 0.68 23 15.5 NA NA 24 2.7 NA NA 25 15
NA NA 26 5.6 NA NA NA = ELISA assay data not available
[0258] The invention further provides pharmaceutical compositions
comprising the RAGE modulating compounds of the invention. The term
"pharmaceutical composition" is used herein to denote a composition
that may be administered to a mammalian host, e.g., orally,
topically, parenterally, by inhalation spray, or rectally, in unit
dosage formulations containing conventional non-toxic carriers,
diluents, adjuvants, vehicles and the like. The term "parenteral"
as used herein, includes subcutaneous injections, intravenous,
intramuscular, intracisternal injection, or by infusion
techniques.
[0259] The pharmaceutical compositions containing a compound of the
invention may be in a form suitable for oral use, for example, as
tablets, troches, lozenges, aqueous, or oily suspensions,
dispersible powders or granules, emulsions, hard or soft capsules,
or syrups or elixirs. Compositions intended for oral use may be
prepared according to any known method, and such compositions may
contain one or more agents selected from the group consisting of
sweetening agents, flavoring agents, coloring agents, and
preserving agents in order to provide pharmaceutically elegant and
palatable preparations. Tablets may contain the active ingredient
in admixture with non-toxic pharmaceutically-acceptable excipients
which are suitable for the manufacture of tablets. These excipients
may be for example, inert diluents, such as calcium carbonate,
sodium carbonate, lactose, calcium phosphate or sodium phosphate;
granulating and disintegrating agents, for example corn starch or
alginic acid; binding agents, for example, starch, gelatin or
acacia; and lubricating agents, for example magnesium stearate,
stearic acid or talc. The tablets may be uncoated or they may be
coated by known techniques to delay disintegration and absorption
in the gastrointestinal tract and thereby provide a sustained
action over a longer period. For example, a time delay material
such as glyceryl monostearate or glyceryl distearate may be
employed. They may also be coated by the techniques described in
U.S. Pat. Nos. 4,356,108; 4,166,452; and 4,265,874, incorporated
herein by reference, to form osmotic therapeutic tablets for
controlled release.
[0260] Formulations for oral use may also be presented as hard
gelatin capsules where the active ingredient is mixed with an inert
solid diluent, for example, calcium carbonate, calcium phosphate or
kaolin, or a soft gelatin capsules wherein the active ingredient is
mixed with water or an oil medium, for example peanut oil, liquid
paraffin, or olive oil.
[0261] Aqueous suspensions may contain the active compounds in
admixture with excipients suitable for the manufacture of aqueous
suspensions. Such excipients are suspending agents, for example
sodium carboxymethylcellulose, methylcellulose,
hydroxypropylmethylcellulose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or
wetting agents may be a naturally-occurring phosphatide such as
lecithin, or condensation products of an alkylene oxide with fatty
acids, for example polyoxyethylene stearate, or condensation
products of ethylene oxide with long chain aliphatic alcohols, for
example, heptadecaethyl-eneoxycetanol, or condensation products of
ethylene oxide with partial esters derived from fatty acids and a
hexitol such as polyoxyethylene sorbitol monooleate, or
condensation products of ethylene oxide with partial esters derived
from fatty acids and hexitol anhydrides, for example polyethylene
sorbitan monooleate. The aqueous suspensions may also contain one
or more coloring agents, one or more flavoring agents, and one or
more sweetening agents, such as sucrose or saccharin.
[0262] Oily suspensions may be formulated by suspending the active
ingredient in a vegetable oil, for example arachis oil, olive oil,
sesame oil or coconut oil, or in a mineral oil such as a liquid
paraffin. The oily suspensions may contain a thickening agent, for
example beeswax, hard paraffin or cetyl alchol. Sweetening agents
such as those set forth above, and flavoring agents may be added to
provide a palatable oral preparation. These compositions may be
preserved by the addition of an anti-oxidant such as ascorbic
acid.
[0263] Dispersible powders and granules suitable for preparation of
an aqueous suspension by the addition of water provide the active
compound in admixture with a dispersing or wetting agent,
suspending agent and one or more preservatives. Suitable dispersing
or wetting agents and suspending agents are exemplified by those
already mentioned above. Additional excipients, for example,
sweetening, flavoring, and coloring agents may also be present.
