WO1996016017A1

WO1996016017A1 - Novel arylpropionic derivatives with analgesic action and the process for the preparation thereof

Info

Publication number: WO1996016017A1
Application number: PCT/EP1995/004567
Authority: WO
Inventors: David Mauleon Casellas; Mª Luisa GARCIA PEREZ; Mª de los Desamparados FOS TORRO
Original assignee: Laboratorios Menarini S.A.
Priority date: 1994-11-23
Filing date: 1995-11-20
Publication date: 1996-05-30
Also published as: ES2109859A1; ES2109859B1; AU4174696A

Abstract

The present invention relates to novel arylpropionic derivatives, namely the salts of (+)-(s)-2-(3-benzoylphenyl)propionic acid with metal ions of formula (I), wherein M+ is the required stoichiometric amount of the cations corresponding to sodium, potassium, calcium, magnesium, zinc or aluminium. The process for the preparation thereof comprises reacting (+)-(S)-2-(3-benzoylphenyl)propionic acid (II) or a salt thereof with a metal hydroxide or salt. Said compounds exhibit high analgesic and anti-inflammatory actions in human therapy.

Description

NOVEL ARVLPROPTONTC DERIVATIVES WITH ANALGESIC ACTION AND THE PROCESS FOR THE PREPARATION THEREOF

The present invention relates to novel arylpropionic derivatives, namely to salts of (+)-(S)-2-( 3-benzoylphenyl)propionic acid with metal ions, to the pharmaceutically acceptable solvates thereof, and to pharmaceutical compositions containing them, having anti-inflammatory and analgesic actions. Moreover, the present invention relates to a process for the preparation of the novel salts, as well as the therapeutical use thereof. TECHNOLOGICAL BACKGROUND

2-(3-Benzoylphenyl)propionic acid, also named ketoprofen, is a known non-steroidal anti-inflammatory agent exhibiting a potent analgesic and antipyretic action. Though ketoprofen has been marketed as a racemic mixture of its (+)-(S) and (-)-(R) enantiomers, its therapeutical activity has been found to lie mainly in the S enantiomer [Yamaguchi T. et al., Folia Pharmacol . Japon ___ , 295 (1987)]. Moreover, the (+)-(S) enantiomer of ketoprofen has been claimed to be a faster acting and more potent analgesic than the racemate, when administered at equal doses [Sunshine A. et al., WO 39/04658].

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. These drawbacks can restrict its use, since its poor solubility makes both the parenteral and oral administrations difficult, and its tendency to cause gastric lesions limits its use in patients prone to gastrointestinal disorders. According to literature, said drawbacks of arylpropionic acids may substantially be overcome by salifying said acids. Examples are ibuprofen [Kwan K.Ch. EP 424028] and ketoprofen [Metz G. EP 136470, BE 882889, Bruzzese T. et al. , DE 2508895] lysine salts; diclofenac choline salt [Di Schiena M. G. EP 521393]; ketoprofen imidazoliu salt [Stradi R. PR 2580641]; or the ketoprofen metal salts, such as the sodium salt [Fujimura H. et al., Oyo Yakuri , 12, 709 (1977)], the calcium salt [Ogiso T. EP 245126], the zinc salt [Buxade A. ES 2016503] or the aluminium salt [Montanari R. DE 3505582] .

(+)-(S)-2-(3-Benzoylphenyl)propionic acid trometha ine salt has also been described [Carganico G. et al., WO 94/11332]; undoubtedly, up to now, no salts with the metal ions according to the present invention have been described in literature.

Nevertheless, in therapy there is a need for compounds with high anti-inflammatory and analgesic activities, free from undesired side-effects. 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. For example, in a conventional analgesia animal model, the phenylbenzoquinone writhing test, compound (I) (as the sodium salt) was observed to have the same analgesic effectiveness as a double dose of racemic ketoprofen sodium salt (Tables I and II), both intravenously and orally.

Moreover, 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 pharmacokinetic 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. et al., WO 89/04658], also showing an additional advantage, since they can be administered to patients prone to gastrointestinal disorders when treated with ketoprofen free acid.

