HK1232430A - Use of derivates of polyunsaturated fatty acids as medicaments - Google Patents

Abstract

Use of 2-Hidroxyderivates of polyunsaturated fatty acids as medicaments or functional foods is disclosed. The present invention relates to the use of 1,2-derivatives of fatty acids in the treatment or prevention of diseases the common aetiology whereof is based on alterations (having any origin) of the lipids of the cell membrane such as, for example, alterations in the level, in the composition or in the structure of said lipids. Furthermore, for diseases wherein regulation of the composition and structure of lipids of a membrane (or of proteins interacting therewith) may induce reversion of the pathological state.

Description

Use of derivatives of polyunsaturated fatty acids as medicaments

The present application is a divisional application of chinese patent application No.201080011939.8, having an application date of 2010, 3/15, entitled "use of a derivative of a polyunsaturated fatty acid as a drug".

Technical Field

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 changes in cell membrane lipids, such as: changes in the levels, composition or structure of these lipids and the proteins with which they interact; and for the treatment of diseases in which modulation of lipid composition and membrane structure and of proteins interacting with them leads to reversal of the pathological state.

Therefore, since the present invention has a wide range of applications, it may be generally included in the fields of medicine and pharmacy.

Background

Cell membranes are structures of tissues that define cells and the organelles that the cells contain. Most biological processes occur in or near membranes. Lipids have not only structural roles but also activities that regulate important processes. Furthermore, modulation of membrane lipid composition also affects the position or function of important proteins involved in controlling cell physiology, such as G-protein or PKC (Escrib et al, 1995, 1997, Yang et al, 2005, Martinez et al, 2005). These and other studies demonstrate the importance of lipids in controlling important cellular functions. Indeed, many human diseases such as cancer, cardiovascular diseases, neurodegenerative diseases, obesity, metabolic disorders, tumors and inflammatory diseases, infectious or autoimmune diseases, and others are associated with changes in the level or composition of lipids in biological membranes, further demonstrating that treatment with fatty acids, in addition to the fatty acids of the present invention that modulate the composition and structure of membrane lipids, can be used to reverse the beneficial effects of these diseases (Escrib a, 2006).

Lipids consumed in the diet regulate the lipid composition of cell membranes (alemny et al, 2007). In addition, a variety of physiological and pathological states can alter lipids in cell membranes (Buda et al, 1994; Escrib, 2006). As an example of a state of inducing physiological changes in membrane lipids, fish living in the river with variable temperature can be mentioned, in which the lipids of the fish undergo important changes (changes in the amount and type of membrane lipids) when the temperature is decreased from 20 ℃ (summer) to 4 ℃ (winter) (Buda et al 1994). These changes allow maintaining their function in cell types of different nature. An example of a pathological process that can affect lipid composition is a neurological disorder or a drug-induced disease (Rapoport, 2008). Thus, it can be said that membrane lipids can determine the correct functioning of various mechanisms of cell signaling.

Changes in membrane lipid composition affect cell signaling and can lead to the development of or reverse disease (Escrib a, 2006). Various studies over the past several years have shown that membrane lipids play a more relevant role than they have been specified to date (Escrib et al, 2008). The traditional view of cell membranes is to specify the role of the pure structure of lipids, as carriers for membrane proteins, which are considered to be the only functional elements of the membrane. The plasma membrane will have an additional role in preventing water, ions and other molecules from entering the cell. However, membranes have other functions of great importance in maintaining health, disease development and healing. Since the body is diseased because cells of the body are diseased, changes in membrane lipids produce changes in the cells, which can lead to the appearance of disease. Likewise, therapeutic, nutritional or cosmetic interventions aimed at modulating the level of membrane lipids can prevent and reverse (cure) pathological processes. In addition, numerous studies have shown that the consumption of saturated and trans-monounsaturated fats is associated with a deterioration in health. In addition to the above mentioned neurological disorders, vascular diseases, cancer and other diseases are also directly associated with membrane lipids (Stender and Dyerberg, 2004). The deterioration of the body is manifested by the appearance of this and other types of disease, which may include metabolic disease, inflammation, neurodegeneration, and the like.

Cell membranes are selective barriers through which cells receive metabolites and information from other cells and the extracellular environment surrounding them. However, membranes serve other very important functions in cells. In one aspect, they are used as carriers for proteins involved in receiving or emitting information that controls important organ functions. These messages, mediated by a number of hormones, neurotransmitters, cytokines, growth factors, etc., activate membrane proteins (receptors), which transmit received signals into cells through other proteins (peripheral membrane proteins), some of which are also located in the membrane. Because (1) these systems function in an amplified cascade, and (2) membrane lipids can regulate the localization and activity of these peripherins, the lipid composition of the membrane can have a major impact on the physiology of the cell. Specifically, the interaction of certain peripherins such as G-protein, protein kinase C, Ras protein, etc. with cell membranes depends on their lipid composition (Vogler et al, 2004, Vogler et al, 2008). In addition, the lipid composition of the cell membrane is affected by the type and amount of lipids in the diet (Escrib et al, 2003). Indeed, nutrient or drug lipid intervention can modulate the lipid composition of the membrane, which in turn can control important cell signaling protein interactions (and thus activity) (Yang et al, 2005).

The fact that membrane lipids are able to control cell signaling may also postulate that they are able to regulate the physiological state of cells, and thus the general health state. Indeed, negative and positive effects of lipids on health have been described (Escrib et al, 2006; Escrib et al, 2008). Preliminary studies have shown that a monounsaturated fatty acid, 2-hydroxyoleic acid, can reverse certain pathological processes such as overweight, hypertension or cancer (alemny et al, 2004, Martinez et al, 2005; Vogler et al, 2008).

Cardiovascular disease is often associated with the hyperproliferation of cells that make up heart and vascular tissue. This hyperproliferation produces cardiovascular deposits in the lumen of the vessels and in the lumen of the cardiovascular system, resulting in a number of diseases such as hypertension, atherosclerosis, ischemia, aneurysms, ictus, infarction, angina, stroke (cerebrovascular accident) and the like (Schwartz et al, 1986). Indeed, it has been suggested that the development of drugs to prevent cell proliferation would be a good alternative to the prevention and treatment of cardiovascular disease (Jackson and Schwartz, 1992).

Obesity is caused by an altered balance between intake and energy expenditure, in part due to changes in the mechanisms that regulate these processes. On the other hand, the disorder is characterized by hyperplasia (increase in cell number) or hypertrophy (increased size) of adipocytes (fat cells), adipocytes (adipocyte). Numerous studies have shown that fatty acids, either free of other molecules or as part of other molecules, can affect many 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, modification of fatty acids may be a strategy to regulate energy homeostasis, i.e. the balance between intake and energy expenditure, and thus the associated processes such as appetite or body weight.

