Analogs of fatty acids, method for their preparing, method for treatment of diseases, pharmaceutical composition and nutrient composition comprising analogs thereof and method for providing body mass loss

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel analogs of fatty acids of the general formula (I): R1-[Xi-CH2]n-COOR2 wherein R1 represents (C6-C24)-alkene with one or more double bond, and/or (C6-C24)-alkyne; R2 represents hydrogen atom or (C1-C4)-alkyl; n represents a whole number from 1 to 12; I represents an uneven number and shows position relatively to COOR2; Xi is chosen independently of one another from the group comprising oxygen (O), sulfur (S) and selenium (se) atom and -CH2 under condition that at least one among Xi is not -CH2 and under condition that if R1 represents alkyne then a carbon-carbon triple bond is located between (ω-1)-carbon atom and (ω-2)-carbon atom, or between (ω-2)-carbon atom and (ω-3)-carbon atom, or between (ω-3)-carbon atom and (ω-4)-carbon atom, and to their salts and complexes. The claimed compounds can be used in treatment and/or prophylaxis of X syndrome, obesity, hypertension, hepatic fatty dystrophy, diabetes mellitus, hyperglycemia, hyperinsulinemia and stenosis. Also, invention relates to methods for preparing novel analogs of fatty acids. Also, invention relates to a nutrient composition comprising indicated analogs of fatty acids and to a method for reducing the total body mass or amount of lipid tissue in humans or animals. Invention provides the development of novel fatty acid analogs-base compositions or methods for suppression of stenosis, restenosis or associated disorders as result of proliferation and mobilization of vessel smooth muscle cells after, for example, traumatic damages of vessels during surgery operation in vessels.

EFFECT: improved preparing method, valuable medicinal properties of analogs.

12 cl, 2 dwg, 7 ex

 

The scope of the invention

The present invention relates to novel analogs of fatty acids. In addition, this invention relates to the use of new analogues of fatty acids for the treatment and/or prevention of syndrome X, obesity, hypertension, fatty liver, diabetes, hyperglycemia, hyperinsulinemia, and stenosis. The invention also relates to methods of obtaining new analogues of fatty acids.

Prior art

In the European patent EP 345.038 described the use of analogues is not subject β-oxidation of fatty acids of the formula:

where alkyl represents a saturated or unsaturated hydrocarbon chain of carbon atoms from 8 to 22, X represents O, S, SO or SO2, a R represents hydrogen or C1-C4alkyl group, for the treatment of hyperglycemic conditions and to reduce the concentration of cholesterol and triglycerides in the blood of mammals.

In PCT/NO95/00195 described alkyl-S-CH2COOR and alkyl-Se-CH2COOR to inhibit oxidative modification of LDL (low density lipoprotein). In addition, this application describes the use of selenium compounds for the treatment of giperglikemicescoa condition and to reduce the concentration of cholesterol and triglycerides.

In PCT/NO99/00135, PCT/NO99/00136 and PCT/NO99/00149 described anal the guy fatty acids of the formula (I)

where n is an integer from 1 to 12, and

- where m is an integer from 0 to 23, and

where i is an odd number which indicates the position relative to COOR, and

- where Xiindependently from each other selected from the group comprising O, S, SO, SO2, Se and CH2and

where R represents hydrogen or C1-C4alkyl,

with the proviso that at least one of Xiis CH2or their salts, prodrugs or complexes.

This formula includes one or more X groups (preferably selenium or sulfur) in positions 3, 5, 7, 9 and so on.

In addition, these PCT applications describe several medical and food applications.

In PCT/NO99/00135 described the use of analogues of fatty acids for the treatment and/or prevention of obesity, hypertension, fatty liver and multilateralism syndrome called "metabolic syndrome or syndrome X. in Addition, this application describes a method of treating or preventing the condition of obesity or excess weight and the way to achieve weight loss or fat loss in humans or animal, not a person. This application also describes a food composition, effective to reduce or prevent the increase in the total mass of those who and or total body fat mass in humans or animal, not a person, as well as the modification, distribution and fat content in animals to improve the quality of the meat or products such as milk and eggs.

In PCT/NO99/00136 described the use of analogues of fatty acids for the treatment and/or prevention of diabetes (both type I and II) and the method of treatment or prevention of hyperglycemia, hyperinsulinemia and reduced insulin sensitivity. Also described food composition effective to reduce or prevent the increase of glucose concentration in human blood or animal, not a person, but also a way of reducing glucose concentration in human blood or animal, not a person.

In PCT/NO99/00149 described the use of analogues of fatty acids for the treatment and/or prevention of primary and/or secondary stenosis, and/or disease caused by a procedural injury of blood vessels and/or abnormal cell proliferation, smooth muscle, and/or an elevated level of homocysteine in plasma.

Thanks X-atom (most preferred sulfur or selenium), which substituted in the carbon chain analogues of the above fatty acids, these compounds will not be subject to β-oxidation in mitochondria on this situation. Thus, the cleavage of these molecules must begin with a methyl end of the fatty acid, and it's pretty slow metaboliceski process. The catabolism of these analogues of fatty acids includes ω-oxidation and shorter chain dicarboxylic acids via peroxisome. The enzymes in the endoplasmic reticulum will be ω-hydroxypyruvate, and then to oxidize gidrauxilirovaniu fatty acid to dicarboxylic acid. This acid can then be shortened the chain by β-oxidation in peroxisome. A study on rats showed that 50% similar TTA (tetradecylthioacetic acid = tetradecylthioacetic acid) was allocated with urine in the form of short sulfoxidation acids within 24 hours after injection. In similar experiments it was found that denaturirovannyj product TTA is formed in vivo. This is due to the microsomal enzyme Δ9-desaturase, which introduces a double bond at position 9 of saturated fatty acids.

It is expected that this denaturirovannyj product has similar effects and/or mediates the biological effects of analogues of saturated fatty acids. It is also likely that the biological effects of analogues of fatty acids can be enhanced by slowing down their catabolism. This can be done through the introduction of double and/or triple links near the methyl end of the fatty acid and/or through the inclusion of alkyl groups, or Halogens in this part of the molecule. Such molecules, i.e. connection according to us is oasim invention, will not be a suitable substrate for microsomal enzymes.

OBESITY AND its ASSOCIATED DISEASES

Obesity is a chronic disease that is widespread in modern society and is associated not only with social status, but also with reduced life expectancy and numerous medical problems, including adverse psychological development, diseases of the reproductive organs, such as polycystic ovarian disease, dermatological disorders such as infections, varicose veins, acanthosis (Acanthosis nigricans) and eczema, exercise intolerance, diabetes mellitus, insulin resistance, hypertension, hypercholesterolemia, cholelithiasis, osteoarthritis, injury to the musculoskeletal system, thromboembolism, cancer, and coronary (ischemic) heart disease.

Therefore, the present invention is the provision of treatment, which is useful when casting weight individuals, obese, back to normal ideal body weight.

Another objective is the provision of treatment of obesity, which leads to the maintenance of a reduced body weight over an extended period of time. In addition, the objective is the reduction or suppression of increase in weight, usually caused by the fat-rich p the soup.

Another challenge is the prevention of obesity and, once treatment is started, developmental delay or preventing the onset of diseases that are a consequence of obesity or secondary to it, such as hypertension and fatty liver. These and other objectives will be clear to experts in the field of technology.

