Method for the synthesis of compounds of formula I and their...

Details Method for the synthesis of compounds of formula I and their... Method for the synthesis of compounds of formula I and their...

2001-03-05

2003-09-02

Badio, Barbara P. (Department: 1616)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C564S155000, C514S516000

Reexamination Certificate

active

06613801

ABSTRACT:

FIELD OF THE INVENTION
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, &bgr;-amyloid and amphoterin, for the management, treatment, control, or as an adjunct treatment of diseases caused by RAGE.
BACKGROUND OF THE INVENTION
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.
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.
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)).
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 &bgr;-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)).
Binding of ligands such as AGEs, S100/calgranulin/EN-RAGE, &bgr;-amyloid, CML (N
&egr;
-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-&kgr;B, and the activation of NF-&kgr;B regulated genes, such as the cytokines IL-1&bgr;, TNF-&agr;, 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-&kgr;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.
Thus, there is a need for the development of compounds that antagonize binding of physiological ligands to the RAGE receptor.
SUMMARY OF THE INVENTION
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, &bgr;-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
In a first aspect, the present invention provides a compound comprising at least one moiety of the formula
wherein L
1
and L
2
are each a hydrocarbon group of from 1 to 6 carbons or a direct bond, and Aryl
1
and Aryl
2
are aryl, wherein each of Aryl
1
and Aryl
2
are substituted by at least one lipophilic group. In a preferred embodiment, the lipophilic group is selected from C
1-6
alkyl, C
1-6
alkoxy, C
1-6
alkylaryl, or C
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.
In a second aspect, the present invention provides compounds of Formula (I):
wherein
R
1
and R
2
are independently selected from
a) —H;
b) —C
1-6
alkyl;
c) -aryl;
d) —C
1-6
alkylaryl;
e) —C(O)—O—C
1-6
alkyl;
f) —C(O)—O—C
1-6
alkylaryl;
g) —C(O)—NH—C
1-6
alkyl;
h) —C(O)—NH—C
1-6
alkylaryl;
i) —SO
2
—C
1-6
alkyl;
j) —SO
2
—C
1-6
alkylaryl;
k) —SO
2
-aryl;
l) —SO
2
—NH—C
1-6
alkyl;
m) —SO
2
—NH—C
1-6
alkylaryl;
n)
o) —C(O)—C
1-6
alkyl; and
p) —C(O)—C
1-6
alkylaryl;
R
3
is selected from
a) —C
1-6
alkyl;
b) -aryl; and
c) —C
1-6
alkylaryl;
R
4
is selected from
a) —C
1-6
alkylaryl;
b) —C
1-6
alkoxyaryl; and
c) -aryl;
R
5
and R
6
are independently selected from the group consisting of hydrogen, C
1
-C
6
alkyl, C
1
-C
6
alkylaryl, and aryl; and wherein
the aryl and/or alkyl group(s) in R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
, R
10
, R
18
, R
19
, and R
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:
a) —H;
b) —Y—C
1-6
alkyl;
—Y-aryl;
—Y—C—
1-6
alkylaryl;
—Y—C
1-6
-alkyl-NR
7
R
8
; and
—Y—C
1-6
-alkyl-W—R
20
;
wherein Y and W are, independently selected from the group consisting of —CH
2
—, —O—, —N(H), —S—, SO
2
—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO
2
—, —SO
2
N(H)—, —C(O)—O—, —NHSO
2
NH—, —O—CO—,
and
c) halogen, hydroxyl, cyano, carbamoyl, or carboxyl; and
R
18
and R
19
are independently selected

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