The neurodegenerative process results in a number of diseases that have different manifestations, but have common characteristics caused by degeneration or dysfunction of cells of the central and/or peripheral nervous system. Some of these neurodegenerative processes involve a significant reduction in the cognitive abilities of patients or a change in their motor abilities. Neurodegenerative, neurological, and neuropsychiatric disorders have a common basis for neuronal degeneration or changes in components of neurons such as lipids (e.g., myelin) or membrane proteins (e.g., adrenergic receptors, 5-hydroxytryptamine receptors, etc.). Such central nervous systems include, inter alia, alzheimer's disease, parkinson's disease, multiple sclerosis, ALS, hippocampal sclerosis and other types of epilepsy, focal sclerosis, adrenoleukodystrophy and other leukodystrophies, vascular dementia, senile dementia, headache including migraine, central nervous system trauma, sleep disorders, dizziness, pain, stroke (cerebrovascular accident), depression, anxiety or addiction. In addition, certain neurological and neurodegenerative diseases can lead to processes that end with blindness, hearing problems, disorientation, emotional changes, and the like.

An example of a well characterized neurodegenerative disorder is alzheimer's disease, which is characterized by the formation of focal spots composed of membrane protein fragments (e.g., amyloid-beta peptides) primarily originating from erroneous peptide processing, followed by accumulation on the outside of the cell, and neurofibrillary tangles of Tau protein. This process is associated with changes in cholesterol metabolism and subsequent changes in 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, senile dementia (or lewy bodies) are associated with pathological accumulation of fibrous aggregates of alpha synuclein, which leads to significant changes in the cellular metabolism of triglycerides (Coles et al, 2001). Indeed, the development of these and other neurodegenerative diseases is associated with changes in serum or cellular lipids such as cholesterol, triglycerides, sphingomyelin, phosphatidylethanolamine, and the like. This in turn suggests that lipids play a crucial role in the correct activity of neurons, nerves, brain, cerebellum and spinal cord, which logically provides an abundance of lipids in the central nervous system. The molecules of the invention have a high or very high potential to reverse many processes associated with neurological, neurodegenerative and neuropsychiatric disorders.

Moreover, different types of sclerosis and other neurodegenerative diseases involve "demyelination", the end result of which is the loss of lipids on the covering of neuronal axons, with consequent changes in the propagation process of electrical signals in which lipids participate. Myelin is an axon that surrounds many neurons and is the fatty layer formed by a series of spiral folds of the plasma membrane of glial cells (Schwann cells). Thus, it is clear that lipids play an important role in the development of neurodegenerative diseases. Furthermore, unmodified natural PUFAs were found to have a suitable preventive effect on the development of the neurodegenerative process (Lane and Farlow, 2005). In fact, the most important lipids in the central nervous system are docosahexaenoic acid, a natural PUFA, and its abundance is altered in many neurodegenerative processes.

Metabolic diseases form a group of diseases characterized by the accumulation or absence of certain molecules. Typical examples are the accumulation of higher than normal levels of glucose, cholesterol and/or triglycerides. Increased levels of glucose, cholesterol and/or triglycerides, both systemic (e.g., increasing plasma levels) and cellular (e.g., in the cell membrane), are associated with changes in cell signaling that lead to different levels of dysfunction, and are often due to errors in the activity of certain enzymes or due to inappropriate control of these proteins. The most important metabolic diseases include hypercholesterolemia (high cholesterol) and hypertriglyceridemia (high triglycerides). These diseases have a high incidence, morbidity and mortality, so their treatment is the first necessity. Other important metabolic diseases include diabetes and insulin resistance, characterized by problems in the control of glucose levels. These metabolic diseases are related to the occurrence of other diseases such as cancer, hypertension, obesity, atherosclerosis and the like. Recently, another disease process has been defined which is closely related to the above mentioned metabolic disorders and which may itself constitute a new type of metabolic pathology (metabolophathy), which is the metabolic syndrome.

The protective effect of certain polyunsaturated fatty acids (PUFAs) on certain diseases has been described by different researchers. For example, PUFAs slow down the development of cancer and have a positive effect against the development of cardiovascular diseases, neurodegenerative diseases, metabolic disorders, obesity, inflammation, etc. (Trombeta et al, 2007, Jung et al, 2008, Florent et al, 2006). These stimuli suggest an important role for lipids (PUFAs) in the etiology of various diseases and in their treatment. However, the pharmacological activity of these compounds (PUFAs) is very limited due to rapid metabolism in the blood and short half-life. Therefore, there is a need to develop PUFAs with a slower metabolism resulting in increased presence in the cell membrane compared to the PUFAs used so far, facilitating the interaction of cell signaling peripherins. The molecules of the present invention are synthetic derivatives of PUFAs, having slower metabolism and significant and markedly superior therapeutic effects compared to natural PUFAs.

Because of the relationship between structural and functional changes of lipids located in cell membranes and the development of various diseases such as cancer, cardiovascular diseases, obesity, inflammation, neurodegeneration and metabolic diseases, which are of different types but have etiologies singly associated with structural and/or functional changes of lipids in membrane cells, the present invention focuses on the use of novel synthetic polyunsaturated fatty acids capable of solving the technical problems associated with the above-mentioned known fatty acids, and thus, they can be effectively used for the treatment of these diseases.

Description of the invention

Brief description of the invention

The present invention focuses on 1, 2-derivatives of polyunsaturated fatty acids (hereinafter: D-PUFA) for the treatment of common diseases whose etiology is associated with a change in the structure and/or function of cell membrane lipids or of proteins interacting with cell membrane lipids, in particular selected from: cancer, vascular diseases, neurodegenerative and neurological disorders, metabolic diseases, inflammatory diseases, obesity and overweight. D-PUFAs have a lower metabolic rate compared to natural polyunsaturated fatty acids (hereinafter: PUFAs) because their degradation by beta-oxidation is hindered by the presence of different atoms at carbon 1 and/or 2, which are different from hydrogen (H). This results in significant changes in the composition of the membrane, modulating the interaction of cell signaling peripherins. This can result, for example, in packaging differences at the surface of the membrane, modulating the anchoring of peripheral proteins involved in the transmission of cellular information. The D-PUFA molecules that are the subject of the present invention therefore have greater activity than PUFAs, showing significantly higher effects on the pharmacological treatment of the identified disease.

As mentioned above, diseases treated with D-PUFA molecules of the invention share the same etiology, which is associated with structural and/or functional (or any other source) changes in cell membrane lipids or structural and/or functional (or any other source) changes in proteins that interact with cell membrane lipids. The following diseases are listed as examples:

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

Vascular diseases: atherosclerosis, ischemia, aneurysm, ictus, cardiomyopathy, angiogenesis, myocardial hyperplasia (cardiac hyperplasia), hypertension, infarction, angina, stroke (cerebrovascular accident), and the like.

Obesity, overweight, appetite control and cellulite.

Metabolic diseases: hypercholesterolemia, hypertriglyceridemia, diabetes, insulin resistance, etc.

