FR2476076A1 - NOVEL NITRILES USEFUL AS ANTI-INFLAMMATORY AND ANTI-ARTHRITIC, AND THERAPEUTIC COMPOSITIONS CONTAINING SAME - Google Patents

Abstract

THE INVENTION CONCERNS COMPOUNDS WITH ANTI-INFLAMMATORY AND ANTIARTHRITIC ACTIVITIES, AND COMPOSITIONS CONTAINING THEM. THE COMPOUNDS OF THE INVENTION INCLUDE THE FOLLOWING: M-FLUOROBENZIMIDOYLACETONITRILE, B-AMINO THIOPHENE-2 ACRYLONITRILE, B-AMINOTHIOPHENE-3 ACRYLONITRILE AND B-OXOTHIOPHENE-3 PROPIONITRILE. THESE COMPOUNDS AND COMPOSITIONS ARE USEFUL TO REDUCE INFLAMMATION AND OR INHIBIT THE PROGRESSIVE DETERIORATION OF THE JOINTS CHARACTERISTIC OF ARTHRITIC DISORDERS IN MAMMALS.

Description

 The present invention relates to novel compositions useful as anti-inflammatories and inhibitors of progressive joint degeneration characteristic of arthritic conditions.

où X représente un atome d' oxygène ou le radical NH ; et le symbole Aryl représente un radical phényle qui peut être substitué par un atome de fluor ou représente un radical thiényle.More particularly, the invention relates to therapeutic compositions comprising one or more compounds of formula (I)

where X represents an oxygen atom or the NH radical; and the Aryl symbol represents a phenyl radical which may be substituted by a fluorine atom or represents a thienyl radical.

 More particularly, the compositions of the invention are in the form of tablets or capsules.

 In one aspect, the invention relates to therapeutic compositions comprising benzoylacetonitrile, o-fluorobenzoylacetonitrile, m-fluorobenzoylaceronitrile, p-fluorobenzoylacetonitrile or mixtures thereof for reducing inflammation and inhibiting joint damage caused by arthritic conditions in mammals. Benzoylacetonitrile and l-fluorobenzoylactonitrile have been described by Dorsch et al, J.A.C.S. 54, 2960 (1932) and by Nakanischi et al, J. Med. Chem., 16 (3), 214 (1973), m-fluorobenzoylacetonitrile and p-fluorobenzoylacetonitrile were both described by Pihl et al, in Reakts.Sposobnost Org. Soedin.

Tartu. Gos. Univ., 5 (1), 27 (1968).

où Xlreprésente un atome d'hydrogène ou un radical m-fluoro ou p-fluoro.The invention also relates to therapeutic compositions comprising benzimidoylacetonitrile, m-fluorobenzimidoylacetonitrile or p-fluorobenzimidoylacetonitrile (or mixtures thereof in any proportions) which reduce inflammation and inhibit joint damage caused by arthritic conditions. in mammals. These active ingredients of the invention and their tautomeric forms can be represented by the following developed formulas

wherein X 1 represents a hydrogen atom or an m-fluoro or p-fluoro radical.

Benzimidoylacetonitrile and p-fluorobenzimidoylacetonide have been described by Lang et al. In J. Med. Chem. 18, 441 (1975) and benzimidoylacetonitrile can be easily prepared by the method of Iwai et al described in Chem, Pharm. Bull. (Tokyo) 12, 1446 (1964). This compound is also marketed by Aldrich Chemical Co. of Milwaukee, Wisconsin as β-imino-hydrocinnamonitrile.

ss-amino thiophène-acrylonitrile-2 ss-amino thiophene-acrylonitrile-3, et ss-oxo thiophènepropionitrile-3 et de nouvelles compositions les renfermant utiles comme anti-inflammatoires et comme inhibiteurs de l'altération progressive des articulations caract6- ristique des affections arthritiques chez les mammifères.The invention also relates to the following new compounds

α-amino thiophene-acrylonitrile-2β-amino thiophene-acrylonitrile-3, and β-oxo thiophene-3-propionitrile and novel compositions containing them useful as anti-inflammatories and as inhibitors of progressive joint degeneration characteristic of affections arthritic in mammals.

 M-Fluorobenzimidoyl acetonitrile is readily prepared by condensation of m-fluorobenzonitrile with acetonitrile in the presence of a base. Suitable bases are sodium hydride and sodium amide.

 To prepare the ss-amino thiophene-acrylonitrile-2 (or -3), thiophenecarbonitrile-2 (or -3) is condensed with acetonitrile, in the presence of a base such as sodium hydride. or sodium amide. If the ss-oxo thiophene-3 compound is desired, it can be obtained by hydrolysis (for example aqueous hydrolysis or alcoholic acid hydrolysis).

The ss-oxo thiophene-3 compound can be prepared directly by condensing a thiophenecarboxylic acid-3 ester with acetonitrile in the presence of a base such as sodium hydride or sodium amide.

et ce composé a été décrit dans le brevet des Etats-Unis d'Amérique nO 2 540 982.The invention also relates to therapeutic compositions comprising B-oxothiophenepropionitrile-2, which reduce inflammation and inhibit joint damage caused by arthritic conditions in mammals. B-oxo thiophanepropionitrile-2 can be represented by the following structural formula

and this compound has been described in U.S. Patent No. 2,540,982.

 The Applicant has discovered that the compounds of formula (I) are very useful for reducing inflammation and inhibiting joint damage in mammals when administered at a dose of between about 1 mg and about 250 mg per kg of body weight. body weight. Such a dose is administered daily or may be administered according to another mode of prescription suitable for reducing inflammation and inhibiting joint damage, for example by administration every other day or three times a week. A preferred dosage to achieve optimal results is to administer about 5 mg to about 100 mg per kg of body weight per day, in unit dosage form such that a subject weighing about 70 kg receives per 24 hours about 0, 35 g to about 7.0 g of active ingredient. This dosage can be adjusted to obtain the optimal therapeutic response. For example, several divided doses may be administered daily or the doses may be reduced proportionally according to the requirements of the therapeutic situation.

A particular advantage of the invention is that the active ingredient can be administered in any suitable manner, for example orally, intravenously, intramuscularly, locally, intra-articularly or subcutaneously.

 To obtain compositions according to the invention which are clear, stable and suitable for parenteral and intraarticular administration, 0.10% to 10.0% by weight of active compound is dissolved in a vehicle consisting of an aliphatic polyalcohol or a mixture of such polyalcohols. Particularly suitable alcohols are glycerin, propylene glycol and polyethylene glycols. Polyethylene glycols are mixtures of non-volatile, normally liquid polyethylene glycols, which are soluble in water and body fluids and have molecular weights of about 200 to 1500. Although the amount of active compound dissolved in such a vehicle can ranging from 0.10 to 10% by weight, it is preferred that the amount of active compound used be from about 3.0 to about 9.0% by weight. Although various mixtures of the aforementioned nonvolatile polyethylene glycols may be used. it is preferred to use a mixture having an average molecular weight of from about 200 to about 400.

 In addition to the active compound, parenteral solutions may also contain various preservatives that can be used to prevent contamination by bacteria and fungi. The preservatives that may be used for this purpose are, for example, myristyl-γ-picolinium chloride, phenylmercuric nitrate, benzalkonium chloride, phenethyl alcohol, (p-chlorophenoxy) -3 propanediol-1,2 methyl or propyl p-hydroxybenzoate and thimerosal. In practice it is also desirable to use antioxidants.

