ES2846824B2 - PRODRUGS OF POLYUNSATURATED FATTY ACIDS AND THEIR MEDICAL USES - Google Patents

Description

DESCRIPTION

PRODRUGS OF POLYUNSATURATED FATTY ACIDS AND MEDICAL USES OF

THE SAME

TECHNICAL FIELD OF THE INVENTION

The present invention relates to prodrugs of polyunsaturated fatty acids, as well as compositions comprising said prodrugs and their medical uses. On the other hand, the present invention also refers to the polyunsaturated fatty acids produced by the metabolism of said prodrugs of the invention, as well as their pharmaceutical compositions and their medical uses.

BACKGROUND OF THE INVENTION

Lipids, including fatty acids, ingested in the diet can regulate the lipid and fatty acid composition of cell membranes. Likewise, these changes in the lipid composition of the membranes influence cell signaling, and may lead to the development of diseases or to reverse them, as well as to prevent them. Similarly, therapeutic, nutraceutical, or cosmetic interventions aimed at regulating membrane lipid levels can prevent and reverse (cure) disease processes.

Currently, it is known that cell membranes are related to multiple cellular processes. On the one hand, they support proteins involved in cell signaling that regulates important organic parameters. This signaling, mediated by numerous hormones, neurotransmitters, cytokines, growth factors, etc., activates membrane proteins (receptors), which propagate the received signal to the interior of the cell through other proteins (peripheral membrane proteins), some of which are which are also located in the membrane. Since (1) these systems function as amplification cascades and (2) membrane lipids can regulate the location and function of these peripheral proteins, the lipid composition of membranes can have an important impact on cell functionality. Specifically, the interaction of certain peripheral proteins, such as G proteins, protein kinase C, Ras protein, etc., with the cell membrane depends on its lipid composition. On the other hand, the lipid composition of cell membranes is influenced by the type and amount of lipids ingested. From this it follows that lipid intake can regulate the lipid composition of membranes, which in turn can control the interaction (and thus the activity) of important cell signaling proteins.

The use of omega-3 polyunsaturated fatty acids, mainly from fish or products derived from marine organisms, has been proposed for therapy in humans on numerous occasions. The fatty acids investigated range from complex mixtures such as fish or algae oils, to the administration of isolated fatty acids or in combinations with very specific ratios.

In general, fatty acids whose chemical structure has an odd number of carbon atoms have not been considered relevant, since, in humans, and in mammals in general, the vast majority of fatty acids present are of even chain, usually between 14 and 24 carbon atoms, the presence of odd chain fatty acids being very rare, being limited to traces. In contrast, the presence of unsaturated fatty acids with an odd number of carbon atoms is more frequent in microorganisms.

Apparently, all polyunsaturated fatty acids are structurally similar, and a light and superficial study of their properties would conclude that they should all have similar therapeutic characteristics. However, the data available in the scientific literature indicate that small structural differences have important effects at the level of biological activity and, therefore, in therapeutic activity.

On the other hand, it is well known that many drugs provide known adverse effects or are toxic to various cells or tissues. Prodrugs or prodrugs are compounds that, when ingested, undergo metabolic reactions and give rise to a drug or medicine, which is the compound or active substance that provides an effect on the health of a patient or subject. The administration of prodrugs thus allows modulating the distribution and absorption of a drug, since its metabolism allows the generation of the corresponding drug only in those cells or tissues in which the metabolic reactions that transform said prodrug occur, obtaining the active compound. In this sense, prodrugs have other advantages such as allowing a delayed or controlled administration of the drug, avoiding accumulations of the drug or active compound, which could produce harmful effects on the body.

In conclusion, it is an objective of the present invention to provide prodrugs, as well as drugs derived from said prodrugs (metabolites), the latter being odd-chain polyunsaturated fatty acids, for the treatment of pathologies related to lipid alterations of the cell membrane. The present invention introduces the use of prodrugs to allow the administration of said drugs in a controlled manner, avoiding possible adverse effects in cases of prolonged administration or in high doses in certain pathologies.

