FR2589156A1 - 4- (3-THIENYL) -PHENYL-ALKANOIC ACIDS, THEIR PREPARATION AND MEDICAMENTS CONTAINING THEM - Google Patents

Abstract

THE COMPOUNDS ACCORDING TO THE INVENTION RESPOND TO GENERAL FORMULA I: (CF DRAWING IN BOPI) IN WHICH R REPRESENTS H OR ALCOHYL 1 TO 4 C; R REPRESENTS IN PARTICULAR H OR ALCOYL 1 TO 10 C, ARALCOYL, DI (ALCOYL) LOWER-AMINO-ALCOYL (LOWER), OR COOR REPRESENTS AN AMID, CONHOH, TETRAZOLYL OR HYDROXYMETHYL GROUP. USE AS ANTI-INFLAMMATORY MEDICINAL PRODUCTS.

Description

4- (3-thienyl) -phenyl-alkanoic acids, their preparation

and drugs containing them.

  Non-steroidal anti-inflammatory agents are

  first choice drugs for the treatment of

  acute and chronic inflammatory and arthritic diseases. In recent years, many enol, arylacetic and arylpropionic acids, and their derivatives, have been reported.

  as new non-steroidal anti-inflammatory agents.

  Although a large number of these compounds have been shown to

  good activity, only a small number of them, such as the indometha-

  Cine, ibuprofen, phenylbutazone, etc. have been commercially successful.

  Gastrointestinal irritation continues to be the main drawback

  of these drugs that are found on the market.

  Indomethacin is one of the most active of these

  but has a high incidence of gastrointestinal side effects, including bleeding and ulceration, and causes migraines, confusion or vertigo in approximately 15% of cases (British Medical Journal 287, ( L983), 41); likewise

  phenylbutazone, another non-inflammatory

  steroid, very old and most powerful, also present

  the serious disadvantage of causing ulcers and

  gastric bleeding, kidney and liver disorders.

  The loss of bone marrow is also another very serious adverse effect of phenylbutazone (British

Medical Journal, 287, (-1983), 41).

  The present invention relates to novel substituted phenylalkanoic acids and their derivatives, having pharmacological properties and which can be used

  as anti-inflammatory and anti-arthritic agents, pre-

  a much greater margin of safety than indomethacin, ibuprofen or phenylbutazone, which are also analgesic agents.

  and antipyretic at low concentrations.

  The present invention also relates to

  transferred from the preparation of these new compounds.

  The compounds according to the invention are new 4- and 4- (3-thienyl) phenylalkanoic acid derivatives.

  many anti-inflammatory drugs

  commercially available steroids, because they are effective at relatively lower concentrations, while providing a margin of safety

satisfactory.

  The new compounds of the invention have proved

  res answer the general formula I

CIOCO S2-

if)

  in which R1 represents H or an indeterminate alkyl group

  lower having 1 to 4 carbon atoms; R2 repesen-

  H or an alkyl group, branched or unbranched, having 1 to 10 carbon atoms, such as "Me" or "Et", etc. or an aralkyl group such as a "benzyl" group or a di (lower alkyl) amino-lower alkyl group,

  such as dimethylaminoethyl or dimethylamino

  propyl, or a pharmaceutically non-toxic ion selected from ammonium ions, alkali metals, alkaline earth metals, etc., or H + in acid salts related to biologically acceptable organic bases,

  such as lysine, etc., or OR2 together in COOR2 behave

  forming groups such as amide (CONH 2) or hydroxamic acid (CONHOH) groups or COOR 2 being replaced by biologically equivalent groups such as tetrazolyl, hydroxymethyl (CH 2 OH) groups, etc. The structures of the compounds described in the context of the invention are determined by their synthetic methods and corroborated by IR (infra-red), NMR (nuclear magnetic resonance), UV (ultraviolet) and spectrographic analyzes. mass, and by correspondence

  calculated and found values for the basic analysis

silence of the respective elements.

  The compounds according to the invention, responding to the

  general formula I, are crystalline and weakly soluble

  or soluble in water. They can be isolated from the mixtures

  by pouring them into ice-cold water and then

  killing an extraction with common organic solvents such as ether, ethyl acetate, CHCl3, CH2Cl2, etc. The compounds can be purified by recrystallization from normal solvents such as EtOH, ethyl acetate, CHCl 3, hexane and the like. or by chromatography on silica gel or alumina, etc., then elution with solvents

  organic in their order of increasing polarities.

  The compounds according to the invention, having the general formula I, exhibit a high degree of anti-inflammatory and anti-arthritic activity, and are valuable for treating arthritic disorders. In addition, the compounds according to the invention have a degree

  useful analgesic activity and antipyretic activity.

