2-sulfamoylbenzoic acid derivatives

Details 2-sulfamoylbenzoic acid derivatives 2-sulfamoylbenzoic acid derivatives

2001-04-27

2002-04-23

Solola, T. A. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S268700, C546S330000, C546S334000, C548S179000, C548S205000, C548S236000, C548S247000, C548S310100, C548S337100, C564S080000, C568S030000

Reexamination Certificate

active

06376671

ABSTRACT:

TECHNICAL FIELD
The present invention relates to novel 2-sulfamoylbenzoic acid derivatives which have an antagonistic effect on both the leukotriene D
4
(hereinafter referred to simply as LTD
4
) receptor and the thromboxane A
2
(hereinafter referred to simply as TXA
2
) receptor, intermediates for their synthesis and their salts and medicines containing them.
BACKGROUND ART
For treatment of allergic diseases including bronchial asthma, anti-allergic agents such as histamine receptor antagonists and mediator release suppressants for mast cells and steroid drugs have been used, and for bronchial asthma, bronchodilators such as xanthine derivatives and stimulators for the &bgr;-sympathetic nerve receptor have been used as well.
In recent years, allergic diseases are recognized as allergic inflammations by their pathological profiles and have been found to be associated with various inflammatory cells and mediators. For example, bronchial asthma is characterized by increased sensitivity of the respiratory tract to various stimuli and defined as involving reversible stenosis of the respiratory tract, mucosal edema of the respiratory tract, mucous supersecretion and infiltration of inflammatory cells onto the walls of the respiratory tract.
Further, with respect to the related mediators, it is suggested that LTD
4
not only has an intense bronchoconstrictor effect but also enhances the permeability of the respiratory tract vessels and mucus secretion, and that TXA
2
not only has a potent bronchoconstrictor effect but also controls the sensitivity of the respiratory tract.
With the above-mentioned movements in research on treatment of allergic diseases, LTD
4
receptor antagonists, TXA
2
synthesis inhibitors and TXA
2
receptor antagonists have been marketed and shown to be more effective than conventional anti-allergic agents.
However, because development of allergic diseases represented by bronchial asthma pathologically involves various mediators in parallel as mentioned above, antagonism against a receptor for a single mediator or inhibition of synthesis of a single mediator has its limit in terms of effect, and development of novel promising anti-allergic agents which show greater therapeutic effects by inhibiting both LTD
4
and TXA
2
, major pathological mediators in allergy.
Compounds which have antagonistic effects on the receptors for both of the two mediators, LTD
4
and TXA
2
, are disclosed in JP-A-3-258759, JP-A-4-154757, JP-A-4-154766, JP-A-5-262736, JP-A-5-279336, JP-A-6-41051 and WO96/11916. These compound are structurally different from the compounds of the present invention and are not expected to have satisfactory therapeutic effects as anti-allergic agents in view of the intensities of their antagonistic effects on the receptors for the major bronchoconstricting mediator LTD
4
and the ratios of their antagonistic activities against the two mediators LTD
4
and TXA
2
.
The present invention has been accomplished in view of the current situations in treatment of allergic diseases and research on their treatment with the aim of providing novel compounds which show potent antagonistic effects on the receptors for LTD
4
and TXA
2
, which are the two major mediators in development of allergic diseases, and therefore are expected to have more excellent therapeutic effects and pharmaceuticals containing them as active ingredients.
DISCLOSURE OF THE INVENTION
In the above-mentioned movements in treatment of allergic diseases and research on their treatment, the present inventors have conducted extensive research with a view to attaining the above-mentioned object and, as a result, found out that the 2-sulfamoylbenzoic acid derivatives of the present invention have antagonistic effects on the receptors for the two mediators LTD
4
and TXA
2
