DE1965343A1 - Medicines, in particular for reducing the viscosity of the mucus and use as a cough suppressant, and process for its production - Google Patents

Description

SOGESPAR SA. FRIBORG / Switzerland

Medicines, in particular for reducing the viscosity of the mucus and use as an antitussive agent, and methods for its Manufacturing

The invention relates to a novel medicament based on of thiazolidine carboxylic acid with interesting physiological properties, in particular for reducing the viscosity of the mucus and Use as a cough suppressant.

This medicinal product is characterized by derivatives of this thiazolidine carboxylic acid with the general formula

H, C CH - COR-

N- R ₃

CH
^R l

where mean:

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R is hydrogen, an alcoyl homocyclic or heterocyclic Aryl ^ aradikal, a hydroxyl group, an alcoyloxy or a homo- or neter ο cyclic η aryloxy radical, an amino group or a Carboxyl group or its ester, it being possible for all of these groups in turn to be substituted again,

R- is an amino or hydroxyl group, an alcoyloxy or a homo- or heterocyclic aryloxy radical, a mono- or dialcoylamino group (NHCH-OH) or morpholine, these groups as well in turn can be substituted,

R, a hydrogen, an alcoyl or a homo- or heterocyclic Aryl radical, a carboxyl group or its ester.

The manufacture of these products is done in a general way such that one has a sulfur- or nitrogen-containing carboxylic acid, with the SH group and the NH group on two adjacent carbon atoms sit, reacts with an aldehyde, forming the thiazolidine ring. This implementation can be in most Cases take place in aqueous solution and sometimes in an alcoholic medium.

Example It

Production of 2-methyl-thiazolidine-4-carboxylic acid (MW 238)

CH-COOH

CH-CH-COOH + CH-CHO> S NH + H ₀ O

SH NH ₂

CH ₃

In a reaction vessel with a capacity of 2 liters, equipped with a stirrer, a cooler, an itermometer and a 250 ml funnel Contents and a pressure equalization pipe, if a stream of nitrogen is passed,

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BATH ORIGINAL.

to displace the oxygen in the air. The implementation takes place here in a nitrogen atmosphere.

Thereupon are entered one after the other;

270, Og 1-cysteine base (2.23 mol) and
1700 g of distilled water.

The mixture is stirred at 15, whereby an incomplete dissolution of the cysteine takes place « 100 g of acetaldehyde (2.27 mol) are then added slowly with stirring over a period of 3/4 to 1 hour using the dropping funnel

ο closed and keeps the temperature between 15 and 20. If necessary is cooled with cold water.

ο After the cysteine has gone into solution, 3 hours at 20

ο
and then stirred at 40 for an hour to complete the reaction. It is left to stand overnight at room temperature, a slight precipitate settling out, which is filtered off. Of the

p__ - value is 3, 8 to 4.
H

The reaction solution is then transferred to a 3 liter flask, whereupon 850 ml of water are then distilled off in vacuo. About the residue 1 liter of absolute alcohol is added slowly and with stirring. After inoculation, the solution is allowed to crystallize in the refrigerator.

The product slowly crystallizes in the form of a voluminous precipitate. It is filtered on a 24 cm filter, carefully squeezed and then washed with "three portions of 100 ml of absolute alcohol. The Precipitate is dried in vacuo at 70 to constant weight. The substance is then sieved and drying is completed under vacuum in a desiccator over calcium chloride.

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Yield 275g = 84%. Melting point: 158-160.

A white product, finely crystalline from light and voluminous, matting Crystals.

For recrystallization, 20 g of the 2-methyl-thiazolidine-4-carbon-

O
acid in 80 ml of distilled water at 90. After adding some charcoal, the mixture is filtered hot and then absolute alcohol is added in an amount of 400 ml. It is left to crystallize in the refrigerator overnight.

After filtration, washing and drying under vacuum at 70, 12 g of the recrystallized acid are obtained, which corresponds to a yield of 60 tfo . Melting point: 163-164.

The solubility of 2-methyl-thiazolidine-4-carboxylic acid is:

ο
1 g at 20 in 12 ml of water

ο
1 g at 20 in 40 ml of methanol or ethanol.

