Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-07-12
2002-05-14
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...
C548S304400, C548S306100, C548S309700, C548S310100, C548S310400, C548S310700
Reexamination Certificate
active
06387938
ABSTRACT:
TECHNICAL FIELD
This invention relates to novel benzimidazole derivatives, and more specifically, 3-(2-(2-phenylethyl)benzimidazol-4-yl)-3-hydroxypropanoic acid and its esters, and compounds and optically active compounds thereof; a process for producing the same; drugs containing at least one of these compounds as the active ingredient, and in particular, a drug for preventing and/or treating diseases exhibiting eosinophilia, bronchial asthma or allergic diseases; otherwise an enhancer for interferon-y production, and in particular, an antitumor agent or an antiviral agent based on the action of enhancing the production of the interferon-&ggr; which is effective in oral administration.
BACKGROUND ART
A phenomenon in which eosinophils increase in blood or tissues, namely differentiating, Inducing or infiltrating phenomenon, is observed in many diseases. It is important from the clinical point of view to differentiate these diseases between certain diseases in which eosinophilia is frequently observed but its direct concern in pathophysiology is no and other diseases in which eosinophils are probably concerned as the main immune cell in the pathophysiology of such diseases. Addison disease, ulcerative colitis and the like diseases can be exemplified as diseases which correspond to the former case. Examples of the latter case include parasite infection, hypereosinophilic syndrome (HES), eosinophilic pneumonia, eosinophilic enterogastritis, bronchial asthma and the like diseases. Since eosinophils are closely related to the pathophysiology of bronchial asthma, so-called eosinophilic bronchitis is recently taking root as a pathophysiology concept. Particularly, there are some common points among movements of eosinophils which are concerned in these diseases. That is, they are summarized into three points of 1) acceleration of eosinophil production and differentiation by eosinophil growth lymphokines mainly including interleukin 5 (IL-5), 2) migration and accumulation of eosinophils into an involved organ by eosinophil chemotactic activity and 3) activation of eosinophils and prolongation of their life survival in the morbid sites. It is considered that the just described three factors or matters exert tissue damage and inflammation inducing actions of eosinophils in these diseases, thereby concerning in their pathophysiology, though there are differences in terms of foci and the degree of clinical symptoms. Also, though there are differences in terms of the increasing degree of eosinophils, atopic dermatitis, allergic rhinitis and the like various diseases can be exemplified as the diseases which exhibit eosinophilia (S. Nakajima and J. Shigehara, Meaning of the Clinical Diagnoses of eosinophils, “Eosinophils” ed. by S. Makino and K. Ishikawa, pp. 165-173, Kokusai Igaku Shuppan, 1991).
In consequence, a compound which controls eosinophils, or inhibits increment or activation of eosinophils in blood or tissues, could be applied to parasite infection, hypereosinophilic syndrome (HES), eosinophilic pneumonia, eosinophilic enterogastritis, bronchial asthma, atopic dermatitis, allergic rhinitis and the like diseases that exhibit eosinophilia.
Under the present situation, only the administration of steroid drugs is attempted as a symptomatic therapy for the treatment of diseases which exhibit eosinophilia, and there are no therapeutic methods which target eosinophils. It is extremely difficult to use steroid drugs, because they frequently cause peculiar side effects such as reduction of resistance against bacterial infection, hyperglycemia, diabetes, gastric ulcer, hyperkalemia, osteoporosis, obesity and the like, and their use is strictly stipulated such as prohibition of sudden termination of their administration. In addition, conventional asthma-treating drugs have been developed mainly based on histamine release inhibition action and the like, and it has been revealed that eosinophils are closely concerned also in this pathophysiology, so that the use of eosinophils as a target could be applied to certain types of asthma which cannot be treated by the conventional method. Under such situation, a compound which has high safety and can strongly control eosinophils seems to be markedly useful in a method of fundamental medical treatment of various diseases in which eosinophilia is concerned, so that realization of such a compound as a pharmaceutical preparation is strongly desired.
With regard to a compound of benzimidazole skeleton having a phenylethyl side chain on its partial structure, JP-A-3-109378 discloses that certain compounds having actions to inhibit both cyclooxygenase (CO) and lipoxygenase (LO) enzymes are useful in treating or alleviating allergic or inflammatory conditions, but it does not disclose their pharmacological data so that the strength of action of each compound and its detailed action mechanism are not clear (the term “JP-A” as used herein means an “unexamined published Japanese patent application”). Also, JP-A-61-65848 discloses a compound which selectively inhibits 5-lipoxygenase and discloses that it is effective in a rat adjuvant arthritis model and inhibits release of SRS-A in rat passive peritoneal anaphylaxis (PPA). However, these prior art benzimidazole derivatives are different from the compounds of the present invention in terms of their structures, and these patents do not disclose about the effect of these derivatives to inhibit increment or activation of eosinophils.
With regard to a compound of benzimidazole skeleton having a carboxylic acid or ester structure on its side chain, U.S. Pat. No. 5,216,003 discloses a compound which is useful as an NMDA antagonist in neurodegenerative diseases and neurotoxin disorders. Structure of this prior art benzimidazole derivative is also different from that of the compound of the present invention, and the patent does not disclose actions against eosinophils.
With regard to the compounds which enhance the production of interferon-&ggr; (hereinafter abbreviated as IFN-&ggr;), JP-A 10-251148 discloses that 1-(carbozole-4-iloxy)-3-[[2-(o-methoxyphenoxy)ethyl]amino]-2-propanol and the optically active compounds thereof which are the promoters of the IFN-&ggr; production have the action of eliminating viral infection, and in particular, that such compounds are capable of reliably eliminating the cause of acute myocarditis associated with viral infection, and effectively treating the acute myocarditis. JP-A 8-143592 discloses that the peptides having the action of promoting the IFN-&ggr; production promote cell propagation in the cell culture of normal mouse hepatic cell line (NCTC Clone 1469) and such peptides specifically promote the IFN-&ggr; production of the cell in such cell culture. Furthermore, JP-A 4-208271 discloses that a promoter for the production of IFN-&ggr; and the compound having the action of promoting interleukine-2 (hereinafter abbreviated as to as IL-2) are capable of producing IFN-&ggr; and IL-2 from the monocyte of human peripheral blood, and such compounds are effective as a therapeutic agent for viral infection.
However, the compounds which promote the IFN-&ggr; production as described above are different in their structure from the compounds of the present invention. In addition, in spite of the disclosure of promoting the cytokine production by directly stimulating the immunocompetent cell, there is no indication of providing the immunocompetent cell with the character of increased basal production rate of IFN-&ggr; under stationary conditions without any immuno stimulation.
With regard to the benzimidazole derivatives, and in particular, 3-(2-(2-phenylethyl)benzimidazol-4-yl)-3-hydroxypropanoic acid and its esters, Kato et al. (The Journal of Immunology, vol.162, pages 7470-7479, 1999) reports that, when such compounds are orally administered and the splenocytes are cultured in the presence of an antigenic stimulant such as concanavalin A and ascarid extract, production of IL-4 and IL-5 is suppressed with simultaneous enhancement in the production of IFN-&ggr;. Howev
Kato Yutaka
Matsuura Kazuyuki
Mizuguchi Kiyoshi
Nakai Yasuhiro
Ohnishi Shuhei
Birch & Stewart Kolasch & Birch, LLP
Mochida Pharmaceutical Co. Ltd.
Morris Patricia L.
LandOfFree
Benzimidazole derivatives 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 derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Benzimidazole derivatives will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2862483