Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-07-07
2001-06-19
Oswecki, Jane (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S394000, C514S397000, C548S255000, C548S266400, C548S304700, C548S306100
Reexamination Certificate
active
06248768
ABSTRACT:
TECHNICAL FIELD
This invention relates to benzimidazole derivatives and pharmacologically acceptable salts thereof, which have both of an interleukin (IL)-4 production inhibitory activity and a phosphodiesterase IV (PDE (IV)) inhibitory activity and are useful as therapeutic or preventive drugs for acute and chronic inflammatory diseases such as atopic dermatitis, allergic rhinitis, bronchial asthma and glomerulonephritis. It also relates to a pharmaceutical composition in which the compound of this invention is used.
BACKGROUND ART
Regarding inflammatory diseases, various medicaments capable of inhibiting acute stage inflammations have been developed in recent years, but medicaments which can effectively inhibit chronic stage inflammations are still scarce so that their development is a pressing problem. Also, an anti-inflammatory drug which can be used without distinctions between acute stage and chronic stage is useful in the clinical field.
Under such circumstances, attempts are being made on the research and development of medicaments having phosphodiesterase IV (PDE (IV)) inhibitory activity. This is based on the information that PDE (IV) is concerned in acute and chronic inflammatory diseases (see for example,
J. Pharmacol. Exp. Ther.,
266(1), 306-313 (1993),
Br. J. Pharmacol. ,
120(2), 289-297 (1997) and
Am. J. Respir. Crit. Care Med.,
149(5), 1153-1159 (1994)). In reality, however, drugs so far developed merely having such an activity are effective for acute inflammatory diseases but cannot exert sufficient effects on chronic inflammatory diseases. It is considered that certain members of cytokine produced by Th2 cells as one of the subgroups of CD4
+
T cells are taking an important role in the onset of inflammatory diseases, and interleukin (IL)-4 among them is particularly concerned in chronic stage inflammatory diseases (see for example,
Am. J. Physiol.,
272 (2 Pt 1), L 253-261 (1997),
Am. J. Respir. Cell Mol. Biol. ,
10(5), 526-532 (1994) and ibid., 13(1), 54-59 (1995)).
In consequence, development of a drug having both PDE (IV) inhibitory activity and IL-4 production inhibitory activity will result in an anti-inflammatory drug which is effective on both acute and chronic inflammatory diseases. At present, PDA-641 has been reported as such a compound (cf.
Allergy Clin. Immunol.,
93, 286 (1994)), but this compound is not satisfactory because of its weak IL-4 production inhibitory activity.
Benzimidazole derivatives have been broadly studies as medicaments. JP-A-3-14579 describes a benzimidazole derivative having an imidazole group and a triazole group, but the compound is disclosed only as a therapeutic agent for heart diseases and a therapeutic agent for duodenal ulcer, so that the compound has not been known as an anti-inflammatory agent (the term “JP-A” as used herein means an “unexamined published Japanese patent application”). International Publication No. WO 94/12461 describes a benzimidazole derivative which has PDE (IV) inhibitory activity and is used in various inflammatory diseases, but the benzimidazole derivative is different from the compound of the present invention in terms of the presence or absence of triazole ring on the condensed phenyl ring, and its effects on both acute and chronic inflammatory diseases are not as expected.
The present invention contemplates providing a compound which has both IL-4 production inhibitory activity and PDE (IV) inhibitory activity and is useful in treating or preventing acute and chronic inflammatory diseases.
DISCLOSURE OF THE INVENTION
As a result of the extensive investigation, the inventors of the present invention have found that the aforementioned object can be achieved by a novel benzimidazole derivative in which a triazole group is introduced into the 5-position of the benzinidazole nucleus, and substituting positions of two alkoxy groups to be substituted on the phenyl group bonded to the 2-position are specified, thereby resulting in the accomplishment of this invention.
