GB2181728A - 4-(3-Thienyl)phenylalkanoic acids and derivatives and process for their preparation - Google Patents

Abstract

Novel non-steroidal, anti-inflammatory agents of 4-(3-thienyl)phenylalkanoic acids and derivatives and salts thereof having the general formula (I) are provided. <IMAGE> Also provided is a process for their preparation comprising subjecting corresponding nitriles to hydrolysis and conversion of substituents: wherein R1 is H or C1-4 alkyl and X is -COOR2, R2 being H, alkyl, aralkyl or dialkylaminoalkyl, ammonium or metal ion, or X is -CONH2, -CONHOH, tetrazolyl or hydroxymethyl.

Description

SPECIFICATION 4-(3-Thienyl)phenylalkanoic acids and derivatives and process for their preparation The non-steroidal anti-inflammatory agents are the drugs offirst choice in the treatment of acute and chronic inflammatory and arthritic disorders. Numerous enolic acids, arylacetic and arylpropionic acids and their derivatives have been reported in recent years as new non-steroidal anti-inflammatory agents. Although many of these have been shown to possess good activity, only a few like indomethacin, ibuprofen, phenylbutazone etc. have been commercially successful. Gastro - intestinal irritation continues to be the principal drawback of the most ofthese commercialiy available drugs.

Indomethacin is one of the most such active drugs but has a high incidance of gastrointestinal side effects, including bleeding and ulceration as well as causing head-aches, confusion our vertigo in about 15% of cases (British Medical Jo urnal.287 1983,41), similarly phenylbutazone another oldest and the most potent non- steroidal anti-inflammatory drug also suffers from serious drawback of gastric ulceration and haemorrhage, renal and hepatic damage. Bone marrow suppression also is another most serious adverse effect of phenylbutazone. (British Medical Journal, 287, 1983,41).

The present invention relates to new substituted phenylalkanoic acids and their derivatives which have pharmacological properties and can be used as anti-inflammatory and anti-arthritic agents having much larger margin of safety than the known indomethacin, ibuprofen or phenylbutazone and also as analgesic and antipyretic agents at low concentrations.

The present invention also relates to methods of preparation of these new compounds.

The compounds of the present invention are 4-(3-thienyl) phenylalkanoic acids derivatives which are new and more active than many ofthe commercially available non-steroidal anti-inflammatory drugs by providing effectiveness at relatively lower concentrations as well as satisfactory margin of safety.

The novel compounds ofthe present invention have been found to have the general formula la in which R1 represents H ora loweralkyl group of 1-4 carbon atoms; R2 represents H oran alkyl group chain of 1-10 (un) branched carbon atoms like 'Me' or 'Et' etc.

oraralkyl group like'benzyl' or di(lower alkyl) amino loweralkyl group like dimethylaminoethyi ordimethylaminopropyl or pharmaceutically non -toxic ion which includes ammonium, alkali metal, alkaline earth metal etc. of H+ in salts of the parent acids with the biologically acceptable organic bases like lysine etc. or OR2together in COOR2functionforming groups like amide (CONH2) or hydroxamicacid (CONHOH) orwhere COOR2 is replaced by biologically equivalent groups like tetrazolyl, hydroxymethyl (CH2OH) etc.

The structures of the compounds described in this invention are determined,bytheir methods of synthesis and corroborated by IR, NMR, UV and Mass spectral analyses and by the correspondence of calculated and found values of elemental analyses ofthe respective elements.

The compounds ofthe present invention ofthe general formula la are crystalline and sparingly soluble or soluble in water. They can be isolated from the reaction mixtures by pouring them into ice-cold water,fol lowed by extraction with common organic solvents like ether, ethyl acetate, CHC13, CH2Cl2 etc. The com- pounds may be purified by recrystallization from normal solvents like EtOH, ethyl acetate, CHC13, hexane etc.

or by chromatography over silica gel or alumina etc., followed buy elation with organic solvents in theincreas- ing order of their polarity.

The compounds of the present invention of the general formula I possess a high degree ofanti- inflammatory and anti-arthritic activities and are of value in the treatment of arthritic disorders. In addition, compounds ofthis invention have a useful degree of analgesic and antipyretic activities. The substances used for comparison are the commercially available nonsteroidal anti-inflammatory drugs namely phenylbut azone, and indomethacin. Some of the compounds of the present invention show superior activity to these known drugs.Thus, for example, the oral effective dose (ED50) of methyl-4-(3-thienyl)phenyl-(x-methyl acetate (Formula I,R1 = R2 = Me) against established adjuvant polyarthritis in rats (B.B.Neubould, Brit J.Pharmacology, 35, 1969,487) is 4.0 mg/kg and is eight times more potent than phenylbutazone but is one third as active as indomethacin. The anti-inflammatory activity of the above compound against carrageenin induced oedema in rats as assessed by Winter's method (C.V. Winter, E.A. Risk lay and G.W. Nuss, Proc. soc. Exp. Biol. Med., 111, (1962),544) is found to be six times more than that of phenylbutazone but one third of that of indomethacin, the ED50 value of the above typical compound being 7.6 mg/kg (p.o.).

