(12) United States Patent
`Sawa
`
`US006274592B1
`US 6,274,592 B1
`*Aug. 14, 2001
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`(54) METHOD FOR STABILIZING
`ARYLCARBOXYLIC ACID, STABILIZER
`THEREOF AND AQUEOUS SOLUTION
`CONTAINING STABILIZED
`ARYLCARBOXYLIC ACID
`
`(75) Inventor: Shirou Sawa, Kobe (JP)
`
`(73) Assignee: Senju Pharmaceutical Co., Ltd.,
`Osaka (JP)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`This patent is subject to a terminal dis
`claimer.
`
`(21) Appl. No.: 09/017,626
`(22) Filed:
`Feb. 2, 1998
`(30)
`Foreign Application Priority Data
`
`Feb. 4, 1997
`
`(JP) ................................................. .. 9-021805
`
`(51) Int. Cl.7 .................... .. A61K 31/436; A61K 31/495;
`A61K 31/52; A61K 47/22
`(52) US. Cl. ............... .. 514/291; 514/230.5; 514/253.04;
`514/253.08; 514/264; 514/300; 514/312;
`514/352; 514/365; 514/420; 514/567; 514/226.2
`(58) Field of Search ............................ .. 546/89, 311, 204,
`546/500, 501; 544/38; 514/291, 226.2,
`352, 365, 420, 567, 264, 300, 253.08, 312,
`230.5, 253.04
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`12/1988 Corbiere ............................. .. 514/420
`4,794,117
`5,942,508 * 8/1999 Sawa ............................... .. 514/2358
`
`FOREIGN PATENT DOCUMENTS
`
`1 336 687
`0 105 635
`0 359 195
`0 621 036
`
`8/1995 (CA) .
`4/1984 (EP) .
`3/1990 (EP) .
`10/1994 (EP) .
`
`1/1995 (EP) .
`0 631 782
`0 824 916 * 2/1998 (EP) .
`0 269 278
`6/1998 (EP) .
`873 526
`7/1961 (GB).
`2 082 456
`3/1982 (GB) .
`93 17716
`9/1993 (W0).
`95 07082
`3/1995 (W0).
`96 29997
`10/1996 (W0).
`W0 9632941 * 10/1996 (W0).
`97 49405
`12/1997 (WO).
`
`OTHER PUBLICATIONS
`
`Kohno et al., Chemical Abstracts, vol. 121, abstract 221074,
`1994.*
`Nozaki et al., Chemical Abstracts, vol. 115, abstract 24529,
`1991.*
`Patent Abstracts of Japan, vol. 1997, No. 04, Apr. 30, 1997
`& JP 08 333246.
`Patent Abstracts of Japan, vol. 1997, No. 04, Apr. 30, 1997
`& JP 08 333265.
`Chemical Abstracts, vol. 122, No. 26, Jun. 26, 1995,
`Abstract No. 322527.
`Patent Abstracts of Japan, vol. 1997, No. 10, Oct. 31, 1997
`& JP 09 157162.
`Patent Abstracts of Japan, vol. 1995, No. 07, Aug. 31, 1995
`& JP 07 097325.
`
`* cited by examiner
`Primary Examiner—Richard L. Raymond
`(74) Attorney, Agent, or F irm—Wenderoth, Lind & Ponack,
`L.L.P.
`(57)
`
`ABSTRACT
`
`A method for stabilizing an arylcarboXylic acid, Which
`comprises adding a heterocyclic base to the arylcarboXylic
`acid or a pharmacologically acceptable salt thereof, a sta
`bilizer thereof and an aqueous solution containing a stabi
`lized arylcarboXylic acid. According to the stabilization
`method of the present invention, arylcarboXylic acid and
`pharmacologically acceptable salts thereof, particularly
`pranoprofen, can be stabilized at every temperature range,
`particularly at loWer temperatures, thereby making the pro
`duction of an aqueous solution to be used as an eye drop,
`nasal drop, ear drop and the like possible.
`
`7 Claims, No Drawings
`
`

`
`US 6,274,592 B1
`
`1
`METHOD FOR STABILIZING
`ARYLCARBOXYLIC ACID, STABILIZER
`THEREOF AND AQUEOUS SOLUTION
`CONTAINING STABILIZED
`ARYLCARBOXYLIC ACID
`
`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 antiin?arnrnatory activity, or a pharrnacologically
`acceptable salt thereof, a stabiliZer thereof and an aqueous
`solution containing a stabilized arylcarboXylic acid.
