HK1232207B - Use of derivates of polyunsaturated fatty acids as medicaments - Google Patents

Description

Use of polyunsaturated fatty acid derivatives as medicines

This application is a divisional application of Chinese invention patent application No. 201080011939.8, filed on March 15, 2010, and entitled “Use of derivatives of polyunsaturated fatty acids as medicines”.

Field of the Invention

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 that interact with them; and for the treatment of diseases in which the regulation of lipid composition and membrane structure and the regulation of proteins that interact with them leads to the reversal of pathological conditions.

Therefore, because the present invention has a broad range of applications, it may be generally included in the fields of medicine and pharmaceutics.

Background Art

Cell membrane is the structure that defines the organization of the organelle that cell and cell comprise.Most of biological processes occur in membrane or near membrane.Lipid not only has structural function but also regulates the activity of important process.And, regulating membrane lipid composition also affects the position or function of important proteins such as G protein or PKC that participate in controlling the physiology of cell (people such as Escribá, 1995,1997, Yang et al., 2005, Martinez et al., 2005).These and other studies have proved the importance of lipid in controlling important cell function.In fact, many human diseases such as cancer, cardiovascular disease, neurodegenerative disease, obesity, metabolic disorder, tumor and inflammatory disease, infectious disease or autoimmune disease and other are relevant with the level of lipid in biomembrane or the variation of composition, further proved that except regulating the composition of membrane lipid and the fatty acid of structure of the present invention, can be used for reversing the beneficial effect (Escribá, 2006) of these diseases with fatty acid treatment.

Lipids consumed in the diet regulate the lipid composition of cell membranes (Alemany et al., 2007). In addition, various physiological and pathological conditions can modify the lipids in cell membranes (Buda et al., 1994; Escribá, 2006). As an example of a condition that induces physiological changes in membrane lipids, fish living in a river with variable temperature can be mentioned, where, when the temperature drops from 20°C (summer) to 4°C (winter), the lipids of the fish undergo important changes (changes in the amount and type of membrane lipids) (Buda et al. 1994). These changes allow them to maintain their function in cell types of different nature. Examples of pathological processes that can affect lipid composition are neurological disorders or drug-induced diseases (Rapoport, 2008). Therefore, it can be said that membrane lipids can determine the correct activity of various mechanisms of cell signaling.

Changes in membrane lipid composition influence cell signaling and can contribute to the development or reversal of disease (Escribá, 2006). Various studies over the past few years have shown that membrane lipids play a more relevant role than has been previously assigned (Escribá et al., 2008). The traditional view of the cell membrane assigns a purely structural role to lipids, acting as carriers of membrane proteins, which were considered the membrane's sole functional element. The plasma membrane would have an additional role, preventing the entry of water, ions, and other molecules into the cell. However, membranes have other functions that are crucial in maintaining health, the development of disease, and healing. Because the body becomes ill because its cells become ill, changes in membrane lipids produce cellular changes that can lead to the development of disease. Similarly, therapeutic, nutritional, or cosmetic interventions aimed at regulating membrane lipid levels can prevent and reverse (cure) pathological processes. Furthermore, numerous studies have shown that the consumption of saturated and trans-monounsaturated fats is associated with worsening health. In addition to the aforementioned neurological diseases, vascular disease, cancer, and other diseases are also directly linked to membrane lipids (Stender and Dyerberg, 2004). The deterioration of the body is manifested in the emergence of this and other types of diseases, which may include metabolic diseases, inflammation, neurodegeneration, etc.

The cell membrane is a selective barrier through which cells receive metabolites and information from other cells and the extracellular environment surrounding them. However, membranes perform other very important functions in cells. In one aspect, they serve as carriers for proteins involved in receiving or sending information that controls important organ functions. These messages, mediated by many hormones, neurotransmitters, cytokines, growth factors, etc., activate membrane proteins (receptors), which transmit the received signals to the cell via other proteins (peripheral membrane proteins), some of which are also located in the membrane. Because (1) these systems act in an amplification cascade, and (2) membrane lipids can regulate the localization and activity of these peripheral proteins, the lipid composition of the membrane can have a major impact on the physiology of the cell. Specifically, the interaction of certain peripheral proteins such as G proteins, protein kinase C, Ras proteins, etc. with the cell membrane depends on its 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 (Escribá et al., 2003). Indeed, nutrient or pharmaceutical lipid manipulations can modulate the lipid composition of membranes, which in turn can control the interactions (and hence the activity) of important cell signaling proteins (Yang et al., 2005).

The fact that membrane lipids are able to control cell signaling also makes it possible to assume that they can regulate the physiological state of the cell and, therefore, the general state of health. In fact, both negative and positive effects of lipids on health have been described (Escribá et al., 2006; Escribá 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 (Alemany et al., 2004, Martinez et al., 2005; Vogler et al., 2008).

Cardiovascular disease is often associated with the excessive proliferation of cells that constitute the heart and vascular tissue. This excessive proliferation produces cardiovascular deposits in the lumen of the vessels and the cavity of the cardiovascular system, leading to many diseases, such as hypertension, atherosclerosis, ischemia, aneurysm, sudden attack, infarction, angina, stroke (cerebrovascular accident) etc. (Schwartz et al., 1986). In fact, it has been proposed that the development of drugs that prevent cell proliferation will be a good alternative for preventing and treating cardiovascular disease (Jackson and Schwartz, 1992).

