Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-10-22
2004-01-13
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S266200, C514S266100, C514S230500
Reexamination Certificate
active
06677344
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a medicament for the prevention or treatment of a disease accompanied with an increase in eosinophils, a pharmaceutical composition for the prevention or treatment of allergic diseases, and a medicament for suppressing an increase in eosinophils.
BACKGROUND ART
Eosinophils are granulocytes comprising 1 to 3% of peripheral blood leukocytes and are believed to be involved in allergic dermatitis or bronchial asthma and other allergic diseases or parasitic infections and other conditions (
Eur. Respir. J. Suppl.
22, 109s, 1996). A disease condition where the ratio of eosinophils in the peripheral blood increases to 6% or more is called “eosinophilia”. This condition is also observed in various skin disease (e.g., herpes, cnidosis, psoriasis, eczema), hematological diseases (e.g., myelocytic leukemia, pernicious anemia), infectious diseases, (e.g., cholera, malaria), and, bone diseases (e.g., sarcoma, rickets, myelitis), etc. in addition to the above diseases.
Eosinophils have granules containing basic cytotoxic proteins called MBP (major basic proteins), ECP (eosinophil cationic proteins), EDN (eosinophil-derived neurotoxins), etc. (
Pharmacol. Rev.
51, 213, 1999). When allergic reactions or inflammation reactions occur, it is believed that eosinophils migrate to and infiltrate into these inflammatory areas, then cause degranulation and release these cytotoxic proteins so as to exacerbate these reactions (
Trends Pharmacol. Sci.
16, 418, 1995). The major cytokines involved in the proliferation and differentiation of eosinophils are IL-5 (Interleukin-5), IL-3 (Interleukin-3), GM-CSF, etc. Further, RANTES or eotaxins and other chemokines play an important role in the accumulation of eosinophils in inflamed sites (
Int. Arch. Allerg. Immunol.
113, 196, 1997,
J. Leukoc. Biol.
59, 1, 1996).
It has been reported that various substances such as steroids (
Br. J. Pharmacol.
101, 821, 1990), phosphodiesterase inhibitors (
J. Pharmacol. Exp. Ther.
278, 1356, 1996), cyclosporins (
Pharmacol. Rev.
51, 213, 1999), and tacrolimus (
Br. J. Pharmacol.
120, 130, 1997) inhibit the functions of eosinophils, but they are not sufficiently satisfactory in terms of efficacy, specificity, side effects, etc. In addition, several anti-allergic agents are known to suppress the functions of eosinophils (
Pharmacol. Rev.
51, 213, 1999), but the main mechanisms of their action is an antagonist action against histamine acceptors. It is unclear to what extent this action on eosinophils is involved in the clinical effects of these medicaments. That is, the relationship between the proliferation or function of eosinophils and the diseases including eosinophilia, allergic diseases and inflammation has not yet been elucidated.
On the other hand, chymase is a serine protease stored in mast cell granules, and widely present in tissues such as the skin, heart, vascular walls, intestines, etc. (
Mast Cell Proteases in Immunology and Biology; Caughey
, G. H., Ed; Marcel Dekker, Inc.; New York, 1995). Recently, it has been reported that administration of human chymase induce infiltration of leukocytes including cosinophils in mice as well as guinea pigs (
Br. J. Pharmacol.
125, 1491, 1998). Further, it has been reported that human chymase acts on the precursor of IL-1&bgr; (Interleukin 1&bgr;) and converts it to active type IL-1&bgr; (
J. Exp. Med.
174, 821, 1991), which is known to induce eosinophil inflation by augmentation of expression of cell adhesion molecules (
Am. J. Respir. Cell. Mo. Biol.
13, 555, 1995, J. Invest. Dermatol. 100, 417, 1993). Moreover, chymase cleaves membrane-bound stem cell factor (SCF) to form soluble SCF (
Proc. Natl. Acad. Sci. U.S.A.
94, 9017, 1997). Further, recently, it has been reported that SCF is involved in the accumulation of eosinophils (
J. Immunol.
156, 3945, 1996). These findings suggest that chymase is related to the role of eosinophils. At the present time, a search is going on for substances which can inhibit the activity of chymase in vivo with the aim of clarifying the role of chymase in the body and the possibility of chymase inhibitors as pharmaceuticals.