  The substances used for comparison are the commercially available nonsteroidal anti-inflammatory drugs, ie phenylbutazone and indomethacin. Some of the compounds of the invention

  have an activity higher than that of these drugs.

  known. For example, the dose administered orally

  effectively (ED50) 4- (3-thienyl) -phenyl-o-methyl

  methyl acetate (formula I, with R1 =% = Me) against the

  adjuvant arthritis in rats (B.B.

  bould, Brit. J. Pharmacology, 35, (1969), 487) is from -

  4.0 mg / kg, and is eight times more potent than phenyl

  butazone, but has one third of the activity of

  Methacin. The anti-inflammatory activity of the above-mentioned compound against carrageen-induced iodine in rats,

  determined by the method of Winter (C.V. Winter, E.A.

  Rislly and G.W. Nuss, Proc. soc. Exp. Biol. Med., 111, (1 962), 544), is found to be six times greater than that of phenylbutazone, but equal to one third of that of

  indomethacin, the DE-50 value of the typical compound

  above being 7.6 mg / kg (oral).

  The ulcerogenic dose (DD50) of this compound in rats (E. Marazsi et al., Arzneim Forsch .: 22, (19f72y, 191) is 180 mg / kg (orally), which

  is approximately 2.5 times and 30 times

  than that of phenylbutazone and that of indigo

  methacine respectively. So this compound presents uemffeilleremar

  safety than phenylbutazone and indomethacin.

  Analgesic activity in mice was studied by the acetic acid induction Writhing method (R. Koster, M. Anderson and EJ De Beer, Fed Proc., 18, (1959), 412) and Phenylquinone induction writhing method (EA Siegumund, RA Cudmas, and Lu, GJ Pharmacol Exp Ther-119, (1957), 184). The ED 50 values of the above-mentioned typical compound in these tests are 30.0 mg / kg (Writhing Induction Test with Acetic Acid) and 5.75 mg / kg (induction Writhing method by phenylquinone) compared with 37, 5 and 31.25 mg / kg for phenylbutazone and 1.6 and 2.48 for indomethacin, respectively. In addition, the above compound has activity

  very important antipyretic in albino rats (U.M.

  Teatino, L. P. Friz, A. Gandini and D. Della Bells, J. Med. Chem. 6, (1963), 248), showing a reduction in the dosage of yeast-induced hyperpyrexia at doses

  from 2.5 to 20 mg / kg (p.o.) (oral route).

  The acute toxicity (single dose, 7-day observation) of the typical compound is 3.690 and 2.330 mg / kg (route -5-

  oral) in mice and rats, respectively.

  Thus, according to the invention, acids are provided

  4- (3-thienyl) phenylalkanoic compounds and their derivatives,

  compound of general formula I wherein R is H or lower alkyl having 1 to 4 carbon atoms; R represents H or a branched or unbranched alkoxy group with 1 to 10 carbon atoms, such as "Me" or "Et", etc., or an aralkyl group such as the "benzyl" group, or a dialcoyl group (lower)

  amino-lower alkyl, such as dimethylamino

  noethyl or the dimethylaminopropyl group, or a phar-

  maceutically non-toxic, selected from ammonium ions, alkali metals, alkaline earth metals, etc., or

  H + in salts of the acids related to the bases

  biologically acceptable genes such as lysine, etc., or OR2 together in COO is provided by forming groups such as amide group (CONH2) or hydroxamic acid (CONHOH), or COOR2 being replaced by groups biologically.

  such as tetrazolyl, hydroxymethyl

(CH2OH), etc.

  According to another characteristic of the present invention,

  In this way, the new compounds are prepared by simple reactions. Thus, the process for the preparation of the compounds according to the invention is carried out in two stages comprising the preparation of 4- (3thienyl) -phenylalkyl nitriles, then the transformation, during a second stage, of these nitriles into the acids. phenylalkanoic acids and their derivatives.

  Nitrile or 4- (3-thienyl) -phenyl-acetonitrile

  Intermediate is a stable compound and is prepared by itself

  from the corresponding 4- (3-thienyl) benzyl halide

  for example bromide, which is itself obtained from the corresponding 3 (p-tolyl) -thiophene, which is well known, by reaction with the desired halo-substituted succinimide, such as by reaction with the desired halosubstituted succinimide, such -6-

  than N-bromosuccinimide. The alkylation of the nitrile

  above gives the corresponding = -alkyl-acetonitriles.

  Thus, it is possible to start from a thiophene con-

  nude, to make it react, for example with N-bromosucci-

  nimide to obtain the corresponding bromide and then convert this bromide to the corresponding acetonitrile by reaction with an alkaline cyanide and then, if desired, to alkylate the acetonitrile using a halogenide

  of alkyl or a suitable dialkyl sulphate to obtain

  the corresponding i-alkyl-acetonitriles which are

  then hydrolyzes to obtain acids according to the invention.

  These acids can be converted into their derivatives of different

your well-known ways.

  We will describe in the following further details of the

transferred from the invention.

