HU206616B - Process for producing pharmaceutical compositions containing pharmaceutically active tetrahydro-naphtalene derivative - Google Patents

Abstract

Pharmaceuticals contg. at least one `E' isomer of tetra:hydro-naphthalene derivs. of formula (I) - where R1:H atom or 1-10C alkyl gp. and opt. also one or several cpds. of medicinal action, but without any synergistic affect, in the proportions used. Active cpds. are formulated with suitable known additives into prep. no. of cyto-protective, as well as into prepns. inhibiting secretion of gastric acid.

Description

The present invention is based on the discovery of the cytoprotective and gastric acid secretion inhibiting activity of the known compounds of formula I, wherein R is hydrogen or C 1 -C 10 alkyl.

The preparation of a compound of formula (I) wherein R is hydrogen and its use as a chemotherapeutic agent (intestinal infections) are first described in U.S. Patent 2562208. The patent discloses the preparation of 4-oxo-4- (5,6,7,8-tetrahydro-2-naphthyl) -2 (E) -butenoic acid, which according to previous nomenclature is P- (6-tetraloyl), among benzene acrylic acid compounds. called acrylic acid. The patent mentions, without further details, that the compounds are active against Gram-negative bacteria and have fungistatic activity. This allows their use in the treatment of certain bacterial infections of the gut. The compound was prepared from tetralin by a Friedel-Crafts reaction with maleic anhydride. D. Papa et al. Am. Chem. Soc., 70, 3356 (1948), is described in more detail in U.S. Patent 2562208. The β-tetralyl derivative was prepared in 50% yield.

United States Patent No. 677,441 to South Africa discloses compounds of formula I wherein R is C 1 -C 10 alkyl. These compounds have vermifugal and vermicidal activity and can thus be used as anthelmintics in human and veterinary medicine. The preparation of ester derivatives is described in two ways: (a) by reaction of acid chlorides and alcohols of aroyl acrylic acids and (b) by reaction of aroyl acrylic acids with methyl iodide in acetone in the presence of potassium carbonate. The procedure is summarized in Chem. Abstr. 70, 68003 (1969). Eur. J. Med. Chem. 23, 45-52. (1988) describe the cytoprotective and gastric acid secretion inhibiting activity of phenyl, substituted phenyl and heteroaromatic compounds.

Surprisingly, our experiments have found that the compounds of formula (I) can be used in fields of activity that are completely different from those known in the art, namely for the pre- or post-treatment of individuals suffering from or susceptible to ulcer.

Gastrointestinal ulcer disease is affecting an increasing proportion of the population. It causes severe pain and bleeding during the active phase of the ulcer. In the conventional mode of medication, the primary goal is to reduce pain and then to heal the damaged tissue. Conventional drugs (pirenzepine, cimetidine, omeprazole, etc.) seek to achieve this goal by reducing gastric acid content and inhibiting gastric acid secretion. With proper medication and diet, ulcers usually heal within 4-6 weeks. However, ulcers often recur, and in such cases medication should be restarted.

In recent times, the so-called so-called. cytoprotective compounds. These compounds increase the ability of the stomach to defend itself, thereby significantly reducing the likelihood of recurrence of the ulcer and preventing ulcers in individuals with probable ulcer disease.

Of course, compounds which, in addition to their cytoprotective effect, also have an inhibitory effect on gastric acid secretion are particularly valuable.

In addition to the cytoprotective effect, the compounds of the present invention also exhibit an inhibitory effect on gastric acid secretion, and it is a further remarkable observation that both effects are sustained in time.

When presenting pharmacological results, the test compounds are designated as follows.

A: 4-Oxo-4- (5,6,7,8-tetrahydro-2-naphthyl) -2 (E) -butenoic acid B: Methyl [4-oxo-4- (5,6,7,8- tetrahydro-2-naphthyl)] - 2 (E) -butenoate

C: Octyl [4-oxo-4- (5,6,7,8-tetrahydro-2-naphthyl)] - (2E) butenoate

The pharmacological activity of the compounds was investigated by the following methods.

Examination of Stomach Damage with Acid Alcohol (Róbert A., Gastroenterology, 1979, 77, 761-767)

Female rats 120-150 g fasted for 24 hours were used for the study. The test substance was injected into the stomach of rats in a Tween 80 suspension by gavage. After a period of time ("pretreatment time"), 0.5 ml (100 wt / g) acid alcohol was added to the animals' stomach by gavage. One hour later, the animals were sacrificed, the stomach was removed, and cut at high curvature. The red-brown bands (hemorrhagic lesions) were weighed and the average total length per stomach was calculated. The potency of the test compound is given relative to the control group. The results obtained are as follows:

Table I

A sign of chemical leach Ed ₅₀ po (pre-treatment: 30 minutes) THE 0.3 mg / kg B 4.1 mg / kg C 6.4 mg / kg Ref .: Sucralfat 150 mg / kg

Acetic acid chronic ulcer model assay (Tagaki et al., Japan Journal of Pharmacology 19, 418-426 (1969)).