`
`BACKGROUND OF THE INVENTION
`
`ArylcarboXylic acid and pharrnacologically acceptable
`salts thereof have been knoWn to be extremely superior
`antiin?arnrnatory agents. HoWever, said arylcarboXylic
`acids, particularly pranoprofen, diclofenac and brornfenac,
`are associated With a problem that they become unstable in
`an aqueous solution.
`
`ArylcarboXylic acid and pharrnacologically 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.
`
`10
`
`15
`
`25
`
`Thus, an aqueous solution has not been provided Which
`contains an arylcarboXylic acid or a pharrnacologically
`acceptable salt thereof, particularly pranoprofen, dicrofenac
`or brornfenac, and Which has sufficient stability at lower
`temperatures.
`
`35
`
`While WO9632941 A1 discloses pranoprofen combined
`with an organic arnine, 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 phar
`rnacologically acceptable salt thereof.
`
`Another object of the present invention is to provide a
`stabiliZer of an arylcarboXylic acid and a pharrnacologically
`acceptable salt thereof, Which contains a heterocyclic base.
`
`(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 rnay
`cornbinedly forrn CH;
`R2, R3, R4, R5, R6, R7 and R8 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 R4 and R5 may form a 4- to 6-rnernbered het
`erocyclic group With the adjacent nitrogen atom and X,
`and R6 and R7 may form a 4- to 6-rnernbered hetero
`cyclic group With the adjacent Y and Z, provided that
`When X is a nitrogen atom, R5 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 Ais a nitrogen atom,
`Y and Z cornbinedly forrn CH and :is a single
`bond,
`to an arylcarboXylic acid of the formula (I):
`
`L1—R1 COOH
`
`(I)
`
`Wherein
`L1 is an optionally substituted heterocyclic group or aryl
`group having not more than 14 carbon atoms; and
`R1 is an optionally substituted alkyl group having not
`more than 4 carbon atoms or a single bond,
`or a pharrnacologically acceptable salt thereof.
`(2) The method of (1) above, Wherein the heterocyclic base
`is a purine base of the formula (III):
`
`0
`
`T11
`
`(III)
`
`Yet another object of the present invention is to provide an
`aqueous solution containing a solubiliZed arylcarboXylic
`acid and a heterocyclic base.
`
`55
`
`o
`
`N
`
`T
`R10
`
`According to the present invention, it has noW been found
`that the addition of a heterocyclic base to an arylcarboXylic
`acid or a pharrnacologically 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
`pharrnacologically acceptable salt thereof, Which corn
`prises adding a heteroryclic base of the formula (II):
`
`Wherein
`R9, R10 and R11 may be the same or different and each is
`a hydrogen atom or an optionally substituted alkyl
`group,
`or a pharrnacologically 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, theobrornine and theophylline.
`(4) The method of (1) above, Wherein the heterocyclic base
`is a pyridonecarboXylic acid of the formula (IV):
`
`Page 2
`
`

`
`Ho2c
`
`0
`
`|
`
`N
`
`in
`
`\ R15
`| /
`ILB
`
`R14
`
`X
`
`US 6,274,592 B1
`
`(IV)
`
`4
`and R6 and R7 may form a 4- to 6-membered hetero
`cyclic group With the adjacent Y and Z, provided that
`When X is a nitrogen atom, R5 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
`X is as de?ned above; and
`R12, R13, R14 and R15 may be the same or different and
`each is a hydrogen atom, a halogen, a carboXyl group,
`an optionally substituted loWer alkyl group, an option
`ally substituted cycloalkyl group, an optionally substi
`tuted acyl group, an optionally substituted aryl group or
`an optionally substituted heterocyclic group;
`Wherein R12 and R13 may form a 4- to 6-membered
`heterocyclic group With the adjacent nitrogen atom and
`X, and R14 and R15 may form a 4- to 6-membered
`heterocyclic group With the adjacent carbon atom,
`provided that When X is a nitrogen atom, R13 is void,
`or a pharmacologically acceptable salt thereof.