The 1-cysteine base is made from the 1-cysteine hydrochloride in usual way.

The acetaldehyde with a boiling point of 21 is in a melted off Ampoule with a content of 100 g, which must be cooled. The dropping funnel is also in the refrigerator a few hours before use cooled to avoid excessive evaporation losses. The dropping funnel also carries a tube for pressure equalization and must be hermetrically sealed with a ground-glass stopper while the acetaldehyde is being introduced be.

Example 2;

Preparation of an ester and an amide

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I!

CH-COOH

S / NH + CH ₃ OH + HCl

CHT

CHT

CH ₃

H, C CH- COOCH ₀

2 I ι

I I

NH. HCl + H "O

CH,

H ₀ C (SH- COOCH,

2 · ι

¹ II

CH

NH. HCl + CHONa H ₂ O

if

-coocH,

NH + NaCl

+ CH OH

H ₀ C CH- COOCH-

NH. HCl + 2 NH,

CH ₃ HC 'CH-CONH-2 ι ι

J '

S Nl

CH,

+ CH OH +

+ NHXl 4

Example 3

Preparation of the methyl ester

A suspension of 100 g is saturated at 20 for 6 to 8 hours 2-methyl-thiazolidine-4-carboxylic acid in 1 liter of methanol with a stream of gaseous hydrogen chloride. Here, the mixture becomes gradual

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homogeneous. The mixture is then refluxed for a further hour and the reaction mixture is left to stand overnight. This is done under vacuum evaporated to dryness. The residue is treated with 500 ml of ether and then left to crystallize. In this way, 400 g of the methyl ester hydrochloride are obtained.

To prepare the base, 20 g of this hydrochloride in 100 ml of methanol are treated with a solution of 2.3 g of sodium in 25 ml Methanol. After the sodium chloride has been separated off, it is evaporated under Vacuum to dryness. The oily residue obtained is distilled in vacuo at 0.1 mm Hg and yields 15 g of the ester base.

Example 4

Preparation of the amide

ο One saturates with a dry ammonia stream between 0 and a solution of 100 g of the hydrochloride of the methyl ester in one liter of methanol. This saturation takes about 6 hours, after which you can get the Let the reaction mixture stand at room temperature for 2 days. Here-

o it is warmed up to 30 for another hour and then the excess ammonia and methanol are distilled off in vacuo *. Of the dry residue is treated with 250 ml of boiling isopropanol. The ammonium chloride is filtered off and the amide is left in the refrigerator crystallize. In this way, 60 g of the crystalline are obtained Product.

The analyzes of these compounds were carried out by quantitative tests, either by potentiometric comparisons with 0, ln-perchloric acid or by alkali acidimetry with Ο, ΐη-teirabtityl ammonium hydroxide and methyl violet as an indicator.

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With regard to the toxicological properties of the inventive Connections were generally found to be a proportionate show low toxicity. The DL 50 in the mouse "is generally more than 500-600 mg / kg per os and 300-400 mg / kg subcutaneous injection. A daily dose of 300 mg / kg for continuous treatment for 60 days in a rat per os showed no toxic effect and the various tests both of the blood composition and of the various organs of the animal did not show any secondary symptoms due to it such treatment.

A number of these compounds have been used in the pharmacological field Tested "in vitro" with regard to their effect on the viscosity of the mucus, namely in comparison with a physiological saline solution.

These experiments showed that one could work with this group of compounds can reduce viscosity by 20-40% after 5 minutes, 30-45% after 10 minutes and 35-65% after 15 minutes.

The 2-methylthiazolidine-4-carboxylic acid already described above was used for these pharmacological and clinical experiments. This is a white product, odorless, relatively light due to fine crystallization with a melting point of 163-164 (not corrected). This product is easily soluble in water as well as in most alcohols and other organic solvents.

The production described above resulted in an optically active one Obtain product, especially since 1-cysteine is used as a starting point is. The levorotatory form is also obtained for this product.

When testing the toxicological properties, it was found that

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that doses below 300 mg / kg do not cause mortality in the animal. Since the DL 50 is no longer of great importance under these conditions the doses given then quickly led to the DL 100.

With subcutaneous application below 2440 mg / kg none was found Animal mortality.

