Pharmaceutical composition for prophylaxis and treatment of lipid metabolism disorder

FIELD: medicine, pharmacology, pharmacy, medicinal biochemistry.

SUBSTANCE: invention proposes a pharmaceutical composition that comprises, in particular, N-(1-octyl-5-carboxymethyl-dimethylindolin-7-yl)-2,2-dimethylpropaneamid or its pharmacologically acceptable salts as inhibitor of enzyme ACAT and inhibitor of HMG-CoA-reductase that represents pravastatin, lovastatin, simvaststin, fluvastatin, rivastatin, atorvastatin, rosuvastatin or pitavastatin used as active component of the composition. The combination of active substances shows the expressed synergistic effect. Invention provides enhancing activity of the composition in clinical applying.

EFFECT: valuable medicinal properties of composition.

71 cl, 2 tbl, 3 ex

 

The technical field

The present invention relates to pharmaceutical compositions for administration simultaneously, separately or sequentially N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide or its pharmacologically acceptable salt and inhibitor of 3-hydroxy-3-methylglutaryl-COA-reductase (hereinafter referred to as a HMG-COA).

The present invention also relates to a method for prevention or treatment of atherosclerosis or xanthomas (especially atherosclerosis), which includes the introduction simultaneously, separately or sequentially an effective amount of N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide or its pharmacologically acceptable salt and inhibitor of HMG-COA-reductase warm-blooded animal (particularly human).

The level of technology

The incidence of atherosclerosis continues to grow with the introduction of the Western diet and the increasing number of older people in society. Because atherosclerosis is the main cause of myocardial infarction, cerebral infarction, apoplexy of the brain and so on, there is a need for its effective prevention and treatment. In addition hyperlipemia (and especially hypercholesterolemia) risk factors for atherosclerosis include hypertension and impaired metabolism of carbohydrates, based on insulinresponsive. There are many cases in which the risk factors cause confusing picture (syndrome X), and their etiology is believed to be interdependent [Diabetes, 37, 1595 (1988)].

Previously, attempts were made to inhibit each of the risk factors, hyperlipemia, hypertension, and insulin resistance, prevention or treatment of atherosclerosis. However, while inhibitors of HMG-COA-reductase type of pravastatin reduced the world and, as a result, have shown efficacy in the inhibition of early atherosclerosis, it is recognized that the effectiveness of one drug is not considered appropriate in the case of patients with severe hyperlipemia or arteriosclerosis [Biochem.Biophys.Acta, 960, 294 (1988)]. Therefore, the necessary medicines and therapeutic methods with new efficiency.

A combination of two or more types of drugs having activity to reduce the level of lipids is known to be effective for hyperlipidemia and atherosclerosis [The Washington Manual Therapeutics, 29thEdition, Department of Medicine, Washington University School of Medicine (1998)]. In addition, it also shows the efficiency of the combination of decreasing the level of lipid agents with novel mechanisms of action, with existing drugs [Diabete & Metabolisme (Paris), 21, 139 (1995)]. For example, in the publication WO 97/16184 specifically described Pharma is eticeskaja composition combination of 2,6-bis(1-methylethyl)-phenyl-[[2,4,6-Tris(1-methylethyl)phenyl]acetyl]sulpham with atorvastatin.

But there are still many unknown aspects regarding what combination of drugs and inhibitors of HMG-COA-reductase give the possibility of a truly effective and safe agents that lower lipid levels, or preventive or therapeutic agent for atherosclerosis. Because some medicines have a strong toxicity [see, for example, Drugs of the Future, 25, 171 (2000)], to avoid toxicity, as it is considered, is important from the point of view of a combined treatment of multiple drugs. Thus, the choice of drug combinations is an important task.

Description of the invention

The study when considering the importance of prevention and treatment of atherosclerosis, the applicants of the present invention have found that the combination of N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide or its pharmacologically acceptable salt and inhibitor of HMG-COA reductase inhibitor is useful as a prophylactic or therapeutic agent (particularly a therapeutic agent for atherosclerosis and xanthoma (especially atherosclerosis). This drug combination, as installed, has a low level of lipid activity, inhibiting effect on the development of atherosclerosis of the aorta, action, Inga is youdim beginning xanthomas, occur in the joints of the extremities, and low toxicity.

The present invention provides a pharmaceutical composition (particularly preventive or therapeutic agent for arteriosclerosis or xanthoma) for introducing simultaneously, separately or sequentially N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide or its pharmacologically acceptable salt and inhibitor of HMG-COA reductase inhibitor.

The present invention also provides a method of prophylaxis or treatment of arteriosclerosis or xanthoma, which includes the introduction simultaneously, separately or sequentially N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide or its pharmacologically acceptable salt and inhibitor of HMG-COA-reductase warm-blooded animal (particularly human).

The active ingredients of the pharmaceutical compositions of the present invention are N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide or its pharmacologically acceptable salt and inhibitor of HMG-COA reductase inhibitor.

