NZ250409A

NZ250409A - [2-(2,6-dichlorophenylamino)phenyl]acetoxy acetic acid ester derivatives and pharmaceutical compositions

Info

Publication number: NZ250409A
Application number: NZ250409A
Authority: NZ
Inventors: Surroca Juan Jose Artus; Jane Lorenzo Rafecas
Original assignee: Prodesfarma Sa
Priority date: 1992-12-14
Filing date: 1993-12-10
Publication date: 1995-07-26
Also published as: PL175116B1; GR1002048B; ES2065242A1; PL301415A1; CA2111169C; PL174822B1; KR100196240B1; AU670139B2; ES2065242B1; CA2111169A1; HU9303551D0; HUT65711A; GR930100500A; AU5217793A; KR940014301A

Description

New Zealand Paient Spedficaiion for Paient Number £50409 250409 f-Ttcj/iiy Duie(a): iSw „ Complete Specification Filed: .'.9: !7,\?3 CIms: Publication Date: .. t. ?!??K P.O. Journal, No: . ...a^ NO DRAWINGS PATENTS FORM NO. 5 Our Ref: JB202508 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION ? lOOfCjgj PHENYLACETIC ACID DERIVATIVES, PROCESS FOR THE PREPARATION THEREOF AND CORRESPONDING USE We, PRODESFARMA S.A., a Spanish Joint-Stock Company of Carrer del Pont Reixat 5, 08960-Sant Just Desvern, Barcelona , Spain hereby declare the invention, for which we pray that a patent may be granted to us and the method by which it is to be performed, to be particularly described in and by the following statement: (followed by page la) PT0567750 1Q- 250 4 0 PHENYLACETIC ACID DERIVATIVES, PROCESS FOR THE PREPARATION THEREOF AND CORRESPONDING USE.

This invention relates to phenylacetic acid derivatives, particularly [2-(2,6-dichloroani1ino)phenyl]acetic acid, commonly known as diclofenac, a product known for its analgesic and antiinflammatory properties. The invention also relates to a process for the preparation of said derivatives and to a process for the use thereof in the preparation of [2—(2,6— dichloroani1ino)phenyl]acetoxyacetic acid, also known for its analgesic and antiinflammatory properties.

Diclofenac (formula I) is a product having analgesic and antiinflammatory properties, known since the 60's and which has been extensively used in sodium salt form orally, rectal-ly and parenteral 1y. In view of some of its adverse side effects (gastrointestinal problems, mainly) numerous attempts have been made to prepare diclofenac derivatives which, while maintaining or improving its analgesic and antiinflammatory properties, have weaker adverse side effects, or allow other forms of administration (e.g. topical). One of the diclofenac derivatives used in therapeutics is [2-(2,6-dichloroanilino)-phenyl]acetoxyacetic acid (formula II), described for the first time in 1984 (EP-P-0 119 932). Nevertheless, the design and preparation of agents having good analgesic and antiinflammatory properties, with little or no side effects and good ways of administration, is still a problem of interest in modern therapeutics.

DESCRIPTION STATE OF THE ART ( I ) (II) (foPowed by page 2) 0 4 0 The preparation of [2-(2,6-dichloroani1ino)phenyl]acet-oxyacetic acid of formula II suffers from the chemical drawback of obtaining a free carboxylic group in the presence of a carboxylic acid ester which has not to be modified. Two solutions have been proposed to solve this problem: (a) carry out hydrogenolysis of the formula II benzyl ester (EP-P-0 119 932), and (b) treat certain esters of the formula II ester with iodine trimethylsi 1ane, prepared in situ from chloro-methylsilane and anhydrous sodium iodide, in an inert atmosphere, using acetonitrile as solvent (ES-P-2 020 146). Such esters are prepared, in turn, from diclofenac by reaction in a heterogenous medium and phase transfer conditions (ES-P-2 020 145).

With regard to process (a), as mentioned in ES-P-2 020 146, the main drawback of the hydrogenolysis process lies in the need to have special equipment to handle the pressurized gases and the concomitant risk of the industrial use of hydrogen and catalysts. Furthermore, the viability of the method is restricted to the use of the formula II esters susceptible of hydrogenolysis and, more precisely, the benzyl ester.

Process (b) apparently represents a solution to the problems inherent in process (a), although chlorotrimethyl-si lane and sodium iodide, both relatively expensive, are used as reactants and acetonitrile, highly toxic, as solvent. Also, by-products or mixtures of solvents (acetonitrileyewater) are generated, with disposal problems.