Obesity can be due to any cause, either genetic or related to the external conditions. Examples of diseases that can lead to obesity or to be the cause of obesity include overeating and bulimia, polycystic ovaries, craniopharyngioma, Prader-Willi syndrome, syndrome Frohlich (Frohlich), type II diabetes, those with growth hormone deficiency, normal variant short, Turner syndrome and other pathological conditions showing reduced metabolic activity.

Also the present invention is the provision of treatment, which is useful in lowering blood pressure.

In addition, the present invention is the provision of treatment that is useful for reducing the concentration of triacylglycerol in the liver. It is expected that this mode will provide a deterrent effect on the development of fatty liver, but also suitable as a treatment method already detected Soboleva who I am.

Compounds of the present invention activate β-oxidation, and reduce the concentration of triglycerides in the liver.

The term "metabolic syndrome" is used to describe multilateralism syndrome, which, among other things, characterized by hyperinsulinemia, insulin resistance, obesity, glucose intolerance, diabetes mellitus type 2, dyslipidemia, or hypertension.

As indicated above, it is expected that the compounds of the present invention will provide a positive effect on all of the States mentioned above, that is, through regulation of homeostasis as glucose and lipids, and thus, it is expected that the compounds of the present invention will be suitable agents for the regulation of certain higher metabolic disease (sometimes called syndrome X).

DIABETES

There are two main forms of diabetes mellitus. One is a type I diabetes, which is also known as insulin-dependent diabetes mellitus (IDDM), and the other is a type II diabetes, which is also known as non-insulin dependent diabetes mellitus (NIDDM). The majority of patients with IDDM have a common pathological picture; almost complete disappearance insulinopenic beta cells of the pancreas, which leads to hyperglycemia.

Accumulated important dock is telsta, showing that a large part of IDDM is caused by progressive destruction of beta cells during the asymptomatic period, often lasting many years. The pre-diabetes can be identified by detection of circulating autoantibodies to islet cells and autoantibodies to insulin.

There is a need in the connection, which would be non-toxic and would not have side effects, but which would prevent clinical IDDM and NIDDM.

Diabetes type I: severe diabetes mellitus, usually with sudden onset before reaching maturity, characterized by low levels of insulin in plasma, polydipsia, polyuria, increased appetite, weight loss and episodic ketoacidosis; also known as IDDM.

Type II diabetes: is often a mild form of diabetes mellitus, often with a gradual onset, usually in adults, characterized by absolute insulin levels in plasma from normal to high, which are relatively low compared to the levels of plasma glucose, also known as NIDDM.

Diabetes type I and II according to the etiological classification are considered "primary" diabetes, respectively.

Secondary diabetes includes pancreatic, extrapancreatic/endocrine or caused by drugs diabetes. In addition, some types of diabetes classification is irout as an exceptional form. They include lipotropics, Metodicheskie diabetes, type of diabetes caused by impaired insulin receptors.

Given the large prevalence of diabetes in our society, and the serious consequences associated with that discussed above, any therapeutic medication, potentially useful for the treatment and prevention of this disease, can have an extremely beneficial effect on health. In the art there is a need to remedy that will reduce the concentration of blood glucose in individuals with diabetes without significant adverse side effects.

Therefore, the present invention is the provision of treatment, which is useful in lowering the level of glucose in the blood, and the treatment of diabetic status.

Another object of the invention is the provision of treatment that is useful for reducing the concentration of insulin in the blood, and increase the effect of the remaining insulin.

STENOSIS

It was found that many pathological conditions associated with proliferation of smooth muscle cells. Such conditions include restenosis, arteriosclerosis, coronary (ischemic) heart disease, thrombosis, myocardial infarction, stroke, neoplasm smooth muscle, such as leiomyoma and leiomyosarcoma intestine and uterus, fibroids or fibroid m the weave.

Each year spend more than half a million intravascular surgical interventions. Although these invasive procedures continues to improve from year to year, as many as 30-50% of the procedures carried out every year, fail as the result of restenosis, i.e. the formation of secondary stenosis. The reduced incidence of restenosis therefore often referred to as the most important factor in the increase in cases of a favorable outcome achieved in the treatment of cardiovascular disease through the use of intravascular surgical interventions such as angioplasty, atherectomy, and procedures using stents and laser technology.

In balloon angioplasty, such as percutaneous intraluminal coronary angioplasty (CVCA), arteries of leg or arm of the patient make a small incision in the artery enter a long hollow tube called a guiding catheter. Then, the guide catheter is inserted a thick guide wire and nonduty balloon catheter and gently promote the blood vessels of a patient using x-ray visualization. Nonduty cylinder advance until then, until he reaches the place of narrowing of the lumen (vessel), the point at which the doctor inflates the balloon one or more than one time to a pressure of about 4-6 psi for AP is sustained fashion 60 seconds. When inflated, the balloon breaks down and destroys plaque and lengthens muscle fibers in the arterial wall beyond its ability to completely shrink back. Although plaque is not removed during this procedure, the destruction of the plaques and the elongation of the arterial wall increases the lumen of the vessel, thus allowing you to increase the blood flow.

Restenosis, which accompanies such procedures, characterized by the aggregation and leukocyte adhesion, proliferation of smooth muscle cells, narrowing of the lumen of the vessel bounded by vasodilatation and increased blood pressure. Reported that smooth muscle cells in the inner layer of the arteries begin the development cycle within approximately 2-3 days after the procedure and proliferate for several days after that (internal hyperplasia).

Compounds that reportedly inhibit the proliferation of smooth muscle in vitro, may have an undesirable pharmacological side effects when used in vivo. Heparin is an example of such compounds, which reportedly inhibits proliferation of smooth muscle cells in vitro, but when using in vivo has the potential harmful side effect of suppressing coagulation.

As can be seen from the above, many problems remain unsolved in the application of inhibitory drugs for effective treatment of mobiles the promotion and proliferation of smooth muscle cells. It would be extremely useful to develop new compositions or methods of suppressing stenosis, restenosis or related disorders because of the proliferation and mobilization of cells, vascular smooth muscle, after, for example, traumatic vascular damage caused during surgery on the blood vessels.

It is expected that the compounds according to the present invention will be effective in the treatment of these diseases.

A detailed description of the invention

The present invention relates to novel analogs of fatty acids of General formula (I):

where R1represents:

- C6-C24alkene with one or more than one double bond, and/or

- C6-C24alkyne, and

where R2represents hydrogen or C1-C4alkyl, and

where n is an integer from 1 to 12, and

where i is an odd number, and shows the position relative COOR2and

where X is independently from each other selected from the group comprising O, S, Se and CH2and

with the proviso that at least one of Xiis CH2and

- with the condition that if R1is an alkyne, then one carbon-carbon triple relations is located between (ω-1) carbon and (ω-2) carbon, or between (ω-2) carbon and (ω-3) ug is herodom, or between (ω-3) carbon and (ω-4) carbon, and

- with the condition that if R1is an alkene, then one of the carbon-carbon double bond is located between (ω-1) carbon and (ω-2) carbon, or between (ω-2) carbon and (ω-3) carbon, or their salts or complexes.

Another aspect of the present invention relates to novel analogs of fatty acids, where the R-group contains one carbon-carbon triple bond.

Another aspect of the present invention relates to novel analogs of fatty acids, where the R-group contains one carbon-carbon double bond. Preferably the carbon-carbon double bond is in position 9 and in the CIS-configuration.

The most preferred embodiment of the present invention pertain to compounds of formula (I), where sulfur or selenium are located in position 3.