The ulcerogenic dose (UD50) ofthis compound in rats (E. Marazsi etal;Arzneim,Forschi: 22, 1972, 191) is 180 mg/kg (p.O.) which is approximately 2.5 times and thirty times morethan that of phenylbutazone and indomethacin respectively. Thus, this compound possesses better safety margin than phenylbutazone and indomethacin.

The analgesic activity was studied in mice by acetic acid induced Writhing method (R. Koster, M. Anderson and E.J. De Beer, Fed. Proc., ia 1959,412) and phenylquinone-induced Writhing method (E.A. Siegumund, R.A. Cudmas and Lu, G. J. PharmacolExp. Ther-1 191957, 184). The ED50 values of the typical compound mentioned above, in these tests, are 30.0 mg/kg (acetic acid-induced Writhing test) and 5.75 mg/kg (Phenylquinone- induced Writhing method) as compared to that of 37.5 and 31.25 mg/kg, for phenylbutazone and 1.6 and 2.48 for indomethacin.

In addition to this, the above compound possesses highly significant antipyretic activity in albino rats (U.M.

Teatino, L.P. Friz, A. Gandini and D. Delia Bells,J. Med. Chem. 6, 1963,248 by showing dose-dependent reduction in yeast-induced hyperpyrexia at doses of 2.5 - 20 mg/kg (p.o.).

The acute toxicity (Single dose, seven days observation) of the typical compound is 3,690 and 2,330 mg/kg (p.o.) in mice and rats, respectively.

Thus according to this invention there is provided 4-(3-thienyl) phenylalkanoic acids and their derivatives having the general formula I in which R1 represents H or a lower alkyl group of 1-4 carbon atoms; R2 represents H oran alkyl group chain of 1-10 (un) branched carbon atoms like (Me' or'Et' etc. oraralkyl group like 'benzyi' ordi(lower alkyl) amino lower alkyl group like dimethylaminoethyl or dimethylaminopropyl or pharmaceutically non toxic ion which includes ammonium, alkali metal, alkaline earth metal etc. or H+ in salts of the parent acids with the biologically acceptable organic bases like lysine etc. or OR2 together in COOR2function forming groups like amide (CONH2) or hydroxamic acid (CONHOH) or where COOR2 is replaced by biologically equivalent groups like tetrazolyl, hydroxymethyl (CH2OH) etc.

According to the additional feature ofthis invention,the novel compounds are prepared by simple reactions.

Thus, the process for the preparation of the compounds ofthis invention is carried out in two stages which comprises in the preparation of 4- (3-thienyl) phenylalkyl nitriles and then the conversion of these nitriles in a second stage to the desired phenylalkanoic acids and their derivatives.

The intermediate nitrile viz. 4- (3-thienyl) - phenyl-acetonitrile is a stable compound and itself is prepared from the corresponding 4-(3-thienyl)-benzyl halide such as bromide which in turn is obtained from the well known corresponding 3-(p-tolyl) thiophene by reaction with necessary halogen substituted succinimide like N-bromosuccinimide. Alkylation of the above nitrile gives the corresponding a-alkyl acetonitriles.

Thus it is possible to start witch a known thiophene, reactthe same with, for example, N - bromosuccinimide to obtain the corresponding bromide, thereafter convert the said bromide to the corresponding acetonitrile by reaction with alkali metal cyanide and thereafter, when desired, alkylate the acetonitrile using appropriate alkyl halide or dialkyl sulfate to give the corresponding a alkyl acetonitriles which are subsequently hydro- lysed to give acids of the present invention. The acids can be converted into their derivatives in well known manners.