BRIEF DESCRIPTION OF THE INVENTION

The present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof:

COOH -CHOH-(CH2)a-(CH=CH-CH2V(CH2)c-CH3

(I)

as a prodrug:

- of a compound of formula (II) or of a pharmaceutically acceptable salt or ester thereof:

COOH -(CH2)a-(CH=CH-CH2MCH2)c-CH3

(II)

or

- of a compound of formula (III) or of a pharmaceutically acceptable salt or ester thereof:

COOH -(CH2)a-(CH=CH-CH2MCH2)3-(CH=CH-CH2Wmr(CH2)c-CH3

(III)

where a is an integer between 1 and 7; b is an integer between 2 and 7; c is an integer between 0 and 7; m is an integer between 0 and (b - 1); and where a+3b+c+3 is an even integer.

The present invention also relates to a prodrug of formula (I), or a pharmaceutically acceptable ester salt thereof:

COOH -CHOH-(CH2)a-(CH=CH-CH2)b-(CH2)c-CH3

(I)

wherein said prodrug is a prodrug:

- of a compound of formula (II) or of a pharmaceutically acceptable salt or ester thereof:

COOH -(CH2) a -(CH=CH-CH2) b -(CH2) c -CH3

(II)

or

- of a compound of formula (III) or of a pharmaceutically acceptable salt or ester thereof:

COOH -(CH2)a-(CH=CH-CH2)m-(CH2)3-(CH=CH-CH2)rb-í-m;-(CH2)c-CH3

(III)

where a is an integer between 1 and 7; b is an integer between 2 and 7; c is an integer between 0 and 7; m is an integer between 0 and ( b - 1); where a +3 b + c +3 is an even integer; and to the pharmaceutical compositions that comprise it, for use as a medicine, in the induction of neuroregeneration and in the prevention and/or treatment of a disease or condition selected from the group consisting of: a neurological or neurodegenerative disease; a cancer; an inflammatory disease; and a metabolic disease.

Additionally, the present invention relates to a pharmaceutically acceptable salt or ester of a compound of formula (II):

COOH -(CH2) a -(CH=CH-CH2) b -(CH2) c -CH3

(II)

or to a pharmaceutically acceptable salt or ester of a compound of formula (III):

COOH -(CH2)a-(CH=CH-CH2)m-(CH2)3-(CH=CH-CH2)rb-í-mr(CH2)c-CH3

(III)

where a is an integer between 1 and 7; b is an integer between 2 and 7; c is an integer between 0 and 7; m is an integer between 0 and ( b - 1); and where a +3 b + c +3 is an even integer.

The present invention also refers to the pharmaceutically acceptable salt or ester of said compounds of formula (II) or of formula (III), for use as a medicine, in the induction of neuroregeneration and in the prevention and/or treatment of a disease or condition selected from the group consisting of: a neurological or neurodegenerative disease; a cancer; an inflammatory disease; and a metabolic disease.

The present invention also relates to a compound of formula (II), or a pharmaceutically acceptable salt or ester thereof:

COOH -(CH2) a -(CH=CH-CH2) b -(CH2) c -CH3

(II)

or to a compound of formula (III), or to a pharmaceutically acceptable salt or ester thereof: COOH -(CH2)a-(CH=CH-CH2)m-(CH2)3-(CH=CH-CH2)rb-í-m;-(CH2)c-CH3

(III)

for use in the induction of neuroregeneration and in the prevention and/or treatment of a neurodegenerative disease.

Additionally, the present invention relates to a pharmaceutical or nutraceutical composition comprising at least one first compound selected from the group consisting of:

- a compound of formula (II) or a pharmaceutically or nutraceutically acceptable salt or ester thereof:

COOH- ( CH ^two )to- ( CH=CH-CH ^two )b- ( CH ^two )c-CH ³

(II)

Y

- a compound of formula (III) or a pharmaceutically or nutraceutically acceptable salt or ester thereof:

COOH -(CH2)a-(CH=CH-CH2)m-(CH2)3-(CH=CH-CH2)rb-í-m;-(CH2)c-CH3

(III)

characterized in that it further comprises a second compound of formula (I), or a pharmaceutically or nutraceutically acceptable salt or ester thereof:

COOH -CHOH-(CH2)a-(CH=CH-CH2)b-(CH2)c-CH3

(I)

where a is an integer between 1 and 7; b is an integer between 2 and 7; c is an integer between 0 and 7; m is an integer between 0 and ( b - 1); where a +3 b + c +3 is an even integer; and at least one pharmaceutically or nutraceutically acceptable excipient.