Obesity is caused by the balance of the change between intake and energy expenditure, partly due to the variation of the mechanism of regulating these processes.On the other hand, the feature of this illness is, the hyperplasia (increase of cell number) or hypertrophy (the size of increase) of adipocyte (fat cell), adipocyte (adipocyte).A large amount of research shows, do not contain other molecules or as the lipid acid of a part for other molecules, can affect many parameters relevant to energy homeostasis, such as body fat mass, lipid metabolism, heat generation and food intake and other (Vogler et al., 2008).In this sense, the modification of lipid acid can be to regulate energy homeostasis, i.e. the balance between intake and energy expenditure, and therefore regulate the strategy of related process such as appetite or body weight.

Neurodegenerative process causes many to have different performances, but has the disease of the common feature caused by the degeneration of central and/or peripheral nervous system cells or dysfunction.Some in these neurodegenerative processes relate to the remarkable reduction of patient's cognitive ability or the variation of their motor ability.Neurodegenerative disease, neurological disease and neuropsychiatric disease have the common basis of the variation of components such as lipid (for example, myelin) or membrane protein (for example, adrenergic receptor, 5-hydroxytryptamine receptor etc.) of neuronal degeneration or neuron.Such central nervous system especially comprises Alzheimer's disease, Parkinson's disease, multiple sclerosis, ALS, hippocampal sclerosis and other types of epilepsy, focal sclerosis, adrenoleukodystrophy and other leukodystrophy, vascular dementia, senile dementia, headache comprising migraine, central nervous system trauma, sleep disorder, dizziness, pain, apoplexy (cerebrovascular accident), depression, anxiety or addiction.In addition, some neurological disease and neurodegenerative disease can cause the process with the outcome such as blindness, hearing problem, disorientation, emotion change.

An example of a well-characterized neurodegenerative disorder is Alzheimer's disease, which is characterized by the formation of plaques composed of membrane protein fragments (e.g., beta-amyloid peptides) that originate primarily from faulty peptide processing, followed by accumulation on the exterior 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, and senile dementia (or Lewy bodies) are associated with the pathological accumulation of fibrillar aggregates of alpha-synuclein, which leads to significant changes in the cellular metabolism of triglycerides (Coles et al., 2001). In fact, the development of these and other neurodegenerative diseases is associated with changes in serum or cellular lipids such as cholesterol, triglycerides, sphingomyelin, phosphatidylethanolamine, etc. This in turn suggests that lipids play a vital role in the proper activity of neurons, nerves, brain, cerebellum, and spinal cord, which logically provides the abundance of lipids in the central nervous system. The molecules of the present invention have high or very high potential to reverse a number of 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 the neuronal axons, with subsequent changes in the propagation processes of electrical signals in which the lipids participate. Myelin is a fatty layer formed by a series of spiral folds surrounding the axons of many neurons and by the plasma membrane of glial cells (Schwann cells). Therefore, it is clear that lipids play an important role in the development of neurodegenerative diseases. Moreover, it was found that unmodified natural PUFAs 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, and its abundance changes in many neurodegenerative processes.

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. Increased levels of glucose, cholesterol and/or triglycerides, both systemically (e.g., increased plasma levels) and at the cellular level (e.g., in the cell membrane), are associated with changes in cell signaling that lead to varying degrees of dysfunction, and are usually 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 high incidence, morbidity and mortality rates, making their treatment a primary necessity. Other important metabolic diseases include diabetes and insulin resistance, which are characterized by problems controlling glucose levels. These metabolic diseases are related to the emergence of other diseases, such as cancer, hypertension, obesity, atherosclerosis, etc. Recently, another disease process has been defined that is closely related to the above-mentioned metabolic disorders and that itself can constitute a new type of metabolic pathology (metabolopathy), namely metabolic syndrome.

The protective effect of certain polyunsaturated fatty acids (PUFAs) against certain diseases has been described by various researchers. For example, PUFAs slow the development of cancer and have a positive effect against the development of cardiovascular diseases, neurodegenerative diseases, metabolic disorders, obesity, inflammation, etc. (Trombetta et al., 2007, Jung et al., 2008, Florent et al., 2006). These stimuli indicate the important role of lipids (PUFAs) in the etiology and treatment of various diseases. However, the pharmacological activity of these compounds (PUFAs) is very limited due to rapid metabolism and short half-life in the blood. Therefore, it is necessary to develop PUFAs that have a slower metabolism than the PUFAs used so far, resulting in an increased presence in cell membranes, which favors the interaction of peripheral proteins in cell signaling. The molecules of the present invention are synthetic derivatives of PUFAs that have a slower metabolism than natural PUFAs and a significant and apparently superior therapeutic effect.

Because of the relationship between changes in the structure and function of lipids located in cell membranes and the development of a variety of diseases of different types but with a single etiology related to changes in the structure and/or function of lipids in membrane cells, such as cancer, cardiovascular disease, obesity, inflammation, neurodegeneration and metabolic diseases, the present invention focuses on the use of new synthetic polyunsaturated fatty acids that are able to solve the technical problems associated with the above-mentioned known fatty acids, and therefore, they can be effectively used to treat these diseases.

Description of the Invention

Summary of the Invention

The present invention focuses on 1,2-derivatives of polyunsaturated fatty acids (hereinafter: D-PUFAs) for the treatment of common diseases whose etiology is linked to changes in the structure and/or function of cell membrane lipids or proteins interacting with them, particularly selected from the group consisting of 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) at carbon 1 and/or 2 impedes their degradation by β-oxidation. This leads to significant changes in membrane composition and modulates the interactions of peripheral proteins involved in cell signaling. This can, for example, result in differences in the packing of membrane surfaces and modulate the anchoring of peripheral proteins involved in the transmission of cellular messages. Consequently, the D-PUFA molecules that are the subject of the present invention have greater activity than PUFAs and exhibit significantly higher efficacy in the pharmacological treatment of the identified diseases.

