WO1994001395A1 - Pro-drug capable of releasing an oxazolidinone and, if need be, an acetamidophenol - Google Patents

Abstract

Pro-drug capable of releasing an oxazolidinone in a physiological medium, characterized in that it comprises a hydroxycarbamate having the unit (1). Said pro-drug is capable of releasing an other active agent owing to the presence of an appropriate grouping on the carbamate oxygen atom. For example, the grouping can be (a), in order to release acetamidophenol.

Description

 PRODUCT CAPABLE OF RELEASING OXAZOLIDINONE AND, IF AN ACETAMIDOPHENOL

The invention relates to a prodrug capable of releasing an oxazolidinone, in particular chlorzoxazone, in a physiological medium; it extends to a prodrug common to an oxazolidinone and an acetamidophenol, capable of releasing both compounds of these two families, in particular chlorzoxazone and paracetamol. The invention also relates to methods of manufacturing these prodrugs.

We know that a "prodrug" (French translation commonly accepted for the English term

"pro-drug") is a precursor of one or more drugs (and therefore the drug itself) which releases the active principle (s) concerned after introduction into the organism: the prodrug has a chemical structure different from that of the drug but , in a physiological medium, by a chemical and / or enzymatic reaction, it regenerates the drug. The advantage of such a prodrug is to eliminate certain drawbacks that the drug may have: pharmaceutical barriers (undesirable organoleptic properties, insufficient solubility, instability ...), pharmacokinetic barriers

(poor resorption, incorrect distribution, too short biological half-life, first pass effects ...).

In addition, these prodrugs can be used to release several active ingredients whose administration in combination is sought, for example a muscle relaxant associated with an analgesic ...; this type of prodrug is designated "common prodrug" (in English "mutual pro-drug"). Oxazolidinones are a family of drugs with muscle relaxation properties (e.g. chlorzoxazone which is the most used, or metaxalone), analgesic properties

REPLACEMENT SHEET l

(e.g. 6-benzoylbenzoxazolone) or tranquilizer properties (e.g. ephenoxalone). These oxazolidinones, which generally act at the level of the central nervous system, have for the most part lipophilic properties which are not very favorable for the crossing of the lipid barriers (hematomeningee barrier). The following publication refers to work carried out to prepare chlorzoxazone prodrugs in order to facilitate this crossing: "H. BUNDGAARD et al. J. Med. Chem., 1989, vol. 32,

2503-2507 and Arch. Pharm. Chemi., Sci. Ed. 1981, vol. 9,; 43-54 "; these prodrugs are derivatives of chlorzoxazone with linear ramifications grafted onto the nitrogen atom. To the inventors' knowledge, this type of prodrug has never been used.

In addition, it is often interesting to combine with oxazolidinones (in particular those which are used as muscle relaxants) another active principle, and more particularly an analgesic such as paracetamol: the two active principles have complementary therapeutic effects and increase the speed of pain-relieving action (see publications: "JK ELENBAAS, Centrally Acting Oral Skeletal Muscle Relaxants, Am. J. Hosp. Pharm., 1980, vol. 37, p 1313-1323; JM WALKER, Parafon Forte Tablets: A Review Of The Literature, Curr. Therap. Res. 1973, vol. 15, p 248-252 "). There is currently no common prodrug for these two types of medication, and certain dosage formulations combine them by simple physical mixing, which can have certain drawbacks (pharmacokinetic behavior different from the two medications, need for dosage manipulation during of manufacturing ...).

The present invention proposes to provide a prodrug capable of releasing an oxazolidinone in a physiological medium.

An object of the invention is to provide a prodrug having physicochemical properties the

REPLACEMENT SHEET making it better to cross A> the pharmaceutical and / or pharmacokinetic barriers than the active ingredient itself.

Another objective is to provide a common prodrug to an oxazolidinone and to another active principle, in particular an acetamidophenol.

The invention proposes in particular to provide a common prodrug to chlorzoxazone and to paracetamol, with a view to eliminating the drawbacks of galenical formulations made from the mixture of these two compounds.

In its most general formulation, the prodrug according to the invention, capable of releasing an oxazolidinone in a physiological medium, comprises a hydroxycarbamate comprising the motif:

0 H 11

In physiological medium (plasma, blood medium, gastrointestinal tract ...), a cyclization reaction occurs by intramolecular nucleophilic attack of the alkoxide anion O- on the carbonyl function C = 0, with expulsion of a leaving group including the oxygen ester. This cyclization leads to an oxazolidinone having the following skeleton:

The rate of cyclization (ensuring the release of Oxazolidinone) is a function of the acidity of the leaving group and of the nucleophilia of the alkoxide anion.

The α and β positions of the hydroxycarbamate can comprise an aromatic ring, substituted or not. We

REPLACEMENT SHEET then has a prodrug capable of releasing a benzoxazolone, comprising the motif:

0

The radical R- | fixed on the aromatic nucleus is chosen according to the active ingredient to be released. It can in particular be constituted by a chlorine atom in position 5 in order to provide a prodrug capable of releasing chlorzoxazone (muscle relaxant); this prodrug therefore has the motif:

Its half-life is of the order of magnitude from a few seconds to a few minutes in a physiological medium (pH: 7.4; T = 37 ° C); this half-life can be modulated by modifying the leaving group (increased half-life for a lower acidity of the leaving group).

The radical R- | attached to the aromatic nucleus can also be constituted by the benzoyl group in position 4 in order to provide a prodrug of 6-benzoyl-benzoxazolone which is an analgesic; this prodrug therefore has the motif:

0 ^H II

As before, the release speed can be modulated by modifying the leaving group

MPLA EMENT (more or less high acidity).