Neurodegenerative diseases, neurological disorders 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 leukodystrophy, vascular dementia, senile dementia, dementia with lewy bodies, multiple system atrophy, prion diseases, headaches including migraine, central nervous system injury, sleep disorders, dizziness, pain, stroke (cerebrovascular accident), depression, anxiety, addiction, memory, learning or cognitive problems and general diseases requiring treatment by a compound of the invention causing neurodegeneration or cessation of nerve regeneration.

Inflammatory diseases, including inflammation, cardiovascular inflammation, tumor-induced inflammation, inflammation of rheumatoid origin, inflammation of infectious origin, respiratory inflammation, acute and chronic inflammation, hyperalgesia of inflammatory nature, edema, inflammation caused by trauma or burns, and the like.

The D-PUFA compounds of the invention are characterized by the following formula (I):

COOR₁-CHR₂-(CH₂)_a-(CH＝CH-CH₂)_b-(CH₂)_c-CH₃

(I)

wherein a, b and c may have independent values between 0 and 7, and R₁And R₂May be an ion, an atom or a group of atoms having independently a molecular weight not exceeding 200 Da.

In a preferred configuration of the invention, a, b and c may have independent values between 0 and 7, R₁Is H and R₂Is OH.

In another preferred configuration of the invention, a, b and c may have independent values between 0 and 7, R₁Is Na and R₂Is OH.

In another preferred configuration of the invention, a and c may have independent values between 0 and 7, b may have independent values between 2 and 7, and R₁And R₂May be ions, atoms or molecular weights thereofIndependently a radical equal to or lower than 200 Da.

Administration of the fatty acids of the invention may be carried out by any means, for example enterally (IP), orally, rectally, topically, by inhalation or by intravenous, intramuscular or subcutaneous injection. Furthermore, administration may be according to the above formula or in any pharmaceutically acceptable derivative from the above formula, for example: esters, ethers, alkyls, acyl, phosphates, sulfates, ethyl, methyl, propyl, salts, complexes, and the like.

Furthermore, the fatty acids of the invention may be administered alone or formulated in pharmaceutical and/or nutraceutical compositions in combination with each other and/or with excipients such as: binders, fillers, disintegrants, lubricants, coatings (coaters), sweeteners, flavoring excipients, coloring excipients, carriers (transporters), and the like, and combinations of all of them. Also, the fatty acids of the present invention may be part of a pharmaceutical and/or nutraceutical composition in combination with other active ingredients.

For the purposes of the present invention, the term "nutrient" is defined as a compound that is taken periodically during a meal and is used to prevent a disease, in which case the cause of the disease is associated with changes in cell membrane lipids.

For the purposes of the present invention, the term "therapeutically effective amount" is an amount that reverses or prevents a disease without exhibiting adverse side effects.

Brief Description of Drawings

FIG. 1. Effect of the compounds in Table 1 on tumor cell growth. The number of living cells (% control) is indicated on the y-axis, depending on the compound used (x-axis). Human lung cancer (A549) cells were cultured in RPMI-1640 with 10% serum in the absence (control) or presence of 250. mu.M of a compound of the invention for 48 hours. The curve represents the number of viable cells (mean error and standard error of the mean of three experiments). The dashed line indicates complete elimination of the cells (0% viability).

FIG. 2. Effect of certain PUFA and D-PUFA molecules of the present invention on the proliferation of A10 vascular cells. The number of cells (% control) is shown on the y-axis, which depends on the fatty acid used (horizontal axis). Cells were incubated in complete medium (control, C), in incomplete medium without supplements (CSS), or in complete medium in the presence of PUFAs (182, 183A, 183G, 204, 205, and 226) or D-PUFAs (182a1, 183A1, 183A2, 204a1, 205a1, and 226a 1). The reduction in proliferation, but still above the value of CSS, indicates that these molecules have the ability to modulate abnormal proliferation of cardiovascular cells, and are not toxic.

FIG. 3

A. Proliferation of adipocytes cultured in the absence (control, C) or in the presence of different D-PUFAs and PUFAs. The number of cells (% control) is indicated on the y-axis, which depends on the fatty acid used (x-axis). As a non-proliferative control, a serum-deficient medium (medium with low serum percentage, MSB) was used.

B. Body weight (% of untreated control) is shown on the Y-axis and compounds used to treat experimental animals are shown on the horizontal axis. On the X-axis, from left to right, the treatment with vehicle (C) first and then with several compounds of the invention is indicated. SHR rats were treated with 200mg/kg of each of the 24 compounds shown in the figure for one month. Each experimental group consisted of six animals and for each series, a group of animals treated with vehicle (water) was used and the results were compared to the weight of animals not receiving any treatment. The letters A, B, N and P indicate the radicals R according to Table 3₁And R₂Combinations of (a) and (b).

FIG. 4

A. Death of P19 cells cultured in the absence of external factors (control, C: 0% neuronal death) and in the presence of NMDA (100% neuronal death). Neuronal death (% of control) is represented on the vertical axis, depending on the fatty acid used (x-axis). The presence of PUFA in the presence of NMDA caused a modest increase in the survival of P19 cells. D-PUFA caused a significant increase in cell viability values, in excess of 200% in the case of 226a 1. Since the number of cells in the culture-treated cells was higher than that of the control cells, it was confirmed that these compounds were not only preventive of neuronal death (anti-neurodegeneration) by NMDA but also neuroregenerative agents.

B.D-226B1PUFA improves the effect of animal models of Alzheimer's disease on the performance of training in the radial maze (radial maze). The Y-axis on the left graph shows the time taken to complete the training and the longitudinal Y-axis on the right graph shows the total number of errors (mean ± standard error of mean) made in performing the programmed training (run time). In both figures, from left to right, the results in healthy mice (control) (first column), in mice with induced alzheimer's disease and treated with water as vehicle (second column) or in mice treated with compound 226B1 (third column) are indicated on the X-axis. Animals with alzheimer's disease spent longer and made more mistakes than healthy mice, were statistically significant differences (, P < 0.05). In contrast, mice with alzheimer's disease treated with compound 226B1 showed no significant difference from healthy animals.

FIG. 5

A. The upper panel is an immunoblot showing the inhibition of the expression of the pro-inflammatory COX-2 protein previously induced by bacterial Lipopolysaccharide (LPS) (C +, 100%) in human macrophages derived from monocyte U937 by the different D-PUFAs of the present invention. In the following figure, the COX-2/COX-1 relationship, expressed as% of control (Y-axis), is shown for the following compounds (X-axis): OOA (2-hydroxy-oleic acid), OLA (182A1), OALA (183A1), OGLA (183A2), OARA (204A1), OEPA (205A1), ODHA (226A 1).