  Thus, there is provided a process for preparing 4- (3-thienyl) phenylacetonitrile of the general formula III wherein R is H and X is CN, reacting 3- (p-tolyl) -thiophene (A. Chrzaszozeweka, Roczniki-Chem.5, 33 (1925): CA 20 1078 (1926) having formula II on N-bromo-succinimide in a nonpolar organic solvent such as an aromatic hydrocarbon, for example benzene, or a halogenated hydrocarbon such as CC14 <a C43 I | E kS /

II IIII

  and then treating the resulting 4- (3-thienyl) benzyl bromide of formula III wherein R 1 is H and X is Br, with alkali cyanide such as NaCN or KCN in a

  suitable organic solvent such as an aro-

  such as benzene or aliphatic alcohols

  such as EtOH, or a halogenated hydrocarbon such as CH2Cl2, or alkyl nitriles such as CH3CN,

  of a suitable phase transfer catalyst (CTP)

  such as halides or tetraalkyl bisulfate

  ammonium or benzyl-trialkylammonium halides, or crown ethers, etc.

  It is also possible to transform the 4- (3-thiardine bromide

  nyl) -benzyl to the corresponding acetonitrile by refluxing with NaCN or KCN in water-miscible organic solvents such as EtOH in aqueous solution, etc. or in polar aprotic solvents such as DMF or DMSO, etc., without using the transfer catalysts

aforementioned phase.

  In addition, when R represents, in the compounds corresponding to formula I of the invention, an alkyl group,

  the 4- (3-thienyl) -phenylacetonitrile prepared as indi-

  above, alkylation with a suitable alkyl halide such as methyl or ethyl iodide or a dialkyl sulfate such as Fie2SO4 or Et2SO4 in a dialkyl carbonate such as di or diethylcarbonate in the presence of an alkaline alkoxide such as methoxide or sodium ethoxide to obtain the nitriles

  25.4- (3-thienyl) -phenylalkyl compounds having the formula III ,. in which

  R1 is a lower alkyl group having 1 to 4 atoms -

carbon and X is CN.

  The above alkylation can also be carried out with an alkyl halide in a two-phase system comprising water and a suitable organic solvent, in the presence of a suitable phase transfer catalyst mentioned above.

  The 4- (3-thienyl) -phenylalkyl nitriles are then hydrolyzed.

  prepared by refluxing with mineral acids such as concentrated hydrochloric acid in acetic acid and / or water, or with hydroxides.

  alkali (NaOH, KOH, etc.) in an aqueous or hydro-

  alcoholic acid to obtain 4- (3-thienyl) -phenylal-

  corresponding canoques of formula I, wherein R 1 is a lower alkyl group having 1 to 4 carbon atoms and R 2 is H, then, if desired, can be trans-

  form H of the COOH group of 4- (3-thienyl) -phenylal-

  canoids of formula I, prepared as above, to an alkyl group such as "Me" using diazomethane or MeOH-H2SO4, or "Et" using EtOH-H2SO4 as alkylation reagents. The same esters can also be prepared by reacting the nitriles with an alkanol

  appropriate in the presence of a mineral acid.

  If desired, the nitrile, acid or ester functions can be converted into amide, tetrazolyl, hydroxymethyl or other derivatives or

  aforementioned salts by conventional methods.

  According to the present invention, there is also provided

  a process for the preparation of 4- (3-thienyl) phenylal-

  canoids and their derivatives in the general formula

  I, wherein R1 is H or an alkyl group

  lower having 1 to 4 carbon atoms; R2 represents

  H or a chain of 1-10 carbon atoms branched (or not) constituting an alkyl group such as "Me" or "Et", etc., an aralkyl group such as a "benzyl" or dialkyl group (lower) aminoalkyl (lower), such as dimethylaminoethyl or dimethylaminopropyl, or a pharmaceutically non-toxic ion selected from ammonium ions, alkali metals, alkaline earth metals, etc., or H + in acid salts related to bases organic biologically acceptable such as lysine etc., or OR together in COOR2 functional forming groups etc., such as amide (CONH2) or hydroxamic acid groups

  (CONHOH), or COOR2 being replaced by organic groups

  logically equivalent, such as tetrazolyl, hydroxy-.

  methyl (CH 2 H), comprising the step of hydrolyzing the 4- (3-thienyl) -phenylalkyl nitrile of formula III wherein R is hydrogen or

  lower alkyl group having 1 to 4 carbon atoms

  bone and X is CN, then, if desired, to submit to

  4- (3-thienyl) -phenylalkanoic acid thus obtained

  form in the formula I, o% corresponds to the definition given above and R is hydrogen, a reaction in a manner known per se to transform the "H" of the "COOH" group into the other meanings of R2 defined herein, the

  salts being prepared in a known manner.

  Among the compounds that are prepared according to the procedure

  d) above, there may be mentioned: 1. 4- (3-thienyl) -phenylacetic acid; 2. 4- (3-thienyl) phenyl-α-methylacetic acid; 3. 5- [4- (3-thienyl) benzyl] tetrazole; 4. Methyl 4- (3-thienyl) -phenyl-acetate; 5. Methyl 4 (3-thienyl) -phenyl-methyl-acetate; 6. N-octyl 4- (3-thienyl) -naphthylmethylacetate

  7. NAN 4- (3-thienyl) -7-phenylmethylacetate

  diethylaminoethyl; 8. 4- (3-thienyl) -vinyl-4-methyl-sodium acetate; 9. 4- (3-Thienyl) -H-phenyl-methyl-aceto-hydroxamic acid; 10. 2 [4- (3-thienyl) -phenyl] -propanol;

  11. 2- [4- (3-thienyl) phenyl] propionamidine.

