HU201473B - Process for producing pharmaceutical compositions against illnesses produced by free radicals - Google Patents

Abstract

The present invention relates to a method for the preparation of pharmaceutical compositions for the treatment of diseases caused by free radicals using a combination of 2,2,4-trimethyl-1,2-dihydroquinoline and glutathione. The essence of the process is that from 0.01 to 99.5% by weight of a 2,2,4-trimethyl-1,2-dihydroquinohn derivative of the formula (I) in which R is hydrogen, Rt is hydrogen. or -SbbMe group and in the latter Me = sodium, potassium, calcium or magnesium - and (ii) 0.5 to 30% glutathione mixture based on the weight of component (i) commonly used in the pharmaceutical industry for 100% wt. mixed with an amount of carrier and / or excipients into a pharmaceutical composition. Scope of the description: 4 pages, Figure 1 EN 201 473 A -1-

Description

This invention relates to 2,2,4-trimethyl-1,2-dihydroquinoline derivatives, preferably 6,6'-methylene-bis (2,2,4-trimethyl) -1,2-trimethyl-1,2-dihydroquinoline derivatives. -dihydroclinoline in combination with 4-methanesulfonic acid salts and glutathione.

In recent years, it has only become known that the common cause of diseases of very different origins is the Free Radicals in Biology, Volume IV, edited by William A. Pryor of the New York Publisher, Academic Press, 1976-1982. J. White et al., 1987, in "Free Radicals Reaction in Medicine" published by Springer Verlag, Berlin, Heidelberf, New York, Tokyo.

Examination of the effects of free radicals has shown that they act as the primary cause of many disorders or as a common cause of the diverse symptoms of some diseases (János Fehér, "Meaning of Free radical reactions in medicine", Biogal Pharmaceuticals, 1985, p. 11). According to White, "recognizing the importance of free radical reactions in biology and medicine is comparable to discovering the structure of DNA, the expression of genetic code, and the effects of prostaglandins" (see p. 13 of the book cited). The clinical relevance and pathogenetic role of free radical reactions in various human diseases is the subject of a detailed study in the above summary book.

Their association with the immune system and their role in certain immunopathological diseases (pages 62-65), rheumatoid arthritis (page 65), atherosclerosis (pages 74-80), myocardial ischemia and infarction (pages 80-83), in liver diseases (p. 99: 105) and in carcinogenesis (p. 87-97), it demonstrates that the pathogen is a free radical in diseases of very different pathogens and causes.

It is known that the 2,2,4-trimethyl-1,2-dihydroquinoline derivatives of general formula (I), which will be described in more detail below, have a significant potentiating effect (i.e., when used together with an antioxidant effect) and ionizing rays in malignant tumors. the sum of the effect of the ionizing radiation and the quinoline derivative separately), they have liver protection against xenobiotics, and they prevent gastrointestinal diseases caused by anti-inflammatory drugs, alcohol-induced damage. British Patent Nos. 162,358 and 2,265,400 to the Federal Republic of Germany. In addition to the listed patents for the pharmacological activity of this type of compound, for example, White, J. et al., 1982, Br. J. Exp. Path, 63: 394; Pollak, Zs., Et al., Strahlentherapie, 154. (7). 499-502 (1978) and by Tonchev, H. et al., Int. J. Tiss. Reac., IV / 4 / 325-330 (1982).

