Title of Invention

NOVEL GEM-DIFLUORO DERIVATIVES OF PHENYLACETAMIDE AND PROCESS FOR PRODUCTION THEREOF

Abstract

The present invention relates to a compound having a formula: wherein: R<sub>1</sub> can be hydrogen, acyl or acyl substituted; R<sub>2</sub> is hydrogen, lower alkyl, lower alkyl substituted, nitro, halogen, methylenedioxy, trifluoromethyl or OR'; Y is oxygen, sulfur or NR" R<sub>3</sub> is hydrogen, lower alkyl, lower alkyl substituted, phenyl, aryl group substituted or metal selected of the group consisting of sodium, potassium, calcium, magnesium, zinc or aluminum; R' and R" are hydrogen, lower .alkyl, lower alkyl substituted, phenyl or aryl substituted; and (a) "lower alkyl" means a straight or branched hydrocarbon chain of from one to four carbon atoms; (b) in the group lower alkyl substituted, one or more the hydrogen atoms are substituted by lower alkyl, lower alkyl substituted, phenyl or aryl substituted (c) in the group aryl substituted, one or more of the hydrogen atoms are substituted by lower alkyl, halogen, nitro, trifluoromethyl or OR'; (d) in the group acyl substituted, one or more of the hydrogen atoms are substituted by lower alkyl, lower alkyl substituted, phenyl or aryl substituted.

Full Text

The present invention relates to new fluorinated phenylacetic and phenylacetamide derivatives and its uses as non-steroidal-antiinflammatory - and antirheumatic agents, having analgesic and antipyretic activities which are useful for the treatment of all pain disorders associated to inflammatory and/or rheumatic diseases. It is well known that many compounds of general formula (I) having a phenylacetic add skeleton present biological activity as antiinflammatory and antirheumatic agents. Besides the antiinflammstory effect most of the compounds in this class have also analgesic and antipyretic activities. Some examples of such substances are diclofenac, flurbiprofen and ibuprofen (Roth, H.J. and Kleemann, A., "Pharmaceutical Chemistry", Vol. 1, Pp. 92-93, John Wiley and Sons, Chichester, r988). US 5,220,064 describes substituted 4'-hydroxy phenylacetic acid and phenylacetamide derivatives having antiinflammatory and analgesic activities. Among the compounds induded in the definition of formula ! of the patent inere are the following: wherein R2 could be hydrogen or lower alkyl, B could be but X must be hydrogen or lower alkyl, i.e. X can not be halogen. Moreover, X is never a gem-difluoro group. Also the aromatic nng always has hydroxyl group at para position. FR 2,499.981 descabes a-synthesis of phenylacetic acid derivative obtained by basic hydrolysis of 7-benzoyl-methylindol-2-one with general formula as followed: Wherein Ri is always methyl and X is hydrogen, never a gem- Important differences in biological activity may commonly be expected based on the difference in eletcoriesgity betiasi ftuonjae and hydrogen ss w as the higner C-F bond strength versus It© aigth of the C-tt toid. In ascfciton, ss a conseqLc.tce of the electron dsrasty, fluorine can function as hydrogen bond acceptor at the active site (Libman, J.F; Greenberg, A. and Dolbier Jr., W.R. "Fluorine Contain Molecules", VCH Publishers, New York, 1988). Indeed, a great variety of biologically active compounds having the so-called ge/77-difluoro function (CF2). such as sugars, nucleic acids, prostaglandins, steroids, are known and have been described in: (i) Welch, J.T. Tetrahedron, 1987, 43, 3123; (ii) Welch, J.T. and Eswarakrishan, S., Fliorine in Bioorganic Chemistry", J.Wiley S. Sons., N. York, 1991. (iii) Barthwick, A.D et a/, J. Med. Chem. 1990 33, 179; (iv) Kornov, A.M. et a/, Tetrsii&tx: Asymmetry, 1995. 