N-(1-Octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide of the present invention is a compound which is described in the publication WO 97/12860 (EP 0866059) and in the corresponding U.S. patent 6063806 (see example 4), and has the following structural formula:

Inhibitor of HMG-COA-reductase, which is one of the active ingredients of the pharmaceutical compositions of the present invention, by its nature, is used as a therapeutic agent, hyperlipemia, and includes all existing in nature substances of microbial origin, semi-synthetic substances derived from them, and fully synthetic substances, examples of which are satinowye compounds such as (+)-(3R,5R) - for 3,5-dihydroxy-7-[(1S,2S,6S,8S,8aR)-6-hydroxy-2-methyl-8-[(S)-2-methylbutyrate]-1,2,6,7,8,8A-hexahydro-1-naphthyl]heptane acid (hereinafter referred to as pravastatin), described in Japanese patent application (Kokai) No. Sho 57-2240 (U.S. patent 4346227), (+)-(1S,3R,7S,8S,8aR)-1,2,3,7,8,8A-hexahydro-3,7-dimethyl-8-[2-[(2R,4R)-tetrahydro-4-hydroxy-6-oxo-1H-Piran-2-yl]ethyl]-1-naphthyl-(S)-2-methylbutyrate (hereinafter called lovastatin), described in Japanese patent application (Kokai) No. Sho 57-163374 (U.S. patent 4231938), (+)-(1S,3R,7S,8S,8aR)-1,2,3,7,8,8A-hexahydro-3,7-dimethyl-8-[2-[(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-Piran-2-yl]ethyl]-1-naphthyl-2,2-dimethylbutyryl (called next, simvastatin), described in Japanese patent application (Kokai) No. Sho 56-122375 (U.S. patent 4444784), (±)-(3R*,5S*,6E)-7-[3-(4-forfinal)-1-(1-methylethyl)-1H-indol-2-yl] - for 3,5-dihydroxy-6-geptanona acid (hereinafter referred to as fluvastatin), described in Japanese patent application (Kohyo) No. Sho 60-500015 (U.S. patent 4739073), (3R,5S,6 the)-7-[4-(4-forfinal)-2,6-di-(1-methylethyl)-5-ethoxymethyleneamino-3-yl] - for 3,5-dihydroxy-6-geptanona acid (hereinafter referred to as devastation), described in Japanese patent application (Kokai) No. Hei 1-216974 (U.S. patent 5006530), (3R,5S)-7-[2-(4-forfinal)-5-(1-methylethyl)-3-phenyl-4-phenylenecarbonyl-1H-paroll-1-yl] - for 3,5-dihydroxyheptanoic acid (hereinafter referred to as atorvastatin), described in Japanese patent application (Kokai) No. Hei 3-58967 (U.S. patent 5273995), (E)for 3,5-dihydroxy-7-[4’-(4’forfinal)-2’-cyclopropylamino-3’-yl]-6-geptanona acid (hereinafter referred to as pitavastatin), described in Japanese patent application (Kokai) No. Hei 1-279866 (U.S. patent 5854259 and 5856336), or (+)-(3R,5S)-7-[4-(4-forfinal)-6-isopropyl-2-(N-methyl-N-methanesulfonamido)pyrimidine-5-yl-3,5-dihydroxy-6(E)-geptanona acid (called then rosuvastatin), described in Japanese patent application (Kokai) No. Hei 5-178841 (U.S. patent 5260440). The U.S. patents mentioned in connection with each inhibitor of HMG-COA reductase inhibitor, is included in this work as a reference for a description of these inhibitor of HMG-COA-reductase inhibitors and other inhibitors of HMG-COA-reductase inhibitors, useful in the inventive combination (including methods of obtaining inhibitors), as described in this paper. Preferred examples are pravastatin, lovastatin, simvastatin, fluvastatin, mevastatin, atorvastatin, rosuvastatin and pitavastatin; preferred examples are pravastatin, lovastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin and pitavastatin. Even the more preferred examples are pravastatin, atorvastatin and pitavastatin, and even more preferable examples are pravastatin and atorvastatin, particularly preferred example is pravastatin.

Planar structural formula of a typical inhibitors of HMG-COA reductase inhibitor is presented below.

pravastatinlovastatin
simvastatinfluvastatin
devastatinatorvastatin
rosuvastatinpitavastatin

N-(1-Octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide and/or inhibitor of HMG-COA-reductase, which are active ingredients of pharmaceutical compositions of the present invention, can be converted into a salt in accordance with conventional techniques, if desired. For example, salt can be obtained by processing each active ingredient in anatoy temperature for from 5 to 30 minutes of the appropriate acid in a solvent (for example, in simple ester, complex ester or alcohol, preferably in a simple ether), followed by or filtration of precipitated precipitated crystals or distillation of the solvent under reduced pressure. Examples of such salts are salts of mineral acids, such as hydrohloride, hydrochloride, hydrobromide, hydroiodide, nitrates, perchlorates, sulfates or phosphates; sulfonates, such as methanesulfonate, triftoratsetata, econsultancy, bansilalpet or p-toluensulfonate; carboxylates, such as fumarate, succinate, citrates, tartratami, oxalates or maleate; or salts of amino acids such as glutamate or aspartate.

