Application of 2-hydroxyderivatives of polyunsaturated fatty acids as medications

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medication for treatment or prevention of disease, which developed on the basis of structural and/or functional, and/or compositional changes of lipids in cell membranes, selected from cancer, vascular diseases, inflammatory diseases, metabolic diseases, obesity and excessive body weight, neurological or neurodegenerative disorders, which represents compound of formula COOR1-CHR2-(CH2)a-(CH=CH-CH2)b-(CH2)c-CH3 (I) or its pharmaceutically acceptable salts and derivatives, selected from esters, ethers, alkyl, acyl, phosphate, sulfate, ethyl, methyl or propyl; in which a and c can have independent values from 0 to 7; b can have independent values from 2 to 7, where R1 is selected from the following radicals: H, Na, K, CH3O, CH3-CH2O and OPO(O-CH2-CH3)2, and R2 is selected from the following radicals: OH, OCH3, O-CH3COOH, CH3, Cl, CH2OH, OPO(O-CH2-CH3)2, NOH, F, HCOO and N(OCH2CH3)2.Invention also relates to application of formula (I) compound and pharmaceutical composition, which contains it.

EFFECT: medications, based on claimed compound, are more efficient than medications of preceding level of technology.

22 cl, 7 dwg, 16 tbl, 10 ex

 

The technical field to which the invention relates

The invention relates to the use of 1,2-derived polyunsaturated fatty acids as medicines, preferably for the treatment of diseases, the etiology of which is based on changes in the lipids of cellular membranes, such as: changes in the level, composition or structure of these lipids and proteins that interact with them; and for treatment of diseases in which the regulation of lipid composition and structure of membranes and proteins that interact with them, with the reverse development of the pathological condition.

Thus, the present invention because of their wide range of applications, probably mainly relates to the field of medicine and pharmaceuticals.

The level of technology

Cell membranes are structures that define the structure of cells and organelles they contain. Most biological processes occur in the membranes or around them. Lipids play a structural role, but also regulate the activity of important processes. In addition, regulation of lipid composition of the membrane also affects the localization or function of important proteins involved in the regulation of cell physiology, such as G-protein or PKC (Escribá et al., 1995, 1997; Yang et al., 2005; Martinez et al., 2005). The results of these and other studies dem will starout value of lipids in the regulation of important cell functions. In fact, many human diseases, such as cancer, cardiovascular disease, neurodegenerative disease, obesity, metabolic disorders, inflammatory processes and diseases, infectious diseases or autoimmune diseases, among others associated with changes in the content or composition of lipids in biological membranes, is further evidence of the positive effects of treatment fatty acids that can be used to reverse the development of these diseases, in addition to the compounds of the present invention that regulate the composition and structure of membrane lipids (Escribá, 2006).

Lipids consumed with food, regulate lipid composition of cell membranes (Alemany et al., 2007). In addition, various physiological and pathological situations can cause changes in the lipids of cell membranes (Buda et al., 1994; Escribá, 2006). As an example of a situation leading to physiological changes in membrane lipids, mention can be made of fish living in rivers with variable temperature, in which the lipids undergo significant changes (changes in the number and types of membrane lipids), when the temperature drops to 20°C (in summer) to 4°C (winter) (Buda et al., 1994). These changes allow the fish to maintain function in cells of different nature. Examples of patologica is of such processes, which may have an impact on the lipid composition, are neurological disorder or caused by drugs diseases (Rapoport, 2008). Therefore, we can conclude that membrane lipids can determine the correct activity of numerous mechanisms of signaling in cells.

Changes in the composition of membrane lipids affect the transmission of signals in cells and can lead to the development of the disease or, on the contrary, its involution (Escribá, 2006). The results of various studies conducted in the past few years show that membrane lipids play a more important role than previously thought (Escribá et al., 2008). Classic view of the cell membrane removes lipids purely structural role, such as the basis for membrane proteins, which, as expected, are the only functional elements of the membrane. The plasma membrane should play one more role, which consists in preventing the penetration of water, ions and other molecules from the environment into the cells. However, membranes have other important functions that relate to health maintenance, disease and healing. Because the body is sick, sick when its cells, changes in membrane lipids leading to changes in the cells, and the latter is s can lead to the development of the disease. Similarly, therapeutic, nutraceutical or cosmetic intervention aimed at regulating the level of membrane lipids can prevent and cancel (to heal) pathological processes. Additionally, the results of numerous studies indicate that consumption of saturated or TRANS-monounsaturated fats have a negative impact on health. In addition to neurological diseases described above, vascular disease, cancer and other directly associated with membrane lipids (Stender and Dyerberg, 2004). Negative impact on health is reflected in the development of these and other types of diseases, which include metabolic diseases, inflammation, neurodegeneration, etc.

Cell membranes are selective barrier, through which the cell gets metabolites and information from other cells and the extracellular environment that surrounds her. However, the membrane is performed in cells other very important functions. On the other hand, they serve as a carrier for proteins involved in receiving or initiating signals that control important organic functions. Data signals, the effect of which is mediated by many hormones, neurotransmitters, cytokines, growth factors, etc., activate membrane proteins (receptors), revogada the received signal into the cell through other proteins (peripheral membrane proteins), some of which are located in the membrane. Because (1) these systems function as amplification stages and (2) membrane lipids can regulate the localization and activity data of peripheral proteins, the lipid composition of membranes can have a big impact on the physiology of cells. In particular, the interaction of some peripheral proteins, such as G-proteins, protein kinase C, Ras protein, etc. with the cell membrane depends on its lipid composition (Vogler et al., 2004; Vogler et al., 2008). In addition, the lipid composition of cell membranes is influenced by the type and quantity of lipids in the diet (Escribá et al., 2003). In fact, nutraceutical or pharmaceutical intervention can regulate lipid composition of the membranes, which, in turn, can provide control of the interaction (and therefore activity) important protein signaling in the cell (Yang et al., 2005).

On the basis of the fact that membrane lipids capable of controlling the transmission of signals in the cell, one can assume that they are able to regulate the physiological status of the cells and therefore overall health. Indeed described both negative and positive effects of lipids on health (Escribá et al., 2006; Escribá et al., 2008). The results of preliminary experiments showed that 2-gidroksilaminov acid, monounsaturated fat is Aya acid, able to turn back the development of some pathological processes, such as overweight, hypertension or cancer (Alemany et al., 2004; Martinez et al., 2005; Vogler et al., 2008).

Often the development of cardiovascular diseases associated with excessive proliferation of cells comprising the tissue of the heart and blood vessels. This hyperproliferate leads to cardiovascular sediments in the inner lumen of the vessels and cavities of the organs of the cardiovascular system, leading to the development of several diseases, such as hypertension, atherosclerosis, ischemia, aneurysm, sudden attack, myocardial infarction, angina, stroke (cerebrovascular event), etc. (Schwartz et al., 1986). In fact, it has been suggested that the development of drugs that prevent cell proliferation, will be a good alternative for the prevention or treatment of cardiovascular diseases (Jackson and Schwartz, 1992).

The cause of obesity is the changed balance between food intake and energy expenditure is partly due to changes in the mechanisms regulating these processes. On the other hand, this condition is characterized by hyperplasia (increase in number of cells) or hypertrophy (increased size) of fat cells, adipocytes. The results of numerous experiments have shown that fatty acids, free or as part of other mo is ekul, can affect a number of parameters related to energy homeostasis, among other things, such as fat mass in the body, metabolism of lipids, thermogenesis and food consumption (Vogler et al., 2008). In this sense, the modification of fatty acids can serve as a strategy for the regulation of energy homeostasis, i.e. the balance between food intake and energy expenditure and, therefore, related processes, such as appetite or body weight.

Neurodegenerative processes lead to the development of several diseases with different clinical manifestations, but with a common feature, namely, that their cause is degeneration or dysfunction of cells of the Central and/or peripheral systems. Some of these neurodegenerative processes include a significant decline in cognitive function in patients or changes in their physical activity. Neurodegenerative, neurological and neuropsychiatric disorders have a common basis: the degeneration of neurons, or changes in their components, such as lipids (e.g., myelin) or membrane proteins (e.g., adrenergic, serotonergic receptors and so on). Such diseases of the Central nervous system include, inter alia, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, sclerosis of the hippocampus, etc the many types of epilepsy, focal sclerosis, adrenoleukodystrophy and other leukodystrophies, vascular dementia, senile dementia, headaches, including migraine, trauma of the Central nervous system, sleep disorders, dizziness, pain, stroke (cerebrovascular event), depression, anxiety or addiction. In addition, some neurological and neurodegenerative diseases can lead to the development of such processes that result in blindness, ear problems, disorientation, mood swings, etc.

An example of a well-known neurodegenerative disorder is Alzheimer's disease, which is characterized by the formation of senile plaques, composed of fragments of membrane proteins (e.g. β-amyloid peptide), formed as a result of incorrect processing of peptides, with the subsequent accumulation on the outside of the cells, and the formation of neurofibrillary tangles of Tau protein. This process is associated with changes in the metabolism of cholesterol and the subsequent change in level of some membrane lipids, such as cholesterol and docosahexanoic acid (Sagin and Sozmen, 2008; Rapoport, 2008). In addition, some neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, senile dementia or dementia with calves Levi), associated with pathological however, the population fibrillar aggregates of the protein α-synuclein, which leads to considerable changes in the metabolism of triglycerides in the cells (Coles et al., 2001). In essence, the development of these and other neurodegenerative diseases associated with changes in serum or cellular lipids, such as cholesterol, triglycerides, sphingomyelin, phosphatidylethanolamine, etc. On the basis of this can again be assumed that lipids play a key role in the proper activity of neurons, nerves, brain, cerebellum and spinal cord, which is logical given the high content of lipids in the Central nervous system. The molecules of this invention have a large or very large potential ability to reverse the development of many processes associated with neurological, neurodegenerative or neuropsychiatric disorders.

In addition, such diseases include various types of multiple sclerosis and other neurodegenerative disorders associated with demyelination, General consequence of which is the loss of lipids in the membrane of the axon of neurons with subsequent changes in the process of conducting electrical signals. Myelin is the fatty layer that surrounds the axons of many neurons and which is formed near the spiral folds of the plasma membrane of glial cells (cells Swanna). Therefore, it is clear that lipids and who play an important role in the development of neurodegenerative diseases. In addition, it was found that unmodified natural PUFA have a slight protective effect against the development of neurodegenerative processes (Lane and Farlow, 2005). In fact, the most important lipid in the Central nervous system is docosahexanoic acid, natural PUFA, and whose contents are changed in many neurodegenerative processes.