Suitable antioxidants are, for example, sodium bisulfite, sodium metabisulfite and sodium formaldehyde sulfoxylate. Generally, about 0.05 to about 0.2% antioxidant is used.

 For intramuscular injection, the preferred concentration of the active compound is between about 0.25 and 0.50 mg / ml of the finished composition. The compounds of formula (I) are also suitable for intravenous administration when diluted with appropriate amounts of water or diluents suitable for this mode of administration such as isotonic glucose. For intravenous administration, initial concentrations of up to about 0.05 to 0.25 mg of active compound / ml are suitable. For intra-articular administration to large joints such as the knee, about 2 to about 20 mg (or even more if needed) of active ingredient per joint per week can be used, with proportionally reduced doses. for smaller joints.

 The active compounds of the invention are preferably administered orally, for example with an inert diluent or with an assimilable edible carrier, or they may be coated in soft or hard gelatin capsules or tableted or even incorporated. directly to food. For oral therapeutic administration, the active compound can be incorporated into excipients and used in the form of tablets, lozenges, capsules, enteric-coated tablets or capsules, elixirs, suspensuions, syrups, cachets and the like. These compositions and preparations must contain at least 0.1% of active compound. The percentage of active compound in these compositions and preparations can of course vary and conveniently ranges from about 2% to about 60% of the weight of the unit form. The amount of active ingredient in such therapeutic compositions is such that an appropriate dosage is obtained. The preferred compositions and preparations according to the invention are prepared such that a unit dose of oral administration contains about 50 to 250 mg of active compound.

 Enteric tablets, tablets, pills, capsules, tablets and capsules may also contain the following components: a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin, or an aromatizing agent such as peppermint oil, Wintergreen essence or a cherry weapon. When the unit dose is in the form of a capsule, it may, in addition to the compounds of the aforementioned type, contain a liquid carrier such as a fatty oil. Various other materials may be present to coat or to modify in another way the physical form of the unit dose. For example, tablets, pills or capsules can be coated with shellac and / or sugar. The active compound may be contained in a syrup or an elixir with sucrose as a sweetening agent, methyl or propyl p-hydroxybenzoate as a preservative, a dye and an aromatizing agent such as a cherry or orange flavoring . Of course all the materials used to prepare these unit forms must have a purity suitable for use in pharmacy and be practically non-toxic to the amounts used.

 The novel compositions of the invention may be in the form of tablets or pills laminated or shaped so that the active ingredient has a prolonged or delayed effect or predetermined sequential effects. For example, a tablet or pill may consist of an inner component and an outer component, the latter enclosing the first. The two components can be separated by an enteric layer that resists disintegration in the stomach and allows the inner component to pass intact into the duodenum or to be released slowly. These enteric coating layers or coatings may be made of various materials such as various polymeric acids or mixtures of polymeric acids and other materials such as shellac, cetyl alcohol, cellulose acetate and the like. A particularly advantageous enteric coating is a copolymer of styrene and maleic acid with materials known to produce enteric disintegration of the coating. Tablets or pills can be stained with appropriate non-toxic dyes to give them a pleasant appearance.

 Experimental adjuvant polyarthritis is a generalized rat-specific disorder with interesting similarities to rheumatoid arthritis. In particular, the histological aspects of these two affections have a remarkable resemblance as shown by C. M. Pearson et al., In Am. J. Pathol. 42, 73 (1963).

EM Glenn, in Am. J. Vet. Res. 27 (116) 339 (1966) defined adjuvant polyarthritis as a permanent and disabling deformity due to diffuse connective tissue involvement around certain sensitive joints of the rat. Zahiri et al, in Can. Med. Ass. J. 101, 269 (1969) have shown that fusiform swelling of distal joints is associated with edema, congestion and synovitis involving pannus formation, all of which precede the final destruction of bone and cartilage. Zahiri et al further indicated that the destruction of articular cartilage was due to an invasive pannus from the marginal synovial membrane that extends over the articular surface and erodes it.
Nonsteroidal anti-inflammatory agents such as indomethacin which inhibit swelling of the paw, which is an infiltrate of inflammatory cells, also prevent damage to the joint and bone. (See S. Wong et al, J. Pharm W Exptl Ther 185, 127 (1973) and GR Bobalick et al, Agents & Actions 4, 364 (1974)). Similarly, inhibition of the progress of arthritis of the paw of the rats treated with the compounds of the invention reduces the associated joint deterioration.

The following tests show the activity of compounds of formula (I) on chronic inflammation of arthritis with adjuvant which is accompanied by joint destruction. Groups of three Wistar strain rats, Royal Hart, each weighing 200 + 10 g, were injected intradermally into the right hind paw of adjuvant.
Freund (human tubercle bacillus dried in a vehicle made of mineral oil) at a dose of 2 mg / kg body weight. The test compound of formula (I) is administered orally in a 1.5% starch carrier at various doses once daily, from day 0 to day 13 after the challenge injection. Control rats are treated in a similar manner by administering only the starch vehicle. On the 14th and 21st days after the challenge injection, the diameter of the injected paw (primary lesion) is measured with a palmer. The volume of the inflamed paws is evaluated from these measurements and the results are expressed as percent inhibition of swelling relative to the controls. At the same time other inflammatory sites such as ears, paws and tail (secondary lesions) are observed and each rat is scored according to the degree of inflammation and swelling. The notation corresponds to a scale from 0 to 24, where 0 represents the total absence of induced arthritic nodules and 24 represents the maximum degree of inflammation. The average score of each treated group is calculated and the effects of each compound are expressed by the percentage inhibition of the value of the controls. The following tables show the results of tests carried out with the compounds of formula (I) to suppress the evolution of arthritis and associated joint deterioration.

 In Table I below are the results obtained when the ingredients of formula (I) are benzoyl acetonitrile, o-fluorobenzoylacetonitrile, m-fluorobenzoylacetonitrile, p-fluorobenzoylacetonitrile and mixtures thereof.

 Table II below shows the results obtained when the active ingredients of formula (I) are benzimidoyl acetonitrile, m-fluorobenzimidoylacetonitrile, p-fluoro-imidoylacetonitrile and mixtures thereof.

 The low mortality observed in the case of rats treated with benzimidoylacetonitrile relative to the control rats or treated with standard compounds is particularly interesting.

Benzimidoylacetonitrile also has a longer duration of action than standard compounds, as shown by the greater suppression of primary and secondary lesions on the 21st day of the observation period.

 Table III below shows the results obtained when the active ingredient of formula (I) is D-amino thiophene acrylonitrile-2, p-amino thiophene-acrylonitrile-3 or p-oxothiophenepropionitrile-3.

 Table IV below shows the results obtained when the active ingredient of formula (I) is p-oxothiophenepropionitrile-2.

 Another method for determining the effect of a drug on conditions caused by inflammation is to measure the effect on ultraviolet-induced erythema in guinea pigs. The flanks of albino guinea pigs are epilated the evening before the test with a conventional mixture of barium sulphide and gum arabic. On the morning of the test at time 0, the animals are kept in a plastic housing pierced with three circular holes. They are exposed to ultraviolet radiation with a Kromayer "Hanovia" lamp, model 10, for 60 seconds.

