Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-12-12
2003-12-30
Ford, John M. (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
06670360
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to optically active pyrrolopyridazine derivatives of formula (I) or pharmaceutically acceptable salts thereof.
This invention further relates to pharmaceutical compositions comprising an optically active pyrrolopyridazine derivative of formula (I) or a pharmaceutically acceptable salt thereof (preferably compositions for prevention or treatment of an ulcerative disease) as an active ingredient.
In another aspect, this invention relates to the use of an optically active pyrrolopyridazine derivative of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition (preferably a composition for the prevention or treatment of an ulcerative disease).
In another aspect, this invention relates to a method for the prevention or treatment of disease (preferably an ulcerative disease), which method comprises administering a pharmaceutically effective amount of an optically active pyrrolopyridazine derivative of formula (I) or a pharmaceutically acceptable salt thereof to a warm-blooded animal (preferably a human) in need of such treatment.
In yet another aspect, this invention relates to a process for the preparation of optically active pyrrolopyridazine derivatives of formula (I) and pharmaceutically acceptable salts thereof.
2. Background Information
It has been considered that an imbalance between aggressive factors and protective factors against the gastric mucous membrane induces a peptic ulcer. Gastric acid secretion is an aggressive factor and suppression of gastric acid secretion is useful in the prevention and treatment of the disease. Anticholinergic drugs, histamine H2 receptor antagonists such as cimetidine and proton-pump inhibitors such as omeprazole have been clinically used as a gastric acid secretory inhibitor. Although these drugs are excellent therapeutic agents for ulcerative disease, the disease may recur after cessation of the therapy. It has been recently reported that
Helicobacter pylori
relates to the recurrence of the ulcerative disease. Actually there have been some attempts to use a gastric acid secretory inhibitor in combination with an antibacterial ag 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 prophylactic and therapeutic agent for gastric ulcer disease.
Some pyrrolopyridazine derivatives that have gastric acid secretory inhibition activity and protect gastric mucous membranes have been described in U.S. Pat. No. 6,063,782, WO 91/17164, WO 92/06979 and WO 93/08190. In Japanese Patent Application Publication Hei 7-247285 the activity against
Helicobacter pylori
of some pyrrolopyridazine derivatives has also been described.
SUMMARY OF THE INVENTION
The inventors have continued an investigation on the pharmacological activities of pyrrolopyridazine derivatives in order to discover compounds that exhibit potent gastric acid secretory inhibition activity, protect gastric mucous membranes and have excellent antibacterial activity against
Helicobacter pylori
for a long time. It was proved that some optically active pyrrolopyridazine derivatives substituted with a trans-alkylcyclopropylmethyl group have such activities and are superior to the corresponding racemate as a medicament.
This invention relates to optically active pyrrolopyridazine derivatives of formula (I) hereinbelow or pharmaceutically acceptable salts thereof.
This invention further relates to pharmaceutical compositions comprising an optically active pyrrolopyridazine derivative of formula (I) or a pharmaceutically acceptable salt thereof (preferably compositions for prevention or treatment of ulcerative disease) as an active ingredient.
In another aspect, this invention relates to the use of an optically active pyrrolopyridazine derivative of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition (preferably a composition for the prevention or treatment of ulcerative disease).
In another aspect, this invention relates to a method for the prevention or treatment of a disease (preferably an ulcerative disease), which method comprises administering a pharmaceutically effective amount of an optically active pyrrolopyridazine derivative of formula (I) or a pharmaceutically acceptable salt thereof to a warm-blooded animal (preferably a human) in need of such treatment.
In yet another aspect, this invention relates to a process for the preparation of optically active pyrrolopyridazine derivatives of formula (I) and pharmaceutically acceptable salts thereof.
An optically active pyrrolopyridazine derivative of the present invention has the following formula:
wherein:
R
1
is a C
1
-C
6
alkyl group;
R
2
and R
3
are each independently a C
1
-C
6
alkyl group;
R
4
is a C
6
-C
10
aryl group which is optionally substituted with one or more 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 halogen; and
A is an imino group, an oxygen atom or a sulfur atom.
DETAILED DESCRIPTION OF THE INVENTION
The C
1
-C
6
alkyl moiety of the alkyl group in the definitions of R
1
, R
2
, R
3
and R
4
and of the halogeno C
1
-C
6
alkyl, C
1
-C
6
alkoxy and halogeno C
1
-C
6
alkoxy group included in the definition of R
4
is, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl or hexyl group; is preferably a C
1
-C
4
alkyl group; more preferably a methyl or ethyl group and most preferably methyl.
The halogen atom included in the definition of R
4
is, for example, a fluorine, chlorine, bromine or iodine atom; preferably a fluorine, chlorine or bromine atom and more preferably a fluorine or chlorine atom.
The C
6
-C
10
aryl group in the definition of R
4
is, for example, a phenyl or naphthyl group; preferably a phenyl group. The number of substituents on the aryl group is from 1 to 5; 1 to 3 is preferable, 1 or 2 is more preferable and 1 is the most preferable. The C
6
-C
10
aryl group is optionally substituted with one or more 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 halogen is preferably, for example, a phenyl, methylphenyl, (trifluoromethyl)phenyl, methoxyphenyl, (trifluoromethoxy)phenyl, (difluoromethoxy)phenyl, fluorophenyl, chlorophenyl, bromophenyl, difluorophenyl, chlorofluorophenyl, dichlorophenyl, trifluorophenyl, trichlorophenyl, naphthyl, methylnaphthyl, methoxynaphthyl, fluoronaphthyl, chloronaphthyl or bromonaphthyl group; more preferably a phenyl, 4-methylphenyl, 4-(trifluoromethyl)phenyl, 4-methoxyphenyl, 4-(trifluoromethoxy)phenyl, 4-(difluoromethoxy)phenyl, 2-, 3- or 4-fluorophenyl, 2-, 3- or 4-chlorophenyl, 4-bromophenyl, 2,4- or 2,6-difluorophenyl, 4-chloro-2-fluorophenyl, 2-chloro-4-fluorophenyl, 2,4- or 2,6-dichlorophenyl, 2,4,6-trifluorophenyl or 2,4,6-trichlorophenyl group; more preferably a 4-fluorophenyl, 4-chlorophenyl, 2,4-difluorophenyl, 4-chloro-2-fluorophenyl, 2-chloro-4-fluorophenyl or 2,4-dichlorophenyl group; most preferably a 4-fluorophenyl or 4-chlorophenyl group.
A is preferably an oxygen or sulfur atom, more preferably an oxygen atom.
The pharmaceutically acceptable salt of the compound of formula (I) is an acid addition salt, for example, a hydrohalogenic acid salt such as hydrofluoride, hydrochloride, hydrobromide and hydroiodide; a nitrate; a perchlorate; a sulfate; a phosphate; a carbonate; a C
1
-C
6
alkylsulfonate which is optionally substituted with fluorine atom(s), such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, pentafluoroethanesulfonate, propanesulfonate, butanesulfonate, pentanesulfonate and hexanesulfonate; a C
6
-C
10
arylsulfonate such as benzenesulfonate and p-toluenesulfonate; a carboxylate, such as acetate
Fujiwara Hiroshi
Hagihara Masahiko
Ito Keiichi
Matsunobu Keiji
Shibakawa Nobuhiko
Ford John M.
Sankyo Company Limited
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