Esters of cholesterol and fatty acids, method of treatment and pharmaceutical or cosmetic composition

 

(57) Abstract:

Describes the new esters of cholesterol and fatty acids, selected from n-3 and n-6 essential fatty acids of General formula I

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where R - R2CO., R2is an alkyl chain, the corresponding n-6 or n-3 essential fatty acids that can be used in therapy, especially in the treatment of cancer and cardiovascular disease. Also describes a pharmaceutical or cosmetic composition and method of treatment. 3 S. and 7 C.p. f-crystals, 1 table.

The invention relates to compositions containing esters of unsaturated acids.

Fatty acids are a specific type of considerable interest as to ensure the healthy tissue and for the treatment of various diseases. Some fatty acids themselves are quite interesting, others interesting in that form of particular metabolites, such as prostaglandins or other saturated with oxygen or oxidized derivative, the third important for both these reasons. Among them are the essential fatty acids (EFAs), which are not produced by organisms, and therefore are essential nutrients. Among EFAs for both the above reasons antenova acid (EPA), DPC is an essential component of cell membranes and a precursor of prostaglandin E1(PGE1); PGE1has many useful actions as antithrombotic, anti-inflammatory, vasodilator, immunomodifying and reduce cholesterol remedy. GLA is an immediate precursor DGLC and quickly turns into DGLC in the body. EPA is also a component of cell membranes and a precursor PGE3which has properties resembling properties PGE3. Another acid is of particular interest as a component of membranes, is docosahexaenoic acid (DHA).

The main ways of turning the main series of EFAs in the body are presented in table. 1.

These schema transformations are usually irreversible, while in humans the series n-3 and n-6 are not interchangeable.

Acid, which by nature all are in CIS-configuration, designated according to the nomenclature as derivatives of the corresponding octadecanol, eicosanol or docosanoic acids, for example, Delta-9,12-octadecadienoic acid or Delta-4,7,10,13,16,19-docosahexaenoic acid, however, the number(eicosapentaenoic acid) or DHA 22:6 n-3 acids (docosahexaenoic acid) are also used, however, inconvenient in the case when the series n-3 and n-6 are acids with the same chain length and the same degree of unsaturation as, for example, acid 22:5. The table shows also trivial names, which more or less are often used for n-series-6. In a series of n-3 18:3 n-3 is a widely used name, namely, alpha-linolenic acid, although the name stereonova acid is more often used to describe acid 18:4 n-3, and sometimes used the names of eicosapentaenoic acid and docosahexaenoic acid. The alpha-isomer of linolenic acid was highlighted earlier than gamma-linolenic acid, and references in the literature simply linolenic acid, especially in the earlier literature, are related to alpha-linolenic acid.

The value of esters of cholesterol with fatty acids has not been previously evaluated, because it was believed that cholesterol is harmful and tends to contribute to disease of the coronary and peripheral arteries. Many people forget that cholesterol is one of the most important components of the body and are essential for the proper formation of cell membranes. Esters of cholesterol make up a large part of the particles sipaeya have special surface receptors, called LDL receptors. The LDL receptors are found in many cell types, but especially a large number of them have many cancer cells. It is well known that LDL receptors are found in cells associated with arteries. Thus, the cholesterol esters of the present invention are effective delivery of these acids in cells that have receptors LDL. They are especially effective delivery of fatty acids in cancer cells and atherosclerotic tissue.