  The compounds according to the present invention can be converted into their pharmaceutically acceptable salts of

any known way.

  They can also be converted into useful preparations by combination with pharmaceutical carriers,

  diluents and / or usual additives thereof.

  The non-limiting examples that follow are used to

illustrate the invention.

EXAMPLE 1

  4- (3-thienyl) -phenylacetic acid.

  A) 4- (3-thienyl) benzyl bromide.

  To a solution of 3- (p-tolyl) -thiophene (34.8g 0.2 mol) and benyl peroxide. (300 mg) in CCl4 (400 ml) -10-

  at reflux, a mixture of N-bromine

  succinimide (34.0 g, 0.191 mol) and benzoyl peroxide

  the (300 mg). After the addition is complete, the reaction mixture is refluxed an additional two hours. The cooled reaction mixture is filtered and the residue is washed with CCl4. The combined CCl4 filtrate is concentrated under pressure

4 '4.

  reduced, and the crude residue is recrystallized from

  xane, to obtain 4- (3-thienyl) benzyl bromide,

  PF 95 C; amount obtained 45.4 g (yield 89.72%).

  B) 4- (3-thienyl) -phenylacetonitrile A solution of 4- (3thienyl) benzyl bromide

  (25.3 g, 0.1 mole) thus prepared and tetra-bisulfate

  butylammonium (3.34 g, 0.01 mol) in dichloroethane (100 ml) was added KCN (9.8 g, 0.15 mol) in 20 ml of water, and the reaction mixture was warmed at 80 C in

  stirring vigorously 4 hours. We separate the organic phase

  It is washed well with water, dried over anhydrous sodium sulfate and evaporated. The crude product obtained is chromatographed on a gel of

  silica, and elution with benzene.

  The product eluted with benzene gives, being concentrated, pure 4- (3thienyl) -phenylacetonitrile, PF

   C (benzene-hexane); quantity obtained 17.2 g (yield

86, 43%).

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

  After stirring for 6 hours, a mixture of 4- (3-

  thienyl) -phenylacetonitrile (9.96 g, 0.05 mol), acetic acid (125 ml) and concentrated HCl (125 ml). The acetic acid is removed under reduced pressure, the reaction mass is poured into ice-cold water and

  filtering the solid matter obtained in the tube, dissolving it

  aqueous solution of sodium bicarbonate is filtered and

  acidifies the bicarbonate layer with hydrochloric acid

  concentrated drique. The separated crude acid was collected and recrystallized from ether-hexane to give pure 4- (3-thienyl) phenylacetic acid as colorless, brilliant crystals, mp 194 ° C; quantity -11-

8.0 g (73.4% yield).

EXAMPLE 2

  4- (3-thienyl) -phenyl-methyl-acetic acid.

  A) 4- (3-thienyl) -phenyl-d-methyl-acetonitrile.

  Anhydrous sodium methoxide is prepared in sodium (5g 0.22 gram atom) in absolute methanol (60 ml), followed by removal of excess methanol under reduced pressure. To the above sodium methoxide, dimethyl carbonate (126 ml, 1.5 moles) and 4 (3-thienyl) phenyl acetonitrile (39.8 g, 0.2 moles) prepared according to the method described in Example 1, and the whole is heated with stirring, while at the same time eliminating the methanol formed during the reaction. After the reaction is complete, excess dimethyl carbonate is removed under reduced pressure and the residue is cooled.

  at room temperature. Dry methanol is added

  (100 ml) and MeI (18.7 ml, 0.3 mole) with stirring,

  and the reaction mixture obtained is heated half a

  hour, then add a new amount of MeI (18.7 ml

  0.3 mole), and heating is continued for one more hour.

  The MeOH is partially removed under reduced pressure and the residue is poured into ice water. The aqueous layer is extracted with chloroform, the chloroform layer is washed with water, dried and evaporated.

  to obtain 4- (3-thienyl) -phenyl-N-methyl-cyanoacetate

  methyl, mp 109 ° C, amount obtained 43.4 g (yield

  , 0%). 4- (3-thienyl) -phenyl-methyl-vinyl is added

  methyl acetate thus obtained to an EtOH solution

  (300 ml) and KOH (30 g) and the reaction mixture was stirred

  4 hours at room temperature. The separating K 2 CO 3 is filtered, and the filtrate is neutralized to pH 7.0 with hydrochloric acid. The ethanol is partially removed under reduced pressure and the residue is poured in.

  in water. The raw product is filtered and recreated

  tallise in hexane to give 4- (3-thienyl) -

  pure phenyl-n-methyl-acetonitrile; PF 110 C, quantity obtained

-12-

held 30.4 g (89.12% yield).