It will be gathered from the foregoing that the preparation on an industrial scale of [2—(2,6-dichloroani1ino)phen-yljacetoxyacetic acid is still a serious technical problem.

DESCRIPTION OF THE INVENTION The object of the present invention are the tertiary alkyl esters of formula III and their pharmaceutically acceptable solvates, where R1 , R2 and R3 are the same or different and are either methyl, ethyl or propyl radicals; or R2 and R3, which are attached as shown by -(R2....R3)-, jointly form a —(CH2 )n — radical where n = 4 or 5. Excepted is the case where R1 = R2 = R3 = CH3. Particularly preferred are the product wherein R1 is methyl and R2 and R3 are both ethyl and 3 250 40 9 the product wherein R1 is methyl and R2 and R3 are jointly a —(CH2)5— radical. Also an object of this patent are the above products for use in therapy, particularly for use as analgesic or antiinflammatory agents.

Also an object of the present invention are the phai— maceutical compositions comprising a therapeutically effec-15 tive amount of one of the above products and adequate amounts of pharmaceutically acceptable excipients, as well as the use of said products for the manufacture of analgesic or antiinflammatory drugs. a process for the preparation of a tertiary alkyl ester of formula III or a pharmaceutical1y acceptable solvate thereof, where R1, R2 and R3 are the same or different and are either methyl, ethyl or propyl radicals; or R2 and R3, which are attached as shown by -(R2....R3)-, jointly form a -(CH2)n-25 radical where n = 4 or 5; comprising the reaction of a diclofenac sodium or potassium salt with the corresponding alkyl haloacetate of formula X-CH2-COO-CR1R2R3, where X is chlorine or bromine; the process being characterized in that the reaction is carried out in an homogenous medium, in the presence 30 of a aprotic solvent in which the starting compounds are soluble.

In a preferred embodiment of the above process, the sodium salt of diclofenac of formula I is reacted with a slight excess of the corresponding tertiary alkyl haloacetate 35 (e.g. chloroacetates of tert.-butyl, 1-ethyl-1-methylpropyl or 1-methylcyclohexyl), in the presence of a high polarity aprotic solvent (e.g. dimethylformamide). The reaction is carried out preferably at a temperature of 50 to 70°C. At the end of the reaction, it is allowed to cool to room tempera- (III) It is also an object of the present invention to provide -4- 25040 ture and an excess of water is added, whereby the major poi— tion of the desired product precipitates out and is thereafter separated by filtration. After purification by recrys-t,allization in aliphatic hydrocarbon type solvents (e.g. petroleum ethers), very pure products with a defined melting point are obtained.

Further to their intrinsic therapeutic utility, the formula III tertiary alkyl esters are also useful as synthesis intermediates for the preparation of [2-(2,6-dichloro-10 ani1ino)phenyl]acetoxyacetic acid of formula II, commercially used as analgesic and antiinflammatory agent. Thus, also an object of this invention is a process for the use of the formula III derivatives for the preparation of the formula II acid from a formula III tertiary alkyl ester or a solvate 15 thereof, where R1, R2 and R3 are methyl, ethyl or propyl radicals; or R2 and R3, which are attached as shown by-(R2....R3)-, jointly form a -(CH2 )n- radical where n = 4 or 5; this process of use being characterized in that the foi— mula III tertiary alkyl ester is treated with an acid or 20 mixture of acids in a solvent. In preferred embodiments of this process, the reaction is carried out in an anhydrous medium, the acids used are trif1uoroacetic, formic, acetic, sulphuric, hydrochloric, methane sulphonic, p-toluene sulphonic or sulphonic acids bonded to perf1uorinated resins and 25 the solvent is the acid or mixture of acids itself or is of the hydrocarbon type (e.g. toluene), halogenated hydrocarbon (e.g. chloroform or methylene chloride), ketone (e.g. methyl-ethylketone, or methylisobutylketone) or ether (methyltert.-butylether or dioxane). Particularly preferred is the case 30 in which the starting product is R1 = R2 = R3 = CH3.

Under the preferred reaction conditions, the formula III tertiary alkyl ester is reacted at a temperature ranging from -10°C to the reflux temperature of the solvent; small amounts up to large excesses of acid (e.g. using the acid or mixture 35 of acids itself as solvent) are used. A preferred process for the isolation of the product consists of adding an excess of water at room temperature to dilute the acid used, after having concentrated the solvent used, when necessary, to separate the end product by filtration and washing with water or an appropriate solvent. If the reaction is carried out with an acid bonded to a resin, in the first place said resin is removed by filtration under solubility conditions of the reaction product. The last stage of the process consists of 5 purifying the product by recrystal1ization in an appropriate solvent (e.g. a hydrocarbon or an ester).

