PL196363B1 - Latch padlock - Google Patents

Abstract

l. A latch padlock consisting of a body and a cylinder locking mechanism, a bow or a pin with a catch at its end and a catch assembly located in its holes, characterized in that the catch assembly comprises a ball (6) mounted in a socket (7) at the height of the catch (5), a pusher (9) located under the ball (6) in a hole (12) with an axis substantially parallel to the longitudinal axis of the catch opening (8) and a rotating element (13) provided with a support face (14) and a recess (15) located perpendicularly to the catch (5) and furthermore in that the catch opening (8) at the entrance of the catch (5) has an annular recess (16) with a diameter (D) greater than the diameter (d) of the catch opening (8) and the part of the bow (2) or the pin (4) that enters the annular recess (16) has a diameter adapted to the diameter (D).

Description

The subject of the invention is new phenylbenzamidine derivatives of 3-methyl-5-amino-4-carboxyisothiazole and their pharmaceutically acceptable salts, a method for their preparation, use in medicine and pharmaceutical compositions containing them.

The new derivatives may find applications in the pharmaceutical industry for the production of drugs with anti-inflammatory, analgesic and antiviral properties.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a well-known class of anti-inflammatory, antipyretic, and analgesic agents whose primary therapeutic indications include the symptomatic relief of inflammation, fever, and mild to moderate pain. A significant limitation of their use is their potential gastrointestinal toxicity, which can lead to adverse events such as perforation and bleeding.

The understanding of the mechanism of action of NSAIDs, which involves inhibition of the enzyme cyclooxygenase (COX), and the subsequent discovery of an inducible prostaglandin synthetase, called cyclooxygenase 2 (COX-2), led to an increased interest in the development of new anti-inflammatory drugs.

Polish patent descriptions 70257, 122568 and 167891 describe derivatives of 3-methyl-5-benzoylaminoisothiazole-4-carboxylic acid with strong antiviral, anti-inflammatory and anticancer properties.

It has now been found that new compounds derived from 3-methyl-5-benzoylaminoisothiazole-4-carboxylic acid exhibit interesting biological properties, making them suitable for therapeutic use. The compounds of the invention are useful as anti-inflammatory, antiviral, and analgesic agents without the gastric and renal toxicity of traditional NSAIDs.

The new compounds are represented by formula I, wherein R1 is a hydrogen atom, a chlorine atom or a lower alkoxy group; R2, R3 and R4 are the same or different and are a hydrogen atom, a lower alkoxy group or a dimethylamino group.

By "lower alkoxy group" is meant a group containing from 1 to 3 carbon atoms.

The new phenylbenzamidine derivatives of 3-methyl-5-amino-4-carboxyisothiazole differ from those known and described so far in the above-mentioned patents and source reports (Z. Machoń: Dissert. Pharm. 1969 2, 135; 1969 4, 325; 1970 6, 395 and A. Jinglodt, Z. Machoń et al.: Arch. Immun. Therap. Exper. 1983 31, 579-689) by the presence of a free carboxyl group in position 4 of the isothiazole ring and a phenylbenzamidine moiety in position 5.

A particularly advantageous new derivative turned out to be the compound of formula la, in which the substituents R1, R2 and R4 constitute a hydrogen atom and R3 is an ethoxy group, i.e. 5-N-(3-methyl-4-carboxyisothiazolo)-N'-(p-ethoxyphenylbenzamidine).

Most nonsteroidal anti-inflammatory drugs reduce hemolysis of erythrocyte membranes. In screening studies, the new compound Ia demonstrated a stronger effect on erythrocyte membrane stabilization than the well-known anti-inflammatory drug ibuprofen. Furthermore, in vitro studies have shown that this compound strongly inhibits limb edema in rats and mice in the carrageenan test and reduces the mass of granulation tissue formed in the granulation test. Compound Ia also demonstrated a strong analgesic effect comparable to that of ibuprofen.

The ulcerogenic effect of the new compound Ia at doses of 100 and 300 mg/kg is many times lower compared to Ibuprofen, one of the least ulcerogenic NSAIDs.