Metabolic diseases form a group of diseases characterized by the accumulation or deficit of certain molecules. A typical example is the accumulation of glucose, cholesterol and/or triglycerides above normal levels. The high content of glucose, cholesterol and/or triglycerides as at the system level (for example, elevated concentrations in the blood plasma)and at the cellular level (e.g., cell membranes), is associated with changes in signal transduction in the cell, leading to dysfunction at different levels, and usually occur due to errors in the activity of certain enzymes or inadequate regulation of such proteins. Among the most important metabolic diseases are hypercholesterolaemia (high cholesterol) and hypertriglyceridemia (high triglycerides). These diseases have a high incidence, morbidity and mortality, and their treatment is neo the durability of the first order. Other important metabolic diseases include diabetes and insulin resistance, characterized by problems with the regulation of glucose. Data metabolic diseases cause the development of other diseases, such as cancer, hypertension, obesity, atherosclerosis, etc. Recently installed another disease that is strongly associated with metabolic disorders described above, and which may represent a new type of metabolite per se, is metabolic syndrome.

Various researchers have described the protective role of some polyunsaturated fatty acids (PUFA) in respect of certain diseases. For example, PUFA inhibit cancer development and have a positive effect against the development of cardiovascular diseases, neurodegenerative diseases, metabolic disorders, obesity, inflammation, etc. (Trombetta et al., 2007; Jung et al., 2008; Florent et al., 2006). Data push and pull factors indicate an important role of lipids (PUFA) in the etiology of various diseases and their treatment. However, the pharmacological activity of these compounds (PUFA) manifests itself in a short period of time due to the rapid metabolism and short half-life in blood. Therefore, it seems necessary to develop PUFA with a slow metabolism, which will lead to increased presence in cleoc the th membrane compared with PUFA, used up to the present time, and will facilitate the interaction of peripheral proteins in signal transduction in the cell. The molecules of this invention are synthetic derivatives of PUFA, have a slower metabolism, and a strong and significantly higher therapeutic effect compared to natural PUFA.

Based on the relationship between structural and functional changes in the lipids located in the cell membrane, with the development of various diseases of different typology, but with the etiology, unitary associated with structural and/or functional changes in the lipid membranes of cells, such as cancer, cardiovascular disease, obesity, inflammation, neurodegenerative and metabolic diseases, the present invention relates to the use of new synthetic polyunsaturated fatty acids, are able to solve technical problems that are typical of known fatty acids mentioned above, and therefore, they are suitable for the effective treatment of these diseases.

Description of the invention

The invention

This invention relates to 1,2-derived polyunsaturated fatty acids (hereinafter: the D-PUFA) for use in the treatment of common diseases, the etiology of which is connected with structurn the mi and/or functional changes in the lipid membranes of cells or proteins, interacting with them, in particular, selected from cancer, cardiovascular diseases, neurodegenerative and neurological disorders, metabolic diseases, inflammatory diseases, obesity and overweight. D-PUFA have low rate of metabolism compared to natural polyunsaturated fatty acids (hereinafter: the PUFA), because the presence of atoms other than hydrogen (H) 1 and/or 2 carbon atoms, blocking its degradation via β-oxidation. This causes significant changes in the composition of membranes, regulating the interaction of peripheral proteins in signal transduction in cells. This can lead, for example, to differences in the packing of the membrane surface, modulating the binding of peripheral proteins that participate in cell proliferation signals. Thus, the molecules of D-PUFA, which are the subject of this invention have higher activity compared with PUFA, demonstrating a significantly higher pharmacological effect for the treatment of these diseases.

As mentioned above, the diseases that can be treated with molecules of the D-PUFA according to the invention, have the same etiology, is associated with structural and/or functional (or any other nature) changes in the lipid membranes of cells or proteins that interact with them.

Subsequent diseases cited as example:

- cancer: liver cancer, breast cancer, leukemia, brain cancer, lung cancer, etc.;

cardiovascular disease: atherosclerosis, ischemia, aneurysm, sudden attack, cardiomyopathy, angiogenesis, cardiovascular hyperplasia, hypertension, myocardial infarction, angina, stroke (cerebrovascular event), etc.;

- obesity, excess weight, control appetite and cellulite;

- metabolic disease: hypercholesterolemia, hypertriglyceridemia, diabetes, insulin resistance, etc.;

- neurodegenerative diseases, neurological and neuropsychiatric disorders: Alzheimer's disease, vascular dementia, a syndrome of Zellweger, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, sclerosis of the hippocampus and other types of epilepsy, focal sclerosis, adrenoleukodystrophy and other types of leukodystrophy, vascular dementia, senile dementia, dementia with calves Levi, multiple system atrophy, prion disease, headaches, including migraines, damage to the Central nervous system, sleep disorders, dizziness, pain, stroke (cerebrovascular event), depression, anxiety, addiction, memory problems, learning or cognitive function and common diseases, to the x need to stop neurodegeneration or neuroregenerative, which are induced by treatment with the compounds according to the invention;

- inflammatory diseases, including inflammation, cardiovascular inflammation, tumor-induced inflammation, inflammation of rheumatoid origin, inflammation infectious origin respiratory inflammation, acute and chronic inflammation, hyperalgesia, inflammatory nature, swelling, inflammation, trauma or burns, etc.

Derivatives of D-PUFA of the present invention have the following formula (I):

COOR1-CHR2-(CH2)a-(CH=CH-CH2)b-(CH2)c-CH3

(I)

where a, b and C can have independent values from 0 to 7, and R1and R2can imagine the ion, atom or group of atoms with a molecular mass of which is independently not greater than 200 Da.

In a preferred structure according to the invention a, b and C can have independent values from 0 to 7, R1is H and R2is HE.

In another preferred structure according to the invention a, b and C can have independent values from 0 to 7, R1is Na, R2is HE.

In another preferred structure according to the invention a and can have independent values from 0 to 7, b can have independent values from 2 to 7, R1and R2can provide ion, the volume or group of atoms, the molecular weight of which is independently equal to or below 200 Da.

Introduction fatty acids according to the invention can be performed by any means, for example enterline (intraperitoneally), orally, rectally, topically, by inhalation or via an intravenous, intramuscular or subcutaneous injection. In addition, you can enter the connection formulas above, or any pharmaceutically acceptable derivative, such as esters, ethers, alkyl derivatives, acylphosphate, phosphate, sulfate, ethylpropane, methylpropane, propylphosphonate, salts, complexes, etc.

In addition, fatty acids according to the invention can enter themselves or be formulated in a pharmaceutical or nutraceutical compositions in which they are United with each other and/or with fillers, such as binders, fillers, disintegrating agents, lubricants, shell, sweeteners, flavorings, colorants, carriers, etc. and combinations of all the above substances. Also fatty acids according to the invention can represent a portion of the pharmaceutical or nutraceutical compositions in combination with other active ingredients.

For the purposes of the present invention, the term "nutraceutical compound" is defined as a connection that regularly consume during meals, and it functions for p is eupresidency diseases, in this case, disease etiology, associated with changes in the lipids of cell membranes.

For the purposes of the present invention the term "therapeutically effective amount" is a quantity that gives the course a reverse development or prevents the disease without any side effects.

Brief description of drawings

Figure 1.The effect of the compounds listed in table 1, on the growth of tumor cells. On the Y-axis presents the number of viable cells (% of control) depending on the use of the compounds (X-axis). Cells of the human lung carcinoma (A) were cultured in medium RPMI-1640 with 10% serum for 48 h in the absence (control) or in the presence of 250 μm of the compounds according to the invention. The graph shows the number of viable cells (mean and standard error of the mean of three experiments). The dashed line represents the total elimination of cells (0% viability).

Figure 2.The influence of some PUFA molecules and D-PUFA of the present invention on the proliferation of vascular cells a10. On the Y-axis presents the number of cells (% of control) depending on the used compound (X-axis). Cells were cultured in complete medium (control), incomplete medium without additives (CSS) or complete medium in the presence of PUFA (182, 183A, 183GWATER, 204, 205, 226) or D-PUFA (A, A, A, A, A and A). Reducing prolifera the AI, but still higher than the values for the CSS environment, indicates that these molecules have the ability to regulate abnormal proliferation of cardiovascular cells without being toxic.

Figure 3.

A. Proliferation of adipocytes, cultured in the absence (control, C) or in the presence of various D-PUFA and PUFA. The Y-axis denotes the number of cells (% of control) depending on the use of fatty acids (X-axis). As nonproliferative control used environment with deficiency of serum (medium low percentage of serum, MSB).

C. the Y-axis denotes the weight (% of untreated control) and the horizontal axis indicates the connection used for the treatment of experimental animals. On the X-axis from left to right first specified processing solvent (S) and then the processing of several compounds according to the invention. Rats SHR were treated for one month, each of the 24 compounds shown in the figure, at a dose of 200 mg/kg Each experimental group consisted of six animals in each series of experiments used the group treated with the carrier (water), the results were compared with the body weight of animals, not subjected to any processing. The letters A, B, N and P indicate the combination of the radicals R1and R2in table 3.

Figure 4.

A. the Death of P19 cells, cultured in the absence of external is their factors (control, From: 0% loss of neurons) and in the presence of NMDA (100% loss of neurons). On the vertical axis indicated the death of neurons (% of control) depending on the use of fatty acids (X-axis). The presence of PUFA induced a slight increase in the survival of P19 cells in the presence of NMDA. D-PUFA induced a significant increase of the survival rate of the cells, more than 200% in the case of compound A. Because the number of cells in cultures treated cells was higher compared with the control, it can be argued that these compounds not only prevent the death of neurons induced by NMDA (onlineregistration action), but are also connections with neuroregenerative agents.

Century, the Influence of D-226B1 PUFA in improving learning in the radial maze model of Alzheimer's disease in animals. On the Y-axis on the left figure indicates the time spent to complete the training, and on the vertical Y-axis on the right figure shows the total number of errors made while performing the programmed learning (mean±standard error of the mean) (time driven). On both figures from left to right on the X-axis shows the test results of healthy mice (control) (first column), in mice with induced Alzheimer's disease and treated water used as solvent (second column) or we is Oh, processed by the connection V (third column). Animals with Alzheimer's disease focused longer and made more errors compared to healthy mice, the differences were statistically significant (*, P<0,05). In contrast to mice suffering from Alzheimer's disease who were treated with compound 226B1, showed no significant differences from healthy animals in a statistically meaningful way.

Figure 5.

