Fused imidazopyridine derivatives as antihyperlipidemic agents

Details Fused imidazopyridine derivatives as antihyperlipidemic agents Fused imidazopyridine derivatives as antihyperlipidemic agents

1998-10-08

2001-05-22

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S034000

Reexamination Certificate

active

06235731

ABSTRACT:

TECHNICAL FIELD
The present invention relates to novel fused imidazopyridine derivatives which are useful for prophylaxis and/or therapy of hyperlipemia, their production and use.
BACKGROUND ART
It has been shown by many epidemiological surveys that, alongside of hypertension and smoking, hypercholesterolemia is one of the three major risk factors for atherosclerotic diseases such as myocardial infarction, angina pectoris, and cerebral infarction. Therefore, adequate control of blood cholesterol concentration is of paramount importance for the prevention and treatment of atherosclerotic diseases such as ischemic heart diseases. As drugs for lowering cholesterol in blood, drugs which inhibit bile acid absorption by binding with bile acid, such as colestyramin and colestipol (disclosed in e.g. U.S. Pat. No. 4,027,009), drugs which inhibit acyl-CoA cholesterol O-acyltransferase (ACAT) to suppress the intestinal absorption of cholesterol, such as melinamide (disclosed in French Patent 1476569), and drugs which inhibit cholesterol biosynthesis, such as lovastatin (U.S. Pat. No. 4,231,938), simvastatin (U.S. Pat. No. 4,231,938), (U.S. Pat. No. 4,444,784), and pravastatin (U.S. Pat. No. 4,346,227), all of which are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), are attracting many attentions. However, inhibition of HMG-CoA reductase results in inhibition of not only cholesterol biosynthesis but also biosynthesis of other vital physiological substances such as ubiquinones, dolichols, and heme A. Accordingly, these drugs are not fully satisfactory for use as medicines in view of the consequent adverse effects.
Meanwhile, liver low-density lipoprotein (LDL) receptors are playing a principal role in cholesterol homeostasis. Cholesterol circulating in the form of LDL is eliminated from plasma by specific LDL receptors, and taken up in the cells by the mechanism of receptor-mediated intracellular uptake. Taken up in the cells, LDL particles are decomposed by the lysosomes, whereupon cholesterol is released to increase the intracellular concentration of free cholesterol. The increased free cholesterol concentration transmits a signal to liver cells to lower the transcription rate of the gene of the key enzyme in the cholesterol biosynthetic pathway, and decrease biosynthesis of cholesterol. Furthermore, the LDL receptor mRNA and protein are down-regulated by increased intracellular cholesterol so that the capacity of liver to eliminate the excess LDL cholesterol from plasma is compromised. Therefore, the mechanism for independent up-regulation of LDL receptors is expected to lower the plasma cholesterol level still more remarkably and it is possible that any drug as up-regulating LDL receptors could be a novel hypolipemic agent.
Incidentally, there is not a single known compound structurally analogous to the compound of the present invention.
In the above state of the art, development of a new type of antihyperlipemic drug having low-density lipoprotein (LDL) receptor up-regulating activity has been awaited.
DISCLOSURE OF INVENTION
The novel fused imidazopyridine derivatives represented by the following formula (I) have been found to possess an excellent LDL receptor up-regulating, blood-lipids lowering, blood-sugar lowering and diabetic complication-ameliorating action. And, the inventors have completed the present invention.
The compound (I) of the present invention is directed to:
(1) a compound of the formula:
wherein ring Q is an optionally substituted pyridine ring;
one of R
0
, R
1
and R
2
is —Y
0
—Z
0
, and the other two groups are a hydrogen, a halogen, an optionally substituted hydroxy group, an optionally substituted hydrocarbon group or an acyl group;
Y
0
is a bond or an optionally substituted divalent hydrocarbon group;
Z
0
