USE OF A PHARMACEUTICAL COMPOUND, COMPOSITIONS AND NUTRACEUTICALS

Abstract

Use of polyunsaturated fatty acid derivatives as medicaments or functional foods. The present invention relates to the use of 1,2-fatty acid derivatives in the treatment or prevention of common diseases whose etiology is based on alterations (of any type) of the cell membrane lipids, for example, changes in levels, in the composition or in the structure of these lipids. In addition, for diseases in which the regulation of lipid composition and of the structure of the membranes (or proteins that interact with membranes) causes the reversion of pathological state.

Description

1 / 59 USE OF A PHARMACEUTICAL COMPOUND, COMPOSITIONS AND NUTRACEUTICALS FIELD OF THE INVENTION

[0001] The present invention relates to the use of 1,2-polyunsaturated fatty acid derivatives as medicaments, preferably for the treatment of diseases whose etiology is based on alterations in cell membrane lipids, such as: alterations in the levels, composition or structure of these lipids and the proteins that interact with them, as well as in the treatment of diseases in which the regulation of lipid composition and membrane structure, as well as the proteins that interact with them, results in the reversal of the pathological state.

[0002] Thus, it is likely that the present invention, due to its wide range of applications, will generally be included in the field of medicine or pharmacy. STATE OF THE ART

[0003] Cell membranes are structures that define the organization of cells and the organelles they contain. Most biological processes occur in or around the membranes. Lipids not only have a structural role, but also regulate the activity of important processes. Furthermore, the regulation of membrane lipid composition also influences the location or function of important proteins involved in controlling cell physiology, such as G proteins or PKCs (ESCRIBÁ et al., 1995, 1997, YANG et al., 2005, MARTINEZ et al., 2005). These and Petition 870200060065, dated 05 / 14 / 2020, page 24 / 183 2 / 59 Other studies demonstrate the importance of lipids in controlling important cellular functions. In fact, several human diseases, such as cancer, cardiovascular diseases, neurodegenerative diseases, obesity, metabolic diseases, inflammatory diseases and processes, infectious diseases, or autoimmune diseases, among others, have been associated with alterations in the levels or compositions of lipids in biological membranes, in addition to demonstrating the beneficial effects that treatments with fatty acids can have in reversing these diseases, as well as those of the present invention, which regulates the composition and structure of membrane lipids (ESCRIBÁ, 2006).

[0004] Dietary lipids regulate the lipid composition of cell membranes (ALEMANY et al., 2007). Furthermore, various physiological and pathological situations can alter the lipids in cell membranes (BUDA et al., 1994; ESCRIBÁ, 2006). As an example of a situation that induces physiological changes in membrane lipids, we can mention fish that live in rivers with temperature variations, whose lipids undergo significant changes (changes in the quantities and types of membrane lipids) when the temperature decreases from 20°C (in summer) to 4°C (in winter) (BUDA et al., 1994). These changes allow the maintenance of their functions in cell types of diverse nature. Examples of pathological processes that can influence lipid composition are neurological diseases or diseases caused by drug use (RAPOPORT, 2008). Therefore, it can be said that membrane lipids can Petition 870200060065, dated 05 / 14 / 2020, page 25 / 183 3 / 59 determine the correct activity of multiple cell signaling mechanisms.

[0005] Changes in the composition of membrane lipids affect cell signaling and can lead to the development of diseases or their reversal (ESCRIBÁ, 2006). Various studies in recent years indicate that membrane lipids play a more important role than previously attributed to them (ESCRIBÁ et al., 2008). The classical view of the cell membrane assigns lipids a purely structural role, as a support for membrane proteins, which should be the only functional elements of the membrane. The plasma membrane would have an additional role, allowing water, ions, and other molecules to enter the cells. However, membranes have other functions of great importance for maintaining health, the occurrence of diseases, and healing. Given that the body is diseased because its cells are diseased, alterations in membrane lipids produce alterations in the cells, and this can lead to the occurrence of diseases.Similarly, nutraceutical and cosmetic interventions aimed at regulating membrane lipid levels can prevent and reverse (cure) pathological processes. Furthermore, several studies indicate that the consumption of saturated and trans-monounsaturated fats is related to health deterioration. In addition to the neurological diseases described above, vascular diseases, cancer, and others may also be directly associated with membrane lipids (STENDER AND DYERBERG, 2004). The deterioration of an organism manifests itself in the appearance of these or other types of... Petition 870200060065, dated 05 / 14 / 2020, page 26 / 183 4 / 59 diseases, which may include metabolic diseases, inflammation, neurodegeneration, etc.

[0006] Cell membranes are the selective barrier through which a cell receives metabolites and information from other cells and the surrounding extracellular environment. However, membranes perform other very important functions in cells. On the one hand, they support proteins involved in receiving or initiating messages that control important organic functions. These messages, which are mediated by many hormones, neurotransmitters, cytokines, growth factors, etc., activate membrane proteins (receptors), which propagate the received signal within the cell through other proteins (peripheral membrane proteins), some of which are also located in the membrane. Given that (1) these systems work as amplification cascades and (2) membrane lipids can regulate the location and activity of these peripheral proteins, the lipid composition of membranes may have a major impact on cell physiology.In particular, the interaction of certain 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). Furthermore, the lipid composition of cell membranes is influenced by the type and quantity of dietary lipids (ESCRIBÁ et al., 2003). In fact, nutraceutical or pharmaceutical lipid interventions can regulate the lipid composition of membranes, which, in turn, can control the interaction (and therefore the activities) of... Petition 870200060065, dated 05 / 14 / 2020, page 27 / 183 5 / 59 important cell signaling proteins (YANG et al., 2005).

[0007] The fact that membrane lipids are able to control cell signaling may also suggest that they are able to regulate the physiological status of cells and therefore the overall state of health. In fact, both the negative and positive effects of lipids on health have been described (ESCRIBÁ et al., 2006; ESCRIBÁ et al., (2008). Preliminary studies demonstrate that 2-hydroxyoleic acid, a monounsaturated fatty acid, is capable of reversing certain pathological processes, such as overweight, hypertension, or cancer (ALEMANY et al., 2004; MARTINEZ et al., 2005; VOGLER et al., 2008).

[0008] Cardiovascular diseases are frequently associated with the excessive proliferation of cells that constitute the heart and vascular tissues. This hyperproliferation results in cardiovascular deposits in the innermost lumen of vessels and cavities of the cardiovascular system, resulting in a wide range of diseases, such as hypertension, atherosclerosis, ischemia, aneurysm, stroke, infarction, angina, stroke (cerebrovascular accidents), etc. (SCHWARTZ et al., 1986). In fact, it has been suggested that the development of drugs that prevent cell proliferation would be a good alternative for the prevention and treatment of cardiovascular diseases (JACKSON AND SCHWARTZ, 1992).

[0009] Obesity is caused by an altered balance between energy intake and expenditure, in part due to changes Petition 870200060065, dated 05 / 14 / 2020, page 28 / 183 6 / 59 in the mechanisms that regulate these processes. On the other hand, this condition is characterized by hyperplasia (increase in the number of cells) or hypertrophy (increase in the size) of fat cells, adipocytes. Several studies show that fatty acids, both free and those that are part of other molecules, can influence several parameters related to energy homeostasis, such as body fat mass, lipid metabolism, thermogenesis, and food intake, among others (VOGLER et al., 2008). In this sense, fatty acid modification could be a strategy to regulate energy homeostasis, that is, the balance between energy intake and expenditure, and therefore, related processes such as appetite or body weight.

[0010] Neurodegenerative processes lead to various diseases with different manifestations, but with the common characteristic of being caused by degeneration or dysfunction of cells in the central and / or peripheral nervous system. Some of these neurodegenerative processes involve a significant reduction in patients' cognitive abilities or alterations in their motor skills. Neurodegenerative, neurological, and neuropsychiatric disorders have a common basis of neuronal degeneration or alteration of their components, such as lipids (e.g., myelin) or membrane proteins (e.g., adrenergic, serotonergic receptors, etc.). Such diseases of the central nervous system include, among others, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, hippocampal sclerosis and other types of epilepsy, focal sclerosis, adrenoleukodystrophy and other leukodystrophies, dementia. Petition 870200060065, dated 05 / 14 / 2020, page 29 / 183 7 / 59 vascular, senile dementia, headaches including migraine, central nervous system trauma, sleep disorders, dizziness, pain, stroke (cerebrovascular accident), depression, anxiety, or others. In addition, certain neurological and neurodegenerative diseases can lead to processes that culminate in blindness, hearing problems, disorientation, mood changes, etc.

[0011] A well-characterized example of a neurodegenerative disorder is Alzheimer's disease, characterized by the formation of senile plaques, composed of membrane protein fragments (e.g., D-amyloid peptide) originating from incorrect peptide processing, followed by accumulation on the outer side of cells, and neurofibrillary tangles of Tau protein. These processes are associated with alterations in cholesterol metabolism and the consequent alteration of the levels of certain membrane lipids, such as cholesterol and docosahexaenoic acid (SAGIN AND SOZMEN, 2008; RAPOPORT, 2008). In addition, several neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, and senile dementia (or Lewy bodies), are associated with the pathological accumulation of fibrillar aggregates of the synuclein protein, which lead to a significant alteration in the cellular metabolism of triglycerides (COLES et al., 2001).In fact, the development of these or other neurodegenerative diseases is associated with alterations in serum or cellular lipids, such as cholesterol, triglycerides, sphingomyelin, phosphatidylethanolamine, etc. This again suggests that lipids play a crucial role in the proper activity of neurons, nerves, brain, cerebellum, and so on. Petition 870200060065, dated 05 / 14 / 2020, page 30 / 183 8 / 59 spinal cord, which is logical given the abundance of lipids in the central nervous system. The molecules of this invention have a high or very high potential to reverse many of the processes associated with neurological, neurodegenerative, and neuropsychiatric disorders.