As mentioned above, the diseases that can be treated with the D-PUFA molecules of the present invention share the same etiology, which is related to changes in the structure and/or function (or any other source) of cell membrane lipids or changes in the structure and/or function (or any other source) of 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, 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 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, Alzheimer's disease, dementia with Lewy bodies, multiple system atrophy, prion diseases, headaches including migraines, central nervous system damage, sleep disorders, dizziness, pain, stroke (cerebrovascular accident), depression, anxiety, addiction, memory, learning or cognitive problems and general diseases that require cessation of neurodegeneration or neuroregeneration by treatment with the compounds of the invention.

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

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

COOR ₁ -CHR ₂ -(CH ₂ ) _a -(CH=CH-CH ₂ ) _b -(CH ₂ ) _c -CH ₃

(I)

wherein a, b and c may have independent values between 0 and 7, and R ₁ and R ₂ may be ions, atoms or atomic groups having a molecular weight independently not exceeding 200 Da.

In a preferred structure of the present invention, a, b and c may have independent values between 0 and 7, _R1 is H and _R2 is OH.

In another preferred structure of the present invention, a, b and c may have independent values between 0 and 7, _R1 is Na and _R2 is OH.

In another preferred structure of the present invention, a and c can have independent values between 0 and 7, b can have independent values between 2 and 7, and _R1 and _R2 can be ions, atoms or atomic groups thereof whose molecular weight is independently equal to or lower than 200 Da.

The administration of the fatty acids of the present invention can be carried out in any manner, for example enterally (IP), orally, rectally, topically, by inhalation or by intravenous, intramuscular or subcutaneous injection. In addition, the administration can be according to the above formula or any pharmaceutically acceptable derivative thereof, for example: ester, ether, alkyl, acyl, phosphate, sulfate, ethyl, methyl, propyl, salt, complex, etc.

In addition, the fatty acids of the present invention can be administered alone or formulated in pharmaceutical compositions and/or nutraceutical compositions in combination with each other and/or with excipients, such as binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavoring excipients, coloring excipients, transporters, and the like, and all combinations thereof. Furthermore, the fatty acids of the present invention can be part of pharmaceutical compositions and/or nutraceutical compositions in combination with other active ingredients.

For the purposes of the present invention, the term "nutrient" is defined as a compound that is regularly ingested during the meal and used to prevent disease, in which case the etiology 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 THE DRAWINGS

Figure 1. Effects of the compounds in Table 1 on tumor cell growth. The y-axis represents the number of viable cells (% control), which depends on the compound used (x-axis). Human lung cancer (A549) cells were cultured for 48 hours in RPMI-1640 with 10% serum in the absence (control) or presence of 250 μM of the compounds of the invention. The curve represents the number of viable cells (mean and standard error of the mean of three experiments). The dotted line represents the complete elimination of cells (0% viability).

Figure 2. Effect of certain PUFA and D-PUFA molecules of the invention on the proliferation of A10 vascular cells. The y-axis shows the number of cells (% control), depending 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 226A1). The decrease in proliferation, while still above the CSS value, indicates that these molecules have the ability to regulate the abnormal proliferation of cardiovascular cells without toxicity.

Figure 3

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

B. Body weight (% of untreated control) is represented on the Y-axis and the compound for processing experimental animals is represented on the horizontal axis. On the X-axis, from left to right, expression is first processed with vehicle (C), then processed with several compounds of this invention. SHR rats are processed one month with each of the 24 compounds shown in the figure at 200mg/kg. Each experimental group is made up of six animals, and for each series, a group of animals processed with vehicle (water) is used, and the result is compared with the weight of the animal that does not receive any treatment. Letters A, B, N and P indicate the combination of radical R ₁ and R ₂ according to Table 3.

Figure 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). The vertical axis represents neuronal death (% of control), which depends on the fatty acid used (x-axis). In the presence of NMDA, the presence of PUFAs causes a moderate increase in the viability of P19 cells. D-PUFAs cause a significant increase in cell viability values, exceeding more than 200% in the case of 226A1. Since the cell number of cultured treated cells is higher than that of control cells, it can be confirmed that these compounds not only prevent neuronal death caused by NMDA (anti-neurodegeneration) but also act as neuroregenerative agents.

B. The effect of D-226B1 PUFA on improving the training performance of an animal model of Alzheimer's disease in a radial maze. The Y-axis of the left graph shows the time it takes to complete the training, and the vertical Y-axis of the right graph shows the total number of errors made in performing the programmed training (mean ± standard error of the mean) (run time). In both figures, from left to right, the X-axis represents the results in healthy mice (control) (first column), the results in mice with induced Alzheimer's disease and treated with water as a vehicle (second column), or the results in mice treated with compound 226B1 (third column). Animals with Alzheimer's disease took longer and made more errors than healthy mice, which was a statistically significant difference (*, P < 0.05). In contrast, mice with Alzheimer's disease treated with compound 226B1 did not show significant differences from healthy animals.

Figure 5

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

B. Shows the anti-inflammatory efficacy of various D-PUFA compounds of the present invention in an animal model of inflammation. Shown is the inhibitory effect of various compounds of the present invention (x-axis) on serum levels (pg/ml) of TNFα induced by LPS in mice (y-axis). This reduction in TNFα is directly correlated with anti-inflammatory effects. The compounds are the same as those in the left panel.

Figure 6. Cholesterol levels (A) and total triglycerides (B) in 3T3-L1 cells. The vertical axis shows the level of cholesterol (A) or triglycerides (B) (% total lipids), depending on the fatty acid used (x-axis). The values shown are the mean ± standard error of the mean of cholesterol and triglycerides compared to the total lipids in the cell membrane, measured by spectrometry (cholesterol) or thin layer chromatography followed by gas chromatography (triglycerides). The graph shows the quantitative values in cells cultured in the absence (control) or presence of the D-PUFA or PUFA listed above.

