FR2683528A1 - gem-Bisphosphonic (gem-Diphosphonic) analogues and prodrugs of non-steroidal anti-inflammatories of arylacetic or arylpropionic type - Google Patents

Abstract

The invention relates to gem-bisphosphonic prodrugs of non-steroidal anti-inflammatories of arylacetic or arylpropionic type corresponding to the general formula (I) or to the general formula (II): in which: . R is either an arylacetyl radical or an arylpropionyl radical, . Z is -(CH2)n- or with n equal to 1, 2 or 3 and where R1 is a methyl or ethyl radical or an alkali metal, . R<2> is either a linear or branched C1 to C6 lower alkyl radical or H, . R<3> is either a linear or branched C1 to C6 lower alkyl radical or H, . X is an alkylene radical possessing 2 to 4 carbon atoms, and to their pharmaceutically acceptable salts.

Description

Prodrugs and gem-bisphosphonic analogues of nonsteroidal antiinflammatory drugs of the arylacetic or arylpropionic type.

Inorganic pyrophosphate is a compound present in many biological media such as plasma, urine or saliva. Studies on this compound have shown that it is a physiological regulator of calcification and that it inhibits the formation, aggregation and dissolution of calcium phosphate as well. The P-O bonds present in this compound and very sensitive to enzymatic hydrolysis, however, limit its therapeutic use by the oral route.

Analogues of inorganic pyrophosphate such as 1,1-bisphosphonates, for their part, exhibit much greater resistance to enzymatic hydrolysis owing to their P-C-P bonds while exhibiting the same physicochemical properties as inorganic pyrophosphate. The regulatory action of the calcification of 1,1-bisphosphonates in fact goes beyond their simple physicochemical properties and also involves an action at the level of cellular mechanisms. Recent studies have shown in particular that these bisphosphonate compounds can alter the morphology of osteoclasts. A certain number of bisphosphonate compounds have therefore found clinical applications in diseases characterized by accelerated bone destruction such as osteoporosis, bone carcinomas, rheumatoid arthritis and inflammatory phenomena. Thus, the protective action of 1-hydroxyethylidene-1,1-bisphosphonic acid (HEBP) and dichloromethylenebisphosphonic acid (C12MBP) was demonstrated in the Arthritis test with Freund's adjuvant, test d chronic inflammation mimicking aspects of human rheumatoid arthritis in rats. It is also known that certain bisphosphonates exhibit an inhibitory action vis-à-vis inflammation mediators such as macrophages and prostaglandins.

It has been proposed in the state of the art to target the bone cells that are the site of inflammation by means of anti-inflammatory drugs mixed with bisphosphonates.

Thus, German patent DE 2 813 165 proposes a pharmaceutical preparation comprising as a mixture a bisphosphonate and acetylsalicylic acid. The American patent US Pat. No. 4,330,530 has meanwhile proposed to mix a bisphosphonate with a gold salt: sodium aurothiomalate.

However, the pharmaceutical preparations described in these patents do not involve compounds resulting from a chemical bond between bisphosphonates and anti-inflammatory molecules but simply non-synergistic mixtures.

The objective of the present invention is to combine the high bone affinity of gem-bisphosphonic compounds with the therapeutic value of non-steroidal anti-inflammatory drugs of the arylacetic or arylpropionic type.

Among the non-steroidal anti-inflammatory molecules of the arylacetic and arylpropionic type, mention may be made, by way of example, of ibuprofen 5, naproxen 6, ketoprofen i, tiaprofenic acid 8 among anti-inflammatory drugs of the arylpropionic type and indomethacin 9 among anti-inflammatory drugs of the arylacetic type.

More precisely, the aim of the invention is to produce prodrugs and analogues which can be conveyed to bone cells constituting the target of the anti-inflammatory molecules and then which can be hydrolyzed at the level of these target cells and thus allow a specific action of the drug. or the like at this level.

The goal sought by this vectorization is to improve the therapeutic index of non-steroidal anti-inflammatory drugs of the arylacetic or arylpropionic type, that is to say to reduce the quantity of active principle administered to the patient while obtaining an identical therapeutic effect or improved.

Another objective of the present invention is to provide an original route of synthesis of these prodrugs and of these analogs.

dans laquelle

est soit un radical arylacétyle, soit un radical arylpropionyle.According to the invention, the gem-bisphosphonic pro drugs of non-steroidal anti-inflammatory drugs of the arylacetic or arylpropionic type correspond to the general formula (I)

in which

is either an arylacetyl radical or an arylpropionyl radical.

