Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
1999-12-22
2002-09-03
Kumar, Shailendra (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S152000, C564S158000, C560S029000, C514S616000, C514S478000
Reexamination Certificate
active
06444849
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel amide derivatives having strong antibacterial activity against Helicobacter pylori.
BACKGROUND ART
Helicobacter pylori is a slightly aerobic gram-negative bacterium which was recently isolated from human gastric mucosa, and various published reports suggest its involvement in inflammation of alimentary tract, formation and recurrence of ulcer, and moreover, gastric cancer (Molecular Medicine, Vol. 31, pp. 1304-1374, 1994).
For the treatment of gastrointestinal ulcers, medicaments such as H
2
blockers or proton pump inhibitors have been used so far. Since relation between Helicobacter pylori infection and gastric ulcer has been being clarified as explained above, an antibacterial agent such as amoxicillin has become practically used in combination, particularly from a viewpoint of prevention of recurrence. However, in most cases, ordinarily used antibacterial agents fail to achieve complete elimination of the bacteria. In addition, they may affect on intestinal bacterial flora due to their broad antibacterial spectra, and they often cause adverse effects such as diarrhea. Therefore, it has been desired to develop an antibacterial agent having potent antibacterial activity in alimentary tract that is specific against. Helicobacter pylori.
The compound represented by the general formula (I) defined herein below wherein R
7
is a benzyl group, and A and Y are an oxygen atom, and R
4
and R
5
are a hydrogen atom, and R
6
is a propyl group, has been reported as intermediates of receptor models (Journal of American Chemical Society, Vol.115, pp. 3548, 1993). However, it has not been known that this compound has an antibacterial activity against Helicobacter pylori.
DISCLOSURE OF THE INVENTION
The inventors of the present invention conducted researches to provide a novel anti-Helicobacter pylori agent, and as a result, they found that the compounds represented by the following general formula have excellent antibacterial activity against Helicobacter pylori and can exhibit potent antibacterial activity in alimentary tract. The present invention was achieved on the basis of these findings.
The present invention thus provides amide derivatives represented by the following general formula (I) and salts thereof, and solvates thereof and hydrates thereof:
wherein X represents R
1
(R
2
)(R
3
)C— where R
1
represents a C
6
-C
8
cycloalkyl group, an optionally substituted C
6
-C
14
aryl group, an optionally substituted heterocyclic residue wherein the heterocyclic residue is one of furan ring, dihydrofuran ring, tetrahydrofuran ring, pyran ring, dihydropyran ring, tetrahydropyran ring, benzofuran ring, dihydrobenzofuran ring, isobenzofuran ring, chromene ring, chroman ring, isochroman ring, thiophene ring, benzothiophene ring, pyrrole ring, pyrroline ring, pyrrolidine ring, imidazole ring, imidazoline ring, imidazolidine ring, pyrazole ring, pyrazoline ring, pyrazolidine ring, triazole ring, tetrazole ring, pyridine ring, pyridineoxide ring, piperidine ring, pyrazine ring, piperazine ring, pyrimidine ring, pyridazine ring, indolizine ring, indole ring, indoline ring, isoindole ring, isoindoline ring, indazole ring, benzimidazole ring, purine ring, quixolizine ring, quinoline ring, phthalazine ring, naphthylidine ring, quinoxaline ring, quinazoline ring, cinnoline ring, pteridine ring, oxazole ring, oxazolidine ring, isoxazole ring, isoxazolidine ring, thiazole ring, thiazylidine ring, isothiazole ring, isothiazolidine ring, dioxane ring, dithian ring, morpholine ring, and thiomorpholine ring, an optionally substituted C
6
-C
14
aryloxy group, or an optionally substituted C
7
-C
15
arylmethyl group; R
2
and R
3
independently represent hydrogen atom or a C
1
-C
5
alkyl group, or R
2
and R
3
may combine to represent a C
2
-C
7
aLkylene group; or
X represents R
7
—A— wherein R
7
represents (i) a C1-C10 alkyl group which may optionally be substituted with an optionally substituted C6-C14 aryl group, an optionally substituted fluorenyl group or an optionally substituted heterocyclic group, (ii) an optionally substituted C6-C14 aryl group or (iii) an optionally substituted heterocyclic group, and A represents an oxygen atom or —N—R
8
where R
8
represents hydrogen atom or a C1-C5 alkyl group,
Y represents an oxygen atom or a sulfur atom,
R
4
and R
5
independently represent hydrogen atom or a C
1
-C
5
alkyl group; and R
6
represents hydrogen atom, a C
1
-C
6
alkyl group which may optionally be substituted with a hydroxyl group, a hydroxyl group or a C
1
-C
6
alkoxy group,
provided that the compounds wherein R
7
is a benzyl group, A and Y are an oxygen atom, R
4
and R
5
are hydrogen atom, and R
6
is a propyl group are excluded, or a salt thereof, or a solvate thereof or a hydrate thereof.
