Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-06-29
2004-03-16
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S364000, C514S253010, C540S575000
Reexamination Certificate
active
06706703
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to bis(5-aryl-2-pyridyl) derivatives or salts thereof, and also to medicinal compositions which comprise the bis(5-aryl-2-pyridyl) derivatives or salts thereof as active ingredients and are useful for the prevention or treatment of allergic immune diseases.
2. Discussion of the Background
IgE, a class of immunoglobulin (Ig), is an allergen-specific molecule produced by IgE producing cells differentiated from B cells, when triggered by contact of immunocytes with an allergen in the body.
IgE is produced in an organ targeted by allergy, and binds to a receptor on surfaces of mast cells which are the principal effector cells in an allergic reaction or basophils (sensitized state). From the mast cells, which are stimulated as a result of intrusion of the allergen into the body after sensitization and the accompanying reaction with the specific IgE, allergic chemical mediators such as histamine, leucotrienes, prostaglandins and PAF, and tissue destructive enzymes such as tryptase are released thereby provoking the immediate responses of an allergic reaction such as increased vasopermeability, smooth muscle constriction or vasodilation. From the stimulated mast cells, cytokines, such as IL-4, which directly activate other immune system cells are also secreted. As a result, eosinophils, basophils or the like infiltrate tissues, and allergic chemical mediators or tissue destructive proteins such as MBP, which are secreted by these inflammatory cells, induces late responses of an allergic reaction to protract and worsen an allergic symptom.
As can be appreciated from the foregoing remarks, an abnormality in IgE production is highly relevant to various allergic immune diseases such as asthma, atopic dermatitis, allergic rhinitis, inflammatory bowel disease, contact dermatitis and allergic ophthalmopathy. It is known that inhibition of IgE production makes it possible to prevent and/or treat these diseases (Emerging Therapeutic Targets In Asthma And Allergy: Modulation Of IgE,
Emerging Therapeutic Targets,
3, 229-240 (1990); Anti-IgE As Novel Therapy For The Treatment Of Asthma,
Curr. Opin. Plum. Med.,
5, 76-80 (1999); Treatment Of Allergic Asthma With Monoclonal Anti-IgE Antibody,
N. Eng. J. Med.,
341, 1966-1973 (1999); Anti-IgE Antibody Therapy For Asthma,
N. Eng. J. Med.,
341, 2006-2008 (1999)).
From the foregoing, IgE is believed to be a substance which takes part in the manifestation of an allergic disease at the onset of the disease. With the objective of developing antiallergic agents, some small molecules with IgE antibody production inhibiting activity have been found and reported to date (WO 98/04058, WO 98/07702, WO 98/16497, JP 10-324631A, WO 99/19291, WO 99/35140, WO 99/38829, WO 99/42446, JP 11-269192A, WO 00/05198, “Yakuri to Chiryo (Basic Pharmacology & Therapeutic)” 22(3), 1369 (1994), JP 1-106818A, JP 7-17506B, JP 8-92216A, JP 8-109177A, WO 96/11682, JP 59-167564A). These compounds, however, involve problems such as low solubility in water, and therefore they are not entirely satisfactory agents in the therapeutic treatment of allergic disease.
SUMMARY OF THE INVENTION
Accordingly, one object of the present invention is to provide a compound having excellent IgE antibody production inhibiting activity and also a medicinal composition comprising the compound as an active ingredient.
Briefly, this object and other objects of the present invention as hereinafter will become more readily apparent can be attained by a bis(5-aryl-2-pyridyl) compound having the following formula (1) or a salt thereof:
wherein A is a substituted or unsubstituted aromatic hydrocarbon group or a substituted or unsubstituted aromatic heterocyclic group, and X is a substituent selected from the group consisting of formulas (2) to (5):
wherein, in formula (2), m is an integer of 1 or 2; in formula (3), n is an integer of 1 to 6; and in formula (4), R is hydrogen or lower alkyl and p is an integer of 1 to 6.
Another aspect of the present invention is a medicinal composition comprising the active bis(5-aryl-2-pyridyl) compound or the salt thereof of the invention.