Compound Ia is also characterized by very low acute toxicity, reaching after p.o. administration in mice: LD50 >2000 mg/kg body weight, and after intraperitoneal administration: 1404 mg/kg body weight; LD50 in rat p.o. and i.p.: > 2000 mg/kg body weight.

The invention also includes physiologically acceptable salts of the compounds of formula I, in particular addition salts formed with mineral acids or with organic acids.

Examples of suitable mineral acids are hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids. Examples of suitable organic acids are maleic, fumaric, succinic, itaconic, citraconic, oxalic, benzoic, p-aminobenzoic, ascorbic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic, aspartamic, methanesulfonic, ethanedisulfonic, benzenesulfonic, toluenesulfonic, glycolic, glutamic, stearic or palmitic acids.

PL 196 363 B1

The new compounds and their salts may be used to treat and alleviate all inflammatory conditions, including pain, inflammation, and fever of various etiologies, symptoms associated with influenza and other viral infections, colds and runny noses, back pain, headaches, toothaches, painful menstruation, sprains, muscle and joint inflammation, including rheumatoid arthritis, neuralgia, and surgical procedures. Furthermore, the new compounds are expected to be used in the treatment of dementia, including senile dementia, especially that associated with Alzheimer's disease.

The derivatives of the invention and their salts can be administered to the patient alone, but it is preferable to administer them in the form of pharmaceuticals.

The pharmaceutical composition having analgesic and anti-inflammatory activity comprises a therapeutically effective amount of at least one compound of formula I or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier and/or diluent.

The pharmaceutical agent according to the invention is administered to a patient requiring treatment in a convenient pharmaceutical unit dose form, by a route of administration appropriate for the type of agent, for example orally, parenterally (intravenously, intramuscularly or subcutaneously) or transdermally.

The selection of the drug dose and dosing regimen depends on the type of disease, age, weight, and health status of the patient and can be determined by a specialist based on known treatment and prophylactic regimens for inflammatory conditions. A suitable dose of a compound of the invention may range from 0.1 to 1000 mg/kg per day, preferably from 0.5 to 100 mg/kg per day. A suitable dose may be administered to the patient once or several times daily, alone or in combination with other therapeutic agents. Such agents may be administered simultaneously as a combined preparation or as independent preparations, or sequentially in an order and time interval determined by the specialist.

The pharmaceutical composition of the invention may be formulated into a variety of pharmaceutical forms well known to those skilled in the art, e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack Publ. Co.

Pharmaceutical forms of drugs for oral administration include tablets, pills, powders, granules, pellets, or capsules. Tablets and granules contain the active ingredient in combination with solid pharmaceutically acceptable carriers such as lactose, sucrose, mannitol, sorbitol, dextrose, calcium and sodium phosphates; granulating and disintegrating agents such as corn or potato starch, gelatin, methylcellulose, polyvinylpyrrolidone; lubricating agents such as magnesium stearate, talc, stearic acid. Tablets or granules may be coated or otherwise processed to provide a dosage unit providing disintegration at a suitable site in the gastrointestinal tract or providing the advantage of prolonged action. A variety of materials may be used to prepare such protective or coating layers, including various polymeric acids and mixtures of polymeric acids with substances such as shellac, cetyl alcohol, or cellulose acetate.

Gelatin capsules may contain the active ingredient dissolved or suspended in, for example, corn oil or other vegetable oils.

Phenylbenzamidine derivatives of formula I can also be used externally in the form of creams and ointments, gels and transdermal patches containing typical ingredients and bases for these pharmaceutical forms enabling absorption of the drug through the skin.

Pharmaceutical forms for injection and infusion include sterile aqueous, aqueous-organic, and non-aqueous solutions, suspensions, dry substances, and tablets for reconstitution or implantation. Suspensions are prepared using excipients that ensure uniform dispersion of the drug substance in the liquid phase, such as polysorbates, lecithin, polyoxyethylene-polyoxypropylene copolymers, peptizers such as phosphates, polyphosphates, and citrates, water-soluble polymers such as carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, gums, or gelatin. Injectables may contain pharmaceutically acceptable excipients, such as pH and buffering agents, tonicity agents, and preservatives. Dry substances are intended for extemporaneous preparation of a solution or suspension by dilution with a suitable solvent.