Z is - (CH2) n - or -CH-CH2- with n equal to 1, 2 or 3 and where
COOR1
R7 is a methyl or ethyl radical or an alkali metal
R2 is either a linear or branched C7 to C6 lower alkyl radical or H;
R3 is either a linear or branched C7 to C6 lower alkyl radical or H.

These compounds exhibit a peptide bond between the gem-bisphosphonic delivery head and the vectorized anti-inflammatory molecule.

According to another aspect of the invention, it is an ester bond which binds the gem-bisphosphonic head to the anti-inflammatory molecule. The prodrugs according to the invention then correspond to the general formula (II) in which

R2, R3 have the same meaning as above;
X is an alkylene radical having 2 to 4 carbon atoms.

The invention also relates to these prodrugs in their pharmaceutically acceptable salt forms. The term “pharmaceutically acceptable salified forms” is understood to mean the forms having a pH close to the physiological pH capable of causing their assimilation by the organism.

According to a preferred variant, the vectorized anti-inflammatory agent of the arylacetic or arylpropionic type is chosen from ibuprofen, naproxen, ketoprofen, tiaprofenic acid or indomethacin. The radical R present in formulas (I) and (II) is then a radical chosen from the group consisting of:

avec un synthon gem-bisphosphonate de formule générale (IV)

The invention also relates to a process for obtaining prodrugs corresponding to general formula (I), consisting in carrying out the peptide coupling of an acid chloride of general formula (III):

with a gem-bisphosphonate building block of general formula (IV)

R, Z, R2, R3 having the same meanings as in general formula (I).

The invention also relates to a process for obtaining non-steroidal anti-inflammatory drugs of arylacetic or arylpropionic type having an ester bond and corresponding to the general formula (II). This process consists in esterifying the acid function of an anti-inflammatory compound with an alcohol bisphosphonate of general formula (V):

X, R2, R3 having the same meanings as in formula (II).

According to a preferred variant the bis-phosphonate alcohol of general formula (V) is obtained from a protected alcohol of general formula (VI)

X having the same meaning as above.

dans laquelle
R4 est soit un radical arylacétyle soit un radical arylpropionyle;
R5 est soit un radical méthyle, soit H;
R2 est soit un radical alkyle inférieur linéaire ou ramifié en C7 en C6 soit H; R8 est soit un radical alkyle inférieur linéaire ou ramifié en C1 en C6, soit H.The invention also relates to gem-bisphosphonic analogs of non-steroidal anti-inflammatory drugs of the arylacetic or arylpropionic type corresponding to the general formula (VII).

in which
R4 is either an arylacetyl radical or an arylpropionyl radical;
R5 is either a methyl radical or H;
R2 is either a linear or branched C7 to C6 lower alkyl radical or H; R8 is either a linear or branched C1 to C6 lower alkyl radical, or H.

as well as their pharmaceutically acceptable salts.

The term “analogs” is understood to mean compounds exhibiting a structural analogy with corresponding drugs. These analogs show a therapeutic activity comparable to the drugs themselves while exhibiting, when they are vectorized by a gem-bisphosphonic head, an improved resistance to hydrolysis allowing their release at the level of the bone target cells.

Preferably, said R4 radical is an arylacetyl or arylpropionyl radical derived from ibuprofen, naproxen, ketoprofen, tiaprofenic acid or indomethacin. The R4 radical present in formula VII is then a radical chosen from the group consisting of:

R6 being either H or a linear or branched C7 to C6 lower alkyl radical or an alkali metal.

The invention also relates to a process for obtaining such analogs comprising 1 ") synthesizing a tetraalkyl arylethenylidene-1,1-bisphosphonate by condensing an arylaldehyde with a tetraalkyl methylene bisphosphonate; 2) reducing the arylethenylidene-1,1 - tetraalkyl bisphosphonate in tetraalkyl 2-arylethylidene1,1-bisphosphonate or in tetraalkyl 2-arylpropylidene-1,1-bisphosphonate.

According to a variant of the invention, said arylaldehyde is chosen from the group consisting of 6-methoxy-2-naphthaldehyde and 4-isobutylbenzaldehyde.