Figure 7

A. Relationship between membrane structure and cellular effects induced by D-PUFAs. The vertical axis represents the cellular effect (% control) relative to the H _II transition temperature (X axis). The effect of each D-PUFA molecule was averaged (average effect per lipid and number of double bonds across all disease models studied) and plotted against the transition temperature. A decrease in the _{H II} transition temperature indicates greater induction of membrane discontinuities, which leads to the presence of anchoring sites for peripheral proteins in the membrane, resulting in better regulation of cell signaling and, therefore, more effective control of certain diseases.

B. Relationship between the therapeutic efficacy of PUFAs (open circles) and D-PUFAs (filled circles). Each point represents the mean of the observed effects for all diseases studied (Y axis: % change relative to the 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 observed therapeutic effect depends on the number of double bonds possessed by the molecule, which in turn correlates with the ability to regulate membrane structure. In this sense, the presence of groups at carbons 1 and 2, which are present in D-PUFAs but not in PUFAs, is essential for enhancing the therapeutic effect of these molecules.

These results suggest that the effects of the lipids included in this invention share a common basis. These correlations (in both cases, with ^r² values of 0.77 and 0.9 for D-PUFA and P<0.05) clearly demonstrate that the structure of the lipids used underlies their effects, and that this occurs through modulation of membrane structure due to the structure-function relationship of each lipid. Indeed, there is extensive research linking human disease to these changes in PUFA levels, demonstrating the important role of lipids in cell physiology.

Detailed Description of the Invention

The broad spectrum of therapeutic applications offered by the D-PUFA molecules of the present invention has led to the widespread assumption that these D-PUFA molecules impart specific structural properties to membranes that allow for the appropriate manipulation of activities in and through these membranes. In other words, many of the abnormalities that lead to a wide range of diseases are caused by significant changes in the levels of certain lipids important for cellular function and/or proteins that interact with membranes, and/or are related to lipid production. These pathological changes that can lead to a wide range of diseases can be prevented or reversed by the synthetic fatty acids described in this 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 changes in biological membrane lipids, or to counterregulation of cellular signaling caused by these changes in these lipids in biological membranes. Furthermore, when the disease is caused by another change, the lipids included in this invention can also be used as pharmaceuticals, provided that the resulting modulation of properties and/or membrane function is able to reverse the pathological process.

For this study of the therapeutic effects of the fatty acids of the present invention, cultured cell lines and animal models of different diseases were used, and the activity of D-PUFA and PUFA in treating different diseases was investigated.

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

Furthermore, in the present invention, compounds are designated using a three-digit number followed by the symbol X1 or X2. The number 1 represents all D-PUFAs used, except for the C18:3ω-6 (γ-linolenic acid)-based series, which appears as number 2. The first two digits of the number represent the number of carbon atoms in the molecule. The third digit represents the number of double bonds. The letter X is replaced by any of the letters A to W (Table 3), which represent specific combinations of _R1 and _R2 in Formula I.

Therefore, particularly preferred compounds of the present invention are identified according to the following abbreviations: 182X1, 183X1, 183X2, 204X1, 205X1, 226X1 and are to be interpreted in light of the above description.

Table 1

Table 2 shows the structures of some of the D-PUFA molecules of the present invention and the PUFAs derived therefrom. As can be seen, the table illustrates some compounds of the present invention having different combinations of values for a, b, and c, and wherein the groups _R and _R are labeled with the letter A, meaning that, as described above, _R is H and _R is OH (see Table 3).

Table 2

Prop: property. S: synthetic. N: natural. OH: hydroxylation at carbon 2 (alpha carbon).

Table 3 shows different combinations of groups R ₁ and R ₂ that can be combined with the values of a, b and c listed in Table 1.

Table 3

Example

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

The synthesized 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 PUFA in the membranes of 3T3 cells treated with 100 μM of these fatty acids for 48 hours. In order to carry out these experiments, the membranes were extracted and total fatty acids were obtained by hydrolysis in an alkaline medium. The methanolic base of these fatty acids was quantified by gas chromatography. The data shown are the average value of four independent measurements of the mass of PUFA divided by the total fatty acids and expressed as a percentage. The standard error of the mean value is also shown. In cell culture, 3T3 cells incubated in the presence of these fatty acids showed higher levels of PUFA (including D-PUFA) and lower levels of saturated fatty acids.

The control corresponds to a culture in which no added natural or synthetic fatty acids are present. Cells in their natural form present PUFAs in their membranes, but the presence of the D-PUFA molecules of the present invention in the culture medium increases these levels of PUFAs in the cell membranes. These results therefore demonstrate that nutritional or pharmaceutical intervention with the compounds of the present invention can effectively modulate the composition of cell membranes.

Table 4

Example 2. L (lamellar) to H _II (hexagonal) transition in DEPE (dielaidoilphosphatidylethanolamine) cell membranes

Tables 5 and 6 show the lamellar-to-hexagonal ( _HII ) transition temperatures in DEPE model membranes. The transition temperatures were determined by differential scanning calorimetry. In all cases, the DEPE:D-PUFA ratio was 10:1 (mol:mol). The lamellar-to-hexagonal transition is an important parameter reflecting the signaling properties of cell membranes. A higher tendency to form the _HII phase when the transition temperature is lowered indicates lower membrane surface pressure, meaning that the polar head groups of phospholipids form a network that is less dense or compact than that formed by lamellar structures (Escribá et al., 2008). When this occurs, some peripheral membrane proteins (such as G proteins, protein kinase C, or Ras proteins) can more readily bind to the membrane, while others have weaker interactions (such as Gα-proteins). Therefore, changes in the _HII transition temperature are important in regulating cellular functions relevant to health and human therapy (Escriba et al., 1995; Vogler et al., 2004; Escriba, 2006).