Another aspect of the invention relates to a pharmaceutical or nutraceutical composition comprising at least one first compound selected from the group consisting of:

- a pharmaceutically or nutraceutically acceptable salt or ester of a compound of formula (II):

COOH-(CH2)a-(CH=CH-CH2)b-(CH2)c-CH3

(II)

Y

- a pharmaceutically nutraceutical acceptable salt or ester of a compound of formula (III):

COOH -(CH2)a-(CH=CH-CH2MCH2)3-(CH=CH-CH2Wmr(CH2)c-CH3

(III)

where a is an integer between 1 and 7; b is an integer between 2 and 7; c is an integer between 0 and 7; and m is an integer between 0 and ( b - 1); where a +3 b + c +3 is an even integer; and at least one pharmaceutically or nutraceutically acceptable excipient.

Another additional aspect of the invention refers to both types of pharmaceutical compositions mentioned above, for use as a medicine, in the induction of neuroregeneration and in the prevention and/or treatment of a disease or condition selected from the group consisting of: a neurological or neurodegenerative disease; a cancer; an inflammatory disease; and a metabolic disease.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1.

A. Illustrative scheme of the cellular metabolism of 2-hydroxydocosahexaenoic acid (DHA-H) giving rise to (6Z,9Z,12Z,15Z,18Z)-heneicosa-6,9,12,15,18-pentaenoic acid (HPA) by means of a-oxidation. DHA-H requires activation by an Acyl-CoA synthetase, in a process dependent on ATP (adenosine triphosphate) and magnesium (Mg2+). DHA-H-CoA would be subject to the activity of 2-hydroxyphytanoyl-CoA lyase (2-hydroxyacyl-CoA lyase 1, HACL1), which would lead to the formation of an intermediate polyunsaturated aldehyde that should contain 5 or 6 double bonds . HACL1 activity is dependent on thiamine pyrophosphate (TPP) and Mg2+, and can be inhibited by a competitive antagonist (eg, oxythiamine). The aldehyde dehydrogenase enzyme would be responsible for the conversion of the intermediate aldehyde into HPA in a NAD+ (Nicotinamide Adenine Dinucleotide) dependent process.

B. DHA-H is metabolically converted to HPA by α-oxidation in HEK293T cells. Intracellular levels of DHA-H (B1 and B3) and HPA (B2 and B4) are plotted on the ordinate axis (nmol/mg protein), versus treatment concentration with the sodium salt of DHA-H (pM). for 24 hours (B1 and B2) or incubation time (h) with a constant concentration of the sodium salt of DHA-H of 30 pM (B3 and B4), including controls without treatment (C), on the abscissa axis. Black bars represent the result in cells without additional stimulation, white bars represent the result after simultaneous treatment with 1 mM oxythiamine and the dashed bars represent the result after treatment with 10 mM oxythiamine. Both DHA-H and HPA increased as a function of concentration and incubation time, with levels of HPA significantly higher than those of DHA-H on exposure to 30 pM DHA-H sodium salt from 24 hours. This increase in e1HPA is inhibited in the presence of 10 mM oxythiamine, demonstrating the involvement of α-oxidation in this metabolic conversion. The bars represent the mean ± standard error, and the statistical analysis was performed by one-way ANOVA and the Tukey multiple assessment test: *p < 0.05 when comparing the levels of HPA with those of DHA-H under the same condition; #, p<0.05 when comparing values in the presence and absence of 10 mM oxythiamine.

C. The endogenous levels of DHA (native non-hydroxylated form of docosahexaenoic acid) in HEK293T are not altered after treatment with the sodium salt of DHA-H. Intracellular levels of DHA are plotted on the ordinate axis (nmol/mg of protein), versus treatment concentration with the sodium salt of DHA-H (pM) for 24 hours (C1) or incubation time (h) with a constant concentration of the sodium salt of DHA-H of 30 pM (C2), including untreated controls (C), on the x-axis. DHA-H sodium salt treatment had no significant effect on DHA levels as a function of concentration or incubation time. The bars represent the mean ± standard error, and the statistical analysis was done using one-way ANOVA and Tukey's multiple assessment test.