In addition, the invention relates to a method for obtaining compounds of formula (I), which carry out:

- protection bromaline by introducing a protective group for hydroxyl;

- introduction to the received protected bromoalkanes acetylene group, followed, when necessary, by alkylation and/or recovery of the acetylene group;

sequential or simultaneous removal of the protective group and bromination;

the interaction of the floor is built connections with the compound of the formula H[Xi-CH 2]n-COOR2where Xi, n and R2such as defined above, followed, when necessary, by hydrogenation of the resulting product.

Specialist in the art it is obvious that bromoalkanes can be obtained by reacting the corresponding alcantera with hydrogen bromide, while it is preferable alcander from 5-9 carbon atoms. In the prior art it is also known that halogenoalkane (bromination) alkanediols is carried out mainly according to one of the groups, while the second group HE then protect by using a well-known protective groups, such as 3,4-dihydro-2H-Piran, trimethylsilyl, tert-butyldimethylsilyl, benzyl or triphenylmethyl (trityl), preferably 3,4-dihydro-2H-Piran, in a suitable polar solvent, such as dichloromethane. Methodology protection, see Green, Protective Groups in Organic Synthesis, Wiley, 2nded., 1991. The introduction of the acetylene group in the resulting protected bromoalkanes carried out by known methods, for example, using alkylenediamine, in particular FOOD-complex acetylenic Li or methylacetylene Li, in a suitable solvent, such as dimethyl sulfoxide or diethyl ether. If necessary, the compound obtained at this stage may be subjected to alkylation in the presence of alkylhalogenide, such as allylbromide, to follow what they are recovering acetylene group in the presence of a suitable catalyst, such as palladium Lindlar catalyst. This reaction is well known in the art and is used in cases when it is necessary to stop the recovery at the stage of obtaining alkene. The protected product is then subjected to sequential or simultaneous removal of protection and bromirovanii. Ways to remove the protection of well-known experts in the art (Green, Protective Groups in Organic Synthesis, Wiley, 2nded., 1991). The compound obtained after removal of the protection, synthesized, subjected to interaction with the compound of the formula H[Xi-CH2]n-COOR2where Xin and R2such as defined in the present description above, followed, when necessary, by hydrogenation of the resulting product. The group R1, which at this stage is fully saturated (alkyl), may contain substituents fluoride, chloride, hydroxy, C1-C4alkoxy, C1-C4alkylthio,2-C5acyloxy or1-C4alkyl, which can be introduced into the compound of formula (I) with other substrates in the stages above. Methods of introduction of Xialso disclosed in EP 345.038 and applications PCT/NO99/00135, PCT/NO99/00136 and PCT/NO99/00149. The specialist is obvious that the compounds according to the invention, in which R2represents a C1-C4al the sludge, can be obtained by methods well known in the art, for example by esterification.

The present invention also relates to the use of compounds of formula (I) as a pharmaceutical and/or nutritional agent. It is expected that these compounds will be essentially the same biological activity as the compounds known from the prior art described above, and the present invention thus relates to the use of these compounds of formula (I) for use as described in these publications.

Thus, the present invention relates to a method of treatment and/or prevention of a condition selected from the group including syndrome X, obesity, hypertension, fatty liver, diabetes, hyperglycemia, hyperinsulinemia and stenosis, in which a person or an animal in need this, introducing an effective amount of the compounds of formula (I)

where R1represents:

- C6-C24alkene with one or more than one double bond, and/or

- C6-C24alkyne and/or

- C6-C24alkyl, substituted in one or more positions of one or more than one compound selected from the group comprising fluoride, chloride, hydroxy, C1-C4alkoxy, C1-C4 alkylthio,2-C5acyloxy or1-C4alkyl, and

where R2represents hydrogen or C1-C4alkyl, and

where n is an integer from 1 to 12, and

where i is an odd number, and shows the position relative COOR2and

where X is independently from each other selected from the group comprising O, S, SO, SO2, Se and CH2and

with the proviso that at least one of Xiis CH2and

- with the condition that if R1is an alkyne, then one carbon-carbon triple relations is located between (ω-1) carbon and (ω-2) carbon or between (ω-2) carbon and (ω-3) carbon, or between (ω-3) carbon and (ω-4) carbon, and

- with the condition that if R1is an alkene, then one of the carbon-carbon double bond is located between (ω-1) carbon and (ω-2) carbon, or between (ω-2) carbon and (ω-3) carbon, and

- with the condition that if R1represents a substituted alkyl, then the substitution is (ω-1) carbon or (ω-2) carbon or (ω-3) carbon, except when the Deputy is a1-C4alkyl, then the substitution is (ω-2) carbon or (ω-3) carbon

or its salts or complex.

Us is Aasee the invention also relates to pharmaceutical compositions for reducing the concentration of cholesterol and triglycerides in the blood of mammals, suppression of oxidative modification of low density lipoprotein containing analogues of fatty acids of General formula (I)

where R1represents:

- C6-C24alkene with one or more than one double bond, and/or

- C6-C24alkyne and/or

- C6-C24alkyl, substituted in one or more positions of one or more than one compound selected from the group comprising fluoride, chloride, hydroxy, C1-C4alkoxy, C1-C4alkylthio,2-C6acyloxy or1-C4alkyl, and

where R2represents hydrogen or C1-C4alkyl, and

where n is an integer from 1 to 12, and

where i is an odd number, and shows the position relative COOR2and

- where Xiindependently from each other selected from the group comprising O, S, SO, SO2, Se and CH2and

with the proviso that at least one of Xiis CH2and

- with the condition that if R1is an alkyne, then one carbon-carbon triple relations is located between (ω-1) carbon and (ω-2) carbon, or between (ω-2) carbon and (ω-3) carbon, or between (ω-3) carbon and (ω-4) carbon, and

- with the condition that if R1PR is dstanley an alkene, then one of the carbon-carbon double bond is located between (ω-1) carbon and (ω-2) carbon or between (ω-2) carbon and (ω-3) carbon, and

- with the condition that if R1represents a substituted alkyl, then the substitution is (ω-1) carbon or (ω-2) carbon or (ω-3) carbon except when the Deputy is a1-C4alkyl, then the substitution is (ω-2) carbon or (ω-3) carbon

or their salts or complexes.

In addition, the present invention relates to a food composition for reducing or preventing the increase in total body mass or total body fat mass in humans or animal containing analogues of fatty acids of General formula (I)

where R1represents:

- C6-C24alkene with one or more than one double bond, and/or

- C6-C24alkyne and/or

- C6-C24alkyl, substituted in one or more positions of one or more than one compound selected from the group comprising fluoride, chloride, hydroxy, C1-C4alkoxy, C1-C4alkylthio,2-C5acyloxy or1-C4alkyl, and

where R2represents hydrogen or C1-C4alkyl, and

where n, not only is em an integer from 1 to 12, and

where i is an odd number, and shows the position relative COOR2and

- where Xiindependently from each other selected from the group comprising O, S, SO, SO2, Se and CH2and

with the proviso that at least one of Xiis CH2and

- with the condition that if R1is an alkyne, then one carbon-carbon triple relations is located between (ω-1) carbon and (ω-2) carbon, or between (ω-2) carbon and (ω-3) carbon, or between (ω-3) carbon and (ω-4) carbon, and

- with the condition that if R1is an alkene, then one of the carbon-carbon double bond is located between (ω-1) carbon and (ω-2) carbon or between (ω-2) carbon and (ω-3) carbon, and

- with the condition that if R1represents a substituted alkyl, then the substitution is (ω-1) carbon or (ω-2) carbon or (ω-3) carbon except when the Deputy is a1-C4alkyl, then the substitution is (ω-2) carbon or (ω-3) carbon

or their salts or complexes.