[0012] Furthermore, distinct types of sclerosis and other neurodegenerative diseases related to demyelination, whose net result is the loss of lipids in the covering of neuronal axons, lead to changes in the process of electrical signal propagation that it involves. Myelin is a layer of fat that surrounds the axons of many neurons and is formed by a series of spiral folds of the plasma membrane of glial cells (Schwann cells). Therefore, it is clear that lipids play an important role in the development of neurodegenerative diseases. In addition, unmodified natural PUFAs have been found to have a moderate preventive effect on the development of neurodegenerative processes (LANE and FARLOW, 2005). In fact, the most important lipid in the central nervous system is docosahexaenoic acid, a natural PUFA whose abundance is altered in many neurodegenerative processes.

[0013] Metabolic diseases form a group of diseases characterized by the accumulation or deficiency of certain molecules. A typical example is the accumulation of glucose, cholesterol, and / or triglycerides above normal levels. 1 Polyunsaturated fatty acids. Petition 870200060065, dated 05 / 14 / 2020, page 31 / 183 9 / 59 Elevated levels of glucose, cholesterol, and / or triglycerides, both at the systemic level (e.g., elevated plasma levels) and at the cellular level (e.g., in cell membranes), are associated with alterations in cell signaling, leading to dysfunction at different levels, and are generally related to errors in the activity of certain enzymes or to inadequate control of such proteins. Among the most important metabolic diseases are hypercholesterolemia (high cholesterol) and hypertriglyceridemia (high triglycerides). These diseases have higher rates of incidence, morbidity, and mortality, so their treatment is a primary necessity. Other important metabolic diseases include diabetes and insulin resistance, characterized by problems in controlling glucose levels. These metabolic diseases are involved in the occurrence of other diseases, such as cancer, hypertension, obesity, atherosclerosis, etc.Recently, another disease process closely related to the metabolic disorders described above has been defined, and which could constitute a new type of metabolopathy in itself – metabolic syndrome.

[0014] The protective role of certain polyunsaturated fatty acids (PUFAs) in certain diseases has been described by different researchers. For example, PUFAs slow the development of cancer and have positive effects against the development of cardiovascular disease, neurodegenerative diseases, metabolic disorders, obesity, inflammation, etc. (TROMBETTA et al., 2007, JUNG et al., 2008, FLORENT et al., 2006). These stimuli indicate the important role of lipids (PUFAs) in the etiology of various diseases. Petition 870200060065, dated 05 / 14 / 2020, page 32 / 183 10 / 59 diseases as well as their treatment. However, the pharmacological activity of these compounds (PUFAs) is quite limited due to rapid metabolism and short half-life in the blood. Therefore, it seems necessary to develop PUFAs with a slower metabolism, resulting in an increased presence in the cell membrane compared to PUFAs used until now, facilitating the interaction of peripheral cell signaling proteins. The molecules of this invention are synthetic derivatives of PUFAs, possess a slower metabolism and a marked and significantly superior therapeutic effect compared to natural PUFAs.

[0015] Due to the relationship between structural and functional alterations of lipids located in the cell membrane with the development of various diseases of different typologies, but with an etiology unitarily related to the structural and / or functional alteration of lipids in cell membranes, such as cancer, cardiovascular disease, obesity, inflammation, neurodegenerative and metabolic diseases, the present invention focuses on the use of new synthetic polyunsaturated fatty acids capable of solving the technical problems associated with the known fatty acids mentioned above and, therefore, useful for the effective treatment of these diseases. DESCRIPTION OF THE INVENTION Brief description of the invention

[0016] This invention focuses on 1,2-derivatives of polyunsaturated fatty acids (hereinafter: D-PUFAs) for use in the treatment of common diseases whose etiology is related to alterations Petition 870200060065, dated 05 / 14 / 2020, page 33 / 183 11 / 59 structural and / or functional modifications of cell membrane lipids or proteins that interact with them, specifically selected from: cancer, vascular diseases, neurodegenerative and neurological disorders, metabolic diseases, inflammatory diseases, obesity, and overweight. D-PUFAs have a lower metabolic rate than natural polyunsaturated fatty acids (hereinafter: PUFAs) because the presence of atoms other than hydrogen (H) on carbons 1 and / or 2 blocks their degradation via β-oxidation. This causes significant changes in membrane composition, regulating the interaction of peripheral cell signaling proteins. This should lead to, for example, differences in membrane surface packaging, modulating the anchoring of peripheral proteins involved in the propagation of cellular messages.Thus, the DPUFA molecules that are the subject of this invention possess a much greater activity than PUFAs, showing a substantially greater effect for the pharmacological treatment of the identified diseases.

[0017] As mentioned above, the diseases treated with the D-PUFA molecules of the invention share the same etiology, which is related to structural and / or functional alterations (or of any other origin) of the lipids of the cell membrane or the proteins that interact with them. The following diseases are listed as examples: • Cancer: liver cancer, breast cancer, leukemia, brain cancer, lung cancer, etc. Petition 870200060065, dated 05 / 14 / 2020, page 34 / 183 12 / 59 • Vascular diseases: atherosclerosis, ischemia, aneurysm, stroke, cardiomyopathy, angiogenesis, cardiac hyperplasia, hypertension, infarction, angina, stroke (cerebrovascular accident), etc. • Obesity, overweight, appetite control, and cellulite. • Metabolic diseases: hypercholesterolemia, hypertriglyceridemia, diabetes, insulin resistance, etc. • Neurodegenerative diseases, neurological and neuropsychiatric disorders: Alzheimer's disease, vascular dementia, Zellweger syndrome, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, hippocampal sclerosis and other types of epilepsy, focal sclerosis, adrenoleukodystrophy and other types of leukodystrophies, vascular dementia, senile dementia, Lewy body dementia, multiple system atrophy, prion diseases, headaches, including migraine, central nervous system injury, sleep disorders, vertigo, pain, stroke (cerebrovascular accidents), depression, anxiety, addictions, memory, learning or cognitive problems and diseases in general that require interruption of neurodegeneration or neuroregeneration induced by treatment with the compounds of the invention. • Inflammatory diseases, including inflammation, cardiovascular inflammation, inflammation-induced tumor, inflammation of rheumatoid origin, inflammation of infectious origin, respiratory inflammation, acute or chronic inflammation, hyperalgesia of inflammatory nature, edema, inflammation resulting from trauma or burns, etc. Petition 870200060065, dated 05 / 14 / 2020, page 35 / 183 13 / 59

[0018] The D-PUFA compounds of the present invention are characterized by the following formula (I): COO Ri-CH R2 - (CH2) a - (CH=CH-CH2) b - (CH2) c-CH3 (I) where a, b and c can have independent values ​​between 0 and 7, and Ri and R2 can be an ion, an atom or a group of atoms with a molecular weight that, independently, does not exceed 200 Da.

[0019] In a preferred embodiment of the invention, a, b and c can have independent values ​​between 0 and 7, Ri is H and R2 is OH.

[0020] In another preferred embodiment of the invention, a, b and c may have independent values ​​between 0 and 7, Ri is Na and R2 is OH.

[0021] In another preferred embodiment of the invention, aec may have independent values ​​between 0 and 7, b may have independent values ​​between 2 and 7, and Ri and R2 may be an ion, an atom or a group of atoms whose molecular weight is independently equal to or less than 200 Da.

[0022] The administration of the fatty acids of the invention can be carried out by any means, for example, by enteral (IP), oral, rectal, topical, inhalation or intravenous, intramuscular or subcutaneous injection. In addition, administration should be either according to the above formula or in any pharmaceutically acceptable derivative thereof, such as: esters, ethers, alkyl, acyl, phosphate, sulfate, ethyl, methyl, propyl, salts, complexes, etc. Petition 870200060065, dated 05 / 14 / 2020, p. 36 / 183 14 / 59

[0023] Furthermore, the fatty acids of the invention can be administered alone or formulated in pharmaceutical or nutraceutical compositions that combine with each other and / or with excipients, such as: binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavoring excipients, coloring excipients, carriers, etc., and combinations thereof. In addition, the fatty acids of the invention can be part of pharmaceutical or nutraceutical compositions in combination with other active ingredients.

[0024] For the purposes of the present invention, the term nutraceutical is defined as a compound ingested regularly during meals and in actions to prevent diseases, in this case, with an etiology linked to alterations in cell membrane lipids.

[0025] For the purposes of the present invention, the term therapeutically effective amount is that which reverses or prevents the disease without producing adverse side effects. BRIEF DESCRIPTION OF THE FIGURES

[0026] Figure 1: The effect of the compounds in Table 1 on the growth of tumor cells. The y-axis represents the number of viable cells (% control) depending on the compound used (x-axis). Human lung cancer cells (A549) were cultured in RPMI-1640 with 10% serum for 48 hours in the absence (control) or presence of 250 μM of the compounds of the invention. The graph represents the number of viable cells (mean and standard error of the mean of three Petition 870200060065, dated 05 / 14 / 2020, page 37 / 183 15 / 59 experiments). The dotted line represents the total elimination of cells (0% viability).