Fatty acids have in General a therapeutic effect in relation to a number of different diseases. As noted here and in other patent publications of the author of the present invention, these fatty acids are of value in the treatment of cancer. Acids, especially gamma-linolenic acid, di-Homo-gamma-linolenic acid, arachidonic acid, eicosapentaenoic acid and docosahexaenoic acid, have beneficial effects on the cardiovascular system and are of value in the treatment of diseases of the coronary and peripheral arteries. These acids can be produced in a limited number in the body of patients suffering from diabetes, but because predstavleniya. Some acids, particularly gamma-linolenic acid, di-Homo-gamma-linolenic acid and eicosapentaenoic acid, have anti-inflammatory action and can be used in the treatment of diseases, leaving the main part of which is an inflammatory process, such as rheumatoid arthritis, osteoarthritis, eczema, colitis, psoriasis and a group of autoimmune diseases. These fatty acids are of particular importance for the brain and are important for the regulation of serious cerebral and psychiatric diseases such as schizophrenia, alcoholism and dementia, including Alzheimer's disease and mnogoaspektnoe dementia. These possible areas of use fatty acids are, however, examples of known fields, and the present invention is not intended simply to the use of fatty acids for the treatment of these specific disorders. The invention consists in the method of delivery of these fatty acids by setting them in the form of cholesterol esters in the treatment of any of the previously mentioned and other diseases.

Another useful property of cholesterol esters in the context of the present invention is absolutely n is: much more stable the fatty acids or their salts, triglycerides or other derivatives. Said well illustrated by their behavior when included in the composition of the creams or ointments for regular local use. In the past we have produced various compositions using mainly fatty acids for local use, used free fatty acids, their salts and triglycerides. Without protection with effective antioxidant such creams and ointments do not save components on the basis of fatty acids from rapid oxidation. In contrast, creams and ointments prepared using salts of cholesterol, behave completely differently. For example, to evaluate their properties, we have prepared creams containing 5% and 10% ether cholesterol-GLA without added antioxidant. In contrast to what is usually observed, these creams have kept pure white color for many months even when stored in containers that are opened daily and thus subjected to repeated exposure to fresh oxygen. This indicates that the esters of cholesterol EFAs extremely resistant to oxidation. As far as we know, this has never been reported, and this fact gives grounds for the use of cholesterol esters is Wendy Erin in the pharmaceutical compositions and formulations for skin care, in cosmetics or in the treatment of skin diseases. The topical preparations are in this case high levels of oxygen exposure, as they are in the form of a thin layer applied to the skin, and therefore a stable form of EFAs is in this case a special value.

As follows from the above, the invention has several aspects.

The first aspect of the invention are esters of cholesterol and n-6 and n-3 essential fatty acids, prinarovie acid and columbino acid because they are new compounds.

The next aspect of the present invention is the use of the previously mentioned esters of new and known, as discussed above pharmaceutical compositions, compositions for skin care and nutritional compositions.

Another aspect of the present invention is the use of esters in the production of medical drugs for the treatment of the above diseases and appropriate methods of treatment in conditions when it is necessary to transport fatty acids into the intracellular space, especially in cancer and atherosclerosis (attaching to the LDL receptor and transport into the cell are principially form fatty acids, not susceptible to easy oxidation. These conditions mainly occur when using the compositions for topical application, however, the stability of the fatty acid has a common value and the greatest value is their use in the form, not requiring the use of an antioxidant.

The last aspect is actually not limited to fatty acids and the above purposes and the far aspect of the invention is, therefore, to use it for the preparation of unsaturated compounds and especially polyunsaturated fatty acids in the form of their esters with cholesterol that are resistant to the action of atmospheric oxygen; or in the preparation method of such resistant to the action of atmospheric oxygen fatty acids, which fatty acids aeriferous cholesterol.

Synthesis of esters

The cholesterol esters are specific molecules that consist of one molecule of cholesterol, esterified with one molecule of the desired fatty acids. They can be obtained by the reaction of cholesterol with the desired fatty acid and essential fatty acid is usually more than 20% by weight reacts fatty acids, preferably 40%, more preferably BlueScope synthesis, or by extraction and purification from natural sources. Ways of carrying out the esterification reaction is well known.