The present invention also relates to a method of achieving weight loss or fat loss in humans or animals in need, when they enter the effective amounts of the compositions, containing analogues of fatty acids of General formula (I)

where Rirepresents:

- C6-C24alkene with one or more than one double bond, and/or

- C6-C24alkyne and/or

- C6-C24alkyl, substituted in one or more positions of one or more than one compound selected from the group comprising fluoride, chloride, hydroxy, C1-C4alkoxy, C1-C4alkylthio,2-C5acyloxy or1-C4alkyl, and

where R2represents hydrogen or C1-C4alkyl, and

where n is an integer from 1 to 12, and

where i is an odd number, and shows the position relative COOR2and

- where Xiindependently from each other selected from the group comprising O, S, SO, SO2, Se and CH2and

with the proviso that at least one of Xiis CH2and

- with the condition that if R1is an alkyne, then one carbon-carbon triple relations is located between (ω-1) carbon and (ω-2) carbon, or between (ω-2) carbon and (ω-3) carbon, or between (ω-3) carbon and (ω-4) carbon, and

- with the condition that if R1is an alkene, then one of the carbon-carbon double tie the th is located between (ω -1) carbon and (ω-2) carbon or between (ω-2) carbon and (ω-3) carbon, and

- with the condition that if R1represents a substituted alkyl, then the substitution is (ω-1) carbon or (ω-2) carbon or (ω-3) carbon except when the Deputy is a1-C4alkyl, then the substitution is (ω-2) carbon or (ω-3) carbon

or their salts or complexes.

Description of figures

Figure 1 is a scheme of synthesis of the compound (Z) 3-thia-heptadec-9-ene acid.

Figure 2 is a scheme of synthesis of 3-thia-15-heptadecene.

Introduction compounds of the present invention

As a pharmaceutical preparation of the compounds of the present invention can be administered to an animal using any suitable technique, including parenterally, intranasally, orally, or by absorption through the skin. They can be administered topically or systemically. The specific route of administration of each agent will depend, for example, from the medical history of the animal.

The invention will be understood more fully by reference to the following examples. They, however, do not limit the invention.

Experimental part

Methods

The methods described below were used as test systems for the compounds described in the prior art those who IKI, and thus also used to test the biological effects of the compounds of the present invention.

Rat line Zucker (fa/fa), obese

Rats Zucker (fa/fa)obese, which were used in this study were grown in the plant for animals U 465 from INSERM pairs, originally granted to Harriet G. Bird Laboratory (Stow, MA, USA). Unless otherwise stated, animals were kept at a constant cycle of light/dark (light from 7.00 to 19.00) at 21±1°and were allowed free access to food and water. Rats were placed in a cage for three. Daily recorded the weight gain.

Wistar rats

Male rats of Wistar Charles River, weighing 280-358 g, bought in AnLab Ltd. (Prague, Czech Republic) and were placed in a cage of wire mesh at a temperature of 22±1°and svetoreguljatory room (light from 7.00 to 19.00). The rats were allowed free access to food and water. Rats were placed in a cage for three. Daily recorded weight gain and food intake.

Intravenous glucose tolerance tests

The male Zucker rats (fa/fa) (aged 5 weeks) were given anesthesia after 5 hours of starvation by intraperitoneal injection of pentobarbital sodium (50 mg/kg). Rats were injected glucose (0.55 g/kg) in the saphenous vein of the leg, and blood samples were collected from the tail vein in tubes treated with heparin, 0.5, 10, 15, 20 and 30 minutes after administration is lukosi. The samples were placed on ice, centrifuged and plasma was stored at -20°until analysis.

Applicationsi hyperinsulinemic clamp

After 21 days of the relevant diet (see above) rats were given anesthesia by injection of xylazine hydrochloride (Rometar SPOFA, Prague, Czech Republic; 10 mg/ml) and ketamine hydrochloride (Narkamon SPOFA, Prague, Czech Republic; 75 mg/ml) and inserted the permanent cannula in the carotid artery and jugular vein, as described Koopmans et al. (Koopmans S.J. et al. Biochim Biophys Acta, 1115, 2130-2138, 1992). Rats subjected to kemuliaan, allowed to recover for two days after surgery, before clamp-studies that were conducted according to the Kraegen et al. (E.W. Kraegen et al. Am J Physiol, 248, E353-E362, 1983). Thus, on the third day after surgery, the rats in normal consciousness, made continuous infusion of porcine insulin (Actrapid, Novo Nordisk, Denmark) in the form of a dose of 6.4 IU/kg per minute to achieve the level of insulin in the plasma in the upper physiological range. The concentration of glucose in arterial blood were fixed (supported) on the basal level of starvation by a variable infusion of 30%glucose solution (weight-volume percentage) (Leciva, Prague, Czech Republic). Blood samples for determination of concentrations of glucose and insulin in plasma was collected every 15 minutes after the start of infusion of glucose. After 90 minutes, the rats stopped the infusion and immediately beheaded, CR is V was selected to separate the plasma, layer of fatty tissue within the liver and epididymis (the epididymis) was dissected and weighed.

Measurement of plasma parameters

Concentrations of glucose (GLU, Boehringer Mannheim, Germany), free fatty acids (NEFA, ACS-ACOD kit; Wako Chemicals, Dalton, USA) and b-hydroxybutyrate (310-A kit; Sigma Diagnostics Inc., St. Louis, USA) were measured using enzymatic methods. The concentration of insulin was determined by radioimmunoassay (CIS bio International, Gif sur Yvette, France), using rat insulin as standard rats Zucker. In rats, Wistar Charles River glucose concentration in plasma was measured using a glucose analyzer Beckman (Beckman Glucose Analyzer (Fullerton, CA, USA). The level of insulin in plasma was measured using a kit for radioimmunoassay from Linco Research Inc. (St. Charles, MO, USA). Phospholipids were measured using the enzymatic method bioMérieux, Marcy-l'etoile, France, triacylglycerol using Technicon Method no. SA4-0324L90, USA and cholesterol using a Technicon Method no. SA4-0305L90, USA.

Getting postnuclear and mitochondrial fractions and measurement of enzymatic activity

Freshly isolated livers from individual old rats Zucker homogenized in ice-cold sucrose buffer (0.25 M sucrose, 10 mm HEPES (N-2-hydroxyethylpiperazine-N'-2-econsultancy acid) (pH 7.4) and 2 mm EDTA (ethylenediaminetetraacetic acid)). Postnuclear and mitochondrial fractions were obtained using preparative differential is centrifugation according to De Duve et al. (De Duve C. et al. Biochem. J., 60, 604-617, 1955). Modification, purity and yield were as described previously (Garras A. et al. Biochim. Biophys. Acta, 1255, 154-160, 1995). Acid-soluble products was measured in postnuclear and mitochondrial enriched fractions using [1-14C]-Palmitoyl-CoA and [1-14C]-Palmitoyl-L-carnitine (Radiochemical Centre, Amersham, England) as substrates, as described previously (Willumsen, N. et al. J. Lipid Res., 34, 13-22, 1993). The activity of carnitine-palmitoyltransferase I and II were measured in postnuclear and mitochondrial fractions, basically as described by Bremer (Bremer J. Biochim. Biophys. Acta, 665, 628-631, 1981), and 3-hydroxy-3-methylglutaryl-CoA-synthase was measured according Clinkenbeard et al. (Clinkenbeard K.D. et al. J. Biol. Chem., 250, 3108-3116,1975) in the mitochondrial fractions.