[0027] Figure 2: The effect of certain PUFAs and DPUFA molecules of the present invention on the proliferation of A10 vascular cells. The y-axis represents the number of cells (% control) depending on the fatty acid used (horizontal axis). Cells were incubated in complete medium (control, C), incomplete medium without supplementation (CSS), or complete medium in the presence of PUFAs (182, 183A, 183G, 204, 205, and 226) or D-PUFAs (182A1, 183A1, 183A2, 204A1, 205A1, and 226A1). The reduction in proliferation, but still above the CSS values, indicates that these molecules have the ability to regulate the abnormal proliferation of cardiovascular cells without being toxic.

[0028] Figure 3: A. Proliferation of adipocytes cultured in the absence (control, C) or presence of different D-PUFAs and PUFAs. The y-axis represents the number of cells (% control) depending on the fatty acid used (x-axis). As a non-proliferation control, a deficient serum medium (medium with a low percentage of serum, MSB) was used. B. The y-axis represents body weight (% of untreated control), and the horizontal axis represents the compounds used in the treatment of experimental animals. The x-axis, from left to right, shows first the treatment with carrier (C) and then the treatment with several of the compounds of the invention. SHR rats were treated for one month with Petition 870200060065, dated 05 / 14 / 2020, page 38 / 183 16 / 59 200 mg / kg of each of the 24 compounds shown in the figure. Each experimental group consisted of six animals, and for each series, one group of animals treated with a carrier (water) was used, and the results were compared with the weight of the animals that did not receive any treatment. The letters A, B, N, and P indicate the combination of the Ri and R2 radicals according to Table 3.

[0029] Figure 4: A. Death of cultured P19 cells in the absence of external factors (control, C: 0% neuronal death) and in the presence of NMDA (100% neuronal death). The vertical axis represents neuronal death (% control) depending on the fatty acid used (x-axis). The presence of PUFAs induced modest increases in P19 cell survival in the presence of NMDA. D-PUFAs induced significant increases in cell survival values, exceeding by more than 200% in the case of 22 6A1. Since the number of cells in the treated cell cultures is higher than in the control cells, it can be stated that these compounds not only prevent NMDA-induced neuronal death (anti-neurodegenerative), but are also neuroregenerative agents. B. The effect of PUFA D-226B1 on improving performance in radial maze exercise in an animal model of Alzheimer's disease. The y-axis in the left figure shows the time taken to complete the exercise, and the vertical y-axis in the right figure shows the total number of errors made. Petition 870200060065, dated 05 / 14 / 2020, p. 39 / 183 17 / 59 implementation of the programmed exercise (mean ± standard error of the mean) (elapsed time). In both figures, from left to right, the results in healthy rats (control) (first column), in rats with induced Alzheimer's disease treated with water as a carrier (second column), or in rats treated with compound 226B1 (third column) are represented on the x-axis. Animals with Alzheimer's disease took longer and made more errors than healthy rats, with the differences being statistically significant (*, P < 0.05). In contrast, rats with Alzheimer's disease treated with compound 226BI did not show significant differences compared to healthy animals.

[0030] Figure 5: A. The upper panel is an immunoblot showing the inhibition of the expression of the pro-inflammatory protein COX-2, previously induced by bacterial lipopolysaccharide (LPS) (C+, 100%) in human U937 monocyte-derived macrophages by a different D-PUFA of the present invention. In the lower panel, the COX-2 / COX-1 ratio in % control (y-axis) is shown for the following compounds (x-axis): OOA (2-hydroxyoleic acid), OLA (182A1), OALA (183A1), OGLA (183A2), OARA (204A1), OEPA (205A1), ODHA (226A1). B. This shows the anti-inflammatory efficacy of different D-PUFA compounds of the present invention in an animal model of inflammation. This shows the inhibitory effect on LPS-induced serum TNFα (pg / ml) levels in rats (y-axis) for different compounds of the invention (x-axis). The reduction Petition 870200060065, dated 05 / 14 / 2020, page 40 / 183 18 / 59 of this factor is directly related to anti-inflammatory medication. The compounds are the same as in the left panel.

[0031] Figure 6: Cholesterol (A) and total triglyceride (B) levels in 3T3-L1 cells. The vertical axis shows cholesterol (A) or triglyceride (B) levels (% of total lipids) depending on the fatty acid used (x-axis). The values ​​presented are the mean ± standard error of the mean of cholesterol and triglycerides compared to total lipids in the cell membrane, measured by spectrophotometric methods (cholesterol) or by thin-layer chromatography followed by gas chromatography (triglycerides). The graphs show the quantified values ​​in cells cultured in the absence (Control) or presence of the D-PUFAs or PUFAs listed above.

[0032] Figure 7: A. Relationship between membrane structure and cellular effects induced by D-PUFAs. This represents, on the ordinate axis, the cellular effects (% control) compared to the Hn transition temperature (x-axis). The average effect of each D-PUFA molecule was determined (average effect of each lipid in all disease models studied and the number of double bonds) and is plotted against the transition temperature. A reduction in the Hn transition temperature indicates a greater induction of membrane discontinuities, resulting in the presence of membrane anchoring sites for peripheral proteins and leading to better Petition 870200060065, dated 05 / 14 / 2020, page 41 / 183 19 / 59 regulation of cell signaling and, therefore, is more effective for controlling certain diseases. B. Relationship between the therapeutic efficacy of PUFAs (empty circles) and D-PUFAs (solid circles). Each point is the average of the observed effect for all diseases studied (Y-axis: changes with respect to the % control) depending on the number of double bonds presented by each molecule (horizontal axis). In both cases, the correlations were significant (P <0.05). It was observed that the therapeutic effect depends on the number of double bonds the molecule possesses, which, in turn, is related to the ability to regulate the membrane structure. In this sense, the presence of a radical on carbons 1 and 2, present in D-PUFAs but not in PUFAs, is essential to increase the therapeutic effect of these molecules.

[0033] These results indicate that the effects of the lipids contained in the present invention have a common basis. These correlations (with r2 values ​​of 0.77 and 0.9 for D-PUFAs, and P <0.05 in both cases) clearly indicate that the structure of the lipids used is the basis of their effect and that this occurs through the regulation of membrane structure, caused by the relationship between structure and function of each lipid. In fact, there is a number of research papers in which human diseases are associated with the alterations described above in PUFA levels, demonstrating the important role of lipids in cellular physiology. DETAILED DESCRIPTION OF THE INVENTION Petition 870200060065, dated 05 / 14 / 2020, page 42 / 183 20 / 59

[0034] The wide spectrum of therapeutic applications offered by the D-PUFA molecules of the present invention leads to the broad assumption that these D-PUFA molecules confer specific structural properties to membranes that allow for the proper processing of activity carried out in and through these membranes. In other words, many of the anomalies that give rise to different types of diseases are caused by significant variations in the levels of certain lipids important for cell function and / or proteins that interact with the membrane and / or are related to lipid production.These pathological changes that can lead to different types of diseases can be prevented or reversed by the synthetic fatty acids described in the present invention, which can be effectively used to treat or prevent any disease whose etiology is related to changes in the levels, composition, structure, or any other alteration of the lipids of the biological membrane, or to a dysregulation of cell signaling as a result of these changes in the lipids of the biological membranes. Furthermore, the lipids contained in the present invention can also be used as medicines when a disease occurs as a result of another change, provided that the result of the modulation of the properties and / or functions of the membrane is capable of reversing the pathological process.

[0035] For this study of the therapeutic effects of the fatty acids of this invention, cultured cell lines and animal models of various diseases were used, and the activity of D-PUFAs and PUFAs to treat different diseases was investigated. Petition 870200060065, dated 05 / 14 / 2020, p. 43 / 183 21 / 59

[0036] The molecular structure of the invention is shown in Tables 1, 2 and 3. Given Formula I, the compounds of the present invention preferably exhibit combinations of the values ​​of a, b and c in Table 1.

[0037] Furthermore, in the invention, the compounds are named with a three-digit number followed by the symbol XI or X2. The number 1 represents all the D-PUFAs used, except the C18:3ω-6 based series (γ-linolenic acid), which appears under the number 2. The first two digits of this number represent the number of carbons in the molecule. The third digit of this number represents the number of double bonds. The letter X is replaced by any letter from A to W (Table 3); these letters from A to W are to represent the specific combination of R1 and R2 of Formula I.