A. On the top panel presents an immunoblot showing the inhibition of the expression of Pro-inflammatory protein SOH-2, previously induced by bacterial lipopolysaccharide (LPS) (C +, 100%) in human macrophages derived from monocytes U937, under the action of various D-PUFA of the present invention. The bottom panel shows the interaction SOH-2/SOH-1 % of control (Y-axis) for the following compounds (X-axis): OOA (2-gidroksilaminov acid), OLA (182A1), OALA (183A1), OGLA (183A2), OARA (204A1), OEPA (205A1), ODHA (226A1).

Century Shows anti-inflammatory effectiveness of various derivatives of D-PUFA of the present invention in models of inflammation in animals. It was shown inhibitory effect on the concentration of TNFα (PG/ml)induced by LPS in mice (Y axis), for different compounds according to the invention (X-axis). The lower level of this factor is directly related to anti-inflammatory treatment. Connections anal is Hecny compounds shown on the left panel.

6.Cholesterol and total triglycerides (C) in cells T-L1. The vertical axis indicates the concentration of cholesterol or triglycerides (In) (% of total lipids) depending on the use of fatty acids (X-axis). Values represent mean±standard error of the mean for cholesterol and triglycerides compared with the total lipids in cell membranes according to the spectrophotometric method (cholesterol) or thin-layer chromatography with subsequent analysis by gas chromatography (triglycerides). Graphs show the set values in cells cultured in the absence (control) or in the presence of D-PUFA or PUFA above.

Fig.7.

A. the Relationship between membrane structure and cellular effects caused by the D-PUFA. On the axis of ordinates shows the cellular effects (% of control) in comparison with the temperature of the phase transition of HII(X-axis). Determined the average effect for each molecule D-PUFA (the average effect of each lipid models all studied diseases and the number of double bonds) and build a graph based on the phase transition temperature. Lowering the temperature of the phase transition of HIIpointed to a greater induction of violating the integrity of the membranes that drive the lo to the emergence of the "anchor" sites for peripheral membrane proteins and for the better regulation of signaling in the cell and, therefore, more effective control of certain diseases.

C. the relationship between therapeutic efficacy of PUFA (unfilled circles) and D-PUFA (filled circles). Each point represents the average effect observed for all the studied diseases (Y-axis: change in % relative to the control value) depending on the number of double bonds present in the molecule (horizontal axis). In both cases, the correlation wore statistical significant (P<0,05). Observed, that therapeutic effect depended on the number of double bonds in the molecule, which, in turn, is connected with the ability to adjust the structure of membranes. In this sense, the presence of a radical with 1 and 2 atoms of carbon in D-PUFA, but not in PUFA, it is important to enhance therapeutic effect of these molecules.

The results obtained indicate that the effects of the lipids included in the scope of the present invention, have a common basis. Data correlation values (r2equal of 0.77 and 0.90 for the D-PUFA and P<0.05 in both cases) clearly indicate that the structure of the used lipids, is the basis for their actions and that it is mediated through the regulation of the membrane structure, based on the interconnections between structure and function for each lipid. In fact, there are a number of research works, in the which human diseases are associated with changes as described above, in the content of PUFA, demonstrating the important role of lipids in cell physiology.

Detailed description of the invention

A wide range of therapeutic applications of molecules D-PUFA of the present invention assumes that the molecules of D-PUFA attach to the membranes of specific structural properties, which ensure correct processing activity carried out in these membranes and through these membranes. In other words, the cause of many anomalies, which cause various diseases are significant changes in the content of some important functions of the cell lipids and/or proteins that interact with membranes and/or associated with the production of lipids. Data pathological changes that may lead to the development of various diseases can be prevented or push them back development using synthetic fatty acids, described in this invention, which can be used effectively for the treatment or prevention of any disease, the etiology of which is associated with changes in composition, structure or any other changes of lipids in biological membranes, or by dysregulation of signaling in the cell, resulting from changes in these lipids in biological membranes. In addition, the lipids included in the scope of the present invention, that the same can be used as drugs in that case, when the disease develops as a result of other changes, provided that the modulation properties and/or functions of the membrane are able to cancel the pathological process.

For this study, therapeutic effects of fatty acids according to the present invention used cultured cell lines and models of various diseases in animals and investigated the activity of D-PUFA and PUFA in the treatment of various diseases.

The structure of the molecules according to the invention are shown in tables 1, 2 and 3. Taking into account formula (I) compounds of the present invention preferably represent combinations of the values of a, b and C, are shown in table 1.

In addition, the invention compounds are denoted by a three digit number followed by the symbol X1 or x2. Figure 1 indicates all used D-PUFA, except for the series, based on C18:3 ω-6 (γ-linoleic acid), which are indicated by the number 2. The first two digits of this number means the number of carbon atoms in the molecule. The third digit of this number represents the number of double bonds. The letter X is replaced by the letters from a to W (table 3), these letters from a to W denote a specific combination of the radicals R1and R2in the formula (I).

Thus, a particularly preferred compound according to this invention are indicated by abbreviations: H, H, H, H, H, H, and after whom the duty to regulate decoding according to the instructions above.

Table 1
D-AGPIabc
Series 182X1623
Series 183X1630
Series 183X2333
Series 204X1243
Series 205X1250
Series 226X1260

Table 2 shows the structures of some molecules of D-PUFA according to the invention and PUFA from which they are derived. As you can see, the table provides some compounds according to the invention with different combinations of values of a, b and C, and in which the radicals R1and R2marked by the letter a, which means, as described above, that 1is N, and R2is HE (see table 3).

Table 2
The title moleculeStructurePropertyReduce seal designation
2-Hydroxy-9,12-octadecadienoic acidCOOH-CHOH-(CH2)6-(CH=CH-CH2)2-(CH2)3-CH3S, OH182A1

2-Hydroxy-9,12,15-octadecatrienoic acidCOOH-CHOH-(CH2)6-(CH=CH-CH2)3-CH3S, OH183A1
2-Hydroxy-6,9,12-octadecatrienoic acidCOOH-CHOH-(CH2)3-(CH=CH-CH2)3-(CH2)3-CH3S, OH183A2
2-Hydroxy-5,8,11,14-eicosatetraenoic acidCOOH-CHOH-(CH2)2-(CH=CH-CH2)4-(CH2)3-CH3S, OH204A1
2-Hydroxy-5,8,11,14,17-eicosapentaenoic acidCOOH-CHOH-(CH2)2-(CH=CH-CH2)5-CH3S, OH205A1
2-Hydroxy-4,8,11,14,17-docosahexaenoic acidCOOH-CHOH-CH2-(CH=CH-CH2)6-CH3S, OH226A1
9,12-Octadecadienoic acidCOOH,-(CH2)7-(CH=CH-CH2)2-(CH2)3-CH3N182
9,12,15-Octadecatrienoic acidCOOH,-(CH2)7-(CH=CH-CH2)3-CH3N183A
6,9,12-Octadecatrienoic acidCOOH,-(CH2)4-(CH=CH-CH2)3-(CH2)3-CH3N183GWATER
5,8,11,14-Eicosatetraenoic acidCOOH,-(CH2)3-(CH=CH-CH2)4-(CH2)3-CH3N204
5,8,11,14,17-Eicosapentaenoic key is lots COOH,-(CH2)3-(CH=CH-CH2)5-CH3N205
4,7,10,13,16,19-Docosahexaenoic acidCOOH,-(CH2)2-(CH=CH-CH2)6-CH3N226
Prop: property. S: a synthetic compound. N: natural. HE: gidrauxilirovanne 2 carbon atom (the α-atom).

Table 3 shows the various combinations of the radicals R1and R2that can be combined with the values of a, b and C, are shown in table 1.

Table 3
Ri
R2
HNaKCH3OCH3-CH2OOPO(O-CH2-CH3)2
OHABCDEF
OCH3G HI
O-CH3COOHJK
CH3LMN
ClAbout
CH2OHPQ
OPO(O-CH2-CH3)2R
NOH S
FT
HCOOUV
N(OCH2CH3)2W

Examples

Example 1. The overall percentage of PUFA in cell membranes treated with D-PUFA and PUFA

Molecule synthetic D-PUFA are hydrophobic molecules, and, therefore, cells exposed to D-PUFA, have a high content of fatty acids on their surface.

Table 4 shows the total percentage of PUFA in cell membranes T treated with 100 µm data of fatty acids within 48 hours For the production of these experiments the membranes were extracted and the total fraction of fatty acids was subjected to hydrolysis in an alkaline environment. Methanol derivatives of these fatty acids were determined by gas chromatogra the Oia. The data represent mean values of four independent determinations of the mass of PUFA, divided by the total number of fatty acids and expressed as a percentage. Also shows the standard error of the mean. In cell cultures T, incubated in the presence of these fatty acids, found higher concentrations of PUFA (including D-PUFA) and a lower concentration of saturated fatty acids.

The control corresponds to the culture without the addition of natural or synthetic fatty acids. In the cells in their natural form PUFA are found in the membranes, but the presence in the environment of the molecules of D-PUFA according to the invention leads to an increase in the content of PUFA in cell membranes. Therefore, on the basis of these results we can assume that the nutraceutical or pharmaceutical compositions of these compounds of the present invention can effectively regulate the composition of cell membranes.

Table 4
Added lipidsThe overall percentage of PUFA
Without lipids (control)32,4±2,1
182A142,3±3,1
183A142,8±2,2
183A244,0±2,6
204A145,5±2,9
205A146,7±3,4
226A148,9±3,7

Example 2. The transition L (lamellar phase)-in-HII(hexagonal phase) in the cell membranes of DEPE (delaydifferential)

In tables 5 and 6 shows the transition temperature (lamellar phase)-in-HII(hexagonal phase) model DEPE membranes. The transition temperature was determined by differential scanning calorimetry. In all cases, the ratio of DEPE:D-PUFA was 10:1 (mol:mol). The transition lamellar phase hexagonal phase is an important parameter that captures the relevant properties of cell membranes to transmit signals. The ability to form phase HIIthat is the higher the lower the transition temperature indicates that the pressure surface of the membranes below, meaning that the polar heads of the phospholipids form a less dense or compact network in comparison with the network formed by lamellar structures (Escribá et al., 2008). When this happens, some peripheral membrane proteins such as G-proteins, proteinase With or protein Ras) easier contact with the membrane, while others are more the labs interaction (for example, Gα-protein); thus, changes in the temperature of the phase transition are important for the regulation of cellular functions, health-related or treatment of a person (Escribá et al., 1995; Vogler et al., 2004; Escribá, 2006).