Immediately after exposure to ultraviolet light, the guinea pigs are treated with the test compound by rubbing the ultraviolet-exposed areas with a cotton swab mounted on a stick which is dipped in solutions at various concentrations of the test compound. 'ethyl alcohol. After 1 and 4 hours, the degree of erythema of each of the three zones is recorded according to the following system: 0 = no erythema 0.5 = incomplete circle or weak erythema 1.0 = complete circle of erythema net.

The maximum score for each animal is 3.0.

 Table V below summarizes the results obtained in this test when using benzimidoylacetonitrile and other drugs known to have a beneficial effect on erythema of warm-blooded animals.

To determine the acute anti-inflammatory activity of benzimidoylacetonitrile, rats of strain Wistar, Royal are used
Hart, weighing 80 to 90 g. The rats are fasted overnight before the test, but are provided with water at will. The compounds to be studied are administered by gavage in the form of an aqueous suspension having a volume of 1.7 ml per 50 g of rat, which corresponds to the volume of hydration used by Winter et al., Proc. Soc. Exp. Biol. Med., 111, 544-547 (1962) 1. The phlogistic agent used is a sterile ordinary suspension of 1% carrageenin in 0.9% aqueous sodium chloride. 0.05 ml is injected with a 0.45 mm diameter needle into the plantar tissue of the right hind paw. Measurements are taken 5 hours after the administration of the drug (4 hours after the test injection). carrageenin). The volumes of the normal paw and the inflamed paw are determined by carrageenin. It is considered that the difference between the two measures is due to edema caused by the administration of carrageenin. The results are expressed by the ratio t / T (edema of the control animals / edema of the treated animals) and a compound is considered to be active if the ratio t / T is greater than 1 41. The following table VI is presented: after the results of this test observed for the indicated doses of benzimidoylacetonitrile, these results showing the effectiveness of this compound compared to known anti-inflammatories.

 The effect of benzimidoylacetonitrile on body temperature in yeast-induced hyperthermia is determined.

Subcutaneous injections were made into the neck skin of groups of three Wistar Royal Hart strain rats each weighing 80 + 5 g, 0.6 ml of a 40% suspension of dry beer yeast in water. distilled. The compounds to be studied are suspended in a 1.5% buffered starch solution and administered at a dose of 250 mg / kg by gavage, 17 hours after the challenge injection. The control rats are treated in a similar manner but only the buffered starch solution is administered to them. At the 19 th hour after the test injection, the rectal temperature of each rat is measured with an electric thermometer. Each experiment is repeated at least once. The results obtained in this test with benzimidoylacetonitrile and known antiinflammatory agents are shown in Table VII below.

 Other features and advantages of the invention will be better understood on reading the following description of several embodiments. In these examples, the compounds of formula (I) consist in particular of benzoylacetonitrile, o-fluorobenzoylacetonitrile, m-fluorobenzoylacetonitrile, p-fluorobenzoylacetonitrile, benzimidoylacetonitrile, m-fluorobenzimidoylacetonitrile, p-fluoroimidoylacetonitrile and their mixtures of ss-amino thiophene-acrylonitrile-2, p-amino thiophene-acrylonitrile-3, p-oxothiophenepropionitrile-3 or D-oxo thiophenepropionitrile-2.

Example 1
Preparation of tablets weighing 50 mg
Per tablet per 10,000 tablets 0.050 g compound of formula (I) 500 g 0.080 g lactose 800 g 0.010 g corn starch (for mixing), 100 g 0.008 g corn starch (for starch) 75 g 0.148 g 1475 g 0.002 g magnesium stearate (1%) 15 g 0.150 g 1490 g
The compound of formula (I), lactose and corn starch (for mixing) is mixed. The corn starch (for the poi) was suspended in 600 ml of water and heated with stirring to form a poi. This paste is used to granulate the mixture of powders.

If necessary, an additional amount of water is used. The wet granules were passed through the 2.38 mm mesh screen and dried at 49 ° C. The dry granules were passed through a 1.00 mesh screen of mesh opening. with 1% magnesium stearate and tableted with a suitable machine.

Example 2
Preparation of an oral suspension or syrup
Ingredients Quantities
Compound of formula (I) 500 mg
Sorbitol solution (70%, National Formulary) 40 ml
Sodium benzoate 150 mg
Saccharin 10 mg
Red dye 10 mg
Cherry flavor 50 mg
Distilled water, qs 100 ml
The sorbitol solution is added to 40 ml of distilled water and the compound of formula (I) is suspended therein. Saccharin, sodium benzoate, flavor and color are added and dissolved. The volume is adjusted to 100 ml with distilled water. Each milliliter of syrup contains 5 mg of the compound of formula (I).

Example 3
Preparation of a parenteral solution
In a solution of 700 ml of propylene glycol and 200 ml of water for injection, 20.0 g of a compound of formula (I) are suspended with stirring. When the suspension is complete, the pH is adjusted to 5.5 with hydrochloric acid and the volume is adjusted to 1000 ml with water for injection. The composition is sterilized, packaged at 2.0 ml (40 mg drug) in 5.0 ml ampoules and sealed under nitrogen.

Example 4
Preparation of a cream for local use
Ingredients Quantities
Compound of formula (I) 1.0 7.

Ethoxylated stearyl alcohol 10.0%
Benzyl alcohol 0.9%
Isopropyl palmitate 5.0%
Glycerin 5.0%
Sorbitol solution (Pharmacopoeia of the United States of America) 5.0 7
Lactic acid qs for pH 4.0-5.0
Water, qs 100.0%
The ethoxylated stearyl alcohol and the isopropyl palmitate are heated to liquefaction. About 95% of the total volume of water is added to a separate container, followed by glycerine and sorbitol solution. The aqueous mixture is boiled and then cooled to 60-750C. The compound of formula (I) is added to the waxy phase, and the mixture is stirred until a clear solution is obtained.

Benzyl alcohol is added and dissolved in the waxy phase. The aqueous phase is passed through a sieve into the waxy phase while maintaining stirring. Both phases are maintained at about the same temperature during transfer. The mixture is cooled while continuing the stirring. At a temperature of 50 to 550C, the remainder of water is added.

The pH is adjusted to 5.0-7.0 with lactic acid. The batch is cooled with stirring to a minimum until the cream takes its final form.

Example 5
Preparation of a product for intra-articular injection
Ingredients Quantities
Compound of formula (I) 2-20 mg
Sodium chloride (physiological saline) 0.9%
Benzyl alcohol (National Formulary) 0.9%
Sodium carboxymethylcellulose 1-5% pH adjusted to 5.0-7.5
Injectable water, qs 100%
Example 6
Preparation of an iniectable suspension of late effect
Ingredients 7 p / v
Compound of formula (I) 0.05-5.0
Polysorbate 80 (United States Pharmacopeia) 0.2 Polyethylene Glycol 4000 (United States Pharmacopoeia) 3.0
Sodium Chloride (United States Pharmacopoeia) 0.8
Benzyl alcohol (National Formulary) 0.9
Hydrochloric acid, qs for pH 6-8
Injectable water, qs 100.0
Example 7
Preparation of coated tablets
Film-coated tablets weighing 500 mg.