  B) 4- (3-thienyl) -phenylmethylacetic acid.

  4- (3-Thienyl) -phenyl-γ-methyl-is hydrolyzed.

  acetonitrile thus obtained with HCl and acetic acid, as described in Example 1, for

  obtain 4- (3-thienyl) -phenyl-o-methyl-acetic acid.

  It is recrystallized from an ether: hexane mixture, and

  has a mp of 1820C, amount obtained 23.84 g (yield

72.0%).

EXAMPLE 3

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

  A mixture of 4- (3-

  thienyl) -phenylacetonitrile (19.9 g, 0.1 mol),

  sodium trure (7.15 g, 0.11 mol) and ammonium chloride (5.35 g, 0.1 mol) in dimethylformamide (100 ml). The reaction mixture is poured into ice water and adjusted to pH 7.0. We filter the product

  in the trunk, it is washed with water and

  crystallizes in ethyl acetate to obtain the

  compound indicated by the title PF 160 C; quantity obtained

13.3 g (yield 54.96%).

EXAMPLE 4

  4- (3-thienyl) -phenyl-methyl acetate o Refluxed on a hot water bath for

  six hours a solution of 4- (3-thienyl) -phenylaceous acid

  (24.0 g, 0.11 mol) in anhydrous MeOH (275 mL)

  and concentrated sulfuric acid (10 ml).

  The methanol is partially removed from the mixture

  reaction under reduced pressure and the residue is poured

  in ice water. It is extracted with ethyl acetate, the organic layer is washed with water and

  it is dried over anhydrous sodium sulphate. The elimination

  Ethyl acetate under reduced pressure gave a crude product which was recrystallized from hot hexane to give the title compound.

  in the form of colorless "white" crystals, PF 56 C,

-13-

  obtained 21, lg (yield 82.01%).

EXAMPLE 5

  Methyl 4- (3-thienyl) -phenyl-o-methyl-acetate In Example 4, 4- (3-thienyl) -phenylacetic acid can be replaced by 4- (3-thienyl) phenyl- α-methyl acetic acid. When you do it, the product

  of the reaction is 4- (3-thienyl) -phenyl-o-methyl-

  methyl acetate. It is recrystallized from hexane

  and it has a mp of 54 C, 80.0% yield.

EXAMPLE 6

  4- (3-thienyl) -phenyl-c-methyl-n-octyl acetate A solution of 4- (3-thienyl) -phenyl-o-methyl-acetic acid (2.32 g) was added dropwise. 0.01 mol) in anhydrous dimethylformamide (20 ml) to a suspension of stirred sodium hydride (0.26 g, 0.011 mol) in

dimethylformamide (10 ml).

  After completion of the reaction (15 minutes), n-octyl iodide (2.40 g, 0.01 mol) was added at room temperature, and stirring was continued.

  six p.m. Dimethyl is partially removed.

  formamide under reduced pressure and the reaction mixture is poured into ice water. The aqueous layer is extracted with benzene, washed with water, dried (Na 2 SO 4) and filtered through a thin layer of silica gel. The solvent is removed

* reduced pressure to obtain 4- (3-thienyl) -phenyl - &% -

  n-octyl methyl acetate, as a viscous oil;

  amount obtained 2.5 g (yield 72.7%).

EXAMPLE 7

  N, N-diethylaminoethyl 4- (3-thienyl) -phenyl-o (-methyl) acetate

  A mixture of 4- (3-thienyl) - is stirred for 20 hours at 80 ° C.

  potassium phenyl-α-methylacetate (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). mole) in

  anhydrous dimethylformamide (20 ml). Partially eliminates

  Then the dimethylformamide is added under reduced pressure, the reaction mixture is poured into ice water and the aqueous layer is extracted with chloroform. The organic phase is washed with water, dried (Na 2 SO 4) and concentrated under reduced pressure to obtain the crude product which is subjected to silica gel column chromatography using

benzene as eluent.

  There is thus obtained 4- (3-thienyl) -phenyl - "- methyl-

  pure N, N-diethylaminoethyl acetate in the form of a

  viscous oil, amount obtained 3.2 g (yield 64.45).

EXAMPLE 8

  Sodium 4- (3-thienyl) -phenyl-o-methylacetate

  4- (3-thienyl) -phenyl-o acid (-

  methylacetic acid (0.1 mole) in a bicarbonate solution

  sodium nate (0.1 mole) in 100 ml of water. The water was completely removed under reduced pressure to give the title compound in 98% yield.

EXAMPLE 9

  4- (3-thienyl) -phenyl-methyl-acetohydroxamic acid To a suspension of hydroxylamine hydrochloride (6.95 g, 0.1 mole) in methanol (40 ml) was added a sodium solution (2 ml). , 3 g, 0.1 gram atom) in methanol (40 ml). Methyl 4- (3-thienyl) -phenyl-methyl-acetate is added portionwise (24.6 g, 0.1 mole), then a solution of sodium (2.1 g, 0, 09 gram atom) in methanol (40 ml), and the reaction mixture is allowed to stand overnight

ambient temperature.