[0264] The pharmaceutical compositions of the invention may also be
in the form of oil-in-water emulsions. The oily phase may be a
vegetable oil, for example, olive oil or arachis oil, or a mineral
oil, for example a liquid paraffin, or a mixture thereof. Suitable
emulsifying agents may be naturally-occurring gums, for example gum
acacia or gum tragacanth, naturally-occurring phosphatides, for
example soy bean, lecithin, and esters or partial esters derived
from fatty acids and hexitol anhydrides, for example sorbitan
monooleate, and condensation products of said partial esters with
ethylene oxide, for example polyoxyethylene sorbitan monooleate.
The emulsions may also contain sweetening and flavoring agents.
[0265] Syrups and elixirs may be formulated with sweetening agents,
for example glycerol, propylene glycol, sorbitol or sucrose. Such
formulations may also contain a demulcent, a preservative and
flavoring and coloring agents. The pharmaceutical compositions may
be in the form of a sterile injectible aqueous or oleaginous
suspension. This suspension may be formulated according to the
known methods using suitable dispersing or wetting agents and
suspending agents described above. The sterile injectable
preparation may also be a sterile injectable solution or suspension
in a non-toxic parenterally-acceptable diluent or solvent, for
example as a solution in 1,3-butanediol. Among the acceptable
vehicles and solvents that may be employed are water, Ringer's
solution, and isotonic sodium chloride solution. In addition,
sterile, fixed oils are conveniently employed as solvent or
suspending medium. For this purpose, any bland fixed oil may be
employed using synthetic mono- or diglycerides. In addition, fatty
acids such as oleic acid find use in the preparation of
injectables.
[0266] The compositions may also be in the form of suppositories
for rectal administration of the compounds of the invention. These
compositions can be prepared by mixing the drug with a suitable
non-irritating excipient which is solid at ordinary temperatures
but liquid at the rectal temperature and will thus melt in the
rectum to release the drug. Such materials include cocoa butter and
polyethylene glycols, for example.
[0267] For topical use, creams, ointments, jellies, solutions of
suspensions, etc., containing the compounds of the invention are
contemplated. For the purpose of this application, topical
applications shall include mouth washes and gargles. The compounds
of the present invention may also be administered in the form of
liposome delivery systems, such as small unilamellar vesicles,
large unilamellar vesicles, and multilamellar vesicles. Liposomes
may be formed from a variety of phospholipids, such as cholesterol,
stearylamine, or phosphatidylcholines. Also provided by the present
invention are prodrugs of the invention.
[0268] Pharmaceutically-acceptable salts of the compounds of the
present invention, where a basic or acidic group is present in the
structure, are also included within the scope of the invention. The
term "pharmaceutically acceptable salts" refers to non-toxic salts
of the compounds of this invention which are generally prepared by
reacting the free base with a suitable organic or inorganic acid or
by reacting the acid with a suitable organic or inorganic base.
Representative salts include the following salts: Acetate,
Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate, Bitartrate,
Borate, Bromide, Calcium Edetate, Camsylate, Carbonate, Chloride,
Clavulanate, Citrate, Dihydrochloride, Edetate, Edisylate,
Estolate, Esylate, Fumarate, Gluceptate, Gluconate, Glutamate,
Glycollylarsanilate, Hexylresorcinate, Hydrabamine, Hydrobromide,
Hydrocloride, Hydroxynaphthoate, Iodide, Isethionate, Lactate,
Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate,
Methylbromide, Methylnitrate, Methylsulfate, Monopotassium Maleate,
Mucate, Napsylate, Nitrate, N-methylglucamine, Oxalate, Pamoate
(Embonate), Palmitate, Pantothenate, Phosphate/diphosphate,
Polygalacturonate, Potassium, Salicylate, Sodium, Stearate,
Subacetate, Succinate, Tannate, Tartrate, Teoclate, Tosylate,
Triethiodide, Trimethylammonium and Valerate. When an acidic
substituent is present, such as --COOH, there can be formed the
ammonium, morpholinium, sodium, potassium, barium, calcium salt,
and the like, for use as the dosage form. When a basic group is
present, such as amino or a basic heteroaryl radical, such as
pyridyl, an acidic salt, such as hydrochloride, hydrobromide,
phosphate, sulfate, trifluoroacetate, trichloroacetate, acetate,
oxlate, maleate, pyruvate, malonate, succinate, citrate, tartarate,
fumarate, mandelate, benzoate, cinnamate, methanesulfonate,
ethanesulfonate, picrate and the like, and include acids related to
the pharmaceutically-acceptable salts listed in the Journal of
Pharmaceutical Science, 66, 2 (1977) p. 1-19.
