Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-08-08
2004-05-11
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S236000
Reexamination Certificate
active
06734181
ABSTRACT:
TECHNICAL FIELD
This invention relates to pyrrolopyridazine derivatives or pharmaceutically acceptable salts thereof; to pharmaceutical compositions comprising a pyrrolopyridazine derivative or a pharmaceutically acceptable salt thereof (preferably compositions for the prevention or treatment of ulcerative disease) as an active ingredient; to the use of a pyrrolopyridazine derivative or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition (preferably a composition for the prevention or treatment of ulcerative disease); or to a method for the prevention or treatment of disease (preferably ulcerative disease), which method comprises administering a pharmaceutically effective amount of a pyrrolopyridazine derivative or a pharmaceutically acceptable salt thereof to a warm-blooded animal (preferably a human).
BACKGROUND OF THE INVENTION
It has been considered that an inbalance between aggressive factors and protective factors against the gastric mucous membrane induces peptic ulcers. Gastric acid secretion is an aggressive factor and suppression of gastric acid secretion is useful in the prevention and treatment of the disease. Anticholinergic agents, histamine H
2
receptor antagonists such as cimetidine and the like and proton pump inhibitors such as omeprazole and the like have been clinically used as a gastric acid secretion inhibitor. Although these agents are excellent therapeutic agents for ulcerative disease, the disease may recur after cessation of the therapy. It has been recently reported that
Helicobacter pylon
relates to recurrence of the ulcerative disease. Actually there have been some attempts to use a gastric acid secretion inhibitor in combination with an antibacterial agent for treatment of the disease.
Accordingly a compound that exhibits potent gastric acid secretory inhibition activity, excellent gastric mucous membrane protection activity and potent antibacterial activity against
Helicobacter pylori
would be expected to be an excellent medicament (preferably a prophylactic and therapeutic agent for ulcerative disease).
Some pyrrolopyridazine derivatives that have gastric acid secretory inhibition activity and gastric mucous membrane protection activity have been known (for example, WO 91/17164, WO 92/06979, WO 93/08190 and the like). The activity against
Helicobacter pylori
of some pyrrolopyridazine derivatives has also been known (for example, Japanese Patent Application Publication Hei 7-247285 and the like).
DISCLOSURE OF THE INVENTION
The inventors have continued an investigation on the pharmacological activities of pyrrolopyridazine derivatives in order to discover a medicament (preferably an agent for ulcerative disease) that exhibits potent gastric acid secretory inhibition activity, protects gastric mucous membranes and has excellent antibacterial activity against
Helicobacter pylori
for a long time. As a result, they found that some pyrrolopyridazine derivatives substituted with specific substituents at the 3-position exhibit potent gastric acid secretory inhibition activity and gastric mucous membrane protection activity and exhibit excellent antibacterial activity against
Helicobacter pylori.
The pyrrolopyridazine derivative, i.e., compound, of the present invention has the following formula:
wherein:
R
1
represents a C
2
-C
6
alkenyl group, a halogeno C
2
-C
6
alkenyl group, a C
3
-C
7
cycloalkyl group which may be optionally substituted with C
1
-C
6
alkyl or a C
3
-C
7
cycloalkyl-C
1
-C
6
alkyl group which may be optionally substituted with C
1
-C
6
alkyl; R
2
represents a C
1
-C
6
alkyl group;
R
3
represents a hydroxymethyl group, a C
2
-C
6
aliphatic acyloxymethyl group, a C
6
-C
10
arylcarbonyloxymethyl group which may be optionally substituted with substituents selected from the group consisting of C
1
-C
6
alkyl, C
1
-C
6
alkoxy and halogeno, a C
1
-C
6
alkoxycarbonyloxymethyl group, a formyl group, a carboxyl group, a C
1
-C
6
alkoxycarbonyl group or a C
6
-C
10
aryloxycarbonyl group which may be optionally substituted with substituents selected from the group consisting of C
1
-C
6
alkyl, C
1
-C
6
alkoxy and halogeno;
R
4
represents a C
6
-C
10
aryl group which may be optionally substituted with substituents selected from the group consisting of C
1
-C
6
alkyl, halogeno C
1
-C
6
alkyl, C
1
-C
6
alkoxy, halogeno C
1
-C
6
alkoxy and halogeno;
A represents an imino group, an oxygen atom or a sulfur atom;
In the formula (I) described above:
The C
1
-C
6
alkyl group in the definition of R
2
or the C
1
-C
6
alkyl moiety included in the definition of R
1
, R
3
or R
4
is, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl t-butyl, pentyl or hexyl group; preferably a C
1
-C
4
alkyl group; more preferably a methyl or ethyl group; and most preferably a methyl group.