Control values correspond to the model membranes in the absence of fatty acids. Lowering the temperature of the phase transition of HIIobserved when using the D-PUFA according to the invention, indicates an increased induction of violating the integrity of the membranes with the "anchor" sites in the membrane peripheral proteins, which leads to better regulation of signaling in the cell and, therefore, greater efficiency in the control of some diseases.

Thus, table 5 shows the transition temperature TH(hexagonal-lamellar phase in the HIIin membranes from DEPE (4 mm) in the presence or absence of 200 μm of various compounds of the present invention, series A.

Table 5
Added lipidsThe temperature of the phase transition
Without lipids (control)64,5
182A151,8
183A1 51,6
183A250,1
204A1to 49.3
205A147,9
226A144,4

Table 6 shows the transition temperature lamellar phase-to-hexagonal phase in the DEPE membranes in the presence of D-PUFA from several series.

Table 6
182183-1183-2204205226
B52,151,951,050,248,345,1
D51,051,149,448,747,543,9
E50,649,8to 49.348,4 46,742,9
G51,050,350,149,647,344,1
About51,751,251,349,748,644,2
R52,251,8to 49.950,048,444,7

Example 3. Linking Gi1-protein (trimer) with a model of cell membrane

Regulation of lipid composition of the membranes resulted in changes in the membrane structure according to differential scanning calorimetry, which caused changes in the localization of G-proteins in model cell membranes, as shown in table 7. The overall result is expressed in the regulation of signaling, leading to reverse the development of various pathological processes, as will be shown below. Table 7 shows the binding heterotrimeric Gi1protein with model membranes of phosphatidylcholine:phosphatidylethanolamine (6:4, mol:the ol) according to the analysis by centrifugation followed by Western blot turns, visualization by chemiluminescence and quantification imaging analysis. For these experiments used a 2 mm phospholipid and 0.1 μm of various D-PUFA, are shown in table 7. Control was a sample of model membranes without fatty acids.

The results of these studies indicate that induced modification of structural and functional properties of the membrane led to the increase in the number of unsaturated bonds. The presence of unsaturated bonds and changes in 1 and 2 carbon atoms reduced the rate of metabolism of PUFA. This fact in relation to the specific effect of these lipids on the structure of membranes indicates that the effect on abnormal cells has a common nature.

Actually took place close correlation between pharmacological effect and the effect they had on the lipid structure of the membrane.

Table 7
Added lipidsBinding of G-protein
Without lipids (control)100±5
182A1312±12
183A1328±9
183A2204A1385±22
205A1406±14
226A1422±26

Example 4. Use of derivatives of 1,2-PUFA treatment for cancer

Cancer is a disease characterized by uncontrolled proliferation of transformed cells. As mentioned above, in addition to specific genetic changes in cancer is characterized by the altered content of membrane lipids, which may affect the transmission of signals in the cell. In this sense, natural PUFA showed some efficacy against the growth of cancer cells (A) at concentrations used for this study, although, given their rapid metabolism, it is unlikely we could achieve greater efficiencies in the body (figure 1). However, the D-PUFA showed a pronounced and significantly higher efficiency compared to unmodified in 1 and 2 carbon atoms of the molecules (figure 1 and table 8) in the same concentrations. These results indicate that changes in the natural polyunsaturated fatty acids lead to molecules with strong anti-tumor activity and a significantly higher activity compared with the natural PUFA and thus the consequently, they have a high applicability in the treatment and prevention of cancer in the application of pharmaceutical and nutraceutical approaches in humans and animals.

For the experiments, the results of which are shown in figure 1, used cultured cells non-small cell carcinoma of the human lung (A) in medium RPMI 1640 with the addition of 10% fetal bovine serum and antibiotics at 37°C and in an atmosphere with 5% CO2. Cells were maintained in culture for 48 h in the presence or in the absence of D-PUFA and PUFA, are shown in table 2, at a concentration of 250 μm. After treatment were counting the number of cells and investigated the mechanism of antitumor activity of compounds using flow cytometry. Figure 1 shows the percentage of survival cells (mistaking him for a 100% relative to untreated tumor cells). These values represent average values of three independent experiments.

In a separate series of experiments the compounds listed in table 3, were used against various types of tumors that are listed in tables 8A, 8B and 8C. Data shows the antitumor efficacy of the compounds according to this invention in the growth of malignant tumor cells of the breast, brain (gliomas) and lungs. Efficacy data are expressed as values IC50(concentration values is soedinenii in microns, resulting in 50% of tumor cell death) after 72 h of incubation. Other experimental conditions were identical to the conditions described in the previous section.

The obtained results clearly indicate that all D-PUFA showed high efficacy against the growth of tumors. In General, it can be noted that the series of compounds a and b showed the best results, and based on this, tested the effectiveness of these series against leukemia and liver cancer (tables 9 and 10). It can also be argued that the series connection 204 and 226, i.e. numbered D-PUFA double rooms unsaturated bonds, are larger, and are the most effective. These results suggest that the pharmacological activity of the compounds of the present invention is subject to the dependency structure-function, which also confirms thesis about the General mechanism of action associated with the structure of each connection, and hence, the unity of invention in this section.

Table 8A shows the effectiveness of the compounds according to the invention on the growth of malignant tumor cells of breast cancer MDA-MB-231, which is expressed in the values of the IC50in micromol.

Table 8A
Series of molecules
Subseries molecules
182183 (1)183 (2)204205226
A388380347381390187
B379267156345208195
C386289168389223210
D277245175281237224
E289319193299284207
F311323181 326275226
G378364159372219213
H402308170363282199
I411274210315261241
J287296221285228235
K375381238317240208
L343306173332253 216
M362407164321216267
N297278186274289222
About286267217298264249
P419349214370301250
Q328312205306247263
R371305172285245204
S388 291189293270211
T391290216317233199
U410344228369272227
V442326241352298215
W391311203311256246

In table 8B shows the effectiveness of the compounds according to the invention in the cells of malignant brain tumors (gliomas) U118, expressed in values of the IC50in micromol.

Table 8B
Ser and molecules
Subseries molecules
182183 (1)183 (2)204205226
A197397372197400214
B198202377396391196
C208n.d.379287442237
D221n.d.385311467241
E213n.d.n.d.224513265
F236401275498261
G205329394342426278
H267408443263439294
I240321432328510327
J254296426296487283
K221257418380474272
L229231460247 435269
M238349407309462306
N247324385315513285
Aboutn.d.370n.d.n.d.n.d.277
Pn.d.285389291432290
Qn.d.282392324419254
R255307454501468267
S203316416462475315
T214368423385427263
U212343380263454342

V231274402345510269
W246n.d.438287443318

In table 8C shows the effectiveness of the compounds according to the invention in the cells of carcinoma of the lung A expressed in the values of the IC50in micromol.

Table 8C
Series of molecules
Subseries molecules
182183 (1)183 (2)204205226
A944200192243394195
B196195197413202198
C635281241521325214
D541326267372364221
E387294243475413209
F354347259392338286
G439273295427407273
H462319219398290247
I673348276459351298
J321281259362416215
K274276237414275250
L385285 283326362221
M286322248375293208
N329379255420384236
About452344318461418264
P328317272387339291
Q293273314348365252
R317258274364417 219
S458341246439293265
T379367279352322243
U255294287270426270
V340320291326325298
W416352212341420302

Table 9 shows the effectiveness of the compounds according to the invention in the cells of human leukemia (Jurkat cells), expressed in values of the IC50in micromol after 72 hours

Table 9
Series of molecules
Subseries molecules
182183 (1)183 (2)204205226
A7131981846237685
B377196184104294175

Table 10 shows the effectiveness of the compounds according to the invention in relation to cell carcinomas of the liver (HepG2 cells), expressed in values of the IC50in micromol after 72 hours

Table 10
Connection182183 (1)183 (2)204205226
A212380380 192401164

All these results indicate that D-PUFA are suitable for the prevention and treatment of cancer, being included in the nutraceutical and pharmaceutical compositions, in humans and animals. Also found that the effectiveness of the D-PUFA correlated with a higher number of double bonds and the modifications 1 and 2 of the carbon atoms is important for the manifestation of antitumor activity of lipids in the treatment. Since these compounds possess anti-tumor activity against various tumor cells, it can be argued that they are molecules with a broad spectrum of antitumor activity and can be widely applied to any form of cancer.

Example 5. Use of derivatives of 1,2-PUFA for the treatment of cardiovascular diseases

In order to study the suitability of D-PUFA for the treatment of cardiovascular diseases used several experimental approaches. In the beginning, evaluate the effectiveness of the compounds according to the invention in the culture of cells of the aorta (cell line a-10). These cells were maintained in culture with complete medium (medium With addition of 10% fetal bovine serum and PDGF) and incomplete environment (Wednesday CSS with the addition of 1% fetal bovine serum without PDGF). Cultivation was carried out for 72 h oppo is ichno to as described in the previous section. After this incubation period was calculated the number of cells using flow cytometry.

In incomplete medium (Wednesday CSS without adding control PDGF) cells had the character of proliferation similar to that observed in the healthy body. The nature of the proliferation taking place in the full environment will be similar to the situation that takes place in a sick body. The presence of D-PUFA led to a significant reduction of proliferation of normal cells of the aorta (A-10) in complete culture medium without proliferative agents in fetal serum, part of the culture medium. In the presence of proliferative agents (cytokines, growth factors, etc.) number of a10 cells was similar to the number in incomplete medium (CSS) with the introduction of the D-PUFA of the present invention (figure 2). In contrast, PUFA showed a slight antiproliferative efficacy or she was absent at all, showing that changes in the molecules of these fatty acids, were significantly increased their pharmacological effects in the treatment of cardiovascular diseases such as hypertension, atherosclerosis, ischemia, cardiomyopathy, aneurysm, sudden attack, angiogenesis, cardiac hyperplasia, myocardial infarction, angina, stroke (cerebrovascular event), etc.

<> The effect on this cell line cannot be considered as a toxic effect for two reasons: (1) in a full environment D-PUFA never induced decrease in cell proliferation below the level typical for cells incubated in incomplete medium; (2) in the cells of the aorta (a10)treated with D-PUFA, there were no signs of a molecular or cellular necrosis, apoptosis or cell death of another type. Since the proliferation of vascular cells is a component of the development of many cardiovascular diseases, D-PUFA are suitable for the prevention and treatment of these diseases through nutraceutical and pharmaceutical approaches in humans and animals.

