Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-05-15
2003-03-04
Seaman, D. Margaret (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S315000, C514S365000, C514S372000, C514S374000, C514S398000, C514S608000, C514S613000, C514S618000, C514S619000, C546S153000, C546S294000, C548S182000, C548S255000, C548S325100, C564S162000, C564S163000
Reexamination Certificate
active
06528528
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to compounds that can be used to treat or prevent inflammatory diseases or atherosclerosis. The present invention also relates to pharmaceutical compositions that can be used to prevent or treat inflammatory diseases or atherosclerosis, and to methods of treating and preventing inflammatory diseases or atherosclerosis. In particular, the compounds of the present invention are inhibitors of the enzyme 15-lipoxygenase and are inhibitors of monocyte chemotaxis.
BACKGROUND OF THE INVENTION
Atherosclerosis is a multifactorial disease characterized by excessive intracellular lipid deposition in macrophages, leading to the formation of foam cells. The accumulation of lipid-loaded foam cells in the subendothelial space leads to formation of fatty streaks, which are the early atherosclerotic lesions. Oxidative modifications of lipids, specifically low-density lipoprotein, has been implicated as a major process in foam-cell formation.
Lipoxygenases are nonheme iron-containing enzymes that catalyze the oxygenation of certain polyunsaturated fatty acids such as lipoproteins. Several different lipoxygenase enzymes are known, each having a characteristic oxidation action. One specific lipoxygenase, namely 15-lipoxygenase (15-LO), has been detected in atherosclerotic lesions in mammals, specifically rabbit and man. The enzyme, in addition to its role in oxidative modification of lipoproteins, is important in the inflammatory reaction in the atherosclerotic lesion. Indeed, 15-LO has been shown to be induced in human monocytes by the cytokine IL4, which is known to be implicated in the inflammatory process.
Inhibitors of 15-LO are especially useful to prevent and treat inflammatory diseases such as asthma, psoriasis, arthritis, and atherosclerosis. While there are several lipoxygenase enzymes, specific inhibition of 15-LO is important in the inflammatory and atherosclerosis process. A characteristic feature of atherosclerosis is the accumulation of cholesterol ester engorged foam cells. Foam cells are derived from circulating monocytes that invade artery walls in response to hypercholesterolemia, and mature into tissue macrophages. The enzyme 15-LO has been implicated in inflammatory disorders and in the origin and recruitment of foam cells (See Harats, et al.,
Trends Cardiovasc. Med.,
1995;5(1):29-36). This enzyme is capable of oxidizing esterified polyenoic fatty acids, such as those found in phospholipids. Treatment of experimental animals with antioxidants which reduced hydroperoxides produced by 15-LO has been shown to retard the progression of atherosclerotic lesions. For example, Sendobry, et al.,
British Journal of Pharmacology,
1997;120:1199-1206 show suppression of atherogenesis in rabbits fed a high-fat diet and treated with a 15-LO inhibitor.
SUMMARY OF THE INVENTION
The present invention provides compounds having the Formula I
heteroaryl, substituted heteroaryl, —NR′R′, or cycloalkyl;
each R′ is independently hydrogen or C
1
-C
6
alkyl;
R
e
is
C
1
-C
18
alkyl, heteroaryl, substituted heteroaryl, naphthyl, benzyl, or dansyl;
each of R
1
, R
2
, R
3
, R
4
, R
5
, R
7
, R
8
, R
9
, R
a
, R
b
, R
c
, and R
d
are independently hydrogen, —OC
1
—C
6
alkyl, —SC
1
—C
6
alkyl, halogen, C
1
-C
6
alkyl, —OH, —CF
3
, —NO
2
, —CN, —CO
2
H, —OCF
3
, —CO
2
C
1
—C
6
alkyl, —SO
3
H, —SO
3
-alkali metal, —NH
2
, —NHC
1
—C
6
alkyl,
—CO
2
C
1
—C
6
alkyl, —SO
3
H, —SO
3
alkali metal, —CN, —CH
2
-halogen,
heteroaryl, substituted heteroaryl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, benzoyl,
—SO
3
H, —SO
3
NR′R′, —CHO, —SO
2
NH
2
, or —NR′R′; or the pharmaceutically acceptable salts thereof, provided that when Y is
Q is not C
1
-C
6
alkyl; further provided that when X is
and Y is —NH, R
b
is not —OH; further provided that when X and Y are
R
e
and Q are not unsubstituted phenyl; further provided that when Y is
R
e
and Q are not both aryl; further provided that when Y is —SO
2
NH— or —SO
2
NC
1
—C
6
alkyl and X is
Q and R
e
are not both unsubstituted phenyl; further provided that when Y is
R
e
is unsubstituted phenyl di- or tri-substituted phenyl; further provided that when Y is
Q is not unsubstituted aryl.
