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WO1996016016A1 - Nouveaux derives d'acide (+)-(s)-2-(3-benzoylphenyl)propionique a action analgesique et procedes de preparation - Google Patents

Nouveaux derives d'acide (+)-(s)-2-(3-benzoylphenyl)propionique a action analgesique et procedes de preparation Download PDF

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Publication number
WO1996016016A1
WO1996016016A1 PCT/EP1995/004554 EP9504554W WO9616016A1 WO 1996016016 A1 WO1996016016 A1 WO 1996016016A1 EP 9504554 W EP9504554 W EP 9504554W WO 9616016 A1 WO9616016 A1 WO 9616016A1
Authority
WO
WIPO (PCT)
Prior art keywords
salt
compound
lysine
propionic acid
glucamine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP1995/004554
Other languages
English (en)
Inventor
David Mauleon Casellas
María Luisa GARCIA PEREZ
María de los Desamparados FOS TORRO
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Laboratorios Menarini SA
Original Assignee
Laboratorios Menarini SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Laboratorios Menarini SA filed Critical Laboratorios Menarini SA
Priority to AU39835/95A priority Critical patent/AU3983595A/en
Publication of WO1996016016A1 publication Critical patent/WO1996016016A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/76—Unsaturated compounds containing keto groups
    • C07C59/84—Unsaturated compounds containing keto groups containing six membered aromatic rings

Definitions

  • (+)-(S) enantiomer of ketoprofen has been claimed to be a faster acting and more potent analgesic than the race ate, when administered at equal doses [Sunshine A. et al., WO 89/04658].
  • Structurally ketoprofen similarly to other arylpropionic acids, has a lipophilic aromatic moiety which is responsible for its poor solubility in water and a free carboxylic group which has been related to its ulcerogenic toxicity.
  • arylpropionic acids may substantially be overcome by salifying them with metals, to give salts such as ketoprofen sodium, zinc or aluminium salt [Fuji ura H. et al., Oyo Yakuri , 1-2, 709 (1977), Buxad ⁇ A. ES 2016503, Montanari R. DE 3505582, respectively]; with basic amino acids such as ibuprofen [Kwan K.Ch. EP 424028] and ketoprofen [Metz G. EP 136470, BE 882889, Bruzzese T.
  • the present invention provides a series of novel compounds showing the cited anti-inflammatory and analgesic actions, together with a very reduced gastrolesivity.
  • the novel salts have a high solubility in water which allows for them to be administered both intramuscularly and intravenously, as well as orally in the form of tablets which are easy to dissolve in a very short time.
  • These novel derivatives exhibit a fast, complete adsorption both in animals and humans, showing an action and analgesic response higher than those of the corresponding racemic ketoprofen salts.
  • said characteristics of the compounds of the present invention allow to attain the same analgesic therapeutical effectiveness using doses lower than those necessary for racemic ketoprofen, either free or salified. Further, the physico-chemical and phar acokinetic properties of the compounds of the present invention give them a therapeutical advantage compared with the use of the (+)-(S) enantiomer of ketoprofen in the free acid form, claimed in the above cited patent [Sunshine A.
  • B + is choline or the protonated form of lysine, arginine, ornithine, D-glucamine, N-methyl-D-glucamine or imidazole.
  • the present invention also provides a process for the preparation of the novel (+)-(S)-2-(3-benzoyl- phenyl)propionic acid salts, as well as the therapeutical use thereof.
  • Object of the present invention are also the solvates of the compounds of formula (I).
  • the present invention also includes all the possible stereoisomers of the compounds of formula (I) as well the mixtures thereof.
  • Preferred compounds of the present invention are those wherein B + is choline or the protonated form of
  • N-methyl-D-glucamine or imidazole N-methyl-D-glucamine or imidazole.
  • Particularly preferred compounds of the present invention are the following ones:
  • the compounds of formula (I) are obtained by reacting (+)- (S)-2-(3-benzoylphen ⁇ l)propionic acid (II)
  • a mixture of water with methanol or ethanol is used and, when employing the sodium salt of the compound of formula (II), ethanol or isopropanol with a low water content are preferably used to promote the precipitation of sodium chloride formed during the reaction.
  • the reaction temperature can vary between 0 * C and the solvent reflux, for a time between 1 and 24 hours.
  • the compounds of the present invention have anti- inflammatory and analgesic characteristics and therefore they can be used in human therapy.
  • the compounds of the present invention are formulated in suitable pharmaceutical forms, according to conventional techniques and excipients, such as those described in Remington's Phramaceutical Handbook, Mack Pub. Co., N.Y., USA.
  • suitable pharmaceutical forms include capsules, tablets, granulates, solutions, syrups and the like, containing 1 to 1000 g per unitary dose.
  • (+)-(S)-2-(3-Benzoylphenyl)propionic acid was reacted with DL-lysine analogously to what described in Example 1.
  • a water-soluble white solid was obtained.
  • (+)-(S)-2-(3-benzoylphenyl)propionic acid 2.0 g, 7.87 mmol
  • the mixture was heated to 60"C for 10 hours, thereafter was evaporated to dryness, to obtain a semi-solid residue which was redissolved in ethanol and evaporated to dryness.
  • the resulting solid was filtered and washed with ethyl ether. 2.52 g (89%) of a white solid were obtained. Elemental analysis: calculated for C 21 H 2 NO: C, 70.56%; H, 7.61%; N, 3.92%. Found: C, 70.12%; H, 7.31%; N, 3.62%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

