Benzimidazole compounds

Details Benzimidazole compounds Benzimidazole compounds

2002-06-05

2004-09-07

Stockton, Laura L. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S387000, C514S242000, C514S255050, C514S274000, C514S312000, C514S367000, C514S369000, C514S375000, C514S381000, C548S305400, C548S251000, C548S181000, C548S159000, C548S221000, C546S273700, C546S157000, C544S405000, C544S298000, C544S182000

Reexamination Certificate

active

06787561

ABSTRACT:

TECHNICAL FIELD
The present invention relates to benzimidazole compounds useful as active ingredients of medicaments.
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 hyperlipidemia 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. Medications currently applied for treatment of hyperlipidemia and arterial sclerosis are those symptomatically lower cholesterol in blood, and no medicament that can be expected to have potency in retracting arterial sclerosis lesions has been used clinically. 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.
It has been suggested that an inhibitor of ACAT, an enzyme involved in intestinal absorption and metabolism of cholesterol, such as imidazole derivatives described in Bio. Med. Chem. Lett., Vol. 5(2), 167-172 (1995) reduces blood cholesterol level and thus suppresses the foaming of macrophages in an animal experiment (for example, piperazine derivatives described in International Publication WO98/54153). However, since these compounds are directed to ACAT inhibitory activity, they do not achieve satisfactory inhibition of the foaming of macrophages, and their effects are insufficient.
Some amide compounds are reported to have ACAT inhibitory action (for example, the amide compounds disclosed in International Publication WO99/25712). However, ACAT inhibitors have recently been recognized to have various toxicities and side effects (for example, Toxycol. Pharmacol., 22, 510-518 (1994); Toxicol. Appl. Pharmacol., 140, 387-392 (1996)). It is considered that medicaments for treatment of arteriosclerosis, which are required to be administered for a long period of time, advantageously have no ACAT inhibitory action with such side effects.
Some benzimidazole compounds are suggested to suppress the foaming of macrophages (for example, the imidazole compounds disclosed in EP849259). However, the compounds are not satisfactory in suppression of the foaming of macrophages and they fail to exert potent effect in vivo because their uptakes into animal bodies are very poor. As medicaments for treatment of arteriosclerosis or hyperlipidemia are taken by patients for a long period of time at home, the medicaments are required to be developed as oral preparations. Therefore, it is essential that these medicaments give a high value of AUC (area under the plasma concentration) that relates to uptake into living bodies through oral administration. However, the conventional imidazole compounds have a problem of poor oral absorbability.
DISCLOSURE OF THE INVENTION
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 hyperlipidemia. In particular, the object of the present invention is to provide a compound that can achieve the desired therapeutic effect by oral administration.
The inventors of the present invention conducted various researches to achieve the foregoing objects, and as a result, they found that novel benzimidazole compounds represented by the formula (I) set out below have activity of suppressing the foaming of macrophages, and are useful as active ingredients of preventive and/or therapeutic medicament of arterial sclerosis and preventive and/or therapeutic medicament of hyperlipidemia. They also found that these compounds can readily be uptaken into living bodies and exert superior therapeutic effect by oral administration. The present invention was achieved on the basis of these findings.
The present invention thus provides benzimidazole compounds represented by the following formula (I):
[in the formula, R
1
represents one or more functional groups on the benzene ring selected from the group consisting of hydrogen atom, a halogen atom, a lower alkyl group, and a lower alkoxy group; R
2
represents hydrogen atom, an alkyl group, or an acyl group; L represents a C
4
-C
8
alkylene group or an ethyleneoxy linking group represented by (CH
2
CH
2
O)
n
CH
2
CH
2
(in the formula, n represents 1 or 2); X represents O or NH (NH may have a functional group on the nitrogen atom); Y represents S or a single bond; and Q represents a 5- or 6-membered heterocyclic group which may have a functional group on the ring (the heterocyclic group may have a condensed ring)] and salts thereof.
According to preferred embodiments of the present invention, provided are the aforementioned compounds and salts thereof, wherein Y is S; the aforementioned compounds and salts thereof, wherein R
1
and R
2
represent hydrogen atom; the aforementioned compounds and salts thereof, wherein L is a C
4
-C
8
alkylene group; the aforementioned compounds and salts thereof, wherein Q is a residue of a heterocyclic ring selected from the group consisting of pyridine, pyrimidine, pyrazine, triazine, quinoline, pyrrole, thiophene, furan, imidazole, pyrazole, triazole, tetrazole, thiazole, thiadiazole, oxazole, oxadiazole, benzimidazole, benzoxazole, and benzothiazole; the aforementioned compounds and salts thereof, wherein X is O; and the aforementioned compounds and salts thereof, wherein Q is a residue of a heterocyclic ring selected from the group consisting of pyridine, thiazole, benzimidazole, benzoxazole and benzothiazole.
As other aspects of the present invention, provided are methods for preparing the compounds represented by the aforementioned formula (I), and medicaments comprising a compound represented by the aforementioned formula (I) or a physiologically acceptable salt thereof as an active ingredient. As preferred embodiments of the aforementioned medicaments, pharmaceutical compositions are provided which comprise the aforementioned compounds or a physiologically acceptable salt thereof as an active ingredient and an additive for pharmaceutical preparation. The medicaments of the present invention are useful as, for example, those for preventive and/or therapeutic treatment of hyperlipidemia and for preventive and/or therapeutic treatment of arteriosclerosis. The medicaments are also useful as agents for suppressing foaming of macrophages, agents for retracting arterial sclerosis lesions, and agents for inhibiting formation of arteriosclerotic lesion.
As further aspects of the present invention, provided are uses of the compounds represented by the aforementioned formula (I) or salts thereof for manufacture of the aforementioned medicaments, and methods for preventive and/or therapeutic treatment of hyperlipidemia and methods for preventive and/or therapeutic treatment of arteriosclerosis, which comprise the step of administering a preventively and/or therapeutically effective amount of the compound represented by the aforementioned formula (I) or a physiologically acceptable salt thereof to a mammal including human.
BEST MODE FOR CARRYING OUT THE INVENTION
In the specification, a lower alkyl group or a lower alkyl moiety of a functional group that contains the lower alkyl moiety (e.g., lower alkoxy group) may be a linear, branched or cyclic alkyl group, o

Affiliated with

Also associated with

Rating

Benzimidazole compounds does not yet have a rating. At this time, there are no reviews or comments for this patent.

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

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3210402