6, 199. Some α,α-difluorophenylacetic acids and α,α-difluorophenylacstamide derivatives were prepared by The selective replacernent of the a-oxo group from a- oxoarylacetates using DAST (diethy lamino sulfur trifluoride) as fiuorinating-reagent (Middleton. W.J. and Bingham. E.M.,J. Org. Chem., 1980, 45. 2883-2887). According to Middleton and Bingham, it could be expected some change on the biological actvity when" two fluorine atoms are introduced in α,α-difluoroarylacetic acid compounds. However, the type and\or intensity of the possible modifications are unpredictable as demonstrated by the examples presented. The difluoro analogue (α,α-difluoro-4-isobutyl-phenylacetic acid) of the synthetic antiinflammatory drug ibufenac (4-isobutyl-phenylacetic acid) prepared by the authors was essentially inactive as an antiinflammatory agent, while the difluoro analogue {α,α-difluoro-a-naphthylacetic acid) of the plant-growth regulate (a-naphthylacetic acid) had a comparable biological activity. Isatins (indol-2,3-diones) of general formula (II) are versatile starting materials for a variety of other important classes of heterocyclic compounds. They can be easily prepared from inexpensive and available anilines (Holt, J.S. et al, J. Chem. Soc, 1958, 1217; Huntress, E.H. et al, J. Am. Chem. Soc, 1949, 71. 745; Maginnity, P.M. et al, J. Am. Chem. Soc, 1951, 73, 3579). Isatins have two different carbonyl groups, the C-3 carbon having a strong ketonic character and, thus suitble to react selectively with DAST (diethylamino sulfur trifiuoride), a speafic reagent for nudeophilic addition to ketone and aldehyde carbonyls, to give gem-difluoroindoles. Tb overcome the difficulties in producing synthetic antiinflammatory and antirheumatic agents with high yields and high biological activities, the present invention provides a process to synthesise novel gem-difluoro derivatives of phenylacetic acid and phenylacetamide from of the fluorination of isatins with DAST and subsequently reaction with alcohols, thiols, water, hydroxides solutions and amines, with concomitant opening of heterocycilc ring. The present invention relates to novel compounds of a formula: wherein: R1 can be hydrogen, acyl or acyl substituted; R2 is hydrogen, lower alkyl, lower alkyl substituted, nitro, halogen, methylenedioxy. trifluoromethyl or OR', Y is oxygen, sulfur or NR"R"'; R3 is hydrogen, lower alkyl, lower alkyl substituted, phenyl, aryl group substituted or metal selected of the group consisting of sodium, potassium, clciu magnesium, zinc or aluminum; R", R'and R"" are hdrogen, lower alkyl, lower alkyl substituted, phenyl or ary! substituted. The terms herein employed have the followrng mesaiings: - "lower alkyf means a straight or branched hydrocarbon chain of from one to four carbon atoms; - "lower alkyl substituted" means the subtution of cme- of mcHB of the hydrogen atnms by lower atkyi, lower alkyl substituted, phenyl or aryl - "aryl substituted" means ttie substilution of one or more of the trydrxogen atoms by lower alkyl, halogen, nitro, trifluoromethyl or OR'; - "halogen" means fluoro, chloro or bromo; - "acyl substituted" means the substitution of one or more of the hydrogen atoms by lower alkyl, lower alkyl substituted, phenyl or aryl substituted. According to the present invention, compounds of formula IV are prepared in two steps: the first is the reaction of an isatin with DAS and, the is (i) a solvolysis of the product of the first step, ttie gem-dfajorcxdndoi (111), with water, metaljc hydroxides, alcohds or thiols, or (ii) reaction with amines. The metalic hydroxrdes can have the cation used in pharmaceutical—compounds (sodium, potassium, calcium, magnesium, zinc or aluminium). These reaction steps can be - reoresented as-foltows: DETAILED-BESCRPnCl>A OF TH£ MaXHa The selective fluorination of isatins followed by the opening of the heterocyclic ring" is a new ri rnterestij apijjuadr to