On décrit de nouveaux sels d'acide (+)-(S)-2-(3-benzoylphényl) propionique de formule (I), où B+ représente choline ou la forme protonée de lysine, arginine, ornithine, D-glucamine, N-méthyl-D-glucamine ou imidazole. Leur procédé de préparation consiste à faire réagir un composé de formule (II) avec lysine, arginine, ornithine, hydroxyde de choline, D-glycamine, N-méthyle-D-glucamine ou imidazole, ou bien à faire réagir un sel du composé de formule (II) avec le sel organique approprié. Ces composés présentent une activité analgésique et anti-inflammatoire élevée.
PCT/EP1995/004554 1994-11-23 1995-11-20 Nouveaux derives d'acide (+)-(s)-2-(3-benzoylphenyl)propionique a action analgesique et procedes de preparation Ceased WO1996016016A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU39835/95A AU3983595A (en) 1994-11-23 1995-11-20 Novel (+)-(s)-2-(3-benzoylphenyl)propionic acid derivatives with analgesic action and the process for the preparation thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ESP9402406 1994-11-23
ES9402406A ES2109858B1 (es) 1994-11-23 1994-11-23 Nuevos derivados del acido (+)-(s)-2-(3-benzoilfenil) propionico con accion analgesica y procedimiento para su obtencion.

Publications (1)

Publication Number Publication Date
WO1996016016A1 true WO1996016016A1 (fr) 1996-05-30

Family

ID=8288066

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1995/004554 Ceased WO1996016016A1 (fr) 1994-11-23 1995-11-20 Nouveaux derives d'acide (+)-(s)-2-(3-benzoylphenyl)propionique a action analgesique et procedes de preparation

Country Status (3)

Country Link
AU (1) AU3983595A (fr)
ES (1) ES2109858B1 (fr)
WO (1) WO1996016016A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2315763A (en) * 1996-07-31 1998-02-11 Procter & Gamble Preparation of an agglomerated detergent composition comprising a surfactant a an acid source
WO1999052528A1 (fr) * 1998-04-11 1999-10-21 Errekappa Euroterapici S.P.A. Preparations pharmaceutiques a base de sels de ketoprofene hydrosoluble et applications correspondantes
JP2009513613A (ja) * 2005-10-28 2009-04-02 フルニエ ラボラトリーズ アイルランド リミテッド 酸と第四級アンモニウムとの塩を調製するための新規な方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5179097A (en) * 1991-06-10 1993-01-12 Angres Isaac A Salts of non-steroidal anti-inflammatory carboxylic acids and anti-lipidemic carboxylic acids
WO1994020449A1 (fr) * 1993-03-09 1994-09-15 Dompe'farmaceutici Spa Sels d'acide 2-(3-benzoylphenyl)propionique et de bases organiques chirales ou achirales, et compositions pharmaceutiques les contenant

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5179097A (en) * 1991-06-10 1993-01-12 Angres Isaac A Salts of non-steroidal anti-inflammatory carboxylic acids and anti-lipidemic carboxylic acids
WO1994020449A1 (fr) * 1993-03-09 1994-09-15 Dompe'farmaceutici Spa Sels d'acide 2-(3-benzoylphenyl)propionique et de bases organiques chirales ou achirales, et compositions pharmaceutiques les contenant

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2315763A (en) * 1996-07-31 1998-02-11 Procter & Gamble Preparation of an agglomerated detergent composition comprising a surfactant a an acid source
WO1999052528A1 (fr) * 1998-04-11 1999-10-21 Errekappa Euroterapici S.P.A. Preparations pharmaceutiques a base de sels de ketoprofene hydrosoluble et applications correspondantes
US6291527B1 (en) 1998-04-11 2001-09-18 Errekappa Euroterapici S.P.A. Pharmaceutical preparations containing hydrosoluble ketoprofen salts and their application
JP2009513613A (ja) * 2005-10-28 2009-04-02 フルニエ ラボラトリーズ アイルランド リミテッド 酸と第四級アンモニウムとの塩を調製するための新規な方法
US7714163B2 (en) 2005-10-28 2010-05-11 Fournier Laboratories Ireland Ltd. Process for preparing quaternary acid and ammonium salts

Also Published As

Publication number Publication date
AU3983595A (en) 1996-06-17
ES2109858B1 (es) 1998-08-16
ES2109858A1 (es) 1998-01-16

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