`(5) The method of (4) above, Wherein the pyridonecarboXy
`lic acid is at least one compound selected from the group
`consisting of lome?oXacin, nor?oXacin, o?oXacin,
`enoXacin, cipro?oXacin and tosu?oXacin.
`(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, ?ufenisal,
`ibufenac, alclofenac, ?urbiprofen, ketoprofen, naproXen,
`mefenamic acid, ni?umic 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) AstabiliZer of an arylcarboXylic acid or a pharmacologi
`cally acceptable salt thereof, Which comprises, as an
`active ingredient, a heterocyclic base of the formula (II):
`
`(III)
`
`R11
`|
`N
`
`/>
`
`N
`
`0
`
`R9
`\N
`
`o
`
`N
`
`1 '
`ILIO
`
`20
`
`Wherein
`R9, R10 and R11 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):
`
`(IV)
`
`35
`
`Ho2c
`
`0
`
`N
`
`ILIZ
`
`|
`
`\ R15
`| /
`ILB
`
`R14
`
`X
`
`(II)
`
`45
`
`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;
`R2, R3, R4, R5, R6, R7 and R8 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 R4 and R5 may form a 4- to 6-membered het
`erocyclic group With the adjacent nitrogen atom and X,
`
`65
`
`Wherein
`X is as de?ned above; and
`R12, R13, R14 and R15 may be the same or different and
`each is a hydrogen atom, a halogen, a carboXyl group,
`an optionally substituted loWer alkyl group, an option
`ally substituted cycloalkyl group, an optionally substi
`tuted acyl group, an optionally substituted aryl group or
`an optionally substituted heterocyclic group;
`Wherein R12 and R13 may form a 4- to 6-membered
`heterocyclic group With the adjacent nitrogen atom and
`X, and R14 and R15 may form a 4- to 6-membered
`heterocyclic group With the adjacent carbon atom,
`provided that When X is a nitrogen atom, R13 is void,
`or a pharmacologically acceptable salt thereof.
`(12) The stabiliZer of (11) above, Wherein the pyridonecar
`boXylic acid is at least one compound selected from the
`group consisting of lome?oXacin, nor?oXacin, o?oXacin,
`enoXacin, cipro?oXacin and tosu?oXacin.
`(13) The stabiliZer of (8) 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, ?ufenisal,
`ibufenac, aldlofenac, ?urbiprofen, ketoprofen, naproXen,
`mefenamic acid, ni?umic acid, metiaZinic acid, protiZinic
`acid, cloniXin, indomethacin and fencloZic acid.
`
`Page 3
`
`

`
`US 6,274,592 B1
`
`5
`(14) The stabilizer of (8) above, wherein the heterocyclic
`base is contained in a proportion of 0.001—5 parts by
`Weight per 100 parts by Weight of the arylcarboXylic acid.
`(15) An aqueous solution containing an arylcarboXylic acid
`or a pharmacologically acceptable salt thereof stabiliZed
`by the method of (1) above and a heterocyclic base of the
`formula (II):
`
`<11)
`
`10
`
`15
`
`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;
`R2, R3, R4, R5, R6, R7 and R8 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 R4 and R5 may form a 4- to 6-membered het
`erocyclic group With the adjacent nitrogen atom and X,
`and R6 and R7 may form a 4- to 6-membered hetero
`cyclic group With the adjacent Y and Z, provided that
`When X is a nitrogen atom, R5 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.
`(16) The aqueous solution of (15) above, Wherein the
`heterocyclic base is a purine base of the formula (III):
`
`3O
`
`35
`
`45
`
`(III)
`
`(IV)
`
`Ho2c
`
`0
`
`|
`
`N
`
`in
`
`\ R15
`| /
`ILB
`
`R14
`
`X
`
`Wherein
`X is as de?ned above; and
`R12, R13, R14 and R15 may be the same or different and
`each is a hydrogen atom, a halogen, a carboXyl group,
`an optionally substituted loWer alkyl group, an option
`ally substituted cycloalkyl group, an optionally substi
`tuted acyl group, an optionally substituted aryl group or
`an optionally substituted heterocyclic group;
`Wherein R12 and R13 may form a 4- to 6membered
`heterocyclic group With the adjacent nitrogen atom and
`X, and R14 and R15 may form a 4- to 6-membered
`heterocyclic group With the adjacent carbon atom,
`provided that When X is a nitrogen atom, R13 is void,
`or a pharmacologically acceptable salt thereof.