[0038] Thus, the principally preferred compounds of this invention are identified by abbreviations: 182X1, 183X1, 183X2, 204X1, 205X1, 226X1, and should be interpreted in accordance with the instructions above. Table 1 D-PUFA abc Series 182X1623 Series 183X1630 Series 183X2333 Petition 870200060065, dated 05 / 14 / 2020, p. 44 / 183 22 / 59 Series 204X1 2 4 3 Series 205X1 2 5 0 Series 226X1 1 6 0

[0039] Table 2 shows the structures of some of the D-PUFA molecules of the invention and the PUFAs from which they are derived. As can be seen, the table illustrates some compounds of the invention with different combinations of values ​​of a, b, c, and where the radicals Ri and R2 are labeled with the letter A, which means, as described above, that Ri is H and R2 is OH (see Table 3). Table 2 Molecule name Structure Prop. Abbrev. 2-hydroxy- acid COOH-CHOH- (CH2) 6- (CH=CH- 9, 12octadecadienoic CH2) 2- (CH2) 3-CH3 s, OH 182A1 2-Hydroxy acid- 9,12,15- COOH-CHOH- (ch2: 1 6-(CH=CH- s, OH 18 3A1 CH2) 3-CH3 octadecatrienoic 2-hydroxyCOOH-CHOH-(CH2)3-(CH=CH6,9,12- S, OH 183A2 octadecatrienoic CH2) 3- (CH2) 3-CH3 Petition 870200060065, dated 05 / 14 / 2020, page 45 / 183 23 / 59 2-hydroxy5,8,11,14eicosatetraenoic acid COOH-CHOH- (CH2) 2- (CH=CHCH2) 4- (CH2) 3-CH3 S, OH 2 04A1 2-Hydroxy- 5,8,11,14,17eicosapentaenoic acid COOH-CHOH-(CH2)2-(CH=CH- CH2) 5-CH3 S, OH 2 05A1 2-Hydroxy- 4,7,10,13,16,19- docosahexaenoic acid COOH-CHOH-CH2-(CH=CH-CH2) 6- CH3 S, OH 22 6A1 9,12octadecadienoic acid COOH- (CH2) 7-(CH=CH-CH2) 2- (CH2)3-CH3 N 182 9,12,15- octadecadienoic acid COOH- (CH2) 7- (CH=CH-CH2) 3-CH3 N 183A Acid 6,9,12octadecatrienoic COOH-(CH2)4-(CH=CH-CH2)3- (CH2)3-CH3 N 183G 5,8,11,14- eicosatetraenoic acid COOH-(CH2)3-(CH=CH-CH2)4- (CH2)3-CH3 N 204 5,8,11,14,17- eicosapentaenoic acid COOH-(CH2)3-(CH=CH-CH2)5-CH3 N 205 Acid 4,7,10,13,16,19- COOH-(CH2)2-(CH=CH-CH2)6-CH3 N 226 docosahexaenoic acid Prop: property. S: synthetic. N: natural. OH: hydroxylated at carbon 2 (α-carbon). Petition 870200060065, dated 05 / 14 / 2020, page 46 / 183 24 / 59

[0040] Table 3 shows the different combinations of radicals Ri and R2 that can be combined with the values ​​of a, b and c listed in Table 1. Table 3 Ri H Na K CH3O CH3-CH2O OPO (O-CH2-CH3) 2

[0041] R2 OH ABCDEF OCH3 GHI O-CH3COOH JK ch3 LMN Cl 0 CH2OH PQ OPO (O-CH2-CH3) 2 R NOH SFT HCOO UVN (OCH2CH3) 2 W Petition 870200060065, dated 05 / 14 / 2020, p. 47 / 183 25 / 59

[0042] These results indicate that the effects of lipids contained in the present invention have a common basis. These correlations (with r2 values ​​of 0.77 and 0.9 for D-PUFAs, and P <0.05 in both cases) clearly indicate that the structure of the lipids used is the basis of their effect and that this occurs through the regulation of membrane structure, caused by the relationship between structure and function of each lipid. In fact, there is a number of research papers in which human diseases are associated with the alterations described above in PUFA levels, demonstrating the important role of lipids in cellular physiology. EXAMPLES Example 1: Percentage of total PUFAs in the membranes of cells treated with D-PUFAs and PUFAs

[0043] Synthetic D-PUFA molecules are hydrophobic, and therefore, cells exposed to these D-PUFAs have high levels of these fatty acids on their surfaces.

[0044] Table 4 shows the total percentage of PUFAs in the membranes of 3T3 cells treated with 100 μM of these fatty acids for 48 hours. To perform these experiments, the membranes were extracted, and total fatty acids were obtained by hydrolysis in a basic medium. The methanolic bases of these fatty acids were quantified by gas chromatography. The data presented are averages of four independent measurements of PUFA mass divided by the total fatty acids and expressed as a percentage. The standard error of the mean is also presented. In cell cultures, 3T3 cells Petition 870200060065, dated 05 / 14 / 2020, page 48 / 183 26 / 59 incubated in the presence of these fatty acids showed higher levels of PUFAs (including D-PUFAs) and lower levels of saturated fatty acids.

[0045] The control corresponds to a culture without the presence of natural aggregates or synthetic fatty acids. Cells in their natural form have PUFAs in their membranes, but the presence of the D-PUFA molecules of the invention increases these levels of PUFAs in the cell membrane. Therefore, these results suggest that nutraceutical or pharmaceutical interventions with these compounds of the present invention can effectively regulate the composition of cell membranes. Table 4 Aggregate Lipid Total PUFA Percentage None (Control) 32.4 ±2.1 182A1 42.3 ±3.1 18 3A1 42.8 ±2.2 18 3A2 44.0 ±2.6 2 04A1 45.5 ±2.9 2 05A1 46.7 ±3.4 22 6A1 48.9 ±3.7 Petition 870200060065, dated 05 / 14 / 2020, page 49 / 183 27 / 59 Example 2: L (lamellar) to Hu (hexagonal) transition in DEPE (diethylidoyl phosphatidylethanolamine) cell membranes

[0046] Tables 5 and 6 show the lamellar-to-hexagonal transition temperature (Hπ) in DEPE model membranes. The transition temperature was determined by differential scanning calorimetry. The DEPE:D-PUFA ratio was 10:1 (mol:mol) in all cases. The lamellar-to-hexagonal transition is an important parameter that reflects the relevant signaling properties of cell membranes. The propensity to form Hn phases, which is greater as the temperature of this transition decreases, indicates that the membrane surface pressure is lower, meaning that the polar heads of the phospholipids form a less dense or compact network than those formed by lamellar structures (ESCRIBÁ et al., 2008).When this occurs, certain peripheral membrane proteins (such as G proteins, protein kinase C, or Ras protein) can more easily bind to the membrane, while others have a poor interaction (e.g., Ga protein). Therefore, changes in the Hn transition temperature are important in regulating cellular functions related to human health and therapy (ESCRIBA et al., 1995; VOGLER et al., 2004; ESCRIBA, 2006).

[0047] Control values ​​correspond to model membranes in the absence of fatty acids. The reduction in the Hn transition temperature obtained using the D-PUFA of the invention indicates an increase in the induction of discontinuities in the membrane, generating anchoring sites in the membrane for peripheral proteins and Petition 870200060065, dated 05 / 14 / 2020, page 50 / 183 28 / 59 leading to better regulation of cell signaling and therefore greater effectiveness in controlling certain diseases.

[0048] Thus, Table 5 shows the transition temperature Th (hexagonal lamellar to Hn) in DEPE membranes (4mM) in the presence or absence of 200μM of various compounds of the present invention from the A series. Table 5 Aggregate lipid Transition temperature None (Control) 64.5 182A1 51.8 18 3A1 51.6 18 3A2 50.1 2 04A1 49.3 2 05A1 47.9 22 6A1 44.4

[0049] Table 6 shows the lamellar-to-hexagonal transition temperature in DEPE membranes in the presence of D-PUFAs from various series. Petition 870200060065, dated 05 / 14 / 2020, page 51 / 183 29 / 59 Table 6 182 183-1 183-2 204 205 226 B 52.1 51.9 51.0 50.2 48.3 45, 1 D 51.0 51.1 49, 4 48.7 47.5 43. 9 E 50, 6 49, 8 49, 3 48.4 46.7 42.9 G 51.0 50.3 50, 1 49, 6 47.3 44, 1 O 51.7 51.2 51.3 49, 7 48, 6 44.2 R 52.2 51.8 49, 9 50, 0 48.4 44.7 Example 3: Binding of the Gii protein (trimer) to a model cell membrane.

[0050] Regulation of membrane lipid composition resulted in changes in membrane structure, as measured by differential scanning calorimetry, which causes variations in the localization of G proteins in the model cell membrane, as shown in Table 7. The net result is a regulation of cell signaling leading to the reversal of several pathological processes, as shown later. Table 7 shows the binding of heterotrimeric Gii protein to model phosphatidylcholine:phosphatidylethanolamine (6:4, mol:mol) membranes, measured by centrifuge analysis, followed by immunoblotting, chemiluminescence visualization, and quantified by image analysis. For these experiments, Petition 870200060065, dated 05 / 14 / 2020, page 52 / 183 30 / 59 were used 2mM of phospholipids and 0.1μM of the different DPUFAs indicated in Table 7. The control is a sample of model membranes in the absence of fatty acids.

[0051] These results indicate that the induced modification in the structural and functional properties of the membrane increases as the number of unsaturations increases. Both the presence of unsaturations and changes in carbons 1 and 2 reduce the rate of PUFA metabolism. This fact, in relation to the special effect of these lipids on membrane structure, indicates that the action on abnormal cells shares a common origin.