The control value corresponds to a model membrane in which no fatty acids are present. The reduction in the H _II transition temperature obtained by using the D-PUFAs of the present invention indicates an increased induction of membrane discontinuities, the creation of anchoring sites in the membrane for peripheral proteins, and a better regulation of cell signaling and, therefore, a greater efficacy in controlling certain diseases.

Table 5 thus shows the transition temperatures _TH (lamellar to hexagonal H _II ) in DEPE membranes (4 mM) in the presence or absence of 200 μM of various compounds of the series A according to the invention.

Table 5

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

Table 6

Example 3. Binding of _{Gi 1} protein (trimer) to model cell membrane

Modulating membrane lipid composition results in changes in membrane structure, as measured by differential scanning calorimetry, which in turn results in changes in the localization of G proteins in model cell membranes, as shown in Table 7. The net result is modulation of cell signaling, leading to the reversal of various pathological processes, as shown later. Table 7 shows the binding of heterotrimeric _Gi1 proteins to model membranes of phosphatidylcholine:phosphatidylethanolamine (6:4, mol:mol), as measured by centrifuge analysis, followed by immunoblotting, chemiluminescence development, and quantification by image analysis. For these experiments, 2 mM phospholipids and 0.1 μM of the various D-PUFAs indicated in Table 7 were used. Controls were model membrane samples in the absence of fatty acids.

These results indicate that increasing the number of unsaturations leads to increased changes in the structural and functional properties of membranes. Both the presence of unsaturation and changes at carbons 1 and 2 reduce the metabolic rate of PUFAs. This fact, coupled with the specific effects of these lipids on membrane structure, suggests a common cause for the effects on abnormal cells.

Indeed, 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 treating cancer

Cancer is a disease characterized by the uncontrolled proliferation of transformed cells. As shown 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, natural PUFAs showed some efficacy against the development of human cancer cells (A549) at the concentrations used in this study, although their metabolic uses may prevent greater efficacy (Figure 1). However, D-PUFAs showed significant and significantly higher efficacy than unmodified molecules at carbons 1 and 2 at the same concentrations (Figure 1 and Table 8). These results indicate that changes in natural polyunsaturated fatty acids produce molecules with strong and significantly greater anti-cancer potential than natural PUFAs, and therefore have a lot of utility in treating and preventing neoplastic diseases in humans and animals through pharmaceutical and nutritional approaches.

For the experiment shown in Figure 1, human non-small cell lung cancer cells (A549) cultured at 37 ° C and 5% CO ₂ in RPMI1640 supplemented with 10% fetal bovine serum and antibiotics were used. The cells were kept in culture for 48 hours in the presence or absence of 250 uM concentrations of D-PUFA and PUFA shown in Table 2. After treatment, cell counts were performed and the mechanisms involved in the anticancer activity of the compounds were evaluated by flow cytometry. Figure 1 shows the percentage of cell viability (100% indicates untreated tumor cells). These values correspond to the average of three independent experiments.

In different series, the compounds listed in Table 3 were used to fight against the different tumor types shown in Table 8A, Table 8B and Table 8C. These figures show the anticancer efficacy of the compounds of the present invention against the growth of breast cancer cells, brain cancer (glioma) and lung cancer. The efficacy data are expressed as _IC50 values (μM concentration value that produces 50% tumor cell death) after 72 hours of incubation. Other experimental conditions are the same as those described in the previous 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 these series were tested for their efficacy against the development of leukemia and liver cancer (Tables 9 and 10). Furthermore, it can be shown that the compounds of series 204 and 226, i.e., the D-PUFAs with even pair numbers that are higher in size, are the most effective. These results suggest a structure-function relationship in the pharmacological activity of the present invention, which also supports the proposition of a common mechanism of action related to the structure of each compound and, therefore, the unity of the invention in this section.

Table 8A shows the efficacy of compounds of the present invention in controlling the growth of breast cancer cells MDA-MB-231, expressed as micromolar _IC50 values.

Table 8A

Table 8B shows the efficacy of compounds of the invention against the growth of brain cancer cells (glioma) U118, expressed as micromolar _IC50 values.

Table 8B

Table 8C shows the efficacy of compounds of the present invention against the growth of lung cancer A549 cells, expressed as micromolar _IC50 values.

Table 8C

Table 9 shows the efficacy of the compounds of the invention against the development of human leukemia (Jurkat cells) with _IC50 micromolar values at 72 hours.

Table 9

Table 10 shows the efficacy of the compounds of the present invention against the development of liver cancer (HepG2 cells). _IC50 micromolar values at 72 hours.

Table 10

All of these results suggest that D-PUFAs, when included in nutritional and pharmaceutical compositions for humans and animals, may be useful for the prevention and treatment of cancer. It was also found that the potential for the effects of D-PUFAs correlates with an increased number of double bonds, and that the presence of changes at carbons 1 and 2 is essential for the anticancer potential of the lipids involved to be at therapeutic levels. Because these compounds have anticancer effects against a wide range of tumor cells, it is clear that they are molecules with a broad anticancer spectrum and may have general application in combating 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-PUFAs for treating cardiovascular disease, several experimental approaches were employed. First, the efficacy of the compounds of the present invention on aortic cells (cell line A-10) in culture was investigated. These cells were maintained in culture in complete medium (C, supplemented with 10% fetal bovine serum and PDGF) and incomplete medium (CSS, supplemented with 1% fetal bovine serum and lacking PDGF). Cultures were performed for a period of 72 hours in a manner similar to that described in the previous paragraph. Following this incubation period, cell counts were performed by flow cytometry.