`(19) The aqueous solution of (18) above, Wherein the
`pyridonecarboXylic acid is at least one compound selected
`from the group consisting of lome?oXacin, nor?oXacin,
`o?oXacin, enoXacin, cipro?oXacin and tosu?oXacin.
`(20) The aqueous solution of (15) 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, sali
`cylic acid, aspirin, ?ufenisal, ibufenac, alclofenac,
`?urbiprofen, ketoprofen, naproXen, mefenamic acid,
`ni?umic acid, metiaZinic acid, protiZinic acid, cloniXin,
`indomethacin and fencloZic acid.
`(21) The aqueous solution of any one of the above (15) to
`(20), Which is an eye drop.
`(22) The aqueous solution of any one of the above (15) to
`(20), Which is a nasal drop.
`(23) The aqueous solution of any one of the above (15) to
`(20), Which is an ear drop.
`
`R11
`|
`N
`
`/>
`
`N
`
`0
`
`R9
`\N
`
`o
`
`N
`
`k '
`ILIO
`
`Wherein
`R9, R10 and R11 may be the same or different and each is
`a hydrogen atom or an optionally substituted alkyl
`group,
`or a pharmacologically acceptable salt thereof.
`(17) The aqueous solution of (16) above, Wherein the purine
`base is at least one compound selected from the group
`consisting of caffeine, theobromine and theophylline.
`(18) The aqueous solution of (15) above, Wherein the
`heterocyclic base is a pyridonecarboXylic acid of the
`formula (IV):
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`The stabiliZing method of the present invention comprises
`the addition of a stabiliZer containing a heterocyclic base as
`an active ingredient to an arylcarboXylic acid, Which is an
`acidic compound and Which has an antiin?ammatory
`activity, or a pharmacologically acceptable salt thereof. For
`example, a heterocyclic base is added to an arylcarboXylic
`acid or a pharmacologically acceptable salt thereof.
`
`55
`
`To be speci?c, an arylcarboXylic acid and a heterocyclic
`base are dissolved in Water and the pH thereof is adjusted
`With boric acid, acetic acid, phosphoric acid and the like,
`Which is folloWed by lyophiliZation Where necessary.
`While the pH varies depending on the kind of arylcar
`boXylic acid, it is generally 5—9, preferably about 6—8.
`Said heterocyclic base may be any as long as it has the
`folloWing formula (II):
`
`65
`
`Page 4
`
`

`
`US 6,274,592 B1
`
`(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;
`R2, R3, R4, R5, R6, R7 and R8 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 R4 and R5 may form a 4- to 6-membered het
`erocyclic group With the adjacent nitrogen atom and X,
`and R6 and R7 may form a 4- to 6-membered hetero
`cyclic group With the adjacent Y and Z, provided that
`When X is a nitrogen atom, R5 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.
`The alkyl of the “optionally substituted loWer alkyl
`group” has 1 to 6 carbon atoms, and may be a linear or
`branched one, such as methyl, ethyl, propyl, isopropyl,
`butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, tert
`pentyl, hexyl, isohexyl, neohexyl and the like.
`The cycloalkyl of the “optionally substituted cycloalkyl
`group” has 3 to 9 carbon atoms, and is exempli?ed by
`cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohep
`tyl and the like.
`The substituents of the above-mentioned loWer alkyl
`group and cycloalkyl group include loWer alkyl group,
`halogen and the like.
`The loWer acyl of the “optionally substituted loWer acyl
`group” may be, for example, formyl group, acetyl group,
`propionyl group, butyryl group, isobutyryl group, valeryl
`group, benZoyl group, naphthoyl group, toluoyl group, sali
`cyloyl group and the like.