Furthermore, the hydroxycarbamate can also comprise a phenoxymethyl radical, substituted or not. We then have a prodrug capable of releasing a 5-phenoxymethyl 2-oxazolidinone, comprising the motif:

0

The radical R2 fixed on the aromatic nucleus of the phenoxy group is chosen as a function of the active principle to be released. It can in particular be constituted by a dimethyl in position 3 and 5 in order to provide a prodrug of metaxalone which is a muscle relaxant; this prodrug therefore has the motif:

0

II

The radical R2 fixed on the aromatic nucleus of the phenoxy group can also be constituted by a methoxy radical in position 2, with a view to providing a prodrug of mephenoxalone which is a tranquilizer; this prodrug therefore has the motif: 0

The prodrug targeted by the invention lends itself to the release of another active principle thanks to the

REPLACEMENT SHEET b presence of an appropriate group on the oxygen atom of the carbamate (ester function). During the cyclization reaction (formation of oxazolidinone), this group will be released with the oxygen carrier by breaking the C-0 bond. This produces a common prodrug capable of releasing two active ingredients in a physiological medium.

According to a first family of common prodrug, the group attached to the oxygen atom is an acetamidophenyl in order to provide a prodrug common to an oxazolidinone and to an acetamidophenol; this prodrug family is characterized by the following motif:

In this prodrug family, it is possible to provide in the α and / or β position the appropriate group to release the desired 1Oxazolidinone; these groups can be those already mentioned, and in particular an aromatic nucleus, substituted or not, fixed in position α and β to provide a prodrug of a benzoxazolone and an acetamidophenol, this prodrug being characterized by the following motif:

The radical of this aromatic nucleus can be a chlorine atom in position 5, while the acetamido group can be in position 4, in order to provide a common prodrug to chlorzoxazone and paracetamol, of formula:

REPLACEMENT SHEET -λr

The half-life of this prodrug in physiological medium (pH: 7.4; T = 37 ° C) is 7 seconds. It has been observed that the release of the two active ingredients is quantitative and simultaneous. These properties remain in human plasma.

It should be emphasized that it is possible to introduce a delay effect, in particular on the release of chlorzoxazone. It suffices to mask the hydroxyl group of the aromatic nucleus by replacing the hydrogen atom with a radical R acyl, alkoxycarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl. A delay effect prodrug is obtained of formula:

This masking slows down the cyclization reaction by causing it to be carried out in two stages: cyclization by migration of the N-0 acyl type releasing paracetamol and the chlorzoxazone substituted on the nitrogen atom, then release of the chlorzoxazone by loss of substituting R. This prolongs the effect of the muscle relaxant without appreciably modifying that of the analgesic.

According to a second family of common prodrugs, the group attached to the oxygen atom of the carbamate is an aliphatic alcohol, with a view to obtaining in particular a prodrug having the motif:

REPLACEMENT SHEET

where R3 is an aliphatic radical, saturated or not.

In this family, the common prodrug with chlorzoxazone and ethchlorvynol (sedative and hypnotic) has the following formula:

0 CH = CH Cl

^H II I

In this same family, the common prodrug with chlorzoxazone and meparfynol (sedative and hypnotic) has the following formula:

The invention extends to the use of the abovementioned compounds comprising one of the motifs (1), (3), (3a), (3b), (4), (4a), (4b), (5), ( 6), (9), or having one of the formulas (7), (8), (10), (11), for obtaining a medicament capable of releasing in vivo either an active principle consisting of an oxazolidinone, in particular chlorzoxazone, 6-benzoylbenzoxazolone, metaxalone, mephenoxalone, either two active principles consisting of the abovementioned active principle and an acetamidophenol, in particular paracetamol or an aliphatic alcohol, in particular ethchlorvynol or meparfynol.

REPLACEMENT SHEET The invention extends to methods of making the aforementioned prodrugs.

A general method of preparation of these prodrugs is characterized in that a chlorocarbonylation reaction of an alcohol or a phenol is carried out using phosgene or a substitute derivative with a view to preparing a chloroformate, the chloroformate obtained on a hydroxyamine having the motif:

ou sur une hydroxyaniline possédant le motif

or on a hydroxyaniline having the motif

et on isole 1'hydroxycarbamate formé.

and isolating the hydroxycarbamate formed.

The chlorocarbonylation reaction is promoted by the addition of a base (N-N dimethylaniline) which captures the hydrochloric acid released during the reaction in the form of an insoluble salt; this is removed by filtration to collect the chloroformate. The condensation of the latter compound on hydroxyamine or hydroxyaniline is advantageously carried out at reflux in anhydrous ether: the hydroxycarbamate precipitates and can be isolated by filtration.

Another preparation route is to use 1,2,2,2,2-tetrachloroethyl chloroformate which is a product available on the market. This particularly advantageous route for manufacturing the prodrug common to an oxazolidinone and to an acetamidophenol comprises the following steps: the 1,2,2,2-tetrachloroethyl chloroformate is condensed on an acetamidophenol in an organic solvent, in particular tetrahydrofuran (THF), presence of a base, in particular pyridine, with a view to obtaining acetamidophenyl carbonate and 1,2,2,2-tetrachloroethyl, this carbonate is condensed on a hydroxyamine having the motif:

ou sur une hydroxyaniline possédant le motifREPLACEMENT SHEET

or on a hydroxyaniline having the motif

dans un solvant organique notamment THF et en présence d'une base, notamment pyridine, et on isole 1'hydroxycarbamate d'acetamidophenyle obtenu.

in an organic solvent in particular THF and in the presence of a base, in particular pyridine, and the acetamidophenyl hydroxycarbamate obtained is isolated.

The stage of condensation of the carbonate on the hydroxyamine or the hydroxyaniline is advantageously carried out in the presence of traces of water which minimize the parasitic reaction of formation of Schiff base and make it possible to increase the yield of hydroxycarbamate.