The new phenylbenzamidine derivatives of formula I, wherein R1 is hydrogen, chlorine or a lower alkoxy group; R2, R3 and R4 are the same or different and are hydrogen, a lower alkoxy group or a dimethylamino group can be obtained from the lactone of formula II. The lactone of formula II is prepared from the corresponding 3-methyl-5-benzoylamino-4-isothiazolecarboxylic acid derivatives of formula III.

PL 196 363 B1

Lactonization of the corresponding 3-methyl-5-benzoylaminoisothiazole-4-carboxylic acid derivatives of formula III is carried out in a known manner either with a chlorinating agent, such as, for example, thionyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus pentachloride or phosphorus oxychloride, [method A] or with methyl, ethyl or propyl chloroformate [method B] or with dicyclohexylcarbodiimide (DCC) [method C]. The reaction medium consists of organic solvents of the aromatic hydrocarbon type, in particular benzene, toluene, xylene, optionally chloroform, methylene chloride, or carbon tetrachloride and dimethylformamide. The reaction is carried out at the boiling point of the solvent, except when DCC is used, when the reaction takes place at room temperature.

A process for the preparation of new phenylbenzamidine derivatives of the formula I, wherein R1 is a hydrogen atom, a chlorine atom or a lower alkoxy group; R2, R3 and R4 are the same or different and are a hydrogen atom, a lower alkoxy group or a dimethylamino group, consists in the reaction of a lactone of the formula II, wherein R1 has the meaning given for the formula I, with an aromatic amine of the formula IV, wherein R2, R3 and R4 have the meaning defined for the formula I, by heating in an organic solvent medium. Aprotic solvents such as carbon tetrachloride, methylene chloride, benzene, toluene, xylene are preferably used.

According to the invention, the reaction is carried out by metering lactone II into an aromatic amine dissolved in an anhydrous solvent at boiling temperature. The reaction mixture is kept at boiling temperature for several hours, after which the product is isolated in a known manner, purified, and optionally converted into a pharmaceutically acceptable salt.

The invention is illustrated by the following examples.

Example 1

6-Phenyl-3-methylisothiazolo[5,4-d]4H-1,3-oxazin-4-one (Lactoz II, R1 = H)

Method A

11.3 g of 3-methyl-5-benzoylaminoisothiazole-4-carboxylic acid (formula III R1 = H), 226 ml of toluene (dried over sodium), and 33.1 cm ^{3 of} thionyl chloride were added to a round-bottomed flask with a reflux condenser, and the mixture was heated to reflux for 8 hours. Then the mixture was evaporated to dryness under reduced pressure. The obtained precipitate was dissolved in methylene chloride, the solution was saturated with gaseous ammonia to a slightly alkaline reaction with litmus. The precipitate was filtered off, and the filtrate was distilled under reduced pressure. 7.8 g of lactone II (R1 = H) was obtained, which was purified by crystallization from ethanol. Mp 130-2°C. Yield 75.2%. Elemental analysis for the formula: C12H8N2O2S (262.28)

Calculated: %C - 59.00; %H - 3.31; %N - 11.46

Found: %C - 59.21; %H- 3.31; %N - 11.21.

Example 2

6-p-Chlorophenyl-3-methylisothiazolo[5,4-d]4H-1,3-oxazin-4-one (Lactone II, R1 = Cl)

Method B

To a flat-bottomed flask with a reflux condenser and magnetic stirrer were added 20 g (0.067 mol) of 5-(p-chlorobenzoyl)amino-3-methyl-4-isothiazolecarboxylic acid (formula III, R1 = Cl), 120 cm3 ^of anhydrous methylene chloride, and 10 ^cm3 (0.092 mol) of anhydrous pyridine. The mixture was heated, and 25 g of ethyl chloroformate was added portionwise while boiling, continuing heating for 10 hours. The reaction mixture was then evaporated to dryness in a vacuum evaporator. 500 ^cm3 of water was added to the residue and stirred for an hour. The precipitate was filtered off and added, with stirring, to 500 ^cm3 of 5% sodium hydroxide solution. The contents were stirred for 15 minutes, after which the precipitate was filtered off again. 18.25 g of crude product (97.73% yield) of lactone II (R1 = Cl) was obtained, which after drying was purified by crystallization from ethanol.