In addition, N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide and/or inhibitor of HMG-COA-reductase, which are active ingredients of pharmaceutical compositions of the present invention, can be converted into their corresponding pharmaceutically acceptable salt by processing each active ingredient basis in accordance with conventional techniques, if desired. For example, pharmacologically acceptable salts can be obtained by processing each active ingredient at room temperature for 5 to 30 minutes appropriate base in a solvent (for example, in a simple ester, complex ester or alcohol, preferably in ethanol) followed by or filtration of precipitated precipitated crystals or distillation of the solvent under reduced pressure. Examples of such salts are inorganic salts, for example, alkali metal salts such as sodium salts, potassium salts and lithium salts, alkaline earth metals such as calcium salt and magnesium salt; metal salts such as aluminum salts, iron salts, salts of copper, Nickel salts and cobalt salts; ammonium salts; and organic salts, for example, amine salts such as tert.-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, salt phenylglycine-Olkiluoto of ester, Ethylenediamine salts, N-methylglucamine, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N,N’-dibenzyl-Ethylenediamine salt, chloroprocaine salt, procainamide salt, diethanolamine salt, N-benzylethanolamine salt, pieperazinove salt, Tetramethylammonium salt, Tris(hydroxymethyl)aminomethane salt, etc., although preferred are alkali metal salts (especially sodium or calcium).

It should be noted that pravastatin, lovastatin, simvastatin, fluvastatin, mevastatin, atorvastatin and pitavastatin include their shape with a closed Laktionova ring or a pharmacologically acceptable salt (preferably the sodium salt or calcium salt) is an inhibitor of HMG-COA-reductase, which is an active ingredient in pharmaceutical preparations the practical composition of the present invention.

In the case of N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide or its pharmacologically acceptable salt and inhibitor of HMG-COA-reductase, which are the active ingredients of the pharmaceutical compositions of the present invention, each geometric isomer or a stereoisomer in the presence of asymmetric carbon atoms or their mixtures are also included in the scope of the present invention.

N-(1-Octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide or its pharmacologically acceptable salt and inhibitor of HMG-COA-reductase, which are the active ingredients of the pharmaceutical compositions of the present invention can exist in the form of their hydrates; each of these hydrates or mixtures thereof are also included in the scope of the present invention.

In the present invention there are no particular limitations to the concept of “introduction at the same time” provided that it relates to the scheme's introduction, which makes it possible introduction almost at the same time. The active ingredients are preferably introduced in the form of a single composition.

Similarly, in the present invention, no specific limitation for the expression “introduction separately or sequentially, provided that it relates to the scheme's introduction, which makes possible the introduction of a separate or sledovatelno, and it includes, for example, the introduction of the first N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide or its pharmacologically acceptable salt, followed by the introduction of an inhibitor of HMG-COA-reductase through a similar period of time, or for the introduction of the first inhibitor of HMG-COA-reductase, followed by the introduction of N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide or its pharmacologically acceptable salt through the corresponding time interval.

The pharmaceutical composition of the present invention preferably includes:

(1) a pharmaceutical composition in which the inhibitor of HMG-COA reductase inhibitor is a pravastatin, lovastatin, simvastatin, fluvastatin, mevastatin, atorvastatin, rosuvastatin or pitavastatin;

(2) a pharmaceutical composition in which the inhibitor of HMG-COA reductase inhibitor is a pravastatin, lovastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin;

(3) a pharmaceutical composition in which the inhibitor of HMG-COA reductase inhibitor is a pravastatin, pitavastatin or atorvastatin; or

(4) a pharmaceutical composition in which the inhibitor of HMG-COA reductase inhibitor is a pravastatin or atorvastatin; or

(5) the pharmaceutical composition in which the inhibitor of HMG-COA-re is ectasy represents pravastatin; or

(6) a pharmaceutical composition in which the inhibitor of HMG-COA reductase inhibitor is a atorvastatin; or

more preferably includes:

(7) the pharmaceutical composition for injection of sulfate N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethyl-propanamide and inhibitor of HMG-COA reductase inhibitor; or

(8) the pharmaceutical composition described in paragraph (7), in which the inhibitor of HMG-COA reductase inhibitor is a pravastatin, lovastatin, simvastatin, fluvastatin, mevastatin, pitavastatin, atorvastatin or rosuvastatin;

(9) the pharmaceutical composition described in paragraph (7), in which the inhibitor of HMG-COA reductase inhibitor is a pravastatin, lovastatin, simvastatin, fluvastatin, pitavastatin, atorvastatin or rosuvastatin; or

(10) the pharmaceutical composition described in paragraph (7), in which the inhibitor of HMG-COA reductase inhibitor is a pravastatin, atorvastatin or pitavastatin;

(11) the pharmaceutical composition described in paragraph (7), in which the inhibitor of HMG-COA reductase inhibitor is a pravastatin or atorvastatin;

and particularly preferably includes:

(12) the pharmaceutical composition described in paragraph (7), for the introduction of sulfate N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide and atorvastatin; or

(13) the pharmaceutical to the position, described in paragraph (7), for the introduction of sulfate N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide and pravastatin.