According to another aspect of the present invention, the present invention provides medicaments, preferably for the treatment of gastric diseases, e.g., gastritis, gastric ulcer, and gastric cancer, which comprise as an active ingredient a substance selected from the group consisting of the aforementioned amide derivatives and pharmaceutically acceptable salts thereof, and solvates thereof and hydrates thereof. The medicaments are preferably provided as pharmaceutical compositions comprising the aforementioned substance as an active ingredient together with one or more pharmaceutically acceptable additives. These medicaments can be used as anti-Helicobacter pylori agents for therapeutic and/or preventive treatment of digestive diseases related to Helicobacter pylori infections for example, gastritis, gastric ulcer, gastric cancer, stomach malignant lymphoma, MALT lymphoma, duodenal ulcer, duodenal carcinoma and the like.
According to further aspects of the present invention, there are provided a method for treating digestive diseases related to Helicobacter pylori infection which comprises the step of administering to a mammal including a human a therapeutically effective amount of a substance selected from the group consisting of the aforementioned amide derivatives and pharmaceutically acceptable salts thereof, and solvates thereof and hydrates thereof and a s of a substance selected from the group consisting of the aforementioned amide derivatives and pharmaceutically acceptable salts thereof, and solvates thereof and hydrates thereof for the manufacture of the above medicaments.
BEST MODE FOR CARRYING OUT THE INVENTION
In the general formula (I), examples of the C
6
-C
8
cycloalkyl group represented by R
1
include, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, and cyclooctyl group. Examples of the C
6
-C
14
aryl group include, for example, aromatic hydrocarbon groups consisting of one ring or two to approximately three condensed aromatic rings such as phenyl group, naphthyl group, and anthryl group.
As the residue of a heterocyclic compound, residues of heterocyclic compounds containing 1 to 4 heteroatoms selected from oxygen atom, sulfur atom, and nitrogen atom, and having 5 to 10 ring-membered atoms in total can be used. More specifically, examples of the residues of heterocyclic compounds include, for example, furan ring, dihydrofuran ring, tetrahydrofuran ring, pyran ring, dihydropyran ring, tetrahydropyran ring, benzofuran ring, dihydrobenzofuran ring, isobenzofuran ring, chromene ring, chroman ring, isochroman ring, thiophene ring, benzothiophene ring, pyrrole ring, pyrroline ring, pyrrolidine ring, imidazole ring, imidazoline ring, imidazohdine ring, pyrazole ring, pyrazoline ring, pyrazolidine ring, triazole ring, tetrazole ring, pyridine ring, pyridineoxide ring, piperidine ring, pyrazine ring, piperazine ring, pyrimidine ring, pyridazine ring, indolizine ring, indole ring, indoline ring, isoindole ring, isoindoline ring, indazole ring, benzimidazole ring, purine ring, quinolie ring, quinoline ring, phthalazine ring, naphthylidine ring, quinoxaline ring, quinazoline ring, cinnoline ring, pteridine ring, oxazole ring, oxazolidine ring, isoxazole ring, isoxazoli
Ando Ryoichi
Chiba Noriko
Kawamura Makoto
Watanabe Kazutoshi
Greenblum & Bernstein P.L.C.
Kumar Shailendra
Mitsubishi Chemical Corporation
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