Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-01-04
2003-06-24
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S225200, C514S225500, C514S225800, C514S226200, C544S032000, C544S034000, C544S035000, C544S038000, C544S039000, C544S040000, C544S041000, C544S042000, C544S043000, C544S044000, C544S045000, C544S046000
Reexamination Certificate
active
06583138
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a heterocyclic ring condensed benzothiazine compound useful as a medicament, a medicament containing the same and processes for producing the same. More specifically, it relates to a novel heterocyclic ring condensed benzothiazine compound useful as a medicament for diseases against which the effect of inhibiting the binding of IgE receptor &ggr; and a tyrosine kinase of 72 kDa is effective.
PRIOR ART
The bronchial asthma and the atopic diseases in human beings appear in consequence of highly intriacate vital reactions. It is suspected that most of these conditions are caused because various chemical mediators liberated from mast cells and basophils, as triggered by antigen-antibody reactions, induce vital disturbances as by contracting such smooth muscles as bronchial muscles and vessels of the pulmonary circulation or enhancing permeability of blood vessels.
As the chemical mediators liberated from mast cells and basophils, histamine, leukotrienes, prostaglandins, TNF, etc. have been known. It is well known that histamine, among other substances mentioned above, is the most significant chemical mediator for the allergic rhinitis and the urticaria in human beings. The leucotrienes comprise leucotrienes B
4
, C
4
, and D
4
and the relation thereof with the asthmatic convulsion has been attracting attention.
Heretofore, the development of medicines for the prevention, alleviation, or elimination of the symptoms of allergic diseases has been aimed at repressing the creation and liberation of such chemical mediators or antagonizing the effects thereof.
Sodium cromoglycate (Intal™) having been marketed since 1969 is a typical example of these drugs.
However, the conventional antiallergic agents typified by Intal™ show difference in the chemical mediator liberation inhibitory concentration between in vitro and in vivo. Moreover, sensitivities to these drugs widely vary from patient to patient and their action mechanisms still remain unknown in many points.
Mast cells and basophils closely relating to allergic diseases have a highly affinitive receptor, Fc &egr; RI, for the IgE antibody on the cell membrane thereof. IgE antibody's binding to this receptor forms a cross-linkage with the. corresponding polyvalent antigen, the intracellular signal transmission mechanism is activated. Then histamine is liberated or leukotrienes and prostaglandins are formed and liberated, thus inducing the onset of the so-called allergic symptoms. It is furthermore considered that the cytokines such as TNF and interleukins thus produced interact with other cells and thus make the diseases chronic.
DISCLOSURE OF THE INVENTION
Under these circumstances, the present inventors have paid their attention to the activation of a non-receptor type tyrosine kinase located at the early stage in the activation of the intracellular signal transmission mechanism upon liberation of chemical mediators from mast cells or basophils. It is known that this tyrosine kinase is activated when it binds to the phosphorylated tyrosine activation motif (TAM) region in the IgE receptor &ggr; chain. By inhibiting this binding to thereby inhibit the activation of the tyrosine kinase of 72 kDa, the activation of the intracellular signal transmission mechanism depending on the IgE antibody in mast cells or basophils can be inhibited. As a result, also the liberation of the above chemical mediators can be inhibited. The present inventors have found out that desired objects can be achieved by using heterocyclic ring condensed benzothiazine compounds represented by the following formula (I), thus completing the present invention.
WO97/33871 discloses a phenothiazine compound as a prophylactic or therapeutic agent for allergic disease of the similar mechanism, but does not disclose nor suggest a compound having a benzene ring containing a hetero atom.
An object of the invention is to provide a novel acridone compound which is effective for prevention or remedy of asthma, allergic coryza, atopic dermatitis, hives, hay fever, gastrointestinal allergy, food allergy and the like, and a pharmacologically acceptable salt thereof, and another object thereof is to provide a medicine containing, as an active ingredient, the compound, a hydrate thereof or a pharmacologically acceptable salt thereof.
That is, the invention is a heterocyclic ring condensed benzothiazine compound represented by the following formula (I), its pharmacologically acceptable salt or hydrates thereof. Formula (I)
Wherein, the ring Het represents an unsaturated heterocyclic ring that may be substituted with from 1 to 3 substituents;
R
1
and R
2
are the same as or different from each other, and each represents halogen atom, a lower alkyl group that may be substituted with halogen, a lower alkoxy group that may be substituted with halogen, a lower alkoxy lower alkyl group, cyano group, carbamoyl group that may have a substituent or a carboxyl group that may have a protective group, and R
1
and R
2
may form a ring along with the carbon atom to which they are bound. The ring may contain oxygen atom, sulfur atom or nitrogen atom, and may have a substituent;
D represents a lower alkylene chain that may have a substituent, a lower alkenylene chain that may have a substituent, a lower alkynylene chain that may have a substituent or
(in the formula, m and 1 represent an integer of from 0 to 6, and the ring A represents a hydrocarbon ring that may have a substituent or a heterocyclic ring that may have a substituent)
Q represents carbamoyl group that may have a substituent, an acyl group, an acyl lower alkyl group, a carboxyl group that may have a protective group, a heteroaryl group that may have a substituent or a formula —NR
20
R
21
. In the formula —NR
20
R
21
, R
20
and R
21
are the same as or different from each other, and each represents hydrogen atom, a lower alkyl group that may be substituted with halogen, a lower alkoxy group that may be substituted with halogen, a lower alkyl group that is substituted with a hydroxyl group, a lower alkoxy lower alkyl group, an aryl group that may have a substituent, an aryl lower alkyl group that may have a substituent, a heteroaryl group that may have a substituent, a heteroaryl lower alkyl group that may have a substituent, an aryloxy group that may have a substituent, an aryl lower alkoxy group that may have a substituent, a heteroaryloxy group that may have a substituent, a heteroaryl lower alkoxy group that may have a substituent, a carboxyalkyl group that may have a protective group, an acyl group, an acyl lower alkyl group that may have a substituent, an acylamino group that may have a substituent, an acylamino lower alkyl group that may have a substituent, a carbamoyl lower alkyl group that may have a substituent, an amino lower alkyl group that may have a substituent, a cyano lower alkyl group, an acyl lower alkyl group, a lower cycloalkyl group, a lower cycloalkyl lower alkyl group or an amidino group that may be substituted with a lower alkyl group. Alternatively, R
20
and R
21
may form a 3- to 8-membered ring along with the nitrogen atom to which they are bound, and the ring may have, as a component constituting the ring, in addition to the carbon atoms at least one selected from the group consisting of a nitrogen atom, a sulfur atom, an oxygen atom and a formula —NR
22
, and may have a substituent.
In the formula —NR
22
, R
22
represents hydrogen atom, a lower alkyl group that may be substituted with halogen, an acyl group, an acyl lower alkyl group that may have a substituent, an aryl group that may have a substituent, a heteroaryl group that may have a substituent, an arylalkyl group that may have a substituent, a heteroarylalkyl group that may have a substituent or a formula
—S(O)
s
—(Y)
u
—R
23
.
In the formula —S(O)
s
—(Y)
u
—R
23
, R
23
represents hydrogen atom, a lower alkyl group that may be substituted with halogen or an aryl group that may have a substituent, Y represents a methylene chain, s represents an integer of from 0 to 2, and u represe
Akasofu Shigeru
Kikuchi Koichi
Miyamoto Mitsuaki
Moriya Katsuhiro
Sakuma Yoshinori
Eisai Co. Ltd.
Yamada Ryoko
Yamada Sumiyo
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