Unlike the process for the preparation of [2-(2,6-dichloroani 1ino)phenyl]acetoxyacetic acid described in ES-P-2 020 146, which uses alkyl (straight or branched chain) or 10 arylalkyl esters as starting products, the process of the invention is specific for tertiary alkyl esters. Thus, unlike the methyl (-COOCH3), primary alkyl (-COOCH2R), secondary alkyl (-C00CHR2), monoarylalkyl (e.g. -COOCH2Ar) and other possible esters, the formula III tertiary alkyl esters in-15 volved in the process of the invention undergo, in a highly specific way, an elimination reaction by treatment with acid, preferably in an anhydrous medium. In the particular case of the process for the preparation of [2-(2,6-dichloroani1ino)-phenyl]acetoxyacetic acid (II), this high specificity is 20 extremely useful, in view of the presence in the molecule of (II) of a primary alkyl ester group which does not have to be modified. Thus, the process of the present invention allows the formula II acid to be prepared with very high yields (over 90% in some cases), with an extraordinary puri-25 ty. Furthermore, the reactants used are common, low-cost acids and the by-products of the elimination are alkenes, non toxic and easily removable (volatile). Other notable advantages afforded by this process are its easy conversion to industrial scale production and the gentleness and safety of 30 its reaction conditions, which are neither dangerous nor involve complex technology.

EXAMPLES Example 1: Preparation of tert. butyl T2-(2.6-dichloroani1i-no)phenv11acetoxv acetate (Formula III where R1 = R2 = R3 = 35 CH3 ) grams of sodium diclofenac were dissolved in 70 ml of dimethylformamide (DMF) under a nitrogen atmosphere and the temperature was raised to between 50 to 70°C. Then 5.6 g of tert. butyl chloroacetate were added and the reaction was 0 4 0 9 continued at the same temperature for 2 hours. The mixture was allowed to cool down to room temperature and an excess of water was added. The product obtained was filtered and dried, to give tert. butyl [2-(2,6-dichloroanilino)phenyl]acetoxy 5 acetate, with an 89% yield. Melting point: 89.5-91.5"C (re-crystallized from petroleum ether).

Example 2: Preparation of 1-ethvl-1-methylpropyl [2-(2.6-dichloroani1ino)phenv11acetoxy acetate (Formula III where R1 10 = CHs and R2 = rs = CH2CH3) Operating in a similar way to Example 1, but replacing the tert. butyl chloroacetate with 1-ethy1-1-methylpropyl chloroacetate (previously prepared according to the synthesis method described in Org. Synth. Coll. Vol. Ill, p. 14-2-4), 15 the title product was obtained with m.p. 78.5-80*C.

Example 3: Preparation of 1-methylcyclohexvl f2-(2.6-dichloroani 1ino)phenvllacetoxv acetate (Formula III where R1 = CH3 and -(R2 ,R3 )- = -(CH2)5-) Operating in a similar way to Example 1, but replacing the tert. butyl chloroacetate with 1-methylcyclohexyl chloroacetate (previously prepared according to the synthesis method described in Org. Svnth. Coll. Vol. Ill, p. 142-4), the title 25 product was obtained with m.p. 60-62*C.

Example 4: Preparation of T2-(2.6-dichloroani1ino)phenv11-acetoxvacetic acid (II) 10 g of tert. butyl [2-(2,6-dichloroani1ino)phenylJacetoxy acetate were stirred under nitrogen in 37 g of trifluoro-acetic acid at room temperature. After one hour's stirring, the mixture was concentrated by evaporation at reduced pressure and the residue was dispersed in water. After filtra-35 tion, washing and drying at 40"C, the title product was obtained with a 76% yield. Melting point 149.5-151*C (recrys-tallized from toluene).

In a similar test, treating 10 of tert. butyl [2-(2,6-dichlo- 2 5 0 4 0 £ roani1ino)phenyl]acetoxy acetate with 34 g of anhydrous formic acid at 50"C for 2 hours, the title product was obtained with a 9156 yield.