The hydroxycarbamate formed precipitates and can be isolated by filtration.

Another way of preparing a prodrug common to oxazolidinone and paracetamol is to use p-aminophenol commercially available as the starting compound; this preparation route is characterized by the following stages: the amino function of p-aminophenol is protected by means of a protective group, a chlorocarbonylation reaction of the compound obtained is carried out by means of phosgene or a substitution derivative in view to prepare an alkoxycarbonylaminophenyl chloroformate, the amino group is deprotected from the chloroformate by means of an acid, an acetylation reaction of the compound obtained is carried out by means of an acetylating agent in order to obtain the chloroformate of 4-acetamidophenyl , this chloroformate is condensed on a hydroxyamine having the motif:

REPLACEMENT SHEET or on a hydroxyaniline having the following motif

dans un solvant organique notamment THF et en présence d'une base, notamment pyridine, et on isole le composé obtenu.

in an organic solvent in particular THF and in the presence of a base, in particular pyridine, and the compound obtained is isolated.

In this preparation route, p-aminophenol is started and the corresponding chloroformate is prepared, which is condensed in a similar manner to the previous route.

To improve the purity of the product and its yield, the step of deprotecting the amino group from the chloroformate is preferably carried out using gaseous hydrochloric acid. A variant of this latter preparation route can be carried out by the following steps: the amino function of p-aminophenol is protected by means of a protective group, a chlorocarbonylation reaction of the compound obtained is carried out using phosgene or a substitution derivative in order to prepare an alkoxycarbonylaminophenyl chloroformate, this chloroformate is condensed on the hydroxyamine have the motif:

ou sur une hydroxyaniline possédant le motif

or on a hydroxyaniline having the motif

dans un solvant organique notamment THF et en présence d'une base, notamment pyridine, en vue d'obtenir un biscarbamate, on déprotège le groupe amino de ce biscarbamate, on réalise une réaction d'acetylation de 1'hydroxycarbamate obtenu au moyen d'un agent acétylant, et on isole le composé obtenu.

in an organic solvent in particular THF and in the presence of a base, in particular pyridine, in order to obtain a biscarbamate, the amino group is deprotected from this biscarbamate, an acetylation reaction of the hydroxycarbamate obtained is carried out by means of an acetylating agent, and the compound obtained is isolated.

In this variant, one passes, not by the synthesis of p-acetamidophenyl chloroformate, but by that of a hydroxy biscarbamate.

REPLACEMENT SHEET HAVE

In these last two preparations, the protection of the amino function is advantageously carried out by means of an N-tert-butoxycarbonyl (BOC) protective group by causing the compound to react with diterbutyl dicarbonate. This mode of implementation avoids the appearance of side reactions.

Furthermore, to prepare the aforementioned delay effect prodrug (formula (8)), it suffices to manufacture the corresponding prodrug comprising the hydroxyl group OH and to functionalize the latter by means of an acyl, alkoxycarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl radical, by an acylation or alkoxycarbonylation or carbamoylation reaction.

The examples which follow illustrate the manufacture of several types of prodrugs in accordance with the invention, their physical characteristics, and their behavior in physiological environments.

EXAMPLE 1 PRODUCT COMMON TO CHLORZOXAZONE AND PARACETAMOL

A - PREPARATION STEPS

1) Synthesis of 4-acetamidophenyl carbonate and 1, 2, 2,2-tetrachloroethyl

To 14.77 g (66 mmol) of chloroformate of 1, 2, 2, 2-tetrachloroethyl in 4 ml of tetrahydrofuran, a mixture consisting of 7 is added dropwise at low temperature (O ° <T <10 ° C) , 71 g (50 mmol) of 4-hydroxyacetanilide and 4.53 ml (55 mmol) of pyridine in 100 ml of distilled THF. The reaction mixture is left under stirring for 4 h at room temperature. The precipitate obtained at the end of the reaction is removed by filtration. The filtrate is evaporated under reduced pressure. The residue present at the bottom of the flask is taken up in dichloromethane. This organic phase is washed with 1N HCl, dried over MgSθ4 and then evaporated under reduced pressure. The raw crystals obtained are washed

REPLACEMENT SHEET λî with petroleum ether. Carbonate

4-acetamidophenyl and 1,2,2,2-tetrachloroethyl is recrystallized from ether. Yield: 93%.

2) Synthesis of N- (5-chloro-2-

5.hydroxyphenyl) 4-acetamidophenyl carbamate, common prodrug

In a reactor containing a mixture consisting of 11.2 g (76 mmol, 2 equivalents) of 5-chloro-2-hydroxyaniline and 13.7 g (38 mmol, 1 equivalent) of 4-acetamidophenyl carbonate and 1 , 2,2,2- tetrachloroethyl dissolved in 280 ml of THF and 15 ml of water, poured dropwise at room temperature 3 ml (38 mmol, 1 equivalent) αe pyridine. The mixture is left stirring for 1 h 30 min. It is evaporated to dryness under reduced pressure, the residue obtained is taken up in an ether / THF mixture (v / v 9/1). This organic phase is washed 3 times with 3N HCl, dried over MgSO4 and then evaporated under reduced pressure. Brown crystals are obtained which are washed with ether in order to remove the 5-chloro-2-hydroxyaniline. 0 After filtration, 4-acetamidophenyl N- (5-chloro-2-hydroxyphenyl) carbamate is obtained with a yield of 81%.