Tablet containing a compound of formula (I) (uncoated)
Ingredients% excess 7 by weight
Compound of formula (I) 2 54,198
Modified starch 35,016
Sodium dioctylsulfosuccinate 70% in ethyl alcohol 0.159
Variable ethyl alcohol
Alginic acid 10,627
Film coating
ingredients
Pharmaceutical coating (Pharmaceutical glaze N 4)% by weight / 0.488
Colloidal Kaolin (National Formulary) 0.032
3,312 cellulose acetate phthalate
Diethyl phthalate 1,418
Opaspray Yellow / Kl-2102 * 0.526 # In countries where the use of Yellow n 5 FD & C is undesirable, white film-coated tablets may be used.

Method of preparation (uncoated tablets) 1. The compound of formula (I) and the modified starch (Primojel) are introduced into a clean Glen Bowl mixer or other suitable mixer. The two ingredients are mixed at 50 rpm for 15 to 20 minutes.

2. The ethyl alcohol is introduced into a clean container having a steam jacket. The alcohol is heated to 550C in the container.

3. A weighed quantity of 70% Aerosol OT in ethyl alcohol is mixed in the hot ethyl alcohol (55 C) of stage n 2.

4. The mixture of stage 1 powders is granulated with the alcoholic solution of sodium dioctylsulfosuccinate stage 3.

An additional amount of hot alcohol (550C) of the NO2 stage is added if necessary to complete the granulation.

5. The wet granules are passed through a clean Fitzmill apparatus equipped with a No. 4A sieve at 1000 rpm and the sieved granules are collected on a suitable number of flat, dry paper-filled cuvettes.

6. Stage 5 cuvettes are placed in a suitable drying oven and dried at 430 ° C overnight.

7. The dried granules are passed through a clean universal stirrer and a 1.41 mm mesh screen.

8. The sieved pellets are treated in stage 7 with a clean Fitzmill apparatus and a 1.41 mm mesh sieve at 2200 rpm.

9. All the granules of Steps 7 and 8 are combined and introduced into a suitable mixer where they are mixed for 10 to 15 minutes. The alginic acid is added and mixed for a total of 20 minutes.

10. The finished material is introduced into polyethylene coated fiber drums.

11. The product obtained is ready to be shaped by compression.

Method of preparation (enteric coating tablets) 1. Uncoated tablets weighing 500 mg containing the compound of formula (I) are introduced into a coating machine equipped with baffles and an air duct at 700 ° C. 10 cm in diameter, and an appropriate exhaust pipe. The tablets should fall freely in cascade when the machine is running. The front opening of the machine is not closed.

2. Pharmaceutical coating No. 4 is introduced onto the cascading tablets of Step 1. When the tablets appear sticky, powder is made with colloidal kaolin (National Formulary).

Kaolin must be added to the inside surface of the coating machine and not directly to the tablets. The machine is made to coat for 3 minutes after dusting.

3. The drying air is turned on and the machine is turned on for 3 minutes. The machine is stopped and the tablets are shaken for 30 minutes or until they are dry.

4. The pharmaceutical coating n04 is poured onto the cascade tablets in stage 3 and is powdered with colloidal kaolin (National Formulary) as for the first coating. The tablets are shaken to dry for 1 hour or until dry.

5. With a suitable high-shear mixer, cellulose acetate phthalate (Pharmacopoeia of the United States of America) is dispersed in methylene chloride and methanol.

6. Diethyl phthalate is added to the mixture of Step No. 5 and stirring is continued until the solution no longer contains particles when examined on a stainless steel spatula.

7. Opaspray K-1-7000 is added to the Stage 6 mixture and stirring is continued.

8. Stage 7 film coating solution is sprayed with a Nordson spray apparatus into the Stage 4 coating machine.

9. Set the Nordson to dispense 450-500 ml / min. The pressure can be varied to obtain this flow.

10. A sample of the level 4 shellac coated tablets is taken from the coating machine. The coated shellac sample is weighed with a suitable scale. Similar samples are taken during the coating cycle to determine the amount of film carried by each tablet.

11. The film coating solution is applied by continuous spraying until a film weighing 50 mg per tablet is obtained. Air drying is carried out during spraying.

12. The finished tablets are tumbled for 4 minutes after completion of spraying. During this period, the hot air supply device and the evacuation device must operate.

13. Finished tablets are introduced into suitably coated drums with a capacity of 10 to 20 kg.

Cover with gauze and let stand for 12 hours before closing.

Example 8
Preparation of m-fluorobenzimidoylacetonitrile
To the 25 ml of ether are added 1.21 g of m-fluorobenzonitrile, 0.52 ml of acetonitrile, 0.5 g of sodium hydride and 0.1 ml of tertiary butanol. The mixture is refluxed on a steam bath for 1 hour. Methanol and water are added. The layers are separated and the aqueous layer is extracted with two 25 ml portions of ether. The combined ether layers were dried over sodium sulfate, passed over diatomaceous earth, diluted with hexanes and evaporated on a boiling water bath. The oil obtained is chromatographed with methylene chloride on silica gel to obtain 0.52 g of an oil which crystallizes. This product is taken up in methylene chloride.

a mixture of hexanes is added and evaporated to obtain an oil which crystallizes. It is recrystallized from carbon tetrachloride to obtain the desired product; F. 67-68 C.

Example 9
Preparation of ss-amino thiophene-acrylonitrile-2
To dry a reactor is flamed by purging with a stream of nitrogen. About 100 ml of ammonia are condensed in the reactor and a small piece of sodium is added to obtain a blue color. The color is turned with ferric chloride and 2.7 g of sodium are added. When the blue color disappeared, 4.8 ml of acetonitrile in 10 ml of ethyl ether are added. The reaction mixture is cooled in a bath of acetone and dry ice and 9.28 g of thiophenecarbonitrile-2 in 25 ml of tetrahydrofuran are added dropwise.

Cooling is continued for 30 minutes, then the ammonia and solvent are allowed to evaporate. 50 ml of water are added and the mixture is extracted with methylene chloride. The methylene chloride extract is dried over sodium sulfate and passed over Magnesol. A hexanes mixture is added and the filtrate is evaporated on a boiling water bath to obtain an oil. This oil is chromatographed on a dry column of silica gel, eluting with methylene chloride. The fraction containing the desired product is taken up in methylene chloride, passed over Magnesol and the filtrate evaporated on a boiling water bath by adding a mixture of hexanes until the oil separates. It is cooled to obtain the desired product in the form of crystals; F. 87-880C.

Example 10
Preparation of D-amino thiophene-acrylonitrile-3
A 500 ml three-necked flask equipped with a mechanical stirrer, gas inlet, dry ice condenser, potassium hydroxide drying tube and tap. 100 ml of ammonia are condensed in the flask and a grain of sodium is added. When the dark blue color persists, it is turned brown by the addition of ferric chloride. 3.2 g of sodium are added and the mixture is allowed to stand for 45 minutes until the blue color disappears. 5.7 ml of acetonitrile and 10 ml of tetrahydrofuran are added and the reaction mixture is stirred for 20 minutes.

The reaction mixture is cooled in a bath of dry ice and acetone and 10.9 g of thiophenecarbonitrile-3 in 25 ml of tetrahydrofuran are added. The reaction mixture is stirred in a cooling bath for 90 minutes and then refluxed for 3 hours. 7.4 g of ammonium chloride are added and the mixture is allowed to evaporate overnight.