Further process details ofthe invention are explained in the following paragraphs : Thus, there is provided a process for the preparation of 4- (3-thienyl)phenylacetonitrile of general formula III wherein R7 is H and is CN, which comprises in subjecting 3-(p - tolyl) thiophene (A. Chrzaszozeweka, Roczniki- Chem.Q 5, 33 (1925);CA20 1078(1926)) offormula II to reaction with N-bromosuccinimide in a non- polar organic solvent like aromatic hydrocarbon e.g. benzene or halogenated hydrocarbon like CCI4.

followed bytreatmentofthe resulting 4-(3-thienyl) benzyl bromide offormula III wherein R1 is H and Xis Br with alkali metal cyanamide like NaCN or KCN ina suitable organic solvent such as aromatic hydrocarbon like benzene or aliphatic lower alcohols like EtOH or halogenated hydrocarbon like CH2CI2 or alkyl nitriles like CH3CN in presence of an appropriate phase transfer catalyst (PTC) such astetraalkyl ammonium halides or hydrogen sulfate or benzyl trialkyl ammonium halides or crown ethers etc.

4-(3-Thienyl)benzyi bromide can also be converted into the corresponding acetonitrile by refluxing with NaCN or KCN in water miscible organic solvents such as aq.EtOH, aq.dioxan, aq-acetone etc. or in polar aprotic solvents like DMF or DMSO etc. without using the above mentioned phase transfer catalysts.

Further, when R1 of the compounds of formula I of this invention represents an alkyl group, 4-(3-thienyl) phenylacetonitrile prepared as mentioned above is subjected to alkylation with appropriate alkyl halide like (m) ethyl iodide or dialkyl sulfate such as Me2SO4 or Et2 S04 in dialkyl carbonate like di(m) ethyl carbonate in presence of an alkali metal alkoxide such as sodium (m) ethoxideto give the corresponding 4-(3thienyl)phenylalkyl nitriles offormula Ill, wherein R1 is a loweralkyl group of 1-4 carbon atoms and X isCN.

The above alkylation with alkakyl halide can also be carried out in a two phase system comprising ofwater and a suitable organic solvent in presence of an appropriate earlier mentioned phase transfer catalyst.

4-(3-Thienyl)phenylalkyl nitriles thus prepared are subsequently hydrolyzed by refluxing with mineral acids likeconc. Hct in acetic acid and/or water or with alkali metal hydroxides (NaOH, KOH etc) in aqueous or aqueous-alcoholic medium to furnish the corresponding 4(3-thienyl)-phenylalkanoic acids of formula I, wherein R1 is a loweralkyl group of 1-4 carbon atoms and R2 is H, whereafter, when desired, H of group in 4-(3-thienyl) phenylalkanoic acids offormula I, prepared as above, can be converted to alkyl group like'Me' using diazomethane or MeOH-H2SO4 orto 'Et' using EtOH-H2SO4 as alkylating reagents. The same esters can also be prepared by reacting the nitriles with appropriate alkanol in presence of mineral acid.

The nitrile, acid of ester functions, when desired, can be converted into amide, tetrazolyl, hydroxymethyl or other forementioned derivatives or salts by conventional methods.

According to this invention there is also provided a process for the manufacture of4-(3-thienyl)- phenylalkanoic acids and their derivatives having the general formula I in which R, represents H or a lower alkyl group of 1-4 carbon atoms;R2 represents H oran alkyl group chain of 1-10 (un)branched carbon atoms like 'Me' or 'Et' etc. or aralkyl group like 'benzyl' or di(lower alkyl) amino lower alkyl group like dimethylaminoethyl or dimethylaminopropyl or pharmaceutically non-toxic ion which includes ammonium, alkali metal, alkaline earth metal etc. or H+ in salts ofthe parent acids with the biologically acceptable organic bases like lysine etc. or OR2 together in COOR2function forming groups like amide (CONH2) orhydroxamic acid (CONHOH) or where COOR2 is replaced by biologically equivalent groups like tetrazolyl, hydroxymethyl (CH2OH) which comprises in subjecting 4-(3-thienyl)phenylalkyl nitrile oftheformula Ill wherein R1 is H ora lower alkyl group of 1-4 carbon atoms and Xis CN,to hydrolysis,followed by, when desired, subjecting the so obtained 4-(3-thienyl) phenylalkanoic acid of the formula I wherein R1 is as defined before and R2 is hydrogen, to reaction in a known mannerto convertthe 'H' ofthe 'COOH' grouptothe other meanings of R2 as herein defined, the salts being prepared in a known manner.

Some of the compounds that can be prepared according to the above process are the following 1. 4-(3-Thienyl) phenylaceticacid.

