Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing heterocyclic carbon compound having only o – n – s,...
Reexamination Certificate
1997-01-16
2001-01-16
Raymond, Richard L. (Department: 1624)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing heterocyclic carbon compound having only o, n, s,...
C435S119000, C514S451000, C514S456000, C549S264000
Reexamination Certificate
active
06174710
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to compounds of the formula (I),
wherein R is (C
1
-C
5
) alkyl or CH
3
(CH
2
)
n
CO—; and n is 1, 2, 3 or 4, which are useful in the treatment of diseases, disorders and adverse conditions caused by
Helicobacter pylori
and are particularly useful in the treatment of gastroduodenal disorders, diseases and adverse conditions caused thereby. This invention further relates to a method of treating
Helicobacter pylori
induced disorders, diseases and adverse conditions and particularly gastroduodenal disorders, diseases and adverse conditions in a mammal comprising administering to said mammal the compound of formula (II),
hereinafter referred to as spirolaxine.
Spirolaxine is a known antibiotic which can be isolated from the microorganism
Chrysosporium pruinosum
ATCC 15155. Spirolaxine is reported to have weak bacteriostatic activity against
Bacillus cereus, Bacillus subtilis
and
Escherichia coli.
Arnone et al., Phytochemistry, 1990, 29, 613-616. Further, spirolaxine is reported to have no antifungal activity against
Aspergillus niger, Botrytis cinerea, Cladosporium cucumerinum, Ophiostoma ulmi
and
Saccharomyces cerevisiae.
Arnone et al., Phytochemistry, 1990, 29, 613-616.
Gastric and duodenal ulcers affect a significant portion of the human population worldwide. Currently, the usual treatment for both gastric and duodenal ulcers involves treatment of the patient with H
2
blockers. While generally effective in healing ulcers, ulcer relapse occurs in up to 90% of patients within a year of discontinuing H
2
blocker therapy. O'Connor, H. J., Postgraduate Medical Journal, 1992, 68, 549-57. Thus, patients must continue the treatment for many years or risk a recurrence of the ulcer. It is now known that ulcer healing drugs such as colloidal bismuth subcitrate (CBS) are helicobactericidal and as such CBS is used in combination with H
2
blockers to treat ulcers. O'Connor, ibid. Additionally, CBS, an H
2
blocker and amoxicillin have been used in combination to treat ulcer patients. O'Connor, ibid.
Helicobacter pylori
has recently been demonstrated to be a major causative agent in gastric and duodenal ulcers and other gastroduodenal disorders, diseases and adverse conditions. Thus, antibiotic therapy to eliminate
Helicobacter pylori
from the gastroduodenal tract would remove the root cause of said gastroduodenal disorders, diseases and adverse conditions and eliminate the need for an ulcer patient to continue long and costly treatment with H
2
blockers and the like. None of the foregoing treatments are capable of 100% eradication of
Helicobacter pylori.
Applicants have now found that spirolaxine and the spirolaxine ethers of the instant invention are potent helicobactericidal compounds. A helicobactericidal compound is a compound which kills
Helicobacter pylori.
Therefore spirolaxine and the spirolaxine ethers of formula (I) of the instant invention possess utility in treating gastroduodenal disorders, diseases and adverse conditions and particularly in treating gastric and duodenal ulcer and preventing gastric cancer.
SUMMARY OF THE INVENTION
This invention is directed to a compound of the formula (I),
wherein:
R is (C
1
-C
5
) alkyl or CH
3
(CH
2
)
n
CO—; and n is 1, 2, 3 or 4.
This invention is particularly directed to the compound of formula (I) wherein R is methyl.
This invention is also directed to a method for treating a mammal suffering from a
Helicobacter pylori
induced disorder, disease or adverse condition comprising administering an effective amount of a compound of formula (I) hereinabove or the compound of formula (II),
also known as spirolaxine, or a pharmaceutical composition thereof.
This invention is particularly directed to a method as described in the preceding paragraph comprising treating said disorder, disease or adverse condition with an effective amount of spirolaxine or a pharmaceutical composition thereof.
