GB2154233A - Aluminium salts of arylalkanoic acids and pharmaceutical compositions containing them - Google Patents

Aluminium salts of arylalkanoic acids and pharmaceutical compositions containing them Download PDF

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GB2154233A
GB2154233A GB08410234A GB8410234A GB2154233A GB 2154233 A GB2154233 A GB 2154233A GB 08410234 A GB08410234 A GB 08410234A GB 8410234 A GB8410234 A GB 8410234A GB 2154233 A GB2154233 A GB 2154233A
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aluminium
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aluminium salt
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Roberto Montanari
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STABIL BIOTERAPICO FARMACHIM
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/52—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen
    • C07C57/58—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen containing six-membered aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/30—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings
    • 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
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • 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
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
    • C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
    • 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

Abstract

The mono, bi and tri-substituted aluminium salts of 2-aryl-propionic acids present a higher therapeutic index than the correspondent free acids. After enteral administration they are well tolerated and present a prompt and high therapeutic activity. The process of their synthesis consists either in reacting a hydrosoluble salt of the 2-arylpropionic acid with an aluminium salt solution in aqueous or organic-aqueous solutions at neutral pH; or in reacting a 2-arylpropionic acid with an aluminium organic derivative in organic solvents.

Description

SPECIFICATION Mono, bi and tri-substituted aluminium salts of the aryl-alkanoic acids and pharmaceutical compositions containing them The present invention refers to aluminium salts of the aryl-alkanoic acids and more specifically to mono, bi and tri-substituted aluminium salts of the 2-arylpropionic acids, characterized by the general formula:
where Ar represents a substituted arylic group selected among 4-isobutylphenyl, 6-methoxy 2-naphtyl, 3-benzoylphenyl, 3-phenoxyphenyl and 2-fluorine-4-biphenylile. x, y and n indicate pure numbers that may have respectively the values: x = 1,2or3; y = 0,1 or2; n = 0-12.
The present invention has besides as object the process of preparation of the aluminium salts of the 2-arylpropionic acids characterized above by the formula I and the pharmaceutical compositions for enteral administrations of said aluminium salts.
The substituted 2-arylpropionic acids are non steroid anti-inflammatory drugs with analgesic and antipyretic property, some of which are estensively used in the clinical practice for the treatment of various illnesses of inflammatory nature; however they produce, with a certain frequency after oral administration, some gastroenteric disturbances accompanied by pyrosis, nausea and vomit, sometimes also of considerable seriousness as intense diarrhoea or gastrointestinal haemorrhage.
The usually known salts of the 2-arylpropionic acids, as the sodic, potassic, ammonium salts, or those formed with organic bases as the morpholine, lysine, diethanolamine, etc. do not present any advantage by eliminating the inconveniences discovered by the use of the corresponding free acids. The Applicant has now discovered, and this fact just represents the principal object of this invention, that the aluminium salts of the 2-arylpropionic acids above indicated, when supplied by enteral route in therapeutic doses, not only reduce considerably the collateral effects connected with the use of the free acids or their common hydrosoluble salts, but they present also a definitely higher therapeutic index, with the benefit of a higher safety margin in their use, particularly in the cases of prolonged treatments of inflammatory illnesses of chronic nature, where just these types of drugs are used with higher frequency and where are consequently observed the collateral effects.
The principal purpose of the present invention is to provide new therapeutically helpful aluminium salts of the 2-arylpropionic acids, that, besides having definitely lower collateral harmful effects then the corresponding 2-arylpropionic free acids, offer also the benefit to present an higher therapeutic index, and besides to supply pharmaceutical compositions suitable to the enteral administrations containing said new salts.