Analysis of the RNA

The allocation of RNA (Chomczynski, P. et al. Anal. Biochem., 162, 156-159, 1987), Northern-blot analysis and slot blotting of RNA onto nylon filters, and hybridization with immobilized RNA was performed as described previously (Vaagenes, H. et al. Biochem. Pharmacol., 56, 1571-1582, 1998). The following cDNA fragments were used as probes: CPT-I (Esser V. et al. J. Biol. Chem., 268, 5817-5822, 1993), CPT-II (Woeltje K.F. et al. J. Biol. Chem., 265, 10720-10725, 1990), 3-hydroxy-3-methylglutaryl-CoA-synthase (Ayté J. et al. Proc. Natl. Acad. Sci. USA, 87, 3874-3878, 1990) and lipase, which are sensitive to hormones (C. Holm et al. Biochim. Biophys. Acta, 1006, 193-197, 1989). The respective levels of expression of RNA was estimated as the number of radioactive probes, gibridizatsiya compliance with the sponding levels of 28S rRNA.

Results

Example 1. The synthesis of new compounds of fatty acids

(A) Counterparts not exposed β-oxidation of fatty acids with carbon-carbon double bond.

Synthesis of compounds in accordance with the present invention is usually carried out in accordance with synthesis TIA-heptadec-9-ene acid:

(Z)HO(O)C-CH2-S-(CH2)5-CH=CH-C7H15

(Z) means the CIS-configuration.

1. Obtain 1-bromo-5-hydroxypentanal

Pentane-1,5-diol, BUT-(CH2)5HE was treated with HBr in benzene and heated under reflux for 24 hours. The mixture of products was chromatographically first with a mixture of hexane-diethyl ether in the ratio of 85:15 to remove dibromide, and then mix in the ratio of 70:30. Output 1-bromo-5-hydroxypentanal amounted to 80%.

1H NMR: 1,81 (-CH2-CH2OH); 1.44MB (-CH2-); 3,35 (-CH2-Br); 3,55 (-CH2-HE); 3,32 (HE); 1,51 (-CH2-CH2Br).

13With NMR: 31,43-32,30 (C2With4); 24,24 (C3); 33,64 (65); 62,11 (C1).

2. Getting 5-(tetrahydropyranyloxy)-1-bromopentane

This connection gave to interact with 3,4-dihydro-2H-Piran in CH2Cl2when 0°C. 2 drops of concentrated HCl was used as catalyst. After removal of solvent, the reaction product was chromatographically in the system hexane-diethyl ether in the ratio 95:5. Output 5-(Tetra is drospirenone)-1-bromopentane was 77%.

1H NMR: 1,45-1,63 (-CH2-); 1,83 (-CH2-CH2O-); 3,38 (-CH2-Br); 3.27 to 3,79 (-CH2-O-); TO 4.52 (-O-CH-O).

13With NMR: 24,9-32,92 (C2-C4); 33,61 (C5); 62,26 (C6); 98,83 (C1in TPR).

3. Obtain 7-(tetrahydropyranyloxy)-1-Heptene

The product of stage 2 was treated with EDA-complex Li-acetylenic in dry dimethyl sulfoxide at 0°C in argon atmosphere. After 4 hours at room temperature the reaction mixture is hydrolyzed with water and the organic products were extracted with diethyl ether. The residue after removal of the ether was chromatographically in the system hexane-diethyl ether in a ratio of 97:3, receiving 7-(tetrahydropyranyloxy)-1-hepten with the release of 62%.

1H NMR: 1,45-1,66 (-CH2-); 3,45-3,82 (-CH2-O); 2,16 (-CH2-C≡); 1,90 (NS≡ -); 4,53 (-O-CH-O-).

13With NMR: 18,27-30.66 per (C3-C6); 62,21 (C7); 68,14 (C1); 84,40 (C2).

4. Obtaining 1-(tetrahydropyranyloxy)-tetradec-6-in

To 1.6 M solution of BuLi in hexane, dissolved in THF (tetrahydrofuran) at 0°in argon atmosphere, and the product of stage 3 was added to a mixture of 1-brometea and N,N-dimethylpropyleneurea. After hydrolysis, extraction and chromatography were isolated 1-(tetrahydropyranyloxy)-tetradec-6-in with the release of 69%.

1H NMR: 0,85 (CH3-); 1,22-1,57 (-CH2-); 2,10 (-CH2-C≡); 3,30-3,84 (-CH2O-);4,55 (-O-CH-O-).

13With NMR: 14,02 (C14; 22,60-31,73 (C2-C13); 18,69-18,71 (C5and C8); 62,23 (C1); 79,91-80,32 (C6and C7).

5. Obtaining 1-(tetrahydropyranyloxy)-tetradec-6-ene

Substituted tetradec-6 in stage 4 was reduced by hydrogen in the presence of Lindlar catalyst (Lindlar) in ethanol. The restoration lasted for 4 hours. The obtained 1-(tetrahydropyranyloxy)-tetradec-6-ene was pure enough for the stage 6 without further purification, but could be isolated with yields of 89% after chromatography.

1H NMR: 0,90 (CHC-); 1,27-1,61 (-CH2-); 3,39-3,89 (-CH2-O); 2,04 (-CH2-C=); 4,59 (-O-CH-O-); LOWER THAN THE 5.37 (-HC=CH-).

13With NMR: 14,07 (C14); 22,65-31,85 (C2-C13); 62,27 (C1); 27,13, 27,19 (C5and C8); 129,60-130,04 (C6and C7).

6. Getting 1-Prometric-b-s

The product of stage 5 bromisovali CBr4when 0°in dichloromethane in the presence of Ph3R. the Reaction mixture was stirred over night. Output 1-Prometric-6-ene was quantitative.

1H NMR: 0,87 (CH3-); 1,27-1,52 (-CH2-); 2,01 (-CH2-C=); 3,39 (-CH2-Br); 1,45 (-CH2-CH2-Br); 1,85 (-CH2-CH2C=); 5,34 (-HC=CH-).

13With NMR: 14,00 (C14); 22,60-32,68 (C2-C13); 26,97, 27,24 (C5and C8); 33,75 (C1); 129,15-130,32 (C6and C7).

7. Receiving (Z) TIA-heptadec-9-ene acid

Bramdean stage 6 in methanol was added 3 equivalents of what HE and 1.5 equivalents HS-CH 2-C(O)HE in methanol in an atmosphere of argon for 30 minutes. After stirring at room temperature for 4 hours boiling under reflux for a further 12 hours, followed by hydrolysis and extraction with diethyl ether, and then acidified to pH 1-2 was isolated product, the compound shown in the title, in the form of a viscous oil with a yield of 60%.

Conducted the following analyses: IR (infrared spectroscopy), 600 MHz1H and13With NMR (nuclear magnetic resonance), MS (mass spectrometry), GC (gas chromatography), GC-MS (mass spectrometry - gas chromatography) methyl ester. The results of NMR are shown below. All values are given in ppm (m-1). No trace of the E-connection was not found.

