Hydroxy-substituted azetidinone compounds useful as...

Details Hydroxy-substituted azetidinone compounds useful as... Hydroxy-substituted azetidinone compounds useful as...

2000-06-15

2002-05-28

Berch, Mark L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S200000

Reissue Patent

active

RE037721

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to hydroxy-substituted azetidinones useful as hypocholesterolemic agents in the treatment prevention of atherosclerosis, and to the combination of a hydroxy-substituted azetidinone of this invention and a cholesterol bioxynthesis inhibitor for the treatment and prevention of atherosclerosis. The invention also relates to a process for preparing hydroxy-substituted azetidinones.
Atherosclerotic coronary heart disease (CHD) represents the major cause for death and cardiovascular morbidity in the western world. Risk factors for atherosclerotic coronary heart disease include hypertension, diabetes mellitus, family history, male gender, cigar smoke and serum cholesterol. A total cholesterol level in excess of 225-250 mg/dl is associated with significant elevation of risk of CHD.
Cholesteryl esters are a major component of atherosclerotic lesions and the major storage form of cholesterol in arterial wall cells. Formation of cholesteryl esters is also a key step in the intestinal absorption of dietary cholesterol. Thus, inhibition of cholesteryl ester formation and reduction of serum cholesterol is likely to inhibit the progression of atherosclerotic lesion formation, decrease the accumulation of cholesteryl esters in the arterial wall, and block the intestinal absorption of dietary cholesterol.
A few azetidinones have been reported as being useful lowering cholesterol and/or in inhibiting the formation of cholesterol-containing lesions in mammalian arterial walls. U.S. Pat. No. 4,983,597 discloses N-sulfonyl-2-azetidinones as anticholesterolemic agents and Ram, et al., in
Indian J. Chem.,
Sect. B. 29B, 12 (1990), p. 1134-7, disclose ethyl 4-(2-oxoazetidin-4-yl)phenoxy-alkanoates as hypolipidemic agents. European Patent Publication 264,231 discloses 1-substituted-4-phenyl-3-(2-oxo-alkylidene)-2-azetidinones as blood platelet aggregation inhibitors. European Patent 199,630 and European Patent Application 337,549 disclose elastase inhibitory substituted azetidinones said to be useful treating inflammatory conditions resulting in tissue destruction which are associated with various disease states, e.g. atherosclerosis.
WO93/102048, published Feb. 4, 1993, discloses substituted &bgr;-lactams useful as hypocholesterolemic agents.
The regulation of whole-body cholesterol homeostasis in humans and animals involves the regulation of dietary cholesterol and modulation of cholesterol biosynthesis, bile acid biosynthesis and the catabolism of the cholesterol-containing plasma lipoproteinis. The liver is the major organ responsible for cholesterol biosynthesis and catabolism and for this reason, it is a prime determinant of plasma cholesterol levels. The liver is the site of synthesis and secretion of very low density lipoproteins (VLDL) which are subsequently metabolized to low density lipoproteins (LDL) in the circulation. LDL are the predominant cholesterol-carrying lipoproteins in the plasma and an increase in their concentration is correlated with increased atherosclerosis.
When intestinal cholesterol absorption is reduced, by whatever means, less cholesterol is delivered to the liver. The consequence of this action is decreased hepatic lipoprotein (VLDL), production and an increase in the hepatic clearance of plasma cholesterol, mostly as LDL. Thus, the net effect of inhibiting intestinal cholesterol absorption is a decrease in plasma cholesterol levels.
The inhibition of cholesterol biosynthesis by 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase (EC1.1.1.34) inhibitors has been shown to be an effective way to reduce plasma cholesterol (Witzum,
Circulation,
80, 5 (1989), p. 1101-1114) and reduce atherosclerosis. Combination therapy of an HMG CoA reductase inhibitor and a bile acid sequestrant has been demonstrated to be more effective in human hyperlipidemic patients than either agent in monotherapy (Illingworth, Drugs, 36 (Suppl. 3) (1988), p. 63-71).
SUMMARY OF THE INVENTION
Novel hypocholesterolemic compounds of the present invention are represented by the formula I
or a pharmaceutically acceptable salt thereof, wherein:
Ar
1
and Ar
2
are independently selected from the group consisting of aryl and R
4
-substituted aryl;
Ar
3
is aryl or R
5
-substituted aryl;
X, Y and Z are independently selected from the group consisting of —CH
2
—, —CH(lower alkyl)— and —C(dilower alkyl)—;
R and R
2
are independently selected from the group consisting of —OR
6
, —O(CO)R
6
, —O(CO)OR
9
and —O(CO)NR
6
R
7
;
R
1
and R
3
are independently selected from the group consisting of hydrogen, lower alkyl and aryl;
q is 0 or 1; r is 0 or 1; m, n and p are independently 0, 1, 2, 3 or 4; provided that at least one of q and r is 1, and the sum of m, n, p, q are r is 1, 2, 3, 4, 5 or 6; and provided that when p is 0 and r is 1, the sum of m, q and n is 1, 2, 3, 4, or 5;
R
4
is 1-5 substituents independently selected from the group consisting of lower alkyl, —OR
6
, —O(CO)
R
6
,

