DE1543150B - Tetracycline guayakol ^ sulfonate and process for its preparation - Google Patents

Description

OH
OH O OH O

2. Process for the preparation of the tetracycline gagaakol-4-sulfonate according to claim 1, characterized in that one tetracycline or its salts in a manner known per se with equimolecular Amounts . Guaiacol-4-sulfonic acid or its salts in a suitable solvent, such as water, methyl or ethyl alcohol, and the reaction product is optionally converted into

OH

OCH,

known manner, such as by evaporating the reaction mixture or by precipitation with a Solvent in which the reaction product is sparingly soluble, such as ether, is isolated.

3. The method according to claim 2, characterized in that the salt of guaiacol-4-sulfonic acid is used the sodium, potassium or preferably the calcium salt is used.

The broad spectrum antibiotic tetracycline is effective against numerous gram-negative and gram-positive bacteria, Rickettsia and related viruses. Because of the insolubility of the tetracycline base, the tetracycline becomes used in the form of the more soluble and more stable hydrochloride. However, this derivative conditional maintaining a very low pH value, so that physiological fluids are neutral pH value on contact with the parenterally administered preparation cause precipitation of the free base, causing irritation or necrosis of the muscle tissue where the preparation is placed has been injected. It is therefore unsuitable for parenteral administration because of its histolytic effect.

When administered orally, the precipitation of tetracycline in the duodenum causes local irritation inhibits certain pancreatic enzymes, lipase and amylase and changes the intestinal flora. Through this side effects of the digestive system, such as vomiting, nausea, gastritis, diarrhea, etc. are caused. Tetracycline can also lead to serious digestive tract complications, which due to infections caused by tetracycline-resistant cocci or fungi, and even to cholera-like ones Syndrome.

It is therefore of the utmost importance to eliminate the occurrence of these side effects, and to do so To this end, numerous attempts have been made to administer tetracycline with various Substances carried out to promote the absorption of the tetracycline in the upper parts of the digestive tract and thereby the diffusion effect to increase.

Of the experiments carried out with simultaneous administration of substances, which Increase the absorption of tetracycline like those mentioned by Kaplan and coworkers (1957) who bound tetracycline to phosphates and glucosamine, as well as those of one and co-workers (1953) who bound tetracycline to citric acid, malic acid, malonic acid and tartaric acid.

Recently, salts or derivatives substituted in the carboxamide group have been produced been made with the aim of better absorption and higher blood levels while reducing side effects to reach z. B. pyrrolidinomethyl tetracycline and lysinomethyl tetracycline.

Furthermore, from British patent specification 964226, tetracycline derivatives are known in which the tetracycline skeleton is substituted by the radical —CH _{2 —SO 3} H. These derivatives are said to have better solubility than the free tetracycline base. Compared to the tetracycline salts, which are more soluble than the free base, they should be more tissue-compatible. Otherwise, however, they should have an antibiotic activity that is roughly in the same order of magnitude as that of tetracycline. Since nothing is done after an increase in activity, it can be assumed that the only advantage of these derivatives over the likewise readily soluble tetracycline salts is their tissue compatibility.

None of these known derivatives therefore shows a change in the therapeutic effect of the tetracycline base.

In chronic bronchitis there is an inflammatory condition in the bronchial mucosa, connected with increased activity of the mucous

glands responsible for clinical manifestations such as cough, sputum, etc. and a strong one promote bacterial infection and exacerbation of the disease. These attacks affect the integrity of the lung tissue by making irreversible anatomical pathological changes cause and progressively lead to a deterioration of the cardiorespiratory picture and to a right insufficiency of the heart.

In such forms of chronic bronchitis, tetracycline administration was prolonged Time from three to six months - as tetracycline is the best tolerated broad spectrum antibiotic and shows a higher effectiveness against numerous germs - to an improvement of the clinical symptomatology and a substantial reduction in exacerbations and superimposed infections that are responsible for the progressive impairment of the cardioresurgical condition.

Other broad spectrum antibiotics are not recommended for these extensive treatments because of their poor tolerance and the often serious side effects.

Tetracycline works against such bronchopulmonary diseases. Bacteria that the Cause relapses and exacerbations, but has no effect on inflammatory conditions Mucous membrane responsible for general symptoms such as cough, sputum, difficulty breathing, etc. are.

Studies have now been carried out on the further development of tetracycline derivatives that specifically for the treatment of these acute as well as chronic diseases of the respiratory tract are as well as a have better solubility, absorption and tolerability than tetracycline. It was found that when reacting guaiacol-4-sulfonic acid with tetracycline a product substance is obtained at the same time

the soothing or bactericidal effect of guaiacol and the antibiotic properties of tetracycline with better tolerance.

The product obtained is extremely effective in diseases of the respiratory system, e.g. B. the Lungs, the bronchi or the upper respiratory tract, otitis or pharyngitis, as well as diseases the kidneys and ureters.

