Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-10-02
2002-06-11
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S461000, C514S231200, C514S231500, C546S141000, C546S142000, C546S167000
Reexamination Certificate
active
06403607
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a novel sulfonamide derivative exhibiting excellent effects in the treatment of peptic ulcer and a drug comprising the derivative as an active ingredient.
BACKGROUND ART
Drug therapy for peptic ulcers has been founded on two essential approaches based on Shay's Balance Theory; inhibition of aggressive factors and potentiation of defensive factors. On the basis of such balance theory, peptic ulcers have been treated for a long time using inorganic drugs such as antacids or by mucosal protective drugs such as isoprene compounds. In the 1980s, a guanidine derivative was developed as an H
2
-receptor antagonist (hereinafter referred to as “H
2
-RA”), an acid secretion inhibitory drug which acts immediately and exhibits a high cure rate as compared with conventional drugs. In addition, in the 1990s, a sulfinylbenzimidazole derivative was developed as a proton pump inhibitor (hereinafter referred to as “PPI”) which is an acid secretion inhibitory drug having different active sites. PPIs exhibited excellent inhibitory gastric acid secretion as compared with H
2
-RAs. In addition, PPIs were reported to exhibit protective effects on the mucosa and to also eliminate
Helicobacter pylori
(hereinafter referred to as “HP”) which is considered to be a cause of peptic ulcer recurrence. Therefore, the development of peptic ulcer remedies was thought to have reached a culmination.
However, since both H
2
-RAs and PPIs, which were generally expected to successfully address the treatment of peptic ulcers, have become widely used, it has become apparent that ulcers frequently recur at a high recurrence ratio after H
2
-RAs is withdrawn when ulcers are thought be cured. In addition, it has been reported that when a PPI is used continuously, hyperplasia of enterochromaffin-like cells, hypergastrinemia, or gastric carcinoid may occur. Therefore, the amount of PPI to be administered has been restricted. Meanwhile, it has been pointed out that an H
2
-RA or PPI exhibits insufficient or no anti-HP effect when used as monotherapy, and thus it has been proposed that an H
2
-RA or PPI be used in combination with an antibacterial drug such as clarithromycin. On the basis of this proposition, clinical trials have been carried out using an H
2
-RA or PPI in combination with a variety of antibacterial drugs. However, such combination therapy for peptic ulcer has not yet become generally established, since the level of elimination of HP does not increase commensurately with the number of drugs employed; a high dose of an antibacterial drug is required; side effects may develop; and resistant bacteria may occur. In addition, peptic ulcer therapy using an H
2
-RA or PPI in combination with two types of antibacterial drugs, i.e., triple therapy, has also been proposed. However, at the present time, a peptic ulcer remedy exhibiting significant anti-HP effects has not been developed. H
2
-RAs or PPIs also have such disadvantages as a correlation between free radicals thereof and lesions of the gastric mucosa. Therefore, although H
2
-RAs or PPIs exhibit a gastric acid secretion inhibitory effect, both are unsatisfactory as peptic ulcer remedies.
In view of the foregoing, an object of the present invention is to provide a compound which exhibits a gastric acid secretion inhibitory effect, anti-HP effect, and a gastric mucus secretion potentiating effect, and which is useful as a peptic ulcer remedy.
DISCLOSURE OF THE INVENTION
The present inventors have performed extensive studies, focusing on aromatic sulfonamide compounds, and have found that a sulfonamide derivative, represented by the following formula (1), exhibits an excellent gastric acid secretion inhibitory effect, anti-HP effect, and gastric mucus secretion potentiating effect as compared with aminobenzyl derivatives disclosed in the patent application previously filed by the present inventors (Japanese Patent Application Laid-Open (kokai) No. 6-72979), and that the sulfonamide derivative is useful as a peptic ulcer remedy. The present invention has been accomplished on the basis of these findings.