Example 3

6-p-Methoxyphenyl-3-methylisothiazolo[5,4-d]4H-1,3-oxazin-4-one (Lactone II, R1 = OMe)

Method C

To 20 g (0.068 mol) of 5-(p-methoxybenzoyl)amino-3-methyl-4-isothiazolecarboxylic acid (formula III, R1 = OMe) was added 600 cm3 ^of anhydrous dimethylformamide (DMF), to the resulting solution was added 14 g of N,N-dicyclohexylcarbodiimide (DCC) and the mixture was stirred at room temperature for 24 hours. The separated precipitate of N,N-dicyclohexylurea (DCK) was filtered off, and the filtrate was evaporated to dryness under reduced pressure. The residue was dissolved in 120 ^cm3 of chloroform, then filtered off impurities, and the solution was evaporated to dryness on a rotary evaporator. 11.7 g of lactone II (R1 = OMe) was obtained, yield 60%, which was crystallized from ethanol. Mp 148-149°C.

PL 196 363 B1

Example 4

5-N-(3-methyl-4-carboxyisothiazole)-N'-(p-ethoxyphenylbenzamidine) (compound Ia, R1=R2=R4=H, R3=OEt)

In a round-bottomed flask with a reflux condenser, 300 ml of anhydrous carbon tetrachloride was added and 22.5 g of freshly distilled p-phenetidine was dissolved, heating to boiling point. Then, 19.5 g of 6-phenyl-3-methylisothiazolo[5,4-d]-4H-1,3-oxazin-4-one was added and heated for 6 hours with constant stirring. After the reaction was complete, the mixture was cooled to 5-10°C and left at this temperature for 12 hours. The separated precipitate was filtered off, and after concentration of the solution, additional crude product was obtained; a total of 16.8 g of light yellow precipitate (51.13% yield), mp 197°C (dec.). The crude product was purified by crystallization from ethanol.

Elemental analysis for formula Ia: C20H19N3O3S (381.4)

Calculated: %C- 62.98, %H- 5.02, %N - 11.02;

Found: %C- 62.87, %H- 5.30, %N - 10.70.

TLC CHCl3:CH3OH (9.5:0.5): Rf =0.4.

Example 5.

Proceeding analogously to Example 4, compounds Ib, Ic, Id, Ie, If were obtained, the melting points of which are given in the table.

Ref. No. R1 R2 R3 R4 Melting point (°C) Ia H H -OEt H 197 (decomposed) Ib H -OMe -OMe -OMe 172 Ic you -OMe H H 143-145 Id -Ome -OMe H H 128-130 Ie -Ome -OEt H H 138-140 If -Ome -N(CH3)2 H H 169-171

Pharmacological research

The anti-inflammatory activity of the compounds according to the invention was determined in in vivo studies on rats (female Wistar strain) and mice (female 129/AoBoy strain) and in vitro. The animals were administered p.o. preparations in the form of a suspension in 0.5% methylcellulose solution in distilled water, at doses of 1, 10 and 100 mg/kg body weight. Ibuprofen (α-methyl-4-(methylpropyl)-phenylacetic acid) produced by Polfa Kutno was used as the reference compound.

Carrageenan-induced edema inhibition test

The studies were performed according to the method described by Winter, Risley, and Nuss (Proc. Soc. Exp. Biol. Med. 1962, 111:544). Limb edema was induced by subcutaneous administration of 0.05 ml of a 1% suspension of carrageenan in 0.9% NaCl warmed to 37°C to the plantar region of the left hind paw of rats. The preparations were administered 1 hour before carrageenan injection, intragastrically by gavage, in a volume of 0.5 ml of the prepared suspension per kilogram of animal body weight (n=7). The control group of animals (n=5) received an equivalent volume of methylcellulose suspension. Limb thickness was measured using a thickness gauge ("Schnelltester") before (baseline thickness) and 1, 3, 6, and 24 hours after carrageenan injection. The increase in the thickness of the rat's paw in subsequent measurements compared to the initial thickness expressed the intensity of swelling.