In this case, the process preferably comprises an additional step consisting in converting said tetraalkyl 2-arylethylidene-1,1-bisphosphonate or tetraalkyl 2-arylpropylidene-1,1-bisphosphonate into disel.

Preferably, said step of transforming said tetraalkyl 2-arylethylidene1,1-bisphosphonate or tetraalkyl 2-arylpropylidene-1,1-bisphosphonate into disel is carried out by: 1) transformation of tetraalkyl 2-arylethylidene-1,1-bisphosphonate or tetraalkyl 2arylpropylidene-1,1-bisphosphonate in ester silylated with bromotrimethylsilane then methanolysis of this ester to phosphonic acid; 20) action of two equivalents of sodium methoxide in methanol.

According to another variant of the invention, said arylaldehyde is ethyl 2- [2- (5 formyl) thienyl] propionate.

In this case, the process preferably comprises an additional step consisting in converting said tetralkyl 2-arylethylidene-1, 1-bisphosphonate or said tetraalkyl 2-arylpropylidene-1,1-bisphosphonate into pentasel.

Advantageously, said step of converting said tetraalkyl 2-arylethylidene-1, 1-bisphosphonate or tetraalkyl 2-arylpropylidene-1,1-bisphosphonate into pentasel is carried out by: 1) converting 2-arylethylidene-1,1-bisphosphonate tetraalkyl or .2 arylpropylidene-1,1-bisphosphonate of tetraalkyl ester silylated with bromotrimethylsilane then methanolysis of this ester to phosphonic acid; 2 ") action of two to five equivalents of sodium hydroxide dissolved in a water / methanol mixture II10.

The invention also relates to a pharmaceutical composition for the curative and / or preventive treatment of bone diseases, characterized in that it comprises as active principle one or more non-steroidal anti-inflammatory drugs of arylacetic or arylpropionic type corresponding to the formulas general (I) or (II) and / or one or more analogues corresponding to the general formula (VII).

The invention will be more easily understood by virtue of the non-limiting exemplary embodiments which follow, illustrating the synthesis of various prodrugs and of various gem-bisphosphonic analogs of non-steroidal anti-inflammatory drugs of the arylacetic or arylpropionic type.

Example 1
This example relates to the synthesis of an ibuprofen prodrug vectorized by a gem-bisphosphonic head. This prodrug 12a is ethyl 2- [2- (4 isobutylphenyl) propionamido] 4,4-bis (diethylphosphono) butyrate and is obtained by peptide coupling of 2- (4-isobutylphenyl) propionyl chloride 39 with 2- ethyl amino-4,4-bis (diethylphosphono) butyrate 10.

10 Preparation of ethyl 2ramino44bis (diethylphosphono) butyrate 10
In a 250 ml round-bottomed flask fitted with magnetic stirring, there are introduced 4,102 moles of ethyl glycinate hydrochloride, 4,102 moles of freshly distilled benzaldehyde, 5,102 moles of triethylamine and 5 g of magnesium sulfate.

The mixture is covered with 50 ml of methylene chloride and stirred at room temperature for two hours. The triethylamine hydrochloride and the magnesium sulfate are filtered off. The methylene chloride is evaporated off. The oily residue is treated with 50 ml of water and extracted with 3 times 50 ml of ether. The ethereal phase is dried over sodium carbonate and the solvent is evaporated off. Ethyl N-benzylidene glycinate is sufficiently pure to be used as is in the next condensation step.

In a 250 ml three-necked flask fitted with a mercury thermometer, a dropping funnel and magnetic stirring, 4,103 moles of sodium ethoxide are dissolved in 50 ml of distilled ethanol.

To this ethylate solution is added dropwise at room temperature 4 10.2 moles of ethyl N-benzylidene glycinate diluted in its volume of ethanol.

4.2 moles of tetraethyl ethenylidenebisphosphonate are then added. The solution is stirred for 15 minutes at room temperature. The ethanol is evaporated off. The oily residue is treated with 50 ml of water and then extracted with 3 times 50 ml of methylene chloride. The organic phase is dried over magnesium sulfate.

The solvent is evaporated off. Ethyl 2- (N-benzylideneamino) -4,4-bis (diethylphosphono) butyrate is sufficiently pure to be used as is in the following hydrolysis step.