  The reaction mixture is carefully acidified with concentrated hydrochloric acid and the precipitated sodium chloride is filtered off with suction. The filtrate is concentrated under reduced pressure and the residue is poured into ice water. The crude product was filtered off with suction and recrystallized twice from ethyl acetate to give the title compound; -15-

  Mp 164-166 ° C., 12.14 g (yield 49.15%).

EXAMPLE 10

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

  A solution of 4- (3-thienyl) -phenyl-α-methyl-methyl acetate (12.3 g, 0.05 mol) in anhydrous ether (400 ° C.) was added.

ml) in a round bottom flask of

  two liters and add drop by stirring continuously

  Then, a solution of lithium aluminum hydride (5.7 g, 0.15 mole) in dry ether (250 ml) was added to give gentle reflux. After the addition is complete, the reaction mixture is stirred at room temperature for one hour and then decomposed thoroughly with sodium potassium tartrate in aqueous solution with external cooling. The organic layer is separated and the aqueous layer is extracted with ether, the combined ether extract is washed with water and dried over anhydrous sodium sulfate. The crude product obtained after removal of the ether is recrystallized from a mixture of

  ether-hexane, to obtain 2- [4 (3-thienyl) -phenyl] -

  propanol; Mp 93 C, amount obtained 9.1 g (yield

83.49%).

EXAMPLE 11

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

  To a solution of 4- (3-thienyl) -phenyl-t-methyl-

  acetonitrile (10.7 g, 0.05 mole) and

  tetrabutylammonium (1.74 g, 0.005 mole) in dichlo-

  romomethane (30 ml), 30% hydrogen peroxide (30 ml) and then 10% aqueous NaOH solution (30 ml) are added with stirring at a temperature of 0.degree. to 5.degree. stir the reaction mixture to the

  room temperature one hour, the organic layer is separated

  It is washed with water and dried over anhydrous sodium sulfate. The organic layer is filtered

  through a thin layer of silica gel, and

  pore to obtain 2- [4- (3-thienyl) -phenyl] -

  pure propionamide; Mp 184 ° C, amount obtained 5.0 g -16-

(yield 43.3%).

  The pharmacological properties of

  some compounds of the invention by standard methods

  well known darts and Table I which follows indicates their acute toxicity (LD50) and their anti-inflammatory activity.

  In the following Table II, the following

  pharmocological properties of the typical compound of Table I with similar properties of certain commercially available nonsteroidal anti-inflammatory drugs, such as phenylbutazone and indomethacin,

  This comparison shows that it presents a

  and / or a margin of safety better

  to these known drugs. Table III indicates

  antipyretic activity data of 4- (3-thienyl) -

  phenyl-c-methyl-methyl acetate.

  TABLE I: Acute-Toxic and Anti-inflammatory Activity 4- (3-thienyl) -phenyl-alkanoic

* Z589156

  of acio derivatives Compound name Acute toxicity

LD50.,

  Edema of the paw in rats, induced by Qarrahineen%

mg / kg p.o.

  (mouse, 24 hours observation) Percent inhibition

1. 4 - --- n;). E yl -

Acetic Acid

(i, 3-thienyl) on) ry-n -

me - .. yl -acetic: etrazole

4,4- (3-thienyl) -phenyl) -

methyl acetate

4- (3-thienyl) -phenyl-W -.

Methyl methylacetate

6. 4- (3-thienyl) -phenyl-4--

sodium methyl-acetate Acid

7. 4- (3- (i'xny)> r "-.:, Z-o -

  Methyl aceetoyl; 2- (4-thyl) phenyl-7-propanol, n-propanol, 4- (3-thienyl) amide; phenyl-sodium acetate

1. 4- (3-thienyl) -phenyl-

  ethylene-ethyl acetate 5: 1 2'75> lcn) V- *

> 1000 *

36905 *

> 10o00 *

> 1000 *

> 1000 *

> 1000 *

) 1000 *

  * DLo One dose - Seven days of observation though. Jo. 4.0 8.0, 0, 0 1.0 4.0 16.0 32.0, 0, 0 2.0 4.0 8.0 16.0 2.5, 0, 0, 0, 0, 0, 0, 0 2.0 4.0 8.0 16.0, 0, 0 2.0 4.0 8.0 16.0, 0 36.9 48, 3 66.9-22.29, 0 67.5 71.3 14.23 69.9 26.0 38.7 51.4 59.4 24.68 56.96 56.34, 96 27.43 32.61 39.78 27.9, 6, 5, 0 71.0 46r15, 92 26.06, 61

43.215

  51.62 TABLE 1 Antiinflammatory activity of 4- (3-triol) phenyl-methyl methyl acetate;

  phenylbutazone and indomethacin '' ..