Claims

WHAT WE CLAIM IS:

1. Phenylacetic acid derivatives of formula III CH2-C00-CH2-C00-C-R2 — *3 1 (III) I 2 and their pharmaceutical^ acceptable solvates, where R , R 3 and R are the same or different and are either methyl, ethyl 2 3 or propyl radicals; or R and R , which are attached as shown 2 3 by -(R ....R )-, jointly form a -(CH«) - radical where n = 4 1 2 3 or 5, with the exception of the case where R = R = R = CH^. 1 2 3

2. The derivative of claim 1 where R is methyl and R and R are both ethyl. 1 2 3

3. The derivative of claim 1 where R is methyl and R and R are jointly a -(CHj)^- radical,

4. The use of phenylacetic acid derivatives of formula III CH2-C00-CH2-C00-C-R2 — (III) 12 3 where R , R and R are the same or different and are either 2 3 methyl, ethyl or propyl radicals; or R and R , which are 2 3 attached as shown by -(R ....R )-, jointly form a "(C^^n" radical where n = 4 or 5, for the preparation of pharmaceutical compositions.

5. The use of claim 4, wherein said pharmaceutical compositions are analgesics or antiinflammatories.

6. A pharmaceutical composition comprising (a) a therapeutically effective amount of a phenylacetic acid derivative of formula III ?i ^\^CH2-C00-CH2-C00-C-R2 — (III) 12 3 where R , R and R are the same or different and are either 2 3 methyl, ethyl or propyl radicals; or R and R , which are 2 3 attached as shown by -(R ....R )-, jointly form a -(CHj)^ radical where n = 4 or 5, and (b) adequate amounts of pharmaceutically acceptable excipients.

7. A pharmaceutical composition as claimed in claim 6 which comprises a phenylacetic acid derivative wherein R1 is methyl 2 3 and R and R are both ethyl.

8. A pharmaceutical composition as claimed in claim 6 which comprises a phenylacetic acid derivative wherein R* is 2 3 methyl and R and R are jointly a ~(CH2)5~ radical. - 10 - "'(.4 09

9. A process for the preparation of phenylacetic acid derivatives of formula III • (III) 1 2 and their pharmaceutical^ acceptable solvates, where R , R 3 and R are the same or different and are either methyl, ethyl 2 3 or propyl radicals; or R and R , which are attached as shown 2 3 by -(R ....R )-, jointly form a -(CH2)n~ radical where n = 4 or 5, comprising the reaction of a sodium or potassium salt of [2-(2,6-dichloroanilino)phenyl]acetic acid with an alkyl haloacetate of formula X-CHj-COO-CR^R^R^ wherein R*, R^ and are as defined in this claim, where X is chlorine or bromine; characterized in that the reaction is carried out in a homogenous medium, in the presence of an aprotic solvent in which the starting compounds are soluble.

10. The process of claim 9, wherein said reaction is carried out with a slight excess of said alkyl haloacetate.

11. The process of claim 9 or claim 8, wherein said aprotic solvent is highly polar. 2 *51 -~?j » I *" J £ 1" $ * ^s?s £ * **4 ? i ~"~° 3 v - 11 -

12. A process of use of the phenylacetic acid derivatives of formula III 12 3 where R , R and R are the same or different and are either 2 3 methyl, ethyl or propyl radicals; or R and R , which are 2 3 attached as shown by -(R ....R )-, jointly form a radical where n = 4 or 5, for the preparation of [2-(2,6-dichloroanilino)phenyl]acetoxyacetic acid, characterized in that said formula III derivatives are treated with an acid or mixture of acids in a solvent.

13. The process of claim 12, wherein said treatment is carried out in an anhydrous medium.

14. The process of claim 12, wherein said acids are trifluoroacetic, formic, acetic, sulphuric, hydrochloric, methane sulphonic, p-toluene sulphonic or sulphonic acids bonded to perfluorinated resins.

15. The process of claim 12, wherein said solvent is the acid or mixture of acids itself or is of the hydrocarbon, halogenated hydrocarbon, ketone or ether type. 2?"* , , A

U u -i II Q 1 ti? <rJ 12

17. A derivative of any one of claims 1-3, substantially as herein described.

18. A phenylacetic acid derivative of claim 1, substantially as described with reference to any one of the Examples.

19. A pharmaceutical composition of any one of claims 6-8, substantially as herein described.

20. A process of any one of claims 9-11, substantially as herein described.

21. A process of any one of claims 12-16, substantially as herein described.

22. A process for the preparation of phenylacetic acid derivatives of formula III as defined in claim 1, substantially as described with reference to any one of the Examples.