As examples with which can be obtained from the esters of cholesterol and fatty acids, are the following. In the beginning a chlorinated fatty acids by the interaction of the pure acid chloride tiomila. Then get ether of cholesterol and fatty acids by mixing the acid chloride of the fatty acid with cholesterol in the presence of dichloromethane or pyridine. The products of the reaction are the ester of cholesterol and fatty acids and hydrogen chloride. Another way of obtaining consists in mixing cholesterol and hydrate p-toluenesulfonic acid in toluene and boiled under reflux together with the desired fatty acid. Water formed during the reaction, gives a toluene azeotrope mixture, which is separated, and the remaining toluene evaporated in vacuum. The remainder, representing a brown oil, purified column chromatography. First elution with hexane removed coming from the front of the impurities, and the target broadcast elute with a mixture containing 5% ether; the solvent is then evaporated. These fatty acid esters are viscous oily vesicaria other unsaturated acids can be obtained similarly. Of particular interest is parinacota acid (18:4 n-3; 9 CIS, 11 TRANS, 13 TRANS, 15 Cys), because it has a strong anti-cancer effects. Interesting also columbina acid (18:3 n-6; 6,9 CIS, 13 TRANS), because it can participate in the operations of fatty acids associated with membranes, not turning into eicosanoids.

The following are specific examples on the synthesis of the following cholesterol esters (I);

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Connection type (1), where R denotes the R2CO., a R2is an alkyl chain, the corresponding n-6 and n-3 essential fatty acid, prinarovie acid or columbinus acid, can be obtained in the following way:

(a) interaction of cholesterol (connection type (2), R1= N) with fatty acids of type (3), where the value of R above, and X = H, in the presence of catalytic amounts of a suitable mineral acid, e.g. p-toluenesulfonic acid, in an inert solvent which forms with water azeotropic mixture, i.e., toluene, xylene, at a temperature in the range of from 100 to 180oC;

(b) interaction of cholesterol (connection type (2), R1= N) with fatty acids of type (3), where the value of R above, and X = H, in the presence of condensing sredina, in a suitable inert solvent, e.g. dichloromethane, at a temperature of 10-40oC;

(C) interaction of cholesterol (connection type (2), R1= H) with anhydrides or bromohydrin fatty acids of type (3), where the value of R above, and X = Cl or Br, in the presence of a suitable base, for example pyridine, in an inert solvent, for example dichloromethane, at a temperature of 0-50oC;

(d) interaction of acetate cholesterol (connection type (2), R1= CH3CO) with fatty acids of type (3), where the value of R above, and X = X1= O(CH2)nCH3(n = 0-2), in the presence of catalytic amounts of alkoxide type Mx1where x1stated previously, and M is an alkaline metal such as sodium or potassium hydroxide, at reduced pressure and at a temperature of 80-120oC.

Preferred compounds are compounds of the type (1), in which

1A) R = (Z,Z,Z)of octadeca-6,9,12-trienoyl C45H74O2< / BR>
1B) R = (Z,Z,Z,Z)eicosa-5,8,11,14-tetraenoic C47H76O2< / BR>
1C) R = (Z,Z,Z,Z,Z)eicosa-5,8,11,14,17-pentaenoic C47H74O2< / BR>
1D) R = (Z,Z,Z,Z,Z,Z)docosa-4,7,10,13,16,19-hexaenoic C49H76O2< / BR>
The original materials of the type (2) and (3) are available and retail X = H

3ACl) R = (Z,Z,Z)of octadeca-6,9,12-trienoyl X = Cl

3BMe) R = (Z,Z,Z,Z)eicosa-5,8,11,14-tetraenoic X = Me

3CMe) R = (Z,Z,Z,Z,Z)eicosa-5,8,11,14,17-pentaenoic X = Me

3DH) R = (Z,Z,Z,Z,Z,Z,)docosa-4,7,10,13,16,19-hexaenoic X = H

Example 1. Obtaining cholesterol ester and (Z,Z,Z) of octadeca-6,9,12-Teenboy acid (1A): a Solution of 556 parts (Z,Z,Z)of octadeca-6,9,12-Teenboy acid (3AH), 773 parts of cholesterol (2A) and 20 parts of monohydrate p-toluenesulfonic acid in 2500 parts of toluene is stirred while boiling under reflux with nozzle Dean-stark removal of water, in the atmosphere of nitrogen. After approximately 5 hours, the formation of water ceases and the mixture is cooled. The solvent is removed in vacuo, the resulting brown oil was dissolved in hexane (2000 parts), the resulting solution was washed with water and dried (over sodium sulfate). The solution was subjected to purification through column chromatography medium pressure (column: 6000 parts Matrex silica, pore size 60 A, particle size 35-70 μm; solvent: hexane). The target fractions are combined, the solvent is removed in vacuum and get the cholesterol ester and (Z, Z,Z)of octadeca - 6,9,12-Teenboy acid (1A) in the form of neperesekayuschiesya oil pale yellow color.