B. The anti-inflammatory efficacy of the different D-PUFA compounds of the invention in animal models of inflammation is shown. The inhibitory effect of different compounds of the invention (X-axis) on the serum levels of TNF α induced by LPS in mice (pg/ml) (y-axis) is shown. The reduction of this factor is directly related to anti-inflammatory drugs. The compounds are the same as in the left panel.

FIG. 6.3 cholesterol levels (A) and total triglycerides (B) in T3-L1 cells. The level of cholesterol (a) or triglyceride (B) (% total lipid) is represented on the vertical axis, depending on the fatty acids used (x-axis). The values shown are the mean values of cholesterol and triglycerides compared to total lipids in the cell membrane ± standard error of the mean values measured by spectroscopic analysis (cholesterol) or thin layer chromatography followed by gas chromatography (triglycerides). The figure shows the quantified values in cells cultured in the absence (control) or presence of the D-PUFA or PUFA listed above.

FIG. 7

A. The relationship between the structure of the membrane and the cellular effects caused by D-PUFA. In the vertical axis with respect to H_IICellular effects of transition temperature (X-axis) (% control). The mean value of the effect of each of the D-PUFA molecules (mean effect per lipid and number of double bonds in all disease models studied) was determined and plotted against the transition temperature. H_IIThe decrease in transition temperature indicates a more induced membrane discontinuity, which leads to the presence of peripherin anchor sites in the membrane and results in better regulation of cell signaling and thus more effective control of certain diseases.

B. The relationship between the therapeutic efficacy of PUFAs (open circles) and D-PUFAs (closed circles). Each point is the average of the effects observed for all the diseases studied (Y axis: change in% relative to control), depending on the number of double bonds provided by each molecule (horizontal axis). In both cases, the correlation was significant (P < 0.05). The therapeutic effect observed depends on the number of double bonds that the molecule possesses, which in turn is correlated with the ability to modulate the membrane structure. In this sense, the presence of groups in carbons 1 and 2 present in D-PUFA rather than PUFA is necessary to enhance the therapeutic effect of these molecules.

These results indicate that the effect of the lipids contained in the present invention have in commonThe basis of (1). These correlations (in both cases, r of 0.77 and 0.9 for D-PUFA)²Values and P < 0.05) clearly indicate that the structure of the lipids used is the basis for their effect and that it occurs through the modulation of the membrane structure caused by the structural functional relationship of each lipid. Indeed, there is a lot of research work on human diseases associated with the above-mentioned changes in PUFA levels, demonstrating the important role of lipids in cellular physiology.

Detailed Description

The broad spectrum of therapeutic applications provided by the D-PUFA molecules of the present invention has led to the extensive assumption that these D-PUFA molecules confer specific structural properties to the membranes that allow for the appropriate manipulation of activity in and through these membranes. In other words, many of the abnormalities that lead to different kinds of diseases are caused by and/or associated with the production of lipids by significant changes in the levels of certain important lipids for cell function and/or proteins that interact with membranes. These pathological changes that can lead to different kinds of diseases can be prevented or reversed by the synthetic fatty acids described in the present invention, which can be effectively used for the treatment or prevention of any disease whose etiology is associated with changes in the level, composition, structure or any other changes of lipids of biological membranes or with the deregulation of cell signaling caused by these changes of these lipids in biological membranes. In addition, the lipids contained in the present invention may also be used as a medicament when a disease occurs due to another change, as long as the result of the modulation of the properties and/or membrane function can reverse the pathological process.

For this study of the therapeutic effect of the fatty acids of the present invention, cultured cell lines and animal models of different diseases were used, and the activities of D-PUFA and PUFA for treating different diseases were studied.

The structures of the molecules of the present invention are shown in tables 1, 2 and 3. Given formula I, the compounds of the invention preferably exhibit the combinations of values of a, b and c shown in table 1.

In addition, in this documentIn the present invention, compounds are named with three number designations followed by the symbol X1 or X2. Number 1 indicates all D-PUFAs used, except based on C18: outside the series of 3 ω -6(γ -linolenic acid), based on C18: the series of 3 omega-6 (gamma-linolenic acid) appears under number 2. The first two digits of the number represent the number of carbons in the molecule. The third digit of the number represents the number of double bonds. The letter X is replaced by any of the letters A to W (Table 3), these letters A to W representing R of formula I₁And R₂A specific combination of (a).

Thus, particularly preferred compounds of the invention are identified according to the following abbreviations: 182X1, 183X1, 183X2, 204X1, 205X1, 226X1 and should be explained in accordance with the above description.

TABLE 1

Table 2 shows the structures of some of the D-PUFA molecules of the invention and the PUFAs derived from them. As can be seen, the table illustrates some of the compounds of the invention having different combinations of values of a, b and c, and wherein the group R₁And R₂Marked with the letter A, which means, as mentioned above, R₁Is H and R₂Is OH (see table 3).

TABLE 2

And (2) Prop: and (4) properties. S: and (3) synthesizing. N: is natural. OH: hydroxylate on carbon 2 (alpha carbon).

Table 3 shows the radicals R which can be combined with the values of a, b and c listed in Table 1₁And R₂Different combinations of (a).

TABLE 3

Examples

Example 1. Percentage of total PUFA in the Membrane of cells treated with D-PUFA and PUFA

Synthetic D-PUFA molecules are hydrophobic and therefore cells exposed to these D-PUFAs have high levels of these fatty acids on their surface.

Table 4 shows the total percentage of PUFAs in the membrane of 3T3 cells treated with 100 μ M of these fatty acids for 48 hours. To perform these experiments, membranes were extracted and total fatty acids were obtained by hydrolysis in alkaline medium. The methanolate group (Methanolic basc) of these fatty acids was quantified by gas chromatography. The data shown are the mass of PUFA divided by the average of four independent measurements of total fatty acids and are expressed as a percentage. The standard error of the mean is also shown. In cell culture, 3T3 cells incubated in the presence of these fatty acids showed higher levels of PUFAs (including D-PUFAs) and lower levels of saturated fatty acids.

The control corresponds to a culture in the absence of added natural or synthetic fatty acids. Cells in their native form present PUFAs in their membranes, but the presence of the D-PUFA molecules of the invention in the culture medium increases these levels of PUFAs in the cell membrane. These results therefore indicate that nutritional or pharmaceutical intervention with these compounds of the invention can effectively modulate the composition of cell membranes.

TABLE 4

Example 2L (lamellar) to H in DEPE (diolaidophosphorylphosphatidylethanolamine) cell membranes_II(hexagonal) transition

Tables 5 and 6 show the layer to hexagonal (H) in the DEPE model membranes_II) The transition temperature. The transition temperature was determined by differential scanning calorimetry. DEPE in all cases: the ratio of D-PUFA is 10: 1 (mol: mol). The lamellar to hexagonal transition is an important parameter reflecting the relevant signalling properties of the cell membrane. Higher H formation when the temperature of the transition is lowered_IIThe trend of the phases indicates that the membrane surface pressure is lower, meaning that the polar head of the phospholipid forms a network that is no denser or tighter than the network formed by the lamellar structure (Escrib et al, 2008.) when this occurs, some peripheral membrane proteins (e.g., G proteins, protein kinase C or Ras proteins) can bind to the membrane more easily, while others have a weak interaction (e.g., G α -protein), so H α -protein_IIChanges in transition temperature are important in regulating cellular functions associated with health and human therapy (Escriba et al, 1995, Vogler et al, 2004; Escriba, 2006).