100 ml of water and 100 ml of chloroform are added and the mixture is filtered.

The aqueous phase is extracted with chloroform, the combined organic solution is washed once with water, dried over magnesium sulfate and filtered through Magnesol. The filtrate is evaporated in vacuo to give an orange oil. 30 ml of benzene and then of petroleum ether are added until the medium is cloudy. Upon cooling, a precipitate is obtained which is collected and recrystallized from benzene to give the desired product as a solid; Mp 67-69.5 ° C.

Example 11
Preparation of B-oxo thiophenepropionitrile-3
1.2 g of p-amino thiopheneacrylonitrile-3 are added to 10 ml of 1N hydrochloric acid. 40 ml of methanol are added and the mixture is stirred for 3 hours. The mixture is evaporated in vacuo to give a residue which is dissolved in 35 ml of hot methanol and treated with activated charcoal. After cooling, petroleum ether is added, the mixture is filtered and the solid collected is discarded. The filtrate is allowed to evaporate and the residue is dissolved in 35 ml of hot isopropanol, filtered and cooled. The solid is collected to obtain the desired product in the form of white tables; F. 87-880C.

 Naturally, various modifications may be made by those skilled in the art to the devices or methods which have just been described solely by way of non-limiting examples without departing from the scope of the invention.

TABLE I
Effects of benzoylacetonitrile and its fluoro derivatives on rat adjuvant arthritis.

<SEP> Dose
<tb><SEP> oral <SEP> Gain <SEP> of <SEP> weight <SEP> Inhibition <SEP> (%) <SEP> Inhibition <SEP> (%) <SEP> by
<tb> Compound <SEP> (mgkg <SEP> of <SEP> average <SEP> (g) <SEP> of <SEP> swelling <SEP> report <SEP> to <SEP> controls
<tb><SEP> poide <SEP> Dead / treated <SEP> (lesion <SEP> primary) <SEP> (lesion <SEP> secondary)
<tb><SEP> corporal) <SEP> at <SEP> 21st <SEP> day <SEP> day <SEP> day <SEP> day <SEP> day <SEP> day <SEP> day
<tb><SEP> 14 <SEP> 21 <SEP> 14 <SEP> 21 <SEP> 14 <SEP> 21
<tb> Normal <SEP> Rats <SEP> - <SEP> 8/186 <SEP> 77 <SEP> 112 <SEP> - <SEP> - <SEP> - <SEP>
witnesses
<tb>"Adjuvant"<SEP> - <SEP> 53/630 <SEP> 36 <SEP> 31 <SEP> 0 <SEP> 0 <SEP> 0 <SEP> 0
<tb> Indomethacin <SEP> 2 <SEP> 8/57 <SEP> 68 * <SEP> 68 * <SEP> 51 * <SEP> 24 * <SEP> 38 * <SEP> 25 *
<tb><SEP> 1 <SEP> 9/54 <SEP> 63 * <SEP> 65 * <SEP> 46 * <SEP> 19 * <SEP> 34 * <SEP> 20 *
<tb><SEP> 0.5 <SEP> 5/54 <SEP> 53 * <SEP> 51 * <SEP> 40 * <SEP> 20 * <SEP> 25 * <SEP> 17 *
<tb><SEP> 0.25 <SEP> 0/9 <SEP> 51 <SEP> 57 * <SEP> 30 * <SEP> 4 <SEP> 22 * <SEP> 4
<tb> Aspirin <SEP> 400 <SEP> 18/57 <SEP> 41 <SEP> 55 * <SEP> 73 * <SEP> 48 * <SEP> 58 * <SEP> 45 *
<tb><SEP> 200 <SEP> 10/66 <SEP> 40 <SEP> 44 <SEP> 48 * <SEP> 27 * <SEP> 26 * <SEP> 17 *
<tb><SEP> 100 <SEP> 18/63 <SEP> 48 <SEP> 53 * <SEP> 36 * <SEP> 13 <SEP> 19 * <SEP> 8
<tb><SEP> 50 <SEP> 2/21 <SEP> 56 * <SEP> 44 <SEP> 23 * <SEP> 3 <SEP> 12 <SEP> 9
Phenylbuta- SEP 150 SEP 2/27 SEP 40 SEP 50 SEP 75 SEP 44 SEP 54 SEP 31
<tb> zone <SEP> 75 <SEP> 2/39 <SEP> 51 * <SEP> 50 * <SEP> 62 * <SEP> 28 * <SEP> 27 * <SEP> 15
<tb><SEP> 37.5 <SEP> 5/39 <SEP> 53 * <SEP> 53 * <SEP> 56 * <SEP> 14 <SEP> 18 <SEP> 13
<tb><SEP> 18.8 <SEP> 2/21 <SEP> 50 * <SEP> 45 <SEP> 31 <SEP> 7 <SEP> 4 <SEP> 8
<tb> TABLEAUI (continued)

<SEP> Dose
<tb><SEP> oral <SEP> Gain <SEP> of <SEP> weight <SEP> Inhibition <SEP> (%) <SEP> Inhibition <SEP> (%) <SEP> by
<tb> Compound <SEP> (mgkg <SEP> of <SEP> average <SEP> (g) <SEP> of <SEP> swelling <SEP> report <SEP> to <SEP> controls
<tb><SEP> poide <SEP> Dead / treated <SEP> (lesion <SEP> primary) <SEP> (lesion <SEP> secondary)
<tb><SEP> corporal) <SEP> at <SEP> 21st <SEP> day <SEP> day <SEP> day <SEP> day <SEP> day <SEP> day <SEP> day
<tb><SEP> 14 <SEP> 21 <SEP> 14 <SEP> 21 <SEP> 14 <SEP> 21
Benzoylaceae SEP 400 SEP 3/18 SEP 31 SEP 72 SEP 81 SEP 72 SEP 84 SEP 82
<tb> tonitrile <SEP> 200 <SEP> 2/13 <SEP> 56 * <SEP> 81 * <SEP> 73 * <SEP> 48 * <SEP> 70 * <SEP> 43 *
<tb><SEP> 100 <SEP> 5/36 <SEP> 49 * <SEP> 65 * <SEP> 63 * <SEP> 48 * <SEP> 70 * <SEP> 43 *
<tb><SEP> 50 <SEP> 6/54 <SEP> 53 * <SEP> 59 * <SEP> 51 * <SEP> 42 * <SEP> 52 * <SEP> 26 *
<tb><SEP> 25 <SEP> 3/36 <SEP> 54 * <SEP> 56 * <SEP> 54 * <SEP> 33 * <SEP> 40 * <SEP> 14
<tb> p-fluoroben- <SEP> 400 <SEP> 3/18 <SEP> 42 <SEP> 64 * <SEP> 75 * <SEP> 63 * <SEP> 72 * <SEP> 45 *
<tb> zoylecetoni- <SEP> 200 <SEP> 3/18 <SEP> 67 * <SEP> 62 * <SEP> 52 * <SEP> 32 * <SEP> 63 * <SEP> 16
<tb> trile <SEP> 100 <SEP> 4/18 <SEP> 63 * <SEP> 71 * <SEP> 46 * <SEP> 32 * <SEP> 44 * <SEP> 10
<tb><SEP> 50 <SEP> 2/36 <SEP> 61 * <SEP> 58 * <SEP> 56 * <SEP> 39 * <SEP> 13 <SEP> 0
<tb><SEP> 25 <SEP> 1/18 <SEP> 55 * <SEP> 48 <SEP> 33 * <SEP> 17 <SEP> 25 <SEP> 0
<tb> m-fluorobenzoylacetone- <SEP> 50 <SEP> 0/21 <SEP> 43 <SEP> 37 <SEP> 40 * <SEP> 27 *
<tb> trile
<tb> o-fluorobenzoylacetone- <SEP> 50 <SEP> 1/18 <SEP> 71 * <SEP> 72 * <SEP> 63 * <SEP> 49 *
<tb> trile
<tb> * Significant difference compared to adjuvant controls.