The particular purpose of the present invention is to provide for a process for the preparation of the new aluminium salts of the 2-arylpropionic acids.
The present invention has therefore as object new therapeutically advantageous aluminium salts of the 2-arylpropionic acids, characterised by the general formula:
where x, y and n indicate pure numbers that can have respectively the values x = 1, 2 or 3. y = 0, 1 or 2; n = 0-12, and Ar represents a substituted aromatic radical selected among 4-isobutylphenyl of the formula 6-methoxy-2-naphtyl of the formula 3-benzoylphenyl of the formula
3-phenoxyphenyl of the formula 2-fluorine-4-biphenylile of the formula
Particularly the present invention supplies the following new aluminium salts, characterized by one of the general formulas:
where Ar and n have the same meaning as above.
Among the new salts of the present invention the following are preferably used in the pharmaceutical composition: the bibasic aluminium salt of the 2-(4-isobutylphenyl) propionic acid having the following formula:
(where n has same meaning as above); The monobasic aluminium salt of the 2-(4-isobutylphenyl) propionic acid having the following formula:
(where n has same meaning as above); The bibasic aluminium salt of the D-2-(6-methoxy-2-naphtyl) propionic acid having the formula:
(where n has same meaning as above); The monobasic aluminium salt of the D-2-(6-methoxy-2-naphtyl) propionic acid having the formula:
(where n has the same meaning as above); The monobasic aluminium salt of the 2-(3-benzoylphenyl) propionic acid having the formula::
(where n has the same meaning as above); The bibasic aluminium salt of the 2-(3-benzoylphenyl) propionic acid having the formula:
(where n has same meaning as above); The bibasic aluminium salt of the 2-(3-phenoxyphenyl) propionic acid having the formula;
(where n has the same meaning as above); The monobasic aluminium salt ofthe 2-(3-phenoxyphenyl) propionic acid having the formula:
(where n has the same meaning as above); The bibasic aluminium salt of the 2-(2-fluorine-4-biphenylyl) propionic acid having the formula:
(where n has the same meaning as above); The monobasic aluminium salt of the 2-(2-fluorine-4-biphenylyl) propionic acid having the formula:
(where n has same meaning as above).
The new aluminium salts of the present invention may be prepared by reacting in aqueous or aqueous-organic solution a hydrosoluble salt of the 2-arylpropionic acid with an equivalent quantity of a hydrosoluble aluminium salt, or - if this is desirable - in purely organic solutions, by reacting a 2-arylpropionic acid with a solution of an aluminium organic derivative, as the isopropoxide ort.butoxide.
For the preparation of the trisubstituted aluminium salts of the 2-arylpropionic acids it is convenient but not indispensable the use of the isopropoxide or the t. aluminium butoxide for the salification of the 2-arylpropionic acids, using from 0.8 to 1.3 moles, preferably from 0.95 to 1.10 moles of the aluminium organic derivative for every three moles of arylpropionic acid, in organic solvents where the reagents are soluble without decomposition. As organic solvents may be used advantageously methanol, ethanol, propanols, butanols, acetone, methylethyl ketone, benzene, toluene and the like.For the preparation of the mono and bisubstituted aluminium salts of the 2-arylpropionic acids it is preferable but not indispensable the use of an inorganic hydrosoluble aluminium salt as e.g. chloride, bromide, sulfate, nitrate; in aqueous or aqueous-organic solution, letting react with a soluble salt of the 2-arylpropionic acid in such a molecular ratio as to use 1 mole or 2 moles of the salt of 2-arylpropionic acid for each mole of the present aluminium salt, in order to obtain respectively the mono or bisubstituted salts.
As hydrosoluble salts of the 2-arylpropionic acids there may be used the alkaline, ammonium or substituted ammonium salts. There are preferably used, to the purpose of the present invention, the sodium potassium, ammonium, triethylammonium, dietanolammonium, triethanolammonium and pyridinium salts. Said soluble salts obviously may be prepared also "in situ". The preparation of the mono and bisubstituted aluminium salts of the present invention is carried out preferably at neutral pH in the presence of an organic solvent in a variable quantity from 15% to 85% in volume, preferably from 35% to 65% in volume, so that there may be obtained the aluminium salt in a betterfiltrable form. To this end may be used, e.g., the following: methanol, ethanol, propanols, butanols, acetone, tetrahydrofuran and dioxane.