The control values correspond to model membranes in the absence of fatty acids. H obtained by Using D-PUFA of the present invention_IIA decrease in the transition temperature indicates an increase in the induction of membrane discontinuities, creating anchoring sites in the membrane of the peripheral proteins and resulting in better regulation of cell signaling and therefore greater efficacy in controlling certain diseases.

Thus, Table 5 shows the transition temperature T in DEPE membranes (4mM) in the presence or absence of 200. mu.M of various compounds of the invention of series A_H(layer to hexagon H)_II)。

TABLE 5

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

TABLE 6

Example 3.Gi₁Binding of protein (trimer) to model cell membranes

Modulation of membrane lipid composition results in changes in membrane structure as measured by differential scanning calorimetry, which results in changes in the localization of G proteins in model cell membranes, as shown in table 7. The net result is modulation of cellular signaling, leading to reversal of various pathological processes, as shown later. Table 7 shows heterotrimers Gi₁Protein and phosphatidylcholine: binding of model membranes of phosphatidylethanolamine (6: 4, mol: mol), as measured by centrifuge analysis followed by immunoblotting, by chemiluminescence visualization and by quantification by image analysis. For these experiments, 2mM phospholipid and 0.1. mu.M of different D-PUFAs indicated in Table 7 were used. The control is a model membrane sample in the absence of fatty acids.

These results indicate that as the unsaturation number increases, the resulting modification in the structural and functional properties of the membrane increases. Both the presence of unsaturation and the change at carbons 1 and 2 reduce the metabolic rate of PUFAs. This fact, which is related to the specific effects of these lipids on membrane structure, suggests that the effects on abnormal cells share a common cause.

In fact, there is a good correlation between pharmacological effects and their effects on lipid membrane structure.

TABLE 7

Example 4 use of 1, 2-PUFA derivatives for the treatment of cancer

Cancer is a disease characterized by the uncontrolled proliferation of transformed cells. As indicated above, in addition to certain genetic changes, cancer is characterized by the presence of altered levels of membrane lipids that may affect cell signaling. In this sense, the natural PUFA showed some efficacy against the development of human cancer cells (a549) at the concentrations used in this study, although its metabolic use might prevent greater efficacy (fig. 1). However, D-PUFA showed significant and significantly higher efficacy than the unmodified molecules at carbons 1 and 2 (fig. 1 and table 8) at the same concentration. These results indicate that changes in natural polyunsaturated fatty acids produce molecules with strong and significantly greater anticancer potential than natural PUFAs and thus have many utility in the treatment and prevention of neoplastic diseases in humans and animals by pharmaceutical and nutritional methods.

For the experiment shown in fig. 1, RPMI1640 supplemented with 10% fetal bovine serum and antibiotics at 37 ℃ and 5% CO was used₂Human non-small cell lung cancer cells (a549) cultured under. The cells were kept in culture for 48 hours in the presence or absence of D-PUFA and PUFA shown in Table 2 at a concentration of 250. mu.M. After treatment, cell counts were performed and studies of the mechanisms involved in the anticancer activity of the compounds were evaluated by flow cytometry. Figure 1 shows the percentage of cell survival (100% indicated to untreated tumor cells). These values correspond to the average of three independent experiments.

In different series, the compounds listed in table 3 were used against different tumor types shown in table 8A, table 8B and table 8C. These figures illustrate the anticancer efficacy of the compounds of the present invention against the growth of breast, brain (glioma) and lung cancer. Number of effectsIs expressed as IC after 72 hours of incubation₅₀Values (μ M concentration values yielding 50% death of tumor cells). Other experimental conditions were the same as those described in the preceding paragraph.

The results clearly show that all D-PUFAs are highly effective against cancer development. Overall, it can be seen that the series of compounds a and B are the best, so the efficacy of these series against the development of leukemia and liver cancer was tested (tables 9 and 10). Also, it can be shown that the compounds of series 204 and 226, i.e., the even number numbered D-PUFAs with higher recovery in size, are most effective. These results indicate that there is a structural functional relationship in the pharmacological activity of the invention, which also favors the proposition of a common mechanism of action related to the structure of each compound and thus the unity of the invention in this section.

Table 8A shows the efficacy of the compounds of the invention in controlling the growth of breast cancer cells MDA-MB-231 with micromolar IC₅₀The values are represented.

TABLE 8A

Table 8B shows the efficacy of the compounds of the invention against brain cancer cell growth (glioma) U118 with micromolar IC₅₀The values are represented.

TABLE 8B

Table 8C shows the efficacy of the compounds of the invention against the growth of lung cancer cell A549 with micromolar IC₅₀The values are represented.

TABLE 8C

Table 9 shows the efficacy of the compounds of the invention against the development of human leukemia (Jurkat cells), IC at 72 hours₅₀Micromolar values.

TABLE 9

Table 10 shows the efficacy of the compounds of the invention against the development of liver cancer (HepG2 cells). IC at 72 hours₅₀Micromolar values.

Watch 10

All these results indicate that D-PUFA, which is included in nutritional and pharmaceutical compositions for humans and animals, can be used for the prevention and treatment of cancer. It was also found that the potential of the action of D-PUFA is associated with an increased number of double bonds, and that the presence of changes at carbon 1 and 2 is essential for the anticancer potential of the relevant lipids at therapeutic levels. Since these compounds have anti-cancer effects against a wide range of tumor cells, it is certain that they are molecules with a broad anti-cancer spectrum and may have general application against the development of any cancer.

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

To investigate the effectiveness of D-PUFA for the treatment of cardiovascular diseases, several experimental approaches were used. First, the efficacy of the compounds of the present invention on aortic cells in culture (cell line A-10) 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, without PDGF). The incubation was carried out for a period of 72 hours in a similar manner as described in the preceding paragraph. After this incubation period, cell counts were performed by flow cytometry.

In incomplete medium (CSS, no additional control PDGF), the cells have proliferative behavior similar to that produced in healthy bodies. The proliferation behaviour occurring in complete medium will be a state similar to that occurring in diseased organisms. In complete media with the proliferation agent present in the fetal serum included in the media, the presence of D-PUFA results in a significant reduction in proliferation of normal aortic (a-10) cells. In the presence of proliferating agents (cytokines, growth factors, etc.), the a10 cell counts were similar to those obtained in incomplete medium (CSS) in the presence of D-PUFA of the invention (fig. 2). In contrast, PUFAs show little or no antiproliferative efficacy, demonstrating that changes made in these fatty acids substantially increase their pharmacological potential for the treatment of cardiovascular diseases such as hypertension, atherosclerosis, ischemia, cardiomyopathy, aneurysm, ictus, angiogenesis, myocardial hyperplasia, infarction, angina, stroke (cerebrovascular accident), and the like.