DISCLOSURE OF THE INVENTION The present invention provides novel salts of formula (I), substantially free from any other stereoisomer,

wherein: M⁺ is the required stoichiometric amount of the cations corresponding to sodium, potassium, calcium, magnesium, zinc or aluminium.

The present invention also provides a process for the preparation of the novel (+)-(S)-2-(3-benzoylphenyl )propionic acid salts, as well as the therapeutical use thereof.

Object of the present invention are also the solvates of the salts of formula (I).

Preferred compounds of the present invention are those wherein M⁺ is the required stoichiometric amount of the cations corresponding to sodium, calcium, zinc or aluminium.

Particularly preferred compounds of the present invention are the following ones:

(+)-(S)-2-( 3-benzoylphenyl)propιonιc acid sodium salt;

(₊)-(S)-2-(3-benzoylphenyl )propιonιc acid calcium salt;

(+ )-(S)-2-( 3-benzoylphenyl)propιonιc acid aluminium salt. According to the present invention, the compounds of formula (I) are obtained by reacting (+)- ( S ) -2- ( 3-benzoylphenyl )propionic acid ( I I )

I I with a metal hydroxide, such as sodium hydroxide, potassium hydroxide, zinc hydroxide or by reacting a (+ )-(S)-2-( 3-benzoylphenyl)propionic acid (II) salt, prepared i situ (preferably the sodium salt) with a metal salt such as calcium chloride, aluminium chloride, zinc chloride, calcium acetate or zinc acetate. Said salts are only mentioned by way of examples, and other salts not affecting negatively the reaction can be used. The metal salt can be present in equimolecular amounts, in an excess or also in a defect. The reaction can be carried out in a solvent or in a mixture of polar solvents such as water, methanol, ethanol, acetonitrile, tetrahydrofuran or acetone. Preferably, a mixture of water with methanol or ethanol is used. The reaction temperature can vary between -5^*C and the solvent reflux, preferably between 10 and 40^*C, for a time between 1 and 24 hours.

The starting (+)-(S)-2-( 3-benzoylphenyl)propionic acid (II) can be prepared following the procedures described in literature, for example by enantioselective synthesis [Fadel A., Synlett . 1, 48 (1992)], or by resolution of racemic ketoprofen through crystallization with chiral amines or enzymatic methods [Nohira H. et al., EP 423467, Sih C.L. et al . , EP 227078, Carganico G. et al. , WO 93/25703, WO 93/25704, Evans C. et al. , WO 93/04189, WO 93/04190, Warneck J. et al . , WO 94/20633]. The compounds of the present invention have anti- inflammatory and analgesic characteristics and therefore they can be used in human therapy.

For the therapeutical use, 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. Examples of such formulations include capsules, tablets, granulates, solutions, syrups and the like, containing 1 to 1000 mg per unitary dose.

The following examples illustrate the preparation and the results of the pharmacological activity tests of the compounds of the present invention, without limiting it. EXAMPLE 1

Preparation of (+ .-(S ) -2- ( 3-benzovlphenvl )propionic acid sodium salt

To a solution of (+)-(S)-2-( 3-benzoyl- phenyl)propionic acid (4.08 g, 16.03 mmol) in ethanol (8 ml), a solution of IN sodium hydroxide (16.03 ml) was added. The mixture was stirred at room temperature for 1/2 hour, thereafter was evaporated to dryness to obtain a semi-solid residue which was rediεsolved in ethanol and evaporated to dryness to obtain a solid, which was digested in ethyl ether (3x50ml), filtered and dried under vacuum. 4.02 g (91%) of the title compound were obtained, as a white solid with melting point

241.3-241.6^*C.

[α]_D ²⁵ = -3.98^* (c = 1.20, water).

IR (KBr): 1650, 1580, 1420, 1330, 1300, 1280, 900, 720, 700, 650 cm^-1.

1H N.M.R. (300 MHz, CD3OD) δ ppm: 1.45 (d, 3H) ; 3.66 (q,

1H); 7.40-7.81 (m, 9H) .