The temperature at which the preparation of the aluminium salts of the present invention is carried out is not critical to the purpose of the reaction, it may widely vary and depends only on the thermal stability of the reagents; in general it is convenient to carry out the preparation of the aluminium salts at a temperature comprised between 10 C and 60"C.
The aluminium salts of the 2-arylpropionic acids of the present invention contain in their molecule an atom of asymmetric carbon in alpha position with respect to the carboxilic group and consequently they may present the configurations "D" or "L", besides the raceme mixture. All these forms, obviously, may be obtained by the subject process and are therefore included in the ambit of the present invention. If the preparation of an aluminium salt of a 2-arylpropionic acid in an optically active form is sought, there may be used as starting material the optically active 2-arylpropionic acid, or, more advantageously, said optically active form may be prepared by reacting an aluminium salt, following the above description, with a diastereoisomeric crystalline salt of the 2-arylpropionic acid formed by optically active organic bases.As organic bases which form disastereoisomeric crystalline salts suitable for the preparation of the aluminium salts of the 2-aryipropionic optically active acids there may be used e.g. one of the following: amphetamine, brucine, cinchonine, cinchonidine, dehydroabiethylammine, ephedrin, phenylethylamine, naphtylethylamine and the like.
The aluminium salts of the 2-arylpropionic acids of the present invention are white matter, insoluble in water and in the most common organic solvents, tasteless, non toxic and pharmacologically active, as was proved by the pharmacological tests on laboratory animals, at variable doses from 0.1 to 250 mg/kg.
In the human therapy and administered doses may range between 0.05 and 25 mg!kg of body weight; however, different dosages may be also used following medical judgement according to each single pathologic case. The aluminium salts of the present invention may be administered by enteral route and to said purposes the active substance is normally formulated in pharmaceutical compositions with suitable pharmaceutically acceptable additives.
Said compositions, comprised within the ambit of the present invention, normally consist in the mixtures of the active substance with proper inert carriers, in the form of capsules, tablets, pills, granules for suspensions, suspensions, suppositories and the like. The used inert carrier may be solid, semisolid or liquid and may act as excipient, covering agent or as dispersion or dilution medium of the active drug.As examples of said carriers the following may be indicated: lactose, dextrose, saccharose, sorbitolo, mannitol, starch, pectine, calcium phosphate, magnesium stearate, liquid paraffin, cocoa butter, alginates, gelatin, methylcellulose, polyoxyethylene sorbitan monolaurate, ethylcellulose acetate and phtalate, acetylcellulose acetate of low density, paraffin wax, mineral wax, vegetal gums, silicones as the liquid polydimethylsiloxane, polyethylene tereftalate, gel of hydrophile polyesters, polyvinyl alcohol, polyvinyl acetate and the like.
It is advantageous, but not essential, to formulate the pharmaceutical compositions of the present invention in dosage units, containing from 1 to 1.000 mg, preferably from 25 to 750 mg of the active substance.
Examples of composition forms in dosage units of active principle include tablets, capsules of hard gelatine, capsules of soft gelatine, powders or proportioned granules for extemporaneuos suspensions, suspensions, suppositories, including one of the aluminium salts of a determined 2-arylpropionic acid in such a quantity to request one or more dosage units for a single therapeutic administration.
The compositions of the present invention will be prepared in a form suitable for the particular ways of administration. Thus, for the oral administration there are used tablets, pills, capsules, powders and granules for extemporaneous suspensions, ready suspensions, and for rectum administration there are used suppositories.
The particular embodiments of the present invention are better illustrated by the following examples, which however, have no limiting character.
Example I - Preparation of the bibasic aluminium salt of the D-2-(6-methoxy-2-naphtyl) propionic acid: 92 gr of D-2-(6-methoxy-2-naphtyl) propionic acid (Naproxen) is dissolved in 600 ml. water containing 28 gr. of carbonate potassium.
To this solution there is added 1.500 ml acetone and then, under stirring, a solution of 133 gr of Al2(S04)3 18 H2O in 400 ml of water, maintaining the pH of the mixture between 6.8 and 7.2 with contemporary addition of a 10% solution of carbonate potassium.
The white precipitate is filtered, washed with water and dried under vacuum until constant weight.