Accordingly, the present invention relates to a benzimidazole derivative represented by formula (I):
[wherein A represents a triazole group; R
1
and R
2
may be the same or different from each other and each represents an aliphatic hydrocarbon radical which may have an alicyclic or aromatic hydrocarbon radical or an alicyclic hydrocarbon radical; R
3
represents a hydrogen atom or a substituent group; and R
4
represents a hydrogen atom or a protective group of the nitrogen atom] or a pharmacologically acceptable salt thereof.
The benzimidazole derivative represented by the just described formula (I) or a pharmacologically acceptable salt thereof (hereinafter, referred to as “compound of the present invention”) has excellent actions of both IL-4 production inhibitory activity and PDE (IV) inhibitory activity and is useful for the treatment of various acute and chronic inflammatory diseases.
Thus, the present invention provides a pharmaceutical composition which comprises an effective amount of the compound of the present invention and a pharmacological carrier.
It particularly provides an anti-allergic or anti-inflammatory agent which comprises an effective amount of the compound of the present invention and a pharmacological carrier.
The present invention also provides use of the compound of the present invention for the production of the aforementioned pharmaceutical composition, therapeutic or preventive agent for acute and chronic inflammatory diseases and anti-allergic or anti-inflammatory agent.
The present invention further provides a method for treating and/or preventing acute and chronic inflammatory diseases, which comprises the step of administering an effective amount of the aforementioned compound of the present invention to patients.
According to the present invention, examples of the triazole group of A include 1,2,4-triazol-1-yl, 1,2,4-triazol-4-yl, 1,2,3-triazol-1-yl and 1,2,3-triazol-2-yl, of which 1,2,4-triazol-1-yl and 1,2,4-triazol-4-yl are preferred and 1,2,4-triazol-1-yl is more preferred.
Examples of the aliphatic hydrocarbon radical in R
1
or R
2
include straight- or branched-chain lower alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl and n-hexyl; and straight- or branched-chain lower alkenyl groups having 2 to 6 carbon atoms, such as vinyl, 1-propenyl, allyl, dimethylallyl, isopropenyl, 1-butenyl, 2-butenyl, 1-methyl-2-butenyl, 1,3-butanedienyl, 1-pentenyl, 2-pentenyl, 2-hexenyl and 1,4-hexanedienyl; of which straight- or branched-chain lower alkyl groups having 1 to 6 carbon atoms are preferred, and methyl, isopropyl and isopentyl are particularly preferred.
Examples of the aliphatic hydrocarbon radical having an alicyclic hydrocarbon radical according to R
1
or R
2
include the aforementioned aliphatic hydrocarbon radicals further having monocyclic alicyclic hydrocarbon radicals having 3 to 7 carbon atoms, which may have a straight- or branched-chain saturated lower alkyl group having 1 to 3 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, 3-isopropyl-cyclohexyl, cyclohexenyl, 2-methyl-2-cyclohexenyl, 3-methyl-2-cyclohexenyl, 4-ethyl-2-cyclohexenyl, cycloheptanyl and cycloheptenyl; or having alicyclic hydrocarbon radicals of cross-linked ring or polycyclic system, such as bicyclobutanyl, bicyclooctanyl, norbornyl, norborenyl and indanyl; and preferred are straight- or branched lower alkyl groups having 1 to 6 carbon atoms substituted with a monocyclic alicyclic hydrocarbon radical having 3 to 7 carbon atoms, more preferably cyclopropylmethyl and cyclopentylmethyl.
Examples of the aliphatic hydrocarbon radical having an aromatic hydrocarbon radical according to R
1
or R
2
include the aforementioned aliphatic hydrocarbon radicals further having an aromatic hydrocarbon radical such as phenyl or naphthyl, of which an aliphatic hydrocarbon radical having phenyl group is preferred, and benzyl, phenylethyl, phenylpropyl and cinnamyl are particularl
Asao Tetsuji
Hosoya Toshiyuki
Inoue Shin'ichi
Kiniwa Mamoru
Kitagawa Kazuhiro
Oswecki Jane
Sughrue Mion Zinn Macpeak & Seas, PLLC
Taiho Pharmaceutical Co. Ltd.
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