EXAMPLE 2

Preparation of (■+.-(S .-2-f .'.-benzovlphenvl .propionin arid aluminium salt

To a solution of (+ )-(S)-2-( 3-benzoyl- phenyl)propionic acid sodium salt (1 g, 3.62 mmol) in water (5 ml), a solution of aluminium trichloride (161 g, 1.21 mmol) in cold water (3 ml) was added. When the addition was completed, water (3 ml) was added and pH was adjusted to 3.5. The formed solid was filtered, digested in methanol and dried under vacuum. 0.51 g of a solid was obtained, with melting point 176.0-177.9'C.

IR (KBr): 1659, 1595, 1581, 1466, 1439, 1282, 710, 640 cm^-1

EXAMPLE 3

Analgesic activity. Phenvlhenzoσuinone writhing t- st

This standard test, based on the procedure by Siegmund et al. [Proc. Soc. Exp. Biol. and Med. , ___ , 729 (1957)] allows to evaluate the analgesic effect of the compounds of the present invention. In this test, Swiss male mice of 20 to 25 g are used, taken in random groups of 6 each. The product under examination is injected intravenously in the tail side vein. The product is administered dissolved in a physiological serum at a concentration suited to the dose to be administered, the volume thereof being 10 ml/kg. Immediately after the injection of the product, a 1.03 M phenylbenzoquinone solution in 1:20 ethanol:water is administered intraperitoneally, the volume being 10 ml/kg. Against each series of tests, a control group is administered systematically with the vehicle only. 5 min. after the administration of the phlogogen agent, the writhings in the animal are counted over a 5 minute period. Lack of writhings indicates a successful outcome. The extent of analgesic protection can be measured in terms of the number of writhings compared with the control animals. Table 1 below shows the analgesic effect as observed for a compound of the present invention as well as the analgesic effect of the racemic ketoprofen sodium salt by way of comparison. Table 2 shows the results obtained with a compound of the present invention compared with ketoprofen sodium salt, both of them being dissolved in physiological serum and administered orally by esophageal catheter 30 minutes prior to the phenylben¬ zoquinone injection.

Table 1. Analgesic effect. Phenylbenzoquinone test (intravenously)

a) Dose equivalent to the amount of ketoprofen injected in each administration of the salt. Table 2. Analgesic effect. Phenylbenzoquinone test (orally)

Compound Dose (mg/Kg)^a % Inhibition

I (M⁺ = Na⁺) 0.50 68.6±7.1

(R,S)-ketoprofen 1 70.8±7.2 sodium salt

a) Dose equivalent to the amount of ketoprofen injected in each administration of the salt.

Claims

1. A compound of formula (I), substantially free from any other stereoisomer,

wherein:

M⁺ is the required stoichiometric amount of the cations corresponding to sodium, potassium, calcium, magnesium, zinc or aluminium; as well as the pharmaceutically acceptable solvates thereof .

2. A compound according to claim 1, wherein M^* is the required stoichiometric amount of the cations corresponding to sodium, calcium, zinc or aluminium.

3. A compound according to the above claims, selected from:

(+)-(S)-2-(3-benzoylphenyl )propιonιc acid sodium salt;

(₊)-(S)-2-(3-benzoylphenyl)propιonιc acid calcium salt;

(+ )-(S)-2-( 3-benzoylphenyl )propιonιc acid aluminium salt.

4. A process for the preparation of a compound of general formula (I) of claim 1, which process comprises reacting a compound of formula (II)

I I with a metal hydroxide selected from sodium hydroxide, potassium hydroxide, zinc hydroxide; or reacting a (+)-(S)-2-(3-benzoylphenyl )propionic acid (II) salt, prepared in situ . with a metal salt selected from calcium chloride, aluminium chloride, zinc chloride, calcium acetate or zinc acetate, the reaction being carried out in a solvent or in a mixture of polar solvents.

5. A process according to claim 4, wherein the salt of compound (II) prepared in situ is the sodium salt.

6. A process according to claim 4, wherein the solvent is water, methanol, ethanol, acetonitrile, tetrahydrofuran or acetone or mixtures thereof.

7. The use of a compound according to any one of claims 1 to 3 for the preparation of a medicament for producing a rapid, high analgesic response in humans.

8. The use of a compound according to any one of claims 1 to 3 for the preparation of a medicament for the treatment of pain and inflammation in humans.

9. Pharmaceutical compositions, containing a therapeutically effective amount of a compound according to claims 1 to 3, together with a pharmaceutically acceptable excipient.