R
6
,
—O(CO)OR
9
, —O(CH
2
)
1-5
OR
6
, —O(CO)NR
6
R
7
, —NR
6
R
7
, —NR
6
(CO)R
7
, —NR
6
(CO)OR
9
, —NR
6
(CO) NR
7
R
8
, —NR
6
SO
2
R
9
, —COOR
6
, —CONR
6
R
7
, —COR
6
, —SO
2
NR
6
R
7
, S(O)
0-2
R
9
, —O(CH
2
)
1-10
—COOR
6
, —O(CH
2
)
1-10
CONR
6
R
7
, —(lower alkylene)COOR
6
, —CH═CH—COOR
6
, —CF
3
, —CN, —NO
2
and halogen;
R
5
is 1-5 substituents independently selected from the group consisting of —OR
6
, —O(CO)R
6
, —O(CO)OR
9
, —O(CH
2
)
1-5
OR
6
, —O(CO)NR
6
R
7
, —NR
6
R
7
, —NR
6
(CO) R
7
, —NR
6
(CO)OR
9
, —NR
6
(CO)NR
7
R
8
, —NR
6
SO
2
R
9
, —COOR
6
, —CONR
6
R
7
, —COR
6
, —SO
2
NR
6
R
7
, S(O)
0-2
R
9
, —O(CH
2
)
1-10
—COOR
6
, —O(CH
2
)
1-10
CONR
6
R
7
, —(lower alkylene)COOR
6
and —CH═CH—COOR
6
;
R
6
, R
7
and R
8
are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and
R
9
is lower alkyl, aryl or aryl-substituted lower alkyl.
R
4
is preferably 1-3 independently selected substituents, and R
5
is preferably 1-3 independently selected substituents. Preferred are compounds of formula I wherein Ar
1
is phenyl or R
4
-substituted phenyl, especially (4-R
4
)-substituted phenyl, Ar
2
is preferably phenyl or R
4
-substituted phenyl, especially (4-R
4
)-substituted phenyl. Ar
3
is preferably R
5
-substituted phenyl, especially (4-R
5
)-substituted phenyl. When Ar
1
is (4-R
4
)-substituted phenyl, R
4
is preferably a halogen. When Ar
2
and Ar
3
are R
4
- and R
5
-substituted phenyl, respectively, R
4
is preferably halogen or —OR
6
and R
5
is preferably —OR
6
, wherein R
6
is lower alkyl or hydrogen. Especially preferred are compounds wherein each of Ar
1
and Ar
2
is 4-fluorophenyl and Ar
3
is 4-hydroxyphenyl or 4-methoxyphenyl.
X, Y and Z are each preferably —CH
2
—.R
1
and R
3
are each preferably hydrogen. R and R
2
are preferably —OR
6
wherein R
6
is hydrogen, or a group readily metabolizable to a hydroxyl (such as —O(CO)R
6
,
—O(CO)OR
9
and

—OR
6
, especially
—O(CO)NR
6
R
7
, defined above).
The sum of m, n, p, q and r is preferably 2, 3 or 4, more preferably 3. Preferred are compounds wherein m, n and r are each zero, q is 1 and p is 2. Also preferred are compounds wherein p, q and n are each zero, r is 1 and m is 2 or 3. More preferred are compounds wherein m, n and r are each zero, q is 1, p is 2, Z is —CH
2
and R is —OR
6
OR
6
, especially when R
6
is hydrogen. Also more preferred are compounds wherein p, q and n are each zero, r is 1, m is 2, X is —CH
2
— and R
2
is —OR
6
, especially when R
6
is hydrogen.
Another group of preferred compounds is that wherein Ar
1
is phenyl or R
4
-substituted phenyl, Ar
2
is phenyl or R
4
-substituted phenyl and Ar
3
is R
5
-substituted phenyl. Also preferred are compounds wherein Ar
1
is phenyl or R
4
-substituted phenyl, Ar
2
is phenyl or R
4
-substituted phenyl, Ar
3
is R
5
-substituted phenyl, and the sum of m, n, p, q and r is 2, 3 or 4, more especially 3. More preferred are compounds wherein Ar
1
is phenyl or R
4
-substituted phenyl, Ar
2
is phenyl or R
4
-substituted phenyl Ar
3
is R
5

Affiliated with

Also associated with

Rating

Hydroxy-substituted azetidinone compounds useful as... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Hydroxy-substituted azetidinone compounds useful as..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Hydroxy-substituted azetidinone compounds useful as... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2850738