Figure 2.

A. Mice treated with the sodium salt of DHA-H show dose-dependent cerebral accumulation of HPA, with DHA-H being undetectable in the brain. Brain levels of HPA ( A1 ) or DHA ( A2 ) are plotted on the ordinate axis (nmol/mg of protein), versus treatment doses with sodium salt of DHA-H (A1) and sodium salt of DHA (A1 and A2) (mg/kg). A1: • WT animals; or 5xFAD. A2: black bars refer to WT animals and white bars to 5xFAD. HPA and DHA levels were determined in the brain of WT and 5xFAD mice after chronic administration of DHA-H sodium salt (4 months; 5 doses/week LV; between 3 and 7 months of age; sacrifice at 7 months). HPA accumulates in the brain of both mouse strains in a similar way, depending on the dose of DHA-H sodium salt administered (A1: • r2= 0.9292, p= 0.0002; or r2= 0.9704, p<0.0001) . DHA levels did not vary significantly between the experimental conditions (A2). Data are shown as mean ± standard error, and statistical analysis was done by one-way ANOVA and Tukey multiple assessment test: *p<0.05 compared to control (vehicle-treated mice).

B. 5xFAD mice treated with DHA-H sodium salt show lipid regulation of brain membranes. Normalized to mean study lipid levels in unmodified animals (WT=unmodified; percent of WT controls) versus pathology/treatment condition are plotted: vehicle-treated WT (black bars), 5xFAD treated with vehicle (open bars) and 5xFAD treated with the sodium salt of DHA-H (20 mg/kg) under the same conditions detailed in section 2A (hatched bars). B1 : phosphatidylethanolamine (PE), B2 : polyunsaturated lipids (5 or more unsaturations), B3 : saturated lipids, B4 : phosphatidylcholine (PC), B5 : phosphatidylinositol (PI), B6 : phosphatidylserine (PS), B7 : cholesterol, B8 : sphingomyelin (including dihydro-sphingomyelin) and B9 : ceramides (including hexosyl- and lactosyl-ceramide). The animals under treatment with the sodium salt of DHA-H present a statistically significant increase in the levels of PE, PI and polyunsaturated lipids, with respect to the animals that only receive vehicle. The bars represent the mean ± standard error, and the statistical analysis was performed by one-way ANOVA and the Tukey multiple assessment test: * p<0.05.

C. 5xFAD mice treated with the sodium salt of DHA-H show cognitive improvement that correlates directly with brain levels of HPA. The number of total errors ( C1 ), errors in the reference memory ( Reference Memory Errors, RME) - ( C2 ) or errors in the working memory ( Working Memory Errors, WME) - ( C3 ), committed, in the ordinate versus brain HPA levels (nmol/mg protein) on the abscissa. Cognitive evaluation was done using the 8-arm radial maze test during the last month of treatment of the same animals shown in Figure 2A. Individual experimental points from the entire animal population under study were plotted and data from 5xFAD animals fitted to an inverse polynomial regression f(x)=y ⁰ +(a/x). The values of r2 and p corresponding to the regression of each parameter are shown below: total errors, RME and WME; versus brain concentration of HPA: C1: r2=0.9146 and p=0.0311; C2: r2=0.9252 and p=0.0243; C3: r2=0.7785 and p=0.0346. The data obtained suggest that minimal increases in brain levels of HPA are associated with an improvement in spatial cognition. Each point on the graphs represents the mean ± standard error for each pathology/treatment condition: • WT vehicle, ▼ WT DHA-H 20 mg/kg; ♦ WT DHA-H 200mg/kg; or 5xFAD vehicle; △ 5xFAD DHA-H 5mg/kg; V 5xFAD DHA-H 20mg/kg; □ 5xFAD DHA-H 50 mg/kg; Or 5xFAD DHA-H 200mg/kg.

Figure 3.