In a 250 ml flask, fitted with magnetic stirring, the ethyl 2- (Nbenzylidèneamino) -4,4-bis (diethylphosphono) butyrate obtained above is mixed with one equivalent of p-toluenesulfonic acid dissolved in 50 ml of ether. The aqueous phase is made alkaline by adding methylene chloride. After drying over sodium carbonate and evaporating off the solvent, ethyl 2-amino-4,4-bis (diethylphosphono) butyrate is isolated in the form of a colorless oil.

2 "Synthesis of 2r (4-isobutylphenyl) propionyl chloride 39
The reaction to form ibuprofen acid chloride 39 is carried out in a known manner in toluene in the presence of an excess of thionyl chloride.

3 Peptide coupling
The acid chloride formed is added at a temperature close to 0, to an equimolecular mixture of ethyl 2-amino-4,4-bis (dietylphosphono) butyrate and triethylamine in tetrahydrofuran.

The synthesis of the compound acylaminoalkylidene-1,1-bisphosphonate of tetraethyl 12a can be summarized by the following reactions

<tb><SEP> H3 <SEP> 113
<tb><SEP> OH <SEP> Cl
<tb><SEP> 113 <SEP> SOC12 <SEP> tC <SEP> C1
<tb><SEP> CH3 <SEP> Toluene <SEP> CH3 <SEP> O
<tb><SEP> 5 <SEP> 39
<tb><SEP> NH2 <SEP> 0P '(OEt) 2 <SEP> c <SEP> {CH3 <SEP> Oii
<tb><SEP> Nil2 \ 1 <<SEP> Et3N <SEP> t <SEP> 0t <SEP> P (OEt)
<tb> EtOOC <SEP> P (OEt) Z <SEP> EtOO <SEP> 3 <SEP> P (OEt)
<tb><SEP> O <SEP> 2
<tb><SEP> 10 <SEP> 12a <SEP> O
<tb>
4 "Selective hydrolysis of the phosphonic and carboxylic ester functions of compound 12a and obtaining disel
The ethyl ester functions are converted into silylated ester functions by the action of trimethylsilane bromide. This selective reaction of the phosphonic esters makes it possible to lead to the acid form of compound 12a after methanolysis.

By the action of five equivalents of 5N sodium hydroxide at reflux in methanol for five hours, the sodium disalt of compound 12a is obtained.

Example 2
This example relates to the synthesis of tetraethyl 20 ′ propylidene-3,3-bisphosphonate 2- (6-methoxy-2-naphthalenyl) propionate 20 'by addition of 2- (6-methoxy naphthalenyl) propionyl chloride 61 ( ibuprofen derivative) with tetraethyl 19 and triethyl 3-hydroxypropylidene-1, 1-bisphosphonate 19 '.

1 Svnthesis of 2- (6-methoxvnaphthalenyl) propionyl chloride 61
This compound is synthesized in the same way as in Example 1.

2 "Synthesis of tetraethyl 19 and triethyl 3-hydroxypropylidene-1.i-bisphosphonate 19 '
The first phase consists in obtaining 3-bromo- (tetrahydropyranyloxy) propane 57.

In a 1 liter three-necked flask equipped with an ascending condenser, magnetic stirring and an alcohol thermometer, 14 10-2 moles of 3bromopropanol and 200 ml of methylene chloride are introduced. The solution is cooled to 0 C.

28 l (T2 mole (2eq) of dihydropyran and then 1410-S mole of para-toluene sulfonic acid are then added dropwise. The solution gradually darkens. The mixture is stirred at room temperature for two hours. The solution is diluted with 400 ml of ether, washed with 100 ml of a 10% aqueous sodium hydroxide solution. The organic phase is dried over magnesium sulphate, filtered and the solvents evaporated. The reaction which takes place is as follows:

The second phase of this synthesis consists in obtaining diethyl 3- (tetrahydropyranyloxy) propylphosphonate 58.

In a 100 ml three-necked flask, equipped with magnetic stirring, an ascending condenser, a mercury thermometer, a dropping funnel and a nitrogen inlet, 68 10-3 moles of finely divided sodium and 30 ml of tetrahydrofuran. 68 103 moles of diethyl phosphite are added dropwise. The solution is stirred until the sodium has been completely consumed.

45 103 moles of 3-bromo-1- (tetrahydropyranyloxy) propane 57 are added. The reaction mixture is brought to reflux with tetrahydrofuran for 20 hours. After cooling, it is treated with 70 ml of 1N sodium hydroxide. Extracted with 3 times 50 ml of ether. The ethereal phase is dried over magnesium sulfate. The following reaction occurs:

The third phase of the synthesis consists in obtaining the 3- (tetrahydropyranyloxy) propylidene -1,1-bisphosphonate of tetraethyl 59.