2. 4- (3-Thienyl) phenyl-a-methyl acetic acid 3. 5-[4-(3-Thienyl) benzyl]tetrazole 4. Methyl -4-(3-thienyl)phenyl acetate 5. Methyl 4-(3-thienyl )phenyl-a-methyl acetate 6. n-Octyl 4-(3-thienyl)phenyl- a methyl acetate 7. N, N-Diethylaminoethyl 4-(3-thienyl)phenyl- a - methyl acetate 8. Sodium 4-(3-thienyl)phenyl- a -methyl acetate 9. 4-(3-Thienyl)phenyl- a -methyl acetohydroxamic acid 10. 2-[4-(3-Thienyl) phenyl] propanol 11. 2-[4-(3-Thienyl) phenyl] propionamide The compounds ofthe present invention can be converted to pharmaceutically acceptable salts thereof in any known manner.

They can also be converted to useful preparations by combining with conventional pharmaceutical car riers, diluents and/or adjuncts thereof.

The invention will now be more fully described in the following examples which are only illustrative and are not limitative.

Example-I 4- (3- Thien ylj phenylacetic acid A) 4-(3- Thienyl)henzyl bromide: To a refluxing solution of 3-(p-tolyl)thiophene (34.8 8, 0.2 mol) and benzoyl peroxide (300 mg) in CCl4(400 ml) was added, portionwise, a mixture of N-bromosuccinimide (34.0 g, 0.191 mol) and benzoyl peroxide (300 mg). After the completion of the addition the reaction mixture was refluxed forfurthertwo hours.The cooled reaction mixture was filtered and the residue was washed with CC14. The combined CCl4filtrate was concentrated under reduced pressure and the crude residue was recrystallised from hexaneto yield 4-(3-thienyl) benzyl bromide m.p. 950; yield 45.4 g (89.72%).

B) 4-(3- Thien yl)phenylacetonftrile: To a solution of 4-(3-thienyl)benzyl bromide (25.3 g, 0.1 mol) thus prepared and tetrabutyl ammonium hydrogen sulphate (3.34g, 0.01 mol) in dichloroethane (100 ml) was added KCN (9.8 g, 0.15 mol) in 20 ml water and reaction mixture was heated at 80"C with vigorous stirring for 4 hours. The orgnic phase was separated, washed well with water, dried over anhydrous sodium sulphate and evaporated. The resulting crude product was chromatographed over silica gel and eluted with benzene. The benzene eluate on concentration gave pure4-(3-thienyl)phenylacetonitrile m.p. 125" (benzene-hexane); yield 17.2 g (86.43%).

C 4-(3- Thienyl)phen ylacetic acid: A mixture of 4-(3-thienyl) phenylacetonitrile (9.95 g, 0.05 mol), acetic acid (125 ml) and concentrated HCI (125 ml) was refluxed with stirring for 6 hours. Acetic acid was removed under reduced pressure, the reaction mass was poured into ice water and the resulting solid was filtered under suction, disssolved in aqueous sodium bicarbonate, filtered and the bicarbonate layer was acidified with concentrated hydrochloric acid.

The separated crude acid was collected and recrystallised from ether-hexaneto yield pure4-(3 thienyl)phenylacetic acid as colourless shining crystals, m.p. 1940; yield 8.0 g (73.4%).

Example-2 4(3- Thienyl)phenyl- a -methyl acetic acid A) 4(3- Thienyljphenyl- a -methylacetonitrlle; Dry sodium methoxidewas prepared by dissolving sodium (5 g, 0.22 g. atom) in absolute methanol (60 ml) and subsequent removal of excess methanol under reduced pressure. To the above sodium methoxidewas added dimethyl carbonate (126. ml, 1.5 mol) and 4- (3-thienyl)-phenylacetonitrile (39.8 g, 0.2 mol) prepared according to the procedure described in example 1 and the contents were heated under stirring with simultaneous removal of methanol, formed during the course ofthe reaction. After completion of the reaction, excess dimethyl carbonate was removed under reduced pressure and residue was cooled to room temperature.To this was added dry methanol (100 ml) and Mel (18.7 ml, 0.3 mol) with stirring and the resulting reaction mixture was heated for0.5 hourfollowed by addition of a fresh quantity of Mel (18.7 ml, 0.3 mol) and heating was continued for another one hour. MeOH was partially removed under reduced pressure and residue was poured into ice-water.The aqueous layer was extracted with chloroform, the chloroform layer was washed with water, dried and evaporated to give methyl 4-(3-thienyl) phenyl-a-methyl-a-cyanoacetate m.p. 109 , yield 43.4 g (90.0%. Methyi-4-(3-thienyl)phenyl-(x-methyl--cyanoacetate, thus obtained was added into a solution of EtOH (300 ml) and KOH (30 g) and the reaction mixture was stirred at room temperature for4 hours. K2CO3that separated out, was filtered and the filtrate was neutralized to pH 7.0 with hydrochloric acid.

