Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-11-01
2001-10-16
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06303642
ABSTRACT:
This invention relates to the use of 2-methyl-thiazolidine-2, 4-dicarboxylic acid and/or its physiologically tolerable salts as mucolytic agents. In Germany, N-acetylcysteine and 2-mercaptoethane sulfonate are used as mucolytic agents, N-acetylcysteine being the most common mucolytic agent. Medical indications include diseases of the respiratory tract that are accompanied by intense secretion of a viscid mucus, such as acute and chronic bronchitis, bronchiectasis, asthmoid bronchitis, bronchial asthma, bronchiolitis, and mucoviscidosis.
Two mechanisms are being discussed as regards the mucolytic action of nucleophile N-acetylcysteine. On the one hand, L-cysteine can be released, and on the other it may be that the free sulfhydryl group of the unchanged substance directly splits up the disulfide bridges of the mucoproteins. The consequence is that the mucous components are fractionated, which is a prerequisite for a decrease in viscosity and improved discharge of the mucus.
A minor portion of L-cysteine is released by hydrolysis, the major portion is released by an amino acid N-deacylase which was detected, for example, in the cytosol of hepatic cells (Wlodek, L., Rommelspacher, H., Susilo, R., Radomski, J. and Hefle, G., Biochem. Pharmacol. 46:917-928 (1993)).
It is generally assumed that N-acetylcysteine is a low-toxic pharmaceutical. However, some barely known reports point to the fact that the toxicity risk N-acetylcysteine poses is underestimated (Estrela, J. M., Saez, G. T., Such, L. and Vina, J., Biochem. Pharmacol. 32:3483-3485 (1983), and Vina, J., Romero, F. J., Saez, G. T. and Pallardo, F. V., Experientia 39:164-165 (1983)). Researchers repeatedly tried to find alternatives because of the fact that N-acetyl cysteine can trigger toxic responses. It is absolutely improper to apply L-cysteine itself as this amino acid is highly toxic and causes the death of brain cells (Karlsen, R. L., Grofova, Y., Malthe-Sorensen, D. und Farnum, E., Exp. Brain. Res. 208:167-180 (1981)). This toxicity can be bypassed if a so-called prodrug is applied, i. e. a predecessor pharmaceutical from which the effective amino acid is released in a controlled way inside the body.
The condensation of carbonyl-containing substances with L-cysteine to thiazolidines has been described before (Susilo, R., Rommelspacher, F. and Hoefle, G., J. Neurochem. 52:1793-1800 (1989)). It is important in this context that said thiazolidines form an L-cysteine reservoir from which the amino acid is released as required. An example of a simply structured thiazolidine is the condensation product of formaldehyde and L-cysteine. Metabolites of this substance proved to be neurotoxic, however. The condensation product of acetaldehyde and L-cysteine is not suited as a predecessor pharmaceutical because it is easily decomposed into its components under physiological conditions (Wlodek, L., Rommelspacher, H., Susilo, R., Radomski, J. and Hefle, G., Biochem. Pharmacol. 46:917-928 (1993)).
It is the problem of this invention to provide a physiologically well tolerable substance that acts as a mucolytic agent suitable for treating diseases of the respiratory tract which are accompanied by intense secretion of mucus, and comprises-less side-effects than the substances used as yet that represent the state of the art.
This problem is solved according to the invention by using 2-methyl-thiazolidine-2,4-dicarboxylic acid and/or its physiologically tolerable salts as mucolytic agents.
It was surprisingly found that 2-methyl-thiazolidine-2, 4-dicarboxylic acid or its physiologically tolerable salts are mucolytic agents.
The synthesis of 2-methyl-thiazolidine-2,4-dicarboxylic acid, its use as a hepaprotective agent, and the manufacture of pharmaceuticals in the form of lozenges or ointments containing 2-methyl-thiazolidine-2, 4-dicarboxylic acid are known from DE-OS 21 16 629. Nothing was known as yet about the mucolytic qualities of 2-methyl-thiazolidine-2, 4-dicarboxylic acid and its physiologically tolerable salts.