In a separate series of experiments rat cardiomyocytes were isolated and cultured in vitro for 24 h, after which he set a number of parameters. First, determine the number, length and width of cells in culture. Observed that all the compounds of series a and b (182-226) were able to increase the number of cells surviving in culture (ranging from 12 to 33%), and their length and width (ranging from 18 to 42%). In addition, these compounds reduced the release of lactate dehydrogenase (LDH) in response to anoxia (decrease within 9-68% for all compounds of the series a and b). These results indicate that the molecules of D-PUFA of the present invention have a protective effect DL the cells of the heart and blood vessels and increase its elasticity, that can be used for the prevention and treatment of cardiovascular diseases of various kinds, such as hypertension, atherosclerosis, ischemia, cardiomyopathy, aneurysm, sudden attack, angiogenesis, cardiac hyperplasia, myocardial infarction, angina, stroke (cerebrovascular event), abnormal blood circulation, etc.

In a separate series of experiments investigated the influence of the molecules D-PUFA of the present invention on blood pressure in SHR rats. In these animals was determined blood pressure and the concentration of apolipoprotein AI (apoA-I). For these experiments, rats with spontaneous hypertension (SHR) were treated for 30 days with vehicle (water) or the compounds according to the invention (at a dose of 200 mg/kg/day, orally). At the end of this period was determined blood pressure and the concentration of apolipoprotein AI in the serum. The results testified to the presence of compounds of the present invention's ability to reduce blood pressure and to induce the expression of apoA-I, indicating that these molecules are suitable for the treatment of hypertension and atherosclerosis (table 11). In these experiments used non-invasive methods for determining blood pressure (cuff method on the tail) and the assessment of gene expression of apoA-I (RT-PCR)described in the literature (Teres et al., 2008). The applicability of the molecules on the present izobreteny is for the treatment of cardiovascular disease is confirmed by their ability to reduce the concentration of cholesterol and triglycerides in the serum (see below).

Table 11 shows the data of the blood pressure (in mm Hg) and the concentration of apoA-I (%) in SHR rats. Average values for SHR rats before treatment was respectively 214 mm Hg and 100%.

Table 11
Connection182183 (1)183 (2)204205226
A204201189205193194
146134311131346324
B201197182202187186
178151285144264 333
F198203191199195202
192146279163319357
L207205194197198200
131125268188376296
N187208194201189199
159189296174293348
P202 201187203194193
184178347153337382
V207199198198191195
166152282161315324

Example 6. Use of derivatives of 1,2-PUFA for the treatment of obesity

On figa shows how PUFA (natural and synthetic compounds able to inhibit the hyperplasia and hypertrophy of fat cells. This experience is used adipocytes 3T3-L1. This effect is already known and has been described previously for unmodified PUFA (Hill et al., 1993). However, the D-PUFA have an enhanced ability to inhibit the proliferation of fat cells (figa). The observed effect in any case is not toxic, because the growth inhibition of fatty CL is current not resulted in reduced cell proliferation below the level for cells, cultivated in incomplete medium (with 1% serum). Used cell culture medium and conditions were similar to those described above.

The results show that the D-PUFA have a high potential ability to inhibit the growth of fat cells and, therefore, suitable for the prevention and treatment of obesity and other processes associated with the accumulation of adipocytes in the body (e.g., cellulitis), or changes in appetite when using nutraceutical or pharmaceutical compositions in animals and humans. Again, the observed effect was shown a correlation with the number of double bonds in the molecules and the presence of modifications 1 and 2 carbon atoms in the lipid molecule.

In addition, several compounds of the present invention used to study their effect on body weight of rats (pigv). In this regard, in rats with spontaneous hypertension (SHR)treated with compounds 182-226 (series a, b, N and P), the observed reduction in body weight after 1 month of treatment at a dose of 200 mg/kg (decrease of 3.2 and 6.9%), partly due to the decrease in food intake and partly by suppressing the proliferation of fat cells (untreated animals, which were fed the same amount of feed, body weight did not drop as significantly as the treated rats). The results of the experiments indicate that the data connection is the link you can use for weight control (obesity and overweight), appetite control and regulation of body fat (cellulite).

Example 7. Use of derivatives of 1,2-PUFA for the treatment of neurodegenerative diseases

In these experiments used a different model of neurodegeneration. First explored P19 cells, when differentiation of neurons induced TRANS-retinoic acid. To do this, P19 cells were incubated in minimum essential medium (α-MEM) supplemented with 10% fetal bovine serum and 2 mm TRANS-retinoic acid at 37°C in an atmosphere with 5% CO2. Cells were incubated in the presence or absence of multiple D-PUFA or PUFA in different concentrations for 24 hours of Neurotoxicity induced 1 μm NMDA. Then counted the number of cells under an optical microscope after staining Trifanova blue. The results of these experiments showed that PUFA have a protective effect against degeneration of neurons, although the effect mediated by the D-PUFA was significantly higher (figa and table 12). From these figures and tables it becomes apparent that the molecules of D-PUFA of the present invention protects neurons from death, because they inhibit NMDA-induced death of neurons, thus, these compounds may be suitable for the prevention and treatment of neurodegenerative diseases such as Alzheimer's disease, multiple sclerosis, Parkinson's disease, leadest ofia etc. It was also shown that the number of cells in the treated cultures is higher compared to cultures without the addition of agents that cause neurodegeneration. In particular, the lack of cell death indicates that the number of P19 cells was higher compared with the control. Therefore, derivatives of D-PUFA of the present invention can be used to stimulate neuroregenerative processes that take place after injuries (accidents) or exposure to toxins.

Table 12 shows a protective effect for neurons from death in P19 cells: inhibition of neuronal death (cells P19) using the D-PUFA of the present invention after NMDA treatment (the latter causing 100% mortality). The loss of control cells without exposure to NMDA were absent (0% mortality). All percentages below 100%, which indicates that protect neurons from death. Negative values indicate that in addition to protecting neurons from death there is a certain proliferation of neurons. In addition, the compounds of the present invention reduced the concentration of α-synuclein (table 13), a protein associated with neurodegenerative processes such as Parkinson's disease, Alzheimer's disease, dementia with calves Levi, multiple system atrophy, prion disease, etc. Therefore, the molecules of the present invention can use the VAT for the prevention and treatment of neurodegenerative, neurodegenerative, neurological and neuropsychiatric processes.

Table 12
182183-1183-2204205226C (NMDA)
A-60-55-70-70-50-230100
B-62-58-66-71-52-222100
F-45-35-36-46-44it is 189100
L-32-21-29-27-35 -117100
V-17-9-18-11-27-86100

Table 13 shows the expression of α-synuclein in cultured neurons (cells P19). C (control) represents the percentage of α-synuclein in untreated cells (100%).

td align="center"> 61
Table 13
182183-1183-2204205226C
A504540413523100
B614338364131
F7152525741
L807673696764
V838789828177

To test the effectiveness of the compounds of the present invention in the induction of neuroregenerative or suppression of neurodegeneration used a model of Alzheimer's disease in animals. In this model, mice develop neurodegeneration, because they Express a number of mutant proteins, leading to brain damage (mouse Alzh). As control animals used B6 mice. Animals in both groups at 3 months were treated with vehicle (water) or different D-PUFA (at a dose of 20 mg/kg daily orally), until they reached 3 months of age. To determine the improvement in cognitive function after processing the test compounds was evaluated behavior belly what's in the radial maze. Animals were kept on a restricted diet to stimulate the appetite. In a symmetric radial maze with 8 compartments did a visual marker to facilitate orientation in animals and in four compartments were placed food (15 mg tablet). Was determined for each animal required to complete training, and the number of errors using the camera connected to the computer. In this sense, animals with Alzheimer's disease had indicators are approximately 50% higher in comparison with healthy animals, that is, as the time required for training, and the number of mistakes made (pigv). In contrast to mice with Alzheimer's disease treated V (Alzh+LP226), showed the parameters of the behavioral responses similar to control animals, which were significantly lower (P<0.05) as compared with animals treated with vehicle (Alzh). In the experiment also tested the effectiveness of the compounds V, A, W, A, V, 226V1, and the results of these evaluation experiments showed the improvement of learning in animals with Alzheimer's disease (respectively 98, 92, 93, 86 and 89 seconds). On the other hand, it is also interesting to note that these same compounds (V, A, W, A, 226V1) resulted in reduction of time required to complete training in control mice (healthy mouse B6), respectively, 8, 11, 12, 18, 16 and 14 seconds. Consequently, it is possible to come to bookmark the teaching, these compounds have high activity not only in relation to neurodegeneration, but neuroregenerative. Among the neurodegenerative processes that can be prevented and treated with molecules of D-PUFA of the present invention, are Alzheimer's disease, Parkinson's disease, syndrome Zellweger, multiple sclerosis, amyotrophic lateral sclerosis, sclerosis of the hippocampus and other types of epilepsy, focal sclerosis, adrenoleukodystrophy and other leukodystrophies, vascular dementia, senile dementia, dementia with calves Levi, multiple system atrophy, prion disease, etc. in Addition, neuroregenerative activity, judging by the effect on mice with Alzheimer's disease and healthy mice B6, can be used for the treatment of other pathological processes which has place the loss of neurons, for example, in an accident, surgery, injuries of different nature or actions of toxins. Molecules of D-PUFA of the present invention can also be used to prevent or treat various neurological and/or neuropsychiatric disorders, such as headaches, including migraine, damage to the Central nervous system, sleep disorders, dizziness, pain, stroke (cerebrovascular event), depression, anxiety, addiction, about the scarcity of memory, learning or cognitive function, and to improve memory and cognitive function in humans.

Example 8. Use of derivatives of 1,2-PUFA for the treatment of inflammatory diseases

The cyclooxygenase (SOH) is an enzyme that is associated with the membrane, capturing her some lipids, and catalyzes their conversion into molecules with inflammatory activity. The binding of this enzyme with the membrane lipids partially depends on the structure of membrane lipids. Increased activity of isoforms SOH and SOH associated with etiopathology of a number of inflammatory diseases through the inhibition of arachidonic acid metabolism with the formation of Pro-inflammatory lipid mediators. Derivatives of D-PUFA of the present invention reproduces a series of cell signals that alter the metabolism of arachidonic acid and inhibit the activity and expression of MOR in monocytes in culture (table 14 and figure 5). Also D-PUFA of the present invention inhibited the production of proinflammatory cytokines (TNF-α) in vivo (table 15 and figure 5). For this purpose mice C57BL6/J were treated with various derivatives (at a dose of 200 mg/kg orally) after the induction of the inflammatory response by intraperitoneal introduction of 20 µg of bacterial lipopolysaccharide (LPS). The results of the experiments clearly indicate the effectiveness of D-UFA of the present invention in the prevention or cancellation of inflammatory processes and pathologies.

