Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-04-23
2003-06-24
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S252130, C514S415000, C514S416000, C514S421000, C544S358000, C544S373000, C548S484000, C548S503000
Reexamination Certificate
active
06583144
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to compounds having inhibitory activity against the biosynthesis of triglycerides and inhibitory activity against the secretion of lipoprotein containing apolipoprotein B, and prophylactic or therapeutic agents for hyperlipidemia comprising the same.
2. Background Art
A change in eating habits and an increase in the aged population have resulted in increased arteriosclerotic diseases. One of major risk factors of this group of diseases is an abnormal increase in cholesterol or triglycerides (hyperlipidemia). For example, the proportion of familial composite hyperlipidemia (FCHL) in patients suffering from cardiac infarction is about 30% which is higher than other basal diseases, and hyperlipidemia is known to be a basal disease which has a high risk of onset of ischemic heart disease (Lipid, 2, 373 (1991)).
Further, hyperlipidemia, which is a complication of obesity or diabetes, has been recognized as a risk factor of arteriosclerosis (Diabetes, 37, 1595(1988) and Int. J. Obesity, 15, 1 (1991).
Among various types of hyperlipidemia, hypertriglyceridemia is known to involve a complication of pancreatitis or the like (Medical Practice, 12, 957 (1995)).
Therefore, the treatment of hyperlipidemia is important for the prevention or treatment of arteriosclerotic diseases, such as ischemic heart diseases and cerebrovascular diseases, or pancreatitis. Further, it has been pointed out that there is a possibility that hyperlipidemia involved in renal diseases progresses renal disorders (Molecular Medicine, 31, 536(1994)). This has led to a proposal on the necessity of treating hyperlipidemia.
For the treatment or prevention of hyperlipidemia and arteriosclerotic diseases, medicaments for inhibiting the biosynthesis of cholesterol, particularly statin compounds (such as lovastatin) as medicaments for inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase and fibrate compounds (such as bezafibrate) as medicaments for reducing the level of triglycerides have been clinically used as pharmaceuticals.
Further, in recent years, reducing the serum triglyceride value and the level of serum apolipoprotein B-containing lipoprotein, which has been considered to induce arteriosclerosis, is expected to be effective in preventing or treating the above diseases (Arterioscler. Thromb., 12, 1284 (1992) and Circulation, 85, 37 (1992)). One of bases for this is that arteriosclerosis is not developed in patients suffering from &bgr;-alipoproteinemia, from whom apolipoprotein B-containing lipoprotein is not detected in blood (Clin. Chem., 34, B9-12 (1988).
Pyrrolecarboxylic acid derivatives, sulfonamide derivatives, biphenyl-2-carboxylic acid derivatives, phenylpiperazine derivatives and the like are known as compounds having the above activity. Further, isoindolone derivatives having a substituent only in their nitrogen atom at the 2-position are known (EP643057A1 and W096/26205).
On the other hand, compounds having piperazine on the benzene in the isoindolone and isoquinolone skeletons are known (WO96/26187). These compounds, however, are different from the compounds of the present invention in the substituent of nitrogen at the 2-position, and, in addition, have activity as fibrinogen receptor antagonist. Therefore, they and the present invention are different form each other in idea.
So far as the present inventors know, compounds having inhibitory activity against the secretion of apolipoprotein B-containing lipoprotein among the compounds having piperazine on the benzene ring in the isoindolone and isoquinoline skeletons are not known.
Accordingly, the development of medicaments, which have activity to reduce the level of serum triglycerides and, based on a novel mechanism of action, activity to reduce the level of apolipoprotein B-containing lipoprotein in blood and, at the same time, do not cause any side effect of the accumulation of lipid such as found in &bgr;-alipoproteinemia within the liver, have been desired for use of these medicaments as prophylactic or therapeutic agents for hyperlipidemia or arteriosclerotic diseases, (The Metabolic Basis of Inherited Disease, Sixth edition, 1139 (1989)).