The mean results of relative (compared to the initial thickness) increase in paw thickness for each group were compared with the corresponding values for the control group. The anti-inflammatory effect of the preparations was expressed as the percentage of inhibition of paw thickness increase (H) calculated according to the formula

H = (AK-AP)/AKx 100%

H - percentage of inhibition of paw thickness growth;

ΔK - relative mean increase in paw thickness in the control group;

ΔP - relative mean increase in paw thickness in the study group.

The results are presented in Table 1.

PL 196 363 B1

Table 1.

The effect of preparation la and ibuprofen on carrageenan-induced limb edema

Preparation Dose [mg/kg body weight] Inhibition of paw thickness growth [%] 1 hour* 3 hours 6 hours 0-6 hours** la 1 31.9 36.9 39.7 36.9 10 37.3 37.2 39.7 37.9 100 47.4 44.5 46.5 45.5 Ibuprofen 1 12.7 36.2 22.0 27.8 10 9.4 45.8 31.4 34.6 100 51.2 62.1 63.4 60.1

* time from carrageenan injection ** calculated relative to the area under the curve

In control animals, maximum swelling was observed 3 and 6 hours after carrageenan injection, and the limb thickness increased by 20 to 60% at that time compared to the value before carrageenan injection.

Compound Ia, similarly to Ibuprofen, exerted a strong anti-inflammatory effect. The maximum anti-inflammatory effect observed at a dose of 100 mg/kg b.w. was approximately 25% lower than that of Ibuprofen, while at lower doses (1 and 10 mg/kg b.w.) it was more potent than Ibuprofen. The theoretical dose causing 40% (ED40) inhibition of paw thickness growth in the carrageenan test during the first 6 hours after carrageenan injection for preparation Ia (ED40 = 9.4 mg/kg b.w.) was lower than for Ibuprofen (ED40 = 12.0 mg/kg b.w.), calculated from the Hill equation.

Granulation test

The granulation reaction according to Meier, Shuler, and Dasaulles (Experientia 1950, 6: 469-471) was induced by implanting two 5 mg pieces of cotton surgical thread subcutaneously into the thoracic region of rats. The test preparations were administered to the animals (n=7) 24 and 48 hours after thread implantation. The control group of animals (n=5) received an equivalent volume of methylcellulose suspension. The implanted threads, along with the formed granulation tissue, were prepared after 7 days, weighed, and the mean weight of the prepared pair of threads was calculated. The results are presented in Table 2.

Table 2.

The effect of the preparation Ia and Ibuprofen on the granulation process induced by the implantation of a cotton surgical thread

Preparation Dose [mg/kg body weight] Relative mean mass of granulation tissue obtained* [%] la 1 67.0 10 74.4 100 76.4 Ibuprofen 1 83.0 10 64.4 100 64.9

* compared to the average granulation tissue mass in the control group

Compound Ia and Ibuprofen significantly reduced (ANOVA test, p<0.05) the mass of granulation tissue formed in the entire range of administered doses from approximately 20% to 35%.

PL 196 363 B1

Analgesic effect

The analgesic effect of the tested preparations was assessed using the so-called "hot plate method" by Woolfe and MacDonald (Jeske J. Pharmacological Methods of Drug Research, PZWL Warsaw, 1955). The pain response was induced by a thermal stimulus – a hot plate at a temperature of 53°C. Thirty, sixty, and ninety minutes after administration of the preparations, a test was performed, measuring the time of onset of the reaction to the thermal stimulus (latency time). An increase in latency time above 20% of the baseline value was considered a positive test result.

The results are presented in Table 3.

Table 3.

Analgesic effect of preparation la and ibuprofen in the hot plate test

Preparation Dose [mg/kg body weight] Average latency [s] Preliminary After 30 minutes After 60 minutes After 90 minutes After 120 minutes la 1 13.0 15.2 14.6 20.2 23.0 (n=5) 10 12.4 13.0 18.0 15.8 16.0 100 18.0 23.8 18.2 22.0 20.2 Ibuprofen 1 16.6 18.4 20.8 22.2 20.6 (n=5) 10 16.6 17.2 28.8 20.4 21.2 Control** 100 17.0 22.0 18.4 21.0 30.6 - 15.4 16.4 17.1 17.7 17.7

* the values of the latency time extended (analgesic effect) above 20% of the initial measurement are highlighted ** mean results of the latency times of a total of 42 mice (in subgroups of 3 mice) from one series of experiments

An increase in reaction time to a thermal stimulus exceeding 20% of the baseline value 30 minutes after administration of compound Ia, similarly to Ibuprofen, was observed at a dose of 100 mg/kg b.w. A significant analgesic effect of preparation Ia at all applied doses (1, 10, and 100 mg/kg b.w.) was observed after 90 minutes. The analgesic effect of Ibuprofen at all doses was observed after 90 and 120 minutes after administration.