Table 14 presents data on the expression of MOR-2 in the culture of monocytes. Inhibition of the expression of MOR-2 in monocytes. The inhibition percentage (compared with a positive control in the presence of LPS, 100%) protein MOR-2 (expression) various derivatives of fatty acids.

L
Table 14
182183-1183-2204205226C (LPS)
A242023173123100
B393329283937
F564636414749
676548475369
V817968437685

Table 15 shows the data of the synthesis of TNF-α (%) in mice: the percentage of TNF-α in the serum after intraperitoneal administration of LPS (at a dose of 20 µg) in mice C57BL6/J (100%).

Table 15
182183-1183-2204205226C (LPS)
A647071245673100
B79817826/td> 6983
F869186468091
L858691497688
V818487428485

These results show that the molecules of the present invention may be suitable for the prevention or treatment of inflammatory diseases, including inflammation, inflammation in the cardiovascular system, inflammation caused by tumors, inflammation, rheumatoid nature, inflammation caused by infection, respiratory inflammation, acute and chronic inflammation, hyperalgesia, inflammatory nature, swelling, inflammation, trauma or burns, etc.

Example 9. Use of derivatives of 1,2-PUFA for the ecene metabolic diseases

Lipids are key molecules in the maintenance of metabolic functions. Processing PUFA led to some slight decrease in the concentration of cholesterol and triglycerides in the cells 3T3-L1. However, the processing of the D-PUFA resulted in a high and a significant decrease in cholesterol and triglyceride levels in these cells. In these experiments, the above cells were incubated in medium RPMI 1640 in the presence of 10% fetal bovine serum at 37°C in an atmosphere of 5% CO2and in the presence or absence of 150 μm of various PUFA or D-PUFA. Cells were incubated for 24 h and then lipids were extracted and determined the concentration of cholesterol and triglycerides, following the methods described previously (Folch et al., 1951).

In a separate series of experiments, rats SHR were treated with various compounds of the present invention (at a dose of 200 mg/kg daily for 28 days, oral) and determined the concentration of cholesterol, triglycerides and glucose in serum using colorimetric methods. Observed that these compounds induced significant (and in many cases expressed) reducing the level of these metabolites (table 16).

The results are shown in Fig.6 and table 16 clearly indicate that D-PUFA can be used as pharmaceuticals for treating or preventing metabolic diseases, such is AK hypercholesterolemia, hypertriglyceridemia, diabetes and insulin resistance in humans and animals using the pharmaceutical and nutraceutical compositions. Simultaneous high cholesterol and triglycerides, high concentration of glucose together with cardiovascular changes and/or body weight changes lead to the development of metabolic syndrome, the prevalence of which begins to increase in Western countries. Compounds of the present invention have a high therapeutic potential for the treatment of metabolic syndrome.

Table 16 shows the data on cholesterol, triglycerides and glucose in rats SHR. In the table below: cholesterol (upper figures), triglycerides (average numbers) and glucose (bottom figures) in the serum of rats SHR treated with molecules described above (at a dose of 200 mg/kg daily, orally for 28 days). Values are expressed as percentages, and ratios in untreated (control) rats have always taken for 100%.

Table 16
Connection182183(1)183(2)20420526
A787679726964
918178777471
848782858279
B897577715859
726676696562
878486898781
F9284767167
887187818378
897685848286
L898283837971
937779827874
948592918587
N927289820 75
936985817372
908492828683
V947584848581
937092817984
937988878489

Example 10. Structural basis of therapeutic effects of 1,2-PUFA derivatives

The results of numerous studies have shown that the intake of lipids or processing them leads to changes in the lipid composition of cell membranes. In addition, setawakysyday a direct impact on the lipid structure of the membrane, that, in turn, regulates the transfer of signals associated with the development of many diseases. 7 shows the correlation between changes in the structure of membranes, caused by various D-PUFA (according to the definition of the phase transition temperature HII), and cellular effects observed in this study. For this purpose, the authors determined the average effect of each of the D-PUFA (mean values for each lipid in all studied diseases in relation to the number of double bonds) and build a graph based on the phase transition temperature. Lowering the temperature of the phase transition of HIIindicates a high induction of the integrity of membranes, creating "anchor" sites for proteins peripheral membrane that leads to better regulation of signaling and, consequently, more effective control of some diseases. To a certain extent on the basis of the fact that complex organisms can metabolize drugs and that some additional mechanisms may function in some types (subtypes) of diseases, it can be assumed that some molecules with fewer double bonds may have a higher pharmacological activity. In General, however, it turned out that therapeutic effect depends on the number of double bonds in the molecule, h is about itself associated with the ability to adjust the structure of membranes. In this sense, the presence of radicals in the 1 and/or 2 carbon atoms in the derivative D-PUFA of the present invention, but not in natural PUFA, it is important to improve therapeutic action of these molecules.

The results obtained indicate that the effects of the lipids included in the scope of the present invention, have a common basis. Data correlation values (r2equal of 0.77 and 0.90 for the D-PUFA and P<0.05 in both cases) clearly indicate that the structure of the used lipids is the basis for their actions and that it is manifested through the regulation of the membrane structure caused by the presence of the dependence structure function for each lipid.

Thus, the present invention in the first aspect relates to compounds of formula (I) or their pharmaceutically acceptable derivatives, in which a, b and C independently can have values from 0 to 7, R1and R2can independently represent an ion, atom or group of atoms with a molecular weight of less than 200 Da, for use in the treatment of diseases caused on the basis of structural and/or functional characteristics of the lipids of the cell membrane selected from cancer, cardiovascular diseases, inflammation, metabolic diseases, obesity, neurodegenerative diseases and neurological disorders.

The second aspect of the present invention is applied to the s, at least one of the compounds of formula (I) or its pharmaceutically acceptable derivatives, in which a, b and C independently can have values from 0 to 7, R1and R2can independently represent an ion, atom or group of atoms with a molecular weight of less than 200 Da to obtain the pharmaceutical and/or nutraceutical composition for the treatment of diseases caused on the basis of structural and/or functional changes of lipids in cell membranes selected from cancer, cardiovascular diseases, inflammation, metabolic diseases, obesity, neurodegenerative diseases and neurological disorders.

The last aspect the present invention relates to a method of therapeutic treatment of diseases in humans and animals, the etiology of which is associated with structural and/or functional changes in the lipids located in the cell membranes selected from cancer, cardiovascular diseases, inflammation, metabolic diseases, obesity, neurodegenerative and neurological disorders, which includes an introduction to the patient a therapeutically effective amount of at least one of the compounds of formula (I) or its pharmaceutically acceptable salts or derivatives, in which a, b and C can have independent values from 0 to 7, R1and R2can independently represent ion, and the om or group of atoms with molecular weight, not exceeding 200 Da.

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1. Means for treating or preventing diseases caused on the basis of structural and/or functional and/or compositional changes of lipids in cell membranes selected from cancer, cardiovascular diseases, inflammatory diseases, metabolic diseases, obesity and overweight, neurological or neurodegenerative disorders, which is a compound of formula (I) or its pharmaceutically acceptable salts and derivatives is selected from esters, ethers, alkyl, acyl, phosphate, sulfate, ethyl, methyl or propyl:

in which a and C can have independent values from 0 to 7, b can have independent values from 2 to 7, where R1selected from the following radicals: H, Na, K, CH3O, CH3-CH2O and ORO(O-CH2-CH3)2and R2selected from the following radicals: HE, och3, O-CH3COOH, CH3, Cl, CH2HE, ORO(O-CH2-CH3)2, NOH, F, NAO and N(och2CH3)2.

2. The tool according to claim 1, characterized in that it contains one of the following six combinations of values a, b and C: a=6, b=2 and C=3; a=6, b=3 and C=0; a=3, b=3 and C=3; a=2, b=4 and C=3; a=2, b=5 and C=0 and a=2, b=6 and C=0.

3. The tool according to claim 2, characterized in that when R1represents H, R2selected from: HE, och3or CH2HE; when R1represents Na, R2selected from: HE or CH3; when R1is K, R2is HE; when R1is CH3Oh, then R2selected from: HE, och3, O-CH3COOH, CH3or SOO; when R1is CH3-CH2O, R2selected from: HE, och3, O-CH3COOH, CH3, Cl, CH2HE, ORO(O-CH2-CH3)2, NOH, F, NAO and N(och2CH3)2; and when R1is ORO(O-CH2-CH3)2, what about the R 2HE is.

4. The tool according to claim 3, wherein R1is N, and R2HE is.

5. Applying at least one of the compounds of formula (I)defined in claim 1 or its salts or pharmaceutically acceptable derivatives selected from esters, ethers, alkyl, acyl, phosphate, sulfate, ethyl, methyl or propyl, where a and C can have independent values from 0 to 7, b can have independent values from 2 to 7, where R1selected from the following radicals: H, Na, K, CH3O, CH3-CH2O and ORO(O-CH2-CH3)2and R2selected from the following radicals: HE, och3, O-CH3COOH, CH3, Cl, CH2OH, ORO(O-CH2-CH3)2. NOH, F, NAO and N(och2CH3)2for preparing a pharmaceutical and/or nutraceutical compositions for treating or preventing diseases caused on the basis of structural and/or functional and/or compositional changes of lipids in cell membranes selected from cancer, cardiovascular diseases, inflammatory diseases, metabolic diseases, obesity and overweight, neurodegenerative or neurological disorders.

6. The use according to claim 5, in which the compound of formula (I) characterized in that it contains one of the following six combinations of values a, b and C: a=6, b2 and C=3; a=6, b=3 and C=0; a=3, b=3 and C=3; a=2, b=4 and C=3; a=2, b=5 and C=0 and a=2, b=6 and C=0.

7. The use according to claim 6, characterized in that when R1represents H, R2selected from: HE, och3or CH2OH, when R1represents Na, R2selected from: HE or CH3; when R1is K, R2is HE; when R1is CH3Oh, then R2selected from: HE, och3, O-CH3COOH, CH3or SOO; when R1is CH3-CH2Oh, then R2selected from: HE, och3, O-CH3COOH, CH3, Cl, CH2OH, ORO(O-CH2-CH3)2, NOH, F, NCOO or N(och2CH3)2; and when R1is ORO(O-CH2-CH3)2, R2HE is.

