Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
1999-11-01
2002-07-23
Low, Christopher S. F. (Department: 1653)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C562S567000, C562S587000, C514S018700, C514S019300, C530S331000, C435S252100, C435S252500
Reexamination Certificate
active
06423869
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a polyol, a method of producing it, and use thereof. More particularly, the invention relates to a bioactive compound of use as a medicine, for example as a prophylactic and therapeutic drug for diseases such as gastric ulcer and duodenal ulcer, and an anti-
Helicobacter pylori
(hereinafter may be referred to as
H. pylori
or HP) agent comprising said compound.
BACKGROUND ART
Being a member of the group of bacteria doing harm in the gastrointestinal tract,
Helicobacter pylori
is a gram-negative microaerophile belonging to the genus Helicobacter and, as suggested, may be a major factor in the recurrences of gastritis, duodenal ulcer and stomach ulcer.
For the treatment of various diseases associated with
Helicobacter pylori
infection, chemotherapy such as a two-drug combined therapy using a bismuth drug and an antibiotic or a three-drug combined therapy using a bismuth drug, metronidazole (U.S. Pat. No. 2,944,061), and either tetracycline (e.g. U.S. Pat. No. 2,712,517) or amoxicillin (U.S. Pat. No. 3,192,198) is being practiced today. The ternary therapy consisting of a gastric proton pump inhibitor, amoxicillin, and clarithromycin has also been found to be effective (Gut, 1995, 37 (Supplement 1): A365) (Gastroenterology, 1996, 110: A171). Such drugs as bismuth drugs, antibiotics, and metronidazole are all administered by the oral route.
Referring to polyols, PCT International Patent Application Publication No. WO93/06838 and Acta Chemical Scandinavica B 36, 515-518 (1982) disclose
respectively, as synthetic intermediates, and Carbohyd. Res., 28 (2), 263-280 (1973) states that
is active against gram-negative bacteria.
For an improved expression of the efficacy of an active ingredient and a reduced risk for side effects, an attempt was made to formulate amoxicillin, for instance, into a gastric mucosa-adhesive composition to prolong its intragastric residence time and let amoxicillin be released at a controlled rate and with consequent improved availability of active ingredients (WO 94/00112). It has been demonstrated that the rate of clearance of
Helicobacter pylori
can be improved by causing an anti-
Helicobacter pylori
substance to stay in the stomach longer to ensure prolonged exposure of the bacteria to the active substance [Scand. J. Gastroenterol., 29, 16-42 (1994)].
However, in order that a sufficient growth-inhibitory concentration may be maintained in the habitat of
Helicobacter pylori
, said bismuth drugs, antibiotics, or metronidazole must be administered daily in massive doses and such therapeutics entail various troubles, for example, the onset of adverse reactions such as vomiting and diarrhea. Under the circumstances, the present invention has for its object to provide a novel medicinal agent having high antibacterial activity, particularly against
Helicobacter pylori
and other bacteria of the genus Helicobacter, and producing clinically rewarding prophylactic and therapeutic responses with a reduced incidence of adverse reactions.
DISCLOSURE OF INVENTION
Under the circumstances, the present invention has for its object to provide a novel medicinal agent having high antibacterial activity, particularly against
Helicobacter pylori
and other bacteria of the genus Helicobacter, and producing clinically rewarding prophylactic and therapeutic responses with a reduced incidence of adverse reactions.
The present invention has for its object to provide a pharmaceutical composition which has enhanced mucosa-adherent activity compared with other gastric mucosa-adherent preparations, and consequently, an extremely improved efficacy of the active ingredient, in particular, an anti-
Helicobacter pylori
composition and a pharmaceutical preparation, for the prophylaxis, treatment or prevention of relapse of gastroduodenal ulcers, which is very satisfactory and favorable in having anti-
Helicobacter pylori
effect, low risk for side effects, sustained effect, and safety.