In a 100 ml three-necked flask equipped with magnetic stirring, an isobaric pouring funnel, an alcohol thermometer and a nitrogen inlet, 15.4 10-3 mole (2.2 eq) of diisopropylamine diluted in 10 ml of tetrahydrofuran. The solution is cooled to -20 ° C. 14.7 i-mole (2.1 eq) of 2.5 M n-butyllithium in hexane are added. After a few minutes of stirring, the solution is cooled to -78 ° C. 710-3 moles of diethyl 3- (tetrahydropyranyloxy) propylphosphonate 58 diluted in 10 ml of tetrahydrofuran are added. The solution is stirred for 5 minutes at -70 ° C. -65 C. It is cooled again to -78 C. and 7.4 10 -3 moles (1.05 eq) of diethyl chlorophosphate diluted in 10 ml of tetrahydrofuran are added. Stirred 15 minutes at -70 C then the solution is gradually warmed to -20 C to complete the reaction. The carbanion is hydrolyzed by adding 15 ml of a 1.5 M solution of NH4Cl. Extracted once with 30 ml of ether and then twice with 30 ml of methylene chloride. All the organic phases are dried over MgSO4. The solvents are filtered and evaporated. The residual oil which has a slight precipitate of diisopropylamine hydrochloride is taken up in ether, refiltered and the ether removed on a rotary evaporator.

Finally, the last phase of the synthesis consists in obtaining tetraethyl 19 and triethyl 19 '3-hydroxypropylidene-1,1-bisphosphonate.

3.6 10-3 moles of 3- (tetrahydropyranyloxy) propylidene-1,1-p.toluenesulphonic are introduced into a 100 ml round-bottomed flask equipped with magnetic stirring. The solution is stirred for two hours at room temperature. The methanol is driven off in a rotary evaporator. The residual oil is treated with 30 ml of water. Extracted with 2 times 30 ml of ether. This extraction makes it possible to separate the alcohol 12, which remains in the water, from the-2-methoxytetrahydropyran. The aqueous phase is taken up and then extracted with 3 times 30 ml of chloroform. The chloroform phase is dried over magnesium sulfate.

After filtration and evaporation of the solvent, the residual oil is chromatographed on silica gel with acetone. A mixture of two alcohols is obtained, tetraethyl 3-hydroxypropylidene-1,1-bisphosphonate (90%) 19 and triethyl 3-hydroxypropylidene-1,1-bisphosphonate 19 '(10%).

3 Svnthesis of 2- (6-methoxy-2-naphthalenyl) propionate of propylidene-3 ~ 3-bisphosphonate of tetraethyl 20 and triethyl 20 '
In a 100 ml three-necked flask fitted with magnetic stirring, a dropping funnel and an alcohol thermometer, 6 i03 moles of 3-hydroxypropylidene-1,1-bisphosphonate (19 (90 So) and 19 are introduced. (10 su)), 609 moles of triethylamine in 25 ml of tetrahydrofuran. The solution is cooled to 0 ° C. 6,103 moles of 2- (6-methoxynaphthalenyl) propionyl chloride 61 diluted in its volume of tetrahydrofuran are gradually added. The solution is stirred for one hour at room temperature. The triethylamine hydrochloride is removed by filtration.

The tetrahydrofuran is evaporated off in a rotary evaporator.

The following reaction occurs

R = Et: 20 (90%); R = Hl 20 '(10X)
4 "Selective hydrolysis of the phosphonic ester functions of compounds 20 and 20 'and obtaining disal forms.

This step is carried out in the same way as in the previous example by the action of bromotrimethysilane and makes it possible to produce the acid form of bisphosphonates 20 and 20 ′. The salified forms are then obtained by the action of the equivalent number of methoxide in methanol.

Example 3
This example relates to obtaining gem-bisphosphonic analogues derived from naproxen.