This invention is more particularly directed to a method as described in the preceding paragraph wherein said gastroduodenal disorder, disease or adverse condition is gastric ulcer, duodenal ulcer or gastric cancer.
This invention is still more particularly directed to a method of treating a mammal suffering from a duodenal ulcer comprising administering to said mammal an effective amount of spirolaxine or a pharmaceutical composition thereof.
This invention also provides a method of treating a mammal suffering from a
Helicobacter pylori
induced disorder, disease or adverse condition comprising administering to said mammal an effective amount of a combination comprising spirolaxine or a compound of formula (I) and an H
2
blocker.
This invention further provides a method of treating a mammal suffering from a
Helicobacter pylori
induced disorder, disease or adverse condition comprising administering to said mammal an effective amount of a combination comprising spirolaxine or a compound of formula (I), an H
2
blocker and colloidal bismuth subcitrate.
This invention further provides a method of treating a mammal suffering from a
Helicobacter pylori
induced disorder, disease or adverse condition comprising administering to said mammal an effective amount of a combination comprising spirolaxine or a compound of formula (I), an H
2
blocker and an antibiotic.
Further, this invention provides a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier.
Yet further, this invention provides a pharmaceutical composition for use in treating
Helicobacter pylori
induced disorders, diseases or adverse conditions comprising a
Helicobacter pylori
treating effective amount of spirolaxine and a pharmaceutically acceptable carrier.
Still further, this invention provides a pharmaceutical composition for use in treating
Helicobacter pylori
induced disorders, diseases or adverse conditions comprising an effective amount of a combination of spirolaxine or a compound of formula (I), an H
2
blocker and a pharmaceutically carrier.
This invention also provides a pharmaceutical composition for use in treating
Helicobacter pylori
induced disorders, diseases or adverse conditions comprising an effective amount of a combination of spirolaxine or a compound of formula (I), an H
2
blocker, colloidal bismuth subcitrate and a pharmaceutically acceptable carrier.
This invention still further provides a pharmaceutical composition for use in treating
Helicobacter pylori
induced disorders, diseases or adverse conditions comprising an effective amount of a combination of spirolaxine or a compound of formula (I), an H
2
blocker, an antibiotic and a pharmaceutically acceptable carrier.
This invention also provides a process for preparing a compound of formula (I),
wherein R is (C
1
-C
5
) alkyl or CH
3
(CH
2
)
n
CO and n is 1, 2, 3 or 4 comprising, (a) when R is (C
1
-C
5
) alkyl, reacting a compound of the formula (II),
with a (C
2
-C
5
)alkyl halide in an alcohol solvent in the presence of a base; and (b) when R is CH
3
(CH
2
)
n
CO and n is 1, 2, 3 or 4, reacting a compound of the formula (II),
with an acyl halide in aqueous alkali.
Still further, this invention provides a process for preparing the compound of formula (II) and the compound of formula (I) wherein R is methyl comprising fermenting a culture of
Sporotrichum pruinosum
ATCC 74278 and isolating said compound of formula (II) or compound of formula (I) wherein R is methyl in substantially pure form.
With respect to the compounds of formulae (I) and (II) of this invention, it is to be understood that there are stereoisomeric forms of said compounds such as optical isomers due to asymmetric carbon atoms and that said stereoisomeric forms are also included within the scope of this invention.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is readily carried out. Thus, the compound of formula (I) wherein R is methyl and the compound of formula (II) are prepared by fermentation of the microorganism
Chrysosporium pruinosum
ATCC 15155 and subsequent isolation from t
Guadliana Mark A.
Huang Liang H.
Kaneko Takushi
Watts Paul C.
Benson Gregg C.
Pfizer Inc.
Raymond Richard L.
Riehardson Peter C.
Ronau Robert T.
LandOfFree
Spirolaxine derivatives for treating gastrobuodenal diseases does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Spirolaxine derivatives for treating gastrobuodenal diseases, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Spirolaxine derivatives for treating gastrobuodenal diseases will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2506687