[0269] Other salts which are not pharmaceutically acceptable may be
useful in the preparation of compounds of the invention and these
form a further aspect of the invention.
[0270] In addition, some of the compounds of the present invention
may form solvates with water or common organic solvents. Such
solvates are also encompassed within the scope of the
invention.
[0271] Thus, in a further embodiment, there is provided a
pharmaceutical composition comprising a compound of the present
invention, or a pharmaceutically acceptable salt, solvate, or
prodrug therof, and one or more pharmaceutically acceptable
carriers, excipients, or diluents.
[0272] The compounds of the present invention selectively act as
modulators of RAGE binding to a single endogenous ligand, i.e.,
selective modulators of .beta.-amyloid-RAGE interaction, and
therefore are especially advantageous in treatment of Alzheimer's
disease and related dementias.
[0273] Further, the compounds of the present invention act as
modulators of RAGE interaction with two or more endogenous ligands
in preference to others. Such compounds are advantageous in
treatment of related or unrelated pathologies mediated by RAGE,
i.e., Alzheimer's disease and cancer.
[0274] Further, the compounds of the present invention act as
modulators of RAGE binding to each and every one of its ligands,
thereby preventing the generation of oxidative stress and
activation of NF-.kappa.B regulated genes, such as the cytokines
IL-1, and TNF-.alpha.. Thus, antagonizing the binding of
physiological ligands to RAGE prevent targeted pathophysiological
consequences and useful for management or treatment of diseases,
i.e., AGE-RAGE interaction leading to diabetic complications,
S100/EN-RAGE/calgranulin-RAGE interaction leading to inflammatory
diseases, .beta.-amyloid-RAGE interaction leading to Alzheimer's
Disease, and amphoterin-RAGE interaction leading to cancer.
I. RAGE AND THE COMPLICATIONS OF DIABETES
[0275] As noted above, the compounds of the present invention are
useful in the treatment of the complications of diabetes. It has
been shown that nonenzymatic glycoxidation of macromolecules
ultimately resulting in the formation of advanced glycation
endproducts (AGEs) is enhanced at sites of inflammation, in renal
failure, in the presence of hyperglycemia and other conditions
associated with systemic or local oxidant stress (Dyer, D., et al.,
J. Clin. Invest., 91:2463-2469 (1993); Reddy, S., et al., Biochem.,
34:10872-10878 (1995); Dyer, D., et al., J. Biol. Chem.,
266:11654-11660 (1991); Degenhardt, T., et al., Cell Mol. Biol.,
44:1139-1145 (1998)). Accumulation of AGEs in the vasculature can
occur focally, as in the joint amyloid composed of
AGE-.beta..sub.2-microglobulin found in patients with
dialysis-related amyloidosis (Miyata, T., et al., J. Clin. Invest.,
92:1243-1252 (1993); Miyata, T., et al., J. Clin. Invest.,
98:1088-1094 (1996)), or generally, as exemplified by the
vasculature and tissues of patients with diabetes (Schmidt, A-M.,
et al., Nature Med., 1:1002-1004 (1995)). The progressive
accumulation of AGEs over time in patients with diabetes suggests
that endogenous clearance mechanisms are not able to function
effectively at sites of AGE deposition. Such accumulated AGEs have
the capacity to alter cellular properties by a number of
mechanisms. Although RAGE is expressed at low levels in normal
tissues and vasculature, in an environment where the receptor's
ligands accumulate, it has been shown that RAGE becomes upregulated
(Li, J. et al., J. Biol. Chem., 272:16498-16506 (1997); Li, J., et
al., J. Biol. Chem., 273:30870-30878 (1998); Tanaka, N., et al., J.