The listed pharmacological publications relate to the effect of 6,6'-methylene bis (2,2,4-trimethyl-1,2-dihydroquinoline), hereinafter referred to as MTDQ, on cirrhosis of the liver, hepatitis, atherosclerosis and malignant tumors. Diszulfonsavsója this compound reduces induced prekurzos secondary amines tumors (see Börzsönyi, M et lecture entitled "Inhibition by an antioxidant of the Carcinogenic effect of nitrosomorpholine Formed in vivo" in the "Proceedings of the VII ^th International Symposium on the N-nitroso Compounds held in Tokyo, 28 ^th September - 1 ^st October 1981, published in Lyon, 1982, No. 41 in IARC Scientific Publications), significantly reduces plaque in atherosclerosis / Sulyok, S., et al. 437-442 (1984)], Immunodulatory Function (J. J. Fehér et al., Drugs Exptl. Clin. Gap. (8-9), 549-562 (1984), and in the preventive and acute treatment of aduit respiratory distress, vasoconstriction, infarction and thrombosis (Török, B. et al., Basic Slit, In. Card. In press). The latter compound is 6,6'-methylene-bis (2,2-dimethyl-4-methanesulfonic acid-1,2-dihydroquinoline), hereinafter referred to as MTDQ-DS, which is used in the form of a salt.

Thus, it is undisputed that the antioxidants / 2,6-di-tert-butyl-para-cresol (BHT) used much earlier and also referred to in those patents; 2,6-di (tert-butyl) -4-methylamizole (BHA); and 6-ethoxy-2,2,4-trimethyl-1,2-dihydroquinoline (EMQ) / (their human use is not possible; their carcinogenicity is disputed but at the same time it is stated that they are potential carcinogens). MTDQ and MTDQ-DS, as well as XAXM / 6,6'-ethylidene-bis (2,2,4-trimethyl-1,2-dihydroquinoline) / are significantly more effective, ie they are the first to meet WHO / FAO 976. and extensive clinical trials. However, in the clinical trial, adverse reactions included, for example, nausea in 5 patients, nausea in 2 patients, mild transaminase elevations in 3 patients, reactive hepatitis 1, nerve disease 1, all of which were reversible / Schratter-Shen. Wien. Clin. Woch, 95 (15), 518-522 (1983). In addition, reversible cholestasis has also been reported in a number of cases, particularly in female patients with mammatory tumor therapy (Fodor, J., et al., Third International Meeting on Progress in Radio-Oncology, March 27-30, 1985, Vienna, Austria).

It is also known that the reduced form of glutathione (gamma-Lglutamyl-L-cysteinylglycine) (hereinafter GHS) is the most important non-protein ethanol derivative in the living organism and its role in hemolysis and glucose phosphate has been continuously recognized since 1953. lack of state. Disruption of GHS concentration within the cell can be assayed, for example, with diazenes, confirming their role in protein synthesis and release of neurotransmitter substances. GHS is effective in the presence of glutathione peroxidase and reductase enzymes, and GHS-2EN 201473 A

Disorders of the GSSG system can cause irreversible damage to the living body. Reference may be made to the book, Free-radicals in Biology, published by the Academic Press (New York, San Francisco, London) in 1976, as well as A. Meister, Life Science 75: 177-190 ( 1974) and by Heindle, H. and Wendel, A., in Febs. Lett., 73, 220-224 (1977). Decreased GHS mucosal content is a cofactor in the induction of toxic gastrointestinal mucosal lesions caused, for example, by various drugs (Strubelt, O., and Hoppenkamps, N., Arch. Int. Pharmaco. Ther., 262-286. 268-278). GSH in Reduced Polymorphic Seed Leukocytes of Diabetic Patients (Chari, SN et al., Am. J. Med. Science, 287: 14-15 (1984)), GSH inhibited redox cycle in tumor cells (Arrick). , B. A. et al., J. Bioi. Chem., 257, 1231-1237 (1982),, and GSH levels are significantly reduced in cerebral hemorrhage and cerebral infarction, and cerebral ischemia and brain tumors (Frithz, G. et al., Eur. Neurol. 21.41-4791982) / and in patients with cirrhosis of the liver, it is also significantly reduced in plasma, regardless of diet, which is associated with a decrease in hepatic tripeptide synthesis capacity (Rajender, K., et al., Gastroenterology 87: 770- 776 (1984).

Regarding MTDQ and MTDQ-DS, János Fehér described in his earlier book: “Unfortunately, high-potency synthetic antioxidants cannot be used in the therapy of human diseases because their effective doses are toxic. However, MTDQ and MTDQ-DS, recently developed by Hungarian authors, are potent, non-toxic antioxidants, and are expected to be of great use in the treatment of free radical pathogenesis in humans ”(see Summary, p. 132).