The effect of this cell line cannot be considered toxic for two reasons: (1) in complete medium, D-PUFA never reduced the induction of cell proliferation to a level below that of cells incubated in complete medium, and (2) aortic (a10) cells treated with D-PUFA showed symptoms of no molecular or cellular necrosis, apoptosis, or any other type of cell death. Because the proliferation of vascular cells is associated with the development of many cardiovascular diseases, D-PUFA's are useful in the prevention and treatment of these diseases in humans and animals by nutritional and pharmaceutical means.

In a different series, rat cardiomyocytes were isolated and cultured in vitro for 24 hours, after which several parameters were measured. First, the number, length and width of cells in culture were measured. It was observed that all compounds of series A and B (182-226) were able to increase the number of cells surviving in culture (between 12% and 33%) as well as their length and width (between 18% and 42%). Furthermore, these compounds caused a reduction in the release of Lactate Dehydrogenase (LDH) caused by hypoxia (reduction between 9% and 68% for all compounds of series a and B). These results indicate that the D-PUFA molecules of the present invention have protective effects on cardiovascular cells and increase their elasticity, which is useful for the prevention and treatment of different kinds of heart and vascular diseases, such as hypertension, atherosclerosis, ischemia, cardiomyopathy, aneurysm, ictus, angiogenesis, myocardial hyperplasia, infarction, angina, stroke (cerebrovascular accident), failed blood circulation (failure blood circulation), etc.

The effect of the D-PUFA molecules of the invention on the blood pressure of SHR rats was investigated in different experimental series. In these animals, both blood pressure and apolipoprotein AI (apoA-I) levels were measured. For these experiments, Spontaneously Hypertensive Rats (SHR) were treated with vehicle (water control) or a compound of the invention (200mg/kg day, oral) for 30 days. At the end of this period, the blood pressure and serum levels of apoA-I of the animals were measured. The results show the ability of the compounds of the invention to lower blood pressure and induce the expression of apoA-I, indicating that these molecules are useful for the treatment of hypertension and atherosclerosis (Table 11). For these experiments, the blood pressure (cuff-tail) method) and the gene expression of apoA-I (RT-PCR) described in the literature (Teres et al, 2008) were determined using an atraumatic method. The effectiveness of the molecules of the invention for the treatment of cardiovascular diseases is enhanced by their ability to reduce serum cholesterol and triglyceride levels (see below).

Table 11 shows the blood pressure (mm Hg) and apoA-I levels (%) in SHR rats. The average values of the SHR before treatment were 214mmHg and 100%, respectively.

TABLE 11

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

Fig. 3A shows how PUFAs (both natural and synthetic) can inhibit proliferation and hypertrophy of adipocytes. For this study, 3T3-L1 adipocytes were used. This effect has long been known and unmodified natural PUFAs have been described previously (Hill et al, 1993). However, D-PUFA has increased potential to inhibit proliferation of adipocytes (fig. 3A). This effect is in any case non-toxic, since inhibition of the growth of adipocytes does not reduce cell proliferation to a level lower than cells cultured in incomplete medium (with 1% serum). The cell culture media and conditions used were similar to those described above.

These results demonstrate that D-PUFA has a high potential to inhibit the growth of adipocytes and, therefore, is useful in the prevention and treatment of obesity and other processes associated with the accumulation of body adipocytes (e.g., cellulite) or changes in appetite in animals and humans by nutritional or pharmaceutical means. The observed effect is again clearly related to the number of double bonds of the molecules used and the presence of modifications at carbons 1 and 2 in the lipid molecules.

In addition, several compounds relevant to the present invention were used to study their effect on rat body weight (fig. 3B). In this regard, Spontaneously Hypertensive Rats (SHR) treated with compounds 182-226 (series A, B, N and P) showed a reduction in body weight (3.2% to 6.9% reduction) after 1 month of treatment with 200mg/kg, partly caused by a reduction in food intake and partly by inhibition of adipocyte proliferation (in untreated animals fed the same amount of food, the weight reduction was less pronounced than in treated animals). These results demonstrate that these compounds are useful for weight control (obesity and overweight), appetite control, and body fat (cellulite) regulation.

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

In these studies, different models of neurodegeneration were used. First, P19 cells were studied in which trans retinoic acid was used to induce neuronal differentiation. To do so, at 37 ℃ and at 5% CO₂P19 cells are incubated in minimal essential medium (α -MEM) supplemented with 10% fetal bovine serum and 2 μ M trans retinoic acid the cells are incubated for 24 hours in the presence or absence of several D-PUFAs or PUFAs at different concentrations.the number of cells is induced with 1 μ M NMDA.

Table 12 shows the protective effect against neuronal death in P19 cells: neuronal death (P19 cells) was inhibited with D-PUFA of the invention after treatment with NMDA (100% death). Control cells without NMDA showed a level of 0% cell death. All percentages below 100% indicate that neuronal death is prevented. Negative values indicate that there is a level of neuronal proliferation in addition to protection against neuronal death. Furthermore, the compounds of the invention reduced the levels of α -synuclein (table 13), a protein associated with neurodegenerative processes such as parkinson's disease, alzheimer's disease, dementia with lewy bodies, multiple system atrophy, prion diseases, and the like. Thus, the molecules of the invention may be used in the prevention and treatment of neurodegenerative, neuroregenerative, neurological and neuropsychiatric processes.

TABLE 12

Table 13 shows the expression of α -synuclein in neuronal cultures (cell P19). C (control) represents the% (100%) of alpha-synuclein in untreated cells.