`The above-mentioned acyl may be substituted by suitable
`substituents Which may be the same or different, such as
`loWer alkyl (e.g., methyl, ethyl, propyl, etc.);
`loWer alkoxy (e.g., methoxy, ethoxy, propoxy, etc.);
`loWer alkylthio (e.g., methylthio, ethylthio, etc.);
`loWer alkylamino (e.g., methylamino, ethylamino, propy
`lamino and the like);
`cyclo(loWer)alkyl such as cyclo(C3—C6)alkyl (e.g.,
`cyclopentyl, cyclohexyl and the like);
`cyclo(loWer)alkenyl such as cyclo(C3—C6)alkenyl (e.g.,
`cycloxenyl, cyclohexadienyl and the like);
`halogen (e.g., ?uorine, chlorine, bromine and iodine);
`amino; amino protecting group; hydroxy; protected
`hydroxy; cyano; nitro; carboxy; protected carboxy;
`sulfo; sulfamoyl; imino; oxo;
`amino(loWer)alkyl (e.g., aminomethyl, aminoethyl and
`the like), carbamoyloxy, hydroxy(loWer)alkyl (e.g.,
`
`15
`
`25
`
`35
`
`45
`
`55
`
`65
`
`8
`hydroxymethyl, 1- or 2-hydroxyethyl, 1- or 2- or
`3-hydroxypropyl and the like); and the like.
`The aryl of the “optionally substituted aryl group” is
`exempli?ed by phenyl, naphthyl and the like, With prefer
`ence given to naphthyl.
`The heterocyclic group of the optionally substituted het
`erocyclic group may contain, besides the carbon atom, at
`least one hetero atom selected from the group consisting of
`a nitrogen atom, sulfur atom and oxygen atom, as the atom
`constituting the ring, and may be a saturated or unsaturated,
`heteromonocyclic or heteropolycyclic group.
`The preferable heterocyclic groups are the folloWing:
`3- to 6-membered unsaturated heteromonocyclic group
`having 1 to 4 nitrogen atoms, such as pyrrolyl,
`pyrrolinyl, imidaZolyl, pyraZolyl, pyridyl, pyrimidinyl,
`pyraZinyl, pyridaZinyl, triaZolyl (e.g., 4H-1,2,4
`triaZolyl, 1H-1,2,3-triaZolyl, 2H-1,2,3-triaZolyl and the
`like), tetraZolyl (e.g., 1H-tetraZolyl, 2H-tetraZolyl and
`the like), triaZinyl (e.g., 1,2,4-triaZinyl and the like),
`and the like;
`3- to 7-membered saturated heteromonocyclic group hav
`ing 1 to 4 nitrogen atoms, such as pyrrolidinyl,
`imidaZolidinyl, piperidinyl, piperaZinyl,
`homopiperaZinyl, and the like;
`saturated heteropolycyclic group having 1 to 4 nitrogen
`atoms, such as quinuclidinyl and the like;
`unsaturated heteropolycyclic group having 1 to 5 nitrogen
`atoms, such as indolyl, isoindolyl, 3H-indolyl,
`indoliZinyl, benZoimidaZolyl, quinolyl, isoquinolyl,
`indaZolyl, phthalaZinyl, naphthyridinyl, quinoxalinyl,
`quinaZolinyl, cinnolinyl, benZotriaZolyl, tetraZolo
`pyridaZinyl (e.g., tetraZolo[1,5-b]pyridaZinyl and the
`like), pteridinyl, carbaZolyl, phenanthrinidyl, acridinyl,
`perimidyl, and the like;
`3- to 6-membered unsaturated heteromonocyclic group
`having 1 to 3 nitrogen atoms and 1 or 2 oxygen atoms,
`such as oxaZolyl, isooxaZolyl, oxadiaZolyl (e.g., 1,2,4
`oxadiaZolyl, 1,3,4-oxadiaZolyl, 1,2,5-oxadiaZolyl and
`the like), and the like;
`3- to 6-membered saturated heteromonocyclic group hav
`ing 1 to 3 nitrogen atoms and 1 or 2 oxygen atoms, such
`as morpholinyl, sydnolyl, and the like;
`unsaturated condensed heterocyclic group having 1 to 3
`nitrogen atoms and 1 or 2 oxygen atoms, such as
`benZofuraZanyl, benZoxaZolyl, benZoxaZinyl,
`benZoxadiaZolyl, and the like;
`3- to 6-membered unsaturated condensed heterocyclic
`group having 1 to 3 nitrogen atoms and 1 or 2 sulfur
`atoms, such as thiaZolyl, isothiaZolyl, thiadiaZolyl (e. g.,
`1,,2,4-thiadiaZolyl, 1,3,4-thiadiaZolyl, 1,2,5
`thiadiaZolyl and the like), and the like;
`3- to 6-membered saturated heteromonocyclic group hav
`ing 1 to 3 nitrogen atoms and 1 or 2 sulfur atoms, such
`as thiaZolidinyl and the like;
`unsaturated condensed heterocyclic group having 1 to 3
`nitrogen atoms and 1 or 2 sulfur atoms, such as
`benZothiaZolyl, benZothiadiaZolyl, and the like;
`3- to 6-membered unsaturated heteromonocyclic group
`having 1 oxygen atom, such as furyl, pyranyl and the
`like;
`3- to 6-membered unsaturated heteromonocyclic group
`having 1 or 2 sulfur atoms, such as thienyl,
`dihydrothienyl, and the like;
`unsaturated condensed heterocyclic group having 1 or 2
`sulfur atoms, such as benZothienyl and the like; and the
`like.