The product obtained by analysis indicates: Al = 8.42% (calc. 8.28%); H2O = 16.98% (calc. 16.56) and corresponds to the formula:
wherein R = 6-methoxy-2-naphtyl. Example 2 - Preparation of the monobasic aluminium salt of the D-2-(6-methoxy-2-naphtyl) propionic acid: Following the previous example, using 66.5 gr of aluminium sulfate, there is obtained the monobasic aluminium salt of the Naproxen that at the analysis indicates: Al = 5.05% (calc. 5.19%); H2O = 4.01% (calc. 3.46%) and corresponds to the formula:
wherein R = 6-methoxy-2-naphtyl.
Example 3 - Preparation of the bibasic aluminium salt of the 2-(2-fluorine-4-biphenylyl) propionic acid: 98 gr of 2-(2-fluorine-4-biphenylyl) propionic acid (Flurbiprofen) is dissolved in 500 ml water containing 28 gr of carbonate potassium. To the solution there is added 1.000 ml acetone and then, under stirring, a solution of 133 gr of aluminium sulfate in 400 ml water, maintaining the pH of the mixture between 6.8 and 7.2 with contemporary addition of a 10% solution of carbonate potassium.
The white precipitate is-filtered, washed first with water and then with acetone and dried under vacuum.
The product obtained indicates by the analysis: Al = 8.76% (calc. 8.38%); H20 = 11,85% (calc. 11.18%) and corresponds to the formula:
wherein R = 2fluorine-4-biphenylyl.
Example 4 - Preparation of the monobasic aluminium salt of the 2-(2-fluorine-4-biphenylyl) propionic acid: 98 gr of Flurbiprofen is dissolved in 500 ml water containing 28 gr of carbonate potassium. To the solution there is added 1.800 ml acetone and then, under stirring, a solution of 66.5 gr of aluminium sulfate in 200 ml water, maintaining the value of pH of the mixture near the neutrality with contemporary addition of a 10% solution of carbonate potassium. The obtained monobasic aluminium salt of the Flurbiprofen indicates the following values by the analysis: Al = 4.31% (calc. 4.76%), H2O = 6.91% (calc. 6.35%) and corresponds to the formula:
wherein R = 2-fluorine-4-biphenylyl.
Example 5-Preparation of the bibasic aluminium salt of the 2-(3-benzoylphenyl) propionic acid: Following the description of the example 1, using the equivalent quantity of 2-(3-benzoylphenyl) propionic acid (Ketoprofen) there is obtained the bibasic aluminium salt that shows by the analysis: Al = 9.02% (calc. 8.13%); H2O 10.35% (calc. 10.84%) and corresponds to the formula:
wherein R = 3-benzoylphenyl.
Example 6 - Preparation of the monobasic aluminium salt of the 2-(3-benzoylphenyl) propionic acid: following the description of example 2, using an equivalent quantity of Ketoprofen there is obtained the monobasic aluminium salt of the 2-(3-benzolyphenyl) propionic acid, having: Al = 4.28% (calc. 4.75%); H2O = 4.01% (calc. 3.17%) corresponding to the formula:
wherein R = 3-benzoylphenyl. Example 7-Preparation of the bibasic aluminium salt of the 2-(3-phenoxyphenyl) propionic acid: following the description of the example 1, using an equivalent quantity of 2-(3-phenoxyphenyl) propionic acid (Fenoprofen), there is obtained the corresponding bibasic aluminium salt having: Al = 8.51% (calc. 8.94%); H2O = 6.22% (calc. 5.96%) corresponding to the formula:
wherein R = 3-phenoxyphenyl.
Example 8 - Preparation of the monobasic aluminium salt of the 2-(3-phenoxyphenyl) propionic acid: following the description of the example 2, using an equivalent quantity of Fenoprofen, there is obtained the corresponding monobasic aluminium salt having: Al = 4.41% (calc. 4.80%); H2O = 6.78% (calc. 6.40%) which corresponds to the formula.
wherein R = 3-phenoxyphenyl.
Example 9 - Preparation of the bibasic aluminium salt of the 2-(4-isobutylphenyl) propionic acid: following the description of the example 1, using an equivalent quantity of the 2-(4-isobutylphenyl) propionc acid (Ibuprofen), there is obtained the corresponding bibasic aluminium salt having: Al = 8.64% (calc. 8.94%); H2O = 16.31% (calc. 15.89%) corresponding to the formula:
wherein R = 4-isobutylphenyl.
Example 10- Preparation of the monobasic aluminium salt of the 2-(4-isobutylphenyl) propionic acid: following the description of example 2, using an equivalent quantity of Ibuprofen, there is obtained the corresponding monobasic aluminium salt having: Al = 5.43% (calc. 5.72%); H2O = 4.02% (calc. 3.81%) which corresponds to the formula:
wherein R = 4-isobutylphenyl.
Example ii - Following the description of the previous example 1, by using one of the following solvents in the place of acetone, there is obtained in any case the bibasic aluminium salt of the Naproxen: methanol, ethanol, propanol, isopropanol, tetrahydrofuran, dioxan.
Example 12 - Following the description of the process as per example 1 with use of equivalent quantity of one of the following aluminium salts in the place of the sulfate, there is obtained in any case the bibasic aluminium salt of the Naproxan: chloride, bromide and nitrate.