SUMMARY OF THE INVENTION
The present inventors have now found that novel nitrogen-containing heterocyclic compounds having piperazine on a benzene ring of isoindolone and isoquinolone skeletons or skeletons similar thereto have high activity to reduce the level of lipid in blood, particularly high activity to reduce the level of triglycerides in blood and high activity to reduce the level of lipoprotein containing apolipoprotein B in blood by virtue of inhibitory activity against the biosynthesis of triglycerides and inhibitory activity against the secretion of lipoprotein containing apolipoprotein B in the liver, and thus are useful as therapeutic and prophylactic agents for hyperlipidemia, arteriosclerotic diseases, and pancreatitis.
Thus, according to the present invention, there is provided a compound represented by formula (I) and pharmaceutically acceptable salt and solvate thereof:
wherein
A represents
group —CR
1
R
2
—(CH
2
)
i
— wherein R
1
and R
2
, which may be the same or different, each represent a hydrogen atom or alkyl having 1 to 6 carbon atoms and i is an integer of 0 or 1,
—CH═CH—,
—O—CH
2
—, or
—S(O)
j
—CH
2
— wherein j is an integer of 0 to 2;
B represents a hydrogen or halogen atom;
X represents
—CR
3
R
4
R
5
wherein R
3
, R
4
, and R
5
, which may be the same or different, each represent a hydrogen atom or phenyl, provided that any one of R
3
, R
4
, and R
5
represents phenyl and one or more hydrogen atoms on phenyl may be substituted by a halogen atom, hydroxy, nitro, phenyl, or alkoxy having 1 to 6 carbon atoms,
—NR
6
R
7
wherein R
6
and R
7
, which may be the same or different, each represent a hydrogen atom, phenyl, or benzyl,
—(CH
2
—CH═C(CH
3
)—CH
2
)
p
—CH
2
CH═C(CH
3
)
2
wherein p is an integer of 0 to 2,
alkyl having 1 to 18 carbon atoms,
cycloalkyl having 3 to 8 carbon atoms,
optionally substituted phenyl,
optionally substituted cinnamyl, or
a five- or six-membered heteroaromatic ring containing up to two hetero atoms;
Y represents —(CH
2
)
q
— wherein q is an integer of 1 to 6,
—CH═CH—,
—NR
8
— wherein R
8
represents a hydrogen atom or alkyl having 1 to 6 carbon atoms,
an oxygen atom, or
a bond;
Z represents carbonyl or a bond;
K represents optionally substituted alkylene having 1 to 6 carbon atoms or a bond;
L represents —CH═CH— or a bond; and
M represents a hydrogen atom,
optionally substituted alkyl having 1 to 6 carbon atoms, optionally substituted cycloalkyl having 3 to 8 carbon atoms,
optionally substituted phenyl,
optionally substituted five- or six-membered, saturated or unsaturated heterocyclic ring containing up to two hetero atoms,
optionally substituted biphenyl, or
optionally substituted diphenylmethyl.
The compounds represented by formula (I) according to the present invention inhibit the biosynthesis of triglycerides in the liver and inhibit the secretion of lipoprotein containing apolipoprotein B from the liver. Therefore, they can exhibit activity to reduce the level of serum triglycerides and activity to reduce the level of lipoprotein containing apolipoprotein B in blood and, at the same time, can prevent accumulation of lipid within hepatic cells.
Accordingly, the compounds represented by formula (I) and pharmacologically acceptable salts and solvates thereof according to the present invention are useful for the prevention or treatment of hyperlipidemia (particularly hyper-very-low-density-lipoproteinemia) and arteriosclerotic diseases, such as cardiac infarction, or pancreatitis induced by hyperlipidemia.
DETAILED DESCRIPTION OF THE INVENTION
Definition
As used herein, the term “alkyl” or “alkoxy” as a group or a part of a group means a straight chain or branched chain alkyl. The term “halogen” used herein means fluorine, chlorine, bromine, or iodine. The term “hetero atom” used herein means a nitrogen, oxygen, or sulfur atom.
Compo
Hiraiwa Yukiko
Katano Kiyoaki
Kuroda Chidsuko
Matsushima Tetsuya
Nakatani Yuuko
Meiji Seika Kaisha Ltd.
Patel Sudhaker B.
Raymond Richard L.
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