1H NMR: 0,86 (CH3-); 1,16-1,60 (-CH2-); 1,99 (-CH2-C=); 2,64 (-CH2-S-); 3,22 (-S-CH2-C(O)OH); 5,33 (HC=CH).

13With NMR: 176,63 (C1); 33,34 (C2); 32,69 (C4); 22,63-31,83 (C5-C7C12-C16); 129,32 and 130,24 (C9C10); 26,98 and 27,19 (C8With11); 14,08 (C17).

C) Counterparts not exposed β-oxidation of fatty acids containing carbon-carbon triple bond.

Synthesis of compounds in accordance with the present invention is carried out in accordance with synthesis of 3-thia-15-heptadecene, as shown in figure 1.

1. The 11-bromo-1(that is, rehydro-2-pyranyloxy)undecane

Pyridine-toluene-4-sulfonate (1.0 g; 4.0 mmol) and 11-bromo-1-undecanol (10.0 g; 400 mmol) was dissolved in dry CH2CH2(200 ml) at ambient temperature was added 3,4-dihydro-2H-Piran (5.0 g; 60 mmol). The reaction mixture was stirred over night. The crude product was purified by flash chromatography on silica gel, which was suirable CH2Cl2. The output of 11-bromo-1(tetrahydro-2-pyranyloxy)undecane amounted to 10.7 g (80%).

2. Getting 14-(tetrahydro-2-pyranol)-2-tetradecene

The propyne gas was passed through a solution of MeLi in diethyl ether (0.8 M; 60 ml; a 51.2 mmol) at a speed selected to provide dephlegmation ether. When heat is no longer allocated, the reaction was considered complete (white suspension). 11-bromo-1(tetrahydro-2-pyranyloxy)undecane (product 2) (13,0 g; to 38.8 mmol) was added drop by drop to this solution over a period of 20 minutes. The reaction mixture was stirred overnight and gently drop was added water (50 ml). The mixture was diluted with diethyl ether and washed with water (5x), dried (MgSO4) and the solvent evaporated. The crude product was purified by flash chromatography with CH2Cl2as eluent. Exit 14-(tetrahydro-2-pyranol)-2-tetradecene was 8.5 g (74%).

3. Obtain 12-tetradecene-1-ol

Pyridine-toluene-4-sulfonate (0.3 g; 1.2 mmol) and alkyne (product 3) was dissolved in this is OLE (25 ml) and heated to 50° With during the night. The solvent is evaporated and distributed between water and CH2Cl2. The aqueous phase is washed with water, dried (MgSO4) and the solvent evaporated. The crude product was purified by flash chromatography with CH2Cl2as eluent. Exit 12-tetradecene-1-ol was 1.5 g (78%).

4. Getting 14-bromo-2-tetradecene

12-tetradecene-1-ol (5.0 g; to 23.8 mmol) was dissolved in hexane (50 ml) was added 10 drops of pyridine. Added to this mix PBr3. The mixture was heated to 60°C for three hours, cooled and added to water drop by drop. The mixture was washed with water, dried (MgSO4) and the solvent evaporated. The crude product was purified by flash chromatography with hexane as the eluent to content of 2.5% EtOAc in hexane. Exit 14-bromo-2-tetradecene was 2.2 g (34%).

5. Obtaining 3-thia-15-heptadecene

KOHN (2.76 g; is 49.0 mmol) was dissolved in methanol (30 ml) and added drop by drop thioglycolic acid (2,04 g; 22,1 mmol) in methanol (25 ml). After 10 minutes, gently drop added 14-bromo-2-tetradecyl (5.5 g; 20,1 mmol) and the mixture was heated to 50°With during the night. The mixture was cooled to 0°and added 30 ml of HCl (pH 1). The precipitate was filtered and washed with water (2x). The solid was dissolved in chloroform (100 ml) and washed with water (1x), dried (MgSO4) and the solvent evaporated. Output connection 14-bromo-2-tetr is decina was 4.4 g (77%).

1H NMR (300 MHz; CDCl3) δ: of 1.26 (10H, sharp m); to 1.3-1.4 (4H, m); of 1.46 (2H, quintet, J=7,0 Hz, ≡CCH2CH2-)and 1.60 (2H, quintet, J=7,0 Hz, -CH2CH2S); or 1.77 (3H, t, J=2,6 Hz, CH3With≡); 2,10 (2H, tq, J=2,6; 7,0 Hz, ≡CCH2-); to 2.65 (2H, t, J=7,3 Hz, -CH2S); of 3.25 (2H, s, -SCH2COOH); the 10.40 (1H, broadened s, -COOH).

13With NMR (75 MHz; CDCl3) δ: 3,35 (CH3With≡); 18,61 (≡CCH2-); 28,60; 28,78; 28,78; 28,97; 29,04; 29,04; 29,34; 29,38; 29,40; 32,70 (-CH2CH2S); 33,32 (-SCH2CO); 75,20 (Month≡ -); 79,31 (Month≡ -); 176,42 (WITH).

(C) Counterparts not exposed β-oxidation of fatty acids, substituted in one or more positions.

One or more hydrogen groups chain fatty acids may be substituted by one or more than one compound selected from the group comprising fluoride, chloride, hydroxy, C1-C4alkoxy, C1-C4alkylthio,2-C6acyloxy or1-C4alkyl. The substituents can, for example, to enter in the connection formula (I) with other substrates for stages 1-4, above.

Finally, the compounds obtained in the above stage (C)can be converted into saturated compounds in the usual reactions of hydrogenation, thus providing R1the group, which is fully saturated (alkyl), but substituted in one or more than one position.

Example 2

Toxicity studies and test for mutagenic activity will be conducted, as described in PCT/N099/00135.

Example 3

Biological activity of new compounds in accordance with the present invention will be determined as described in the above experimental part or as disclosed in the above publications.

Example 4

New fatty acids with triple bonds on ω-end (for example, 3-thia-15-heptadecene) were studied in experiments on the feeding of rats Zucker obese. Used two different doses of the fatty acid, 50 and 150 mg per kg of body weight per day (mg/kg/day). Investigated the following parameters: cholesterol levels in the blood plasma, mitochondrial fatty acid oxidation in the liver and peroxisomal oxidation of fatty acids in the liver.

The new compounds of the present invention reduces the level of cholesterol in blood plasma dose-dependent manner, providing a 40%reduction at the highest used level. This decrease is more than 2 times higher than the value of reduction of cholesterol obtained using known analog saturated fatty acids - TTA (tetradecylthioacetic acid) equivalent dose (TTA and tested the connection according to the invention differ in that the connection according to the invention (3-thia-15-heptadecyl) contains troino the link, blocking ω-oxidation).

Mitochondrial fatty acid oxidation was increased almost 4-fold in the presence of the highest dose of the new containing a triple bond compounds. This increase is more than 6 times exceeded the amount of increase in mitochondrial fatty acid oxidation, which was observed in the presence of an equivalent dose of TTA.

The activity of the mitochondrial enzyme CPT-II, which regulates the rate of mitochondrial fatty acid oxidation, increased by 160% in the presence of a new containing a triple bond compounds, compared with just 40%increase of enzyme activity in the presence of TTA.

Peroxisomal oxidation of fatty acids was increased 10-fold in the presence of compounds containing a triple bond, compared with doubling the oxidation in the presence of TTA.