Example 13 - 6.9 gr of D-2-(6-methoxy-2-naphtyl) propionic acid is dissolved in 70 ml benzene. To the solution there is added under stirring, at 40"C, 2.5 grof aluminium t.butoxide dissolved in 50 ml of benzene.
After 10 minutes stirring the white precipitate is filtered, washed with benzene and dried under vacuum. The trisubstituted aluminium salt of the Naproxen in anhydrous form is obtained.
Example 14 - Following the description of the previous example with use of an equivalent quantity of one of the following 2-arylpropionic acids, there is obtained in any case the corresponding trisubstituted aluminium salt in anhydrousform: Ibuprofen, Fenoprofen, Ketoprofen and Flurbiprofen.
Example 15- 6.9 gr of Naproxen is dissolved in 50 ml of isopropanol at 50 C. To the solution there is added under stirring 20 ml of a isopropanolic 0.5M solution of isopropoxide aluminium. The precipitate is filtered and dried under vacuum. The trisubstituted aluminium salt of the Naproxen in anhydrous form is obtained.
Example 16 - Following the description of the previous example with use of an equivalent quantity of one of the following 2-arylpropionic acids, there is obtained the corresponding trisubstituted aluminium salt in anhydrousform: Ibuprofen, Fenoprofen, Ketoprofen, Flurbiprofen.
Example 17-Tablets are prepared, each containing as active principle 130 mg of bibasic monohydrate aluminium salt of the 2-(3-benzolylphenyl) propionic acid, quantity corresponding to 100 mg of Ketoprofen.
Said substance, of course, may be replaced by any other compound characterized in the formula I and the amount of the active principle may be increased or reduced on the basis of the activity of each single used substance: Active Principle 130 mg Starch 35 mg Lactose 23 mg Ethyl cellulose 2 mg (in ethanol at 20%) Alginic acid 7 mg Mg-stearate 1 mg Talc 2 mg 200 mg The mixture of the active principle, lactose and starch is filtered through a 44 mesh sieve. The resulting product is mixed with the ethylcellulose solution and then the whole is filtered through a 12 mesh sieve. The obtained granulated substance is dried at 50"C and the dry substance is filtered through a 16 mesh sieve.
The other ingredients are mixed together and the resulting mixture is filtered through a 60 mesh sieve. The thus obtained powder is mixed with the granules and the whole is charged into a tablet making machine in order to obtain tablets of 200 mg weight.
Example 18 - There are prepared capsules, containing each 200 mg of active principle selected among the compounds characterized by the formula 1, having the following composition: active principle 200 mg lactose 48 mg Mg-stearate 2 mg 250 mg The components are filtered through a 44 mesh sieve and with the resulting mixture hard gelatine capsules of 250 mg. each are made.
Example 19 - Suppositories are prepared, each containing as active principle 326 mg of bibasic aluminium salt of the D-2-(6-methoxy-2-naphtil) propionic acid, a quantity corresponding to 250 mg of Naproxen. Said substance, of course, may be replaced by any other compound characterized by the formula 1 and the quantity of the active principle may be increased or reduced on the basis of the activity of each of the used substances: active principle 326 mg cocoa butter q.s. to 2.000 mg The active principle is powdered and filtered through a 60 mesh sieve. The powder is then suspended in the necessary quantity of melted cocoa butter, using the minimum necessary amount of heat.
The melted mixture is poured into the suppository dies of 2 gr capacity and then allowed to cool.
Example 20 - Granules for oral suspensions are prepared, containing as active principle the aluminium salt of the Flurbiprofen. Said substance, of course, may be replaced by any other compound characterized by the formula land the quantity of the acitve principle may be increased or reduced on the basis of the activity of each of the single used substances: active principle 1.582 gr Na-saccharinated 2.1 50 go Na-citrate anhydrouse 0.140 gr Na-benzoate 0.080 gr Tween 40 0.006 gr NaCI 0.750 gr Raspberry flavour q.s.
Vanillin 0.005 gr Saccharose (60 mesh) 24.550 gr red coloring q. s.
The Tween 40 is mixed with the liquid flavours and the Na-saccharinated is added.
To the mixture the other ingredients are added, excepted the saccharose; the whole is well mixed, then poured in a tablet making machine. The obtained tablets are powdered and the the powder is filtered through a 80 mesh sieve. To the resulting mixture there is then mixed the saccharose, and the whole is enclosed in small bottles.