`
`Page 5
`
`

`
`US 6,274,592 B1
`
`9
`The aryl group and heterocyclic group are optionally
`substituted by one or more substituents selected from the
`group consisting of hydroxyl group, halogen atom, aliphatic
`alkyl group, aromatic alkyl group, aliphatic carboxylic acid
`group, aromatic carboxylic acid group, aliphatic carboxylate
`group, aromatic carboxylate group, aliphatic ether group,
`aromatic ether group, aliphatic alcohol group, aromatic
`alcohol group, aliphatic aldehyde group, aromatic aldehyde
`group, aliphatic amino group, aromatic amino group and the
`like, Which are optionally substituted by halogen atom.
`The 4- to 6membered ring formed by R4 and R5 With the
`adjacent nitrogen atom and X, and the 4- to 6-membered
`heterocyclic ring formed by R6 and R7 With the adjacent Y
`and Z may be, for example, thienyl group, furyl group,
`pyrrolyl group, imidaZolyl group, pyraZolyl group, thiaZolyl
`group, isothiaZolyl group, oxaZolyl group, isooxaZolyl
`group, oxadiaZolyl group, thiadiaZolyl group, triaZolyl
`group, pyridyl group, pyraZinyl group, pyrimidinyl group,
`pyridaZinyl group, triaZinyl group, dithiaZolyl group, diox
`olanyl group (e.g., 1,3-dioxolanyl group), dithiolyl group,
`pyrrolidinyl group, thiaZiadinyl group, dithiaZiadinyl group,
`morpholinyl group, oxaZinyl group, thiaZinyl group, piper
`aZinyl group, piperidinyl group, pyranyl group, thiopyranyl
`group and the like.
`The above-mentioned heterocyclic base is speci?cally
`exempli?ed by a purine base having a purine skeleton and a
`pyridonecarboxylic acid having a pyridine skeleton or
`pyridaZine skeleton.
`The purine base is a compound of the formula (II) Wherein
`A is a nitrogen atom, Y and Z may combinedly form CH and
`:is a single bond. It is represented by the formula (III):
`
`15
`
`25
`
`(III)
`
`35
`
`R11
`|
`N
`
`N
`
`R9
`\N
`
`o
`
`0
`
`N
`
`ILIO
`
`Wherein
`R9, R10 and R11 may be the same or different and each is
`a hydrogen atom or an optionally substituted alkyl
`group,
`and exempli?ed by caffeine, theobromine, theophylline and
`salts thereof.
`The pyridonecarboxylic acid is a compound of the for
`mula (II) Wherein A is a carbon atom, Y and Z are each CH
`and :is a double bond. It is represented by the formula
`(IV):
`
`45
`
`(W)
`
`55
`
`O
`
`HO c
`2
`
`|
`
`| \
`
`R15
`
`N
`
`ILIZ
`
`R14
`
`/
`x
`
`ILB
`
`Wherein
`X is as de?ned above; and
`R12, R13, R14 and R15 may be the same or different and
`each is a hydrogen atom, a halogen, a carboxyl group,
`
`65
`
`10
`an optionally substituted loWer alkyl group, an option
`ally substituted cycloalkyl group, an optionally substi
`tuted acyl group, an optionally substituted aryl group or
`an optionally substituted heterocyclic group;
`Wherein R12 and R13 may form a 4- to 6-membered
`heterocyclic group With the adjacent nitrogen atom and
`X, and R14 and R15 may form a 4- to 6-membered
`heterocyclic group With the adjacent carbon atom,
`provided that When X is a nitrogen atom, R13 is void.
