WO1987000048A1

WO1987000048A1 - Pharmaceutical compositions and alimentary products for human comsumption for the treatment and/or prevention of diseases caused by free radical reactions and a process for the inhibition of free radical reactions in the human organism

Info

Publication number: WO1987000048A1
Application number: PCT/HU1986/000041
Authority: WO
Inventors: József BARA; Vilmos BA^"R; Elo^"d ESZTERGÁLY; János FEHÉR; Zsuzsanna POLLÁK
Original assignee: Ferris Épito^"Ipari Szövetkezeti Közös Vállalat
Priority date: 1985-07-11
Filing date: 1986-07-10
Publication date: 1987-01-15
Also published as: HU194734B; JPS63500595A; EP0229812A1

Abstract

Pharmaceutical compositions and alimentary products for human consumption for the treatment and/or prevention of diseases caused by free radical reactions, comprising (i) a dihydroquinoline of formula (I), wherein X1 is a sulfo group or a group of the formula -SO2-NH2 (a) or -SO2-O-Me (b) and in the latter M stands for an alkali metal, and X2 is either hydrogen or its meaning is identical with that of X1, R1 stands for a hydrogen atom or an alkyl group, and each R represents independently a halogen or hydrogen atom or a hydroxy, alkoxy, alkyl, aryl, aryloxy or -NR2R3 group, and in the latter R2 and R3 represent, independently from each other, a hydrogen atom or alkyl or aryl group, (ii) ascorbic acid or isoascorbic acid or an alkali metal, calcium or magnesium salt or an ester formed with a fatty acid thereof or a mixture of such compounds, and (iii) optionally a water-soluble inorganic hydrocarbonate salt and/or sodium thiosulfate.

Description

PHARMACEUTICAL COMPOSITIONS AND ALIMENTARY PRODUCTS FOR HUMAN CONSUMPTION FOR THE TREATMENT AND/OR PREVENTION OF DISEASES CAUSED BY FREE RADICAL REACTIONS AND A PROCESS FOR THE INHIBITION OF FREE RADICAL REACTIONS

IN THE HUMAN ORGANISM

Technical field

The invention relates to pharmaceutical compositions and alimentary products for human consumption, for the treatment and/or prevention of diseases caused by free radical reactions. The invention relates further to a process for the inhibition of free radical reactions in the human organism.

Background art

It is known for example from the Hungarian patent specification No. 185,208 that the dihydroquinolines of the formula

CH X

wherein X₁ is a sulfo group or a group of the formula (a) or

(b )

and in the latter Me stands for an alkali metal, and X₂ is either hydrogen or its meaning is identical with that of X₁, effectively inhibit free radical reactions. They act very effectively in vivo, too and their further advantage resides in their low toxicity.

Our studies on the action of the dihydrocuinolines of the formula (II) revealed that they can be used with success in the prevention of diseases caused by free radical reactions, in addition to their favourable therapeutic effect. The following particular advantages of these compounds can be mentioned. a) They are able to reduce the atherosclerotic index, by preventing risk factors (LDL/HDL and LDL+VLDL/KDL cholesterol fractions), of atherogenesis primarily by substantially increasing the protective HDL fraction and decreasing the detrimental LDL fraction and the VLDL fraction serving as the source of the former, respectively, and the lysosomal enzyme fraction, the presence of which being a precondition of the impairing effect of LDL on the vascular wall. b) They prevent or significantly reduce the risk of myocardial infarctions in consequence of their ability to inactivate hypoxia-dependent endoperoxide formation, which originates free radicals, as well as their capacity to release oxygen in situ from said endoperoxides. c) They protect all cellular and subcellular membranes of the human organism, e.g. of the liver, the brain, and the myocardium, primarily due to their membrane stabilizing effect. d) They reduce the incidence of malignant neoplasms elicited by carcinogens and nitrosamine precursors, respectively, primarily by inhibiting free radical reactions and by autonitrosification. e) They reduce the liver impairing action and thrombosis inducing effect of xenobiotics and drugs, e.g. contraceptives. Of our relevant publications of considerably high number we would like to refer to the following ones:

Zs. Pollak et al: "Effects on serum lipids and biliary cholesterol concentrations of a new dihydrocυinoline-type hypclipidemic agent in experimental juvenile atherosclerosis", Proc. 16th ISF Congress, Budapest, 1059 - 1067, 1983;