Carry out the test as follows:

hours, the fasted female rat is exposed to anesthesia under ether anesthesia. Close to the pylorus, 25 µl of a 20% acetic acid solution is injected into the subserotic layer into the glandular portion of the stomach. Then the abdominal wall is closed and the animal is given food and drink according to the animal's needs. On the 5th day after surgery, start treatment for 10 days with a single daily dose. So the surgery

On the 15th day following HU, kill the rats and remove the stomach. The ulcer is evaluated by measuring the diameter of the necrotic areas and calculating their area. The curative effect of the test compound is calculated according to the following formula:

ulcer area (control) - ulcer area (test substance) ulcer area (control)

The results obtained are as follows:

Table 2

Compound sign Dose Healing rate THE 10 mg / kg p.o. 61% Ref .: Sucralfat 500 mg / kg p.o. 55%

Investigation of the inhibitory effect of gastric acid secretion using pylorus ligatura [Shay et al (Gastroenterology, 5,43-61,1945)]

Carry out the test as follows:

Test substances were administered orally in 0.5 ml / 100 mg body weight of a tween suspension 30 minutes prior to pylorus ligation to female Wistar rats fasted for 20 hours. Four hours after surgery, the animals were sacrificed and their gastric acid content was determined by titration with 0.01 N sodium hydroxide solution with phenolphthalein indicator. Gastric pH was determined using a Radelkis OP211 / 1.

The results obtained are as follows:

Table 3

Compound sign Ed ₅₀ po (pre-treatment: 30 minutes) THE 43 mg / kg B 50 mg / kg

The therapeutic significance of the compounds of the present invention is further enhanced by the fact that they exert bactericidal activity against Campylobacter pylori, a bacterium whose gastrointestinal presence negatively influences the healing of gastrointestinal ulcers, and is significantly more likely to cause ulceration, 754 (1988)].

The efficacy of the compounds against Campylobacter pylori was tested by agar diffusion and agar dilution. The assays were performed with cultures of Campylobacter pylori isolated from five different human ulcer patients. Compound A had a MIC (minimum inhibitor concentration) of 100 pg / ml and Compound B had a 250 pg / ml.

The toxicity data of the compounds of the invention are also favorable - no mortality was observed in the test animals following a single oral dose of 500 mg / kg body weight.

The present invention therefore relates to a process for the preparation of an active ingredient of the formula I in which R is at least one of hydrogen or C 1 -C 10 alkyl and optionally one or more known therapeutic agents which do not produce synergistic effects in said composition. comprising preparing the active ingredient (s) in a known manner in admixture with a conventional pharmaceutical excipient and / or carrier to form a cytoprotective or gastric acid secretion inhibiting pharmaceutical composition.

The active ingredient of the formula (I) may be formulated into pharmaceutical compositions by admixing with non-toxic inert solid or liquid carriers and / or excipients which are conventionally suitable for parenteral or enteral administration. Suitable carriers include, for example, water, gelatin, lactose, lactose, starch, pectin, magnesium stearate, stearic acid, talc, vegetable oils such as peanut oil, olive oil and the like. It can be used. The active ingredient may be in the form of conventional pharmaceutical compositions, such as in particular solid forms such as round or square tablets, dragees, capsules such as gelatin capsules, pills and the like. in the form of.

The amount of solid carrier can vary over a wide range, preferably from about 1 mg to about 500 mg. The compositions may optionally contain conventional pharmaceutical excipients such as preservatives, stabilizers, wetting agents, emulsifying agents, and the like. may also be included. They may be prepared by conventional techniques such as sieving, mixing, granulating and pressing the components in the case of solid compositions. The compositions may also be subjected to other conventional pharmaceutical techniques such as sterilization.

A preferred embodiment of the tablet formulation is a filler, e.g. microparticulate cellulose and / or polyvinylpyrrolidone, a disintegrator, e.g. starch and / or carboxylmethyl starch and an anti-adhesive lubricant, e.g. containing magnesium stearate and / or talc.

A preferred embodiment of the capsule form comprises the inert filler, disintegrant and glidant as described above.