B - PRODROGUE OBTAINED

5 Formula: C-- ₅ Hι ₃ ClN2θ4, M = 320.73 Characteristics: Pt F.: 194 ° C

Calculated elementary analysis C% 56.17 H% 4.09 N% 8.73 found 56.11 4.08 8.63

30 IR (KBr): 3400 and 3327 cm ^-1 (V _N _ _H carbamate and amide), 3400-3200 cm ^-1 ( ^" / oH>" ^{1724 cm_1} (^ C = ₀ carbamate), 1647 cm ^-1 (~ fc = 0 amide), 1605 cm ^-1 (* / c = _C aromatics), 1529 and 1502 cm ^-1 (^ NH- _C O - ^ -

35 ¹ H NMR (DMSOd6): 2.04 (3H, 2 peaks, CH ₃ ), 6.87 (H _α , d, αβ = 8.63 Hz, aromatic), 7.00 (Hβ, dd, J _αβ = 8.63 Hz and J γ = 2.6 Hz, aromatic), 7.11; 7.14; 7.58; 7.61 (4H, system AA 'BB' ô _A = 7.13, δ _B = 7.60, J _AB = 8.95 Hz),

REPLACEMENT SHEET 7.64 (Hy, d, J _β "= 2.6 Hz aromatic), 9.08 (1H, s, OH), 9.99 (1H, s, NH), 10.15 (1H, s, NH ).

Behavior in physiological medium: tj 2 = ^~ seconds at 5. pH 7.4 and 37 ° C.

EXAMPLE 2 PRODUCT COMMON TO CHLORZOXAZONE AND TO

PARACETAMOL

0 PREPARATION STEPS

1) Synthesis of tert-butyl N- (4-hydroxyphenyl) carbamate

A solution, consisting of 14.63 g 5 (65 mmol) of diterbutyl dicarbonate and 60 ml of distilled tetrahydrofuran (THF), is poured dropwise into a 500 ml two-necked reactor containing 7.1 g

(65 mmol) of p-aminophenol dissolved in 350 ml of THF at low temperature (0 ° <T <10 ° C). The reaction mixture 0 is kept stirring for 24 h at room temperature. The brown solid obtained after evaporation under reduced pressure of the THF is dissolved in ethyl acetate. This organic phase is washed 3 times with water and then dried over MgSθ4. Ethyl acetate is removed under

25 reduced pressure. The pure tert-butyl N- (4-hydroxyphenyl) carbamate is recovered in the form of a light brown powder. Yield: 93%.

2) Synthesis of 4-tert-butoxycarbonylaminophenyl chloroformate

In a 500 ml three-necked reactor, 10.4 g (50 mmol) of tert-butyl N- (4-hydroxyphenyl) carbamate mixed in solution in 200 ml of anhydrous ethyl acetate are mixed with 40 ml of a solution 1.93 M phosgene in toluene (75 mmol). The whole is maintained under an inert atmosphere (argon current) between 0 ° C and + 5 ° C. Then added dropwise with stirring, 6.34 ml (50 mmol) of N, N-dimethylaniline (DMA) in solution

REPLACEMENT SHEET AS in 5 ml of ethyl acetate. After the addition of DMA, the reaction medium is kept at low temperature (0 <T <10 ° C) and with stirring for 1 h, then the temperature is gradually raised in order to remove the excess phosgene. The reaction mixture is then left to return to ambient temperature and then filtered. The filtrate is washed with 0.1 N HCl and the organic phase dried over MgSθ4 is evaporated under reduced pressure. The chloroformate is recrystallized in the form of white needles from chloroform. Yield: 93%.

3) Synthesis of 4-aminophenyl chloroformate hydrochloride

In a two-necked reactor containing 2 g (7.38 mmol) of 4-tert-butoxycarbonylaminophenyl chloroformate dissolved in 55 ml of distilled THF, 99% hydrochloric acid gas is bubbled slowly over 4 h. During its formation, the hydrochloride of 4-aminophenyl chloroformate precipitates in the reaction medium. The precipitate, recovered by filtration is washed with ether and then dried quickly under reduced pressure. 1.46 g of very irritating powder are obtained. Yield: 95%.

4) Synthesis of chloroformate

4-acetamidophenyl

In a 500 ml reactor, 1.50 g (7.2 mmol) of hydrochloride suspended in 300 ml of distilled THF and 100 ml of acetyl chloride (large excess) are mixed. The reaction mixture is kept under stirring for 4 h at room temperature. Evaporated to dryness under reduced pressure and recovered 1.32 g of gray crystals which are washed with petroleum ether and then dried. Yield: 86%.

5) Synthesis of 4-acetamidophenyl N- (5-chloro-2-hydroxyphenyl) carbamate, common prodrug

7.40 g (50 mmol) of 5-chloro are dissolved

REPLACEMENT SHEET Λ b

2-hydroxyaniline in 100 ml of anhydrous ether. To this solution brought to reflux, are then slowly added 5.33 g (25 mmol) of 4-acetamidophenyl chloroformate: there is formation during the addition of a yellow precipitate corresponding to 5-chloro-2 hydrochloride -hydroxyaniline, insoluble in ether. The reaction medium is kept under stirring and at reflux for 4 h, then filtered. The filtrate obtained is washed with 3N HCl. The ethereal phase is dried with MgSO 4 and then evaporated under reduced pressure. The prodrug is recovered in the form of brown crystals. Yield: 81%.

EXAMPLE 3 PRODUCT COMMON TO CHLORZOXAZONE AND TO

PARACETAMOL

The 4-tert-butoxycarbonylaminophenyl chloroformate is obtained according to the operating protocol described in Example 2, steps 1) and 2), then the condensation and deprotection reactions are carried out as follows:

Synthesis of 4-tert-butoxycarbonylaminophenyl N- (5-chloro-2-hydroxyphenyl) carbamate Procedure as in Example 2-5) but introducing 5.43 g (20 mmol) of 4-tert-butoxycarbonylaminoρhenyl chloroformate . The expected product is obtained with 85% yield.