[0052] In fact, there was a good correlation between the pharmacological effects and the effects they have on the structure of the lipid membrane. Table 7 Lipid aggregate G protein binding None (Control) 100 ± 5 182A1 312 ± 12 18 3A1 328 ± 9 183A2 17 ± 357 204A1 385 ± 22 Petition 870200060065, dated 05 / 14 / 2020, page 53 / 183 31 / 59 05A1 6A1 406 ± 14 422 ± 26 Example 4: Use of 1,2-PUFA derivatives for cancer treatment.

[0053] Cancer is a disease characterized by the uncontrolled proliferation of transformed cells. As indicated above, in addition to some genetic alterations, cancer is characterized by the presence of altered levels of membrane lipids that can influence cell signaling. In this sense, natural PUFAs showed some efficacy against the development of human cancer cells (A549) at the concentrations used in this study, although their metabolic use likely prevented greater efficacy (Figure 1). However, D-PUFAs showed marked and significantly greater efficacy than unmodified molecules at carbons 1 and 2 (Figure 1 and Table 8) at the same concentrations.These results indicate that changes in natural polyunsaturated fatty acids result in molecules with strong antitumor potency, significantly greater than that of natural PUFAs, and therefore have great utility in the treatment and prevention of tumor diseases through pharmaceutical and nutraceutical approaches in humans and animals.

[0054] For the experiments shown in Figure 1, human non-small cell lung cancer cells (A549) cultured in RPMI 1640 were used, supplemented with 10% of Petition 870200060065, dated 05 / 14 / 2020, page 54 / 183 32 / 59 fetal bovine serum and antibiotics, at 37°C and 5% CO2. The cells were maintained in culture for 48 hours in the presence or absence of D-PUFAs and PUFAs indicated in Table 2 at a concentration of 250 μM. After treatment, cell counting was performed, and the study of the mechanisms involved in the antitumor activity of the compounds was evaluated by flow cytometry. Figure 1 shows the percentage of cell survival (100% being assigned to untreated tumor cells). These values ​​correspond to the averages of three independent experiments.

[0055] In a separate series, the compounds listed in Table 3 were used against different types of tumors shown in Tables 8A, 8B, and 8C. These graphs show the antitumor efficacy of the compounds of this invention against the growth of breast cancer, brain cancer (glioma), and lung cancer cells. Efficacy data are expressed as IC50 values ​​(concentration values ​​in μM that produce death in 50% of tumor cells) after 72 hours of incubation. The other experimental conditions are identical to those described in the previous paragraph.

[0056] The results clearly indicate that all D-PUFAs are highly effective against tumor development. Overall, it can be seen that the A and B series of compounds are the best, so the efficacy of these series against the development of leukemia and liver cancer (Tables 9 and 10) was tested. Furthermore, it can be argued that the compounds of the 204 and 226 series, i.e., D-PUFAs numbered with the larger even number of unsaturations, are more Petition 870200060065, dated 05 / 14 / 2020, page 55 / 183 33 / 59 effective. These results indicate the existence of a structure-function relationship in the pharmacological activity of the present invention, which also supports the thesis of a common mechanism of action related to the structure of each compound and, therefore, of the unity of the invention in this section.

[0057] Table 8A shows the effectiveness of the compounds of the invention in controlling the growth of MDA-MB-231 breast cancer cells, expressed in micromolar IC50 values. Table 8A Subseries of series of molecules 182 183 (1) 183 (2) 204 205 226 A 388 380 347 381 390 187 B 379 267 156 345 208 195 C 386 289 168 389 223 210 D 277 245 175 281 2 224 E 289 319 193 299 284 207 F 311 323 181 326 275 226 G 378 364 159 372 219 213 H 402 308 170 363 282 199 Petition 870200060065, dated 05 / 14 / 2020, page 56 / 183 34 / 59 I 411 274 210 315 261 241 J 287 296 221 285 228 235 K 375 381 238 317 240 208 216 267 N 297 278 186 274 289 222 O 286 267 217 298 264 249 P 419 349 214 370 301 250 172 285 245 204 S 388 291 189 293 270 211 T 391 290 216 317 233 199 U 410 344 228 369 272 227 311 256 246

[0058] Table 8B shows the effectiveness of the compounds of the invention against the growth of brain cancer (glioma) U118 cells, expressed in micromolar IC50 values. Petition 870200060065, dated 05 / 14 / 2020, page 57 / 183 35 / 59 Table 8B Subseries of series of molecules 182 183 (1) 183 (2) 204 205 226 A 197 397 372 197 400 214 B 198 202 377 396 391 196 C 208 na 379 287 442 237 D 221 na 385 311 467 241 E 213 na na 224 513 265 F 236 354 401 275 498 261 G 205 329 394 342 426 278 H 267 408 443 263 439 294 I 240 321 432 328 510 327 J 254 296 426 296 487 283 K 221 257 418 380 474 272 L 229 231 460 247 435 269 M 238 349 407 309 462 306 N 247 324 385 315 513 285 Petition 870200060065, dated 05 / 14 / 2020, page 58 / 183 36 / 59 O on 370 on on on 277 P on 285 389 291 432 290 Q on 282 392 324 419 254 R 255 307 454 501 468 267 423 385 427 263 U 212 343 380 263 454 342 V 231 274 402 345 510 269 W 246 na 438 287 443 318

[0059] Table 8C shows the effectiveness of the compounds of the invention against the growth of A549 lung cancer cells, expressed in micromolar IC50 values. Table 8C Subseries of series of molecules 182 183 (1) 183 205 226 (2) 204 A 944 200 192 243 394 195 B 196 195 197 413 202 198 Petition 870200060065, dated 05 / 14 / 2020, page 59 / 183 37 / 59 CD AND FGH I JKLMNOPQR ST 281 241 521 325 214 326 267 372 364 221 294 243 475 413 209 347 259 392 338 286 273 295 427 407 273 319 219 398 290 247 348 276 459 351 298 281 259 362 416 215 276 2 414 275 250 285 283 326 362 221 322 248 375 293 208 379 255 420 384 236 344 318 461 418 264 317 272 387 339 291 273 314 348 365 252 258 274 364 417 219 341 246 439 293 265 367 279 352 322 243 Petition 870200060065, dated 05 / 14 / 2020, page 60 / 183 38 / 59 U 255 294 287 270 426 270 V 340 320 291 326 325 298 W 416 352 212 341 420 302

[0060] Table 9 shows the efficacy of the compounds of the invention against the development of human leukemia (Jurkat cells). IC50 micromolar values ​​at 72 hours. Table 9 Subseries of series of 183 183 molecules 182 (1) (2) 204 205 226 A 713 198 184 62 376 85 B 377 196 184 104 294 175

[0061] Table 10 shows the efficacy of the compounds of the invention against the development of liver cancer (HepG2 cells). IC50 micromolar values ​​at 72 hours. Table 10 Compound 182 183 (1) 183 (2) 204 205 226 A 212 380 380 192 401 164 Petition 870200060065, dated 05 / 14 / 2020, page 61 / 183 39 / 59

[0062] All these results indicate that D-PUFAs are useful for the prevention and treatment of cancer when included in nutraceutical or pharmaceutical compositions in humans and animals. It was also discovered that the potency of DPUFA action is correlated with the increased number of double bonds and that the presence of changes at carbons 1 and 2 is essential for the antitumor potency of lipids to be relevant at a therapeutic level. Given that these compounds have an antitumor effect against a wide range of tumor cells, it can be stated that they are molecules with a broad antitumor spectrum and may be of general application against the development of any cancer. Example 5: Use of 1,2-PUFA derivatives for the treatment of cardiovascular disease.

[0063] To investigate the usefulness of D-PUFA for the treatment of cardiovascular diseases, several experimental approaches were used. First, the efficacy of the compounds of the invention in cultured aortic cells (A-10 cell line) was investigated. These cells were maintained in culture with complete medium (C, supplemented with 10% fetal bovine serum and PDGF) and incomplete medium (CSS, supplemented with 1% fetal bovine serum and PDGF). The cultures were maintained for a period of 72 hours in a manner similar to that described in the previous paragraph. After this incubation period, cell counts were performed by flow cytometry. Petition 870200060065, dated 05 / 14 / 2020, page 62 / 183 40 / 59

[0064] In incomplete medium (CSS, without extra PDGF control), cells exhibit proliferative behavior similar to that produced in a healthy body. The proliferative behavior that occurs in complete medium would be a situation similar to that which occurs in a pathological organism. The presence of D-PUFA caused a significant reduction in the proliferation of normal aortic cells (A-10) in complete culture medium with proliferative agents present in fetal serum included in the culture medium. In the presence of proliferative agents (cytokines, growth factors, etc.), A10 cell counts were similar to those obtained in incomplete medium (CSS) with the presence of the D-PUFA of the present invention (Figure 2).In contrast, PUFAs have shown little or no antiproliferative efficacy, demonstrating that changes made to these fatty acids substantially increase their pharmacological potential for treating cardiovascular diseases such as hypertension, atherosclerosis, ischemia, cardiomyopathies, aneurysm, stroke, angiogenesis, cardiac hyperplasia, infarction, angina, stroke (cerebrovascular accidents), etc.

[0065] The effects on these cell lines cannot be considered toxic for two reasons: (1) in complete medium, DPUFAs never induced reductions in cell proliferation below the levels of cells incubated in incomplete medium, and (2) Aortic (A10) cells treated with D-PUFAs showed no signs of molecular or cellular necrosis or apoptosis, or any other type of cell death. As vascular cell proliferation is involved in the development of several cardiovascular diseases, D-PUFAs are useful for the Petition 870200060065, dated 05 / 14 / 2020, page 63 / 183 41 / 59 prevention and treatment of these diseases through nutraceutical and pharmaceutical approaches in humans and animals.