It is preferred to use 2-methyl-thiazolidine-2, 4-dicarboxylic acid and/or its physiologically tolerable salts for treating diseases of the respiratory tract that are accompanied by intense secretion of mucus.
Use is particularly preferred in the case of diseases of the respiratory tract that are accompanied by intense secretion of a viscid mucus, such as acute and chronic bronchitis, bronchiectasis, asthmoid bronchitis, bronchial asthma, bronchiolitis, and mucoviscidosis.
2-Methyl-thiazolidine-2,4-dicarboxylic acid surprisingly reduces the viscosity of bronchial mucus. Equimolar concentrations of 2-methyl-thiazolidine-2,4-dicarboxylic acid and N-acetylcysteine show a similar efficacy when the mucus is comparatively low-viscous. As previous studies were carried out in phosphate buffer but the SH-group of the thiazolidine derivatives is activated particularly by cytosolic and membrane-bound enzymes (Susilo, R., Rommelspacher, F. and Hoefle, G., J. Neurochem. 52:1793-1800 (1989) and Wlodek, L., Rommelspacher, H., Susilo, R., Radomski, J. and Hefle, G., Biochem. Pharmacol. 46:917-928 (1993)), it may be assumed that the mucolytic activity of 2-methyl-thiazolidine-2, 4-dicarboxylic acid is even more intense in vivo.
It was further found, surprisingly, that 2-methyl-thiazolidine-2, 4-dicarboxylic acid causes a reduction in the formation of free radicals and an increase in the concentration of sulfhydryl groups in the organism. Thus this compound has a cytoprotective and anti-inflammatory effect. This substance therefore is clearly superior to all compounds known as yet, e. g. N-acetylcysteine. The toxic side-effects known from N-acetylcysteine can be considerably reduced by using 2-methyl-thiazolidine-2, 4-dicarboxylic acid as a mucolytic agent.
Pyruvate, a completely harmless physiological substance, is formed as a by-product when L-cysteine is released from 2-methyl-thiazolidine-2,4-dicarboxylic acid. Unlike N-acetylcysteine, 2-methyl-thiazolidine-2,4-dicarboxylic acid is therefore very well tolerated. There are even indications that pyruvate has a protective effect (Rastellini, C., Cicalese, L., Zeevi, A., Mattes, C., Stauko, R. T., Starzl, T. E. and Rao, A. S., Transplant. Proceed. 27:3383-3384 (1995)). Pyruvate is physiologically formed from glucose and is needed in the tricarboxylic acid cycle for producing the cell's energy. It can therefore be expected that a slow enzymatic release of L-cysteine in the cells of the body or in the bronchi has a retarding effect which would give rise to hope for a more lasting efficacy as compared to N-acetylcysteine.
The salts of 2-methyl-thiazolidine-2,4-dicarboxylic acid used according to the invention are produced in a generally known way by reacting 2-methyl-thiazolidine-2, 4-dicarboxylic acid with the respective bases.
Another object of this invention are pharmaceuticals that, in addition to the common substrates and diluents, contain 2-methyl-thiazolidine-2,4-dicarboxylic acid and/or its physiologically tolerable salts as mucolytic agents. The pharmaceuticals of the invention can be designed for oral, rectal, subcutaneous, intravenous or intramuscular administration, or for inhalation.
The pharmaceuticals of the invention are produced in a generally known way using the common solid or liquid substrates or diluents and the commonly used adjuvants of pharmaceutical engineering, their dosage depending on the intended application. Preferred preparations are forms of application suitable for oral administration or for inhalation. Such forms of application include tablets, film tablets, lozenges, capsules, pills, powder, solutions or suspensions, depot systems, or solutions for inhalation.
Parenteral preparations such as injection solutions can also be taken into consideration, of course. Another example of suitable preparations is suppositories.
The respective tablets can be produced, for example, by intermixing the active ingredient with known adjuvants, e. g. inert diluents such as dextrose, sugar, sorbitol, mannite, polyvinylpyrrolidone, blasting agents such as corn starch or
Rommelspacher Hans
Susilo Rudy
Wlodek Lidia
Criares Theodore J.
Kim Jennifer
Susilo Rudy
Wood Phillips VanSanten Clark & Mortimer
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