The effects of inventions

As the pharmaceutical composition for administration simultaneously, separately or sequentially N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide or its pharmacologically acceptable salt and inhibitor of HMG-COA reductase inhibitor of the present invention, has excellent lowering lipid levels action, has an excellent inhibitory effect on the development of atherosclerosis of the aorta, exhibits excellent inhibitory effect on the development of xanthomas found in the joints of the limbs, and it has low toxicity, it can be useful as a preventive or therapeutic agent (particularly, a therapeutic agent) in the case arteriosclerosis or xanthoma (especially atherosclerosis) in warm-blooded animals (particularly humans).

Industrial application

N-(1-Octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide or its pharmacologically acceptable salt, which are the active ingredient of the pharmaceutical compositions of the present invention can be easily obtained in accordance with methods described in the publication WO 97/12860 (EP 0866059) or the corresponding paten the e U.S. 6063806.

In addition, an inhibitor of HMG-COA-reductase, which is an active ingredient of the pharmaceutical compositions of the present invention, can be easily obtained in accordance with the method described in Japanese patent application (Kokai) No. Sho 57-2240 (U.S. patent 4346227), Japanese patent application (Kokai) No. Sho 57-163374 (U.S. patent 4231938), Japanese patent application (Kokai) No. Sho 56-122375 (U.S. patent 4444784), Japanese patent application (Kohyo) No. Sho 60-500015 (U.S. patent 4739073), in Japanese patent application (Kokai) No. Hei 1-216974 (U.S. patent 5006530), Japanese patent application (Kokai) No. Hei 3-58967 (U.S. patent 5273995), Japanese patent application (Kokai) No. Hei 1-279866 (U.S. patent 5854259 and 5856336), or in Japanese patent application (Kokai) No. Hei 5-178841 (U.S. patent 5260440).

As the pharmaceutical composition for administration simultaneously, separately or sequentially N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide or its pharmacologically acceptable salt and inhibitor of HMG-COA reductase inhibitor of the present invention, has excellent lowering lipid levels action, has an excellent inhibitory effect on the development of atherosclerosis of the aorta, exhibits excellent inhibitory effect on the development of xanthomas found in the joints of the extremities, and has a low toxicity, it can be useful as a preventive or therapeutic agent (particularly the tee therapeutic agent) in the case of arteriosclerosis or xanthoma (especially atherosclerosis).

This combination of N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide or its pharmacologically acceptable salt and inhibitor of HMG-COA reductase inhibitor of the present invention provides a higher efficiency levels that produce results unachievable by the introduction of a specific inhibitor of HMG-COA reductase inhibitor or one dimethylpropanamide derived.

N-(1-Octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide or its pharmacologically acceptable salt and inhibitor of HMG-COA-reductase, which are active ingredients of pharmaceutical compositions of the present invention can be obtained in the form of separate pharmaceutical product in order to enter an inhibitor of HMG-COA reductase inhibitor and derived dimethylpropanamide separately or in a single pharmaceutical preparation containing a mixture of an inhibitor of HMG-COA reductase inhibitor and derived dimethylpropanamide for introducing them at the same time.

In the case of using the pharmaceutical compositions of the present invention as a prophylactic or therapeutic agent for the above diseases N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide or its pharmacologically acceptable salt and inhibitor of HMG-COA-reductase, which are active ingredients of pharmaceuticalcompanies of the present invention, can be entered separately or after mixing with a pharmacologically acceptable carrier or diluent, etc. and can be administered orally in the form of tablets, capsules, granules, powders or syrups, etc. or parenterally in the form of injections or suppositories, etc.