  OTHER AGENTS PHILD.GISTIQUES CAIEZ L.ES RA'fS Com- Test aucarra- 'Cotton balls f) së gahteen Egg albumin,' Dextrane Bradyinine ranulomas ches (rats DE, - (o mg / kg Dxrn rdliiert

  p.o.) nDose 9 Inhibitose., V, h- -Dose Inhi Dose t oso - [nh'-

  p, o, t bition at p.o.btio + p.o bitionp.0. bition. po bition (1) (2) (3) (3a) (4) (4s) (5) (5a) (6) (6a) (t) (7a)

......,. ...... I I

4- (3-thio- 7.6

nyl) -phenyl-

methyl

aclate of

methyl -

Phenylbutazone, 6 tO 35tZ4

0 35.4

  , 0 54.9 10010 70P7 100e0 21i6 25? 0 "1 5oto100

1004.0

1000 6 8, 61 M

Indomethacin 26 mm - "19 4

2 7 '/

21W7,1

  10010 81; 7 10 (0Fe 11.9 50.0 12, W 0 28, g

--- 1 5 19, .5

P t

3, 0 9,

(to follow next pageO o'r ao.

IA: 1.I :: AI ItI -

(after)" '

  ANTI-ARTHRITIC, ULCEROGENB 'AND ANAEGESIC ACTIVITIES OF 4- (3-thienyl) -phenyl-o -

  Methyl Methyl Acetate, Liphenyl Tetonazone and Indomethacin S LC Analgesic Activity

ARTHRITIS BY DOSE ULCEROGEN_

  COMPOUND ADJUVANT FOR LES.RATS, .. WRIING TEST WITH

  (established). 'MALES, THE TEST WRITHING WITH

  (ertsblie.chemg /, p..50i .. * INF1 TION BY ACID INDUCTION BY PHENYL-

  ratsmg / kg, p.o .: ACETIQLE ', IN QIJINONE AT RATS

  DE50 mg / kg RATS DE50: mg / kg p.o. DE.50, mg / kg bw.

  p.o. - (8) (9) ";.".: .. r (10) ó11)

4- (3-thienyl) -. ...

  pheenyl -, methyl .. 4.0 180 .. 25 25 methyl acetate. : Phenylbutazone 3215 7715. :: 37t5 31.25 Indomethacin 1.23 6t O: 1 6 2:48 a. Table 2: Antipyretic activity of Methyl Methyl Acetate Dose Number of Pyrexia Rea Reagent mgkg of animals 240 minutes after application p.oO Witness

4- (3-thienyl)

phényl.d4_

methyl-acetates

methyl ester

2P, 5 10

0 10

1o-.o ,. "-.O

, 0 10

0 - 10

_, o; 1

+1,220 + DO, 4

+126 + 0 17 ..

+0.61 + Oll

+0.50 + 0.19 -;

-. _ .. '.: .- :. r-

0 1144. o -ut 1

+01, --- '@ 0 030 -

__ __ O0rO 59o 1, 0 91 "0- 1P25

Claims (12)