is a basic group which may be bonded via oxygen, nitrogen, —CO—, —CS—, —SO
2
N(R
3
)— (wherein R
3
is a hydrogen or an optionally substituted hydrocarbon group), or
—S(O)n— (wherein n is 0, 1 or 2); and
{overscore (-----)} is a single bond or a double bond, or a salt thereof,
(2) a compound of above (1), wherein R
0
is —Y
0
—Z
0
, wherein Y
0
and Z
0
are of the same meanings as defined in above (1),
(3) a compound of above (1), wherein Z
0
is a group with a molecular weight of not greater than 1000,
(4) a compound of above (1) which is a compound of the formula:
wherein ring Q is an optionally substituted pyridine ring;
A and B independently are an optionally substituted divalent hydrocarbon group which may be bonded via —CON(R
4a
)—, —CO— or —N(R
4a
)—;
X is a bond, oxygen, sulfur, —N(R
5
)CO—, —CO(R
5
)—, —CO— or —N(R
5
)—,
Y is a bond, —CH═CH— or
Z is —CO—, —COO—, —CON(R
3
)—, —SO
2
N(R
3
)— or —S(O)m— (wherein m is 0, 1 or 2);
R
1
and R
2
independently are a hydrogen, a halogen, an optionally substituted hydroxy group, an optionally substituted hydrocarbon group or an acyl group;
R
3
, R
4
, R
4a
and R
5
independently are a hydrogen or an optionally substituted hydrocarbon group; or
R
3
and A, R
4
and A, R
4
and B, R
4
and R
5
, or R
4
and R may independently be bonded to each other to form a ring;
R is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; and
{overscore (-----)} is a single bond or a double bond, or a salt thereof,
(5) a compound of above (1) which is a compound of the formula:
wherein ring Q is an optionally substituted pyridine ring;
A and B independently are an optionally substituted divalent hydrocarbon group which may be bonded via —CON(R
4a
)—, —CO— or —N(R
4a
)—;
X is a bond, oxygen, sulfur, —N(R
5
)CO—, —CO(R
5
)—, —CO— or —N(R
5
)—;
Y is a bond, —CH═CH— or
Z is —CO—, —COO—, —CON(R
3
)—, —SO
2
N(R
3
)— or —S(O)m— (wherein m is 0, 1 or 2);
R
1
and R
2
independently are a hydrogen, a halogen, an optionally substituted hydroxy group, an optionally substituted hydrocarbon group or an acyl group;
R
3
, R
4
, R
4a
and R
5
independently are a hydrogen or an optionally substituted hydrocarbon group; or
R
3
and A, R
4
and A, R
4
and B, R
4
and R
5
, or R
4
and R independently may be bonded to each other to form a ring;
R is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; and
{overscore (-----)} is a single bond or a double bond, or a salt thereof,
(6) a compound of above (5), wherein A and B independently are an alkylene group; X is a bond; and
R
3
and R
4
independently are a hydrogen or an optionally substituted alkyl, cycloalkyl, alkenyl, aralkyl or aryl group,
(7) a compound of above (5), wherein ring Q is an unsubstituted pyridine ring; X is a bond; Y is a bond,
A and B independently are a C
1-15
alkylene group; R
1
and R
2
independently are a hydrogen;
R
3
and R
4
independently are a hydrogen or a C
1-15
alkyl, C
3-8
cycloalkyl, C
2-18
alkenyl, C
7-16
aralkyl or C
6-14
aryl group; and R is a C
6-14
aryl group,
(8) a compound of above (1) which is a compound of the formula:
wherein ring Q is an optionally substituted pyridine ring;
ring Q
1
is an optionally substituted nitrogen-containing heterocyclic ring;
A
1
is a bond or an optionally substituted divalent hydrocarbon group which may be bonded via —CON(R
4a
)—, —CO— or —N(R
4a
)—;
B is an optionally substituted divalent hydrocarbon group;
X is a bond, oxygen, sulfur, —N(R
5
)CO—, —CO(R
5
)—, —CO— or —N(R
5
)—;
Y is a bond, —CH═CH— or —CH═CH
R
1
and R
2
independently are a hydrogen, a halogen, an optionally substituted hydroxy group, an optionally substituted hydrocarbon group or an acyl group;
R
3
, R
4a
and R
5
independently are a hydrogen or an optionally substituted hydrocarbon group; or
R
3
and A
1
may be bonded to each other to form a ring;
R is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; and
{overscore (-----)} is a single bond or a double bond, or a salt thereof,
(9) a compound of above (8), wherein ring Q is an unsubstituted pyridine ring; R
1
and R
2
are a hydrogen;
R
3
is a hydrogen or a C
1-15
alkyl, C
3-8
cycloalkyl, C
2-1

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