Such preparations can be prepared with well-known methods using auxiliary substances, such as fillers (for example, organic fillers, including derivatives of sugars, such as lactose, sucrose, glucose, mannitol and sorbitol; starch derivatives such as corn starch, potato starch, α-starch and dextrin, cellulose derivatives such as crystalline cellulose, Arabic gum, dextran & pullulan; and inorganic excipients including silicate derivatives such as the anhydride of light silicic acid, synthesized aluminum silicate, calcium silicate and metasilicate of manualupdate, phosphates such as acidic calcium phosphate, carbonates such as calcium carbonate; and sulfates such as calcium sulfate), lubricants (e.g. stearic acid and a salt of stearic acid and metal, such as calcium stearate and magnesium stearate, talc, colloidal silicon dioxide, waxes, such as beeswax and spermaceti wax, boric acid, adipic acid, sulphates, such as Sul is at sodium, glycol, fumaric acid, sodium benzoate, DL-lecithin, laurilsulfate, such as sodium lauryl sulfate and lauryl sulfate, magnesium derivative of silicic acids such as silicic acid anhydride and silicic acid hydrate, and the above-described starch derivatives), binders (for example, hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, macrogol (macrogol), the above fillers and similar compounds), dispersing agents (for example, cellulose derivatives such as nizkozameshhennoj hydroxypropylcellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose and internally connected (sewn) sodium carboxymethyl cellulose and chemically modified starches and cellulose, such as carboxymethylstarch, sodium salt of carboxymethyl amylum and internally connected (sewn) polyvinylpyrrolidone), emulsifiers (for example, colloidal clay, such as bentonite and the Whigs, metal hydroxides such as magnesium hydroxide and aluminum hydroxide anionic surface-active agents, such as sodium lauryl sulfate and calcium stearate, cationic surface-active agents, such as benzylaniline, and non-ionic surface-active agents, such as polyoxyethyleneglycol ether, polyoxyethylene ester of fatty acids and of sorbitol and with whom you can ether of sucrose and fatty acids), stabilizers (for example, a complex parahydroxybenzoate esters, such as methyl-p-hydroxybenzoate and propyl-p-hydroxybenzoate, alcohols, such as chlorobutanol, benzyl alcohol and phenethyl alcohol, benzylaniline, phenols such as phenol and cresol, thimerosal, dehydroacetic acid and sorbic acid), corrective additives (for example, commonly used sweetening agents, acidifying agents and fragrances) and thinners.

Dosage and enter the ratio of N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide or its pharmacologically acceptable salt and inhibitor of HMG-COA reductase inhibitor can be changed in accordance with the activity of each active connection and symptoms, age, body weight and other various conditions of the patient.

Although the dose varies depending on symptoms, age and so on, the appropriate dose have a lower limit of 0.1 mg (preferably 0.5 mg) and an upper limit of 1000 mg (preferably 500 mg) single dose in the case of oral administration, and a lower limit of 0.01 mg (preferably 0.05 mg) and an upper limit of 100 mg (preferably 50 mg) for introduction in the case of parenteral injection for adults (e.g., person) from one to six times a day, this introduction can be carried out simultaneously, separately or sequentially dependent on the STI from symptoms.

It should be noted that in the case of applying the present invention for the prevention or treatment of atherosclerosis dose of an inhibitor of HMG-COA reductase inhibitor can be reduced to a lower dose than the dose when used for certain purposes as protivogipertonicheskoe agent. In addition, the dose can be reduced additionally due to the wonderful effects of the combined action of N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide or its pharmacologically acceptable salt.

In addition, although the ratio of the dose of N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide or its pharmacologically acceptable salt and inhibitor of HMG-COA reductase inhibitor, the active ingredients of the pharmaceutical compositions of the present invention may vary in a wide interval, the ratio of the dose of N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide or its pharmacologically acceptable salt and inhibitor of HMG-COA reductase inhibitor can be, for example, in the range of from 1:500 to 500:1, more usually from 1:100 to 100:1, more preferably from 1:10 to 10:1 and most preferably from 1:5 to 5:1. When N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide is used in conjunction with pravastatin as an inhibitor of HMG-COA reductase inhibitor, preferably of IP is to alsowhat ratio of from 1:2.5 to 2.5:1; when with him as an inhibitor of HMG-COA reductase inhibitor is atorvastatin, it is preferable to use a ratio of from 1:2.5 to 5:1. (All relationships are mass relations.)

The present invention is described below in more detail with examples, tests and example recipes, but the scope of the invention is not restricted by them.

The test example 1

Lowering the level of lipid effect

In experiments using male F1b hamsters age eleven weeks. Animals are placed in metal cages and provide free access to food, which contains 0.05% cholesterol and 10% coconut oil, and water. The active agents are administered orally in the form of a suspension in a 5% solution of the Arabian gums once a day for 7 days. Animals not fed for 17 hours after the last injection of the active ingredients and through this time under anesthesia taken blood samples. Serum lipids measured by enzymatic method. The results obtained are presented in table 1. In the table, “OH” means total cholesterol, “LOP” means lipoprotein very low density, “LDL” refers to low-density lipoprotein, “HDL” means high-density lipoprotein, and connection And means sulfate N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide.

Table 1
The concentration of cholesterolAtherogenic index
OHLonp+LDLLHP
Control253,0189,463,63,0
Pravastatin (3 mg/kg)244,0170,673,32,3
Compound A (30 mg/kg)to 170.9109,062,01,8
Compound A (30 mg/kg) + pravastatin (3 mg/kg)151,186,964,21,4

Although the introduction of one of pravastatin or sulfate N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide accordingly lowers total serum cholesterol and serum levels lonp+LDL cholesterol, when both the active agent are used in combination, these effects are even enhanced. In addition, although the introduction of one of pravastatin or sulfate N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide reduces atherogenic index lipoproteins (VLDL+LDL cholesterol/HDL cholesterol), an indicator of sensitivity to atherosclerosis, this effect becomes stronger when the two active ingredients are used in the combination.