The C
2
-C
6
alkenyl group or C
2
-C
6
alkenyl moiety of the halogeno C
2
-C
6
alkenyl group in the definition of R
1
is, for example, a vinyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-pentenyl or 2-hexenyl group; preferably a C
2
-C
4
alkenyl group, more preferably a C
3
-C
4
alkenyl group; still more preferably a 2-propenyl or 2-butenyl group; and most preferably a 2-butenyl group.
A typical example of a halogeno C
2
-C
6
alkenyl group in the definition of R
1
is, for example, a 2,2-difluorovinyl, 3-fluoro-2-propenyl, 3-chloro-2-propenyl, 3-bromo-2-propenyl, 3-iodo-2-propenyl, 3,3-difluoro-2-propenyl, 2,3-dichloro-2-propenyl, 3,3-dichloro-2-propenyl, 2,3-dibromo-2-propenyl, 3,3-dibromo-2-propenyl, 4,4,4-trifluoro-2-butenyl, 5-fluoro-2-pentenyl or 6-fluoro-2-hexenyl group; preferably a 3-chloro-2-propenyl, 3,3-difluoro-2-propenyl, 3,3-dichloro-2-propenyl or 4,4,4-trifluoro-2-butenyl group; and more preferably a 3-chloro-2-propenyl, 3,3-difluoro-2-propenyl or 3,3-dichloro-2-propenyl group.
The C
3
-C
7
cycloalkyl moiety of the C
3
-C
7
cycloalkyl group which may be optionally substituted with a C
1
-C
6
alkyl group or of the C
3
-C
7
cycloalkyl-C
1
-C
6
alkyl group which may be optionally substituted with a C
1
-C
6
alkyl group in the definition of R
1
is, for example, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group; preferably a C
3
-C
6
cycloalkyl group; more preferably a cyclopropyl, cyclopentyl or cyclohexyl group; and most preferably a cyclopropyl group.
A typical example of the C
3
-C
7
cycloalkyl group which may be optionally substituted with a C
1
-C
6
alkyl group in the definition of R
1
is, for example, a cyclopropyl, 2-ethylcyclopropyl, 2-thylcyclopropyl, 2-ropylcyclopropyl, 2-exylcyclopropyl, cyclobutyl, 2-methylcyclobutyl, cyclopentyl, 2-methylcyclopentyl, 2-ethylcyclopentyl, cyclohexyl, 2-methylcyclohexyl or cycloheptyl group; preferably a cyclopropyl, 2-methylcyclopropyl, 2-ethylcyclopropyl, cyclobutyl, cyclopentyl, 2-methylcyclopentyl, cyclohexyl or 2-methylcyclohexyl group; more preferably a cyclopropyl, 2-methylcyclopropyl, cyclopentyl, 2-methylcyclopentyl, cyclohexy or 2-methylcyclohexyl group; and most preferably a cyclopropyl or 2-methylcyclopropyl group.
A typical example of the C
3
-C
7
cycloalkyl-C
1
-C-
6
alkyl group which may be optionally substituted with a C
1
-C
6
alkyl group in the definition of R
1
is, for example, a cyclopropylmethyl, 2-cyclopropylethyl, 2-methylcyclopropylmethyl, 2-(2-methylcyclopropyl)ethyl, 3-(2-methylcyclopropyl)propyl, 6-(2-methylcyclopropyl)hexyl, 2-ethylcyclopropylmethyl, 2-propylcyclopropylmethyl, 2-hexylcyclopropylmethyl, cyclobutylmethyl, 2-methylcyclobutylmethyl, cyclopentylmethyl, 2-cyclopentylethyl, 2-methylcyclopentylmethyl, 2-(2-methylcyclopentyl)ethyl, 2-ethylcyclopentylmethyl, cyclohexylmethyl, 2-cyclohexylethyl, 2-methylcyclohexylmethyl, 2-(2-methylcyclohexyl)ethyl or cycloheptylmethyl group; preferably a cyclopropylmethyl, 2-cyclopropylethyl, 2-methylcyclopropylmethyl, 2-(2-methylcyclopropyl)ethyl, 2-ethylcyclopropylmethyl, cyclobutylmethyl, 2-methylcyclobutylmethyl,
Fujiwara Hiroshi
Hagihara Masahiko
Iwabuchi Haruo
Matsunobu Keiji
Shibakawa Nobuhiko
Bernhardt Emily
Frishauf Holtz Goodman & Chick P.C.
Sankyo Company Limited
Styles Camelia
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