Biol. Chem,. 275:25781-25790(2000)). RAGE expression is increased
in endothelium, smooth muscle cells and infiltrating mononuclear
phagocytes in diabetic vasculature. Also, studies in cell culture
have demonstrated that AGE-RAGE interaction caused changes in
cellular properties important in vascular homeostasis.
II. RAGE AND CELLULAR DYSFUNCTION IN THE AMYLOIDOSES
[0276] Also as noted above, the compounds of the present invention
are useful in treating amyloidoses and Alzheimer's disease. RAGE
appears to be a cell surface receptor which binds .beta.-sheet
fibrillar material regardless of the composition of the subunits
(amyloid-.beta. peptide, A.beta., amylin, serum amyloid A,
prion-derived peptide) (Yan, S.-D., et al., Nature, 382:685-691
(1996); Yan, S-D., et al., Nat. Med., 6:643-651 (2000)). Deposition
of amyloid has been shown to result in enhanced expression of RAGE.
For example, in the brains of patients with Alzheimer's disease
(AD), RAGE expression increases in neurons and glia (Yan, S.-D., et
al., Nature 382:685-691 (1996)). The consequences of AB interaction
with RAGE appear to be quite different on neurons versus microglia.
Whereas microglia become activated as a consequence of A.beta.-RAGE
interaction, as reflected by increased motility and expression of
cytokines, early RAGE-mediated neuronal activation is superceded by
cytotoxicity at later times. Further evidence of a role for RAGE in
cellular interactions of A.beta. concerns inhibition of
A.beta.-induced cerebral vasoconstriction and transfer of the
peptide across the blood-brain barrier to brain parenchyma when the
receptor was blocked (Kumar, S., et al., Neurosci. Program, p
141-#275.19 (2000)). Inhibition of RAGE-amyloid interaction has
been shown to decrease expression of cellular RAGE and cell stress
markers (as well as NF-.kappa.B activation), and diminish amyloid
deposition (Yan, S-D., et al., Nat. Med., 6:643-651 (2000))
suggesting a role for RAGE-amyloid interaction in both perturbation
of cellular properties in an environment enriched for amyloid (even
at early stages) as well as in amyloid accumulation.
III. RAGE AND PROPAGATION OF THE IMMUNE/INFLAMMATORY RESPONSE
[0277] As noted above, the compounds of the present invention are
useful in treating inflammation. For example, S100/calgranulins
have been shown to comprise a family of closely related
calcium-binding polypeptides characterized by two EF-hand regions
linked by a connecting peptide (Schafer, B. et al., TIBS,
21:134-140 (1996); Zimmer, D., et al., Brain Res. Bull., 37:417-429
(1995); Rammes, A., et al., J. Biol. Chem., 272:9496-9502 (1997);
Lugering, N., et al., Eur. J. Clin. Invest., 25:659-664 (1995)).
Although they lack signal peptides, it has long been known that
S100/calgranulins gain access to the extracellular space,
especially at sites of chronic immune/inflammatory responses, as in
cystic fibrosis and rheumatoid arthritis. RAGE is a receptor for
many members of the S100/calgranulin family, mediating their
proinflammatory effects on cells such as lymphocytes and
mononuclear phagocytes. Also, studies on delayed-type
hypersensitivity response, colitis in IL-10 null mice,
collagen-induced arthritis, and experimental autoimmune
encephalitis models suggest that RAGE-ligand interaction
(presumably with S100/calgranulins) has a proximal role in the
inflammatory cascade.
IV. RAGE AND AMPHOTERIN
[0278] As noted above, the compounds of the present invention are
useful in treating tumor and tumor metastasis. For example,
amphoterin is a high mobility group I nonhistone chromosomal DNA
binding protein (Rauvala, H., et al., J. Biol. Chem.,
262:16625-16635 (1987); Parkikinen, J., et al., J. Biol. Chem.