Before the use the necessary water is added to make 60 ml suspension. Each 5 ml of said suspension contains 131 mg of monohydrate bibasic aluminium salt of the Flurbiprofen, corresponding to 100 mg of free acid.
Example 21 - Chewable tablets are prepared containing as active principle the bihidrate monobasic aluminium salt of Flurbiprofen, each containing a quantity of 116 mg active principle, corresponding to 100 mg of free acid. Said substance, of course, may be replaced by any other compound characterized by the formula I and the quantity of the active principle may be increased or reduced on the basis of the activity of each used substance.
116 gr of the active principle, 261 gr of mannitol, 70 gr of glycine and 40 gr of Na-saccharinated are charged in a mixer. The whole is mixed for 15 minutes. Then the solid flavours(0.5 gr of apricot flavour and 1.5 gr of cherry flavour) are added. After mixing well for 10 minutes the mixture is micronized. In a mixer there is added 5 gr of Mg-stearate and 1 gr of polyethylenglycol (Carbowax 6000) having average P.M. between 6000 and 7500. The whole is mixed for 15 minutes. The mixture is compressed and then granulated in a 20-40 mesh mill. The obtained granules are mixed for 15' with 4 gr of granulated Mg-stearate (20-40 mesh) and then with 1 gr of Carbowax 6000. By the obtained mixture there are prepared tablets in the requested form, to the purpose of obtaining tablets of 0.5 gr having the following composition.
active principle 0.116 gr mannitol 0.261 gr Na-saccharinated 0.040 gr Glycine 0.070 gr Mg-stearate 0.009 gr Carbowax 6000 0.002 gr Flavours 0.002 gr 0.500 gr TestA.
For the assessment of the acute gastric tolerability in the rat of the aluminium salts of the 2-arylpropionic acids, male animals of the average body weight of 230.9 g 1.4 gr of the Sprague-Dawley (C. River breeding) stock have been tested housed at a temperature of 22 + 1"C and at the relative humidity of 60 + 5% and randomized in groups of 8 animals for every single product to be tested, besides the group of control animals.
For the test each animal was put in a separate cage and kept fasting for 24 hours before the beginning of the treatment. All the tested substances were administered orally, suspended in a 5% solution of arabic gum in such a concentration that each animal was given 5 ml/kg of the suspension (for the controls only the solution of arabic gum was administered). After 6 hours from the administration the animals were sacrificed to be subjected to autopsy.
SUBSTANCE REMARKS Control: No damage or wound KET-AI at gastrical level: 12 mg/kg 6/8 no alteration 2/8 pointform haemorrhages at duodenal level: 8/8 undamaged NAP-AI at gastric level: 30 mg/kg 5/8 no alteration 3/8 pointform haemorrhages at duodenal level: 8/8 undamaged FLU-AI at gastric level: 12 mg/kg 6/8 no wound 1/8 pointform haemorrhage 1/8 filiform haemorrhage at duodenal level: 8/8 undamaged (KET-AI = Ketoprofen bibasic Al salt, NAP-AI = Naproxen Al bibasic salt, FLU-AI - Flurbiprofen bibasic Al salt).
Testy The assessment of the anti-inflammatory activity in living rats of the aluminium salts of the present invention was proved by the carrageenin edema test on the rat's paw. The substances were administered by oral route as specified in the experiment A, an hour before the carrageenin each to a group of 10 animals (stock and housing: see above).
SUBSTANCE % ofinhibition to the controls in the course of time.
gmglkg) Ihour 2hours 3hours 4hours 5hours KET-AI (12) 38 65 58 43 44 NAP-AI(30) 52 54 29 17 16 FLU-Al (12) 33 48 39 30 25 Test C.
There was assessed the inhibiting activity of the contractions provoked by phenylquinone of the bibasic aluminium salt of the Ketoprofen in the mouse (Swiss) of female sex, of the average body weight of 22.6 + 0.2 gr. The substance to be tested was administered by oral route in the same way as in experiment A, an hour before the test, to a group of 5 animals for each single dose:
Substance and dose No. ofcontractions Inhibition DE50 (mg/kg) over 30 minutes % (mg/kg) CONTROL 17.2 1.0 KET-Al (3) p9.6 6 0.5 44.2 KET-Al (6) 7.8 54.7 4.5 KET-AI (12) 6.4t1.1 62.8 Test D.
For the assessment of the acute toxicity by the oral route of the aluminium salts of the present invention rats of female sex of Swiss stock have been used, housed at the temperature of 22"C with relative humidity of 80%. The single substances were administered at variable doses under form of 5% suspension in arabic gum. During the experiment the animals were kept under watch in order to note the symptomatology caused by the administration of the tested substance and the autopsy was carried out within 4 hours post-mortem.
The DL50 values were assessed by the known techniques and the following values were found: Substance DL50mg/kg per Os KET-AI > 3.000 NAP-AI > 3.000 FLU-AI > 2.000