Ethanol was partially removed under reduced pressure and the residue was poured into water.

The crude product was filtered and recrystallised from hexaneto yield pure 4-(3-thienyl)phenyl-&alpha;-methyl acetonitrile m.p. 1100, yield 30.4 g (89.12%).

B) 4-(3-Thienyl)phenyl-&alpha;-methylacetic acid : The 4-(3-thienyl )phenyl-a-methyl acetonitrile thus obtained was hydrolysed with HCI and acetic acid, as described in example 1 to yield 4-(3-thienyl)phenyl-a-methyl acetic acid. It was recrystallised from etherhexane and had m.p. 1820, yield 23.84 g (72.0%).

Example-3 5- [4- (3- Thienyl)benzyd tetrazole Amixtureof4- (3-thienyl)phenylacetonitrile (19.9g, 0.1 mol), sodium azide (7,15 g,0.1 1 mol) and ammonium chloride (5.35g, 0.1 mol) in dimethyl formamide (100 ml)was heatedfor7 hours at 1300C.The reaction mixture was poured into ice-water and its pH was adjusted to 7.0. The crude product wasfiltered under suction, washed with water and recrystallised from ethyl acetate to yield the title compound m.p. 1600; yield 13.3 g (54.96%).

Example-4 Methyl 4r3-thienyl) phenyl acetate A solution of 4-(3-thienyl)phenylacetic acid (24.0 g, 0.11 mol) in dry MeOH (275 ml) and concentrated sul phuricacid (10 ml) was refluxed on a hotwaterbath for six hours.

Methanol was partially removed from the reaction mixture under reduced pressure and the residue was poured into ice-water. It was extracted with ethyl acetate, the organic layer was washed with water and dried overanhydrous sodium sulphate. Removal of ethyl acetate under reduced pressure gave crude product which was recrystallised from hot hexanetoyield the title compound as colourless white crystals, m.p. 56 , yield 21.1 g (82.01%).

Example-5 Methyl4-(3-thienyl)phenyl-&alpha;-methylacetate In example 4, 4-(3-thienyl)phenylacetic acid can be substituted by 4- (3-thienyl)phenyl-a-methyl acetic acid.

When this was done, the product of the reaction was methyl 4-(3-thienyl)phenyl-&alpha;p-methylacetate. It was recrystallised from hexane and had m.p. 540, yield (80.0%).

Example-6 n-Octyl4-(3-thienyl)phenyl-&alpha;-methylacetate A solution of 4- (3-thienyl)phenyl-a-methyl acetic acid (2.32 g, 0.01 mol) in dry dimethyl formamide (20 ml) was added dropwiseto a stirred suspension of sodium hydride (0.26 g, 0.011 mol) in dimethyl formamide (10 ml).

Afterthe reaction had ceased (15 min) n-octyl iodide (2.40 g, 0.01 mol) was added at room temperature and stirring was continued for eighteen hours. Dimethyl formamide was partially removed under reduced pressure and reaction mixture was poured into ice-water. The aq. layerwas extracted with benzene, washed with water, dried (Na2SO4) and filtered through a thin layer of silica gel. The solvent was removed under reduced pressure to yield n-octyl 4-(3-thienyl)phenyl-a-methyl acetate as viscous oil, yield 2.5 g (72.7%).

Example-7 N. N-Diethylaminoethyl 463-thienyl)phenyl-os-methyl acetate A mixture of potassium 4- (3-thienyl) phenyl - a - methyl acetate (4.05 g, 0.015 mol), N, N-diethylaminoethyl chloride (2.71 g, 0.02 mol) and 18-crown-6 (0.264 g, 0.001 mol) in dry dimethyl formamide (20 ml)was stirred for 20 hours at 80 . Dimethyl formamide was partially removed under reduced pressure, reaction mixture was poured into ice-water and aq.layer was extracted with chloroform. The organic phase was washed with water, dried (Na2SO4) and concentrated under reduced pressure to yield crude product which was subjected to column chromatography on silica gel using benzene as eluant.

This yielded pure N, N- diethylaminoethyl-4-(3-thienyl)-phenyl-&alpha;-methyl acetate as viscous oil, yield 3.2 g (64.45%).

Example-8 Sodium 4-(3-thienyl)phenyl-&alpha;-methylacetate 4- (3-Thienyi)phenyl-a-methylacetic acid (0.1 mol) was dissolved in a solution of sodium bicarbonate (0.1 mol)in 100 ml of water. Water was completely removed under reduced pressure to yield the title compound in 98% yield.