The test example 2

Influence on the development of atherosclerotic lesions in rabbits fed cholesterol

Male new Zealand white rabbits (Kitayama Labes, Japan) weighing 1.5 kg hearty fed a mixed diet (RC-4, Oriental Bioservice, Japan), supplemented with 0.5% cholesterol, 3% peanut oil, in total, for 10 weeks.

The mode of feeding includes feeding cholesterol/fatty foods at 40 g for the first 2 weeks, 50 g for 4 weeks, 60 g in the last 4 weeks. 2 weeks after the start of feeding induced chronic endothelial injury in the abdominal aorta and the right femoral artery surgically sterile nylon monofilament through the saphenous artery of the right paw at the level of the diaphragm. Monofilament fix and hold in place during the remaining 8 weeks of the study. Animals are distributed randomly on the basis of total cholesterol level after 2-week feeding cholesterol/fats. Inhibitor of HMG-COA reductase and ACAT inhibitor administered orally as separately and in combination for 8 weeks after surgery.

(i) the Atherosclerotic region

The femoral artery photograph to conduct morphometric analysis using a digital camera (Coolpix 990, trade name: product of Canon, Inc.), which soedinenii computer. The degree of atherosclerosis of the aorta is estimated as the ratio of the area of surface damage to the internal surface area of the aorta using Photo-retouch (“Adobe Photoshop 5,0”, trade name: product of Adobe Systems Inc.) and the program Scion image, NIH Imaging (Scion Image 1.61c MacOs”, the production company Scion Corporation).

(ii) the Extracellular deposition of lipids

Rabbits anaesthetize with intravenous injection of pentobarbital sodium (25 mg/kg) and injected with saline using the device for perfusion at constant pressure of 100 mm RT. Art. After perfusion of the aorta cut out and photographed. The right femoral artery analyze the damaged cross-sections of art. The right femoral artery is fixed in fixer Methanol Carnoy for at least 24 hours. The segments are buried in paraffin and divided into parts with an interval of 5 μm. Five tapes four serial sections of each segment is cut at intervals of 80 μm. The area of each strip is treated with a dye Elastica-Masson.

A digital image of each plot is obtained using a digital camera (Fujix CCD camera system HC-2500: production company Fuji Photo Film Co., Ltd.), which is attached to a Leica microscope with a magnification of 2.5. The area of each damaged component is determined using Adobe Photoshop 5.0 (Adobe) to assess the quality of damage. On plots treated with the dye is Elastica-Masson, light green area is defined as the extracellular matrix (ACM), and extracellular vacuoles and gaps (white areas) is defined as extracellular lipid deposits (ASD). EKO was measured at an average value by dividing the area of the damaged component on the area of damage using Adobe Photoshop 5.0 and Scion Image 1.61 MacOs.

The results obtained are presented in table 2. In this table, the connection And the mean sulfate N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide.

Table 2
The ratio of the atherosclerotic regionASD (mm2)
Control57,415,5
Pravastatin (10 mg/kg)58,316,6
Compound A (5 mg/kg)45,810,7
Compound A (5 mg/kg) + pravastatin (10 mg/kg)of 40.93,0

As shown by the above results, although the connection And reduces atherosclerotic lesion area of the femoral artery and SAIs, and pravastatin does not affect the area and SAIs, when using both the active agent, these synergistic effects are amplified.

Example formulations 1

Tablets

The sodium salt is pravastatin (10.0 mg), sulfate N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide (30.0 mg), lactose (408,0 mg), cornstarch (50 mg) and magnesium stearate (2.0 mg) are mixed and formed into a tablet using teletrauma machine to obtain tablets containing 500 mg. per tablet may be coated (preferably the coating on the basis of sugar), if necessary.

1. Pharmaceutical composition for the prevention and treatment of lipid metabolism disorders, comprising as active ingredient N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide or its pharmacologically acceptable salt and inhibitor of HMG-COA reductase inhibitor.

2. The pharmaceutical composition according to claim 1, in which the inhibitor of HMG-COA reductase inhibitor is a pravastatin, lovastatin, simvastatin, fluvastatin, mevastatin, atorvastatin, rosuvastatin or pitavastatin.

3. The pharmaceutical composition according to claim 2, in which the inhibitor of HMG-COA reductase inhibitor is a pravastatin, lovastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.

4. The pharmaceutical composition according to claim 3, in which the inhibitor of HMG-COA reductase inhibitor is a pravastatin, atorvastatin or pitavastatin.

5. The pharmaceutical composition according to claim 4, in which the inhibitor of HMG-COA reductase inhibitor is a pravastatin or atorvas is Athyn.

6. The pharmaceutical composition according to claim 5, in which the inhibitor of HMG-COA reductase inhibitor is a pravastatin.

7. The pharmaceutical composition according to claim 5, in which the inhibitor of HMG-COA reductase inhibitor is a atorvastatin.

8. The pharmaceutical composition according to any one of claims 1 to 7, in which the pharmacologically acceptable salt of N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide is a sulfate of N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide.