It has now been found that when the condensation products of 2,2,4-trimethyl-1,2-dihydroquinoline or its substituted derivatives and aliphatic aldehydes with the exception of the 6-position, their acid addition salts and their alkanesulfonic acid salts at the 4-carbon atom, preferably methanesulfonic acid salts, , when used in an amount tolerated and officially authorized by the body with 0.5-30% by weight of glutathione, the side effects of using antioxidants as defined herein are not, or significantly reduced, and the antioxidant and therapeutic effects of the antioxidants are further increased . This finding is all the more surprising for one skilled in the art when one considers that these effects are not observed in vitro outside the living organism, and this is probably due to the combination of the present invention with enzymes involved in and associated with glutathione metabolism in the living body. changes, restores, regulates its functions.

While not wishing to be bound by any theory, it is believed that the above extremely beneficial effects are exerted by the following mechanism.

The combination of the present invention not only raises GSH levels in the body in proportion to the amount of glutathione ingested, but to a much greater extent, presumably by restoring or improving tripeptide synthesis ability in the liver for protein metabolism and detoxification, and for the body's immune responses. .

SUMMARY OF THE INVENTION The present invention relates to a process for the preparation of pharmaceutical compositions for use in human and veterinary medicine using 2,2,4-trimethyl-1,2-dihydroquinoline derivatives. The process of the present invention comprises (i) providing, in an amount from 0.012 to 99.5% by weight, of a 2,2,4-trimethyl-1,2-dihydroquinoline derivative of formula (I) wherein R is R 1 is hydrogen or -SO ₃ Me and in the latter Me is a mixture of sodium, potassium, calcium or magnesium and (ii) 0.5-30% by weight of component (i) is used in the pharmaceutical industry, mixed with carriers and / or excipients in amounts sufficient to 100% by weight to form a pharmaceutical composition, feed or feed additive.

The carrier and excipient used in the process of the present invention are commercially available materials well known in the art. The antioxidants may be prepared as described in the relevant literature cited above. Glutathione is a commercially available material.

The pharmaceutical compositions of the present invention include, in particular, encapsulated compositions, tablets, water-soluble injectable solutions or soluble powders, of course, compositions comprising the components (i) and (ii) of the combination according to the invention, for simultaneous or sequential administration. for the purpose. The amount of the combination according to the invention in these compositions will depend on a number of factors, such as the nature of the symptom being treated, the condition, age and weight of the subject being treated, and the body surface area.

The active compound combination of the present invention prevents gastrointestinal mucosal damage, hormonal contraceptive thromboembolism, and liver damage caused by non-steroidal anti-inflammatory drugs. Further, the active compound combination according to the invention is effective in preventing and treating, for example, thrombosis, infarction, atherosclerosis, pancreatitis, diabetes-induced angiopathy and other lipid peroxidation-related diseases.

Reference will be made to the foregoing with respect to the advantages of the compositions of the present invention.

Abbreviations used in the specification for compound names and their respective specific chemical names are given below:

-3HU 201473 A

MTDQ = 6.6'-Methylenebis (2,2,4-trimethyl-1,2-dihydroquinoline)

MTDQ-DS = 6.6'-Methylenebis (2,2-dimethyl-4-methanesulfonic acid-1,2-dihydroquinoline)

XAX-M = 6,6'-Ethylidene-bis (2,2,4-trimethyl-1,2-dihydroquinoline)

BHT = 2,6-di-tert-butyl-para-cresol

BHA = 2,6-di (tert-butyl) -4-methylanisole

EMQ = 6-ethoxy-2,2,4-trimethyl-1,2-dihydroquinoline

The following examples are intended to illustrate the process of the invention.

Example 1

Human pharmaceutical preparation

100 parts by weight of MTDQ and 30 parts by weight of glutathione are mixed and the resulting mixture is formulated into 200-200 mg of active compound combination in gastric soluble capsules. The recommended average daily dose of this capsule is 20-30 pieces.