Example - 9 4-(3-Thienyl)phenyl-&alpha;-methyl acetohydroxamic acid To a suspension of hydroxylamine hydrochloride (6.95 g, 0.1 mol) in methanol (40 ml)was added a solution of sodium (2.3 g, 0.1 g atom) in methanol (40 ml). Methyl 4-(3-thienyl)phenyl-a-methyl acetate (24.6 g, 0.1 mol) was added portionwise followed by a fresh addition of a solution of sodium (2. 1 g, 0.09 g atom) in methanol (40 ml) and the reaction mixture was allowed to stand overnight at ambienttemperature.

The reaction mixture was cautiously made acidic with concentrated hydrochloric acid and the precipitated sodium chloride was filtered under suction. The filtrate was concentrated under reduced pressure and the residue was poured into ice-water. The crude product was filtered under suction and recrystallised twice from ethylacetateto yield thetitle compound m.p.164-66 ,yield 12.14 g (49.15%).

Example- 10 2-[4-(3- Thienyl)phenyll propanol A solution of methyl 4-(3-thienyl)phenyl-a-methyl acetate (12.3 g, 0.05 mol) in dry ether (400 ml) was taken in a two litre round bottom flask and a solution of lithium aluminium hydride (5.7 g, 0.15 mol) in dry ether (250 ml) was added dropwise with continuous stirring so as to produce a gentle reflux. After completion ofthe addition, reaction mixture was stirred at ambient temperature for one hour and then carefully decomposed with aqueous sodium potassium tartratewith external cooling. The organic layer ways separated and aqueous layer ways extracted with ether, the combined ether extract was washed with water and dried over anhydrous sodium sulphate.The crude product, obtained after removal of ether was recrystallised from ether-hexaneto yield 2-[4-(3-thienyl)phenyl] propanol, m.p. 93 , yield 9.1 g (83.49%).

Example- 1 1 2-[4-(3- Th,enyi)phenyljornpionamide To a solution of 4-(3-thienyl)phenyl-a-methyl acetonitrile (10.7 g, 0.05 mol) and tetrabutyl ammonium hydrogen sulphate (1.74 g, 0.005 mol) in dichloro methane (30 ml) was added with stirring 30% hydrogen peroxide (30 ml) followed by 10% aq. NaOH (30 ml) at 0-5 C. Thereafter, the reaction mixture was stirred at room temperature for one hour, organic layer was separated, washed with water and dried over anhydrous sodium sulphate.The organic layer was filtered through athin layer of silica gel and evaporated to yield pure 2-[4-(3-thienyl) phenyl] propionamide, m.p. 184 , yield 5.0 g (43.3%).

The pharmacological properties of a few compounds ofthe invention have been studied by well known standard procedures and the following Table I explains their acute toxicity (LD50) and anti-inflammatory ac- tivity.

In the following Table li we have compared pharmacological properties of the typical compound of Table I with similar properties of some ofthecommercially available non-steroidal anti-inflammatory drugs such as phenylbutazone and indomethacin. Comparison shows that it has superior activity and/or better safety margin over these known drugs. The antipyretic activity data of 4-(3-thienyl)phenyl-a-methyl acetate is given in table lil.

Table - I: Acute toxicity & anti-inflammatory activity of 4-(3-thienyl)phenylalkanoic acid derivatives S1. Acute LD50 Carrageenin induced rat No. Name of Compound mg/kg p.o. pawoedema (mice,24 hr (observation) mg/kg p.o. Percentage inhibition 1. 4-(3-thienyl)phenyl 681 4.0 25.0 acetic acid 8.0 36.9 25.0 48.3 50.0 66.9 2. 4-(3-thienyl)-phenyl-a- 2275 1.0 22.29 methyl acetic acid 4.0 40.0 16.0 67.5 32.0 71.3 3. 5-[4-(3-thienyl)benzyl] tetrazole > 1000* 200.0 14.23 4.Methyl4-(3-thienyl)phenyl acetate > 1000* 200.0 69.9 5. Methyl4-(3-thienyl)phenyl-&alpha;- 5010 2.0 26.0 methyl acetate 3690** 4.0 38.7 8.0 51.4 16.0 59.4 6. Sodium 4-(3-thienyl)phenyi 1710 2.5 24.68 -a-methyl acetate 10.0 56.96 40.0 56.34 160.0 75.96 7. 4-(3-thienyi)phenyl- - > 1000* 25.0 27.43 methyl acetohydroxamic acid 50.0 32.61 100.0 39.78 200.0 27.9 8. 2-[4-(3-thienyl)phenyl] > 1000* 2.0 25.6 Propanol 4.0 30.5 8.0 40.0 16.0 71.0 9. 2-[4-(3-thienyl)phenyl] > 1000* 200.0 46.15 propionamide 10. Sodium4-(3-thienyl)phenyl > 1000i 200.0 80.92 acetate 11. Ethyl 4-(3-thienyl)phenyl > 1000i 2.0 26.06 -a-methyl acetate 4.0 25.61 8.0 43.215 16.0 51.62 *LDo ** Single dose- seven days observation Table II Anti-inflammatory activity of Methyl 4-(3-thienyl)phenyl-&alpha;-methyl acetate phenylbutazone and in Other philogestic agents in rats Compound Carrageenin Egg Albumin Kaolin Branykinnin Cotton Pallet Gra Test (Rats Dose Dose Dextran Dose nuloma in Rats ED50 mg/kg p.o. %Inhi- p.o. %Inhi- Dose p.o. %Inhi- Dose %Inhi p.o. (3) p.o. %Inhi- p.o.