Synthesis of 4-aminophenyl N- (5-chloro-2-hydroxyphenyl) carbamate hydrochloride

In a 1 L reactor, 10 g (26.4 mmol, 1 equivalent) of 4- tert-butoxycarbonylamino-phenyl N- (5-chloro-2-hydroxyphenyl) carbamate are dissolved in 250 ml of THF and then 300 are added. ml (8 moles, 300 equivalents) 99% formic acid. Then poured into the reactor 32 ml (32 mmol, 1.2 equivalent) of a solution of hydrochloric acid IN in THF. The mixture

REPLACEMENT SHEET reaction is kept stirring and at room temperature for 24 h. Evaporated to dryness under reduced pressure. A beige-colored powder is obtained which is washed hot with ether, then dried on a log. 7 g of 4-aminophenyl N- (5-chloro-2-hydroxyphenyl) carbamate are recovered. Yield: 84%.

Synthesis of 4-acetamidophenyl N- (5-chloro-2-hydroxyphenyl) carbamate, common prodrug

20 g (63.5 mmol, 1 equivalent) of N-(2-hydroxy-5-chlorophenyl) 4-aminophenyl carbamate hydrochloride are available in 10 ml of THF with magnetic stirring. 25.6 ml (31.7 moles, 5 equivalents) of pyridine are added and then acetic anhydride (8 cm, 80.7 mmol, 2 equivalents) is then poured dropwise. 15 minutes after the addition, the mixture is evaporated to dryness under reduced pressure and then the residue obtained at the bottom of the reactor is taken up in an AcOEt / THF mixture (v / v: 9/1). This organic phase is washed twice with 1N HCl, dried over MgSO 4 and then evaporated under reduced pressure. The common prodrug is recovered in the form of a brown powder which is washed with ethyl acetate and then with ether. Yield: 76%.

EXAMPLE 4 PRODUCT COMMON TO CHLORZOXAZONE AND TO

METACETAMOL

A - PREPARATION STEPS

1) Synthesis of chloroformate

3-acetamidophenyl

The procedure is as in Example 2-step 2) but by introducing 7.79 g (50 mmol) of 3-acetamidophenol. Chloroformate is obtained in the form of white needles. Condensation of chloroformate

3-acetamidophenyl with 5-chloro-2-hydroxyaniline is carried out according to the conditions of Example 2-5). The prodrug is obtained with a yield of 98%.

REPLACEMENT SHEET λ ^~ h

Formula: C- _\ 5H1 ₃ ClN2θ, M = 320.73

Characteristics: Pt F.: 218 ° C

Calculated elementary analysis C% 56.17 H% 4.09 N% 8.73 found 56.11 4.09 8.68

•1710 cm ^-1 1605 cm- '

•

¹ H NMR (DMSO): 2.00 (3H, s, CH3), 6.40 (1H, m), 7.10 (7H, m) 9.71 (1H, s), 10.0 (1H, s).

Behavior in physiological medium: t- | / 2 = 7.5 seconds at pH 7.4 and 37 ° C.

EXAMPLE 5 PRODUCT COMMON TO CHLORZOXAZONE AND TO

TRICHLOROETHANOL

Synthesis of 2,2,2-trichloroethyl N- (5-chloro-2-hydroxyphenyl) carbamate

14.8 g (0.1 mol) of 5-chloro-2-hydroxyaniline are dissolved in 200 ml of anhydrous ether. To this solution brought to reflux, then slowly added 7.2 ml (50 mmol) of 2,2,2-trichloroethyl chloroformate: there is formation during the addition of a yellow precipitate corresponding to the hydrochloride of 5 -chloro-2-hydroxyaniline, insoluble in ether. The reaction medium is kept under stirring and at reflux for 4 h, then filtered. The filtrate obtained is washed with 3N HCl. The ethereal phase is dried with S04 and then evaporated under reduced pressure. The 2,2,2-trichloroethyl carbamate N- (5-chloro-2-hydroxyphenyl) carbamate is recovered in the form of brown crystals. Yield 91%.

Formula: C ₉ H7C1 N03, M = 318.97

Characteristics: Pt F.: 118.5 ° C

Calculated elementary analysis C% 33.89 H% 2.21 N% 4.39 found 33.89 2.19 4.38

REPLACEMENT SHEET IR (KBr): 3147 cm ¹ (* NH carbamate), 3264 cm ¹ (* _θ -H- ⁾ '1704 cm ^-1 (^ C = 0 carbamate), 1613, 1600 cm ^-1 (- / c = _C aromatic ), 1547 and 1510 cm ^-1 ( ^* ^ _N H- _CO - ⁾ *

¹ H NMR (CD3OCD3): 4.94 (2H, s, CH ₂ ), 6.95 (2H, m, aromatics), 7.95 (1H, m, aromatics), 8.26 (1H, s, OH ), 9.24 (1H, s, NH).

Behavior in physiological medium: t- | / 2 = 3 minutes at pH 7.4 and 37 ° C.

EXAMPLE 6 PRODUCT OF CHLORZOXAZONE AND

PARACETAMOL WITH DELAY EFFECT

Synthesis of 4-acetamidophenyl N- (2-acetoxy-5-chlorophenyl) carbamate

In a 250 ml reactor, a mixture consisting of 2 g (6.2 mmol) of a common prodrug with chlorzoxazone and paracetamol dissolved in 20 ml of distilled THF and 50 ml is heated at 50 ° C. for 24 hours. large excess) of acetyl chloride. The reaction mixture is then left to return to ambient temperature while maintaining stirring for an additional 24 h. It is evaporated under reduced pressure and then 50 ml of petroleum ether are added to this solution in order to precipitate the carbamate. Filter and recover white crystals which are dried under reduced pressure. Yield: 84%.