In incomplete culture medium (CSS, without additional control PDGF), cells exhibited a proliferation behavior similar to that observed in a healthy body. The proliferation behavior observed in complete culture medium would be a state similar to that observed in a diseased body. In complete culture medium with proliferation agents present in fetal serum included in the culture medium, the presence of D-PUFAs resulted in a significant reduction in the proliferation of normal aortic (A-10) cells. In the presence of proliferation agents (cytokines, growth factors, etc.), A10 cell counts were similar to those obtained in incomplete culture medium (CSS) in the presence of D-PUFAs of the present invention ( FIG. 2 ). In contrast, PUFAs exhibited little or no antiproliferative efficacy, demonstrating that modifications to these fatty acids substantially increase their pharmacological potential for the treatment of cardiovascular diseases such as hypertension, atherosclerosis, ischemia, cardiomyopathy, aneurysm, stroke, angiogenesis, myocardial hyperplasia, infarction, angina, stroke (cerebrovascular accident), and the like.

The effects on this cell line cannot be considered toxic for two reasons: (1) D-PUFAs never reduced the induction of cell proliferation below that of cells incubated in complete medium, and (2) aortic (A10) cells treated with D-PUFAs showed no signs of 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-PUFAs may be used to prevent and treat these diseases in humans and animals through nutritional and pharmaceutical approaches.

In 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 the cells in culture were measured. It was observed that all compounds from series A and B (182-226) were able to increase the number of cells surviving in culture (by between 12% and 33%), as well as their length and width (by between 18% and 42%). Furthermore, these compounds caused a decrease in the release of lactate dehydrogenase (LDH) induced by hypoxia (by between 9% and 68% for all compounds from series A and B). These results suggest that the D-PUFA molecules of the present invention have a protective effect on cardiovascular cells and increase their elasticity, which could be used to prevent and treat various heart and vascular diseases, such as hypertension, atherosclerosis, ischemia, cardiomyopathy, aneurysms, stroke, angiogenesis, myocardial hyperplasia, infarction, angina, stroke (cerebrovascular accident), and faulty blood circulation.

In a separate series of experiments, the effects of the D-PUFA molecules of the present invention on blood pressure in SHR rats were investigated. In these animals, both blood pressure and apolipoprotein AI (apoA-I) levels were measured. For these experiments, spontaneously hypertensive rats (SHRs) were treated with either vehicle (water control) or a compound of the present invention (200 mg/kg/day, orally) for 30 days. At the end of this period, the animals' blood pressure and serum apoA-I levels were measured. The results demonstrate the ability of the compounds of the present invention to lower blood pressure and induce apoA-I expression, suggesting that these molecules may be useful in treating hypertension and atherosclerosis (Table 11). For these experiments, blood pressure (cuff-tail method) and apoA-I gene expression (RT-PCR) as described in the literature (Terés et al., 2008) were determined using non-invasive methods. The effectiveness of the molecules of the present invention for treating cardiovascular disease is reinforced by their ability to lower serum cholesterol and triglyceride levels (see below).

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

Table 11

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

FIG3A shows how PUFAs (both natural and synthetic) can inhibit the proliferation and hypertrophy of adipocytes. For this study, 3T3-L1 adipocytes were used. This effect is already known and has been previously described for unmodified natural PUFAs (Hill et al., 1993). However, D-PUFAs have an increased potential to inhibit the proliferation of adipocytes ( FIG3A ). This effect is non-toxic in any case, as the inhibition of adipocyte growth does not reduce cell proliferation to levels below those of cells cultured in incomplete medium (with 1% serum). The cell culture medium and conditions used were similar to those described above.

These results demonstrate that D-PUFAs have a high potential to inhibit the growth of adipocytes and, therefore, are useful for the prevention and treatment of obesity and other processes associated with the accumulation of body fat cells (e.g., cellulite) or changes in appetite in animals and humans, either by nutritional or pharmaceutical means. The observed effects again showed a clear correlation with the number of double bonds in the molecules used and the presence of modifications at carbons 1 and 2 in the lipid molecule.

In addition, use some compounds relevant to the present invention to study their effects (Fig. 3 B) on the body weight of rats. In this regard, spontaneously hypertensive rats (SHR) treated with compound 182-226 (series A, B, N and P) showed a decrease in body weight (reducing by 3.2% to 6.9%) after 1 month of treatment with 200mg/kg, which was partly caused by the decrease in food intake and partly by the inhibition of adipocyte proliferation (in the untreated animals fed with the same amount of food, weight loss was not as significant as in the treated animals). These results demonstrate that these compounds can be used for the control (obesity and overweight), appetite control and body fat (cellulite) regulation of body weight.

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

In these studies, different neurodegeneration models were used. First, P19 cells were studied in which trans-retinoic acid was used to induce neuronal differentiation. To do this, P19 cells were incubated in minimal essential medium (α-MEM) supplemented with 10% fetal bovine serum and 2 μM trans-retinoic acid at 37°C in the presence of 5% _CO₂ . The cells were incubated for 24 hours in the presence or absence of several D-PUFAs or PUFAs at varying concentrations. Neurotoxicity was induced with 1 μM NMDA. Subsequently, the number of cells was counted by light microscopy in the presence of trypan blue. These experiments showed that PUFAs have a protective effect against neuronal degeneration, although the effect mediated by D-PUFAs is much higher ( FIG. 4A and Table 12 ). It is evident from this figure and this table that the D-PUFA molecules of the present invention prevent neuronal death because they inhibit NMDA-induced neuronal death, making these substances useful for the prevention and treatment of neurodegenerative diseases such as Alzheimer's disease, sclerosis, Parkinson's disease, leukodystrophies, and the like. It was also shown that the number of cells in the treated cultures was higher than in the cultures without the addition of the neurodegenerative agent. Specifically, the negative value for cell death indicated that the number of P19 cells was higher than in the control. Therefore, the D-PUFA compounds of the present invention can be used to promote neuroregeneration processes, such as those resulting from traumatic processes (accidents) or toxic agents.