(1) (2) (3a) (4) (4a) (5) (5a) (6) (6a) (7) (7a) Methyl-4- 7.6 100.0 35.4 100.0 54.9 100.0 70.7 100.0 21.6 25.0 19.4 ss-thienyl) 50.0 25.7 phenyl-&alpha;- 100.0 24.7 methyl Phenylbutazone 45.6 100.0 35.4 100.0 68.6 100.0 81.7 100.0 11.9 50.0 12.7 100.0 28.8 Indomethacin 2.6 - - - - - - - - 1.5 19.5 3.0 39.0 Table - II Antiarthritic, Ulcerogenic and analgesic activities of Methyl 4-(3-thienyl) phenyl-&alpha;-methyl acetate, phenylbutazone and indomethacin Analgesic Activity Adjutant Ulcerogenic arthritis dose in male Acetic acid-induced Phenyl quinone (Estd) in rats UD50 writhing inrats induced writhing rats ED50 mg/kg p.o. ED50 ; mg/kg p-o in rats ED50 ; Compound mg/kg p.o. mg/kg p.o.

(8) (9) (10) (11) Methyl 4-(3-thienyl) 40 180 30.2 5.75 phenyl-&alpha;-methyl acetate Phenylbutazone 32.5 77.5 37.5 31.25 Indomethacin 1.23 6.0 1.6 2.48 Table - Ill: Antipyretic activity of methyl 4-(3-thienyl)phenyl-&alpha;-methyl acetate Dose Number Degree of pyrexia % Reduc Compound mg/kg of 240 min. after tion p.o. animals administration Control - 20 + 1.22 + 0.42 - Methyl 4 (3-thienyl) 1.25 10 +1.26 #0.17 phenyl-- methyl acetate 2.5 10 +0.61 #0.11 50.0 5.0 10 +0.50 +0.19 59.0 10.0 10 +0.44 #0.12 67.0 20.0 10 +0.11 +0.030 91.0

Claims (32)

1. A 4-(3-thienyl)phenlalkanoic acid or a derivative or salt thereof having the following general formula:

wherein R1, is a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, and Xis -COOR2 (wherein R2 is H, a straight-chain or branched alkyl group having 1 to 10 carbon atoms, an aralkyl group, a di(loweralkyl)amino lower alkyl group, a pharmaceutically non-toxic ion, or H+ in a salt of the parent acid with a biologically-acceptable organic base), or a group which is biologically equivalent to -COOR2 as defined.

2. Acompound according to Claim 1, wherein X is - COOCH2CH2N(CH3)2 or - COOCH2CH2CH2N(CH3)2

3. Acompolund according to Claim 1, wherein X is -CONH2or -CONHOH.

4. A compound according to Claim 1,wherein X is a tetrazolyl or hydroxymethyl group.

5. Acompound according to Claim 1,wherein Xis -COOR2, and R2 isan ammonium, alkali metal, or alkaline earth metal ion.

6. 4-(3-thienyl)phenylacetic acid.

7. 4-(3-thienyl)phenyl-&alpha;-methyl acetic acid.

8. 5-[4-(3-thienyl)benzyl]tetrazole.

9. Methyl 4-(3-thienyl) acetate.

10. Methyl 4-(3-thienyl)phenyl-&alpha;-methyl acetate.

11. n-Octyl 4-(3-thienyl)phenyl-a-methyl acetate.