TABLE II
Effects of benzimidoylacetonitrile and its fluoro derivatives on rat adjuvant arthritis.

<SEP> Dose
<tb><SEP> oral <SEP> Gain <SEP> of <SEP> weight <SEP> Inhibition <SEP> (%) <SEP> Inhibition <SEP> (%) <SEP> by
<tb> Compound <SEP> (mgkg <SEP> of <SEP> average <SEP> (g) <SEP> of <SEP> swelling <SEP> report <SEP> to <SEP> controls
<tb><SEP> poide <SEP> Dead / treated <SEP> (lesion <SEP> primary) <SEP> (lesion <SEP> secondary)
<tb><SEP> corporal) <SEP> at <SEP> 21st <SEP> day <SEP> day <SEP> day <SEP> day <SEP> day <SEP> day <SEP> day
<tb><SEP> 14 <SEP> 21 <SEP> 14 <SEP> 21 <SEP> 14 <SEP> 21
<tb> Normal <SEP> Rats <SEP> - <SEP> 8/186 <SEP> 77 <SEP> 112 <SEP> - <SEP> - <SEP> - <SEP>
witnesses
<tb>"Adjuvant"<SEP> - <SEP> 53/630 <SEP> 36 <SEP> 31 <SEP> 0 <SEP> 0 <SEP> 0 <SEP> 0
<tb> Indomethacin <SEP> 2 <SEP> 8/57 <SEP> 68 * <SEP> 68 * <SEP> 51 * <SEP> 24 * <SEP> 38 * <SEP> 25 *
<tb><SEP> 1 <SEP> 9/54 <SEP> 63 * <SEP> 65 * <SEP> 46 * <SEP> 19 * <SEP> 34 * <SEP> 20 *
<tb><SEP> 0.5 <SEP> 5/54 <SEP> 53 * <SEP> 51 * <SEP> 40 * <SEP> 20 * <SEP> 25 * <SEP> 17 *
<tb><SEP> 0.25 <SEP> 0/9 <SEP> 51 <SEP> 57 * <SEP> 30 * <SEP> 4 <SEP> 22 * <SEP> 4
<tb> Aspirin <SEP> 400 <SEP> 18/57 <SEP> 41 <SEP> 55 * <SEP> 73 * <SEP> 48 * <SEP> 58 * <SEP> 45 *
<tb><SEP> 200 <SEP> 10/66 <SEP> 40 <SEP> 44 <SEP> 48 * <SEP> 27 * <SEP> 26 * <SEP> 17 *
<tb><SEP> 100 <SEP> 18/63 <SEP> 48 <SEP> 53 * <SEP> 36 * <SEP> 13 <SEP> 19 * <SEP> 8
<tb><SEP> 50 <SEP> 2/21 <SEP> 56 * <SEP> 44 <SEP> 23 * <SEP> 3 <SEP> 12 <SEP> 9
<tb> TABLE II (continued)

<SEP> Dose
<tb><SEP> oral <SEP> Gain <SEP> of <SEP> weight <SEP> Inhibition <SEP> (%) <SEP> Inhibition <SEP> (%) <SEP> by
<tb> Compound <SEP> (mgkg <SEP> of <SEP> average <SEP> (g) <SEP> of <SEP> swelling <SEP> report <SEP> to <SEP> controls
<tb><SEP> poide <SEP> Dead / treated <SEP> (lesion <SEP> primary) <SEP> (lesion <SEP> secondary)
<tb><SEP> corporal) <SEP> at <SEP> 21st <SEP> day <SEP> day <SEP> day <SEP> day <SEP> day <SEP> day <SEP> day
<tb><SEP> 14 <SEP> 21 <SEP> 14 <SEP> 21 <SEP> 14 <SEP> 21
<tb> Phenylbutazone <SEP> 150 <SEP> 2/27 <SEP> 40 <SEP> 50 * <SEP> 75 * <SEP> 44 * <SEP> 54 * <SEP> 31 *
<tb><SEP> 75 <SEP> 2/39 <SEP> 51 * <SEP> 50 * <SEP> 62 * <SEP> 28 * <SEP> 27 * <SEP> 15
<tb><SEP> 37.5 <SEP> 5/39 <SEP> 53 * <SEP> 53 * <SEP> 56 * <SEP> 14 <SEP> 18 <SEP> 13
<tb><SEP> 18.8 <SEP> 2/21 <SEP> 50 * <SEP> 45 <SEP> 31 <SEP> 7 <SEP> 4 <SEP> 8
<tb> Benzimidoyleate- <SEP> 100 <SEP> 0/15 <SEP> 46 <SEP> 65 * <SEP> 68 * <SEP> 60 * <SEP> 57 * <SEP> 46 *
<tb> tonitriol <SEP> 50 <SEP> 1/24 <SEP> 31 <SEP> 49 * <SEP> 63 * <SEP> 62 * <SEP> 59 * <SEP> 48 *
<tb><SEP> 25 <SEP> 1/9 <SEP> 41 <SEP> 38 <SEP> 33 * <SEP> 32 * <SEP> 33 * <SEP> 16 *
<tb> p-fluorobenzi- <SEP> 100 <SEP> 1/18 <SEP> 78 * <SEP> 67 * <SEP> 53 * <SEP> 29 * <SEP> 49 * <SEP> 22 *
<tb> midoylaceto- <SEP> 50 <SEP> 4/36 <SEP> 66 * <SEP> 57 * <SEP> 43 * <SEP> 25 * <SEP> 27 * <SEP> 8
<tb> nitrile <SEP> 25 <SEP> 2/18 <SEP> 53 <SEP> 50 <SEP> 26 <SEP> 14 <SEP> 14 <SEP> 9
<tb> m-fluoroenzimi- <SEP> 50 <SEP> 1/18 <SEP> 64 <SEP> 60 <SEP> 40 * <SEP> 7 <SEP> - <SEP> doylacetonitrile
<tb> * Significant difference compared to adjuvant controls.

TABLE III
Effect of thiophene derivatives on arthritis of rat adjuvant.