Table 12 shows the protective effect against neuronal death in P19 cells: D-PUFAs of the present invention inhibited neuronal death (P19 cells) after treatment with NMDA (100% death). Control cells without NMDA showed a 0% cell death level. All percentages below 100% indicate that neuronal death was prevented. Negative values indicate that there was a level of neuronal proliferation in addition to protection against neuronal death. In addition, the compounds of the present invention reduced the level of α-synuclein (Table 13), a protein associated with neurodegenerative processes such as Parkinson's disease, Alzheimer's disease, Lewy body dementia, multiple system atrophy, prion disease, etc. Therefore, the molecules of the present invention can be used to prevent and treat neurodegenerative processes, neuroregenerative processes, neurological processes, and neuropsychiatric processes.

Table 12

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

Table 13

In order to test the efficacy of the compound of the present invention in inducing nerve regeneration or inhibiting neurodegeneration, an animal model of Alzheimer's disease is used. In this model, mice develop neurodegeneration because they express a series of mutant proteins (Alzh mice) that cause brain damage. B6 mice are used as healthy animal controls. Both groups of animals are treated with vehicle (water) or various D-PUFA (20mg/kg, oral administration daily) for 3 months since their 3-month old age. In order to judge whether cognitive improvement occurs after treatment, animal behavior is monitored in a radial maze. Animals are kept on a strict restricted diet so that they have an appetite. In a symmetrical 8-arm radial maze, visual markers are placed to facilitate the orientation of the animal, and food (15mg pieces) is placed in four arms. The time and number of errors each animal spends in training are measured using a camera attached to a computer system. In this sense, according to the time spent in performing training and the number of errors made, Alzheimer's animals have a value (Fig. 4 B) that is approximately 50% higher than that of healthy animals. On the contrary, the mice suffering from Alzheimer's disease (Alzh+LP226) treated with 226B1 showed behavioral parameters similar to those of the control animals, and were significantly (P < 0.05) lower than the animals treated with vehicle (Alzh). In this regard, the effectiveness of compounds 183B1, 205A1, 205B1, 226A1, 226V1 was also tested, showing an improvement in the animals suffering from Alzheimer's disease (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 spent to complete the experiment in the control animals (B6 healthy mice), which was 8s, 11s, 12s, 18s, 16s and 14s, respectively. Therefore, it can be concluded that these compounds have a significant activity in preventing neurodegeneration and neural regeneration. Neurodegenerative diseases that can be prevented and treated with the D-PUFA molecules of the present invention include 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, Alzheimer's disease, dementia with Lewy bodies, multiple system atrophy, prion diseases, and the like. Furthermore, the neuroregenerative activity demonstrated by the effects in both Alzheimer's mice and healthy B6 mice suggests that treatment can be applied to processes where neuronal loss has occurred as a result of accidents, surgery, trauma of various natures, or due to certain toxins. The D-PUFA molecules of the present invention can also be used to prevent or treat various neurological and/or neuropsychiatric problems, such as headaches including migraines, central nervous system damage, 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 treating inflammatory diseases

Cyclooxygenases (COX) are enzymes that bind to membranes, remove certain lipids from them, and catalyze their conversion into molecules that can have inflammatory activity. The binding of the enzyme to membrane lipids is partly due to the structure of the membrane lipids. Increased activity of COX 1 and COX 2 isoforms has been associated with the pathogenesis of various inflammatory diseases, which is by inhibiting arachidonic acid metabolism to produce pro-inflammatory lipid mediators. The D-PUFA compounds of the present invention produce a series of cellular signals that alter the metabolism of arachidonic acid, and as a result, they inhibit the activity and expression of COX in monocytes in culture (Table 14 and Figure 5). Furthermore, the D-PUFA of the present invention inhibits the production of pro-inflammatory cytokines (TNF-α) in vivo (Table 15 and Figure 5). For this purpose, after inducing an inflammatory response in C57BL6/J mice by intraperitoneal injection of 20 μg of bacterial lipopolysaccharide (LPS), these mice were treated with various derivatives (200 mg/kg, orally). These results clearly demonstrate the effectiveness of the D-PUFAs of the present 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 (compared to the positive control in the presence of LPS, 100%).

Table 14

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

Table 15

These results show that the molecules of the present 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 inflammation and chronic inflammation, hyperalgesia of inflammatory nature, edema, inflammation caused by trauma 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 resulted in some modest reductions in cholesterol and triglyceride levels in 3T3-L1 cells. However, D-PUFA treatment caused a significant and dramatic decrease in cholesterol and triglyceride levels in these cells. For these experiments, the cells were incubated in RPMI 1640 medium at 37°C and 5% _CO2 in the presence of 10% fetal bovine serum and in the presence or absence of 150 μM of various PUFAs or D-PUFAs. The cells were incubated for 24 hours and then subjected to lipid extraction, and cholesterol and triglyceride levels were measured according to previously described procedures (Folch et al., 1951).