Effect on cell membranes

The effect of stabilizing erythrocyte membranes was measured according to the method developed by Seeman and Weinstein (Biochem Pharmacol. 1966, 15, 1753-1766) modified by Inglot and Wolna (Biochem Pharmacol. 1968, 17, 269-279). Stabilizing cell membranes is characteristic of some anti-inflammatory compounds. Rabbit erythrocytes were used. The preparations were dissolved

-3 2 in DMSO and then diluted with phosphate buffer. Concentrations used ranged from 10 ^-3 to 10 ² mg/ml. In this test, in a hypotonic phosphate buffer environment, in which 50% erythrocyte hemolysis is established, the addition of preparations increased hemolysis (labilization) or decreased it (stabilization of erythrocyte membranes). The results are presented in Figure 1.

Compound Ia exerted a significant, very strong in vitro stabilizing effect on erythrocyte membranes at the highest concentration used, i.e., 100 mg/ml. Ibuprofen did not significantly affect erythrocyte membranes in this test.

Ulcerogenic effect

The evaluation of the ulcerogenic effect of the Ia preparation was carried out on female rats of the WISTAR strain weighing 150-250 g. The ulcerogenic effect of the preparation on the gastric mucosa of rats was compared with the effect of Ibuprofen and related to the condition of the mucosa of the control group of animals.

The number of rats in each group was n=5. Two independent experiments were performed.

Preparation Ia was administered to rats orally in the form of a suspension of 3% Tween in H2O in a volume of 0.7 ml/kg of body weight every 24 hours for 5 consecutive days. The control group of animals received a suspension of 3% Tween in H2O in a volume of 0.7 ml/kg of body weight at the same time intervals. The tested groups of animals

PL 196 363 B1 The animals and the control group were placed in cages that prevent coprophagy for 12 hours before and 10 hours after the first dose. Food was withheld from the animals, but they had free access to water for 12 hours before and 10 hours after the last dose. Twenty-four hours after the last dose, the animals were decapitated, their stomachs were dissected, and mucosal lesions were assessed under a biological microscope. The degree of gastric mucosal damage was scored on a scale of 1-5:

0° - no change or mild /+/ or moderate /++/ hyperemia;

1° - severe hyperemia /+++/ or presence of erosions;

2° - presence of 1-2 ulcers;

3° - presence of 3-4 ulcers;

4° - presence of 5-10 ulcers;

5° - more than 10 ulcers or bleeding into the gastric lumen.

The degree of hyperemia was assessed on a scale of 0-3:

- lack /-/;

- mild hyperemia /+/;

- moderate hyperemia /++/;

- severe hyperemia /+++/.

Statistical analysis was performed using Microsoft Excel 5.0 and STATISTICA for Windows rei. 4.0 in an ANOVA model. Hypotheses were tested at a significance level of 0.05.

The results of observations made by two independent observers 24 hours after the last administration of the preparation, assessing the degree of gastric mucosa hyperemia on a scale from /-/ to /+++/, the number of erosions and ulcers and the presence of bleeding into the gastric lumen, are presented in graphs 2 and 3.

After administration of Ia at a dose of 100 mg/kg body weight, no ulcerations were observed in the rat mucosa. After administration of the same dose of ibuprofen, ulcerations or bleeding occurred in 6 of 10 observed animals (mean value of 1.3 ulcerations per rat from 2 experiments). After administration of Ia at a dose of 300 mg/kg body weight, gastric mucosal ulcerations occurred in 2 of 10 animals (mean value 0.15), while after administration of the same dose of ibuprofen, lesions occurred in 6 of 10 animals (mean value 1.95). Mucosal damage in the form of varying degrees of hyperemia and erosions was observed in all groups of animals tested. No statistically significant difference was observed in the degree of mucosal damage after administration of preparation Ia at doses of 100 and 300 mg/kg body weight compared to the control group of animals. Ibuprofen caused more damage to the mucosa of rats than preparation Ia (statistically significant differences).