Still another aspect of the present invention is a medicinal composition comprising the active bis(5-aryl-2-pyridyl) compound or the salt thereof in combination with a pharmacologically acceptable carrier.
Yet another aspect of the present invention is a method of treating a subject for an allergic immune disease by administering the bis(5-aryl-2-pyridyl) derivative or the salt thereof of the invention to a subject.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
As a result of the investigative work by the present inventors, the present compound has been found to exhibit an excellent IgE antibody production inhibiting activity and also good solubility in water, and therefore are useful in the treatment of allergic immune diseases.
Illustrative of the lower alkyl moiety in “lower alkyl groups”, “halogeno(lower alkyl) groups”, “hydroxy(lower alkyl) groups”, “lower alkoxy(lower alkyl) groups”, “lower alkoxy groups”, “(lower alkyl)thio groups”, “(lower alkyl)amino groups”, “(lower alkyl)sufonylamino groups”, “(lower alkoxy)carbonyl groups” and “lower alkanoyl groups” as used herein are linear, branched or cyclic alkyl groups having 1 to 6 carbon atoms. Suitable examples of lower alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, cyclopropyl, and cyclohexyl. Further, suitable halogen atoms include fluorine, chlorine, bromine and iodine.
In formula (1), the aromatic hydrocarbon group represented by A preferably has 6 to 14 carbon atoms, with phenyl or naphthyl being more preferred and phenyl being particularly preferred. Preferred examples of the aromatic heterocyclic group include 5- to 10-membered heterocyclic groups each of which contains one or two nitrogen, oxygen or sulfur atoms, with pyridyl, thienyl, furyl, benzofuryl and benzothienyl groups being more preferred. These groups may contain 1 to 3 substituents. Suitable examples of such substituents include lower alkyl groups, halogeno(lower alkyl) groups, hydroxy(lower alkyl) groups, lower alkoxy(lower alkyl) groups, lower alkoxy groups, halogen atoms, hydroxy group, cyano group, (lower alkyl)thio groups, amino group, mono- or di-(lower alkyl)amino groups, (lower alkyl)sufonylamino groups, formyl group, carboxyl group, (lower alkoxy)carbonyl groups, lower alkanoyl groups, pyrrolidinyl group and alkylenedioxy groups.
Preferred specific examples of these substituents include methyl, t-butyl, trifluoromethyl, hydroxymethyl, methoxymethyl, methoxy, ethoxy, isopropoxy, fluoro, chloro, hydroxy, cyano, methylthio, amino, dimethylamino, methanesulfonylamino, pyrrolidinyl, formyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, acetyl, and methylenedioxy.
Among the groups represented by X, preferred is the group of formula (3) in which n is an integer of 2 to 4 and the group of formula (4) in which p is an integer of 2 to 4.
Preferred specific examples of the bis(5-aryl-2-pyridyl) derivative (1) of the present invention include 1,4-bis[5-(3,4,5-trimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepine dimethanesulfonate, 1,4-bis[5-(4-amino-3,5-dimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepine tetrahydrochloride, 1,4-bis[5-(4-dimethylamino-3,5-dimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepine, 1,3-bis[4-[5-(3,4,5-trimethoxyphenyl)-2-pyridyl]-1-piperazinyl]propane, and N,N′-bis[5-(3,4,5-trimethoxyphenyl)-2-pyridyl]-N,N′-dimethylethylenediamine dimethanesulfonate.
Compound (1) of the present invention can be produced, for example, by the following sequence of reaction steps, although no particular limitation is imposed on the method of synthesis employed.
wherein A and X have the same meanings as defined above, Y
1
and Y
2
each are halogen or—OSO
2
(C
q
F
2q+1
) in which q is 0 or an integer of 1 to 4, and Z is dihydroxyboron, di(lower alkoxy)boron, di(lower alkyl)boron, diha
Ishiwata Hiroyuki
Kabeya Mototsugu
Oda Soichi
Sato Seiichi
Shibasaki Manabu
Kowa Co. Ltd.
Liu Hong
Shah Mukund J.
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