paaie tmpiitant phTTvacjtica! compotmcfe a, a-c6fltiorop hej-iylacet ic sasi Tterojves and a.a-dtfluorophenylacetamide derivatives. The reaction of isatin or substituted isatins with PAST is carried out by contacting directly the reagents at 60°C in the absence of solvent or, at room temperature in the presence of solvents such as CH2CI2 or CCI4. The product is the correspondent indol compound. Isatins used in the present invention have differert groups attached at hefterocycltc atom and/or at the aromatic ring-In the f-esait invention, it was found the ribKteophfficity of C-2 of indol compounds is enhanced by the presence of the gem-dtflyoro oup, aiding the further reaction of the indol compound. withthervneakaiitM 1 Hjcteophtltc reagents with simultaneous opening of the heterocycHc nng. Indeed, 1-€K:etyl-2-oxp-3,3-difluoro-indol is highly reactive with nucleophilic solvents and, moreover, it reacts easily with" amines producing-gem-difluoro-phenylacetamide derivatives. The following examples are illustrative of the invention and represent preferred embodiments. Other modifications may be readily produced by suitable variations of the rpactions and of the substituent groups in the compounds. Example 1: Fluorination of Isatins with DAST: To a 100 ml two neck round bottom-flask containing 6,3 mmoles of isatin (or substituted isatins) dissolved in 15 ml of dichloromethane, were added 3,4 ml (25.3 mmoles) of DAST. The mixture was magnetically stirred at room temperature dunng 6 hours. The solution was cooled and 5ml of cold water were dropwise introduced into the flask. The organic phase was separated and washed twice with 5ml of cold water. The organic phase consisting on dichloromethane solution was dried under sodium sulfate and evaporated. Some of obtained difluoro derivatives are presented in table below: bxampie i: Synthesis of the gem-difluorophenylacetic acid, salt and ester derivatives The difluoro-2-oxoindol obtained in the precedent examples was dissolved in a suitable nucleophylic solution,e.g anhydrous alcohol or thiol or acetone/water or v\/ater hydroxide solution and the mixture was stirred at room temperature for 24 hours. The correspondent ester, thioester, acid or metalic salt was obtained, respectively. Example 3: Synthesis of the-gem-difluoroplTenjrtactamide derivatives To a 100 mj two neck round bottom flask was introduced 1g-(4,7mniuO of Acyl-difluoroxindole, 20ml of dichloromethane and 47 mmoles of the suitable substituted amine. The mixture was stirred at the room temperature for 2 hours, the organic phase was extracted three times with 10ml of HCI 0,6N followed by a washing step witb 10mi of water for three times. The product'was dried under sodium sulfate and the" solvent evaporated resulting in the corresponding α,α difluorophenylacetamide com'pound. Examples of antiinflammatory and antirheumatic agents with anaJgesic and antipyretic activities of the present invention indude, among oth«:s. ttre compounds erf Table 4. Some examples of preferred compounds are named in Table 5 below. Table 5; Some preferred compounds Included in general formula IV of the present invention: Comp. Compound Name (1) H-mypTop - (2) NnsDpropy -α,α-difluoro-2-(N-acetamide)-5-methylphenylacetamide (3) N-isopropyl -α,α-difluoro-2-(N-acetamide)-3-methylphenylacstamide "(4) N-isopropyl-α,α-difluoro-2-{N-acetamide)-5-nitro-phenylacetamide (5) N-isopropyl-α,α-difluoro-2-(N-acetamide)-5-chloro-phenylacetamide (6) N-isopropyl-α,α-difluoro-2-(N-acetamide)-3,5-dibromophenylacetamide (7) N-isopropyl-α,α-difluoro-2-(N-acetamide)-6-trifiuoromethylphenylacetamide 4 (8) N-isopropyl-α,α-difluoro-2-(N-acetamide)-3-trifluoromethylphenylacetamide (9) N-isopropyl-α,α-difiuoro-2-(N-acetamide)-4,5-methylenedioxiphenylacetamide (10) N-isopropyl-α,α-d!fluoro-2-(N-chloroacetamide)-phenylacetannide (11) N-isopropyl-α,α-difluoro-2-(N-benzoyl)=phenylacetamide (12) N-isopropyl-α,α-difIuoro-2-(N-4'-chlorobenzoyl)-phenylacetamide (13) N-isopropyl-α,α-difluoro-2-(N-2',4'-dichloroben2oyl)-phenylacetamide (14) N-isopropyl-α,α-difluoro-2-(N-2',6'-dichlorobenzoyl)-phenylacetamide (15) N-isopropyl-α,α-difluoro-2-(N-benzoyl)-5-methylphenylacetamide (16) N-isopropyl-α,α-difluoro-2-(N-benzoyl)-5-nitrophenylacetamide (17) N-lsopropyl-α,α-difiuoro-2-(N-4'-chlorobenzoyl)-5-methylphenylacetamide (18) N-sopropylKx,a-difluoro-2-(N-2\4' (19) i-Dpopyl-α,α-ciifIuoo-2■N-26'-cic±3T3tezc0-5-methyl (20) N-phenyl-α,α-difluoro-2-(N-acetarrHd€)-phenylacetamide (21) lhenylKx,a-difluoro-2-(N-ac2aTacte)-5-rnBitryDtytacet (22) N-ptTeriyl-α,α-difiuoro-2-(N-acetamida)-6-triliuQmmethyphenylacetamide (23) N-phenyl-α,α-difluoro-2-(N-2',6'-dichloiobgrrzDyl)-ptTenylacetainide (24) N-phsnyl-α,α-difluoro-2-( N-4"-dikaxjbeTZE)i1yiacam»de (25) NI-pteyj-Kx,a-fuo>2-(-a:gtaEgid3:HJflta ifl lytai ritfTTHde ;2B) t4-(4'-chlorophenyl)-α,α-difluoro-2-(N-acetamide)-ptienylacetamide ;27) N-(4'-chlorophenyl)-α,α-difluoro-2-(N-acetamide)-5methylphenylacetamide 28 N-(4'-chlorophenyl)-α,α-diflL]oro-2-(N-acetamide)-5nitrophenylacetamide 29) N-(4'-chlorophenyl)-α,α-difluoro-2-(N-chloroacetamide)-phenylacetamide 30) N-(2,4-difluorophenyl)-α,α-difluoro-2-(N-acetamide)-phenylacetamide 31) N-(2,4-difluorophonyl)-α,α-difIuoro-2-(N-acetamide)-5-methyiphenylav>jtamide 32) N-(-2,4difluorophenyl)-α,α 33) N-{-2,4difluorophenyl)-α,α-difiuoro-2-(N-benzoyl)-ptienylacetamide 34) N-benzyi-a, ne-difltjQrQ-2-(N-benzoylV-phenylacetamide 35) N-benzyl-α,α-difIuoro-2-(N-acetamide)-phenylacetamide 36) N-benzyl-α,α-difluoro-2-(N-acetamide)-5-nitrophenylacetamid§ (3J) N-ben2yl-α,α-difluoro-2-(N-2',6'-dicl1lorobenzoyl)-phenylacetamide (38) α,α-difluoro-2-(N-acetamide)-phenylacetic acid (39) α,α-difluoro-2-(N-acetamide)-3-methylphenylacetic acid (40) α,α-difIuoro-2-(N-acetamide)-5-chlorophenylacetic acid (41) a, a-difluoro-2-(N-acetamide)-5-nitrophenylacetic acid (42)_ a.a-difluoro-2-(N-acetamide)-6rtrifluoromethylphenylacetic acid (43) α,α-difiuoro-2-(N-chloroacetamide)-3-methylphenylaceticacid (44) α,α-difluoro-2-(N-chloroacetamide)-5-chlorophenylacetic acid (45) α,α-difiuoro-2-(N-ch!oroacetamide)-5-nitrophenylacetic acid (46) α,α-difluoro-2-(N-chloroacetamide)-3,5-djbromophenylacetic acid (47) α,α-difiuoro-2-(N-ben2oyl)-5-nitrophenylacetic acid (48) α,α-difluoro-2-(N-ben2oyl)-5-chlorophenylacetic acid (49) α,α-difluoro-2-(N-benzoyl)-3-methyiph«iy»tic acid (50) α,α-difluoro-2-(N-benzoyl)-6-tniyiJiJgifciy)haTylarat!C acid (51) α,α-difluoro-2-(N-2',4'-didilorobenzoy!)-phenylacetic acid (52) α,α-difluoro-2-(N-2',6'-dii:hlord3STZoHienyfacetic add (53) α,α-difiuoro-2-(f'-ctTlnrDtenzDyl)iDfTenylacefe add (54) α,α-difIuoro-2-(N-4'-chloiQbenzDyl)-5-nitraphenytacetic acid (S) methyl α,α-difiuoro-2-(N-acetarnide)-pterp»flacetB (55) methyl a.a-difluoro-2-(N-acetam]iJ&)-5TitiviphsTyteteiB () methyl α,α-difluoro-2-(N-acetamide)-5-Pritrophenylacetate (59) methyl α,α-difluoro-2-(benzoyl)-phenylacetate (60) methyl α,α-difIuoro-2-(N-4'-chlorobenzoyl)-phenylacetate (61) Methyl α,α-difluoro-2-(N-2',4'-dichlorobenzoyl)-phenylacetate (62) Methyl α,α-difIuoro-2-(N-2',6'-dichlorobenzoyl)-phenylacetate (63) «thyl a,cc-difluoro-2-(N-acetamide)-phenylacetate (64) ethyJ α,α-dtfluofo-2-(N-4'-chlorobenzoyl)-phenylacetate (65) ettryl α,α-difluoro-2-(N-2',4'-dichiorQhenzoyO-ptienylactate (66) isopropyl α,α-difluofo-2-(N-2',6'-dicWorobenzoyi)-phef!ytacetate (67) Isopropyl α,α-difiuoro-2-(N-acetamide)-phenylacetate (68) Isopropyl α,α-dif1uoro-2-(N-4'-chlorobenzoyl)-phenylacetate (69) Isopropyl α,α-difluoro-2-(N-2',4'-dichloroben2oyl)-phenylacetate (70) Isopropyl α,α-clifluoro-2-(N-2',6'-dichlorobenzoyl)-phenylacetate (71) nbuthyl α,α-clifIuoro-2-(N-acetamide)-phenylacetate (72) nbuthyl α,α-difluoro-2-(N-4'-chlorobenzoyl)-phenylacetate (73) nbuthyl α,α-difluoro-2-(N-2',4'-dichlorobenzoyl)-phenylacetate (74) nbuthyl α,α-difluoro-2-(N-2',6'-dichlorobenzoyl)-phenylacetate (75) sodium α,α-difluoro-2-amino-3-methyl-phenylacetate (76) sodium α,α-difluoro-2-amino-phenyiacetate (77) sodium α,α-difluoro-2-amino-5-methyl-phenylacetamide (78) potassium α,α-difluoro-2-amino-5-nitro-phenylacetate (79) potassium α,α-difluoro-2-amino-5-chloro-phenylacetate (80) potassium α,α-difIuoro-2-amino-6-trifluoromethyl-phenylacetate Example 4: Antinflammatory assay (cell migration and protein extravasation): Forty four mate Swiss mics (20-30 g), from our own coiony, were lodged in a room with controlled temperature (23 - 2*C) and lighting (lights on from 7:00 to 19:00h), with free access to lab chow and tap water. induction of pleurisy mate mice (2D-25 g) were treated orally with 50-200 mg/kg of the compounds, 1 hour before the inflammatory stimullus. Pleurisy was induced by the tecnique of Specter (1956), modified for mice as teached by Henriques et al., (1990). Briefly, an adapted needle (13X5 gauge) was carefully inserted 2 mm through the parietal pleura into the right side of the thoracic cavity, under light ether anaesthesia, to enable a 50 ul injection of either carrageenan (300mg cavity-1) or sterile saline in contrel groups. The animals were killed 4 h alter injection carrageenan.Their thoracic cavities were washed with 1 ml of PBS containrng heparin (20 iu ml-1) and the fluid lavage collecd for assessement of leukocyte accumulation and Evans blue extravasation. Leucocyte counts The pleural lavage fluid collected was diluted 40 times in Turk's solution and total leukocyte counts were made in Neubauer chambers under light microscopy. Differential leukocyte counts were determined in cytocentrifuged smears stained with May-Grunwald-Giemsa dye using an oil immersion objective (100x). Protein extravasation For these experiments, mice were given an intravenous injection of Evans blue (25 mg kg-1) 24 h before the inflammatory stimulus. The pleural lavage fluid was collected at the same times and as described above, centrifuged (2,500 rpm for 10 min) and the absorbance of the cell free supernatant was read in a spectrophotometer (Schimadzu, Japan) at 600 nm. Statistical analysis Results are presented as means + s.d.rneans and were statistically evaluated by analysis of variance followed by the Newman-Keuls-student t-test. The significance level was set at P Resuits: TotaJ leukocyte were inhibited from 3.44 ± 0.14 x 106 (carageenan injected group) to 1.68 ± 0.17x 106 (Compound: N-Isopropyd α,α difluoro 2 (N-acetamide) phenylacetamide (MG06)), 2.3 ± 0.56 (compound: N-Phenyl a.a-difluoro-2-(N-acetamide-)-phenylacetamide (MG07)), 2,43 ± 0.35 (compound: N-4' phnenyl α,α difluoro-2-(N-actamide)-phenylacetarmide (MG08). Neutrophils were inhibited from 1.93 ±0.46 x 106 (carrageenan group) to 0.28 ±0.03x106 (MG06), 0.57 ±0.12x106 (MG07), 0.49 ± 0.18 x 10® (MG08). Pre-treatment with MG06, MG07 or MG08 inhibited in 63%, 43% 45% respectively, the protein extravasation induced by intra-thoracic injection of carrageenan. CLAIM 1- A compound having a formula: wherein: R1 can be hydrogen, acyl or acyl substituted; R2 is hydrogen, lower alkyl, lower alkyl substituted, nitro, halogen, methylenedioxy, trifluoromethyl or OR'; Y is oxygen, sulfur or NR-R'"; R3 is hydrogen, lower alkyl, lower alkyl substituted, phenyl, aryl group substituted or metal selected of the group consisting of sodium, potassium, clcium, magnesium, zinc or aluminum; R', R'' and R''are hydrogen, lower alkyl, lower alkyl substituted, phenyl or aryl substituted; and (a) in the group C1-C4 alkyl substitued, one or more the hydrogen atoms are substituted by by lower alkyl, lower alkyl substituted phenyl or aryl substituted (b) in the group aryl substituted, one or more of the hydrogen atoms are' substituted by lower alkyl, halogen, nitro, trifluoromethyl or OR'; (c) in the group acyl substituted, one or more od the hydrogen atoms are substituted by lower alkyl, lower alkyl substituted, phenyl or aryl substituted. 