As the result of their intensive research, the inventors of the present invention synthesized a novel polyhydric alcohol (polyol) of the following general formula
[wherein R
1
represents amino which may be substituted; R
2
represents carboxy which may be esterified or amidated; R
3
, R
4
, R
5
, and R
6
each represent hydroxy which may be protected; Q represents aryl which may be substituted], which is structurally distinct in that the following defined group:
[Q and R
2
are the same meaning as defined above] is directly bound to a carbon atom, and discovered that, because of this unique chemical structure, the above compound displays remarkable inhibitory activity against the bacteria doing harm in the gastrointestinal tract, particularly high anti-Helicobacter activity, with clinically favorable pharmacological characteristics such as a low risk for adverse effects. The present invention has been developed on the basis of the above finding.
In view of the above state of the art, the inventors of the present invention have discovered that the effectiveness of active ingredients (e.g. anti
Helicobacter pylori
effect) can be potentiated by incorporating an agent (e.g. a curdlan and/or a low-substituted hydroxypropylcellulose) which swells a viscogenic agent, in the objective gastric mucosa adhesive composition containing an active ingredient (e.g. anti
Helicobacter pylori
substance), and that the composition has favorable safety characteristics and an enhanced adhesion to the mucosa.
The present invention, therefore, relates to:
(1) a compound of the formula (I):
wherein R
1
represents amino which may be substituted; R
2
represents carboxy which may be esterified or amidated; R
3
, R
4
, R
5
, and R
6
each represent hydroxy which may be protected; Q represents aryl which may be substituted; or a salt thereof,
(2) the compound according to (1), wherein R
1
is an acylamino group or an amino group substituted by a hydrocarbon group which may be substituted,
(3) the compound according to (2), wherein the acylamino group is an amino group substituted by an amino acid residue,
(4) the compound according to (3), wherein the amino acid residue is an &agr;-amino acid residue,
(5) the compound according to (1), wherein R
1
is an amino group or a group represented by the formula:
wherein R
7
is an amino which may be substituted with a &agr;-L-amino acid residue which may be substituted with a &agr;-L-amino acid residue, R
8
is a hydrocarbon group which may be substituted; R
2
represents a carboxy group; R
3
, R
4
, R
5
, and R
6
each represents a hydroxy group; Q represents a phenyl group,
(6) the compound according to (5), which is represented by the formula (V):
wherein R
7
and R
8
are of the same meaning as defined in (5),
(7) the compound according to (5), wherein R
8
is a C
1-10
alkyl group, a C
6-14
aryl-C
1-6
alkyl group, a C
2-10
alkenyl group or a C
2-10
alkynyl group, each of which may be substituted,
(8) the compound according to (7), wherein R
8
is a C
1-6
alkyl group or a C
2-6
alkenyl group,
(9) the compound according to (7), wherein R
7
is an amino group which may be substituted with a valyl group, a valylvalyl group, a valylisoleucyl group or a valylleucyl group,
(10) the compound according to (8), wherein R
8
is an isobutyl group or an allyl group,
(11) the compound according to (1), wherein R
1
is an amino group,
(12) a compound according to (1), which is (S)-3-[(2S,3R,4R,5S)-2,3,4,6-tetrahydroxy-5-(L-valyl-L-valyl-L-leucyl)aminohexanoyl]amino-3-phenylpropionic acid,
(13) a compound according to (1), which is (S)-3-[(2S,3R,4R,5S)-2,3,4,6-tetrahydroxy-5-(L-valyl-L-isoleucyl-L-leucyl)aminohexanoyl]amino-3-phenylpropionic acid,
(14) a compound according to (1), which is (S)-3-[(2S,3R,4R,5S)-2,3,4,6-tetrahydroxy-5-(L-valyl-L-leucyl-L-leucyl)aminohexanoyl]amino-3-phenylpropionic acid,
(15) a compound according to (1), which is (S)-3-[(2S,3R,4R,5S)-2,3,4,6-tetrahydroxy-5-(L-valyl-L-leucyl)aminohexanoyl]amino-3-phenylpropioni
Akiyama Yohko
Izawa Motoo
Kamiyama Keiji
Miyagawa Ken-ichiro
Nakano Yoshitaka
Chao Mark
Low Christopher S. F.
Lukton David
Ramesh Elaine M.
Takeda Chemical Industries, Inc.
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