1 "Synthesis of 6-methoxy-2 naphthaldehyde
6-Methoxy-2-naphthaldehyde 70 is obtained with a good yield by first preparing the organolithium of 2-bromo-6-methoxynaphthalene by halogen-metal exchange with n-butyllithium at -78 C in the ether. The organometallic derivative formed condenses on dimethylformamide and leads, after hydrolysis, to 6-methoxy-2-naphthaldehyde 70. The reaction which takes place is as follows:

2 "Synthesis of tetraalkyl arylethenylidenebisphosphonate 64
200 ml of distilled tetrahydrofuran are poured into a 500 ml three-necked flask, fitted with magnetic stirring, an isobaric pouring funnel and an alcohol thermometer. The solution is cooled to 00C and a stream of nitrogen in the assembly. 10.1 moles (2 eq) of titanium tetrachloride diluted in 25 ml of distilled carbon tetrachloride are added dropwise with good stirring.

Still at 0 ° C., 5 10.2 moles of aromatic aldehyde 70, diluted in 10 ml of tetrahydrofuran, then 5 10.2 moles of ethylene bisphosphonate, also diluted in 10 ml of tetrahydrofuran, are added. 2 10 −1 mole (4 eq) of N-methylmorpholine diluted in 35 ml of tetrahydrofuran are added to oOC over the space of half an hour. The ice bath is removed and the solution is stirred at room temperature under a static nitrogen atmosphere for about twenty hours. Hydrolysis is carried out with 50 ml of water. The organic phase is extracted with 3 times 50 ml of ether and then dried over magnesium sulfate. After filtration, the solvents are evaporated off.

The reaction that takes place is as follows:

3 Synthesis of tetraethyl 2-arylethylidene 11-bisphosphonate 23a
In a 250 ml flask surmounted by an ascending condenser and equipped with a magnetic stirring, one weighs 13 10-3 moles of sodium borohydride which one covers with 50 ml of distilled ethanol. 13 10-3 moles of tetraethyl 64 arylethenylidene bisphosphonate, diluted in 100 ml of ethanol, are then added. The solution is stirred at room temperature for two hours. The excess sodium borohydride is destroyed by adding dilute hydrochloric acid (1N). The ethanol is driven off in a rotary evaporator. Treated with 50 ml of water. The organic phase is extracted with 3 times 50 ml of ether and then dried over magnesium sulphate.

The reaction that takes place is as follows:

4 "Synthesis of tetraethyl 2-arvlpropvlidene-L1-bisphosphonate 21a
In a 100 ml three-necked flask, fitted with magnetic stirring, a mercury thermometer, an isobaric pouring funnel and an ascending condenser, are introduced 10.2 moles of tetraethyl arylethenylidene bisphosphonate 64 and 40 ml of distilled tetrahydrofuran. Is added with good stirring and without exceeding 25 "C 1.2 10.2 mole of methylmagnesium iodide 3M dissolved in ether. The clear solution becomes cloudy and the carbanion formed precipitates. The solution is stirred at room temperature for half an hour then poured into 50 ml of 1N hydrochloric acid. The organic phase is extracted with 3 times 50 ml of ethyl acetate and then dried over magnesium sulfate.

The reaction that takes place is as follows

5 Hydrolysis of ester functions and preparation of sodium salts of tetraethyl 2-arylethylidene and 2-arylprnpylidene-11-bisphosphonates 21c 23c
The hydrolysis of the phosphonic ester functions is carried out first.
Into a 100 ml flask equipped with magnetic stirring and surmounted by a calcium chloride guard are introduced 5 10-3 moles of tetraethyl gem bisphosphonate (>,>, respectively) and 20 ml of methylene chloride. 32.2 moles of bromotrimethylsilane (6 eq) are added all at once; the solution is stirred at room temperature for 48 hours. The solvent and the excess of bromotrimethylsilane are driven off under reduced pressure. Twice 20 ml of methylene chloride are added and the mixture is driven off again.

The next step is to switch from gem-bisphosphonic acids to their salts. Into a 100 ml round-bottomed flask are introduced 10-3 moles of gem-bisphosphonic acid and 20 ml of methanol. Two equivalents of sodium methoxide are gradually added, also in solution in 20 ml of methanol. The precipitated sodium disalt (21c 23 c) is filtered through a Buchner funnel, washed with dry ether and then dried at 60 ° C. under a vane pump vacuum.

Example 4
This example relates to obtaining gem-bisphosphonic analogs derived from ibuprofen.