Suiyok et al: "Liver lipid peroxidation induced by cholesterol and its treatment with a dihydroquinoline type radical scavenger in rabbits", Acta Physiologica Hung., 64, (3-4), 437-442, 1984; and

Feher et al: "Biochemical markers in carbon tetrachloride and galactosamine induced acute liver injuries; effects of dihydroquinoline type antioxidants", Brit. J. Ex. Path., 63, 394-400, 1982. The considerable instability of the compounds of the formula (II) (they are readily oxidized particularly on the effect of air and light) inhibits the utilization of their preventive and curative effect. Their oxidative disintegration manifests itself also in blue decolourization. This is probably due to the fact that the methylene bridge linking the two dihydroquinoline moieties is transformed into a hydrol, and one has to reckon also with the transformation of the NH groups containing mobile H-atoms into -N-N-binding. These transformations also affect the biological activity of the compounds of the formula (II), i.e. aconsiderable decrease of the peroxide decomposing ability and scavenger effect of these compounds can be observed. Accordingly, if one wish to utilize the compounds of the formula (II) without the above-mentioned problems, combinations have to be found in which the maintainance of their biological activity is warranted. A sine qua non prerequisite of the preventive combinations warranting regular presence of the active substance in the organisn implies the uniform intensity of the biological activity in any of the circumstances of their use. The curative pharmaceutical compositions must, of course, meet similar-standards.

The Hungarian patent specification No. 162,358 discloses the preparation of dihydroquinolines of similar type as well as of pharmaceutical compositions containing such compounds as active agent. The active agents described in this patent specification are dihydroquinoline derivatives in the case of which mere than two dihydroquinoline molecules are connected together through methylene bridges, but these molecules are not substituted in the 4th position. The disadvantage of these derivatives resides in their limited solubility or non-solubility in water and, as a consequence, in their limited absorbability.

Disclosure of invention

The invention is aiming at the elaboration of pharmaceutical compositions and alimentary products for human consumption which are free of the above disadvantages, that is, they are absolutely stabile, soluble in water and absorbable.

It has been recognized that the above requirements are met by a composition comprising (i) a dihydroquinoline of the formula

wherein

X₁ is a sulfc group or a group of tne formula

—SO₂ — NH₂ (a) or

—SO₂— O —Me (b)

in the latter M stands for an alkali metal , and X₂ is either hydrogen or its meaning is identical with that of X₁,

R₁ stands for a hydrogen atom or a C_{1 -4} aIkyl group, and each R represents independently a halogen or hydrogen atom or a hydroxy, C_{1 -8} alkoxy, C_{1 -12} alkyl, aryl, aryloxy or -NR₂R₃ group, and in the latter R₂ and R₃ represent, independently from each other, a hydrogen atom or a C_{1 -8} alkyl or aryl group, (ii) ascorbic acid or isoascorbic acid or an alkali metal, calcium or magnesium salt or an ester formed with a C_10-20 straight or branched chained fatty acid thereof or a mixture of such compounds, and (iii) optionally a water-soluble inorganic hydrocarbonate salt and/or sodium thiosulfate. It has been namely recognized that components (i) and (ii) synergically increase the activity of each other and component (iii) protects components (i) and (ii) from the chemical decomposition.

Thus, the present invention relates, on the one hand, to pharmaceutical compositions and alimentary products for human consumption for the treatment and/or prevention of diseases caused by free radical reactions. The compositions of the invention are characterized by comprising

(i) a dihydroquinoline of the formula

wherein

X₁ is a sulfo group or a group of the formula

SO₂ — NH₂ (a)

SO₂ — O— Me (b)

and in the latter M stands for an alkali metal, and X₂ is either hydrogen or its meaning is identical with that of X₁, R₁ stands for a hydrogen atom or a C_{1 -4} alkyl group, and each R represents independently a halogen or hydrogen atom or a hydroxy, C_{1 -8} alkoxy, C_1-12 alkyl, aryl, aryloxy or -NR₂R₃ group, and in the latter R₂ and R₃ represent, independently from each other, a hydrogen atom or a C_1-8 alkyl or aryl group,

(ii) ascorbic acid or isoascorbic acid or an alkali metal, calcium or magnesium salt or an ester formed with a C_10-20 straight or branched chained fatty acid thereof or a mixture of such compounds, taken in an amount of 0.5 to 35 parts by weight based on 100 parts by weight of component (i) , and (iii) optionally a water-soluble inorganic hydrocarbonate salt, taken in an amount of 1 to 10 parts by weight based on 100 parts by weight of component (i) , and/or sodium thiosulfate, taken in an amcunt of 0.2 to 5 parts by weight based on 100 parts by weight of component (i).