8. The use according to claim 7, wherein R1is N, and R2HE is.

9. Pharmaceutical or nutraceutical composition for the treatment or prevention of diseases caused on the basis of structural and/or functional and/or compositional changes of lipids in cell membranes selected from cancer, cardiovascular diseases, inflammatory diseases, metabolic diseases, obesity and overweight, neurological or neurodegenerative disorders, containing at least one compound of formula (I) defined in claim 1 or its salt, or f is rmaceuticals acceptable derivatives, selected from esters, ethers, alkyl, acyl, phosphate, sulfate, ethyl, methyl or propyl, in which a and C can have independent values from 0 to 7, b can have independent values from 2 to 7, where R1selected from the following radicals: H, Na, K, CH3O, CH3-CH2O and ORO (O-CH2-CH3)2and R2selected from the following radicals: HE, och3, O-CH3COOH, CH3, Cl, CH2HE, ORO(O-CH2-CH3)2, NOH, F, NAO and N(OCH2CH3)2.

10. The composition according to claim 9, in which the compound of formula (I) characterized in that it contains one of the following six combinations of the values of a, b and C: a=6, b=2 and C=3; a=6, b=3 and C=0; a=3, b=3 and C=3; a=2, b=4 and C=3; a=2, b=5 and C=0 and a=2, b=6 and C=0.

11. The composition according to claim 10, characterized in that when R1represents H, R2selected from: HE, och3or CH2OH, when R1represents Na, R2selected from: HE or CH3; when R1is K, R2is HE; when R1is CH3Oh, then R2selected from: HE, och3, O-CH3COOH, CH3or SOO; when R1is CH3-CH2Oh, then R2selected from: HE, och3, O-CH3COOH, CH3, Cl, CH2OH, ORO(O-CH2-CH3)2, NOH, F, NCOO or N(och2CH3)2; and when R1is ORO (OH-sub> 2-CH3)2, R2HE is.

12. The composition according to claim 11, wherein R1is N, and R2is HE.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a new lipid compound of general formula , wherein n=0; R1 and R2 are identical or different, and may be specified in a group of substitutes consisting of a hydrogen atom, a C1-C7alkyl group, a halogen atom and a C1-C7alkoxy group; X represents COR3 or CH2OR4, wherein R3 is specified in a group consisting of hydrogen, hydroxy, C1-C7alkoxy and amino; and R4 is specified in a group consisting of hydrogen, C1-C7alkyl or C1-C7acyl, Y represents C9-C21 alkene with one or more double bonds in E- or Z-configurations with the chain Y being unsubstituted and containing a double bond in the ω-3 position; provided R1 and R2 cannot simultaneously represent a hydrogen atom.

EFFECT: invention refers to pharmaceutical compositions containing the lipid compounds which are used for treating and/or preventing the conditions related to high NFkB functions, treating and/or preventing an inflammatory disease or a condition, lower plasma insulin and/or blood glucose levels, treating insulin resistance, treating and/or preventing peripheral tissue insulin resistance and/or diabetic condition, eg type 2 diabetes mellitus.

45 cl, 1 tbl, 1 dwg, 31 ex

The invention relates to new bicyclic aromatic compounds of General formula (I) having the ability to bind RXRand pharmaceutical compositions based on them, which can be used in medicine, veterinary medicine and in cosmetics

FIELD: chemistry.

SUBSTANCE: maleic acid derivatives having general formula

have metallo-β-lactamase inhibiting activities. It is possible to recover anti-bacterial activities of β-lactam antibiotics against metallo-β-lactamase producing bacteria by combining the compound of general formula (I) with β-lactam antibiotics. The metallo-β-lactamase inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 denotes C2-6-alkyl; C3-7-cycloalkyl, where said cycle can be substituted with a hydroxyl group or can be condensed with an aryl; hydroxymethyl; - C1-3-alkylene phenyl, where said phenyl group can be substituted with a hydroxyl group, C1-6-alkyl group, hydroxymethyl group, a -COOM group, where M denotes a hydrogen atom or a pharmaceutically acceptable cation, a -CO-NR22R23 group, where R22 and R23, which can be identical or different, denote a hydrogen atom or C1-6-alkyl, wherein the alkyl can additionally be substituted with an aminocarbonyl, or R22 and R23, together with a nitrogen atom with which they are bonded, can form a five- or six-member saturated heterocyclic ring containing 1-2 oxygen or nitrogen atoms, and the heterocycle can be substituted with a hydroxyl group or a C1-6-alkanoyloxy group, a -O-R24 group, where R24 denotes C1-6-alkyl, wherein the alkyl is optionally substituted with an aminocarbonyl, an amine group, a guanidine group or a five- or six-member saturated heterocycle, having 1-2 nitrogen atoms, -COOM, where M denotes a hydrogen atom, C1-6-alkyl or a pharmaceutically acceptable cation, or a five- or six-member unsaturated heterocycle, having 1-2 nitrogen atoms; - C0-1 alkylene heterocycle, where said heterocycle is a five- or six-member saturated or unsaturated heterocycle containing one nitrogen or oxygen atom and can be substituted with a hydroxyl group; - O-C1-6-alkyl; or - S-C1-6-alkyl, R2 denotes C1-6-alkyl, C3-7-cycloalkyl, where said cycle can be substituted with a hydroxyl group or can be condensed with an aryl; or - C1-3-alkylene phenyl, each M1 independently denotes a hydrogen atom, a pharmaceutically acceptable cation.

EFFECT: new metallo-β-lactamase inhibitor acts as a medicament for inhibiting inactivation of β-lactam antibiotics and recovering anti-bacterial activities.

18 cl, 3 tbl, 98 ex

FIELD: chemistry.

SUBSTANCE: method of producing a polycarboxylic acid composition involves: (a) oxidation of a multiphase reaction medium containing an oxidisable starting aromatic compound, a solvent and water, in a primary oxidation zone to obtain a starting suspension containing crude terephthalic acid; (b) oxidative combustion of at least a portion of said starting suspension in a combustion zone to obtain a combustion product suspension having one or more of the following characteristics: (i) contains less than 9000 ppm isophthalic acid; (ii) contains less than 15000 ppm benzoic acid, (iii) contains less than 64 ppm 4,4'-dicarboxybiphenyl, (iv) contains less than 70 ppm 2,6-dicarboxyfluorenone, (v) contains less than 12 ppm 2,7-dicarboxyfluorenone, (vi) contains less than 12 ppm 9-fluorenone-2-carboxylic acid, (vii) contains less than 4 ppm 4,4'-dicarboxystilbene, (viii) contains less than 6 ppm 4,4'-dicarboxyanthraquinone; (c) cooling at least a portion of said combustion product suspension in a cooling zone to obtain a cooled suspension containing cooled liquid and solid phases; and (d) using the solvent cleaning system to remove at least one aromatic impurity containing benzoic acid, para-toluic acid, 4-carboxy-benzaldehyde and/or trimellitic acid, present in the solvent cleaning charge, fed into said solvent cleaning system, where said cooled liquid phase of said cooled suspension forms at least 20 wt % of said solvent cleaning charge.

EFFECT: invention discloses systems for more efficient and cheap production of polycarboxylic acid.

112 cl, 30 dwg, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds- unsaturated fatty hydroxy acid of general formula , where Rn=R1=R=H, and 10≤n≤14, except 16-hydroxy-2- hexadecenoic acid and 15-hydroxy-2-pentadecenoic acid; or where Rn=R=H, R1=F, CI or Br, and 5≤n≤14. These unsaturated fatty hydroxy acids are suitable for obtaining an antiradical, anti-inflammatory, antipruritic dermatocosmetological composition and/or for treating disorders associated with keratinisation and pigmentation and/or for accelerating wound healing. The unsaturated fatty hydroxy acids of general formula (I) can also be used to prepare a dermatocosmetological composition for treating psoriasis, itching and/or atopic dermatitis.

EFFECT: high efficiency of using the composition.

11 cl, 2 tbl, 13 ex

FIELD: improved method for oil production.

SUBSTANCE: target oil, enriched in HODE, or esters thereof is obtained by controlled oxidation of linoleic acid and/or linolenic acid or esters thereof in presence of oxidation catalyst. Oxidation is stopped when total HODE or ester content is more than 5 %, and/or content of isomeric 9-hydroxy-10,12-octadecadienic acid (9-HODE) or esters thereof is more than 1,5 %; and hydroperoxides formed in oxidation process are reduced with reducing agent in presence of antioxidant. Invention is also relates to oil enriched in 9-HODE or esters or salts thereof having an lipolytic action; to drug or food additive for obesity treatment; cosmetic for local treatment of cellulite. Compound for controlling of adipocyte lipolytic activity and hydrolysis of triglycerides accumulated in adipocytes is also disclosed.

EFFECT: novel pharmaceutical composition for obesity treatment.

11 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel omega-3 lipid compounds of general formula (I) or to their pharmaceutically acceptable salt, where in formula (I): R1 and R2 are similar or different and can be selected from group of substitutes, consisting of hydrogen atom, hydroxy group, C1-C7alkyl group, halogen atom, C1-C7alkoxy group, C1-C7alkylthio group, C1-C7alkoxycarbonyl group, carboxy group, aminogroup and C1-C7alkylamino group; X represents carboxylic acid or its carbonate, selected from ethylcarboxylate, methylcarboxylate, n-propylcarboxylate, isopropylcarboxylate, n-butylcarboxylate, sec-butylcarboxylate or n-hexylcarboxylate, carboxylic acid in form of triglyceride, diglyceride, 1-monoglyceride or 2-monoglyceride, or carboxamide, selected from primary carboxamide, N-methylcarboxamide, N,N-dimethylcarboxamide, N-ethylcarboxamide or N,N-diethylcarboxamide; and Y stands for C16-C22 alkene with two or more double bonds, which have E- and/or Z-configuration.

EFFECT: described are pharmaceutical and lipid compositions, which contain said compounds, for application as medications, in particular, for treatment and/or prevention of peripheral insulin resistance and/or condition of diabetes, for instance, type 2 diabetes, increased levels of triglycerides and/or levels of non-HDL cholesterol, LDL cholesterol and VLDL cholesterol, hyperlipidemic condition, for instance, hypertriglyceridemia (HTG), obesity or condition of excessive body weight, fatty liver disease, for instance, non-alcoholic fatty liver disease (NAFLD) or inflammatory disease or condition.

60 cl, 3 tbl, 65 ex

FIELD: chemistry, organic.

SUBSTANCE: invention relates to butterfat industry, namely to methods of processing butterfat raw materials in order to obtain mixture of higher fatty acids, used in petrochemical, paint and varnish, food and other branches of industry. Method of obtaining mixture of higher fatty acids is realised by reagentless hydrolysis of oil in presence of free fatty acids, extracted from oil, with further distillation of obtained fatty acids mixture, free fatty acids being introduced in mixture, which is to be split, in form of distillate, obtained during sunflower oil distillation, mixing it with sunflower oil with the following ratio of constituting components in mixture which is being split, wt %: sunflower oil 55-80; distillated, obtained in sunflower oil distillation - 45-20.