`Examples of the pyridonecarboxylic acid include nor
`?oxacin: [1 -ethyl-6-?uoro-1,4-dihydro-4-oxo-7-(1
`piperaZinyl)-3-quinolinecarboxylic acid], o?oxacin: [(:)-9
`?uoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperaZinyl)
`7-oxo-7H-[1,2,3-de]-1,4-benZoxaZine-6-carboxylic acid],
`enoxacin: [1-ethyl-6-?uoro-1,4-dihydro-4-oxo-7-(1
`piperaZinyl)-1,8-naphthyridine-3-carboxylic acid], cinoxa
`cin: [1-ethyl- 1,4-dihydro-4-oxo-[1 ,3]-dioxolo[4,5-g]
`cinnoline-3-carboxylic acid], cipro?oxacin: [1-cyclopropyl
`6-?uoro- 1,4-dihydro-4-oxo-7-(1 -piperaZinyl)-3
`quinolinecarboxylic acid], spar?oxacin: [5-amino-1
`cyclopropyl-7-(cis-3,5-dimethyl-1-piperaZinyl)-6,8
`di?uoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid],
`tosu?oxacin: [(:)-7-(3-amino-1-pyrrolidinyl)-1 -(2,4
`di?uorophenyl)-6-?uoro-1,4-dihydro-4-oxo- 1
`naphthyridine-3-carboxylic acid], ?eroxacin: [6,8-di?uoro
`1-(2-?uoroethyl)-1,4dihydro-7-(4-methyl-1-piperaZinyl)-4
`oxo-3-quinolinecarboxylic acid], levo?oxacin: [(—)-(S)-9
`?uoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperaZinyl)
`7-oxo-7H-pyrido[1,2,3-de][1,4]benZoxaZine-6-carboxylic
`acid], lome?oxacin: [1-ethyl-6,8-di?uoro-1,4-dihydro-7-(3
`methyl-1-piperaZinyl)-4-oxo-3-quinolinecarboxylic acid],
`5,8-dihydro-8-ethyl-2-(1-piperaZinyl)-5-oxopyrido[2,3-d]
`pyrimidinecarboxylic acid, 7-(3-amino-1-pyrrolidinyl)-1
`ethyl-6-?uoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3
`carboxylic acid, 7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl
`6-?uoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic
`acid, 1 -cyclopropyl-6-?uoro-7-(3-methylamino-1
`pyrrolidinyl)-1 ,4-dihydro-4-oxo- 1,8-naphthyridine-3
`carboxylic acid, 7-(3-amino-3-methyl-1-pyrrolidinyl)-1
`cyclopropyl-6-?uoro-1,4-dihydro-4-oxo-1,8-naphthyridine
`3-carboxylic acid and the like, and salts thereof and the like.
`The pharmacologically acceptable salts of purine base and
`pyridonecarboxylic acid include, for example, acid addition
`salts With inorganic acid such as hydrochloric acid, sulfuric
`acid, phosphoric acid and the like, organic acid such as
`acetic acid, lactic acid, succinic acid, methanesulfonic acid,
`maleic acid, malonic acid, gluconic acid and the like, or
`amino acid such as aspartic acid, glutamic acid and the like;
`metal salts such as sodium salt, potassium salt and the like;
`and the like.
`The arylcarboxylic acid to be used for the stabiliZation of
`the present invention may be any compound as long as it has
`the folloWing formula (I):
`
`(I)
`
`L1—R1 COOH
`Wherein
`L1 is an optionally substituted heterocyclic group or aryl
`group having not more than 14 carbon atoms; and
`R1 is an optionally substituted alkyl group having not
`more than 4 carbon atoms or a single bond.
`The heterocyclic group in the optionally substituted het
`erocyclic group having not more than 14 carbon atoms may
`be exempli?ed by those mentioned above, and the substitu
`ents of said heterocyclic group are also exempli?ed by those
`mentioned above.