<SEP> Dose
<tb><SEP> oral <SEP> Gain <SEP> of <SEP> weight <SEP> Inhibition <SEP> (%) <SEP> Inhibition <SEP> (%) <SEP> by
<tb> Compound <SEP> (mgkg <SEP> of <SEP> average <SEP> (g) <SEP> of <SEP> swelling <SEP> report <SEP> to <SEP> controls
<tb><SEP> poide <SEP> Dead / treated <SEP> (lesion <SEP> primary) <SEP> (lesion <SEP> secondary)
<tb><SEP> corporal) <SEP> at <SEP> 21st <SEP> day <SEP> day <SEP> day <SEP> day <SEP> day <SEP> day <SEP> day
<tb><SEP> 14 <SEP> 21 <SEP> 14 <SEP> 21 <SEP> 14 <SEP> 21
<tb> Normal <SEP> Rats <SEP> - <SEP> 8/186 <SEP> 77 <SEP> 112 <SEP> - <SEP> - <SEP> - <SEP>
Controls <SEP>"adjuvent"<SEP> - <SEP> 56/630 <SEP> 36 <SEP> 31 <SEP> 0 <SEP> 0 <SEP> 0 <SEP> 0
<tb> Indomethacin <SEP> 2 <SEP> 8/57 <SEP> 68 <SEP> 68 <SEP> 51 <SEP> 24 <SEP> 38 <SEP> 25
<tb><SEP> 1 <SEP> 9/54 <SEP> 63 <SEP> 65 <SEP> 46 <SEP> 19 <SEP> 34 <SEP> 20
<tb><SEP> 0.5 <SEP> 5/54 <SEP> 53 <SEP> 51 <SEP> 40 <SEP> 20 <SEP> 25 <SEP> 17
<tb><SEP> 0.25 <SEP> 0/9 <SEP> 51 <SEP> 57 <SEP> 30 <SEP> 4 <SEP> 22 <SEP> 4
<tb> Aspirin <SEP> 400 <SEP> 18/57 <SEP> 41 <SEP> 55 <SEP> 73 <SEP> 48 <SEP> 58 <SEP> 45
<tb><SEP> 200 <SEP> 10/66 <SEP> 40 <SEP> 44 <SEP> 48 <SEP> 27 <SEP> 26 <SEP> 17
<tb><SEP> 100 <SEP> 18/63 <SEP> 48 <SEP> 53 <SEP> 36 <SEP> 13 <SEP> 19 <SEP> 8
<tb><SEP> 50 <SEP> 2/21 <SEP> 56 <SEP> 44 <SEP> 23 <SEP> 3 <SEP> 12 <SEP> 9
<tb> Phenylbutazone <SEP> 150 <SEP> 2/27 <SEP> 40 <SEP> 50 <SEP> 75 <SEP> 44 <SEP> 54 <SEP> 31
<tb><SEP> 75 <SEP> 2/39 <SEP> 51 <SEP> 50 <SEP> 62 <SEP> 28 <SEP> 27 <SEP> 15
<tb><SEP> 37.5 <SEP> 5/39 <SEP> 53 <SEP> 53 <SEP> 56 <SEP> 14 <SEP> 18 <SEP> 13
<tb><SEP> 18.8 <SEP> 2/21 <SEP> 50 <SEP> 45 <SEP> 31 <SEP> 7 <SEP> 4 <SEP> 8
<ss-amino-thiophene- <SEP> 200 <SEP> 6/18 <SEP> 36 <SEP> 53 <SEP> 70 <SEP> 61 <SEP> 80 <SEP> 57
<tb> acrylonitrile-2 <SEP> 100 <SEP> 2/18 <SEP> 45 <SEP> 51 <SEP> 49 <SEP> 27 <SEP> 25 <SEP> 16
<tb><SEP> 50 <SEP> 1/33 <SEP> 54 <SEP> 50 <SEP> 44 <SEP> 23 <SEP> 21 <SEP> 6
<tb> TABLE III (continued)

<SEP> Dose
<tb><SEP> oral <SEP> Gain <SEP> of <SEP> weight <SEP> Inhibition <SEP> (%) <SEP> Inhibition <SEP> (%) <SEP> by
<tb> Compound <SEP> (mgkg <SEP> of <SEP> Dead / Treated <SEP> Medium <SEP> (g) <SEP> of <SEP> Swelling <SEP> Report <SEP> to <SEP> Controls
<tb><SEP> poide <SEP> at <SEP> 21st <SEP> day <SEP> (lesion <SEP> primary) <SEP> (lesion <SEP> secondary)
<tb><SEP> corporal) <SEP> day <SEP> 14 <SEP> day <SEP> 21 <SEP> day <SEP> 14 <SEP> day <SEP> 21 <SEP> day <SEP> 14 <SEP > day <SEP> 21
<ss-amino-thiophene- <SEP> 50 <SEP> 2/18 <SEP> 47 <SEP> 54 <SEP> 52 <SEP> 41 <SEP> - <SEP> Acrylonitrile-3
<tb> ss-oxothiophene- <SEP> 50 <SEP> 1/18 <SEP> 53 <SEP> 50 <SEP> 61 <SEP> 26 <SEP> - <SEP> propionitrile-3
<tb> TABLE IV
Effects of ss-oxothiophenepropionitrile-2 on arthritis in rat adjuvant.

<SEP> Dose <SEP> Oral <SEP> Dead / Treated <SEP> Gain <SEP> of <SEP> Weight <SEP> Inhibition <SEP> (%) <SEP> Inhibition <SEP> (%) <SEP> by
<tb> Compound <SEP> (mg / kg <SEP> of <SEP> average <SEP> of <SEP> swelling <SEP> ratio <SEP> to <SEP> controls
<tb><SEP> poide <SEP> at <SEP> 21st <SEP> day <SEP> (g) <SEP> (lesion <SEP> primary) <SEP> (lesion <SEP> secondary)
<tb><SEP> corporal) <SEP> day <SEP> day <SEP> day <SEP> day <SEP> day <SEP> day
<tb><SEP> 14 <SEP> 21 <SEP> 14 <SEP> 21 <SEP> 14 <SEP> 21
<tb> Normal <SEP> Rats <SEP> - <SEP> 8/186 <SEP> 77 <SEP> 112 <SEP> - <SEP> - <SEP> - <SEP>
Controls <SEP>"adjuvent"<SEP> - <SEP> 56/630 <SEP> 36 <SEP> 31 <SEP> 0 <SEP> 0 <SEP> 0 <SEP> 0
<tb> Indomethacin <SEP> 2 <SEP> 8/57 <SEP> 68 <SEP> 68 <SEP> 51 <SEP> 24 <SEP> 38 <SEP> 25
<tb><SEP> 1 <SEP> 9/54 <SEP> 63 <SEP> 65 <SEP> 46 <SEP> 19 <SEP> 34 <SEP> 20
<tb><SEP> 0.5 <SEP> 5/54 <SEP> 53 <SEP> 51 <SEP> 40 <SEP> 20 <SEP> 25 <SEP> 17
<tb><SEP> 0.25 <SEP> 0/9 <SEP> 51 <SEP> 57 <SEP> 30 <SEP> 4 <SEP> 22 <SEP> 4
<tb> Aspirin <SEP> 400 <SEP> 18/57 <SEP> 41 <SEP> 55 <SEP> 73 <SEP> 48 <SEP> 58 <SEP> 45
<tb><SEP> 200 <SEP> 10/66 <SEP> 40 <SEP> 44 <SEP> 48 <SEP> 27 <SEP> 26 <SEP> 17
<tb><SEP> 100 <SEP> 18/63 <SEP> 48 <SEP> 53 <SEP> 36 <SEP> 13 <SEP> 19 <SEP> 8
<tb><SEP> 50 <SEP> 2/21 <SEP> 56 <SEP> 44 <SEP> 23 <SEP> 3 <SEP> 12 <SEP> 9
<tb> TABLE IV (continued)