Example 2. Obtaining cholesterol ester and (Z,Z,Z)of octadeca-6 is cooled to 5-10oC and under stirring in nitrogen atmosphere are added dropwise 257 parts (Z,Z,Z)of octadeca-6,9,12-trainerflorida (3ACl) for 30 minutes. The mixture is allowed to mix at room temperature for 20 hours. After removal under vacuum of the solvent was added hexane (1000 parts) and the resulting solution was washed with 2 M aqueous solution of hydrochloric acid (300 parts) and water (3 x 300 parts). The organic layer is dried (over sodium sulfate) and the solvent is removed in vacuum, obtaining a brown oil. This oil is purified through column chromatography (column: 1000 pieces Matrex silica, pore size 60 A, particle size 35-70 μm; solvent: hexane). The target fractions are combined, the solvent is removed in vacuum and get the cholesterol ester and (Z,Z, Z)of octadeca-6,9,12-Teenboy acid (1A) in the form of neperesekayuschiesya oil pale yellow color.

Example 3. Obtaining cholesterol ester and (Z,Z,Z,Z,Z)eicosa-5,8,11,14, 17-pentaenoic acid (1C): a Solution of 330 parts of cholesterolaemia (2B), 270 parts of methyl ester (Z,Z,Z,Z,Z)eicosa-5,8,11,14,17 - pentaenoic acid (3CMe) and 5 parts of ateleta sodium stirred and heated in vacuum (110oC/0.01 mm RT.CT.) within 4 hours. After cooling, the residue was subjected to purification on a chromatographic column delovogo ether in hexane).

The target fractions are combined, the solvent is removed in vacuum and get the cholesterol ester and (Z,Z,Z,Z,Z)eicosa-5,8,11,14,17 - pentaenoic acid (1C) in the form of colorless neperesekayuschiesya oil.

Instead of using methyl ester (Z,Z,Z,Z,Z)eicosa - 5,8,11,14,17-pentaenoic acid (3CMe) an equivalent amount of methyl ester (Z,Z,Z, Z)eicosa-5,8,11,14-tetraenoic acid (3BMe) get the cholesterol ester and (Z, Z, Z, Z, Z)eicosa-5,8,11,14-tetraenoic acid (1B) in the form of colorless neperesekayuschiesya oil.

Example 4. Obtaining cholesterol ester and (Z,Z,Z,Z,Z,Z)docosa - 4,7,10,13,16,19-hexaenoic acid (1D): to a solution of 118 parts of cholesterol (2A), 69 parts of dicyclohexylcarbodiimide and 41 part 4-dimethylaminopyridine in dichloromethane (2000 parts) are added dropwise under nitrogen atmosphere, 100 parts of (Z,Z,Z,Z,Z,Z)docosa - 4,7,10,13,16,19-hexaenoic acid (3DH). The mixture is stirred at room temperature for 2 hours and filtered to remove the formed precipitate of dicyclohexylamine. The filtrate is evaporated in vacuum at room temperature and the residue was subjected to purification through column chromatography medium pressure (column: 10000 piece Matrex silica, pore size 60 A, particle size 35-70 μm; solvent: 9:1 hexane: diethyl ether). Aleksanova acid, (1D) in the form of colorless neperesekayuschiesya oil.