In a different experimental series, SHR rats were treated with various compounds of the invention (200 mg/kg daily, 28 days, oral), and the levels of cholesterol, triglycerides, and glucose in the serum were measured by colorimetry. 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 Figure 6 and Table 16 clearly demonstrate that D-PUFAs can be used as pharmaceuticals for the treatment or prevention of metabolic diseases such as hypercholesterolemia, hypertriglyceridemia, diabetes, and insulin resistance in humans and animals through pharmaceutical and nutritional approaches. The combination of high cholesterol and triglyceride levels, high glucose levels, and cardiovascular and/or weight changes leads to the "metabolic syndrome," which is increasing in Western societies. The compounds of the present invention have great potential for the treatment of metabolic syndrome.

Table 16 shows the levels of cholesterol, triglycerides, and glucose in SHR rats. The table shows the values of cholesterol (top numbers), triglycerides (middle numbers), and glucose (bottom numbers) in the serum of SHR treated with the above molecules (200 mg/kg per day, orally, for 28 days). Each value is expressed as a percentage, and the value in untreated (control) rats is always considered to be 100%.

Table 16

Example 10. Structural Basis for the Therapeutic Effects of 1,2-Derivatives of PUFAs

Numerous studies have shown that lipid ingestion or treatment leads to changes in the lipid composition of cell membranes. Furthermore, this composition has a direct effect on membrane lipid structure, which in turn regulates cell signaling and is implicated in the development of many diseases. Figure 7 shows the correlation between the changes in membrane structure (as measured by the H _II transition temperature) produced by different D-PUFAs and the cellular effects observed in this study. To this end, we determined the average effect of each D-PUFA (average for each lipid across all diseases studied relative to the number of double bonds) and plotted the results against the transition temperature. A decrease in the H _II transition temperature indicates a greater induction of discontinuities in the membrane, which creates docking sites for peripheral membrane proteins leading 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 can operate in some types (subtypes) of diseases suggests that some molecules with fewer double bonds may have greater pharmacological activity. However, in general, it appears that the therapeutic effect depends on the number of double bonds in the molecule, which itself is related to the ability to regulate membrane structure. In this sense, the presence of groups present at carbon 1 and/or 2 in the D-PUFA compounds of the invention, but not in natural PUFAs, is key to enhancing the therapeutic effect of these molecules.

These results indicate that the effects of the lipids included in the present invention have a common basis. These correlations (in both cases, for D-PUFA, with ^r2 values of 0.77 and 0.9, and P < 0.05) clearly indicate that the structure of the lipids used is the basis of their effect, and that this occurs through the modulation of membrane structure, resulting from the structure-function relationship of each lipid.

Therefore, in a first aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable derivative, wherein a, b and c can independently have values from 0 to 7, and _R1 and _R2 can be ions, atoms or atomic groups independently having a molecular weight of not more than 200 Da, for use in treating diseases based on structural changes and/or functional characteristics of cell membrane lipids, which diseases are selected from: cancer, vascular diseases, inflammation, metabolic diseases, obesity, neurodegenerative diseases and neurological disorders.

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 for the preparation of a pharmaceutical composition and/or a nutraceutical composition for the treatment of diseases based on structural and/or functional changes in lipids in cell membranes, wherein a, b and c can independently have values from 0 to 7, and _R1 and _R2 can be ions, atoms or atomic groups independently having a molecular weight of not more than 200 Da, wherein the disease is 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 diseases in humans and animals whose common etiology is associated with structural and/or functional changes in lipids located in cell membranes, selected from the group consisting of cancer, vascular diseases, inflammation, metabolic diseases, obesity, neurodegeneration and neurological diseases, the method comprising administering to the 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 can have independent values between 0 and 7, and R ₁ and R ₂ can be ions, atoms or atomic groups independently having a molecular weight of not more than 200 Da.

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 U.S.A., 91, 8234

Coles et al. 2001. J Biol Chem, 277, 6344

· Escribá et al. 1995. Proc Natl Acad Sci U.S.A., 92, 7595

Mail et al. 1997. Proc. Natl. Acad. Sci USA., 94, 11 375

Escriba et al. 2003. Hypertension, 41, 176

·Escriba 2006.Trends Mol Med, 12, 34

Escriba 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

·Rapoport2008.Postraglandins Leukot.Essent.Fatty Acids79, 153-156

· 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, 13 811

Trombetta et al. 2007. Chem Biol Interact., 165, 239

Vogler et al. 2004. J. Biol Chem, 279, 36540

Vogler et al. 2008. Biochim Biophys Act, 1778, 1640

Yang et al. 2005. Mol Pharmacol., 68, 210

Claims (5)

1. Use of the compound in the preparation of a medicament for treating cancer, wherein the compound is selected from: COOH-CHOH-(CH ₂ ) ₆ -(CH=CH-CH ₂ ) ₂ -(CH ₂ ) ₃ -CH ₃ (182A1), COONa-CHOH-(CH ₂ ) ₆ -(CH=CH-CH ₂ ) ₂ -(CH ₂ ) ₃ -CH ₃ (182B1) and COOH-CHOH-(CH ₂ ) ₂ -(CH=CH-CH ₂ ) ₄ -(CH ₂ ) ₃ -CH ₃ (204A1). 2. The application according to claim 1, wherein the compound is COONa-CHOH-(CH ₂ ) ₆ -(CH＝CH-CH ₂ ) ₂ -(CH ₂ ) ₃ -CH ₃ (182B1). 3. The application according to claim 1, wherein the compound is COOH-CHOH-(CH ₂ ) ₆ -(CH＝CH-CH ₂ ) ₂ -(CH ₂ ) ₃ -CH ₃ (182A1). 4. The application according to claim 1, wherein the compound is COOH-CHOH-(CH ₂ ) ₂ -(CH＝CH-CH ₂ ) ₄ -(CH ₂ ) ₃ -CH ₃ (204A1). 5. The application according to any one of the preceding claims, wherein the cancer is selected from: breast cancer, glioma, lung cancer, leukemia, and liver cancer.