268:19726-19738 (1993)) which has been shown to interact with RAGE.
It has been shown that amphoterin promotes neurite outgrowth, as
well as serving as a surface for assembly of protease complexes in
the fibrinolytic system (also known to contribute to cell
mobility). In addition, a local tumor growth inhibitory effect of
blocking RAGE has been observed in a primary tumor model (C6
glioma), the Lewis lung metastasis model (Taguchi, A., et al.,
Nature 405:354-360 (2000)), and spontaneously arising papillomas in
mice expressing the v-Ha-ras transgene (Leder, A., et al., Proc.
Natl. Acad. Sci., 87:9178-9182 (1990)).
[0279] Amphoterin is a high mobility group I nonhistone chromosomal
DNA binding protein (Rauvala, H. and R. Pihlaskari. 1987. Isolation
and some characteristics of an adhesive factor of brain that
enhances neurite outgrowth in central neurons. J. Biol. Chem.
262:16625-16635. (Parkikinen, J., E. Raulo, J. Merenmies, R. Nolo,
E. Kajander, M. Baumann, and H. Rauvala. 1993. Amphoterin, the 30
kDa protein in a family of HIMG1-type polypeptides. J. Biol. Chem.
268:19 726-19738).
V. RAGE AND ERECTILE DYSFUNCTION
[0280] Relaxation of the smooth muscle cells in the cavernosal
arterioles and sinuses results in increased blood flow into the
penis, raising corpus cavernosum pressure to culminate in penile
erection. Nitric oxide is considered the principle stimulator of
cavernosal smooth muscle relaxation (See Wingard C J, Clinton W,
Branam H, Stopper V S, Lewis R W, Mills T M, Chitaley K. Antagonism
of Rho-kinase stimulates rat penile erection via a nitric
oxide-independent pathway. Nature Medicine 2001
January;7(1):119-122). RAGE activation produces oxidants (See Yan,
S-D., Schmidt A-M., Anderson, G., Zhang, J., Brett, J., Zou, Y-S.,
Pinsky, D., and Stem, D. Enhanced cellular oxidant stress by the
interaction of advanced glycation endproducts with their
receptors/binding proteins. J. Biol. Chem. 269:9889-9887, 1994.)
via an NADH oxidase-like enzyme, therefore suppressing the
circulation of nitric oxide. Potentially by inhibiting the
activation of RAGE signaling pathways by decreasing the
intracellular production of AGEs, generation of oxidants will be
attenuated. RAGE blockers may promote and facilitate penile
erection by blocking the access of ligands to RAGE.
[0281] The calcium-sensitizing Rho-kinase pathway may play a
synergistic role in cavernosal vasoconstriction to maintain penile
flaccidity. The antagonism of Rho-kinase results in increased
corpus cavemosum pressure, initiating the erectile response
independently of nitric oxide (Wingard et al.). One of the
signaling mechanisms activated by RAGE involves the Rho-kinase
family such as cdc42 and rac (See Huttunen H J, Fages C, Rauvala H.
Receptor for advanced glycation end products (RAGE)-mediated
neurite outgrowth and activation of NF-kappaB require the
cytoplasmic domain of the receptor but different downstream
signaling pathways. J Biol Chem 1999 Jul. 9;274(28):19919-24).
Thus, inhibiting activation of Rho-kinases via suppression of RAGE
signaling pathways will enhance and stimulate penile erection
independently of nitric oxide.
[0282] Thus, in a further aspect, the present invention provides a
method for the inhibition of the interaction of RAGE with
physiological ligands. In a preferred embodiment of this aspect,
the present invention provides 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 compound of
the present invention, preferably a pharmacologically effective
amount, more preferably a therapeutically effective amount. In a
preferred embodiment, at least one compound of Formula (I) is
utilized, either alone or in combination with one or more known
therapeutic agents. In a further preferred embodiment, the present
invention provides method of prevention and/or treatment of RAGE
mediated human diseases, treatment comprising alleviation of one or
more symptoms resulting from that disorder, to an outright cure for
that particular disorder or prevention of the onset of the
disorder, the method comprising administration to a human in need
thereof a therapeutically effective amount of a compound of the
present invention, preferably a compound of Formula (I).