The present invention relates, on the other hand, to a process for the inhibition of free radical reactions in the human organism. The essence of this process is administering a therapeutically effective amount of a compound of the formula

wherein

X₁ is a sulfo group or a group of the formula

— SOO₂ — NH₂ (a)

— SO₂—O —Me (b)

and in the latter M stands for an alkali metal, and X₂ is either hydrogen or its meaning is identical with that of X₁, R₁ stands for a hydrogen atom or a C_1-4 alkyl group, and each R represents independently a halogen or hydrogen atom or a hydroxy, C_{1 -8} alkoxy, C_1-12 alkyl, aryl, aryloxy or -NF₂R₃ group, and in the latter R₂ and R₃ represent, independently from each other, a hydrogen atom or a C_{1 - 8} alkyl or aryl group, as component (i) and, simultaneously or separately component (ii) and optionally component (ii) in the above-identified ratios. Said therapeutically effective amount of component (i) is suitably a daily dosage of 0.8 to 1.4 g.

Turning back to formula (I), the alkyl groups and the alkyl moieties of the alkoxy groups can be straight or branched chained. As an example methyl, ethyl, propyl, isopropyl, butyl, octyl and dodecyl groups, respectively, methoxy, ethoxy, propoxy, isopropoxy and octyloxy groups are mentioned. The aryl groups and the aryl moiety of the aryloxy groups are suitably phenyl or naphthyl groups, being optionally substituted by e.g. the above-mentioned alkyl or alkoxy group (s) or halo atom(s ) .

The compounds of the formula (I) are either known from the Hungarian patent specification No. 185 208 or are of analogous structure. All the compounds of the formula (I) can be prepared by well-known methods.

The amount of component (i) based on the total amount of the pharmaceutical compositions and alimentary products for human consumption according to the present invention is suitably 0.04 to 75 % by weight. The actual amount of this component depends on the type of the product to be prepared. If e.g. a mineral water is to be prepared, the minimum quantity of component (i) is actually 0.04 % by weight. In the case of preparing a tablet suitable for peroral administration the amount of component (i) can be as high as 75 % by weight. Beyond components (i), (ii) and (iii) the pharmaceutical compositions and the alimentary products for human consumption according to the present invention can contain usual carriers, surfactants and other well-known adjuvants. These pharmaceutical compositions and alimentary products may take the usual forms of such products, said forms being well known to a person skilled in the art.

The pharmaceutical compositions and alimentary products according to the present invention contain preferably sodium or calcium L-ascorbate or palmitic or stearic ascorbate or isoascorbate, more preferably palmitic isoascorbate, as component (ii).

The pharmaceutical compositions and alimentary products according to the present invention contain a component (iii) suitably in the case if a liquid product is prepared. It is highly preferred to use sodium hydrocarbonate and/or sodium thiosulfate as component (iii). Industrial applicability

The pharmaceutical compositions according to the present invention can be prepared in the form of e.g. tablets, coated tablets, powders or in any other form suitable for peroral administration. Semolina, wheat, bran and wheat germ are advantageous vehicles for this purpose, though other conventional vehicles can be used. Tween 60, methylcellulose or polyvinylpyrrolidone can be used as surface-active substances or emulsifiers, respectively. Fremixing of the surface-active substance with components (i) and (ii) is preferred. In these compositions the amount of component (i) is adjusted to ensure a daily dosage of suitably 0.8 to 1.4 g., administered in 2 to 6 doses. In accordance with the present invention cne can prepare as alimentary products for human consumption foods and beverages, for example tea, cocoa powder, sweeteners, mineral water or any other beverages or foods for regular consumption containing components (i) and (ii). Prevention of the impairing effect of free radical reactions in the human organism by the regular consumption of these foods and beverages equals that obtained by the administration of the previously mentioned pharmaceutical compositions. Obviously, estimation of the quantity of the daily ingestion of these food and beverage preparations is essential during their production, i.e. the ratio of using component (i) has to be based on the suggested daily dosage of 0.8-1.4 g of this component. By means of the administration of the pharmaceutical compositions as well as the consumption of alimentary products according the present invention, the permanent presence of components (i) and (ii) in the human organism can be readily achieved. Accordingly, these components (i) and (ii) act as highly potent scavengers preventing imparing free radical reactions. The effect should be attributed primarily to their action reducing significantly formation of lipid peroxidation end-products and of substances reacting with thiobarbituric acid. In consequence, synthesis of

Thromboxane A₂, being harmful from various viewpoints (inducing aggregation, vasoconstriction, damaging of the vascular wall, enhancing plaque formation, and even playing a role in the methastasis formation of malignant tumours), will be inhibited in the organism.