The intraperitoneal administration of doses below 2440 mg / kg ψ also showed no mortality in the animal.

2-Methylthiazolidine-4-carboxylic acid was found in a male Wistar rat given for one and three months. At daily doses of 10, 250 and 500 mg / kg, there was no mortality in the entire animals established.

Examination of the blood composition and the various organs also showed no secondary effects whatsoever Substance.

k In addition, with various doses, a mucus viscosity lowering was obtained Effect of the compounds according to the invention in comparison determined with a physiological saline solution. The viscosity values in centipoises were determined immediately after application, after 5 minutes, after 10 minutes and after 15 minutes after combining the substance with 2 ml of sputum, which taken directly from patients with chronic bronchitis.

These tests have shown that in comparison with the physiological Saline solution, the compounds according to the invention bring about a very significant reduction in the viscosity of the mucus by the in the results given in the table below were achieved:

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immediately after after after

5 min ^{10 min 15 min}

NaCl solution 100% 100% 100% 100%

30 mg '■ 71% 62% 60% 51%

50 mg 49% 48% 40% 40%

100 mg 36% 32% 30% 30%

It should be noted that these values are always calculated back were compared to the saline solution, which was made 100% each time.

The 2-methylthiazolidine-4-carboxylic acid was also administered orally at 10 mg / kg used on horses with chronic bronchitis and in some cases with emphysema. After two to four days of the Depending on the case, one could apply the cessation of breathing difficulties determine.

Such results were also obtained in dogs with the same doses. These results were obtained by using the product orally in an amount of 10 mg / kg.

The following further compounds according to the invention also have achieved satisfactory results:

2-ethyl-thiazolidine-4-carboxylic acid

2-methyl-thiazolidine-4-carboxylate of 2-amino-2-thiazolidine, 2-methyl-thiazolidine-4-sodium carboxylate 2-methyl-N-methyl-thiazolidine-4-carboxylic acid 2-methylthiazolidine-4-carboxylic acid amide 2-ethyl-thiazolidine-4-carboxamide 2-methyl-N-methyl-thiazolidine-4-carboxamide N-methyl amide of 2-methyl-thiazolidine-4-carboxylic acid NN-dimethyl amide of 2-ethyl-thiazolidine-4-carboxylic acid

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- ίο -

2-methyl-thiazolidine-4-methyl-carboxylate
2-ethyl-thiazolidine- 4-ethyl carboxylate

Pharmaceutical use in humans was by mouth in the form of powder, tablets or dragees, which were obtained by mixing the active ingredient with a certain number of Additives and carriers to make this active ingredient in the pharmaceutical bring usable form. The content of active ingredient was generally 100 mg, for example in that a tablet had the following composition:

2-Me thyl ^{r-thiazolidine-4-carboxylic} acid 100 mg Lactose 90 mg Polyvinyl pyrrolidon 2 mg Silica 1 mg Cereal starch 46 mg Magne siumstear at 1 mg Talc 10 mg

250 mg

Aqueous solutions have been used in the same way for treatments to be able to carry out by fogging. Finally, the active ingredient can also be used in the form of suppositories.

The active ingredient can also be in the solutions or suspensions in

Mixture with other ingredients are introduced to create a /

to achieve therapeutic, antitussive effects. He is also applicable in the form of sterile solutions for injections.

For example, a solution for an intramuscular injection contains 3 injections *.

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Z-Methyl-thiazolidine-4-carboxamide 100 mg

Sodium Chloride 2.5 mg

Preservative 1 ml

The substances with the effects of reducing the viscosity of the mucus are used often used in conjunction with antibiotics for therapeutic purposes. It was therefore also tested "in vitro" whether the 2-methyl-thiazolidine-4-carboxylic acid interferes with the antibiotic effect of oxytetraicycline hydrochloride.

These experiments have shown that, a combination of this compound in various mixing ratios with oxytetracycline hydrochloride neither a decrease nor an increase of the antibiotic effectiveness can be seen.

For clinical trials with the medicament according to the invention the patients were divided into three different groups. One first group of 20 patients with chronic bronchitic difficulties were treated with solutions of 5, 10 and 20% active Active ingredient as an aerosol, with a saline solution being used for comparison.