Formula: C17H1 ₅ ClN2θ ₅ , M = 362.77

Elementary analysis calculated C% 56.29 H% 4.17 N% 7.72 found 56.00 4.07 7.50

IR (KBr): 3400 and 3331 cm ^-1 (V _NH ), 1741 cm ^"1 (V _{NC = 0} _ ₀ and ^ OC≈O - * '1661 cm ^-1 (NC≈O- ^' ¹ 605 cm - '(- / c ₌ aromatic _c ), 1533 and 1505 cm ^-1 (V _NH _ _{C = 0} ).

¹ H NMR (CD3COCD3): 2.08 (3H, s, CH3, amide), 2.34 (3H, s,

REPLACEMENT SHEET 2.0 CH3, ester), 7, 1 1 - 7, 69 (6H, AA system 'BB' and

2H aromatic), 8.17 (2H, m, aromatic), 8.86 (1H, s,

NH), 9.26 (1H, s, NH).

EXAMPLE 7: COMMON PRODROUGAL TO 6-

BENZOYLBENZOXAZOLONE AND PARACETAMOL

A - PREPARATION STEPS

1) Synthesis of 2-amino-5-benzoylphenol

In a 500 ml reactor, 12 g of 6-benzoylbenzoxazolinone (50 mmol) are dissolved in 100 ml of sodium hydroxide (2.5M) then heated at reflux for 4 h. After the reaction mixture has cooled, the medium is acidified by adding 3M hydrochloric acid, then the mixture is left stirring for 1 hour. Ethyl acetate is added to the mixture and the aqueous phase is recovered, which is neutralized with Na2CO3. A brown residue is obtained which is washed with petroleum ether and dried over sintered glass. Yield: 98%.

2) Synthesis of 4-acetamidophenyl N- (4-benzoyl-2-hydroxyphenyl) carbamate

In a reactor containing a mixture consisting of 8.1 g (38 mmol) of 2-amino-5-benzoylphenol and 13.7 g (38 mmol) of 4-acetamidoρhenyl carbonate and of 1,2,2,2- tetrachloroethyl in solution in 280 ml of THF and 15 ml of water, 3 ml (38 mmol) of pyridine are added dropwise at room temperature. The mixture is left stirring for 1 hour. Evaporated to dryness under reduced pressure, the residue obtained is then washed with 3N HCl. Filtered, then the precipitate is taken up in THF. The organic phase is dried over MgSO4, then evaporated under reduced pressure. A brown paste is obtained, which, taken up in a minimum of THF, precipitates by adding petroleum ether. Brown crystals are obtained with a yield of 61%.

REPLACEMENT SHEET zA

B - PRODROGUE OBTAINED

Formula: C22 ^H 18 ^N 2 ° 5 ' ^M = 390.40 Characteristics: Pt F.: 177 ° C

Calculated elemental analysis C% 67.68 H% 4.64 N% 7.17 found 67.34 4.58 7.11

IR (KBr): 3420 cm ^-1 and 3350 cm ^-1 (- / _NH carbamate and amide), 3600 cm ^-1 to 3200 cm ^-1 (QH) ¹⁷ 56 cm ^-1 (- _c0 carbamate), 1660 cm ^-1 (^ CO amide), 1635 cm ^-1 (-co), 1599 cm- '(Vç = C aromatic), 1502 cm ^" ' (^ NH-CO) -

¹ H NMR (DMSOd6) 2.06 (3H, 2 peaks, CH ₃ ) 7.13-7.86 (12H, m, aromatic H)

9.03 (1H, s, OH), 9.96 (1H, s, NH), 10.06 (1H, s, NH).

EXAMPLE 8 PRODUCT COMMON TO METAXALONE AND PARACETAMOL

A - PREPARATION STEPS

1) Synthesis of 3- (3,5-dimethylphenoxy) -1- chloro-2-propanol In a 250 ml reactor, the solution is dissolved

10.38 g (85 mmol) of 3, 5-dimethylphenol in 20 ml of epichlorohydrin (25.5 mmol), then 0.17 g of piperidine hydrochloride is added and the reaction mixture is kept under stirring at a temperature of 100 ° C for 6 h. Evaporated to dryness under reduced pressure. The oily yellow residue is taken up with an equal volume of chloroform. The organic phase is acidified by adding 5 ml of concentrated HCl, then washed 3 times with water and dried over MgSθ4. The organic solvent is removed by evaporation under reduced pressure. The oily residue of yellow color obtained is purified on an HPLC preparative column. Yield: 71%.

REPLACEMENT SHEET 2) Synthesis of 3- (3,5-dimethylphenoxy) -1- phthalimido — 2-propanol

6.51 g of potassium phthalimide (35 mmol) are heated at reflux for 24 h with 6.43 g of 3- (3,5-dimethylphenoxy) -1-chloro-2-propanol (30 mmol) dissolved in 35 ml of DMF. An orange-colored solution is obtained, to which either add an equal amount of chloroform and then the mixture is washed 3 times with water. The organic phase is recovered from which the pthalimide is removed by washing with 0.2 N sodium hydroxide solution. It is washed 3 times with water and then the organic phase is dried over MgSO4, and the solvent is removed by evaporation under reduced pressure. A brown oil is obtained which is purified by preparative chromatography. Yield: 44%, Pt F.: 85 ° C.

3) Synthesis of 3- (3,5-dimethylphenoxy) -1- amino-2-propanol

9.45 g of 3- (3,5-dimethylphenoxy) -1- phthalimido-2-propanol (30 mmol) and 3 ml of hydrazine hydrate are dissolved in 150 ml of methanol, then the mixture is heated to reflux for 1 h 30. The solution is acidified with ice-cold 10% HCl so as to obtain a pH of

3. The solution is cooled to 0 ° C, the precipitate formed is removed by filtration. The filtrate is recovered and basified by adding 1% sodium hydroxide, then the product is extracted with chloroform. The organic phase is dried over MgSO 4 and then evaporated under reduced pressure, whitish crystals are recovered. Yield: 93%, mp: 84 ° C.