[0283] In this method, factors which will influence what
constitutes an effective amount will depend upon the size and
weight of the subject, the biodegradability of the therapeutic
agent, the activity of the therapeutic agent, as well as its
bioavailability. As used herein, the phrase "a subject in need
thereof" includes mammalian subjects, preferably humans, who either
suffer from one or more of the aforesaid diseases or disease states
or are at risk for such. Accordingly, in the context of the
therapeutic method of the invention, this method also is comprised
of a method for treating a mammalian subject prophylactically, or
prior to the onset of diagnosis such disease(s) or disease
state(s).
[0284] In a further aspect of the present invention, the RAGE
modulators of the invention are utilized in adjuvant therapeutic or
combination therapeutic treatments with other known therapeutic
agents.
[0285] The term "treatment" as used herein, refers to the full
spectrum of treatments for a given disorder from which the patient
is suffering, including alleviation of one, most of all symptoms
resulting from that disorder, to an outright cure for the
particular disorder or prevention of the onset of the disorder.
[0286] The following is a non-exhaustive listing of adjuvants and
additional therapeutic agents which may be utilized in combination
with the RAGE modulators of the present invention:
[0287] Pharmacologic Classifications of Anticancer Agents: [0288]
1. Alkylating agents: Cyclophosphamide, nitrosoureas, carboplatin,
cisplatin, procarbazine [0289] 2. Antibiotics: Bleomycin,
Daunorubicin, Doxorubicin [0290] 3. Antimetabolites: Methotrexate,
Cytarabine, Fluorouracil [0291] 4. Plant alkaloids: Vinblastine,
Vincristine, Etoposide, Paclitaxel, [0292] 5. Hormones: Tamoxifen,
Octreotide acetate, Finasteride, Flutamide [0293] 6. Biologic
response modifiers: Interferons, Interleukins,
[0294] Pharmacologic Classifications of Treatment for Rheumatoid
Arthritis (Inflammation) [0295] 1. Analgesics: Aspirin [0296] 2.
NSAIDs (Nonsteroidal anti-inflammatory drugs): Ibuprofen, Naproxen,
Diclofenac [0297] 3. DMARDs (Disease-Modifying Antirheumatic
drugs): Methotrexate, gold preparations, hydroxychloroquine,
sulfasalazine [0298] 4. Biologic Response Modifiers, DMARDs:
Etanercept, Infliximab Glucocorticoids
[0299] Pharmacologic Classifications of Treatment for Diabetes
Mellitus [0300] 1. Sulfonylureas: Tolbutamide, Tolazamide,
Glyburide, Glipizide [0301] 2. Biguanides: Metformin [0302] 3.
Miscellaneous oral agents: Acarbose, Troglitazone [0303] 4.
Insulin
[0304] Pharmacologic Classifications of Treatment for Alzheimer's
Disease [0305] 1. Cholinesterase Inhibitor: Tacrine, Donepezil
[0306] 2. Antipsychotics: Haloperidol, Thioridazine [0307] 3.
Antidepressants: Desipramine, Fluoxetine, Trazodone, Paroxetine
[0308] 4. Anticonvulsants: Carbamazepine, Valproic acid
[0309] In a further preferred embodiment, the present invention
provides a method of treating RAGE mediated diseases, the method
comprising administering to a subject in need thereof, a
therapeutically effective amount of a compound of Formula (I) in
combination with 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. In a further preferred
embodiment, the present invention provides the pharmaceutical
composition of the invention as described above, 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.
[0310] Generally speaking, the compound of the present invention,
preferably Formula (I), is administered at a dosage level of from
about 0.01 to 500 mg/kg of the body weight of the subject being
treated, with a preferred dosage range between 0.01 and 200 mg/kg,
most preferably 0.1 to 100 mg/kg of body weight per day. The amount
of active ingredient that may be combined with the carrier
materials to produce a single dosage will vary depending upon the
host treated and the particular mode of administration. For
example, a formulation intended for oral administration to humans
may contain 1 mg to 2 grams of a compound of Formula (I) with
an
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