In a preferred embodiment of the compounds of Formula I, X is
In another preferred embodiment of the compounds of Formula I, R′ is hydrogen or methyl.
In another preferred embodiment of the compounds of Formula I, X is —O—.
In another preferred embodiment of the compounds of Formula I, X is
In another preferred embodiment of the compounds of Formula I, R′ is hydrogen.
In another preferred embodiment of the compounds of Formula I, R
c
is —OCH
3
, hydrogen, —OCH
2
CH
3
, halogen, -S-methyl, or —OCF
3
.
In another preferred embodiment of the compounds of Formula I, Y is
In another preferred embodiment of the compounds of Formula I, X is
In another preferred embodiment of the compounds of Formula I, Y is
In another preferred embodiment of the compounds of Formula I, R
c
is hydrogen, hydroxy, —OC
1
—C
6
alkyl, halogen, C
1
-C
6
alkyl, —SC
1
—C
6
alkyl, —CF
3
, or—OCF
3
.
Also provided is a method of treating or preventing atherosclerosis, the method comprising administering to a patient having atherosclerosis or at risk of having atherosclerosis a therapeutically effective amount of a compound of Formula I
heteroaryl, substituted heteroaryl, —NR′R′, or cycloalkyl;
each R′ is independently hydrogen or C
1
-C
6
alkyl;
R
e
is
C
1
-C
18
alkyl, heteroaryl, substituted heteroaryl, naphthyl, benzyl, or dansyl;
each of R
1
, R
2
, R
3
, R
4
, R
5
, R
7
, R
8
, R
9
, R
10
, R
a
, R
b
, R
c
, and R
d
are independently hydrogen, —OC
1
—C
6
alkyl, —SC
1
—C
6
alkyl, halogen, C
1
-C
6
alkyl, —OH, —CF
3
, —NO
2
, —CN, —CO
2
H, —OCF
3
, —CO
2
C
1
—C
6
alkyl, —SO
3
H, —SO
3
-alkali metal, —NH
2
, —NHC
1
—C
6
alkyl,
—CO
2
C
1
—C
6
alkyl, —SO
3
H, —SO
3
alkali metal, —CN, —CH
2
-halogen,
heteroaryl, substituted heteroaryl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, benzoyl,
or the pharmaceutically acceptable salts thereof.
Also provided is a method of treating or preventing inflammation, the method comprising administering to a patient having inflammation or at risk of having inflammation a therapeutically effective amount of a compound of Formula I
heteroaryl, substituted heteroaryl, —NR′R′, or cycloalkyl;
each R′ is independently hydrogen or C
1
-C
8
alkyl;
R
e
is
C
1
-C
18
alkyl, heteroaryl, substituted
heteroaryl, naphthyl, benzyl, or dansyl;
each of R
1
, R
2
, R
3
, R
4
, R
5
, R
7
, R
8
, R
9
, R
10
, R
a
, R
b
, R
c
, and R
d
are independently hydrogen, —OC
1
—C
6
alkyl, —SC
1
—C
6
alkyl, halogen, C
1
-C
6
alkyl, —OH, —CF
3
, —NO
2
, —CN, —CO
2
H, —OCF
3
, —CO
2
C
1
—C
6
alkyl, —SO
3
H, —SO
3
-alkali metal, —NH
2
, —NHC
1
—C
6
alkyl,
—CO
2
C
1
—C
6
alkyl, —SO
3
H, —SO
3
alkali metal, —CN, —CH
2
-halogen,
heteroaryl, substituted heteroaryl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, benzoyl,
or the pharmaceutically acceptable salts thereof.
The present invention provides a pharmaceutically acceptable composition comprising a compound of Formula I.
Also provided is a method of inhibiting 15-lipoxygenase, the method comprising administering to a patient in need of 15-lipoxygenase inhibition a 15-lipoxygenase inhibiting amount of a compound of Formula I
heteroaryl, substituted heteroaryl, —NR′R′, or cycloalkyl;
each R′is independently hydrogen or C
1
-C
6
alkyl;
C
1
-C
18
alkyl, heteroaryl, substituted heteroaryl, naphthyl, benzyl, or dansyl;
each of R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
, R
10
, R
a
, R
b
, R
c
, and R
d
are independently hydrogen, —OC
1
—C
6
alkyl, —SC
1
—C
6
alky
Connor David Thomas
Roark William Howard
Sexton Karen Elaine
Sorenson Roderick Joseph
Leon Andrew J.
Seaman D. Margaret
Warner-Lambert & Company
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