2 • A compound according to claim 1 wherein Y is NR-R", R1 is acyl, acyl substituted and R2 is hydrogen, methyl, nitro, trifluoromethyl, methylenedioxy, fluoro, chloro, bromo or OR 3 - A compound according to claim 1 wherein Y is COOH with the provisos that Ri must be acyl or acyl substituted and R2 can not be 5-methl. 4 - A compound accordingJa claim 1 wherein Y is COOR' with the provisos that R1 is acyl substituted and R2 is hydrogen, methyl, nitro, trifluoromethyl. methylenedioxy," fluoro, chloro or bromo. 5 - A compound according to claim 1 wherein Y is OM, M being sodium, potassium, calcum, magnesium, zinc or aluminum with the provisos that R1 must be hydrogen and R2 is hydrogen, methyl, nitro. methylenedioxy, trifiuoromethyl, fluoro, chloro or bromo. 6 - A compound according to claim 2 wherein R1 is acetyl, R2 is hydrogen and R" is hydrogen and R'" is isopropyl. 7 - A compound according to claim 3 wherein R1 is acetyl and R2 is hydrogen. 8 - A compound according to claim 4 wherein R1 is acetyl, R2 is 5-Mehtyl and R' is methyl. 9 - A compound according to claim 5 wherein R2 is 3-Methyl and M is sodium. 10 - A process for producing a compound of formula: wtTerein Ri, R2, R3 and Y are as ctefined in claim 1, which process uai'pises tte (a) reacting indol-2,3-dione or iTTdDl-2,3-diune having Ri and R2 as substituents with diettiylamino sulfur trifluoride to obtain the correspondent gem-difiuoroMiiidal; araJ (ij) r&rfctir^the product of step (a) with a suitatile nudeophiUc r^i^ffrt ta c^n tte tTCterocyd' ring to obtain the correspoEElent ge/77-difIuoro de/.vative of ph^^^etic acid, its esters, salts and phenylacetamide. 11 - A process according to claim 10 wherein the step (a) is carried out at 60°C in the absence of solvent. 12 - A process according to claim 10 wherein the step (a) is carried out at room temperature in the presence of a suitable solvent. 13 - A process according to claim 12 wherein the suitable solvent is dichloromethane 14 - A process according to any one of daims 10 to 13 wherein the nucleophiiic reagent is ananhydnous alcohol, thid, a mixture of acetone and water or an aqueous solution to produce a compound as defined in claims 3 to 5. 15, A process according to any one of claims 10 to 13 wherein the nucleophlllc reagent is an amine optionally substituted to produce a compound as defined in claim 2. 16 - A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 as an active ingredient in admixture or otherwise associated with a pharmaceutically acceptable diluent or carrier. 17 - A pharmaceutical composition according to claim 16 wherein the active ingredient is N-lsopropyl α, α-difluoro-2-(N-acetamide)-phenylacetamide. 18 - A pharmaceutical composition according to claim 16 wherein the active ingredient is α, α-difluoro-2-(N-acetamide)-phenylacetic acid. 19 - A pharmaceutical composition according to claim 16 wherein the active ingredient is Methyl a, a-difIuoro-2-{N-acetamide)-5- Methyl-phenylacetate. 20 - A pharmaceutical composition according to claim 16 wherein the active ingredient is Sodium α,α-difluoro-2-amino-3- Methyl -phenlacetate. 21. A compound substantially as hereinbefore described. 22. A process for producing a compound substantially as hereinbefore described. 23. A pharmaceutical composition substantially as hereinbefore described .

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