[0066] In a separate series, rat cardiomyocytes were isolated and cultured in vitro for 24 hours, after which a series of parameters were measured. First, the number, length, and width of cells in the culture were measured. It was observed that all compounds from series A and B (182-226) were able to increase the number of cells that survived in culture (between 12% and 33%), their length, and their width (between 18% and 42%). Furthermore, these compounds induce a decrease in anoxia-induced lactate dehydrogenase (LDH) release (reductions between 9% and 68% for all compounds from series A and B).These results indicate that the D-PUFA molecules of the present invention have a protective effect on cardiovascular cells and increase their elasticity, which can be used to prevent and treat vascular heart diseases of various types, such as hypertension, atherosclerosis, ischemia, cardiomyopathy, aneurysm, stroke, angiogenesis, cardiac hyperplasia, infarction, angina, stroke (cerebrovascular accidents), defective blood circulation, etc.

[0067] In a separate experimental series, the effect of the D-PUFA molecules of the present invention on the blood pressure of SHR rats was studied. In these animals, both blood pressure and apolipoprotein AI (apoA-I) levels were measured. For these experiments, spontaneously hypertensive rats (SHR) were treated for 30 days with transport (water control) or compounds of the invention. Petition 870200060065, dated 05 / 14 / 2020, page 64 / 183 42 / 59 (200 mg / kg per day, orally). At the end of this period, the blood pressure and serum apoA-I levels of these animals were measured. The results show the ability of the compounds of the present invention to lower blood pressure and induce apoA-I expression, indicating that these molecules are useful in the treatment of hypertension and atherosclerosis (Table 11). For these experiments, non-invasive methods for determining blood pressure (cuff-tail method) and gene expression for apoA-I (RT-PCR) described in the literature (TERÉS et al., 2008) were used. The usefulness of the molecules of the present invention for the treatment of cardiovascular diseases is reinforced by their ability to reduce serum cholesterol and triglyceride levels (see below).

[0068] Table 11 shows blood pressure (mm Hg) and apoA-I levels (%) in SHR rats. The mean SHR values ​​before treatment were 214 mmHg and 100%. Table 11 Compound 182 183 (1) 183 (2) 204 205 226 204 201 189 205 193 194 A 146 134 311 131 346 324 201 197 182 202 187 186 B ​​178 151 285 144 264 333 F 198 203 191 199 195 202 Petition 870200060065, dated 05 / 14 / 2020, p. 65 / 183 43 / 59 192 146 279 163 319 357 L 207 205 194 197 198 200 131 125 268 188 376 296 293 348 P 202 201 187 203 194 193 184 178 347 153 337 382 Example 6: Use of 1,2-PUFA derivatives for obesity treatment.

[0069] Figure 3A shows how PUFAs (both natural and synthetic) are able to inhibit hyperplasia and hypertrophy of adipose cells. For this study, 3T3-L1 adipocytes were used. This effect was already known and had been previously described for unmodified natural PUFAs (HILL et al., 1993). However, D-PUFAs have an increased potency to inhibit adipose cell proliferation (Figure 3A). This effect is not toxic in any case, since the inhibition of adipose cell growth did not produce reductions in cell proliferation below the levels of Petition 870200060065, dated 05 / 14 / 2020, page 66 / 183 44 / 59 cells cultured in incomplete medium (with 1% serum). The cell culture media and conditions used were similar to those described above.

[0070] These results demonstrate that D-PUFAs have a high potential to inhibit the growth of adipose cells and, therefore, for the prevention and treatment of obesity and other processes related to the accumulation of body adipocytes (e.g., cellulite) or appetite changes through nutraceutical or pharmaceutical approaches in animals and humans. The observed effect, once again, showed a clear correlation with the number of double bonds of the molecules used and the presence of modifications at carbons 1 and 2 of the lipid molecule.

[0071] Furthermore, several compounds related to the present invention were used to study their effect on the body weight of rats (Figure 3B). In this regard, spontaneously hypertensive rats (SHR) treated with compounds 182226 (series A, B, N and P) showed reductions in body weight after one month of treatment with 200 mg / kg (reductions from 3.2% to 6.9%), caused in part by a decrease in food intake and in part by the inhibition of adipose cell proliferation (in untreated animals fed the same amount of food, the weight loss was not as pronounced as in treated animals). These results demonstrate that these compounds can be used in the control of body weight (obesity and overweight), in appetite control and in the regulation of body fat (cellulite). Petition 870200060065, dated 05 / 14 / 2020, page 67 / 183 45 / 59 Example 7: Use of 1,2-PUFA derivatives for the treatment of neurodegenerative diseases

[0072] In these studies, different models of neurodegeneration were used. First, P19 cells were studied, where neuronal differentiation was induced with trans-retinoic acid. To do this, P19 cells were incubated in minimal essential medium (a-MEM) supplemented with 10% fetal bovine serum and 2 μM of trans-retinoic acid at 37°C in the presence of 5% CO2. The cells were incubated in the presence or absence of various D-PUFAs or PUFAs at different concentrations for 24 hours. Neurotoxicity was induced with 1 μM of NMDA. Subsequently, the number of cells was counted by optical microscopy in the presence of trypan blue. These experiments showed that PUFAs have a protective effect on neuronal degeneration, although the effect mediated by D-PUFAs is much greater (Figure 4A and Table 12).This figure and table clearly show that the DPUFA molecules of the present invention protect against neuronal death, since they inhibit NMDA-induced neuronal death, so that these substances may be useful for the prevention and treatment of neurodegenerative diseases, such as Alzheimer's disease, sclerosis, Parkinson's disease, leukodystrophy, etc. It was also shown that the number of cells in treated cultures is greater than in cultures where no neurodegenerative agents were added. In particular, the negative cell death values ​​indicate that the number of P19 cells is greater than in a control situation. Therefore, the D-PUFA compounds of the present invention can be used to promote neuroregenerative processes, such as... Petition 870200060065, dated 05 / 14 / 2020, page 68 / 183 46 / 59 such as those produced by traumatic processes (accident) or toxic agents.

[0073] Table 12 shows the protective effect against neuronal death in P19 cells: inhibition of neuronal death (P19 cells) with D-PUFA of the present invention after treatment with NMDA (100% death). Control cells without NMDA showed a 0% level of cell death. All percentages below 100% indicate protection against neuronal death. Negative values ​​indicate that in addition to protecting against neuronal death, there is also a level of neuronal proliferation. Furthermore, the compounds of the present invention decrease the levels of asynuclein (Table 13), a protein that is associated with neurodegenerative processes such as Parkinson's disease, Alzheimer's disease, Lewy body dementia, multiple system atrophy, prion diseases, etc. Therefore, the molecules of the present invention can be applied for the prevention and treatment of neurodegenerative, neurological, and neuropsychiatric processes. Table 12 182 183- 1 183- 2 204 205 226 C (NMDA) A -60 -55 -70 -70 -50 -230 100 B -62 -58 -66 -71 -52 -222 100 F -45 -35 -36 -46 -44 -189 100 Petition 870200060065, dated 05 / 14 / 2020, page 69 / 183 47 / 59 L -32 -21 -29 -27 -35 -117 100 V -17 -9 -18 -11 -27 -86 100

[0074] Table 13 shows the expression of α-synuclein in neuronal cultures (P19 cells). C (control) represents the % of α-synuclein in untreated cells (100%). Table 13 182 183- 1 183- 2 204 205 226 AC 50 45 40 41 35 23 100 B 61 43 38 36 41 31 F 71 61 52 52 57 41 L 80 76 73 69 67 64 V 83 87 89 82 81 77