, which play important roles in development of allergic diseases, and have more excellent therapeutic effects than the above-mentioned receptor antagonists against a single mediator and inhibitors against synthesis of a single mediator. The present inventors have accomplished the present invention on the basis of this discovery.
Namely, the present invention provides 2-sulfamoylbenzoic acid derivatives represented by general formula (I):
(wherein R1 and R2 which may be the same or different, are hydrogen atoms, C
3-8
cycloalkyl groups, optionally substituted C
1-6
alkyl groups, optionally substituted aryl groups or form, together with the ring
a condensed ring represented by formula
which may be substituted with an optionally substituted C
1-6
alkyl group, an amino group, a cyano group, a nitro group, a hydroxyl group, a halogen atom or a C
1-5
alkoxy group, X is an oxygen atom, a nitrogen atom, a sulfur atom or —CH═CH—, R3 is an optionally substituted phenylsulfonylamino group, an optionally substituted phenylsulfonyl group or an optionally substituted phenylsulfoxide group, R4 is a hydrogen atom or an ester residue, n is an integer of from 2 to 6, A is —O—B—, —B—O—, —S—B—, —B—S— or —B—, and B is a C
1-6
alkylene group or a C
2-5
alkenylene group, provided that the cases wherein R1 is a C
1-6
alkyl group, a C
3-8
cycloalkyl group or a phenyl group, R2 is a hydrogen atom, A is a vinylene group, and X is a sulfur atom are excluded) or salts, hydrates or solvates thereof.
The present invention also provides, as useful intermediates for their synthesis, benzylamine derivatives represented by general formula (II):
(wherein R1 and R2 which may be the same or different, are hydrogen atoms, C
3-8
cycloalkyl groups, optionally substituted C
1-6
alkyl groups, optionally substituted aryl groups or form, together with the ring
a condensed ring represented by formula
which may be substituted with an optionally substituted C
1-6
alkyl group, an amino group, a cyano group, a nitro group, a hydroxyl group, a halogen atom or a C
1-5
alkoxy group, X is an oxygen atom, a nitrogen atom, a sulfur atom or —CH═CH—, R3 is an optionally substituted phenylsulfonylamino group, an optionally substituted phenylsulfonyl group or an optionally substituted phenylsulfoxide group, n is an integer of from 2 to 6, A is —O—B—, —B—O—, —S—B—, —B—S— or —B—, and B is a C
1-6
alkylene group or a C
2-5
alkenylene group, provided that the cases wherein R1 is a C
1-6
alkyl group, a C
3-8
cycloalkyl group or a phenyl group, R2 is a hydrogen atom, A is a vinylene group, and X is a sulfur atom are excluded) or salts thereof, benzaldehyde derivatives represented by general formula (IIIa):
(wherein R1 and R2 which may be the same or different, are hydrogen atoms, C
3-8
cycloalkyl groups, optionally substituted C
1-6
alkyl groups, optionally substituted aryl groups or form, together with the ring
a condensed ring represented by formula
which may be substituted with an optionally substituted C
1-6
alkyl group, an amino group, a cyano group, a nitro group, a hydroxyl group, a halogen atom or a C
1-5
alkoxy group, A′ is —B′—O— or —B′—, and B′ is a C
1-6
alkylene group) or salts thereof, benzonitrile derivatives represented by general formula (IV):
(wherein R1 and R2 which may be the same or different, are hydrogen atoms, C
3-8
cycloalkyl groups, optionally substituted C
1-6
alkyl groups, optionally substituted aryl groups or form, together with the ring
a condensed ring represented by formula
which may be substituted with an optionally substituted C
1-6
alkyl group, an amino group, a cyano group, a nitro group, a hydroxyl group, a halogen atom or a C
1-5
alkoxy group, and X is an oxygen atom, a nitrogen atom, a sulfur atom or —CH═CH— or salts thereof and amine derivatives represented by general formula (V):
H
2
N—(CH
2
)
n
—R
3
(wherein n is an integer of from 2 to 6,and R3 is an optionally substituted phenylsulfonylamino group, an optionally substituted phenylsulfonyl group or an optionally substituted phenylsulfoxide group) or salts thereof. The present invention further provides a pharmaceutical, anti-allergic agent and leukotriene and thromboxane A
2
antagonistic agent containing a 2-sulfamoylbenzoic

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