Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-10-16
2001-09-11
Stockton, Laura L. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S269400, C548S144000
Reexamination Certificate
active
06288236
ABSTRACT:
TECHNICAL FIELD
The present invention relates to benzimidazole compounds. More precisely, the present invention relates to novel bis-type benzimidazole compounds which are useful as an active ingredient of a medicament for therapeutic and preventive treatment of hyperlipemia, arterial sclerosis and the like, or useful as an additive of a silver halide photosensitive material, a liquid crystal material and the like.
BACKGROUND ART
In recent years, patients with so-called adult diseases such as arterial sclerosis, hypertension, and diabetes mellitus have been continuously increasing with prolongation of life expectancy. In particular, patients with hyperlipemia and arterial sclerosis derived therefrom have been remarkably increasing due to excessive intake of high calorie and high cholesterol food, which have become a serious social problem. Medicaments currently used for drug therapy of hyperlipemia and arterial sclerosis are those symptomatically lower cholesterol in blood, and therefore, they cannot be expected to have potency in retracting arterial sclerosis lesions, per se. Arterial sclerosis is characterized by lesions of intimal hyperplasia and lipid accumulation in blood vessels, and it has been elucidated from recent biochemical findings that foaming of macrophages plays a main role in the formation of arterial sclerosis lesions. Accordingly, suppression of the foaming of macrophages may possibly prevent arterial sclerosis by inhibiting formation of arterial sclerosis lesions, or achieve radicular treatment of arterial sclerosis by retraction of arterial sclerosis lesions. However, no medicament having such activity has been known.
Therefore, an object of the present invention is to provide a compound having activity of suppressing the foaming of macrophages, and is useful as an active ingredient of a medicament for preventive and/or therapeutic treatment of arterial sclerosis. Another object of the present invention is to provide a compound having the aforementioned activity, and is useful as an active ingredient of medicament for preventive and/or therapeutic treatment of hyperlipemia.
DISCLOSURE OF THE INVENTION
The inventors of the present invention conducted various research to achieve the foregoing objects, and as a result, they found that novel benzimidazole compounds represented by the formulas set out below have activity of suppressing the foaming of macrophages, and are useful as active ingredients of preventive and therapeutic medicament of arterial sclerosis and preventive and therapeutic medicament of hyperlipemia. The present invention was achieved on the basis of this finding.
According to the first aspect of the present invention, there are provided benzimidazole compounds represented by the following formula (IA):
wherein, Y represents a single bond or sulfur atom; Z represents oxygen atom, sulfur atom or N—R
4
; R
1
and R
2
independently represent hydrogen atom, a halogen atom, an alkyl group, a haloalkyl group, an aryl group, an alkoxy group, an aryloxy group, an alkoxycarbonyl group, a carbamoyl group, a sulfamoyl group, an acylamino group, a sulfonylamino group, cyano group, hydroxyl group, or nitro group; R
3
and R
4
independently represent hydrogen atom, an alkyl group, an acyl group, a sulfonyl group, an alkoxycarbonyl group, a sulfamoyl group, or a carbamoyl group; n and m each independently represent an integer of 1, 2 or 3, and where n or m represents 2 or 3, two or three R
1
or R
2
which may be the same or different substitute on the benzene ring, respectively; and L represents a linking group selected from a group consisting of a C
2-12
alkylene group, and an alkylene group containing one or more phenylene groups or ether groups and having 4-12 atoms that constitute a full length of a linking chain; provided that R
1
and R
2
do not represent the same substituents when Y is sulfur atom, Z is N—R
4
, n=m, and R
3
and R
4
represent the same substituents.
According to the second aspect of the present invention, there are provided benzimidazole compounds represented by the following formula (IB):
wherein, Y represents a single bond or sulfur atom; R
5
represents hydrogen atom, a halogen atom, an alkyl group, a haloalkyl group, an aryl group, an alkoxy group, an aryloxy group, an alkoxycarbonyl group, a carbamoyl group, a sulfamoyl group, an acylamino group, a sulfonylamino group, cyano group, hydroxyl group, or nitro group; R
6
represents hydrogen atom, an alkyl group, an acyl group, a sulfonyl group, an alkoxycarbonyl group, a sulfamoyl group, or a carbamoyl group; n represents an integer of 1, 2 or 3, and when n represents 2 or 3, two or three R
5
which may be the same or different substitute on the benzene ring, respectively; L represents a linking group selected from a group consisting of a C
2-12
alkylene group, and an alkylene group containing one or more phenylene groups or ether groups and having 4-12 atoms that constitute a full length of a linking chain; and Q represents a substituted or unsubstituted 5- or 6-membered heterocyclic group, or a substituted or unsubstituted condensed heterocyclic group containing 8-10 ring-membered atoms.
The present invention further provides methods for preparing the compounds represented by the above formula (IA) or (IB), medicaments comprising the compounds represented by the above formula (IA) or (IB), and methods for manufacturing the medicaments comprising the compounds represented by the above formula (IA) or (IB). As a preferred embodiment of the medicament of the present invention, there is provided a pharmaceutical composition which comprises the aforementioned compound as an active ingredient together with a pharmaceutical additive. The pharmaceutical compositions of the present invention are useful as, for example, a preventive and/or therapeutic medicament for hyperlipemia, a preventive and/or therapeutic medicament for arterial sclerosis, an agent for suppressing foaming of macrophages, an agent for retracting arterial sclerosis lesions, an agent for inhibiting the formation of arterial sclerosis lesions, a cholesterol-lowering agent and the like. Use of the compounds represented by the above formula (IA) or (IB) for the manufacture of the aforementioned pharmaceutical composition is also provided as an aspect of the present invention.
According to further aspects of the present invention, there are provided a method for preventive and/or therapeutic treatment of a disease selected from a group consisting of hyperlipemia and arterial sclerosis, which comprises the step of administering a preventively or therapeutically effective amount of the compound represented by the above formula (IA) or (IB) to a patient, and a method for preventive and/or therapeutic treatment of a disease caused by the foaming of macrophages, which comprises the step of administering a preventively or therapeutically effective amount of the compound represented by the above formula (IA) or (IB) to a patient.
Best Mode for Carrying out the Invention
In the above formula (IA), Y represents a single bond or sulfur atom. When Y represents a single bond, the carbon atom between the two nitrogen atoms of the imidazole ring to which R
3
binds (2-position carbon atom of the benzimidazole ring) directly binds to the linking group L. Among them, Y is preferably sulfur atom. Z represents oxygen atom, sulfur atom, or N—R
4
, thereby a condensed heterocyclic ring containing Z represents benzoxazole, benzothiazole, or benzimidazole ring.
R
1
and R
2
independently represent a hydrogen atom, a halogen atom, an alkyl group, an aryl group, an alkoxy group, an aryloxy group, an alkoxycarbonyl group, carbamoyl group, sulfamoyl group, an acylamino group, a sulfonylamino group, cyano group, hydroxyl group, or nitro group, and n and m independently represent an integer of 1,2, or 3. It is preferred that R
1
and R
2
independently represent hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an acylamino group, sulfonylamino group, or an alkoxycarbonyl group, and it is particularly preferred that they
Aikawa Kazuhiro
Aoki Kozo
Birch & Stewart Kolasch & Birch, LLP
Fuji Photo Film Co. , Ltd.
Stockton Laura L.
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