12. N,N-Diethylaminoethyl 4-(3-thienyl)phenyl-cu-methyl acetate.

13. Sodium 4-(3-thienyl)henyl-&alpha;-methyl acetate.

14. 4-(3-thienyl)phenyl-&alpha;-methyl acetohydroxamic acid.

15. 2-[4-(3-thienyl)phenyl] propanol.

16. 2-[4-(3-thienyl)phenyl] propionamide.

17. A process for the manufacture of a 4-(3-thienyl)-phenylalkanoic acid or a derivative orsaltthereof having the general formula la

(wherein R, is a hydrogen atom or a lower alkyl group having 1 to 4carbon atoms, and R2 is a hydrogen atom ora straight-chain or branched alkyl group having 1 to 10 carbon atoms, an aralkyl group,a di(loweralkyl)amino loweralkyl group, a pharmaceutically non-toxic ion, or H+ in a salt of the parent acid with a biologically-acceptable organic base), which comprises subjecting a 4-(3-thienyl)phenylalkyl nitrile ofthe formula Il

(wherein R1 is H or a lower alkyl group of 1-4 carbon atoms) to hydrolysis to obtain the 4-(3 thienyl)phenylaikanoic acid of the formula I wherein R1 is as defined before and R2 is hydrogen, and, where appropriate, reacting said acid in a known manner to substitute forthe hydrogen in the COOH group one of the other groups or ions as defined for R2 hereinbefore.

18. A process according to claim 17, wherein 4-(3-thienyl)-phenylacetonitrile as a starting material is obtained by (a) reaction 3-(p-tolyi)-thiophene with N-bromosuccinimide in a non-polar organic solvent, (b) treating the resulting 4-(3-thienyl)benzyl bromide with KCN or NaCN in a suitable organic solvent in the presence or absence of an appropriate phase transfer catalyst, and (c) subjecting the 4-(3-thienyl)phenylacetonitrile obtained to alkylation using the appropriate alkyl halide in the presence of a single phase or two phase solvent system having an organic solvent and a suitable catalyst to give the corresponding 4-(3-thienyl)phenylalkyl nitrile.

19. A process according to claim 18, wherein in the reaction between N-bromosuccinimide and 3-(p-tolyl)thiophenethe non-polar organic solvent is an aromatic hydrocarbon or a halogenated hydrocarbon.

20. A process according to claim 19, wherein the non-polar organic solvent is tetrachloromethane.

21. A process according to claim 18 or 19, wherein in step (b), the 4-(3-thienyl)benzyl bromide is reacted with KCN or NaCN in the presence of, as organic solvent, an aromatic hydrocarbon, a lower aliphatic alcohol, a halogenated hydrocarbon, or an alkylnitrile, and as phase transfer catalyst, tetraalkyl ammonium halide or hydrogen sulphate, benzyl trialkyl ammonium halide, or crown ethers.

22. A process according to claim 21, wherein the organic solvent is dichioromethane, cyanomethane, ethanol or benzene.

23. A process according to Claim 18 or 19, wherein step (b) is carried out in the presence of an aqueous water-miscible organic solvent or a polar aprotic solvent in the absence of phasetransfercatalyst.

24. A process according to Claim 23, wherein the water-miscible organic solvent is ethanol, dioxane, or acetone.

25. A process according to Claim 23, wherein the polar aprotic solvent is dimethylformamide (DMF).

26. A process according to any of claims 18 to 25, wherein in step (c) the 4-(3-thienyl)phenyl acetonitrile is subjected to said alkylation in presence of a dialkyl carbonate.

27. A process according to Claim 26, wherein the dialkyl carbonate is dimethyl carbonate.

28. A process according to any of claims 18 to 25, wherein in step (c) 4-(3-thienyl)phenylacetonitrile is subjected to alkylation in the presence of a two-phase solvent medium having water and an organic solvent using a phase transfer catalyst.

29. A process according to Claim 28, wherein the phase transfer catalyst is a tetralkyl ammonium halide or hydrogen sulfate.

30. A process according to Claim 17, wherein the hydrolysis ofthe4-(3-thienyl)phenylalkyinitrile is carried out by refluxing either (i) with mineral acids in acetic acid and/orwater or (ii) with strong alkalies in an aqueous alcoholic medium.

31. A process for the preparation of 4-(3-thienyl)phenylalkanoic acids and/or their derivates or salts of formula I as herein defined, substantially as herein described or as described in any ofthe Examples.

32. A pharmaceutical preparation comprising a compound of formula las claimed in Claim 1,and a pharmaceutically acceptable carrier, diluent and/or adjuvant.