claims   1. 4- (3-Thienyl) -phenyl-alkanoic acids and their derivatives having the general formula I, 03 <oOK T   wherein R1 is H or lower alkyl   with 1 to 4 carbon atoms; R2 represents H or a branched or unsubstituted alkyl group with 1 to 10 atoms   carbon, such as "Me" or "And" -, or an aral group   coyle such as a benzyl group or dialkoyl (lower) -   amino-alkyl such as a dimethylaminoethyl group or   dimethylaminopropyl, or a pharmaceutically non-ionic   selected from ammonium ions, alkali metal   alkaline earth metals, or H + in salts of the related acids with organic bases   biologically acceptable such as lysine, or OR2   appears in COOR2 behaves forming groups such as amide (CONH2) or hydroxyamic acid (CONHOH), or COOR2 being replaced by groups   biologically equivalent, such as tetrazol lyle, hydroxymethyl (CH2OH).   2. 4- (3-Thienyl) -phenyl-alkanoic acids and their derivatives having the general formula I: [4- (3-thienyl) -phenyl-acetic acid; T4- (3-thienyl) -phenyl-α-methyl-acetic acid; 5- [4- (3-thienyl) benzyl] tetrazole; methyl 4- (3-thienyl) -phenyl-acetate; Methyl 4- (3-thienyl) phenyl-OC-methyl-acetate; n-octyl 4- (3-thienyl) -phenyl-11-methylacetate;   N, N-diethyl 4- (3-thienyl) -phenyl-O-methyl-acetate   thylaminoéthyle; Sodium 4- (3-thienyl) -phenyl-O-methyl-acetate;   4- (3-thienyl) -phenyl-o-methyl-acetohydroxy-   amic; 2- [4- (3-thienyl) phenyl] -propanol;   2-14- (3-thienyl) -phenyl) -propionamide.   3. Process for the preparation of 4- (3-thienic acid)   nyl) -phenyl-alkanoic compounds and their derivatives corresponding to the general formula I   wherein R1 is H or a lower alkyl group   with 1 to 4 carbon atoms; R2 represents   H or an alkyl group with 1 to 10 carbon atoms, branch   whether or not, such as "Me" or "Et *", or an aralkyl group   such as a "benzyl" or dialkyl (lower) amino   (lower) alkyl such as a dimethylaminoethyl or diethylaminopropyl group, or a pharmaceutically non-toxic ion selected from ammonium, alkali metal, alkaline earth metal, or H + ions in salts of the acids with organic bases   biologically acceptable such as lysine, or OR2   appears in COOR2 behaves forming groups such as amide (CONH2) or hydroxyamic acid (CONHOH), or COOR2 being replaced by groups   biologically equivalent, such as tetrazol   lyle, hydroxymethyl (CH20H), characterized in that one   undergoes hydrolysis to a 4- (3-thienyl) -phenyl nitrile   alkyl-n-alkyl having the general formula III wherein R1 is H or lower alkyl having 1 to 4 carbon atoms and X is CN, and if   it is desired, the 4- (3-thienyl) -phenyl   nyl-alkanoic thus obtained having the formula I o R1 is as defined above and R2 is hydrogen, in a known manner, to transform the   "He of the COOH group in other meanings of R2 de-   previously finished, the salts being prepared in a known manner. 4. Method according to claim 3, characterized in that said 4- (3thienyl) -phenyl-alkyl nitrile of formula III (R = H, X = CN) is that obtained by reacting 3- (p-tolyl) -thiophene in formula II with N-bromosuccinimide in a non-polar organic solvent, by treating the obtained 4- (3-thienyl) benzyl bromide having the general formula III (R1 = H, X = Br) , by KCN or NaCN in a   appropriate organic solvent, in the presence or absence of a catalyst   appropriate phase transfer, and then subjecting the 4- (3-   3D thienyl) -phenylacetonitrile thus obtained an alkylation by means   of a suitable alkyl halide, in the presence of a sol-   single-phase or two-phase with an organic solvent in the presence   a suitable catalyst to obtain the 4- (3-thienyl) -phenyl-   corresponding alkoyl 5. Method according to claim 4, characterized in that   performs the reaction involving N-bromosuccinimide and   formula II using -24 -   aromatic hydrocarbon or halocarbon   as CC14, as a non-polar organic solvent.   6. Process according to claim 4, characterized in that the compound of formula III (R1 = H, X = Br) is reacted with KCN or NaCN (i) in the presence of   organic solvents such as aromatic hydrocarbons, e.g.   benzene, or lower aliphatic alcohols, for example EtOH, X cd hydrocarbons. halgis, for example, CH 2 Cl 2, or aitrilahl] 1, by tx. 1RCN requires a phase transfer catalysis such as a tetraalkylammonium halide or bisulfate, or a benzyltrialkylammonium halide, or crown ethers, or (ii) at the reflux temperature in the presence of organic solvents miscible with water, for example EtOH in aqueous solution, dioxane in aqueous solution of acetone in aqueous solution or aprotic polar solvents, such as DMF, in the absence of a catalyst of phase transfer.   7. The method of claim 4; characterized in oe   subjecting said alkylation to 4- (3-thienyl) -   phenyl-actconitrile in the presence of a dialkyl carbonate   coyle, for example dimethyl carbonate.   8. Process according to claim 4, characterized   in that said alkylation is carried out with 4- (3-lenyl) -   phenylacetonitrile in the presence of a two-phase solvent medium comprising water and an organic solvent using a known phase transfer catalyst, such as   a tetraalkylammonium halide or bisulfate.   9. Process according to claim 3, characterized in   the hydrolysis of 4- (3-thienyl) nitrile is carried out   phenyl-alkyl by reflux either (i) with mineral acids in acetic acid and / or water (ii) with   akai1 strong in a hydro-alcoholic environment.   10. Process according to claim 5, characterized   in that the compound responding to the formula is reacted   mule III (= H, X = Br) Ar KCN or NaCN (i) in the presence -25-   organic solvents such as aromatic hydrocarbons   such as benzene, or aliphatic alcohols   lower ticks, eg EtOH, or hydrocarbons   halogenated bures, for example CH 2 CL 2, or an alkyl nitrile, for example CH 3 CN, in the presence of a phase transfer catalyst such as a halide or a bisulfate   of tetra-alkyl ammonium, or a benzyl halide   trialkylammonium, or crown ethers or (ii) at the reflux temperature, in the presence of water-miscible organic solvents, for example EtOH in aqueous solution, dioxane in aqueous solution, acetone in aqueous solution or aprotic polar solvents such as DMF, in the absence of phase transfer catalyst, 11. Process according to claim 7, characterized in that 4- (3-thienyl) phenylacetonitrile is subjected to   said alkylation in the presence of a biphase solvent medium   containing water and an organic solvent, using   a known phase transfer catalyst, such as   halide or a tetraalkylammonium bisulfate.   Pharmaceutical preparation, characterized in that it comprises a compound corresponding to formula I and according to claim 1 or 2, and carriers, diluents and / or additives thereof, pharmaceutically acceptable.