Claims (35)

1. Aluminium salts of the 2-arylpropionic acids characterized by the general formula:
wherein Ar represents a substituted arylic group selected among 4-isobutylphenyl, 6-methoxy-2-naphtyl, 3-phenoxyphenyl, 3-benzoylphenyl and 2-fluorine-4-biphenylyl; x, y and n indicate pure numbers which may have respectively the values of x = 1,2 or 3; y = 0,1 or 2 and n = 0 - 12.
2. Aluminium salts, according to the previous claim, characterized by the fact that they are optically active.
3. Aluminium salts according to the previous claim characterized by the formula
wherein x, y and n have the same meaning as the one indicated above.
4. Aluminium salt according to the claims 1,2 and 3 characterized by the formula
wherein n has the same meaning as the one indicated above.
5. Aluminium salt according to the claims 1,2 and 3, characterized by the formula
wherein n has the same meaning as the one indicated above.
6. Aluminium salt according to the claims 1, 2 and 3, characterized by the formula
wherein n has the same meaning as the one indicated above.
7. Aluminium salts according to the claims 1 and 2, characterized by the formula
wherein x, y and n have the same meaning as the one indicated above.
8. Aluminium salt according to the claims 1,2 and 7, characterized by the formula
wherein n has the same meaning as the one indicated above.
9. Aluminium salt according to the claims 1, 2 and 7, characterized by the formula
wherein n has the same meaning as the one indicated above.
10. Aluminium salt according to the claims 1,2 and 7 characterized by the formula
wherein n has the same meaning as the one indicated above.
11. Aluminium salts according to the claims 1 and 2, characterized by the formula
wherein x, y and n have the same meaning as the one indicated above.
12. Aluminium salt according to the claims 1,2, and 11, characterized by the formula
wherein n has the same meaning as the one indicated above.
13. Aluminium salts according to the claims 1,2 and 11, characterized by the formula
wherein n has the same meaning as the one indicated above.
14. Aluminium salt according to the claims 1,2 and 11, characterized by the formula
wherein n has the same meaning as the one indicated above.
15. Aluminium salts according to the claims 1 and 2, characterized by the formula
wherein x, y and n have the same meaning as the one indicated above.
16. Aluminium salt according to the claims 1,2 and 15, characterized by the formula
wherein n has the same meaning as the one indicated above.
17. Aluminium salt according to the claims 1,2 and 15, characterized by the formula
wherein n has the same meaning as the one indicated above.
18. Aluminium salt according to the claims 1,2 and 15, characterized by the formula
wherein n has the same meaning as the one indicated above.
19. Aluminium salts according to the claims 1 and 2, characterized by the formula
wherein x, y and n have the same meaning as the one indicated above.
20. Aluminium salt according to the claims 1,2 and 19, characterized by the formula
wherein n has the same meaning as the one indicated above.
21. Aluminium salt according to the claims 1,2 and 19, characterized by the following formula
22. Aluminium salt according to the claims 1,2 and 19, characterized by the formula
wherein n has the same meaning as the one indicated above.
23. Pharmaceutic compositions containing as active principle an aluminium salt described in the claims and 2, characterized by the fact that said compositions contain at least one carrier pharmaceutically acceptable.
24. Pharmaceutic composition following the previous claim wherein the active principle is one of those described in one of the claims 3 to 18.
25. Pharmaceutic compositions according to the claims 23 and 24, in which the dosage units contain from 1 to 1.000 mg, preferably from 25 to 750 mg of the active principle.
26. Pharmaceutic compositions according to the claims 23, 24 and 25, substantially as described in one of the examples from 17 to 21.
27. Process for the preparation of aluminium salts of the 2-arylpropionic acids, described in the claims from 1 to 22, said process being characterized by the fact that a hydrosoluble salt ofa 2-arylpropionic acid is reacted in aqueous or aqueous organic solution with an equivalent quantity of an aluminium salt, or a 2-arylpropionic acid is reacted in a purely organic solution with an equivalt quantity of an organic aluminium derivative.
28. Process according to the previous claim, characterized by the fact that a 2-arylpropionic acid is reacted in an organic solvent with an organic aluminium derivative selected among the isopropoxide or t.butoxide ones in such a molar proportion to use from 0.8 to 1.3, preferably from 0.9 to 1.1 moles of the organic aluminium derivative for every 3 moles of the present 2-arylpropionic acid.
29. Process according to the claim 27 characterized by the fact that a hydrosoluble salt of a 2-arylpropionic acid is reacted at neutral pH in aqueous or aqueous organic solution with an aqueous solution of a hydrosoluble aluminium salt in such a molecular proportion to use 1 mole or 2 moles of the salt of the 2-arylpropionic acid for each mole of the employed aluminium salt.
30. Process according to the previous claim, characterized by the fact that the reaction mixture contains a quantity from 15% to 85%, preferably from 35% to 65% in volume of a hydrosoluble organic solvent selected among methanol, ethanol, propanols, acetone, tetrahydrofuran and dioxane.
31. Process according to the claims 27, 29 and 30, characterized by the fact that the hydrosoluble salt of the 2-arylpropionic acid is that of sodium, potassium, ammonium, triethylammonium, diethanolammonium, triethanolammonium and pyridinium.
32. Process according to the claims 27,29,30 and 31, characterized by the fact that the hydrosoluble aluminium salt is the choride, bromide, sulfate or nitrate.
33. Process for the preparation of aluminium salts of the 2-arylpropionic acids, described in one of the claims from 1 to 22, substantially as described in one of the examples from 1 to 16.
34. Aluminium salts of the 2-arylpropionic acids, described in one of the claims from 1 to 22, prepared according to the claims 27 to 33.
35. Everything as described and exemplified.
GB08410234A 1984-02-16 1984-04-19 Aluminium salts of arylalkanoic acids and pharmaceutical compositions containing them Withdrawn GB2154233A (en)