In a preferred embodiment of the formulation in the form of a suspension, the active ingredient is uniformly dispersed in the aroma, e.g. raspberry or strawberry flavor, coloring agent, food coloring, viscosity enhancing agent, e.g. Carbopol, a wetting agent, e.g. Tweent and a preservative, e.g. in syrup containing sodium benzoate.

The following examples illustrate the preparation of pharmaceutical compositions containing the compounds of formula (I), but are not intended to limit the scope of the invention to these formulations:

Example 1

Tablet containing 4-oxo-4- (5,6,7,8-tetrahydro-2-naphthyl) -2 (E) -butyric acid

HU 206 616 Β

Ingredients:

4-oxo-4- (5,6,7,8-tetrahydro-2-naphthyl) 2 (E) -butenoic acid 10.0 mg magnesium stearate 2.0 mg talc 10.0 mg starch 90.0 mg lactose , 0 mg

250.0 mg

The above amount of active ingredient is mixed with the indicated amounts of excipients, homogenized, granulated, then fluidized-dried and compressed into 250 mg average tablets of 10 mg active ingredient each.

The preparation of the active compounds of the pharmaceutical compositions of the present invention is illustrated by the following examples:

Example 1

4-Oxo-4- (5,6,7,8-tetrahydro-2-naphthyl) -2 (E) butenoic acid

4.8 g (0.05 mol) of maleic anhydride are dissolved in anhydrous dichloromethane, and 6.26 g (0.05 mol) of tetralin are added. The solution was cooled to 0 ° C and aluminum chloride catalyst was added in several portions while stirring. After stirring at room temperature for 4 hours, the red-brown reaction mixture was poured into ice-water containing 10 ml cc hydrochloric acid. From the yellow emulsion, dichloromethane was evaporated in vacuo. The product crystallizes out of the aqueous solution. Recrystallize from toluene.

Yield: 10 g (87%) of the title compound Melting point: 145-148 ° C.

Example 2

Methyl- [4-oxo-4- (5,6,7,8-tetrahydro-2-naphthyl)] - 2- (E) -2-butenoate

4-Oxo-4- (5,6,7,8-tetrahydro-2-naphthyl) -2 (E) -butenoic acid (2.62 g, 0.011 mol) was suspended in acetone (15 ml) followed by 2.76 g (0.02 mol). potassium carbonate and 2.83 g (0.02 mol) of methyl iodide are added. The reaction mixture is cooled to 0 ° C, the precipitated potassium iodide is filtered off and the filtrate is evaporated. The residual yellow oil was dissolved in dichloromethane (20 mL), extracted with 5% sodium bicarbonate solution (2 x 5 mL) and 1N hydrochloric acid (2 x 5 mL). The separated organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated. The product precipitated as a yellow crystalline material upon addition of petroleum ether, which was filtered off and washed with a little petroleum ether. The material was recrystallized from ethanol.

Yield: 2.13 g (76%) of the title compound. Melting point: 57-58 ° C.

Example 3

Octyl [4-oxo-4- (5,6,7,8-tetrahydro-2-naphthyl)] - (2E) butenoate

4-Oxo-4- (5,6,7,8-tetrahydro-2-naphthyl) - (2E) -butenoic acid (2.53 g, 11 mmol) was dissolved in anhydrous dichloromethane (60 mL). 1.3 g (0.01 mol) of n-octanol and 0.1 g of 4-dimethylaminopyridine are added. The yellow solution is cooled to 0 ° C and then 2.26 g (11 mmol) of dicyclohexylcarbodiimide are added slowly with stirring at 0 ° C in anhydrous dichloromethane. The reaction mixture was then stirred at 0 ° C for three hours and then at room temperature for two hours. The precipitated dicyclohexylurea was removed by filtration, and the filtrate was extracted twice with 5 ml of 5% sodium carbonate solution, 5 ml of saturated sodium chloride solution and 5 ml of 1 N hydrochloric acid. After drying over anhydrous sodium sulfate, the solution was evaporated to give the title compound as a yellow oil.

Weight: 2.6 g

Yield: 75%.

Claims (1)

The process comprises as active ingredient at least one of the E isomers of the compounds of formula I wherein R is hydrogen or (C 1 -C 10) -alkyl, and optionally one or more known therapeutic agents which do not result in synergistic effects in the particular composition. characterized in that the active ingredient (s) produced in known manner are mixed with a conventional pharmaceutical excipient and / or carrier to form a cytoprotective or gastric acid secretion inhibiting pharmaceutical composition.