Guanidinomethyl cyclohexane carboxylic acid ester derivatives

Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters

Reexamination Certificate

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Details

Type

Reexamination Certificate

Status

active

Patent number

06831190

Description

ABSTRACT:

FIELD OF THE INVENTION
The present invention is related to novel compounds comprising an antibacterial action, especially with a strong antibacterial action against
helicobacter pylori,
and pharmaceutically acceptable salts thereof, anti-
helicobacter pylori
agents comprising one or more compounds of the present invention, and also pharmaceutically compositions for anti-
Helicobacter pylori
comprising one or more compounds of the present invention and pharmaceutically acceptable carriers. The present invention is also related to methods of treatment for patients infected with
helicobacter pylori
comprising administration of an effective dose of one or more compounds of the invention to the patients, and usages of one or more compounds of the invention for preparation of a medicament for the treatment of
helicobacter pylori.
BACKGROUND
Helicobacter pylori
has been an remarked bacterium for investing lesion of a stomach and duodenum for the report by Wallen and Marshal, in Australia, in 1983 (Lancet ii: 1437-1442 (1983)). It has been known that the
helicobacter pylori
is a helicoid microaerophile gram-negative bacillus, adjusts its life environment by producing urease, and lives in tunica mucosa of stomach and duodenum, and also causes or recauses inflammations or ulcerations.
It was reported that the United States Public Health Research Institute presented the recommendation which means to use a combination of antiulcerative agents and antibacterial agents extermination of
helicobacter pylori
(Chem. Indust. Daily Rep. Heisei 6.7.18) because
Helicobacter pylori
is considered to be strong correlation with crisis and recurrence of peptic ulcer.
Antibiotics such as amoxicillin, cephalexin, clarislomycin (Jap. Clinic, vol. 51, No. 12, 1993), and synthetic antibacterial agents such as, ophroxacine, cyprofloxane, (APMIS, Suppl, 1007-1014, 1992) have been known as the useable compounds for extermination of
helicobacter pylori
and bacteria expulsion. Minocyline has also been known to be used for diseases caused by
helicobacter pylori,
such as gastritis (Japanese Patent Publication No. Hei 6-508635 (95/508635)).
In Japan too, while the relation between
helicobacter pylori
and peptic ulcer has been studied as the subject from now on, a movement has been raised, which investigates the corresponding to the
helicobacter pylori
has been studied with the combination of antibiotics such as amoxicillin and omeplazol, lansoplazol which comprises inhibition activity to a proton pump and are used on clinics as antiulceration agents.
Since
helicobacter pylori
is a bacterium producing urease and adjusts its life environment with the urease activity, a method for solving the above problem by using compounds with an inhibition action against the above urease activity has been known. For example, Japanese Patent Laid-Open No. 4-217950/1992 reports that aminomethylcyclohexane carboxylic acid phenyl ester group comprise the inhibition activity against the urease activity, and also inhibition action of protease, therefore it discloses useful compounds as drugs which are antiulceration agents and so on. In the above publication, a compound of which an amino group was changed to a guanidino group, or a compound shown as the following Formula (XIV) was disclosed, and reports that the above mentioned compounds showed 88.7% of ulceration restraining ratio against an ethanol hydrochloride ulceration.
However, the above publication does not make clear about the urease inhibition activity of the compounds. Since the aim of the present invention is to provide compounds with the urease inhibition activity, it is considered that the present inventors have expected the possibility of the above mentioned compound having the urease inhibition activity.
Further, in Japanese Patent Laid-Open No. 7-118153/1995, 2-[4[(3-methoxypropoxy)-3-methylpyridine-2-ilu]methylsulfinyl-1H-benzimidazol, that is the compound shown as Formula (XV) was disclosed as a compound with the inhibition activity against urease.
As administered antibiotics and synthetic antibacterial agents pass through digestive tract, are absorbed in intestine are metabolic-distributed among-going into blood, being excreted with feces and so on, when the above drugs pass through the intestine causes extinction of many bacteria living in the intestines and casting the balance of enterobacterium. Therefore the longer-term dose of such drugs should be avoided. Accordingly, compounds which comprise selectively strong antibacterial agents against the
helicobacter pylori
have been expected.
As
hericobacter pylori
is a bacterium living in stomach, antibacterial compounds in which their antibacterial activity component acts effectively in stomachs, the antibacterial activity becomes weak as the compounds moves from duodenum to small intestines and, after all, the antibacterial activity vanishes would be expected to appear. A compound called benexarte hydrochloride has been known as a compound which has a chemical stability in stomach, and was decomposed as moving to small intestines (Progress in Medicine vol. 6, extra edition No. 1, 442 (1986)), and it is reported that the anti-
helicobacter pylori
activity of this compound was MIC 25-50 g/ml (Disease of
systema digestorium
and
helicobacter pylori,
P 91, Medical Review).
The present inventors took into consideration the above mentioned background and studied compounds with specific and effective antibacterial activity against
helicobacter pylori
and have achieved the present invention. And the present invention provides compounds comprising superior growth inhibition ability against
helicobacter pylori,
but do not have the activity against esylhiacori,
staphylococcus aureus,
methacycline resistant bacterium, and so on, and a characteristics which is extremely speedy decomposed by actions of decomposition enzyme in intestinum or blood.
U.S. Pat. No. 4,220,662 discloses guanidino methyl cyclohexane carboxylic acid. And as its ester body, U.S. Pat. No. 4,348,410 discloses a phenylester substituted with a group of halogen, lower alkoxy, formyl, lower alkanoylphenyl or a group of the formula —(CH2)nCOOR3 was useful for an anti-ulceration agents as a protease inhibitor, wherein R3 of said formula —(CH2)nCOOR3 is hydrogen, lower alkyl, phenyl, anisyle or alkoxycarbonylmethyl, and n is from 0 to 2. U.S. Pat. No. 4,478,995 discloses 6-benzyloxy carbonylphenyl ester was a useful antiulceration agents. Further also, it has also been well-known that such ester bodies were useful proteolytic enzyme inhibitors or antiulceration agents (Japanese Patent Publication No. 63-24988/1988, Japanese Patent Publication No. 63-24994/1988, Japanese Patent Publication No. 63-1940/1988, Japanese Patent Publication No. 63-32065/1988, Japanese Patent Publication No. 63-2255/1988, Japanese Patent Laid-Open No. 57-48960/1982, Japanese Patent Publication No. 64-2102/1989, Japanese Patent Publication No. 63-46743/1988, Japanese Patent Publication No. 64-2103/1989, Japanese Patent Publication No. 2-4588/1990, Japanese Patent Publication No. 64-2089/1989, Japanese Patent Publication No. 64-2086/1989, Japanese Patent Publication No. 64-2084/1989).
Moreover, it has also been well-known that phenyl ester which is substituted with halogen, lower alkyl, cyano, phenyl, benzyloxycarbonyl or phenoxycarbonyl group was useful to
Escherichia coli
(M. Kato et al., Biol. Pharma. Bull., 16 (2), 120-124 (1993)).
DETAILED DESCRIPTION OF THE INVENTION
The present invention is related to antibacterial agents against
helicobacter pylori
comprising guanidinomethyl cyclohexane carboxylic acid ester which is shown in the following Formula (I-1) and pharmaceutically acceptable salts thereof.
In the above Formula (I-1), Ar′ is phenyl group, biphenyl group or naphthyl group, which has at least one substituent selected from the group consisting of halogen atom, cyano group, nitro group, carboxyl group, alkyl group having one to eighteen carbon atoms, alkoxy group having one to eighteen carbon atoms, cycloalkyl grou

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