To illustrate these effects of the pharmaceutical compositions and alimentary products according to the present invention, the results of the following in vitro experiments are presented. Lipid oxidation was studied by using the method of Y, T. Lew and A. L. Taope]

(Food Technol. 1 6 , 104-106, 1962) in a system containing i.ater, unsaturated fats (oil), haematin, sodium 6,6'-methylene-bis(2,2-dimethyl-1,2-dihydroquinoline-4-methanesulfonate) (abbreviation: MTDQ-DS) and an adequate quantity of sodium L-ascorbate. The so-called induction period being required to reach peroxide number 40 was recorded. Results are shown on following Table.

Change of the induction period in function of the concentrations of the active substances MTDQ-DS and sodium L-ascorbate

Induction period (hour) in the MTDQ-DS presence of concentration 0 % 0.0176 % 0.00176 % of sodium L-ascorbate

0.02 % 11. 3 28 15.4 0.04 % 21 34 24 0 % 0 7 . 9 1 Data of the Table clearly show that components (i) and (ii) act synergically.

Modes of carrying out the invention The invention is illustrated by the following examples, without restricting the scope of protection.

Example 1 5.98 g. of sodium 6,6'-methylene-bis(2,2-dimethyl-1,2-dihydroquinoline-4-methanesulfonate) containing 2 moles of crystall water and 1.98 g. of sodium L-ascorbate are mixed with 200 g. of wheat bran. The mixture is homogenized and stored in tightly closed packages. Suggested daily dose amounts to 20 to 40 g.

Example 2

18 g. of sodium 6,6'-methylene-bis(2,2-dimethyl-1,2-dihydroquinoline-4-methanesulfonate) are added to 200 g. of semolina. 0.2 g. of calcium L-ascorbate are rubbed with an identical amount of Tween 80 and added to the above mixture. The mixture is homogenized, granulated with a small amount of starch solution, then dried and pressed into tablets of 1.5 g. The tablets are coated with polyvinylpyrrolidone. Suggested daily dosage: 3x1 tablet.

Example 3

0.9 g. of palmitic isoascorbate are mixed with 0.09 g. of Tween 80 emulsifier and added to 18 g. of sodium 6,6'-methylene-bis(2,2-dimethyl-1,2-dihydroquinoline-4-methanesulfonate salt) and 200 g. of wheat germ. The mixture is homogenized, granulated with starch solution, then dried and pressed into tablets of 0.5 g. Suggested daily dosage: 3x1-2 tablets. Example 4

200 g. of wheat bran and 0.065 g. of magnesium isoascorbate are mixed and 10 g. of 6,6'-methylene-bis(2,2-dimethyl-1,2-dihydroquinoline-4-methanesulfonic amide) are added thereto. The mixture is homogenized and the homogeneous powder is distributed into packages of 5 g. Suggested daily dosage: 3 packages.

Example 5 80 g. of sodium 6,6'-methylene-bis(2,2-dimethyl-1,2-dihydroquinoline-4-methanesulfonate) are added to 1000 g. of instant cocoa povrder and mixed with 1 g. of sodium L-ascorbate and 0.1 g . of sodiumhydrogencarbonate. The mixture is homogenized. Suggested daily dosage: 3x3.5 g.

Example 6

250 g. of sodium 6,6'-methylene-bis(2,2-dimethyl-1,2-dihydroquinoline-4-methansulfonate) are mixed with 1500 g. of sorbite and 5 g. of calcium L-ascorbate. The mixture is homogenized. The suggested daily dosage of this sweetener amounts to 4 to 6 g.

Example 7

120 g. of sodium 6,6'-methylene-bis(2,2-dimethyl-1,2-dihydroquinoline-4-methansulfonate), 10 g. of sodium isoascorbate and 4 g. sodium thiosulfate are dissolved in 100 1. of mineral water. If the pH-value of the thus-obtained solution is below 7.1, a value of 7.2 to 7.4 is adjusted by using sodium hydrocarbonate. The suggested daily dosage of this mineral water is 0.6 to 0.7 1.

