Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-06-05
2004-11-09
Morris, Patricia L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S199000
Reexamination Certificate
active
06815455
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.
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 hyperlipidemia.
DISCLOSURE OF THE INVENTION
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.
The compounds represented by the formula (I) according to the present invention have an inhibitory action against the foaming of macrophages independent from the ACAT inhibitory activity, and achieve remarkable effects in preventive and/or flit therapeutic treatment of arteriosclerosis based on the action. As benzimidazole compounds, available compounds include those known as active ingredients of medicaments for other applications (for example, the compounds of International Patent Publication W095/34304) or those known as synthetic intermediates for drugs, agricultural chemicals or the like (for example, Chim. Chronika., Vol. 9(3), 239-246 (1980)). However, as demonstrated in the examples, the benzimidazole compounds known so far fail to inhibit the foaming of macrophages, and specific action of the compounds of the present invention are not suggested in view of these compounds.
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; R
3
represents one or more functional groups (including hydrogen atom) on the ring containing the nitrogen atom and A; A represents O, CH
2
or CH that forms a double bond with an adjacent carbon atom; L represents a C
4
-C
8
alkylene group or an ethyleneoxy bridging group represented by (CH
2
CH
2
O)
n
CH
2
CH
2
(in the formula, n represents 1 or 2); X represents O, S or methylene group; and m represents 0 or 1] and salts thereof.
The present invention also provides benzimidazole compounds represented by the following formula (II):
[in the formula, R
11
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
12
represents hydrogen atom, an alkyl group, or an acyl group; R
13
represents one or more functional groups on the piperidine ring selected from the group consisting of hydrogen atom, an alkyl group, an aryl group, hydroxy group, an alkoxy group, an amino group, an acyl group, cyano group, a carbamoyl group, and an alkoxycarbonyl group; L
1
represents a C
4
-C
8
alkylene group; and X represents O, S, or methylene group] and salts thereof.
As other aspects of the present invention, provided are methods for preparing the compounds represented by the aforementioned formula (I) or (II), and medicaments comprising a compound represented by the aforementioned formula (I) or (II) 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 (II) 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 (II) 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, or a combination thereof. For example, an alkyl group having 1-4 carbon atoms (for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group and the like) may be used. A halogen atom referred to in the specification may be any of fluorine atom, chlorine atom, bromine atom and iodine atom.
An alkyl group or an alkyl moiety of a functional group that contains the alkyl moiety (e.g., an alkoxy group, an alkanoyl group and the like) referred to in the specification may be linear, branched or cyclic alkyl group, or a combination thereof. An example includes an alkyl group having 1-8 carbon atoms (e.g., methyl group, ethyl group, butyl group, octyl group and the like), and a preferred example includes an alkyl group having 1-4 carbon atoms (e.g., methyl group, ethyl group, n-propyl group, n-butyl group). An aryl group or an aryl moiety of a functional group that contains th
Aikawa Kazuhiro
Aoki Kozo
Kawakami Masayuki
Yan Yongzhe
Fuji Photo Film Co. , Ltd.
Morris Patricia L.
LandOfFree
Benzimidazole compounds and drugs containing the same 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 and drugs containing the same, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Benzimidazole compounds and drugs containing the same will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3305651