Accordingly, the present invention provides a sulfonamide derivative represented by the following formula (1):
[wherein A represents a nitrogen atom or a group —C(R
1
)═;
Z represents a single bond, an oxygen atom, a sulfur atom, an imino group, —N(R
2
)—(CH
2
)
n
—, —N(R
2
)—(CH
2
)
n
—N(R
3
)—, —N(R
2
)—(CH
2
)
n
—O—, —N(R
2
)—(CH
2
)—S—, —N(R
2
)—(CH
2
)
n
—NHSO
2
—, —N(R
2
) —CH
2
CH═CH—, —O(CH
2
)
n
—N(R
3
)—, or —N(R
2
)—(CH
2
)
n
—O—CH
2
—;
Ar
1
represents an aromatic hydrocarbon group, or a saturated or unsaturated heterocyclic group;
Ar
2
represents a phenyl group, an alkyl group, a naphthyl group, a quinolyl group, an isoquinolyl group, a thienyl group, or a pyridyl group, which may have one through three substituents selected from among a halogen atom, an alkyl group, an alkoxy group, an acetamido group, and a nitro group;
R
a
represents a hydrogen atom, a morpholinoyl group, an alkoxy group, or an aminoalkoxy group;
R
b
represents a hydrogen atom, a halogen atom, an alkyl group, or an alkoxy group;
R
c
represents a hydrogen atom, or an alkyl group or a halogenobenzenesulfonyl group, which may have a substituent;
R
1
represents a hydrogen atom, or R
1
and R
2
together form a trimethylene group;
R
2
represents a hydrogen atom, an alkyl group, a dialkylaminoalkyl group, a benzyl group, a halogenophenyl group, or a halogenobenzenesulfonyl group, R
2
and R
1
together form a trimethylene group, or R
2
and R
3
together form an ethanedioyl group or an alkylene group;
R
3
represents a hydrogen atom, an alkyl group, a hydroxyoxalyl group, an alkanoyl group, a sulfonyl group, an alkoxycarbonyl group, or a halogenobenzenesulfonyl group, or R
3
and R
2
together form an ethanedioyl group or an alkylene group;
n is a number of 2-4; and
Z is not —N(R
2
)—CH
2
—CH═CH— when Ar
2
is an isoquinolyl group], or a salt thereof.
The present invention also provides a drug comprising, as an active ingredient, a sulfonamide derivative represented by formula (1) or a salt thereof.
The present invention also provides a pharmaceutical composition comprising a sulfonamide derivative represented by formula (1) or a salt thereof and a pharmaceutically acceptable carrier therefor.
The present invention also provides use of a sulfonamide derivative represented by formula (1) or a salt thereof as a drug.
The present invention also provides a method for treating peptic ulcer comprising administration of an effective dose of a sulfonamide derivative represented by formula (1) or a salt thereof.
BEST MODE FOR CARRYING OUT THE INVENTION
In formula (1), A represents a nitrogen atom or a group —C(R
1
)═. When A is a nitrogen atom, a pyridine ring is formed; when R
1
is a hydrogen atom, a benzene ring is formed; and when R
1
and R
2
together form a trimethylene group, a tetrahydroquinoline ring is formed.
In a group represented by Z in formula (1), a halogen atom of a halogenophenyl group or a halogenobenzenesulfonyl group represented by R
2
or R
3
may be a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. In R
2
and R
3
, the alkyl group or the alkyl moiety of the dialkylaminoalkyl group is preferably a C1-C4 alkyl group. Specific examples include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group, and a t-butyl group. Of these, a methyl or ethyl group is preferable, and a methyl group is more preferable. An alkoxy moiety of an alkoxycarbonyl group is preferably a C1-C4 alkoxy group. Specific examples include a methoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group, an n-butoxy group, an i-butoxy group, a sec-butoxy group, and a t-butoxy group. Of these, a t-butoxy group is preferable; and a t-butoxycarbonyl group is preferable as an alkoxycarbonyl group. Examples of alkylene groups formed by R
2
and R
3
include a methylene group, an ethylene group, and a trimethylene group. Of
Hidaka Hiroyoshi
Inoue Tsutomu
Nakano Hiroyuki
Sasaki Tomomitsu
Umezawa Isao
Hidaka Hiroyoshi
Robinson Binta
Rotman Alan L.
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