10 Synthesis of isobutylbenzaldehyde LI
The first step in this synthesis is to form 4-isobutylbenzoic acid.

Into a 500 ml three-necked flask, equipped with magnetic stirring, an ascending refrigerant and a mercury thermometer, 12 10.2 moles of 4-isobutylacetophenone and 6 1ff3 moles (5% by mole) of hydrogen sulphate are introduced. tetrabutylammonium. 225 ml of 48 "chlorometric sodium hypochlorite (48 1052 mol) are poured onto this mixture. The solution is stirred vigorously and gradually heated to 70 ° C. After one hour of heating, the solution turns white and the reaction becomes exothermic. This exothermicity has passed, the temporarily interrupted heating is continued for 4 hours to complete the reaction. After cooling, the solution is washed with 3 times 100 ml of ether in order to remove the unreacted 4-isobutylacetophenone. The aqueous phase is taken up and acidified. Extracted again with 3 times 100 ml of ether. This second ethereal phase is dried over magnesium sulfate. After filtration and evaporation of the solvent, 4-isobutylbenzoic acid is recrystallized from an ethanol / water mixture.

The second step of this synthesis consists in reducing the benzoyl chloride obtained into alcohol.

In a 250 ml round-bottomed flask, 4,102 moles of 4-isobutylbenzolque acid, 50 ml of toluene and 12,102 moles of thionyl chloride are introduced. The reaction mixture is brought to reflux of toluene for two hours.

The toluene and the excess thionyl chloride are evaporated off under reduced pressure.

The 4-isobutylbenzoyl chloride is taken up in tetrahydrofuran and added dropwise to 41fi2 moles of sodium borohydride suspended in 50 ml of tetrahydrofuran. The solution is stirred at room temperature for two hours.

The sodium borohydride is neutralized with a solution of potassium carbonate. Extracted with 3 times 50 ml of ether. The ethereal phase is dried over magnesium sulfate. After filtration and evaporation of the ether, the isobutylbenzyl alcohol 4 is chromatographed on silica gel with a 1/10 ethyl acetate / hexane mixture.

The third and final step consists in oxidizing the alcohol obtained.

61.5 1073 moles (1.5 eq) of pyridinium chlorochromate, 80 ml of methylene chloride and then 41 10-3 moles of 4-isobutylbenzyl alcohol are introduced into a 250 ml flask. The solution is stirred at room temperature for 1 hour 30 minutes. 80 ml of ether are added. The supernatant liquid is carefully decanted from the black gum which has formed during the reaction. The latter is washed with 3 times 20 ml of ether. All of the organic phases are filtered through Celite. The ether is evaporated off under reduced pressure.

2 "Tetraalkyl arylethenylidene bisphosphonate synthesis 65
Compound 65 is obtained by following a protocol identical to the protocol described in Example 3-2 /.

3 Svnthesis of tetraethyl 2-arvlethvlidene-1.1-bisphosphonate 24a
Compound 24a is obtained by following a protocol identical to that described in Example 3-3 l.

4 Synthesis of tetraethyl 2-arylpropylidene-1,1-bisphosphonate 22a
Compound 22a is obtained by following a protocol identical to that described in Example 3-4 /.

Preparation of the sodium salts of tetraethyl 2-arvethylidene and 2-arylpropylidene-1,1-bisphosphonates 24c and 22c.

This step is carried out identically to that described in example 3-5%
Example 5
This example relates to the synthesis of a gem-bisphosphonic analog of tiaprofenic acid.

1 Synthesis of ethyl 2- [2- (S-formyl) thienyl] propionate 72
Compound 72 is obtained by reacting VILSMEIER-HACK with ethyl 2- (2thienyl) propionate 73.

6 10.2 moles of distilled dimethylformamide are introduced into a 100 ml three-necked flask fitted with magnetic stirring, an ascending condenser and a mercury thermometer. 6,102 moles of phosphorus oxychloride are added. The mixture, the temperature of which reaches 50 C, takes on a red tint. It is left to stand without stirring for half an hour. 32.2 moles of ethyl 2- (2-thienyl) propionate are added all at once. The reaction mixture is stirred for two hours at 100 ° C. After returning to room temperature, the viscous mass obtained is diluted in 50 ml of methylene chloride and then poured over ice cubes. The aqueous phase is made alkaline by the gradual addition of potassium carbonate. Extracted with 3 times 50 ml of methylene chloride. All the organic phases are dried over magnesium sulphate. After filtration and evaporation of the solvent, ethyl 2- [2- (5-formyl) thienyl] propionate 72 is obtained.