Example 6.

Pharmaceuticals

Example tablet composition:

Active ingredient: compound la 100mg Excipients: Corn starch 40mg Colloidal silicon dioxide 2mg Stearic acid 2mg Povidone K-30 6mg Pregelatinized starch 10mg Microcrystalline cellulose 40 mg Lactose 400 mg Total weight: 600mg Sample capsule composition: Active substance - compound Ia 100mg Excipients: Corn starch 20mg Colloidal silica 2mg Talk 3mg Mannitol 200mg Total weight: 325mg

PL 196 363 B1

Claims (10)

1. Phenylbenzamidine derivatives of 3-methyl-5-amino-4-carboxyisothiazole represented by the general formula I in which R1 is hydrogen, chlorine or C1-C3 alkoxy; R2, R3 and R4 are the same or different and represent a hydrogen atom, a C1-C3 alkoxy group or a dimethylamino group, and the pharmaceutically acceptable salts thereof. 2. A derivative according to claim 1 1 which is 5-N- (3-methyl-4-carboxyisothiazole) -N '- (p-ethoxyphenylbenzamidine). 3. A process for the preparation of phenylbenzamidine derivatives of 3-methyl-5-amino-4-carboxyisothiazole of the general formula I, in which R1 represents a hydrogen atom, a chlorine atom or a C1-C3 alkoxy group; R2, R3 and R4 are the same or different and represent a hydrogen atom, a C1-C3 alkoxy group or a dimethylamino group, characterized in that the lactone of formula II, where R1 is as defined in formula I, is reacted with an aromatic amine of formula III, in which R2, R3 and R4 are as defined for formula I, by heating them in an organic solvent medium, the crude product is isolated and purified in a known manner, then optionally converted into a pharmaceutically acceptable salt. 4. The method according to p. The process of claim 3, wherein the lactone of formula II is dosed into a solution of the aromatic amine of formula III in an anhydrous aprotic solvent. 5. Process for the production of a lactone of formula II, wherein R1 is hydrogen, chlorine or C1-C3 alkoxy, characterized by lactonization with a 3-methyl-5-benzoylaminoisothiazole-4-carboxylic acid derivative of formula III, wherein R1 is meaning as in formula II in the presence of: a) a chlorinating agent, preferably thionyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus pentachloride or phosphorus oxychloride; or b) C1-C3 alkyl chloroformate, preferably methyl, ethyl or propyl chloroformate; or c) dicyclohexylcarbodiimide. 6. The method according to p. The process of claim 5, wherein the lactonization reaction is carried out in an organic solvent selected from aromatic hydrocarbons, halogenated aliphatic hydrocarbons and dimethylformamide. Use of a phenylbenzamidine derivative of 3-methyl-5-amino-4-carboxyisothiazole as defined in claim 1 1 and pharmaceutically acceptable salts thereof for the manufacture of a pharmaceutical for the treatment of an inflammatory disease. 8. Pharmaceutical composition with analgesic, anti-inflammatory and antiviral activity containing pharmaceutically acceptable carriers and / or diluents, characterized in that the active substance is a phenylbenzamidine derivative of 3-methyl-5-amino-4-carboxyisothiazole as defined in claim 1. 1 or a pharmaceutically acceptable salt thereof. 9. The agent according to claim 1 A formulation as claimed in claim 8 which is in a form suitable for oral administration. 10. The agent according to claim 1 The pharmaceutical composition according to claim 8, in the form of a tablet or capsule. PL 196 363 B1 Drawings The average number of ulcers Fig.2. Ulcerogenic effect of preparation Ia on the rat gastric mucosa after oral administration Mucosal lesion degree ra Control 2.05 100 mg / kg 300 mg / kg * difference with Ibuprofen statistically significant (p <0.01) difference with control statistically not significant ** difference with Ibuprofen statistically significant (p <0.02) difference with statistically insignificant Fig. 3. Degree of damage to the rat gastric mucosa by the preparation Ia