Watch 13

To test the efficacy of the compounds of the invention to induce nerve regeneration or inhibit neurodegeneration, an animal model of alzheimer's disease was used. In this model, mice develop neurodegeneration because they express a series of muteins that cause brain damage (Alzh mice). B6 mice were used as healthy animal controls. Both groups of animals were treated with vehicle (water) or with various D-PUFA (20mg/kg, oral daily) for a period of 3 months from their 3 month age. To determine whether cognitive improvement occurred after treatment, animal behavior was monitored in the radial maze. The animals were kept on a strictly restricted diet in order to have their appetite. In the symmetrical 8-arm radial maze, visual markers were placed to facilitate orientation of the animals, and food (15mg pieces) were placed in the four arms. The time taken for each animal to complete the training and the number of errors were measured using a camera attached to a computer system. In this sense, alzheimer animals had values about 50% higher than healthy animals, depending on both the time taken to perform the training and the number of errors made (fig. 4B). In contrast, alzheimer's mice treated with 226B1 (Alzh + LP226) exhibited behavioral parameters similar to those of control animals and significantly (P < 0.05) lower than those of vehicle-treated animals (Alzh). In this regard, compounds 183B1, 205a1, 205B1, 226a1, 226V1 were also tested for efficacy, showing improvement 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 a reduction in the time taken to complete the experiment in control animals (B6 healthy mice), 8s, 11s, 12s, 18s, 16s and 14s, respectively. Therefore, it can be concluded that these compounds have significant activity in preventing neurodegeneration and nerve regeneration. Neurodegeneration that may be prevented and treated with the D-PUFA molecules of the present invention include alzheimer's disease, parkinson's disease, Zellweger's 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, multiple system atrophy, prion diseases, and the like. Furthermore, the neuroregenerative activity, demonstrated by the effects in both alzheimer-afflicted mice and healthy B6 mice, treatment can be applied in processes where neuronal loss has occurred as a result of accidents, surgery, trauma of different nature or due to certain toxins. The D-PUFA molecules of the invention may also be used to prevent or treat various neurological and/or neuropsychiatric problems, such as headache including migraine, central nervous system injury, sleep disorders, dizziness, pain, stroke (cerebrovascular accident), depression, anxiety, addiction, memory, learning or cognitive problems, and to enhance memory and cognitive abilities in humans.

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

Cyclooxygenase (COX) is an enzyme that can bind to membranes, removing certain lipids from them and catalyzing their conversion into molecules that can have inflammatory activity. The binding of this enzyme to membrane lipids is due in part to the membrane lipid structure. The increased activity of the COX 1 and COX 2 isoforms has been associated with the pathogenesis of various inflammatory diseases by inhibiting arachidonic acid metabolism to produce pro-inflammatory lipid mediators. The D-PUFA compounds of the invention produce a series of cellular signals that alter the metabolism of arachidonic acid and, as a result, they inhibit COX activity and expression in monocytes in culture (table 14 and figure 5). Further, the D-PUFA of the present invention inhibited the production of proinflammatory cytokines (TNF- α) in vivo (table 15 and fig. 5). For this purpose, C57BL6/J mice were treated with various derivatives (200mg/kg, oral) after induction of an inflammatory response in these mice by intraperitoneal injection of 20. mu.g of bacterial Lipopolysaccharide (LPS). These results clearly demonstrate the efficacy of the D-PUFA of the invention to prevent or reverse inflammatory processes and pathologies.

Table 14 shows COX-2 expression in monocytes in culture. Inhibition of COX-2 expression in monocytes. Percent inhibition of COX-2 protein levels (expression) by various fatty acid derivatives (100% compared to positive control in the presence of LPS).

TABLE 14

Table 15 shows the production of TNF- α (%) in mice: percentage of TNF-. alpha.in serum (100%) after intraperitoneal injection of LPS (20. mu.g) in C57BL6/J mice.

Watch 15

These results show that the molecules of the invention can be used to prevent or treat inflammatory diseases, including inflammation, cardiovascular inflammation, inflammation caused by tumors, inflammation of rheumatic origin, inflammation caused by infections, respiratory inflammation, acute and chronic inflammation, hyperalgesia of inflammatory nature, edema, inflammation caused by wounds or burns, etc.

Example 9 use of 1, 2-PUFA derivatives for the treatment of metabolic diseases

Lipids are key molecules for maintaining metabolic function. PUFA treatment produced some modest reductions in cholesterol and triglyceride levels in 3T3-L1 cells. However, D-PUFA treatment caused a significant and significant reduction in cholesterol and triglyceride levels in these cells. For these experiments, at 37 ℃ and 5% CO₂The cells were incubated in RPMI1640 medium in the presence of 10% fetal bovine serum and in the presence or absence of 150. mu.M of a different PUFA or D-PUFA. Cells were incubated for 24h and then subjected to lipid extraction, and cholesterol levels and triglyceride levels were measured according to the procedure previously described (Folch et al, 1951).

SHR rats (200mg/kg daily, 28 days oral) were treated with various compounds of the present invention in different experimental series, and the levels of cholesterol, triglycerides and glucose in serum were measured colorimetrically. It was observed that these compounds induced a significant (and in many cases significant) reduction in the levels of these metabolites (table 16).

The results shown in fig. 6 and table 16 clearly indicate that D-PUFA can be used as a pharmaceutical for the treatment or prevention of metabolic diseases such as hypercholesterolemia, hypertriglyceridemia, diabetes, insulin resistance, etc. in humans and animals by pharmaceutical and nutritional methods. The combination of high levels of cholesterol and triglycerides, high glucose and cardiovascular changes and/or body weight changes causes a "metabolic syndrome" that begins to increase in western society. The compounds of the invention have great potential for the treatment of metabolic syndrome.

Table 16 shows the levels of cholesterol, triglycerides and glucose in SHR rats. This shows the values of cholesterol (top number), triglycerides (middle number) and glucose (bottom number) in the serum of SHR treated with the above molecule (200mg/kg per mesh, oral, 28 days). The values are expressed as percentages and the values in untreated (control) rats are always considered to be 100%.

TABLE 16

Example 10 structural basis for therapeutic Effect of 1, 2-derivatives of PUFA

Numerous studies have shown that lipid uptake or treatment results in changes in the lipid composition of cell membranes. In addition, such compositions have a direct effect on membrane lipid structures, which in turn regulate cell signaling and are involved in the development of many diseases. FIG. 7 shows the change in structure of membranes produced by different D-PUFAs (as by H)_IIMeasured by transition temperature) and the cellular effects observed in this study. For this purpose, we determined the average effect of each D-PUFA (average of each lipid for all diseases studied relative to the number of double bonds) and plotted the results against the transition temperature. H_IIThe reduction in transition temperature indicates that discontinuities in the membrane are more induced, which results in docking sites for peripheral membrane proteins that lead to better regulation of cell signaling and thus to more effective control of certain diseases. The fact that, to some extent, complex organisms can metabolize drugs and some additional mechanisms can operate in some types (subtypes) of disease suggests that some molecules with fewer double bonds may have greater pharmacological activity. However, in general, it appears that the therapeutic effect is dependent onThe number of double bonds of the molecule, which itself is related to the ability to adjust the structure of the membrane. In this sense, the presence of groups in carbons l and/or 2, which occur in the D-PUFA compounds of the invention, rather than in the natural PUFAs, is critical to enhancing the therapeutic effect of these molecules.

These results indicate that the effects of the lipids contained in the present invention have a common basis. These correlations (in both cases, r of 0.77 and 0.9 for D-PUFA)²Values, and P < 0.05) clearly indicate that the structure of the lipid used is the basis for its effect, and that it occurs through the regulation of the membrane structure, resulting from the structural functional relationship of each lipid.