Applications Claiming Priority (1)

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IT19644/84A IT1175941B (en) 1984-02-16 1984-02-16 MONO, BI AND TRI-SUBSTITUTED ALUMINUM SALTS OF ARYL-ALCANOIC ACIDS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

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US4831058A (en) * 1986-10-01 1989-05-16 Boots Company Plc Therapeutic agents
FR2665897A1 (en) * 1990-08-20 1992-02-21 Rhone Poulenc Sante PROCESS FOR THE TRANSFORMATION OF (R) -3-PROPIONIC ACID (BENZOYL-3-PHENYL) PROPIONIC (-) TO S (+) ISOMER
WO1992018455A1 (en) * 1991-04-15 1992-10-29 Ethyl Corporation Resolution of ketoprofen
WO1996016017A1 (en) * 1994-11-23 1996-05-30 Laboratorios Menarini S.A. Novel arylpropionic derivatives with analgesic action and the process for the preparation thereof

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GB1154345A (en) * 1965-06-11 1969-06-04 Merck & Co Inc Substituted p-Cyclohexylphenylacetic Acids and their Derivatives, and Reduction Products
GB1276261A (en) * 1969-04-09 1972-06-01 Syntex Corp Improvements in or relating to naphthyl acetic acid derivatives
GB1291386A (en) * 1969-03-24 1972-10-04 Syntex Corp Improvements in or relating to 2-(6'-substituted-2'-naphthyl) propionic acid derivatives and salts thereof
GB1394391A (en) * 1971-03-22 1975-05-14 Teikoku Hormone Mfg Co Ltd Process for preparing aluminium salts of carboxylic compounds
GB1451541A (en) * 1974-02-16 1976-10-06 Lilly Co Eli Aluminum salts of substituted phenyl-alkanoic acids and pharma ceutical suspensions prepared therefrom core-sampling device for obtaining a core sample from a loose
GB1491498A (en) * 1973-10-29 1977-11-09 Eisai Co Ltd 2-(substituted phenyl)-propionic acids and their pharmaceutical compositions
GB1527563A (en) * 1975-12-15 1978-10-04 Upjohn Co Propionic acid derivatives
GB2079600A (en) * 1980-06-20 1982-01-27 Upjohn Co Compositions comprising ibuprofen salts

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1154345A (en) * 1965-06-11 1969-06-04 Merck & Co Inc Substituted p-Cyclohexylphenylacetic Acids and their Derivatives, and Reduction Products
GB1291386A (en) * 1969-03-24 1972-10-04 Syntex Corp Improvements in or relating to 2-(6'-substituted-2'-naphthyl) propionic acid derivatives and salts thereof
GB1276261A (en) * 1969-04-09 1972-06-01 Syntex Corp Improvements in or relating to naphthyl acetic acid derivatives
GB1394391A (en) * 1971-03-22 1975-05-14 Teikoku Hormone Mfg Co Ltd Process for preparing aluminium salts of carboxylic compounds
GB1491498A (en) * 1973-10-29 1977-11-09 Eisai Co Ltd 2-(substituted phenyl)-propionic acids and their pharmaceutical compositions
GB1451541A (en) * 1974-02-16 1976-10-06 Lilly Co Eli Aluminum salts of substituted phenyl-alkanoic acids and pharma ceutical suspensions prepared therefrom core-sampling device for obtaining a core sample from a loose
GB1527563A (en) * 1975-12-15 1978-10-04 Upjohn Co Propionic acid derivatives
GB2079600A (en) * 1980-06-20 1982-01-27 Upjohn Co Compositions comprising ibuprofen salts

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4831058A (en) * 1986-10-01 1989-05-16 Boots Company Plc Therapeutic agents
FR2665897A1 (en) * 1990-08-20 1992-02-21 Rhone Poulenc Sante PROCESS FOR THE TRANSFORMATION OF (R) -3-PROPIONIC ACID (BENZOYL-3-PHENYL) PROPIONIC (-) TO S (+) ISOMER
WO1992003404A1 (en) * 1990-08-20 1992-03-05 Rhone-Poulenc Rorer S.A. Process for transforming (benzoyl-3 phenyl)-2 propionic acid into an s(+) isomer
WO1992018455A1 (en) * 1991-04-15 1992-10-29 Ethyl Corporation Resolution of ketoprofen
WO1996016017A1 (en) * 1994-11-23 1996-05-30 Laboratorios Menarini S.A. Novel arylpropionic derivatives with analgesic action and the process for the preparation thereof
ES2109859A1 (en) * 1994-11-23 1998-01-16 Menarini Lab Novel arylpropionic derivatives with analgesic action and the process for the preparation thereof

Also Published As

Publication number Publication date
DE3505582A1 (en) 1985-08-22
IT8419644A0 (en) 1984-02-16
IT1175941B (en) 1987-08-12
GB8410234D0 (en) 1984-05-31

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