<SEP> Dose <SEP> Oral <SEP> Dead / Treated <SEP> Gain <SEP> of <SEP> Weight <SEP> Inhibition <SEP> (%) <SEP> Inhibition <SEP> (%) <SEP> by
<tb> Compound <SEP> (mg / kg <SEP> of <SEP> average <SEP> of <SEP> swelling <SEP> ratio <SEP> to <SEP> controls
<tb><SEP> poide <SEP> at <SEP> 21st <SEP> day <SEP> (g) <SEP> (lesion <SEP> primary) <SEP> (lesion <SEP> secondary)
<tb><SEP> corporal) <SEP> day <SEP> day <SEP> day <SEP> day <SEP> day <SEP> day
<tb><SEP> 14 <SEP> 21 <SEP> 14 <SEP> 21 <SEP> 14 <SEP> 21
<tb> Phenylbutazone <SEP> 150 <SEP> 2/27 <SEP> 40 <SEP> 50 <SEP> 75 <SEP> 44 <SEP> 54 <SEP> 31
<tb><SEP> 75 <SEP> 2/39 <SEP> 51 <SEP> 50 <SEP> 62 <SEP> 28 <SEP> 27 <SEP> 15
<tb><SEP> 37.5 <SEP> 5/39 <SEP> 53 <SEP> 53 <SEP> 56 <SEP> 14 <SEP> 18 <SEP> 13
<tb><SEP> 18.8 <SEP> 2/21 <SEP> 50 <SEP> 45 <SEP> 31 <SEP> 7 <SEP> 4 <SEP> 8
<tb> ss-oxo <SEP> thiophene- <SEP> 200 <SEQ> 2/18 <SEP> 34 <SEP> 54 <SEP> 72 <SEP> 29 <SEP> 72 <SEP> 32
<tb> propionitrile-2 <SEP> 100 <SEP> 3/18 <SEP> 52 <SEP> 69 <SEP> 58 <SEP> 42 <SEP> 58 <SEP> 10
<tb><SEP> 50 <SEP> 3/36 <SEP> 56 <SEP> 48 <SEP> 46 <SEP> 18 <SEP> 46 <SEP> 0
<tb> TABLEAUV
Comparative effects of local anti-inflammatory agents, especially benzimidoylacetonitrile, on the occurrence of erythema in guinea-pigs.

Vehicle <SEP> for <SEP> Application <SEP> Drug <SEP> Concentraion <SEP> (%) <SEP> of <SEP> Number <SEP> Score <SEP> (average)
<tb> cation <SEP> local <SEP> drug <SEP> in <SEP> animals <SEP>
<tb><SEP> vehicle <SEP> 1 <SEP> h <SEP> 4 <SEP> h
<tb> Ethanol <SEP> Control <SEP> - <SEP> 40 <SEP> 2.5 <SEP> 3.0
<tb><SEP> Indomethacin <SEP> 1 <SEP> 16 <SEP> 0.7 * <SEP> 2.5
<tb><SEP> 0.5 <SEP> 8 <SEP> 1.5 <SEP> 2,4
<tb><SEP> 0.25 <SEP> 8 <SEP> 1.8 <SEP> 2.5
<tb><SEP> Aspirin <SEP> 1 <SEP> 4 <SEP> 1.9 <SEQ> 2.8
<tb><SEP> Phenylbutazone <SEP> 1 <SEP> 8 <SEP> 0.5 * <SEP> 2,4
<tb><SEP> Benzimidoylacetonitrile <SEP> 2 <SEP> 8 <SEP> 0.6 * <SEP> 2.7
<tb><SEP> 1 <SEP> 4 <SEP> 1.0 <SEP> 2,8
<tb> * Statistically significant activity.

TABLE VI
Effects of anti-inflammatory agents on carrageenin edema of the rat's paw.

<Tb>

<SEP> Dose
<tb> Compound <SEP> (mg / kg <SEP> of <SEP> Number <SEP> Report <SEP> t / T
<tb><SEP> weight <SEP> of <SEP> rats
<tb><SEP> corporal)
<tb><SEP>.<September>
<Tb>

Witnesses <SEP> - <SEP> 64 <SEP>
<tb> Benzimidoylacated
<tb> tonitrile <SEP> 250 <SEP> 8 <SEP> 2,2
<tb> Aspirin <SEP> 250 <SEP> 32 <SEP> 2,8
<tb> Phenylbutazone <SEP> 250 <SEP> 32 <SEP> 2,3
<tb> Indomethacin <SEP> 25 <SEP> 32 <SEP>. <SEP> 2.9
<tb> TABLE VII
Effects of various drugs on the body temperature of hyperthermic rats.

<SEP> Dose <SEP> Rats <SEP> rendered <SEP> hyperthermal <SEP> by <SEP> injec
Compound <SEP> (mg / kg <SEP> of <SEP> tion <SEP> of <SEP> yeast
<tb><SEP> weight <SEP> Number <SEP> Lowering <SEP> of <SEP> la
<tb><SEP> corporal) <SEP> body temperature <SEP>
<tb><SEP> (C)
<tb> Witnesses <SEP> - <SEP> 156 <SEP> 0
<tb> Benzimidoylacetonitrile <SEP> 250 <SEP> 6 <SEP> 1.4 *
<tb> Aspirin <SEP> 250 <SEP> 15 <SEP> 1.5 *
<tb> Phenylbutazone <SEP> 250 <SEP> 15 <SEP> 1.5 *
<tb> Indomethacin <SEP> 250 <SEP> 21 <SEP> 2.5 *
<tb> * Significant lowering compared with hyperthermic controls.

Claims (10)

1. New compounds having the following formula

 in which X represents an oxygen atom and the Aryl symbol denotes a thienyl-3 radical, X may also represent the NH radical and the Aryl symbol represents a phenyl radical substituted in meta by a fluorine atom or represents a thienyl radical.  2. New compound according to claim 1, characterized in that it consists of m-fluorobenzimidoylacetonitrile.  3. New compound according to claim 1, characterized in that it consists of p-aminothiophene-2 acrylonitrile.  4. New compound according to claim 1, characterized in that it consists of β-aminothiophene-3 acrylonitrile.  5. New compound according to claim 1, characterized in that it consists of 3-oxothiophene-3-propionitrile.  6. New medicaments useful in particular for reducing inflammation and / or inhibiting progressive deterioration of the articulations characteristic of arthritic conditions in mammals, characterized in that they consist of a compound according to any one of claims I to 5.  Antiarthritic composition in the form of a unit dose for reducing inflammation and / or inhibiting the gradual deterioration of the joints characteristic of arthritic conditions in mammals, characterized in that it contains an amount allowing the administration of approximately 1 mg at about 250 mg per kg of body weight of one or more drugs according to claim 6.  8. Composition according to claim 7, characterized in that it is in the form of a tablet or a capsule.  9. Composition according to claim 7, characterized in that X represents NH and that it is in the form of a tablet with enteric coating or a capsule.  10. Composition according to claim 7, characterized in that it contains an amount of active ingredient equal to the daily dose to be administered.  II. Composition according to Claim 7, characterized in that the active ingredient is m-fluorobenzimidoylacetonitrile, 2-aminothiophene-acrylonitrile, 3-aminothiophene-3-acrylonitrile, or 3-oxothiophene-3-propionitrile.