Example 5

Experiments were carried out to assess the effect of displacement of atom X in different positions relative to the carboxyl end of analogues of fatty acids according to the invention. In these experiments measured the activity (nmol/min/mg/protein) mitochondrial β-oxidation in the liver analogues of fatty acids according to the invention containing a sulfur atom in the 3, 5 and 7 positions relative to the carboxyl end. Activity was 0.81±0.16 for sulfur in the 3rd position, 0,61±0,06 to sulfur is in the 5th position, 0,58 0,09 to sulfur is in the 7th position. The activity for palmitic acid, used as control, non-blocking β-oxidation, was 0.47±0,06. The results obtained indicate that β-oxidation really locked analogs of fatty acids according to the invention and this effect decreases with distance of the atom X, slowing down β-oxidation, from the carboxyl end of the molecule.

Example 6

Soft gelatin capsule

For the manufacture of shell capsules use a solution containing (wt.%):

gelatin27
glycerin9
nipagin0,2
zinc sulfate4,5
distilled water100

As filler capsules use a composition containing:

(Z) TIA-heptadec-9-ANOVA acid100 mg
sunflower oil50 mg

Soft gelatin capsules get the drip method, well known in the prior art.

Example 7

Food for laboratory animals

Composition of feed:

3-thia-15-heptadecan 0,4%
gelatin4,8%
wheat bran5,7%
vitamins and minerals7,7%
corn starch25,4%
milk11,6%
casein25,7%
yeast8,7%
beef fat9%
sunflower oil1%

The above composition is prepared by simple mixing of components in accordance with traditional technology and Packed in standard packaging weight of 0.25, 0.5 and 1 kg

1. New analogues of fatty acids of General formula (I)

where R1represents a C6-C24alkene with one or more than one double bond, or

With6-C24alkyne,

R2represents hydrogen or C1-C4alkyl, n is an integer from 1 to 12,

i is an odd number, and shows the position relative COOR2,

Xiindependently from each other selected from the group comprising O, S, Se and CH2and

with the proviso that at least one of Xiis CH2and

with the proviso that if R1is an alkyne, then what is the carbon-carbon triple relations is located between (ω -1) carbon and (ω-2) carbon, or between (ω-2) carbon and (ω-3) carbon, or between (ω-3) carbon and (ω-4) carbon, and

with the proviso that if R1is an alkene, then one of the carbon-carbon double bond is located between (ω-1) carbon and (ω-2) carbon, or between (ω-2) carbon and (ω-3) carbon

or their salts or complexes.

2. New analogues of fatty acids according to claim 1, where R1-group contains one carbon-carbon triple bond.

3. New analogues of fatty acids according to claim 1, where R1-group contains one carbon-carbon double bond.

4. New analogues of fatty acids according to claim 3, where the carbon-carbon double bond is in position 9.

5. New analogues of fatty acids according to claim 3, where the carbon-carbon double bond is in the CIS-configuration.

6. New analogues of fatty acids according to one of claims 1 to 5, where Xi=3represents sulphur.

7. New analogues of fatty acids according to one of claims 1 to 5, where Xi=3represents selenium.

8. The method of obtaining the compounds of formula (I), in which

protection bromaline by introducing a protective group for hydroxyl;

introduction in the received protected bromoalkanes acetylene group, followed, when necessary, by alkylation and/or reset is the establishment of an acetylene group;

sequential or simultaneous removal of the protective group and bromination;

the interaction of the compounds with the compound of the formula H[Xi-CH2]n-COOR2where Xin and R2such as defined in claim 1, followed, when necessary, by hydrogenation of the resulting product.

9. The method of treatment and/or prevention of a condition selected from the group including syndrome X, obesity, hypertension, fatty liver, diabetes, hyperglycemia, hyperinsulinemia and stenosis, in which a person or an animal, not a person in need, is administered an effective amount of the compounds of formula (I)

where R1represents a C6-C24alkene with one or more than one double bond and/or

With6-C24alkyne and/or

With6-C24alkyl, substituted in one or more positions of one or more than one compound selected from the group comprising fluoride, chloride, hydroxy, C1-C4alkoxy, C1-C4alkylthio,2-C5acyloxy or1-C4alkyl,

R2represents hydrogen or C1-C4alkyl,

n is an integer from 1 to 12,

i is not is to maintain the number and indicates the position relative COOR 2,

Xiindependently from each other selected from the group comprising O, S, SO, SO2, Se and CH2and

with the proviso that at least one of Xiis CH2and

with the proviso that if R1is an alkyne, then one carbon-carbon triple relations is located between (ω-1) carbon and (ω-2) carbon, or between (ω-2) carbon and (ω-3) carbon, or between (ω-3) carbon and (ω-4) carbon, and

with the proviso that if R1is an alkene, then one of the carbon-carbon double bond is located between (ω-1) carbon and (ω-2) carbon, or between (ω-2) carbon and (ω-3) carbon, and

with the proviso that if R1represents a substituted alkyl, then the substitution is (ω-1) carbon or (ω-2) carbon or (ω-3) carbon, except when the Deputy is a1-C4alkyl, then the substitution is (ω-2) carbon or (ω-3) carbon

or its salts or complex.

10. Pharmaceutical composition for lowering the concentration of cholesterol and triglycerides in the blood of mammals, inhibition of oxidative modification of low density lipoprotein containing analogues of fatty acids of General formula (I)

where R1represents a

With6-C24alkene with one or more than one double bond, and/or C6-C24alkyne, and/or C6-C24alkyl, substituted in one or more positions of one or more than one compound selected from the group comprising fluoride, chloride, hydroxy, C1-C4alkoxy, C1-C4alkylthio,2-C5acyloxy or C1-C4alkyl, and

R2represents hydrogen or C1-C4alkyl,

n is an integer from 1 to 12,

i is an odd number, and shows the position relative COOR2,

Xiindependently from each other selected from the group comprising O, S, SO, SO2, Se and CH2and

with the proviso that at least one of Xiis CH2and

with the proviso that if R1is an alkyne, then one carbon-carbon triple relations is located between (ω-1) carbon and (ω-2) carbon, or between (ω-2) carbon and (ω-3) carbon, or between (ω-3) carbon and (ω-4) carbon, and

with the proviso that if R1is an alkene, then one of the carbon-carbon double bond is located between (ω-1) carbon and (ω-2) carbon, or between (É -2) carbon and (ω-3) carbon, and

with the proviso that if R1represents a substituted alkyl, then the substitution is (ω-1) carbon or (ω-2) carbon or (ω-3) carbon, except when the Deputy is a1-C4alkyl, then the substitution is (ω-2) carbon or (ω-3) carbon

or its salts or complex.

11. Food composition for reducing or preventing the increase in total body mass or total body fat mass in humans or animal, not a person, containing analogues of fatty acids of General formula (I)

where R1represents a C6-C24alkene with one or more than one double bond, and/or C6-C24alkyne, and/or C6-C24alkyl, substituted in one or more positions of one or more than one compound selected from the group comprising fluoride, chloride, hydroxy, C1-C4alkoxy, C1-C4alkylthio,2-C5acyloxy or C1-C4alkyl, and

R2represents hydrogen or C1-C4alkyl,

n is an integer from 1 to 12,

i is an odd number, and shows the position relative COOR2,

X independently from each other selected from the group comprising O, S, SO, SO2, Se and CH2and

with the proviso that at least one of Xiis CH2and

with the proviso that if R1is an alkyne, then one carbon-carbon triple relations is located between (ω-1) carbon and (ω-2) carbon, or between (ω-2) carbon and (ω-3) carbon, or between (ω-3) carbon and (ω-4) carbon, and

with the proviso that if R1is an alkene, then one of the carbon-carbon double bond is located between (ω-1) carbon and (ω-2) carbon, or between (ω-2) carbon and (ω-3) carbon, and

with the proviso that if R1represents a substituted alkyl, then the substitution is (ω-1) carbon or (ω-2) carbon or (ω-3) carbon, except when the Deputy is a1-C4alkyl, then the substitution is (ω-2) carbon or (ω-3) carbon

or their salts or complexes.