The invention thus relates to the tetracycline guaiacol-4-sulfonate of the formula

OH O

OH

OCH,

The invention also relates to a process for the preparation of tetracycline guaiacol-4-sulfonate, which is characterized in that tetracycline or its salts are known per se Way with equimolecular amounts of guaiacol-4-sulfonic acid or their salts in a suitable solvent such as water, methyl or ethyl alcohol, converts and the reaction product, if appropriate, in a manner known per se, such as by evaporation of the Reaction mixture or by precipitation with a solvent in which the reaction product is difficult is soluble, like ether, isolated.

The salt of guaiacolsulphonic acid is preferably sodium, potassium or especially sodium preferably the calcium salt.

The invention is illustrated by the following exemplary embodiments.

example 1

1 mol of tetracycline base is treated with the equivalent amount (49 g) of 2% strength aqueous sulfuric acid. The equivalent amount of calcium guaiacol-4-sulfonate in 5% aqueous solution is added to the solution. The addition is carried out slowly with stirring in order to prevent the CaS0 ₄ crystals formed from occluding particles of the other components. The mixture is stirred after V ₂ hours and then immediately concentrated to a volume of 11 in vacuo at a temperature not above 400 ^{° C.}

Then 21% pure ethyl alcohol are added and the mixture is cooled to 15 ° C. for complete precipitation of the calcium sulphate. The precipitate is filtered off and the filtrate is evaporated in vacuo at a temperature not higher than 4O ⁰ C. Finally, 630 g of tetracycline guaiacol-4-sulfonate are obtained.

Example 2

0.5 mol of calcium guaiacol-4-sulfonate (224 g) are dissolved in ϊ Γ pure ethyl alcohol and 0.5 mol treated pure sulfuric acid; the whole is then concentrated in vacuo at 40.degree. The calcium sulfate formed is filtered off and an aliquot of the guaiacol-4-sulfonic acid formed is determined.

1 mol of tetracycline in base form is suspended in 1.5% alcohol. Then the equivalent amount of Add the above solution and heat the mixture moderately to complete dissolution. Then the mixture is evaporated to half the volume in vacuo and then with 21

treated with anhydrous ether, which precipitates the product. The mixture is cooled to 0 ° C. and filtered, washing three or four times with a total of 500 ml of ether.

After vacuum drying at low temperature, 632 g of tetracycline guaiacol-4-sulfonate are obtained.

The obtained according to Examples 1 and 2 tetracycline guaiacol-4-sulfonate is a yellow crystalline powder, soluble a melting point of 190 ⁰ C. results in the UV absorption spectrum in aqueous solution in water and ethanol, and insoluble in ether and has defined two well Maxima at 276 and 360 ηΐμ and two minima at 255 and 323 πΐμ.

The tetracycline guaiacol-4-sulfonate shows one Synergism between an antibiotic and an anti-inflammatory effect on the mucous membrane of the Respiratory system, thereby reducing bronchial secretions.

In clinical trials, 52 patients were treated with tetracycline guaiacol-4-sulfonate (TGS) and 10 patients treated with tetracycline hydrochloride (T-HCl) (1 g each day, divided into four doses all 6 hours). The duration of treatment was between 7 and 30 days. The cases were broken down as follows:

Acute bronchitis

Bronchiectasis

Chronic bronchitis ....

Results:

excellent

Well

unchanged

gastric intolerance

TGS group

10

35

61.5%

21.2%

9.6%

3.8%

T-HCl group

50% 30% 20%

The gastric intolerance disappeared with prolonged treatment.

In 50 patients of the TGS group who had phlegmatic disease at the start of treatment showed, these symptoms disappeared in 80% of all cases. The comparative figure for the T-HCl group was at 50%.

In further clinical trials it was found that TGS in doses of 1.5 g per day (divided doses in Administered at intervals of 6 hours) over a period of 7 to 15 days with excellent up to good healing results in about 80% of all cases (broncho-pulmonary infections) no side effects or caused counter-indications and tolerability was very good. There was no antibiotic resistance on. There was a significant decrease in typical catarrhal symptoms (fever, cough, Sputum, spasms). In the case of chronic clinical pictures, a good removal of the Secretions in the airways and the resolution of spasms can be observed.

A number of animal pharmacological studies have continued, namely at Cats, rats, mice and rabbits, as well as a number of microbiological tests carried out.

When administered orally with the probe, TGS has a lethal dose LD ₅₀ of 4.4 ± 0.3552 g / kg for rats, while this value for tetracycline according to Cunningham and coworkers (Antibiotics Annual, 1953-54, 63) is 3 g / kg lies.