[0075] To test the effectiveness of the compounds of the present invention in inducing neuroregeneration or inhibiting neurodegeneration, an animal model of Alzheimer's disease was used. In this model, mice develop neurodegeneration because they express a series of mutant proteins that lead to brain damage (Alzh mice). B6 mice were used. Petition 870200060065, dated 05 / 14 / 2020, p. 70 / 183 48 / 59 as healthy animal controls. Both groups of animals were treated for a period of three months with the carrier (water) or with various D-PUFAs (20 mg / kg, daily, orally) from the age of 3 months. To determine if cognitive improvement occurred after treatment, animal behavior was monitored in the radial maze. The animals were kept on a restricted diet to maintain their appetite. In a symmetrical 8-arm radial maze, visual markers were placed to facilitate animal orientation, and food (15 mg) was placed in four of the arms. The time each animal took to complete the exercise and the number of errors were measured using a camera coupled to a computer system. In this sense, the Alzheimer's animals had values ​​approximately 50% higher than healthy animals, both in the time they took to perform the exercise and in the number of errors committed (Figure 4B).In contrast, Alzheimer's rats treated with 226B1 (Alzh + LP226) showed behavioral parameters similar to those of control animals and significantly (P <0.05) lower than those treated with the carrier (Alzh). In this sense, the efficacy of compounds 183B1, 205A1, 205B1, 226A1, and 226V1 was also tested, showing improvements in animals with Alzheimer's disease (times of 98, 92, 93, 86, and 89 seconds, respectively). On the other hand, it is also interesting that these same compounds (183B1, 205A1, 205B1, 226A1, 226B1, and 226V1) also produced reductions in the times required to complete the experiment in control animals (healthy B6 rats) of 8s, 11s, 12s, 18s, 16s, and 14s, respectively. Therefore, it can be concluded that these... Petition 870200060065, dated 05 / 14 / 2020, page 71 / 183 49 / 59 compounds have significant activity against neurodegeneration and in neuroregeneration. Among the neurodegenerative processes that could be prevented and treated with D-PUFA molecules of the present invention are Alzheimer's disease, Parkinson's disease, Zellweger syndrome, multiple sclerosis, amyotrophic lateral sclerosis, hippocampal sclerosis and other types of epilepsy, focal sclerosis, adrenoleukodystrophy and other types of leukodystrophy, vascular dementia, senile dementia, Lewy body dementia, multisystem atrophy, prion diseases, etc. Furthermore, in neuroregenerative activity, evidenced by the effect in both Alzheimer's rats and healthy B6 rats, the treatment can be applied to processes in which neuronal loss has occurred as a result of an accident, surgery, trauma of a different nature, or due to certain toxins.The D-PUFA molecules of the present invention can also be used for the prevention or treatment of various neurological and / or neuropsychiatric problems, such as headaches including migraines, central nervous system injury, sleep disorders, dizziness, pain, stroke (cerebrovascular accidents), depression, anxiety, addictions, memory, learning or cognitive problems, and to improve memory and cognitive ability in humans. Example 8: Use of 1,2-PUFA derivatives for the treatment of inflammatory diseases.

[0076] Cyclooxygenase (COX) is an enzyme that can bind to membranes, taking certain lipids from there and catalyzing Petition 870200060065, dated 05 / 14 / 2020, page 72 / 183 50 / 59 its conversion into molecules that may have inflammatory activity. The binding of this enzyme to membrane lipids is due, in part, to the lipid structure of the membrane. Increased activity of COX 1 and 2 isoforms has been associated with the etiopathogenesis of a number of inflammatory diseases by inhibiting arachidonic acid metabolism for the production of pro-inflammatory lipid mediators. The D-PUFA compounds of the present invention produced a series of cellular signals that alter arachidonic acid metabolism and, consequently, inhibit COX activity and expression in cultured monocytes (Table 14 and Figure 5). In addition, the D-PUFA of the present invention inhibited the production of pro-inflammatory cytokines (TNF-α) in vivo (Table 15 and Figure 5). To this end, C57BL6 / J rats were treated with the different derivatives (200 mg / kg, orally) after inducing an inflammatory reaction in them by intraperitoneal injection of 20 mg of bacterial lipopolysaccharide (LPS).These results clearly indicate the effectiveness of the D-PUFA of the present invention in preventing or reversing inflammatory processes and pathologies.

[0077] Table 14 shows COX-2 expression in cultured monocytes. Inhibition of COX-2 expression in monocytes. Percentages of inhibition (compared to the positive control in the presence of LPS, 100%) of COX-2 protein levels (expression) by various fatty acid derivatives. Petition 870200060065, dated 05 / 14 / 2020, pp. 73 / 183 51 / 59 Table 14 182 183- 1 183- 2 204 205 226 C (LPS) A 24 20 23 17 31 23 100 B 39 33 29 28 39 37 F 56 46 36 41 47 49 L 67 65 48 47 53 69 V 81 79 68 43 76 85

[0078] Table 15 shows TNF-α production (%) in rats: percentage of TNF-α in serum after intraperitoneal injection of LPS (20 pg) in C57BL6 / J rats (100%). Table 15 182 183-1 183-2 204 205 226 C (LPS) A 64 70 71 24 56 73 100 B 79 81 78 26 69 83 F 86 91 86 46 80 91 L 85 86 91 49 76 88 V 81 84 87 42 84 85 Petition 870200060065, dated 05 / 14 / 2020, page 74 / 183 52 / 59

[0079] These results show that the molecules of the present invention may be useful for preventing or treating inflammatory diseases, including inflammation, cardiovascular inflammation, inflammation caused by tumors, inflammation of rheumatic origin, inflammation caused by infection, respiratory inflammation, acute and chronic inflammation, hyperalgesia of an inflammatory nature, edema, inflammation resulting from trauma or burns, etc. Example 9: Use of 1,2-PUFA derivatives for the treatment of metabolic diseases.

[0080] Lipids are essential molecules for maintaining metabolic functions. Treatments with PUFAs produced some modest reductions in cholesterol and triglyceride levels in 3T3-L1 cells. However, treatments with D-PUFAs resulted in marked and significant reductions in cholesterol and triglyceride levels in these cells. For these experiments, the aforementioned cells were incubated in RPMI 1640 medium in the presence of 10% fetal bovine serum at 37°C with 5% CO2, and in the presence or absence of 150μM of different PUFAs or D-PUFAs. The cells were incubated for 24h and then subjected to lipid extraction, and cholesterol and triglyceride levels were measured following the procedures described previously (FOLCH et al., 1951).

[0081] In a separate experimental series, SHR rats were treated with various compounds of the present invention (200 mg / kg per day, 28 days, orally), and serum cholesterol, triglyceride, and glucose levels were measured by methods Petition 870200060065, dated 05 / 14 / 2020, page 75 / 183 53 / 59 colorimetric. It was observed that these compounds induce significant (and, in many cases, marked) reductions in the levels of these metabolites (Table 16).

[0082] The results shown in Figure 6 and Table 16 clearly indicate that D-PUFAs can be used as medications for the treatment or prevention of metabolic diseases, such as hypercholesterolemia, hypertriglyceridemia, diabetes, and insulin resistance in humans and animals, through pharmaceutical and nutraceutical approaches. The combination of high cholesterol and triglyceride levels, high glucose, along with cardiovascular disease and / or body weight changes leads to metabolic syndrome, which is beginning to increase in Western societies. The compounds of the present invention have great therapeutic potential for the treatment of metabolic syndrome.

[0083] Table 16 shows the cholesterol, triglyceride, and glucose levels in SHR rats. It shows the value of cholesterol (top number), triglycerides (middle number), and glucose (bottom number) in the serum of SHRs treated with the molecules described above (200 mg / kg per day, orally, 28 days). The values ​​are expressed as a percentage and, in untreated rats (control), they were always considered as 100%. Petition 870200060065, dated 05 / 14 / 2020, pp. 76 / 183 54 / 59 Table 16 Compound 182 183 (1) 183 (2) 204 205 226 78 76 79 72 69 64 A 91 81 78 77 74 71 84 87 82 85 82 79 89 75 77 71 58 59 B 72 66 76 69 65 62 87 84 86 89 87 81 92 78 84 76 71 67 74 94 85 92 91 85 87 92 72 89 82 80 75 N 93 69 85 81 73 72 90 84 92 82 86 83 V 94 75 84 84 85 81 Petition 870200060065, dated 05 / 14 / 2020, page 77 / 183 55 / 59 93 70 92 81 79 84 93 79 88 87 84 89 Example 10: Structural basis of the therapeutic effects of 1,2-PUFA derivatives

[0084] Numerous studies have demonstrated that ingestion or treatment with lipids results in changes in the lipid composition of cell membranes. Furthermore, this composition has a direct effect on the lipid structure of the membrane, which, in turn, regulates cell signaling and is related to the occurrence of many diseases. Figure 7 shows the correlation between changes in membrane structure produced by different D-PUFAs (as measured by the transition temperature Hn) and the cellular effects observed in this study. To this end, the average effect of each of the D-PUFAs was determined (average of each lipid for all diseases studied in relation to the number of double bonds), and the results were plotted against the transition temperature.The reduction in the Hn transition temperature indicates a greater induction of discontinuities in membranes, creating docking sites for peripheral membrane proteins, which leads to better regulation of cell signaling and, therefore, more effective control of certain diseases. To some extent, the fact that complex organisms can metabolize drugs and that some additional mechanisms may be operating in some types (subtypes) of diseases suggests that some of the molecules with fewer double bonds may have greater activity. Petition 870200060065, dated 05 / 14 / 2020, pp. 78 / 183 56 / 59 pharmacological. However, in general, it seems that the therapeutic effect depends on the number of double bonds in the molecule, which, in turn, is related to the ability to regulate membrane structure. In this sense, the presence of radicals on carbons 1 and / or 2, found in the D-PUFA compounds of the present invention, but not in natural PUFAs, is essential to increase the therapeutic effect of these molecules.

[0085] These results indicate that the effects of lipids contained in the present invention have a common basis. These correlations (with r2 values ​​of 0.77 and 0.9 for D-PUFAs and P <0.05 in both cases) clearly indicate that the structure of the lipids used is the basis of their effect and that this occurs through the regulation of the membrane structure, caused by the relationship between the structure and function of each lipid.

[0086] Thus, the present invention relates, in a first aspect, to compounds of formula (I) or their pharmaceutically acceptable derivatives, where a, b, c, independently, may have values ​​from 0 to 7, and Ri and R.2 may be an ion, an atom or a group of atoms with a molecular weight not exceeding 200 Da independently, for use in the treatment of diseases based on structural alterations and / or functional characteristics of the cell membrane lipids selected from: cancer, vascular disease, inflammation, metabolic diseases, obesity, neurodegenerative diseases and neurological disorders.