The effectiveness of the product was not very clearly pronounced with the 5% solution, but it was clearly ascertainable and almost the same as with the 10 and 20% solutions. A clear reduction in the viscosity of the sputum was found here and parallel here an increase in its volume. It still seemed that the solution also increased the volume of secretion by 20%, sometimes causing bronchial clogging in patients who had difficulty in expectoration. '

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In a second group of 10 patients, this time only the solution with 10 ° Jo of active ingredient was used, again in comparison with the same amount of a saline solution, ie 2x2 ml per day in the morning and in the evening.

This treatment with an aerosol gave the following results: (as mean of 10 patients each)

after 0 5 10 15 30 minutes

NaCl solution (0.9%). 155.0 149.6 145.2 150.8 157.3 Substance solution (10%) 173.2 112.4 90.1 73.5 61.2

At the same time, these results were checked and confirmed by the histochemical determination of fibers ADN and sMPS of the mucus,

It should be emphasized here that there are no visible effects on the mucous membranes.

• In a third group of 20 patients with chronic bronchitis, the product was given in 10 cases in the form of 4-6 tablets of 100 mg * and in 10 other cases in the form of an intramuscular injection of 3 ml. A solution of 10% was also used in the morning and in the evening for 7 days, with 10 untreated patients being observed at the same time. The therapeutic effectiveness in this application form showed itself more slowly and with less effect, but also here again had an influence on the viscosity of the sputum and the change in its volume. Here, too, the histochemical examinations confirmed the results obtained.

Viscosity measurements of the slime showed the mean of all investigated Cases of the following results:

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Without treatment
Orally
Inject. in the

Days after starting treatment

012 3 4567

152.1 148.6 150.5 149.2 147.5 149.6 --- 150.3 167.5 146.3 122.1 105.2 88.2 67.6 58.7 55.00 171 , 4 132.1 95.3 71.4 62.3 52.2

You can see a significant reduction in the viscosity of the Detect mucus either by injection or orally. In the latter case, the result is evident but slower and the treatment must be extended accordingly. In this context it is important to note that it is very well tolerated to point out this active ingredient, both for general use and by injection, if this is slow is performed.

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Claims (1)

PATENT CLAIMS 1. Medicines, especially to reduce the viscosity of the mucus and use as an antitussive agent based on thiazolidine-carboxylic acid, characterized by derivatives of this acid the general formula CH-COR ₉ where mean: R ^ is a hydrogen, an alcoyl-yhomocyclic or heterocyclic Aryl radical, a hydroxyl group, an alcoyloxy or a homo- or heterocyclic aryloxy, an amino group or a Carboxyl group or its ester, it being possible for all of these groups in turn to be substituted again, R is an amino or hydroxyl group, an alcoyloxy or a homocyclic or heterocyclic aryloxy group, a mono- or dialcoylamino group (NHCH _? OH) or morpholine, which group can also be substituted in turn, R is hydrogen, an alcoyl or a homo- or heterocyclic Aryl radical, a carboxyl group or its ester. 2. Medicament according to claim 1, characterized by 2-methyl-thiazolidine-4-carboxylic acid. 3. Medicament according to claim 1, characterized by 2-methyl-thiazolidine-4-carboxylic acid eamid. 009830/1954 4. Medicament according to claim 1, characterized by a mixture of the active ingredient with a suitable pharmaceutical carrier. 5. Medicament according to claim 4, characterized by its processing for powders, tablets, coated tablets, capsules, suspensions, solutions, injection solutions, sprays and suppositories. ' o \ Process for the production of a medicament according to claims 1-3, characterized in that a sulfur- and nitrogen-containing carboxylic acid of the formula CH- - CH - COR_ I ² I SH ^NHR - ₃ is reacted with an aldehyde of the formula R-CHO, whereupon the obtained acid by means of an alcohol or an ammonia derivative it can be converted into an ester or an amide. 7. The method according to claim 6, characterized in that the implementation is carried out in water or in an alcoholic medium. 8. The method according to claim 6, characterized in that the implementation is carried out in an inert atmosphere, for example under nitrogen. 9. The method according to claim 6, characterized in that a lower Excess of the aldehyde is used. 009830/1954