In further tests, the following LD ₅₀ values were found for TGS:

Orally

Intraperi-

toneal
Intravenously

Rats

365 ± 38.6 mg / kg
118.3 ± 5.14 mg / kg

Mice

4.4 ± 0.3552 g / kg

645 ± 28.63 mg / kg 209 ± 26.44 mg / kg

The semichronic and chronic toxicity of TGS in rats were also determined. in the The first case was a 60-day treatment, in the second case a monthly treatment with daily doses of 400 mg / kg made with a nasogastric tube or introduced orally. A control experiment was run for comparison and all animals became the same Subjected to diet.

A haematological examination was carried out before and after the experiment and after the Attempt a pathological-anatomical examination as well as a histological examination of the liver, the kidneys, adrenal glands, heart, lungs and intestines. None of the tests found noticeable differences between the group of treated animals and the control animals.

The weight curve was also determined; there became a slight difference between 'the TGS group and the group of control animals, but this is still within the error limit. For example, in the chronic test, the mean weight gain of the TGS group was 248.6 ± 29.4% (Comparative value of the control group 252.6 ± 18.4%).

Wood's fluorescence method was used to study how TGS is in the organism of rats when administered orally at a dose of 250 mg (200 g tetracycline base) every 4 hours distributed. The experiment showed that the TGS is and also quickly distributed over the whole organism lingered in this for a long time. Yellow fluorescence occurred in the stomach for 0 to 2 hours, which Lasted 3 to 4 hours. In the small intestine, large intestine, liver, kidney, lungs, muscle tissue, plasma and urine the yellow fluorescence appeared every 2 to 3 hours and persisted after 5 hours on. An accumulation of TGS was also observed. 60% of the dose was given in 24 hours removed from the urine, the following 20 to 30% in 48 to 72 hours.

It has been shown in cats that TGS when administered intravenously at a dose of 30 mg / kg no significant change in respiratory rate, arterial pressure, heart rhythm, des EKG and smooth muscle activity and tone. Minor changes (breathing stimulation, arterial overpressure) were observed at a dose of 50 mg / kg.

Furthermore, comparative tests were carried out on the tetracycline level in the plasma of rabbits and in Rat lungs performed after administration of TGS and T-HCl. The tetracycline was through Fluorescence analysis of the tetracycline-barbituric acid-Ca complex determined.

In the first case there were 100 mg / kg TGS and 67 mg / kg T-HCl (same tetracycline equivalent) introduced as solutions through the gastric tube. The maximum value in plasma was reached after 1 hour with T-HCl and after 2 hours with TGS. The former was 70% of the Maximum value of TGS. In the period from 2 to 24 hours after administration, the value for T-HCl was consistently at around 50% of the value for TGS.

In the second case, rats were given 10 mg / kg TGS and T-HCl (based on the tetracycline base) intravenously administered. The rats were sacrificed after 1, 2 and 4 hours, respectively, and that from the pulmonary tissue extracted tetracycline was determined by fluorescence analysis. After 1 hour the tetracycline level was with TGS by 128% higher than with T-HCl after 2 hours by 21% and after 4 hours by 15%.

The following results were obtained in further tests:

Table A.

Tetracycline level ^ g / g) 1, 4 and 12 hours after repeated intravenous administration of TGS

and T-HCl every 4 hours

number of
Laboratory animals Treatment with 1 Time (hours)
4th 12th 5
5 ■ - TGS
T-HCl 12.3 ± 1.17
4.4 ± 0.98 7.4 ± 0.64
5.2 ± 0.32 6.90 ± 0.47
1.14 ± 0.08

Table B.

wj tetracycline level ^ g / g) 2, 6 and 12 hours after repeated intravenous administration of TGS

and T-HCl every 12 hours

number of
Laboratory animals Treatment with 2 ' Time (hours)
6th 12th 5
5 TGS
T-HCl 3.6 ± 0.30
4.5 ± 0.30 3.4 ± 0.30
2.7 ± 0.25 " 2.5 ± 0.03
1.9 ± 0.15

About the possible loss of activity of tetracycline when combined with guaiacol-4-sulfonic acid To determine the activity of the product was compared with tetracycline hydrochloride as a standard. The microbiological tests were carried out with Bacillus cereus var. Mycoides (A. T. C. C. 9634) using the cylinder-plate diffusion method accomplished; they show an activity of 690 micrograms per milligram.

Since tetracycline guaiacolsulfonate contains 68.4% tetracycline, no loss of activity can be observed.

The compound can be used in the usual pharmaceutical Forms are administered, e.g. B. in coated tablets, syrups, suppositories, etc., alone or in combination with other drugs. Experiments did not show any noticeable in the pharmaceutical forms mentioned Loss of activity.

209520/425

Claims (1)

Claims: 1. Tetracycline-guaiacol-4-sulfonate of the formula H ⁺ CH ₃ - N - CH ₃ HH OH CONH,