9. The pharmaceutical composition according to claim 1, in which the pharmacologically acceptable salt of N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide is a sulfate of N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide and inhibitor of HMG-COA reductase inhibitor is a pravastatin.

10. The pharmaceutical composition of claim 8, in which the pharmacologically acceptable salt of N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide is a sulfate of N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide and inhibitor of HMG-COA reductase inhibitor is a atorvastatin.

11. Set for the prevention and treatment of lipid metabolism disorders, including various containers, in which at least one of these containers contains N-(1-octyl-5-carboxyla the Il-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide or its pharmacologically acceptable salt, and at least one different container contains an inhibitor of HMG-COA reductase inhibitor.

12. Set according to claim 11, in which the inhibitor of HMG-COA reductase inhibitor is a pravastatin, lovastatin, simvastatin, fluvastatin, mevastatin, atorvastatin, rosuvastatin or pitavastatin.

13. Set indicated in paragraph 12, in which the inhibitor of HMG-COA reductase inhibitor is a pravastatin, lovastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.

14. Set in item 13, in which the inhibitor of HMG-COA reductase inhibitor is a pravastatin, atorvastatin or pitavastatin.

15. Set 14, in which the inhibitor of HMG-COA reductase inhibitor is a pravastatin or atorvastatin.

16. Set indicated in paragraph 15, in which the inhibitor of HMG-COA reductase inhibitor is a pravastatin.

17. Set indicated in paragraph 15, in which the inhibitor of HMG-COA reductase inhibitor is a atorvastatin.

18. Set according to any one of § § 11-17, in which the pharmacologically acceptable salt of N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide is a sulfate of N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide.

19. Set according to claim 11, in which the pharmacologically acceptable salt of N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide is a sulfate of N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethyl is openemed and inhibitor of HMG-COA reductase inhibitor is a pravastatin.

20. Set according to claim 11, in which the pharmacologically acceptable salt of N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide is a sulfate of N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide and inhibitor of HMG-COA reductase inhibitor is a atorvastatin.

21. The use of N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide or its pharmacologically acceptable salt to obtain drugs for use in combination with an inhibitor of HMG-COA-reductase inhibitors in the prevention or treatment of atherosclerosis.

22. Use item 21, where the inhibitor of HMG-COA reductase inhibitor is a pravastatin, lovastatin, simvastatin, fluvastatin, mevastatin, atorvastatin, rosuvastatin or pitavastatin.

23. The application of article 22, where the inhibitor of HMG-COA reductase inhibitor is a pravastatin, lovastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.

24. The application of item 23, where the inhibitor of HMG-COA reductase inhibitor is a pravastatin, atorvastatin or pitavastatin.

25. The application of paragraph 24, in which the inhibitor of HMG-COA reductase inhibitor is a pravastatin or atorvastatin.

26. Use A.25, in which the inhibitor of HMG-COA reductase inhibitor is a pravastatin.

27. Use A.25, in which the inhibitor of HMG-COA-R is ductase represents atorvastatin.

28. The use according to any one of p-27, where the pharmacologically acceptable salt of N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide is a sulfate of N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide.

29. Use item 21, where the pharmacologically acceptable salt of N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide is a sulfate of N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide and inhibitor of HMG-COA reductase inhibitor is a pravastatin.

30. Use item 21, where the pharmacologically acceptable salt of N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide is a sulfate of N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide and inhibitor of HMG-COA reductase inhibitor is a atorvastatin.

31. Use item 21, where the specified combination use composition according to any one of claims 1 to 10.

32. The use of N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide or its pharmacologically acceptable salt to obtain drugs for use in combination with an inhibitor of HMG-COA reductase inhibitor for the prevention or treatment of xanthoma.

33. Use p, where the inhibitor of HMG-COA reductase inhibitor is a pravastatin, lovastatin, simvast the tin, fluvastatin, mevastatin, atorvastatin, rosuvastatin or pitavastatin.

34. Use p, where the inhibitor of HMG-COA reductase inhibitor is a pravastatin, lovastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.

35. The application 34, where the inhibitor of HMG-COA reductase inhibitor is a pravastatin, atorvastatin or pitavastatin.

36. Use p, where the inhibitor of HMG-COA reductase inhibitor is a pravastatin or atorvastatin.

37. Use p, where the inhibitor of HMG-COA reductase inhibitor is a pravastatin.

38. Use p, where the inhibitor of HMG-COA reductase inhibitor is a atorvastatin.

39. The use according to any one of PP 37, where the pharmacologically acceptable salt of N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide is a sulfate of N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide.

40. Use p where pharmacologically acceptable salt of N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide is a sulfate of N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide and inhibitor of HMG-COA reductase inhibitor is a pravastatin.

41. Use p where pharmacologically acceptable salt of N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-timetype is UNAMID is a sulfate of N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide and inhibitor of HMG-COA reductase inhibitor is a atorvastatin.