EFFECT: reduction of consumption of sunflower oil in formulation without reducing productivity of reagentless hydrolysis process.

1 cl, 2 ex, 2 tbl

FIELD: chemistry, organic, fatty acids.

SUBSTANCE: invention relates to process of obtaining mixture of higher fatty acids that are widely used in chemical, petrochemical, varnish-and-paint, tyre and other industry branches. The process involves isolation of fatty acids from the fat raw material with their subsequent distillation. Fatty acids, at that, will be released from sunflower oil by means of its distillation at the temperature 230-260°C and residual pressure 0.13-0.8 kPa, the distillate thus obtained will be repeatedly subjected to distillation at the temperature 210-220°C and residual pressure 0.67-1.33 kPa. The process enables one to reduce 2.5-5-fold unit discharge of the oil for production of distilled fatty acids, to simplify technology of obtaining distilled fatty acids and improve quality of the distilled fatty acids.

EFFECT: simplification of technology of obtaining and improvement of quality of distilled fatty acids.

2 cl, 2 tbl, 2 ex

FIELD: fat-and-oil industry.

SUBSTANCE: invention provides a method for preparing higher unsaturated fatty acid mixture for use in food processing, varnish-and-paint, and other industries. Method comprises distillation of fat feedstock, in particular sunflower oil, at 230-260°C and pressure 0.12-0.8 KPa to give distillate with acid number 130-160 mg KOH/g and subsequent reagent-free hydrolysis of distillate under autoclaving conditions (217-225°C and 2.0-2.5 MPa) for 3-4 h at fat-to-oil ratio 1:0.5. Method has following advantages: specific consumption of oils to prepare higher unsaturated fatty acid mixture is reduced by a factor 3-5; product preparation technology simplified owing to lesser number of process steps (from 3 to 2); total time of high-temperature action on far feedstock is reduced excepting second period of reagent-free hydrolysis; process is made wasteless because of elimination of bottom residues (goudrons) upon distillation of fatty acid.

EFFECT: enhanced process efficiency.

2 tbl, 2 ex

The invention relates to the field of synthesis of adhesive materials, in particular the technology of production of cobalt salts of polyhydric carboxylic acids, which are widely used in tire, rubber, paint and other industries

The invention relates to a method for producing metal salts of fatty acids, the so-called metal Soaps used as additives for polymer compositions
The invention relates to a method for oleic acid, whereby carry out the hydrogenation of fatty acids of tall oil on the catalyst Ni/kieselguhr at a temperature of 140-160oC and a pressure of 0.5-1.0 MPa for 0.5-1.0 hours

FIELD: chemistry.

SUBSTANCE: invention relates to novel omega-3 lipid compounds of general formula (I) or to their pharmaceutically acceptable salt, where in formula (I): R1 and R2 are similar or different and can be selected from group of substitutes, consisting of hydrogen atom, hydroxy group, C1-C7alkyl group, halogen atom, C1-C7alkoxy group, C1-C7alkylthio group, C1-C7alkoxycarbonyl group, carboxy group, aminogroup and C1-C7alkylamino group; X represents carboxylic acid or its carbonate, selected from ethylcarboxylate, methylcarboxylate, n-propylcarboxylate, isopropylcarboxylate, n-butylcarboxylate, sec-butylcarboxylate or n-hexylcarboxylate, carboxylic acid in form of triglyceride, diglyceride, 1-monoglyceride or 2-monoglyceride, or carboxamide, selected from primary carboxamide, N-methylcarboxamide, N,N-dimethylcarboxamide, N-ethylcarboxamide or N,N-diethylcarboxamide; and Y stands for C16-C22 alkene with two or more double bonds, which have E- and/or Z-configuration.

EFFECT: described are pharmaceutical and lipid compositions, which contain said compounds, for application as medications, in particular, for treatment and/or prevention of peripheral insulin resistance and/or condition of diabetes, for instance, type 2 diabetes, increased levels of triglycerides and/or levels of non-HDL cholesterol, LDL cholesterol and VLDL cholesterol, hyperlipidemic condition, for instance, hypertriglyceridemia (HTG), obesity or condition of excessive body weight, fatty liver disease, for instance, non-alcoholic fatty liver disease (NAFLD) or inflammatory disease or condition.

60 cl, 3 tbl, 65 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing ethylenically unsaturated acids and esters thereof of the following formula: R3-C(=(CH2)m)-COOR4 , where R3 and R4 each independently represent hydrogen or an alkyl group, and m equals 1, by reacting alkanoic acid or an alkanoic acid ester of formula R3-CH2-COOR4, where R3 and R4 each independently represent hydrogen or an alkyl group with a methylene or ethylene source of formula , where R5 and R6 are independently selected from C1-C12 hydrocarbon groups or H; X is O or S; n is an integer from 1 to 100; and m equals 1, in the presence of a catalyst system to an ethylenically unsaturated acid or ester as a product, where the product in form of an acid or ester is then brought into contact with a dienophile to eliminate the undesirable colour of the product, where the dienophile is a compound of formula: where Z is selected from a group consisting of -C(O)Y, -CN, -NO2 or halogen; Y is selected from a group consisting of hydrogen, alkyl, hetero, -OR, halogen or aryl; R, R1 and R2 independently denote hydrogen, alkyl or aryl, and hetero denotes N, S or O. The heteroatoms can be unsubstituted or substituted with one or more groups consisting of hydrogen, alkyl, -OR, aryl, aralkyl or alkaryl, where R is as defined for Y; Z' can denote any group selected above for Z, or can also denote hydrogen, alkyl, aryl or hetero; or Z and Z1 together can form a -C(O)Y(O)C- group so that the dienophile forms a cyclic group of formula , where R1 and R2 are as defined above, Y is hetero as defined above, or Y is an alkylene group of formula -(CH2)s-, where s equals 1, 2 or 3.

EFFECT: obtained products comes into contact with a dienophile to eliminate the undesirable colour of the product.

37 cl, 2 dwg, 10 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds, represented by the following formula (I) and their pharmaceutically acceptable salts, where values for groups R1, R4-R6, Ra, m, n, Y, X are determined in the invention formula. Said compounds are used as preparations for enhancing growth of axons and prevention of diseases associated with histone diacetases, in particular tumours or diseases associated with cell proliferation.

EFFECT: compounds in accordance with the claimed invention can be used as anti-cancer, antidiabetic agents and anti-neurodegenerative agents in case of diseases such as Alzheimer's disease, Huntington's disease, spinocerebral ataxia and spinal muscular atrophy in people.

18 cl, 44 dwg, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a new lipid compound of general formula , wherein n=0; R1 and R2 are identical or different, and may be specified in a group of substitutes consisting of a hydrogen atom, a C1-C7alkyl group, a halogen atom and a C1-C7alkoxy group; X represents COR3 or CH2OR4, wherein R3 is specified in a group consisting of hydrogen, hydroxy, C1-C7alkoxy and amino; and R4 is specified in a group consisting of hydrogen, C1-C7alkyl or C1-C7acyl, Y represents C9-C21 alkene with one or more double bonds in E- or Z-configurations with the chain Y being unsubstituted and containing a double bond in the ω-3 position; provided R1 and R2 cannot simultaneously represent a hydrogen atom.

EFFECT: invention refers to pharmaceutical compositions containing the lipid compounds which are used for treating and/or preventing the conditions related to high NFkB functions, treating and/or preventing an inflammatory disease or a condition, lower plasma insulin and/or blood glucose levels, treating insulin resistance, treating and/or preventing peripheral tissue insulin resistance and/or diabetic condition, eg type 2 diabetes mellitus.

45 cl, 1 tbl, 1 dwg, 31 ex

FIELD: chemistry.

SUBSTANCE: invention relates to derivatives of 3-aminocaprolactam of formula (I): , where X represents -CO-R1 or -SO2-R2, R1 represents alkyl (with the exception of 5-methylheptanyl and 6-methylheptanyl, where radical R1 is bonded to carbonyl in position 1), halogenalkyl, alkoxy (with the exception of tret-butyloxy), alkenyl, alkinyl or alkylamino radical from 4-20 carbon atoms (for example, from 5-20 carbon atoms, 8-20 carbon atoms, 9-20 carbon atoms, 10-18 carbon atoms, 12-18 carbon atoms, 13-18 carbon atoms, 14-18 carbon atoms, 13-17 carbon atoms) and R2 is alkyl radical from 4-20 carbon atoms (for example, from 5-20 carbon atoms, 8-20 carbon atoms, 9-20 carbon atoms, 10-18 carbon atoms, 12-18 carbon atoms, 13-18 carbon atoms, 14-18 carbon atoms, 13-17 carbon atoms); or to its pharmacologically acceptable salt. Invention also relates to application and pharmacological composition, which has anti-inflammatory activity, based on said compounds.

EFFECT: obtaining new compounds and based on them pharmacological composition, which can be applied for obtaining medications for treatment, relief or prevention of inflammatory disease symptoms.

57 cl, 62 ex

FIELD: chemistry.

SUBSTANCE: invention relates to chemistry of derivative transition metal and can be used in chemical industry while producing transition metal carboxylate and refers to improved method of zirconium carboxylate production through interreacting of zirconium chloride with carboxylate derivatives of general formula RCOOM, where R-linear and branched alkyl CnH2n+1 or non-saturated acid residue, where n=0-16, and M - proton or cation of alcali metal, in which alkali acid of aliphatic or non-saturated acids are used as RCOOM compounds, interacting of zirconium chloride with the compounds leads to solvent absence in solid with mechanical activation at mole ratio ZrCl4: RCOOM within 1<m<4.5, where m is integral and broken number with the following extraction of derived zirconium carboxylate with an organic solvent.

EFFECT: duration decrease and efficiency increase of zirconium carboxylate production; elimination of chemically pollutant effluents formation.

5 cl, 1 tbl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to application of compounds with formula R2=R1-X, where R1 and R2 have 23 to 35 carbon atoms in sum, X represents primary alcohol functional group -CH2OH or carboxyl group -COOH, R1 is saturated linear hydrocarbon chain with 9 carbon atoms, and R2 is linear hydrocarbon chain, which is saturated or unsaturated, including 1 to 4 unsaturated double links.

EFFECT: producing formulations suited for application to hypercholesterolemia therapy and prophylaxis.

3 cl, 4 tbl, 6 ex

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

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