[0087] A second aspect of the present invention relates to the use of at least one compound of formula (I), or its Petition 870200060065, dated 05 / 14 / 2020, p. 79 / 183 57 / 59 pharmaceutically acceptable derivatives, where a, b and c, independently, may have values ​​from 0 to 7, and Ri and R2 may be an ion, an atom or a group of atoms with a molecular weight not exceeding 200 Da, independently, for the preparation of a pharmaceutical and / or nutraceutical composition for the treatment of diseases based on structural and / or functional alterations of lipids in selected cell membranes of: cancer, vascular diseases, inflammations, metabolic diseases, obesity, neurodegenerative diseases and neurological disorders.

[0088] The last aspect of the present invention relates to a method for the therapeutic treatment of diseases in humans and animals, whose common etiology is related to structural and / or functional alterations of lipids located in selected cell membranes of: cancer, vascular disease, inflammation, metabolic diseases, obesity, neurological and neurodegenerative diseases, comprising administering to the patient a therapeutically effective amount of at least one compound of formula (I) and / or its pharmaceutically acceptable salts or derivatives, where a, b and c may have independent values ​​between 0 and 7, and Ri and R2 may be an ion, an atom or a group of atoms with a molecular weight not exceeding 200 Da, independently. Petition 870200060065, dated 05 / 14 / 2020, pp. 80 / 183 58 / 59 REFERENCES ALEMANY et al., 2004. Hypertension, 43 249 ALEMANY et al., 2007. Biochim Biophys Acta, 1768, 964 BUDA et al., 1994. Proc Natl Acad Sci USA, 91, 8234 COLES et al., 2001. J Biol Chem, 277, 6344 ESCRIBÁ et al., 1995. Proc Natl Acad Sci USA, 92, 7595 MAIL et al., 1997. Proc. Natl. Acad. Sci USA, 94, 11 375 ESCRIBÁ et al., 2003. Hypertension, 41, 176 ESCRIBÁ, 2006. Trends Mol Med, 12, 34 ESCRIBÁ et al., 2008. J Cell Mol Med, 12, 829 FLORENT et al., 2006. J Neurochem., 96, 385 FOLCH et al., 1951. J Biol Chem, 191.83 JACKSON and SCHWARTZ, 1992. Hypertension, 20, 713 JUNG et al., 2008. Am J Clin Nutr 87, 2003S LANE and FARLOW, 2005. J Lipid Res, 46, 949 MARTINEZ et al., 2005. Mol Pharmacol., 67, 531 REPORT, 2008. Postraglandins Leukot. Being. Fatty Acids 79 , 153 – 156 Petition 870200060065, of 14 / 05 / 2020, p. 81 / 183 59 / 59 SAGIN and SOZMEN, 2008. J Lipid Res, 46, 949 SCHWARTZ et al., 1986. Circ Res 58, 427 STENDER and DYERBERG, 2004. Ann Nutr Metab., 48, 61 TERÉS et al. , 2008. Proc. Natl. Acad. Sci USA, 105, 811 TROMBETTA et al., 2007. Chem Biol Interact., 165, 239 VOGLER et al., 2004. J. Biol Chem, 279, 36 540 VOGLER et al., 2008. Biochim Biophys Act, 1778, 1640 YANG et al., 2005. Mol Pharmacol., 68, 210 Petition 870200060065, 14 / 05 / 2020, pág. 82 / 183

Claims

1 / 4 CLAIMS 1. Use of at least one compound, said compound being selected from COOH-CHOH-(CH2)6-(CH=CH-CH2)2-(CH2)3-CH3 (182A1), COOH-CHOH-(CH2)3-(CH=CH-CH2)3-(CH2)3-CH3 (183A2), COOH-CHOH-(CH2)2-(CH=CHCH2)4-(CH2)3-CH3 (204A1), COOH-CHOH-(CH2)2-(CH=CH-CH2)5-CH3 (205A1), COOH-CHOH-CH2-(CH=CH-CH2)6-CH3 (226A1) or the sodium salt of COOH-CHOH-(CH2)6-(CH=CH-CH2)2- (CH2) 3-CH3 (182A1), COOHCHOH- (CH2) 3- (CH=CH-CH2) 3- (CH2) 3-CH3 (18 3A2), COOH-CHOH- (CH2) 2- (CH=CH-CH2) 4- (CH2) 3-CH3 (204A1), COOH-CHOH-(CH2) 2-(CH=CH-CH2) 5-CH3 (205A1) or COOH-CHOH-CH2-(CH=CH-CH2)6-CH3 (226A1) characterized in that it is for the manufacture of a pharmaceutical or nutraceutical composition for the treatment of cancer.

2. Use according to claim 1, characterized in that said compound is COOH-CHOHCH2-(CH=CH-CH2)6-CH3 and said pharmaceutically acceptable salt is the sodium salt of COOH-CHOH-CH2-(CH=CH-CH2)6CH3.

3. Use, according to claim 1, characterized in that said cancer is selected from the group consisting of lung cancer, breast cancer, brain cancer, leukemia and liver cancer.

4. Pharmaceutical composition characterized in that it comprises: (a) a compound as defined in claim 1, and (b) an excipient, wherein said compound is at least one selected from COOH-CHOH-(CH2)6-(CH=CH-CH2)2-(CH2)3-CH3 (182A1), COOH-CHOH-(CH2)3-(CH=CH-CH2)3-(CH2)3-CH3 (183A2), COOH-CHOH-(CH2)2-(CH=CHCH2)4-(CH2)3-CH3 (204A1), COOH-CHOH-(CH2)2-(CH=CH-CH2)5-CH3 (205A1), COOH-CHOH-CH2-(CH=CH-CH2)6-CH3 (226A1) or the sodium salt of COOH-CHOH-(CH2)6- (CH=CH-CH2) 2- (CH2) 3-CH3 (182A1), COOHCHOH- (CH2) 3- (CH=CH-CH2) 3- (CH2) 3-CH3 (18 3A2), COOH-CHOH- (CH2) 2- (CH=CH-CH2) 4- (CH2) 3-CH3 (204A1), COOH-CHOH-(CH2) 2-(CH=CH-CH2) 5-CH3 (205A1) or COOH-CHOH-CH2-(CH=CH-CH2)6-CH3 (226A1), and wherein said pharmaceutical composition is for use in the treatment of cancer.

5. Nutraceutical composition characterized in that it comprises (c) a compound as defined in claim 1, and (d) an excipient, wherein said compound is at least one selected from Petition 870260065061, dated 02 / 07 / 2026, page. 16 / 18 3 / 4 from COOH-CHOH-(CH2)6-(CH=CH-CH2)2-(CH2)3-CH3 (182A1), COOH-CHOH-(CH2)3-(CH=CH-CH2)3-(CH2)3-CH3 (183A2), COOH-CHOH-(CH2)2-(CH=CHCH2)4-(CH2)3-CH3 (204A1), COOH-CHOH-(CH2)2-(CH=CH-CH2)5-CH3 (205A1), COOH-CHOH-CH2-(CH=CH-CH2)6-CH3 (226A1) or the sodium salt of COOH-CHOH-(CH2)6-(CH=CH-CH2)2-(CH2)3-CH3 (182A1), COOHCHOH- (CH2) 3- (CH=CH-CH2) 3- (CH2) 3-CH3 (18 3A2), COOH-CHOH- (CH2) 2- (CH=CH-CH2) 4- (CH2) 3-CH3 (204A1), COOH-CHOH-(CH2) 2-(CH=CH-CH2) 5-CH3 (205A1) or COOH-CHOH-CH2-(CH=CH-CH2) 6-CH3 (226A1), and wherein said nutraceutical composition is for use in the treatment of cancer.

6. Composition, according to any one of claims 5 and 6, characterized in that it is administered via enteral (IP), oral, rectal, topical, inhalation, or intravenous, intramuscular, or subcutaneous injection.

7. Use according to claim 1, characterized in that said compound is selected from: COOH-CHOH-(CH2)6-(CH=CH-CH2)2-(CH2)3-CH3 (182Al), COOH-CHOH-(CH2)3-(CH=CH-CH2)3-(CH2)3-CH3 (183A2), COOH-CHOH-(CH2)2-(CH=CH-CH2)4-(CH2)3-CH3 (204Al), Petition 870260065061, dated 02 / 07 / 2026, page 17 / 18 4 / 4 COOH-CHOH-(CH2) 2-(CH=CH-CH2) 5-CH3 (205A1) and COOH-CHOH-CH2-(CH=CH-CH2) 6-CH3 (226A1).

8. Use according to claim 1, characterized in that said compound is COOH-CHOHCH2-(CH=CH-CH2)6-CH3.

9. Use according to claim 1, characterized in that said compound is COOH-CHOH(CH2) 6-(CH=CH-CH2) 2-(CH2) 3-CH3 or the sodium salt of COOHCHOH- (CH2) 6- (CH=CH-CH2) 2- (CH2) 3-CH3.

10. Use according to claim 1, characterized in that said compound is COOH-CHOH(CH2) 2-(CH=CH-CH2) 4-(CH2) 3-CH3 or the sodium salt of COOH-CHOH(CH2) 2-(CH=CH-CH2) 4-(CH2) 3-CH3. Petition 870260065061, dated 02 / 07 / 2026, page 18 / 18

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