1. Experimental Example

Treatment of cirrhosis of the liver

20 LATI-cultured CFLP strains of 20-25 g of mice of each sex were collected per group and maintained on normal LATI medium.

The control group receives 1 mg / kg of sunflower oil for diet.

The positive control group received 2 ml / kg body weight of carbon tetrachloride once subcutaneously.

The treated group received MTDQ 100 mg / kg / day and glutathione 30 mg / kg / day, starting 8 days prior to administration of carbon tetrachloride, mixed in the diet.

The next group receives MTDQ only, in the same way as the previous group.

Each group (except sunflower oil treated and positive control) receives carbon tetrachloride on day 9 as described in the positive control group.

Until day 14 of the experiment, the treated groups receive the active ingredients. On day 14, the animals are sacrificed and malondialdehyde precursors with levels typical of lipid peroxidation are measured from the liver by reaction with thiobarbituric acid. The measured values are as follows:

control: 0.14 µg / g positive control: 1.38 µg / g treated with the combination of the invention: 0.38 µg / g MTDQ only treated: 0.72 µg / g

Light microscopic examination of the morphological image also confirmed the difference in severity.

2. Experimental Example

Treatment of infarction

Experimental studies were performed on mongrel dogs with 5-5 animals per group after premedication-Droperidol-Fentanyl-Atropin, with lumbar thoracotomy under intratracheal narcosis. We tied the ramus descendes anterior art. coronary arteries during the origin of the first ramus obliqus (test ligatura).

Continuous ECG monitoring revealed the occurrence and extent of arrhythmia and the effect of the therapy applied.

Experimental groups:

1) Ligatures without treatment of animals control group.

2) 150 mg / kg ligature animals intravenously treated with MTDQ-DS.

3) Intravenous GSH treated ligation animals, 20 mg / kg.

4) Ligature animals treated with MTDQ-DS and GSH combined therapy. Treatment was given intravenously with MTDQ-DS at 150 mg / kg and GSH at 20 mg / kg.

Ligatures produced ventricular extrasystoles, the number of which per minute (so-called VES / min) was 15 at the second minute after the ligature and 60 at the 8th minute.

For groups 2-3-4, treatment was started at 10 minutes.

In Group 1, a very large infarction occurred with ventricular flutter and despite repeated electrical defibrillation, the dogs died. Serious extensive abnormalities were observed in myocardial samples.

In group 2, 10 minutes after treatment, the VES / min average decreases to 10, and electrical defibrillation is successful. In myocardial samples, the severity and extent of the abnormalities were on average 30% relative to group 1.

In group 3, VES / min decreases to 15 within 2-3 minutes after treatment, but this effect is only temporary because it increases from 5 minutes. By the 7th minute after treatment, he had reached 40. Large and severe abnormalities were seen in myocardial samples.

In group 4, VES / min falls below 10 at the second minute after treatment, signs of infarction were present, arrhythmia was uncharacteristic, and electrical activity was relatively stable during the acute period. Thus, there was little or no difference in myocardial samples including the infarct area compared to healthy controls.

Claims (2)

PATENT CLAIMS A process for the preparation of a pharmaceutical composition for use in the treatment of diseases caused by free radicals, characterized in that (i) 0.012-99.5% by weight of a 2,2,4-trimethyl-1,2-1,2-trimethyl-1 -dihidrokmolin derivative - wherein R is hydrogen, R₁ is hydrogen or -SO ₃ Me Me group and the latter is sodium, potassium, calcium or magnesium atom - and (ii) based on the weight of component (i) 0.5 A blend of -30% glutathione is mixed with a carrier and / or excipient used in the pharmaceutical art to make up to 100% w / w of a pharmaceutical composition. 2. A process according to claim 1 wherein component (i) is 6,6'-methylenebis (2,2,4-trimethyl-1,2-dihydroquinoline) or its 4-methanesulfonic acid salt.