2 "Tetraalkyl arylethenylidene bisphosphonate synthesis 69
Compound 69 is synthesized according to a protocol identical to that described in Example 320 /.

3 Synthesis of tetraalkyl 2-arylethylidene-1.1-bisphosphonate 25a
Compound 25 is synthesized according to a protocol identical to that described in Example 3-3%

4 "Preparation of sodium salt 25c
The hydrolysis of the phosphonic ester functions of compound 25a is carried out according to a protocol analogous to the protocol according to Example 3-5 /.

The formation of the sodium pentasalt of compound 25b takes place in parallel with the saponification of the carboxylic ester function. In a 100 ml round-bottomed flask are introduced 5 10 -3 moles of compound 25b, 5 ml of 5N sodium hydroxide (5 eq) and 50 ml of methanol. The reaction mixture is brought to reflux for 5 hours. The 25c sodium pentasel is filtered through a Buchner funnel, washed with dry ether and then dried at 60 ° C. under a vane pump vacuum.

Example 6
This example relates to the synthesis of an ibuprofen prodrug vectorized by a gem-bisphosphonic head. This prodrug is tetraethyl 2- [2- (4-isobutylphenyl) propionamido] ethylidene-1,1-bisphosphonate 16a.

1 preparation of ibuprofen primary amide
2 1ff2 moles of 2- (4-isobutylphenyl) propionyl chloride diluted in its volume of tetrahydrofuran are poured dropwise into a 100 ml three-necked flask onto 10 ml of a concentrated solution of ammonium hydroxide cooled to 0 C. After stirring for one hour at room temperature, 2- (4-isobutylphenyl) propionamide is extracted with 3 times 40 ml of ethyl acetate. All of the organic phases are washed with 40 ml of water. After drying over magnesium sulfate and then evaporating off the solvent, the amide is recrystallized from ethyl acetate.

2 addition of 2- (isobutylphenyl) propionamide on ethenylidene B tetraethyl bisphosphonate 31
16 10-3 of diisopropylamine dissolved in 20 ml of tetrahydrofuran are introduced into a 100 ml three-necked flask. Is added dropwise at -70 C 16 10-3 of n-butyllithium dissolved in hexane. After a few minutes of stirring, 16 lff3 moles of 2-arylpropionamide are gradually added. Stirring is maintained for five minutes between -70 C and -600C.

The solution is again cooled to -70 ° C., then 16 10 -3 moles of tetraethyl ethenylidene-1,1-bisphosphonate 31 in solution in their volume of tetrahydrofuran are added slowly. The mixture is stirred for fifteen minutes at -70 C, then gradually warmed to -20 C to complete the reaction. 20 ml of a dilute solution (5N) of ammonium chloride are added at this temperature. The solution brought to room temperature is extracted with 3 times 40 ml of ethyl acetate. The organic phase is dried over magnesium sulfate and filtered. The solvents are driven off with a roavapor. The oily residue obtained is chromatographed on silica gel with a 10/1 ethyl acetate / ethanol mixture.

Claims (5)

1. Non-steroidal anti-inflammatory gem-bisphosphonic drugs of arylacetic or arylpropionic type corresponding to the general formula (II):

in which

is either an arylacetyl radical or an arylpropionyl radical. X is an alkylene radical having 2 to 4 carbon atoms; R2 is either a linear or branched C1 to C6 lower alkyl radical or H; R3 is either a linear or branched C1 to C6 lower alkyl radical or H; as well as their pharmaceutically acceptable salts. 2. Prodrugs according to claim 1 characterized in that said radical R is a radical derived from ibuprofen, naproxen, ketoprofen, tiaprofenic acid or indomethacin chosen from the group consisting of:

3. Process for obtaining prodogues according to one of claims 1 or 2, characterized in that it consists in esterifying the acid function of an anti-inflammatory compound with an alcohol bisphosphonate of general formula (V):

X, R2, R3 having the same meanings as in claims 1 or 2. 4. Method according to claim 3 characterized in that the bisphosphonate alcohol of general formula (V) is obtained from a protected alcohol of general formula (VI):

X having the same meaning as in claim 1. 5. Pharmaceutical composition for the curative and / or preventive treatment of bone diseases characterized in that it comprises as active principle one or more non-steroidal anti-inflammatory drugs of arylacetic or arylpropionic type corresponding to general formula (II).