The purpose

Esters of cholesterol can be assigned for local use, for oral, parenteral (subcutaneous, intramuscular, intravenous), enteral, rectal, vaginal application or other acceptable method. They can be made in the form of tablets, hard or soft gelatin capsules, lozenges, emulsions, enteral or parenteral compositions, foams, ointments, creams, lotions, suppositories, vaginal suppositories, or other known user-friendly form. They can be administered in the form of pharmaceutical dosage forms or in the form of food, which are used for medical purposes, or to sustain, as well as in compositions for skin care. Esters of cholesterol, which can be used in these different compositions may contain more than 20 wt.% ether the desired fatty acid relative to total fatty acids, preferably more than 40%, most preferably more than 70%, and ideally more than 90%.

Doses for oral, parenteral or local destination can be prepared so that the resulting dosage ether holster is In the case, if the dose is prepared in the form of compositions for oral or parenteral destination or type of food, the content of ester cholesterol in them may be from 0.01 to 60% by weight of the entire composition, preferably from 0.1 to 30 wt.%, and most preferably from 1 to 10 wt.%.

The compositions can be prepared with the objective of maintaining the health of or treatment of any disease that is influenced by fatty acids, in particular for the treatment of cancerous tumors whose cells have a large number of LDL receptors, and after receiving preparations containing esters of cholesterol, can easily capture large amounts of fatty acids.

The invention is further illustrated by the following examples of compositions.

Examples of compounds

1. Soft gelatin capsules containing 100 mg, 200 mg, 500 mg or 750 mg of cholesterol ester-GLA.

2. Hard gelatin capsules containing 100 mg, 200 mg, 500 mg or 750 mg of cholesterol ester-GLA.

3. Tablets or other dosage forms for oral assignments, including skim, chocolate or enteral or parenteral nutrients, containing from 0.1 to 50 wt.% ester cholesterol-GLA.

4. Compositions for local purpose is To.

5. Tablets containing 100 mg, 250 mg, 500 mg or 750 mg of cholesterol ester-GLA.

6. Emulsion for enteral or parenteral destination, the content of ester cholesterol-GLA which comprises from 0.1% to 20%.

7 - 12. The compositions according to the PP 1-6 ether, ester cholesterol-DGLC.

1. Esters of cholesterol and fatty acids, selected from n-3 and n-6 essential fatty acids of General formula I

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where R - R2CO., R2is an alkyl chain, the corresponding n-3 or n-6 essential fatty acids.

2. Esters under item 1, showing the ability to ensure the delivery of fatty acids in a stable is not subject to the free oxidation form inside cells.

3. Esters under item 2, have anticancer and protivoleprosnami properties.

4. Live on p. 2 having the ability to reduce complications from diabetes, such as neuropathy, retinopathy and cardiovascular disease, anti-inflammatory properties and improves immunity.

5. The method of treatment of conditions that are required to facilitate the transport of fatty acids into the cell, or when you want a stable form of acid, not subject to easy oxidation, characterized in that prescribed for pickup what alastrina.

6. The method according to p. 5, intended for the treatment of cancer or atherosclerosis.

7. The method according to p. 5, is intended for treatment of complications of diabetes such as neuropathy, retinopathy and cardiovascular diseases, diseases in which play an important role in inflammatory processes such as rheumatoid arthritis, osteoarthritis, eczema, colitis, psoriasis and a group of autoimmune diseases, cerebral and mental diseases such as schizophrenia, alcoholism, dementia, including Alzheimer's disease and mnogoaspektnoe dementia.

8. The method according to any of paragraphs.5 to 7, characterized in that the cholesterol ester is administered in the form of a preparation at a daily dose of from 1 mg to 100 g, preferably from 100 mg to 20 g, most preferably from 500 mg to 10 g

9. Pharmaceutical or cosmetic composition based on fatty acids, characterized in that it contains an ester of cholesterol and fatty acids, selected from n-3 and n-6 essential fatty acids, and the content of the ether relative to the total content of fatty acids is more than 20 wt.%, preferably more than 40%, most preferably more than 70%, and ideally more than 90%.

10. The composition according to p. 9, otlichayas from 0.1 to 30 wt.% and most preferably from 1 to 10 wt.%.

 

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