4) Synthesis of N- {[2-hydroxy-3- (3,5-dimethylphenoxy) Ipropyl) 4-acetamidophenyl carbamate, prodrug common to metaxalone and paracetamol

In a 500 ml reactor, 11.5 g (32 mmol) of 4-acetamidophenyl carbonate and of

1, 2,2,2-tetrachloroethyl, in 235 ml of THF and 10 ml of H2θ. It is added dropwise at room temperature

6.25 g (32 mmol) 3- (3,5-dimethylphenoxy) -1-amino-2-

ACEMENT propanol dissolved in a minimum of THF. We introduce

3.90 g of N, N-dimethylaminopyridine (DMAP, 32 mmol) then the mixture is allowed to stir for 4 h. The solvent is evaporated off under reduced pressure and the residue obtained is taken up in an ether-chloroform mixture (v / v: 1/2). The organic phase is washed 3 times with 3N HCl and then dried over MgSθ4- After evaporation of the solvent, white crystals are obtained. Yield: 72%.

B - PRODROGUE OBTAINED

Formula: C2θH24N2θs, M = 372.4 Pt F.: 128 ° C

Elementary analysis calculated C% 64.50 H% 6.49 N% 7.52 found 63.62 6.40 7.34

IR (KBr): 3200 cm ^-1 to 3600 cm ^-1 broad band ( _N H carbamate and amide and QH) '1710 cm-' (- Q _Û carbamate), 1663 cm- '(^ o amide).

¹ H NMR (DMSOd ₆ ): 2.03 (3H, s, CH ₃ ), 2.22 (6H, s, 2CH ₃ ), 3.04 to 3.44 (3H, m, CH ₂ and CH), 3.84 to 3.94 (2H, m, CH ₂ ), 5.1 (1H, solid, OH), 6.55 (3H, 1 peak with shoulder, aromatic H), 7.01, 7.04, 7.52, 7.55 (4H, AA system 'BB', δ A = 7.02, 6 B = 7.53, J _AB = 7.5Hz, aromatic H), 7.74 (1H, t, NH ), 9.96 (1H, s, NH).

EXAMPLE 9 PRODUCT COMMON TO MEPHENOXALONE AND PARACETAMOL

A - PREPARATION STEPS

1) Synthesis of 3- (2-methoxyphenoxy) -1- chloro-2-propanol

The procedure is the same as that used for the synthesis of 3- (3, 5-dimethylphenoxy) -1-chloro-2-propanol described in Example 8-1).

REPLACEMENT SHEET An oily yellow residue is obtained and purified on an HPLC preparative column. Yield: 66%.

2) Synthesis of 3- (2-methoxyphenoxy) -1- phthalimido-2-propanol

The experimental protocol is identical to that described in Example 8-2). However, very pale yellow crystals are obtained by adding an ether-petroleum ether mixture to the very dense oily residue. Yield:

88%, mp F.: 85 ° C.

3) Synthesis of 3- (2-methoxyphenoxy) -1-amino-2-propanol The operating protocol is analogous to that described in Example 8-3).

Yield: 73%. Very pale yellow crystals. PT: 89 ° C.

4) Synthesis of N- {[2-hydroxy-3- (2-metoxyphenoxy)] propyl) 4-acetamidophenyl carbamate, prodrug common to mephenoxalone and paracetamol

In a 500 ml reactor, 11.5 g (32 mmol) of 4-acetamidophenyl carbonate and 1,2,2,2-tetrachloroethyl are dissolved in 235 ml of THF and 10 ml of H2θ. 6.30 g (32 mmol) of 3- (2-methoxyphenoxy) -1-amino-2-propanol dissolved in a minimum of THF are added dropwise at room temperature. 3.90 g of N, N-dimethylaminopyridine (DMAP, 32 mmol) are introduced and then the mixture is left under stirring for 4 h. The solvent is evaporated off under reduced pressure and the residue obtained is taken up in an ether-chloroform mixture (v / v: 1/2). The organic phase is washed 3 times with 3N HCl and then dried over MgSO4. After evaporation of the solvent, white crystals are obtained. Yield: 70%.

REPLACEMENT SHEET B - PRODROGUE OBTAINED

Formula: C19H22 2O6.M = 374.4 Pt F. 108 °: C Elementary analysis calculated C% 60.95 H% 5.92 N% 7.48 found 60.64 5.85 7.42

IR (KBr) and ¹ H NMR (DMSOdδ): Spectral characteristics similar to those described in Example 8.

REPLACEMENT SHEET

Claims

 2b CLAIMS 1 / - Prodrug capable of releasing an oxazolidinone in a physiological medium, characterized in that it comprises a hydroxycarbamate comprising the motif: 0 H II

2 / - Prodrug according to claim 1, capable of releasing a benzoxazolone, characterized in that it comprises the motif: 0 ^H II

3 / - Prodrug according to claim 2, characterized in that it comprises the motif: 0 H II

where R- | = 5 - Cl in order to be able to release the chlorzoxazone, or else R-j = 4 - C5H5C in order to be able to release the 0 6-benzoylbenzoxazolone. REPLACEMENT SHEET ùPt 4 / - Prodrug according to claim 1, characterized in that it comprises the motif: 0 ^» He

where R2 = 3.5 - (CH3Î2 in order to be able to release metaxalone, or else R = 2 - OCH3 in order to be able to release mephenoxalone. 5 / - Prodrug according to one of claims 1, 2, 3 or 4 capable of releasing both an oxazolidinone and an acetamidophenol, characterized in that it comprises the motif:

6 / - Prodrug according to claims 2 and 5 capable of releasing both a benzoxazolone and an acetamidophenol, characterized in that it comprises the motif:

7 / - Common prodrug with chlorzoxazone and paracetamol, in accordance with claims 3 and 6, REPLACEMENT SHEET characterized in that it has the following formula

8 / - Prodrug common to chlorzoxazone and to paracetamol capable of releasing these compounds with a retarding effect, characterized in that it has the formula defined in claim 7, in which the hydrogen atom of the hydroxyl group OH is replaced by an acyl, alkoxycarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl radical. 9 / - Prodrug according to claim 2, capable of releasing both a benzoxazolone and an aliphatic alcohol, characterized in that it comprises the motif: 0 ^H II

where R3 is an aliphatic radical, saturated or not. 10 / - Prodrug common to chlorzoxazone and ethchlorvynol according to claims 3 and 9, characterized in that it has the following formula: 0 CH ₌ CH Cl ^H II I

11 / - Prodrug common to chlorzoxazone and meparfynol, in accordance with claims 3 and 9, REPLACEMENT SHEET 23 characterized in that it has the following formula: 0 CH, CH, H || | ^{2 3}

12 / - Use of a hydroxycarbamate comprising the motif: 0 ^H II

for obtaining a medicament capable of releasing in vivo an oxazolidinone, in particular chlorzoxazone, 6-benzoyl-benzoxazolone, metaxalone or mephenoxalone. 13 / - Use of a hydroxycarbamate comprising the motif:

for obtaining a medicament capable of releasing in vivo both an oxazolidinone and an acetamidophenol, in particular paracetamol. 14 / - Use of the compound of formula:

for obtaining a medicament capable of releasing in vivo at REPLACEMENT SHEET 3) both chlorzoxazone and paracetamol. 15 / - Use of the compound of formula:

where R is an acyl, alkoxycarbonyl or alkyl or dialkylaminocarbonyl radical, for obtaining a medicament capable of releasing in vivo with a delayed effect of both chlorzoxazone and paracetamol. 16 / - Use of a hydroxyphenyl carbamate comprising the motif: 0 ^H II

where R3 is an aliphatic radical, saturated or not, for obtaining a medicament capable of releasing in vivo both a benzoxazolone and an aliphatic alcohol, in particular ethchlorvynol or meparfynol. 17 / - A method of manufacturing a prodrug according to one of claims 1 to 11, characterized in that one carries out a chlorocarbonylation reaction of an alcohol or a phenol using phosgene or a substitution derivative in order to prepare a chloroformate, the chloroformate obtained is condensed on a hydroxyamine having the motif:

or on a hydroxyaniline having the motif:

REPLACEMENT SHEET and isolating the hydroxycarbamate formed. 18 / - Process for the manufacture of a prodrug according to claim 5 comprising the acetamidophenyl radical, characterized in that the 1,2,2,2-tetrachloroethyl chloroformate is condensed on an acetamidophenol in an organic solvent, in particular tetrahydrofuran ( THF), in the presence of a base, in particular pyridine, in order to obtain acetamidophenyl carbonate and 1,2,2,2-tetrachloroethyl, this carbonate is condensed on a hydroxyamine having the motif:

or on a hydroxyaniline having the motif:

in an organic solvent, in particular THF and in the presence of a base, in particular pyridine, and the acetamidophenyl hydroxycarbamate obtained is isolated. 19 / - A method according to claim 18 for manufacturing the common prodrug according to claim 7, characterized in that the chloroformate of 1,2,2,2-tetrachloroethyl is condensed on 4-acetamidophenol (paracetamol) in a solvent organic, in particular tetrahydrofuran, in the presence of pyridine, the carbonate obtained is condensed on 5-chloro 2-hydroxyaniline, and the compound obtained is isolated. 20 / - Process for manufacturing the common prodrug according to claim 5, characterized in that the amino function of paraaminophenol is protected by means of a protective group, a chlorocarbonylation reaction of the compound obtained is carried out using phosgene or of a substitution derivative in order to prepare an alkoxycarbonylaminophenyl chloroformate, the amino group is deprotected from the chloroformate by means of an acid, an acetylation reaction of the compound obtained is carried out by means of a FE-t LLE DE RE LI ^' .isïEWT acetylating agent in order to obtain 4-acetamidophenyl chloroformate, this chloroformate is condensed on a hydroxyamine having the motif:

or on a hydroxyaniline having the motif

in an organic solvent in particular THF and in the presence of a base, in particular pyridine, and the compound obtained is isolated. 21 / - Manufacturing process according to claim 20, characterized in that the amino group is deprotected from chloroformate by means of gaseous hydrochloric acid. 22 / - Process for manufacturing the common prodrug according to claim 5, 0 characterized in that the amino function of p-aminophenol is protected by means of a protective group, a chlorocarbonylation reaction of the compound obtained is carried out by means phosgene or a substitution derivative in order to prepare an alkoxycarbonylaminophenyl chloroformate, this chloroformate is condensed on the hydroxyamine having the motif:

30 or on a hydroxyaniline having the motif

in an organic solvent, in particular THF, and in the presence of a base, in particular pyridine, in order to obtain a biscarbamate, the amino group is deprotected from this biscarbamate, an acetylation reaction of the hydroxycarbamate obtained is carried out using '' an acetylating agent, and the compound obtained is isolated. 23 / - Manufacturing process according to one of claims 20 or 22, characterized in that the amino function is protected by means of a protective group N-tert-butoxycarbonyl (BOC) by causing the compound to react with the diterbutyl dicarbonate. 24 / - Process for obtaining the delay effect prodrug according to claim 8, characterized in that the OH group of the prodrug according to claim 7 is functionalized by means of an acyl, alkoxycarbonyl, alkylaminocarbonyl or dialkylamino radical - carbonyl, by an acylation or alkoxycarbonylation or carbamoylation reaction. REPLACEMENT SHEET