Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-12-20
2003-03-04
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S321000, C514S322000, C514S324000, C514S326000, C514S331000, C544S319000, C544S362000, C544S364000, C544S366000, C544S367000, C544S382000
Reexamination Certificate
active
06528514
ABSTRACT:
TECHNICAL FIELD
The present invention relates to an IgE antibody production inhibitor and an autoimmune disease suppressant which are characterized by comprising a heterocyclic amide compound having a specific structure or a pharmaceutically acceptable salt thereof as an active ingredient.
BACKGROUND ART
The incidence of allergic diseases such as bronchial asthma, allergic rhinitis, allergic dermatitis, etc. has been increasing remarkably in recent years and is a serious social concern today. These allergic diseases are classified as Type I allergic reaction and the mechanism of pathogenesis of these diseases is suspected to be as follows.
Namely, in the first phase, the invasion of an antigen into the body results in interactions of macrophages, T cells, B cells, etc. causing production of an IgE antibody which is closely involved in Type I allergic reaction and the body is sensitized as this IgE antibody is bound to the receptors on tissue mast cells or blood basophils. In the second phase that ensues, the antigen reinvading the body attaches to the IgE antibody bound to the receptors and the resulting antigen-antibody reaction triggers a degranulation causing an extracellular release of various mediators such as histamine, SRS-A, etc. Further, in the third phase, the released mediators induce various allergic reactions owing to their smooth muscle-contacting action, vascular permeability-enhancing action, secretion-stimulating action and the like.
Many of the therapeutic agents and prophylactic agents for allergic diseases which have been developed and put on the market are drugs acting on the above-mentioned second phase or third phase. Since the basic cause of allergic diseases is the production of IgE antibodies in the body, any drug which could inhibit or suppress the production of IgE antibodies should be expected to have a remarkable efficacy for radical therapy in light of the above mechanism of pathogenesis.
Furthermore, in many cases, autoimmune diseases such as systemic lupus erythematosus, Hashimoto's thyroiditis, myasthenia gravis, rheumatoid arthritis, Guillain-Barré syndrome, glomerulonephritis, systemic erythematosus, etc. accompany an abnormal regulation of cellular immunity and humoral immunity and are associated with an abnormality or enhancement of the effector function of T cells, B cells and macrophages which is directed to autoantigens in the blood. The activation of such cellular components against autoantigens is considered to be related to the derangement of the feedback system relevant to autogenous resistance.
An autoimmune disease produces symptoms in one or more specific sites of the various organs of the body but is characterized in that such symptoms have much in common in the multiple sites. Moreover, there is a characteristic tendency that these symptoms are invariably chronic, subside unaccountably at times or flare up spontaneously, and are even associated with symptoms in other organs in the manner of a chain reaction.
It is generally acknowledged that such autoimmune diseases cause the appearance of autoantibodies in the blood, inappropriate Class II antigen expression, macrophage activation, and T-cell infiltration into target organs, and the like. However, the trigger mechanism involved in the activation of autoimmune diseases has not been made clear, nor has the mechanism of progression of autoimmune diseases been elucidated. Therefore, both prophylactic and therapeutic methods are still in quite unsatisfactory state today.
For suppressing of autoimmune diseases, various therapeutic methods inclusive of administration of drugs such as gold salts, methotrexate, antimalarials, glucocorticoids (e.g. methylprednisolone), etc.; plasmapheresis; resistance induction, etc. have been attempted but in efficacy as well as in terms of side effects, none have proved satisfactory enough.
There is an urgent need, therefore, for the development of drugs which could suppress autoimmune diseases with little risk for side effects.
SUMMARY OF THE INVENTION
In the above state of the art, the present invention has an object to provide a pharmaceutically useful IgE antibody production inhibitor comprising a substance having IgE antibody production inhibitory action as an active ingredient. A further object of the invention, in the above state of the art, is to create an entirely new autoimmune disease suppressant.
The first aspect of the present invention is an IgE antibody production inhibitor comprising a heterocyclic amide compound of the following general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient;
wherein R represents a hydrogen atom, alkyl, —CHO, —COOH, —CONH
2
, —COR
1
, —COOR
1
, —CONHOR
1
, —CONHR
1
, CONR
1
R
1′
, —CONHSO
2
R
1
, —COSR
1
, —COCOR
2
, —COCOOR
2
, —CONHCOOR
2
, —COCONR
3
R
4
, —CSXR
1
, —SO
2
WR
1
, —SO
2
NR
1
R
1′
, or —SO
2
E;
R
1
and R
1′
may be the same or different and each represents alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle or heterocyclic alkyl;
R
2
, R
3
and R
4
may be the same or different and each represents a hydrogen atom, alkyl or arylalkyl, or R
3
and R
4
of —NR
3
R
4
may be combined each other to form a heterocycle;
X represents a single bond, an oxygen atom, a sulfur atom, or —NH—;
W represents a single bond, —NH—, —NHCO—, —NHCOO— or —NHCONH—;
E represents hydroxyl group or amino;
R
5
, R
6
and R
7
may be the same or different and each represents a hydrogen atom or alkyl, or one of R
5
, R
6
and R
7
represents aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl or heteroarylalkenyl, with each of the remaining two representing a hydrogen atom;
M represents a carbon atom or a nitrogen atom and when M represents a nitrogen atom, R
6
does not exist;
Y represents cycloalkyl, aryl or heteroaryl;
Z represents a hydrogen atom, —CF
2
R
8
, —CF
2
CONR
9
R
10
, —CF
2
COOR
9
, —COOR
9
, —CONR
9
R
10
, a group of the following formula (i), a group of the following formula (ii), or a group of the following formula (iii);
R
8
represents a hydrogen atom, halogen, alkyl, perfluoroalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, hydroxyalkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl or heteroarylalkenyl; R
9
and R
10
may be the same or different and each represents a hydrogen atom, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, heterocyclic alkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl or heteroarylalkenyl, or R
9
and R
10
of —NR
9
R
10
may be combined each other to form a heterocycle;
wherein
a, b, c and d respectively represents a carbon atom or one of a, b, c and d represents a nitrogen atom with each of the remaining three representing a carbon atom;
R
11
, R
12
, R
13
and R
14
may be the same or different and each represents a hydrogen atom, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halogen, trifluoromethyl, cyano, nitro, —N
17
R
17′
, —NHSO
2
R
17
, —OR
17
, —COOR
17
, —CONHSO
2
R
17
or —CONR
17
R
17′
; provided that when one of a, b, c and d represents a nitrogen atom, R
11
, R
12
, R
13
or R
14
combined to the nitrogen atom mentioned for a, b, c or d does not exist;
R
15
and R
16
may be the same or different and each represents a hydrogen atom, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halogen, trifluoromethyl, cyano, nitro, —NR
17
R
17′
, —NHSO
2
R
17
, —OR
17
, —COOR
17
, —CONHSO
2
R
17
or —CONR
17
R
17′
;
R
17
and R
17′
maybe the same or different and each represents a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl or trifluoromethyl, or R
17
and R
17′
of —NR
17
R
17′
may be combined each other to form a heterocycle;
A represents an oxygen atom, a sulfur atom or —NR
18
—; R
18
represents a hydrogen atom, alkyl, cycloalkyl or cycloalkylalkyl;
n represents 0 or 1;
said alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heterocycle and heterocy
Imada Teruaki
Kobayashi Fujio
Komorita Naruyasu
Kuwahara Shigeki
Naito Koji
Shah Mukund J.
Truong Tamthom N.
Welfide Corporation
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