There are chymase inhibitors such as low molecular weight chymase inhibitors such as shown in textbooks (
Protease Inhibitors
; Barrett et al., Eds; Elssevier Science B. V.; Amsterdam, 1996), &agr;-keto acid derivatives reported as peptide type inhibitors (WO93-25574,
Proc. Natl. Acad. Sci. USA,
1995, 92, 6738), &agr;,&agr;-difluoro-&bgr;-keto acid derivatives (Japanese Unexamined Patent Publication (Kokai) No. 9-124691), tripeptide inhibitors (WO93-03625), phosphoric acid derivatives (Oleksyszyn et al.,
Biochemistry
30, 485, 1991), peptide like inhibitors such as trifluoromethylketone derivatives (WO96-33974, Japanese Unexamined Patent Publication (Kokai) No. 10-53579) and acetoamide derivatives (Japanese Unexamined Patent--Publication (Kokai) No. 10-7661, Japanese Unexamined Patent Publication (Kokai) No. 10-53579, Japanese Unexamined Patent Publication (Kokai) No. 11-246437, WO99-41277, WO98-18794, WO96-39373), non-peptide type inhibitors such as triazine derivatives (Japanese Unexamined Patent Publication (Kokai) No. 8-208654 and Japanese unexamined Patent Publication (Kokai) No. 10-245384), phenol ester derivatives (Japanese Unexamined Patent Publication (Kokai) No. 10-87567), cephem derivatives (Japanese Unexamined Patent Publication (Kokai) No. 10-87493), isoxazole derivatives (Japanese Unexamined Patent Publication (Kokai) No. 11-1479), imidazolidine derivatives (WO96-04248), hydantoin derivatives (Japanese Unexamined Patent Publication (Kokai) No. 9-31061), quinazoline derivatives (WO97-11941), etc. have been reported, but no satisfactory medicament or treatment method using inhibition of the activity of chymase as a strategy for treatment has yet been established.
DISCLOSURE OF THE INVENTION
The object of the present invention is to provide safe medicament for the prevention or treatment of diseases accompanied with an increase in eosinophils, which suppresses the progress of the condition, prevents progress of complications, and improves the quality of life of the patient.
The present inventors engaged in intensive studies to attain the above object and, as a result, found that a chymase inhibitor specifically reduces the number of eosinophils in the peripheral blood, elucidated the relationship between chymase activity and the increase in number of eosinophils, whereby the present invention is completed.
In accordance with the present invention, there is provided a medicament for the prevention or treatment of diseases involving an increase of eosinophils having a chymase inhibitor as its effective ingredient.
In accordance with the present invention, there is also provided a pharmaceutical composition for the prevention or treatment of allergic diseases containing an amount of a chymase inhibitor suppressing an increase in the eosinophils and a pharmaceutically acceptable vehicle.
In accordance with the present invention, there is further provided a medicament for the suppression of an increase in eosinophils having a chymase inhibitor as its effective ingredient.
BEST MODE FOR CARRYING OUT THE INVENTION
In this specification, the diseases involving an increase in eosinophils include diseases whose onset is caused by an increase of eosinophils, diseases whose conditions are aggravated by an increase in eosinophils, and diseases whose cure is delayed by an increase in eosinophils. These diseases include, for example, allergic diseases such as bronchial asthma, allergic rhinitis, allergic conjunctivitis, cnidosis, and eczema.
The chymase inhibitor able to be used in the present invention can be selected as a substance inhibiting chymase activity by the use of methods workable by persons skilled in the art. As the method of selection, for example, the method of Example 1 explained below may be used. The compounds obtained in this way include known compounds previously reported as chymase inhibitors, for example, the low molecular weight chymase
Fukami Harukazu
Watanabe Naohiro
Burns Doane , Swecker, Mathis LLP
Daiichi Suntory Pharma Co., Ltd.
Spivack Phyllis G.
LandOfFree
Chymase inhibitor for the treatment of eosinophilia does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Chymase inhibitor for the treatment of eosinophilia, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Chymase inhibitor for the treatment of eosinophilia will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3204410