12. The way to achieve weight loss or fat loss in humans or animal, not a human, in need, in which they administered an effective amount of a composition containing analogues of fatty acids of General formula (I)

where R1represents a C6-C24alkene with one or more than one double bond, and/or C6-C24alkyne, and/or C6-C24alkyl, substituted in one or more positions of one or more than one compound selected from the group comprising fluoride, chloride, hydroxy, C1-C4alkoxy, C1-C4alkylthio, C2-C5acyloxy or C1-C4alkyl, and

R2represents hydrogen or C1-C4alkyl,

n is an integer from 1 to 12,

i is an odd number, and shows the position relative COOR2,

Xiindependently from each other selected from the group comprising O, S, SO, SO2, Se and CH2and

with the proviso that at least one of Xiis CH2and

with the proviso that if R1is an alkyne, then one carbon-carbon triple relations is located between (ω-1) carbon and (ω-2) carbon, or between (ω-2) carbon and (ω-3) carbon, or between (ω-3) carbon and (ω-4) carbon, and

with the proviso that if R1is an alkene, then one of the carbon-carbon double bond is located between (ω-1) carbon and (ω-2) carbon, or between (ω-2) carbon and ω -3) carbon, and

with the proviso that if R1represents a substituted alkyl, then the substitution is (ω-1) carbon or (ω-2) carbon or (ω-3) carbon, except when the Deputy is a1-C4alkyl, then the substitution is (ω-2) carbon or (ω-3) carbon

or their salts or complexes.



 

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SUBSTANCE: invention relates to a medicinal agent used in arresting syndrome of systemic inflammatory response. Agent comprises, mg: diphosphopyridine nucleotide, 0.3-100 and inosine, 40.0-1200. Proposed medicinal agent can comprise additionally inhibitor of angiotensin-converting enzyme, mainly, lisinopril, 2.5-100 and cardiac glycoside, mainly, digoxin, 0.07-0.3. The new medicinal agent possesses the capacity for arresting syndrome of systemic inflammatory response being independently of etiology of its rise, and allows obtaining the expressed and stable curative effect for short times.

EFFECT: improved and valuable properties of medicinal agent.

5 cl, 4 tbl, 4 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention describes valsartan salts chosen from the group involving monosodium, monopotassium, disodium, dipotassium, magnesium, calcium, bis-diethyl (or dipropyl, or dibutyl)-ammonium salts or their hydrates, and mixtures of these salts also. Also, invention relates to a method for their preparing and a pharmaceutical composition comprising thereof. Proposed salts can be in crystalline, partially crystalline, amorphous or polymorphous form. Prepared salts show high quality of crystalline lattices that is a base for chemical and physical stability of new compounds.

EFFECT: improved preparing method, improved and valuable properties of salts.

11 cl, 11 tbl, 16 ex

FIELD: medicine, cardiology, endocrinology.

SUBSTANCE: method involves administration of amlodipine in the dose 5 mg, once in the same time and metformin in the dose 500 mg, 2 times per 24 h in patients at the background of individually selected hypocaloric diet. Treatment is carried out for 8 weeks, not less. Method provides optimization of intravascular activity of platelets due to correction of primary homeostasis and the level of their antioxidant protection. Invention can be used for rapid optimization of functions of platelets at metabolic syndrome.

EFFECT: improved and enhanced method for optimization.

2 ex

FIELD: medicine, cardiology, endocrinology.

SUBSTANCE: method involves administration of simvastatin in patients in the dose 5 mg, once before night, and nebivolol in the dose 5 mg, once in the same time on the background of individually selected hypocaloric diet. Treatment is carried out for 24 weeks, not less. Method provides optimization of intravascular activity of platelets due to normalization of lipid composition of their membranes and enhancing level of antioxidant protection. Invention can be used in correction of lipid activity of platelet membranes and activity at metabolic syndrome.

EFFECT: improved correction method.

2 ex

FIELD: medicine and biopharmacology.

SUBSTANCE: claimed biotransplant contains mesenchyme stem cells (MSC) obtained from fetal, donor or autologous material. Tissue is desagregated, obtained cell suspension is resuspended and cultivated on growth medium containing transferrin, insulin, fibroblast growth factor and heparin to accumulate mature stroma in cells. Method for treatment of lung hypertension includes intravenous drip-feeding of MSC in amount of 50-500 millions cells in 50-100 ml of physiological solution.

EFFECT: method for treatment of improved effectiveness having no undesired side effects.

6 cl

FIELD: medicine, therapy.

SUBSTANCE: invention relates to a method for treatment of arterial hypertension. Method involves administration of one or some medicinal preparations in biorhythmical sequence taken among the following order: papaverin, common wormwood tincture - at 7.00 - 9.00 a. m.; thrombo-ACC, rheopro, clopidogrel - at 9.00 - 11.00 a. m.; No-Spa - at 11.00 a. m.; trental - at 11.15 a. m.; atenolol, propranolol, metoprolol, nifedipin, verapamil, cordaron, valerian, motherwort - at 11.30 a. m.; polyvitamins, fenules - at 1.00 p. m.; No-Spa - at 4.00 p. m.; trental - at 4.15 p. m.; hypothiazid, furosemid, verospiron, captopril, enalapril, prestarium, quinapril, ramipril, losartan, valsartan - at 4.30 p. m.; No-Spa - at 7.00 p. m.; trental - at 7.15 p. m.; atenolol, propranolol, metoprolol, nifedipin, verapamil, cardura, valerian, motherwort, phenazepam, coaxil, paxil - at 7.30 p. m.; ginseng - at 9.00 p. m.; Essentiale, simvastatin, lovastatin - at 11.00 p. m. Method provides recovery of levels synchronization in organization of organ-forming systems that allows carrying out the effect on the arterial pressure value in the corresponding time of day.

EFFECT: improved treatment method.

1 tbl, 2 dwg, 1 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a combined medicinal agent used in treatment of arterial hypertension. The proposed agent comprises the combination of enalapril maleate and hydrochlorothiazide as an active component, and also sodium hydrocarbonate, starch, lactose, iron oxide and stearate as accessory substances. The proposed agent is stable in storage and releases the active component easily.

EFFECT: improved and valuable properties of agent.

8 cl, 1 tbl, 5 ex

FIELD: chemico-pharmaceutics.

SUBSTANCE: the present innovation deals with decreasing blood level of homocysteine and normalizing myocardial state in case of ischemic cardiac disease. The suggested preparation contains pyridoxine hydrochloride (vitamin B6), cyanocobalamin (vitamin B12), folic acid (vitamin Bc) being designed as a tablet at the following ratio of components in g per 1 tablet of 0.31-0.37 g: pyridoxine hydrochloride 0.003-0.005; cyanocobalamine 0.000005-0,000007; folic acid 0.004-0.006; additional substances - the rest. The composition suggested is of high synergistic effect.

EFFECT: higher efficiency of therapy and prophylaxis.

1 ex, 1 tbl

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