42. Use p, where as the specified combination use composition according to any one of claims 1 to 10.

43. Method for the prevention and treatment of lipid metabolism disorders in a warm-blooded animal, which includes the introduction in combination an effective amount of N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide or its pharmacologically acceptable salt and inhibitor of HMG-COA-reductase warm-blooded animal.

44. The method according to item 43 prevention and treatment of atherosclerosis in a warm-blooded animal suffering from or prone to atherosclerosis.

45. The method according to item 44, where the inhibitor of HMG-COA reductase inhibitor is a pravastatin, lovastatin, simvastatin, fluvastatin, mevastatin, atorvastatin, rosuvastatin or pitavastatin.

46. The method according to item 45, where the inhibitor of HMG-COA reductase inhibitor is a pravastatin, lovastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.

47. The method according to item 46, where the inhibitor of HMG-COA reductase inhibitor is a pravastatin, atorvastatin or pitavastatin.

48. The method according to p, where the inhibitor of HMG-COA reductase inhibitor is a pravastatin or atorvastatin.

49. The method according to p, where the inhibitor of HMG-COA reductase inhibitor is a pravastatin.

50. The method according to p, where the inhibitor of HMG-COA reductase inhibitor is a atorvastatin.

51. The method according to any of paragraphs 44 to 50, in which the pharmacologically acceptable salt of N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide is a sulfate of N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide.

52. The method according to item 44, in which the pharmacologically acceptable salt of N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide is a sulfate of N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide and inhibitor of HMG-COA reductase inhibitor is a pravastatin.

53. The method according to item 44, in which the pharmacologically acceptable salt of N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide is a sulfate of N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethyl-propanamide and inhibitor of HMG-COA reductase inhibitor is a atorvastatin.

54. The method according to item 44, in which N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide or its pharmacologically acceptable salt and inhibitor of HMG-COA reductase inhibitor is administered in the form of mixed medicines warm-blooded animal suffering from or Prednisolonum to atherosclerosis.

55. The method according to item 44, in which N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide or its pharmacologically acceptable salt and inhibitor of HMG-COA reductase inhibitor is administered separately, but is also a warm-blooded animal, suffering from or Prednisolonum to atherosclerosis.

56. The method according to item 44, in which N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide or its pharmacologically acceptable salt and inhibitor of HMG-COA reductase inhibitor is administered separately and not simultaneously warm-blooded animal suffering from or Prednisolonum to atherosclerosis.

57. The method according to any of PP-56, where a warm-blooded animal is a human.

58. The method according to item 43 prevention or treatment of xanthoma in a warm-blooded animal suffering from or prone xanthoma.

59. The method according to § 58, where the inhibitor of HMG-COA reductase inhibitor is a pravastatin, lovastatin, simvastatin, flashstate, mevastatin, atorvastatin, rosuvastatin or pitavastatin.

60. The method according to p, where the inhibitor of HMG-COA reductase inhibitor is a pravastatin, lovastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.

61. The method according to p, where the inhibitor of HMG-COA reductase inhibitor is a pravastatin, atorvastatin or pitavastatin.

62. The method according to p, where the inhibitor of HMG-COA reductase inhibitor is a pravastatin or atorvastatin.

63. The method according to item 62, where the inhibitor of HMG-COA reductase inhibitor is a pravastatin.

64. The method according to item 62, where the inhibitor of HMG-COA reductase inhibitor is a atorvastatin.

66. The method according to § 58, in which the pharmacologically acceptable salt of N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide is a sulfate of N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide and inhibitor of HMG-COA reductase inhibitor is a pravastatin.

67. The method according to § 58, in which the pharmacologically acceptable salt of N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide is a sulfate of N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide and inhibitor of HMG-COA reductase inhibitor is a atorvastatin.

68. The method according to § 58, in which N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide or its pharmacologically acceptable salt and inhibitor of HMG-COA reductase inhibitor is administered in the form of mixed medicines warm-blooded animal suffering from or Prednisolonum to xanthoma.

69. The method according to § 58, in which N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide or its pharmacologically acceptable salt and inhibitor of HMG-COA reductase inhibitor is administered separately, but ignoreme is but a warm-blooded animal, suffering from or Prednisolonum to xanthoma.

70. The method according to § 58, in which N-(1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl)-2,2-dimethylpropanamide or its pharmacologically acceptable salt and inhibitor of HMG-COA reductase inhibitor is administered separately and not simultaneously warm-blooded animal suffering from or Prednisolonum to xanthoma.

71. The method according to any of PP-70, where a warm-blooded animal is a human.



 

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and/or stereoisomeric forms of the compounds I and/or physiologically acceptable salts of the compounds I where R1means phenyl, phenyl, substituted once with halogen, the rest of the heterocycle of the following groups: morpholine, pyrrolidine; R2means N; R3means -(C1-C4)-alkyl-C(O)-N(R6)-R7where R6and R7together with the nitrogen to which they are bound, form a residue of formula IIa, IIe

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< / BR>
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< / BR>
where A, B, X, Z, R1-R10have the meanings indicated in the claims, as well as the way they are received and drug based on these compounds

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