Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-02-02
2001-08-14
Raymond, Richard L. (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S230500, C514S253040, C514S253080, C514S264110, C514S300000, C514S312000, C514S352000, C514S365000, C514S420000, C514S567000, C514S226200
Reexamination Certificate
active
06274592
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a method for stabilizing arylcarboxylic acid, which is an acidic compound and which has an antiinflammatory activity, or a pharmacologically acceptable salt thereof, a stabilizer thereof and an aqueous solution containing a stabilized arylcarboxylic acid.
BACKGROUND OF THE INVENTION
Arylcarboxylic acid and pharmacologically acceptable salts thereof have been known to be extremely superior antiinflammatory agents. However, said arylcarboxylic acids, particularly pranoprofen, diclofenac and bromfenac, are associated with a problem that they become unstable in an aqueous solution.
Arylcarboxylic acid and pharmacologically acceptable salts thereof have been also known to be stabilized by adding an antioxidant, by adjusting the pH, concentration and ionic strength thereof, by shutting out the light, and the like. These methods, nevertheless, cannot provide sufficient stability at lower temperatures.
Thus, an aqueous solution has not been provided which contains an arylcarboxylic acid or a pharmacologically acceptable salt thereof, particularly pranoprofen, dicrofenac or bromfenac, and which has sufficient stability at lower temperatures.
While WO9632941 A1 discloses pranoprofen combined with an organic amine, it does not disclose the heterocyclic base to be used in the present invention.
SUMMARY OF THE INVENTION
It is therefore an object of the present invention to provide a method for stabilizing an arylcarboxylic acid and a pharmacologically acceptable salt thereof.
Another object of the present invention is to provide a stabilizer of an arylcarboxylic acid and a pharmacologically acceptable salt thereof, which contains a heterocyclic base.
Yet another object of the present invention is to provide an aqueous solution containing a solubilized arylcarboxylic acid and a heterocyclic base.
According to the present invention, it has now been found that the addition of a heterocyclic base to an arylcarboxylic acid or a pharmacologically acceptable salt thereof leads to successful stabilization thereof, particularly pranoprofen, at every temperature range, particularly at low temperatures.
Thus, the present invention provides the following.
(1) A method for stabilizing an arylcarboxylic acid or a pharmacologically acceptable salt thereof, which comprises adding a heteroryclic base of the formula (II):
wherein
A and A′ are each a carbon atom or a nitrogen atom;
X is a carbon atom or a nitrogen atom;
Y and Z are each a carbon atom or Y and Z may combinedly form CH;
R
2
, R
3
, R
4
, R
5
, R
6
, R
7
and R
8
may be the same or different and each is a hydrogen atom, a halogen, a carboxyl group, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted acyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group,
wherein R
4
and R
5
may form a 4- to 6-membered heterocyclic group with the adjacent nitrogen atom and X, and R
6
and R
7
may form a 4- to 6-membered heterocyclic group with the adjacent Y and Z, provided that when X is a nitrogen atom, R
5
is void; and
is a single bond or a double bond, provided that when A is a carbon atom, Y and Z are each CH and
is a double bond, and when A is a nitrogen atom, Y and Z combinedly form CH and
is a single bond,
to an arylcarboxylic acid of the formula (I):
L
1
—R
1
COOH (I)
wherein
L
1
is an optionally substituted heterocyclic group or aryl group having not more than 14 carbon atoms; and
R
1
is an optionally substituted alkyl group having not more than 4 carbon atoms or a single bond,
or a pharmacologically acceptable salt thereof.
(2) The method of (1) above, wherein the heterocyclic base is a purine base of the formula (III):
wherein
R
9
, R
10
and R
11
may be the same or different and each is a hydrogen atom or an optionally substituted alkyl group,
or a pharmacologically acceptable salt thereof.
(3) The method of (2) above, wherein the purine base is at least one compound selected from the group consisting of caffeine, theobromine and theophylline.
(4) The method of (1) above, wherein the heterocyclic base is a pyridonecarboxylic acid of the formula (IV):
wherein
X is as defined above; and
R
12
, R
13
, R
14
and R
15
may be the same or different and each is a hydrogen atom, a halogen, a carboxyl group, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted acyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group;
wherein R
12
and R
13
may form a 4- to 6-membered heterocyclic group with the adjacent nitrogen atom and X, and R
14
and R
15
may form a 4- to 6-membered heterocyclic group with the adjacent carbon atom, provided that when X is a nitrogen atom, R
13
is void,
or a pharmacologically acceptable salt thereof.
(5) The method of (4) above, wherein the pyridonecarboxylic acid is at least one compound selected from the group consisting of lomefloxacin, norfloxacin, ofloxacin, enoxacin, ciprofloxacin and tosufloxacin.
(6) The method of (1) above, wherein the arylcarboxylic acid is at least one compound selected from the group consisting of ibuprofen, diclofenac, 2-naphthoic acid, 2-naphthylacetic acid, 2-naphthoxyacetic acid, bromfenac, pranoprofen, salicylic acid, aspirin, flufenisal, ibufenac, alclofenac, flurbiprofen, ketoprofen, naproxen, mefenamic acid, niflumic acid, metiazinic acid, protizinic acid, clonixin, indomethacin and fenclozic acid.
(7) The method of (1) above, wherein the heterocyclic base is added in a proportion of 0.001-5 parts by weight per 100 parts by weight of the arylcarboxylic acid.
(8) A stabilizer of an arylcarboxylic acid or a pharmacologically acceptable salt thereof, which comprises, as an active ingredient, a heterocyclic base of the formula (II):
wherein
A and A′ are each a carbon atom or a nitrogen atom;
X is a carbon atom or a nitrogen atom;
Y and Z are each a carbon atom or Y and Z may combinedly form CH;
R
2
, R
3
, R
4
, R
5
, R
6
, R
7
and R
8
may be the same or different and each is a hydrogen atom, a halogen, a carboxyl group, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted acyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group,
wherein R
4
and R
5
may form a 4- to 6-membered heterocyclic group with the adjacent nitrogen atom and X, and R
6
and R
7
may form a 4- to 6-membered heterocyclic group with the adjacent Y and Z, provided that when X is a nitrogen atom, R
5
is void; and
is a single bond or a double bond, provided that when A is a carbon atom, Y and Z are each CH. and
is a double bond, and when A is a nitrogen atom, Y and Z combinedly form CH and
is a single bond.
(9) The stabilizer of (8) above, wherein the heterocyclic base is a purine base of the formula (III):
wherein
R
9
, R
10
and R
11
may be the same or different and each is a hydrogen atom or an optionally substituted alkyl group,
or a pharmacologically acceptable salt thereof.
(10) The stabilizer of (9) above, wherein the purine base is at least one compound selected from the group consisting of caffeine, theobromine and theophylline.
(11) The stabilizer of (8) above, wherein the heterocyclic base is a pyridonecarboxylic acid of the formula (IV):
wherein
X is as defined above; and
R
12
, R
13
, R
14
and R
15
may be the same or different and each is a hydrogen atom, a halogen, a carboxyl group, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted acyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group;
wherein R
12
and R
13
may form a 4- to 6-membered heterocyclic group with the adjacent nitrogen atom and X, and R
14
and R
15
may form a 4- to 6-membered heterocyclic group with the adjacent carbon atom, provided that when X is a nitrogen atom
Raymond Richard L.
Senju Pharmaceutical Co. Ltd.
Wenderoth , Lind & Ponack, L.L.P.
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