Example 8

One proceeds as in Example 7 but instead of sodium

6,6'-methylene-bis(2,2-dimethyl-1-1,2-dihydroquinoline-4-methansulfonate) sodium 6,6'-methylene-bis(2,2-dimethyl -8-hydroxy-1,2-dihydroquinoline-4-methansulfonate) is used.

Example 9 One proceeds as in Example 7 but instead of sodium 6,6'-methylene-bis(2,2-dimethyl-1,2-dihydroquinoline-4-methansulfonate) sodium 6,6'-methylene-bis(2,2-dimethyl-5-amino-1,2-dihydroquinoline-4-methansulfonate) is used.

Example 10

One proceeds as in Example 7 but instead of sodium 6,6'-methylene-bis(2,2-dimethyi-1,2-dihyaroquinoIine-4-methansulf onate) sodium 6,6'-methylene-bis(2,2-dimethyI-7-ethyl-1,2-dihydroquinoline-4-methansulfonate) is used.

Claims

What is claimed is:

1. Pharmaceutical compositions and alimentary products for human consumption for the treatment and/or prevention of diseases caused by free radical reactions, c o m p r i s i n g

(i) a dihydroquinoline of the formula

wherein

X₁ is a sulfo group or a group the formula

—SO₂—NH₂ (a) or

—SO₂—O— Me (b )

and in the latter M stands for an alkali metal, and X₂ is either hydrogen or its meaning is identical with that of X₁, R₁ stands for a hydrogen atom or a C_{1 -4} alkyl group, and each R represents independently a halogen or hydrogen atom or a hydroxy, C_{1 -8} alkoxy, C_1-12 alkyl, aryl, aryloxy or -NR₂R₃ group, and in the latter R₂ and R₃ represent, independently from each other, a hydrogen atom or a C_{1 -8} alkyl or aryl group, (ii) ascorbic acid or isoascorbic acid or an alkali metal, calcium or magnesium salt or an ester formed with a C_{10- 20} straight or branched chained fatty acid thereof or a mixture of such compounds, taker in an amount of 0.5 to 35 parts by weight based on 100 parts by weight of component (i), and

(iii) optionally a water-soluble inorganic hydrocarbonate salt, taken in an amount of 1 to 10 parts by weight based on 100 parts by weight of component (i), and/or sodium thiosulfate, taken in an amount of 0.2 to 5 parts by weight based on 100 parts by weight of component (i).

2. The composition or product as claimed in claim 1, c h a r a c t e r i z e d by containing

0.04 to 75 % by weight of component (i).

3. The composition or product as claimed in claim 1, c h a r a c t e r i z e d by containing sodium 6,6'-methylene-bis(2,2-dimethyl-1,2-dihydroquinoline-4-methansulfonate) as component (i).

4. The composition or product as claimed in claim 1, c h a r a c t e r i z e d by containing sodium L-ascorbate as component (ii).

5. The composition or product, as claimed in claim 1, c h a r a c t e r i z e d by containing calcium L-ascorbate as component (ii).

6. The composition or product as claimed in claim 1, c h a r a c t e r i z e d by containing palmitic isoascorbate as component (ii).

7. The composition or product as claimed in claim 1, c h a r a c t e r i z e d by containing sodium hydrocarbonate as component (iii).

8. Process for the inhibition of free radical reactions in the human organism, c h a r a c t e r i z e d by administering a therapeutically effective amount of a compound of the formula

wherein X₁ is a sulfo group or a group of the formula

— SO₂ — NH₂ (a) or

—SO₂—O— Me (b),

and in the latter M stands for an alkali metal, and X₂ is either hydrogen or its meaning is identical with that of X₁, R₁ stands for a hydrogen atom or a C_{1 -4} alkyl group, and each R represents independently a halogen or hydrogen atom or a hydroxy, C_1-8 alkoxy, C_1-12 alkyl, aryl, aryloxy or -NR₂R₃ group, and in the latter R₂ and R₃ represent, independently from each other, a hydrogen atom or a C_1-8 alkyl or aryl group, as component (i) and, simultaneously or separately, (ii) ascorbic acid or isoascorbic acid or an alkali metal, calcium or magnesium salt or an ester formed with a C_10-20straight or branched chained fatty acid thereof or a mixture of such compounds, taken in an amount, of 0.5 to 35 parts by weight based on 100 parts by weight of component (i), and

9. Process as claimed in claim 8, c h a r a c t e r i z e d by administering daily 0.8 to 1.4 g. of component (i).