`The aryl of the “optionally substituted aryl group having
`not more than 14 carbon atoms” may be exempli?ed by
`
`Page 6
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`

`
`US 6,274,592 B1
`
`11
`those mentioned above, and the substituents of said aryl
`group are also exempli?ed by those mentioned above.
`The alkyl of the “optionally substituted alkyl group hav
`ing not more than 4 carbon atoms” may be, for example, a
`linear or branched one such as methyl, ethyl, propyl,
`isopropyl, butyl, isobutyl, tert-butyl and the like.
`Examples of the arylcarboxylic acid include naphthoic
`acid-related compounds, salicylic acid-related compounds,
`phenylacetic acid-related compounds, pyraZolone-related
`compounds, anthranilic acid-related compounds, indoleace
`tic acid-related compounds, fencloZic acid-related com
`pounds and salts thereof and the like.
`Examples of the naphthoic acid-related compounds
`include 2-naphthoic acid, 2-naphthylacetic acid,
`2-naphthoxyacetic acid and the like.
`Examples of the salicylic acid-related compounds include
`salicylic acid, aspirin, ?ufenisal, ethenZamide, benorylate
`and the like.
`Examples of the phenylacetic acid-related compounds
`include ibufenac, alclofenac, ?urbiprofen, ketoprofen,
`naproxen, ibuprofen, bromfenac, pranoprofen, namoxylate,
`fenoprofen and the like.
`Examples of the pyraZolone-related compounds include
`aminopyrine, phenylbutaZone, aZapropaZone, cinopenta
`Zone and the like.
`Examples of the anthranilic acid-related compounds
`include mefenamic acid, ni?umic acid, diclofenac, metiaZ
`inic acid, protiZinic acid, clonixin, ?ufenamic acid, ketopro
`fen and the like.
`Examples of the indoleacetic acid-related compounds
`include indomethacin, intraZole and the like.
`The amount of the heterocyclic base to be added to the
`arylcarboxylic acid or a pharmacologically acceptable salt
`thereof is preferably about 0.001—5 parts by Weight per 100
`parts by Weight of the arylcarboxylic acid or pharmacologi
`cally acceptable salt thereof.
`The stabiliZer of the arylcarboxylic acid and a pharma
`cologically acceptable salt thereof contains a heterocyclic
`base as an active ingredient, and the amount thereof is about
`the same as the amount mentioned above.
`The solvent to be used for the aqueous solution of the
`present invention may be, for example, puri?ed Water,
`particularly distilled Water for injection. The concentration
`of the active ingredient of the aqueous solution, i.e. aryl
`carboxylic acid, can be markedly increased by a heterocyclic
`base, preferably to 0.1—10 (W/v)%.
`The heterocyclic base to be used for the aqueous solution
`of the present invention may be those mentioned above.
`Said aqueous solution may contain various additives as
`appropriate, such as buffer, isotoniZing agent, solubiliZer,
`antiseptic, thickener, chelating agent, aromatic and the like.
`Examples of the buffer include phosphate buffer, borate
`buffer, citrate buffer, tartrate buffer, acetate buffer, amino
`acid and the like.
`Examples of the isotoniZing agent include sugars such as
`sorbitol, glucose, mannitol and the like, polyhydric alcohols
`such as glycerol, propylene glycol and the like, salts such as
`sodium chloride and the like, and the like.
`Examples of the solubiliZer include non-ionic surfactants
`such as polyoxyethylenesorbitan monoolate, polyoxyethyl
`eneoxystearic acid triglyceride, polyethylene glycol, poly
`oxyethylene hydrogenated castor oil and the like, and the
`like.
`Examples of the antiseptic include quaternary ammonium
`salts such as benZalkonium chloride, benZethonium
`chloride, cetylpyridinium chloride and the like,
`p-hydroxybenZoates such as methyl p-hydroxybenZoate,
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`12
`ethyl p-hydroxybenZoate, propyl p-hydroxybenZoate, butyl
`p-hydroxybenZoate and the like, benZyl alcohol, phenethyl
`alcohol, sorbic acid, salts thereof, thimerosal, chlorobutanol,
`sodium dehydr