Thus, the present invention relates in a first aspect to a compound of formula (T) or a pharmaceutically acceptable derivative, wherein a, b and c may independently have a value from 0 to 7, and R₁And R₂Can be an ion, an atom or independently a group of atoms having a molecular weight not exceeding 200Da, for use in the treatment of a disease based on structural changes and/or functional characteristics of cell membrane lipids, selected from: cancer, vascular disease, inflammation, metabolic disease, obesity, neurodegenerative disease, and neurological disorder.

A second aspect of the present invention relates to the use of at least one compound of formula (I) or a pharmaceutically acceptable derivative thereof, wherein a, b and c may independently have a value from 0 to 7, and R is a number from 0 to 7, for the preparation of a pharmaceutical and/or nutraceutical composition for the treatment of a disease based on a structural and/or functional change of lipids in the cell membrane₁And R₂May be an ion, an atom or independently a group of atoms having a molecular weight of not more than 200Da, selected from: cancer, vascular disease, inflammation, metabolic disease, obesity, neurodegenerative disease, and neurological disorder.

A final aspect of the invention relates to a method for the therapeutic treatment of human and animal diseases of common etiology associated with structural and/or functional changes of lipids located in cell membranes, selected from: cancer, vascular disease, inflammation, metabolic disease,Obesity, neurodegeneration and neurological diseases, comprising administering to a patient a therapeutically effective amount of at least one compound of formula (I) and/or a pharmaceutically acceptable salt or derivative thereof, wherein a, b and c may have independent values between 0 and 7, and R₁And R₂May be an ion, an atom or independently a group of atoms having a molecular weight of not more than 200 Da.

Reference to the literature

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Claims (16)

1. A compound of formula (I) or a pharmaceutically acceptable salt or derivative thereof:

COOR₁-CHR₂-(CH₂)_a-(CH＝CH-CH₂)_b-(CH₂)_c-CH₃

(I)

wherein a and c may have independent values of 0 to 7, b may have independent values between 2 and 7, and R₁And R₂Can be ions, atoms or radicals having a molecular weight independently equal to or lower than 200Da, for use in therapy orPrevention of a disease based on structural and/or functional and/or compositional changes in cell membrane lipids, said disease being selected from the group consisting of: cancer, vascular diseases, inflammatory diseases, metabolic diseases, obesity and overweight, neurological diseases or neurodegenerative diseases.

2. The compound of formula (I) according to claim 1, characterized by having one of the following six combinations of 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 a2, b6 and c 0; wherein R is₁Selected from the following groups: H. na, K, CH₃O、CH₃-CH₂O and OPO (O-CH)₂-CH₃)₂And R is₂Selected from the following groups: OH, OCH₃.O-CH₃COOH、CH₃、Cl、CH₂OH、OPO(O-CH₂-CH₃)₂NOH, F, HCOO and N (OCH)₂CH₃)₂。

3. The compound according to claim 2, selected from: 182X1, 183X1, 183X2, 204X1, 205X1, and 226X 1.

4.A compound according to claim 3, selected from: 182a1, 183a1, 183a2, 204a1, 205a1, and 226a 1.

5. Use of at least one compound of formula (I) or a salt or a pharmaceutically acceptable derivative thereof, wherein a and c may have independent values between 0 and 7, b may have independent values between 2 and 7, and R is for the manufacture of a pharmaceutical and/or nutraceutical composition for the treatment or prevention of a disease based on structural and/or functional and/or compositional changes in cell membrane lipids₁And R₂May be an ion, an atom or a group of atoms having a molecular weight independently equal to or lower than 200Da, said disease being selected from: cancer, vascular disease, inflammatory disease, metabolic disease, obesity and overweight, and neurodegenerationSexual or neurological disorders.

6. The use according to claim 5, wherein the compound of formula (I) is characterized by having one of the following six combinations of 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, where R is₁Selected from the following groups: H. na, K, CH₃O、CH₃-CH₂O and OPO (O-CH)₂-CH₃)₂And R is₂Selected from the following groups: OH, OCH₃.O-CH₃COOH、CH₃、Cl、CH₂OH、OPO(O-CH₂-CH₃)₂NOH, F, HCOO and N (OCH)₂CH₃)₂。

7. Use according to claim 6, wherein the compound of formula T is selected from the following: 182X1, 183X1, 183X2, 204X1, 205X1, and 226X 1.

8. The use according to claim 7, wherein the compound of formula I is selected from the following: 182a1, 183a1, 183a2, 204a1, 205a1, and 226a 1.

9. A pharmaceutical and/or nutraceutical composition comprising at least one compound of formula (I) or a salt or a pharmaceutically acceptable derivative thereof, wherein a and c may have independent values between 0 and 7, b may have independent values between 2 and 7, and R₁And R₂May be an ion, an atom or a group of atoms having independently a molecular weight not exceeding 200 Da.

10. The composition of claim 9, wherein the compound of formula (I) is characterized by having one of the following six combinations of 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; a2, b 4 and c3; a-2, b-5 and c-0; and a ═ 2, b ═ 6, and c ═ 0, where R is₁Selected from the following groups: H. na, K, CH₃O、CH₃-CH₂O and OPO (O-CH)₂-CH₃)₂And R is₂Selected from the following groups: OH, OCH₃、O-CH₃COOH、CH₃、Cl、CH₂OH、OPO(O-CH₂-CH₃)₂NOH, F, HCOO and N (OCH)₂CH₃)₂。

11. The composition of claim 10, wherein the compound of formula I is selected from the following: 182X1, 183X1, 183X2, 204X1, 205X1, and 226X 1.

12. The composition of claim 11, wherein the compound of formula I is selected from the following: 182a1, 183a1, 183a2, 204a1, 205a1, and 226a 1.

13. A method for the therapeutic treatment or prevention of a disease in humans and animals, the common cause of which is associated with a structural and/or functional and/or compositional change in lipids located in the cell membrane, said disease being selected from the group consisting of: cancer, vascular diseases, inflammatory diseases, metabolic diseases, obesity and overweight, and neurological or neurodegenerative diseases; the method comprises administering to the patient a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein a and c can have independent values from 0 to 7, b can have independent values between 2 and 7, and R₁And R₂May be an ion, atom or group of atoms having a molecular weight independently equal to or lower than 200 Da.

14. The method of claim 13, wherein the applied compound of formula I is characterized by having one of the following six combinations of 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 a2, b6 and c0, wherein R₁Selected from the following groups: H. na, K, CH₃O、CH₃-CH₂O and OPO (O-CH)₂-CH₃)₂And R is₂Selected from the following groups: OH, OCH₃、O-CH₃COOH、CH₃、Cl、CH₂OH、OPO(O-CH₂-CH₃)₂NOH, F, HCOO and N (OCH)₂CH₃)₂。

15. The method of claim 14, wherein the compound of formula I is selected from: 182X1, 183X1, 183X2, 204X1, 205X1, and 226X 1.

16. The method of claim 15, wherein the compound of formula I is selected from: 182a1, 183a1, 183a2, 204a1, 205a1, and 226a 1.