Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-08-22
2002-03-26
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S394000, C514S395000, C424S653000
Reexamination Certificate
active
06362169
ABSTRACT:
TECHNICAL FIELD
The present invention relates to an antibacterial composition against
Helicobacter pylori.
More particularly, the invention relates to drugs containing the antibacterial composition, remedies for diseases of digestive organs, e.g., gastritis, gastroduodenitis, erosive gastritis, gastric erosion, erosive duodenitis, gastric ulcer and duodenal ulcer, caused by the infection with
Helicobacter pylori
which is bacteria difficult to be eradicated by usual antibacterial materials such as antibiotics and synthetic antibacterial agents, a process for preparing them, and pharmaceutical preparations related to the antibacterial composition.
BACKGROUND ART
It is known that
Helicobacter pylori
is bacteria causing active chronic gastritis and is also greatly associated with gastric ulcer and duodenal ulcer. It is acknowledged that by eradication of infecting
Helicobacter pylori,
active chronic gastritis is cured and relapse of gastric ulcer and duodenal ulcer is remarkably decreased.
For treatment to eradicate
Helicobacter pylori,
there have been used, for example, antibacterial agents such as amoxicillin, ampicillin, clarithromycin, ofloxacin and tetracycline, bismuth preparations such as colloidal bismuth subcitrate and bismuth subsalicylate, antiprotozoals such as tinidazole and metronidazole, proton pump inhibitors such as omeprazole and lansoprazole, or drugs for gastrointestinal ulcer which are H
2
blocker such as cimetidine and ranitidine. At present, one or two are selected from the antibacterial agents, and one or two are selected from the bismuth preparations, the antiprotozoals and the drugs for gastrointestinal ulcer, and a combination of two or three agents selected from the respective groups is administered for the treatment.
However, such a combination has a relatively short duration of action and accordingly requires high doses and repeated administrations such as 3 or 4 times per day. Thus, there are problems that the administration is troublesome and adverse effect is easy to occur owing to high doses. These problems are considered to be caused by that the residence time of the administered agents in stomach is short and the antibacterial agent is low in antibacterial activity and is unstable under acidic condition in stomach.
On the other hand, with respect to rifamycin-related antibacterial agents, it is known that rifampicin, rifabutin and compounds involved in the present invention have an antibacterial activity to
Helicobacter pylori
(WO 97/09047, 1997). However, rifampicin is not suitable owing to high minimum inhibitory concentration (MIC). Rifabutin is known to exhibit a synergistic effect on minimum inhibitory concentration by combination use with a proton pump inhibitor or a bismuth preparation (WO 97/02039, 1997). However, synergistic effects under acidic condition corresponding to environment in stomach and on bactericidal activity have not been known. Also, there has not been known any effect of administration of a combination of a rifamycin derivative represented by formula (I) or its physiologically acceptable salt in the present invention with a proton pump inhibitor or a bismuth preparation.
DISCLOSURE OF INVENTION
As a result of making an intensive study in order to solve the above problems, the present inventors have found an antibacterial composition which shows synergistic effects on both the growth inhibitory activity and the bactericidal activity to
Helicobacter pylori
under an acidic environment and have made it clear that this antibacterial composition is effective for the treatment to eradicate
Helicobacter pylori,
thus they have accomplished the present invention.
That is to say, the present invention relates to an antibacterial composition comprising:
(1) a rifamycin derivative of the formula (I) or a physiologically acceptable salt thereof:
wherein
X
1
is an oxygen atom or a sulfur atom,
R
1
is an acetyl group or a hydrogen atom,
R
2
is a hydrogen atom, a hydroxyl group or an alkyl group having 1 to 3 carbon atoms, and
R
3
is a group of the formula:
wherein
R
4
and R
5
are the same or different and each is an alkyl group having 1 to 3 carbon atoms or a group of the formula:
in which k is an integer of1 to 3, a group of the formula:
where in R
6
and R
7
are the same or different and each is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and X
2
is an oxygen atom, a sulfur atom, a carbonyl group, a group of the formula:
in which R
8
and R
9
are the same or different and each is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, or R
8
and R
9
are joined to form a group: —(CH
2
)
l
— in which l is an integer of 1 to 4 or a group of the formula:
in which m is 0 or 1, R
10
is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a group of the formula: —(CH
2
)
n
X
3
in which n is an integer of 1 to 4 and X
3
is an alkoxy group having 1 to 3 carbon atoms, a vinyl group, an ethynyl group or a group of the formula:
and
(2) a proton pump inhibitor (a) or a bismuth preparation (b), wherein the components (1) and (2) are used in amounts producing a synergistic effect against
Helicobacter pylon
(Claim 1).
Further, the present invention relates to the antibacterial composition of Claim 1, wherein said rifamycin derivative (I) or its physiologically acceptable salt is a compound in which X
1
is an oxygen atom, R
1
is an acetyl group, R
2
is a hydroxyl group, and R
3
is 4-isobutylpiperazinyl group (Claim 2).
Further, the present invention relates to the antibacterial composition of Claim 1 or 2 wherein said proton pump inhibitor is a member selected from the group consisting of omeprazole, lansoprazole, leminoprazole, pantoprazole and robeprazole (Claim 3).
Further, the present invention relates to the antibacterial composition of Claim 3 wherein said proton pump inhibitor is lansoprazole (Claim 4).
Further, the present invention relates to the antibacterial composition of Claim 1 or 2, wherein said bismuth preparation is a member selected from the group consisting of colloidal bismuth subcitrate and bismuth subsalicylate (Claim 5).
Further, the present invention relates to the antibacterial composition of Claim 5, wherein said bismuth preparation is bismuth subsalicylate (Claim 6).
Further, the present invention relates to the antibacterial composition of any one of Claims 1 to 6, which is effective for the treatment to eradicate
Helicobacter pylori
(Claim 7).
The present invention relates to a drug containing (1) the antibacterial composition of any one of Claims 1 to 7 as an effective component, and (2) a pharmacologically acceptable carrier (Claim 8).
The present invention relates to a remedy for diseases of digestive organs containing (1) the antibacterial composition of any one of Claims 1 to 7 as an effective component, and (2) a pharmacologically acceptable carrier (Claim 9).
The present invention relates to a process for producing drugs which comprises mixing (1) the antibacterial composition of any one of Claims 1 to 7 and (2) a pharmacologically acceptable carrier (Claim 10).
The present invention relates to a process for producing remedies for diseases of digestive organs which comprises mixing (1) the antibacterial composition of any one of Claims 1 to 7 and (2) a pharmacologically acceptable carrier (Claim 11).
The present invention relates to a pharmaceutical preparation comprising:
(1) a rifamycin derivative of the formula (I) or a physiologically acceptable salt thereof:
wherein
X
1
is an oxygen atom or a sulfur atom,
R
1
is an acetyl group or a hydrogen atom,
R
2
is a hydrogen atom, a hydroxyl group or an alkyl group having 1 to 3 carbon atoms, and
R
3
is a group of the formula:
wherein R
4
R
5
are the same or different and each is an alkyl group having 1 to 3 carbon atoms or a group of the formula:
in which k is an integer of 1 to 3, a group of the formula:
wherein R
6
and R
7
are the same or different and each is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and X
2
Fujii Kenji
Hidaka Takayoshi
Hosoe Kazunori
Yamashita Katsuji
Armstrong Westerman & Hattori, LLP
Kaneka Corporation
Weddington Kevin E.
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