A. Mice treated with the sodium salt of DHA-H show tumorous accumulation of HPA, with DHA-H being undetectable, in xenographic tumors of U118 cells. The levels of DHA (black bars) and HPA (open bars) (pmoles/mg of tissue) in the tumor are plotted on the ordinate axis against the treatment condition (vehicle and DHA-H 200 mg/ kg) on the abscissa axis. 3-month-old NUDE (immunosuppressed) mice were injected subcutaneously with 7.5.106 U118 cells (grade IV human glioblastoma multiforme). Tumor growth was allowed subcutaneously for 10 days before the start of oral treatments (vehicle or sodium salt of DHA-H 200 mg/kg), which were maintained for 42 days until sacrifice. Lipid analysis of xenographic tumors revealed the absence (undetectable levels) of DHA-H. The bars represent the mean ± standard error for each treatment condition.

B. Tumor HPA levels inversely correlate with tumor size in xenographic models. Tumor size (cm3), on the ordinate axis, is plotted against HPA levels (pmoles/mg of tissue) in the tumor, on the abscissa axis, for two treatment conditions: o vehicle and • salt sodium of DHA-H 200 mg/kg. The presence of HPA in the tumor of the animals treated with the sodium salt of DHA-H has a statistically significant linear relationship with the volume of the tumor (A2), where: r2= 0.4296 and p= 0.0029.

Figure 4.

A. DHA-H is a prodrug that is metabolically converted to HPA by aoxidation in U118 cells. Intracellular levels of DHA (black bars), DHA-H (white bars) and HPA (hatched bars) are plotted on the ordinate axis (nmol/mg protein), versus treatment conditions: Control (C) and sodium salt of DHA-H 150 pM (48 h), in the presence or absence of a simultaneous treatment with oxythiamine 1 and 10 mM, on the abscissa axis. Both DHA-H and HPA were increased in cells treated with the sodium salt of DHA-H. This increase in HPA is inhibited in the presence of 1 and 10 mM oxythiamine, demonstrating the involvement of α-oxidation in this metabolic conversion. Bars represent mean ± standard error, and statistical analysis was performed by one-way ANOVA and Tukey's multiple assessment test: * p < 0.05 when only HPA levels are compared.

B. The metabolic conversion of DHA-H to HPA is necessary for an antitumor effect. Cell viability (% of control -C- without oxythiamine) is represented on the axis of ordered, against the treatment conditions: Control (C- black bars) and the sodium salt of DHA-H 150 pM, 48 h (white bars) in the presence and absence of simultaneous treatment with oxythiamine 1 mM, on the abscissa axis . Treatment with DHA-H on U118 cells reduces culture viability significantly, while treatment with oxythiamine (by itself) has no effect on cell viability. However, when treatment with DHA-H sodium salt is done simultaneously with oxythiamine, the anti-proliferative effect of this compound decreases significantly compared to the effect without oxythiamine. Bars represent mean ± standard error, and statistical analysis was performed by one-way ANOVA and Tukey's multiple assessment test: * p < 0.05 when compared to control (C); # p < 0.05 when comparing the effect of DHA-H in the presence and absence of oxythiamine.

Figure 5.

A . Viability of U118 cells in culture after treatment with the sodium salt of DHA-H, the sodium salt of DHA and HPA. Cell viability (% of control without treatment) is represented on the ordinate axis, against the different treatment conditions, on the abscissa axis: Control (black bar), sodium salt of DHA-H (150 pM, 48h - white bar), DHA (150 pM, 48h - hatched bar) and HPA (150 pM, 48h - grid bar). Treatment with HPA under the same conditions induces a much more evident degree of mortality on the crop than that induced by DHA-H (prodrug) or DHA (natural analog). This effect could be due to a mixture of anti-proliferative effect and toxic effects of HPA, which would not be attributable to DHA-H or DHA under the same experimental conditions. Bars represent mean ± standard error, and statistical analysis was performed by one-way ANOVA and Tukey's multiple assessment test: * p < 0.05 when compared to control.

B. Intracellular levels of HPA in U118 cells in culture, treated with the sodium salt of DHA-H and HPA. HPA levels (nmol/mg of protein) are plotted on the ordinate axis against treatment conditions, on the abscissa axis: sodium salt of DHA-H (150 pM, 48 h - black bar) and HPA (5-150 pM, 48h - gray bars). The administration of 150pM of the sodium salt of DHA-H gives rise to HPA levels equivalent to those generated by the treatment itself with HPA at 5pM. Treatment with 150 pM HPA results in markedly higher intracellular levels of HPA than is generated by the same concentration from prodrug administration. The bars represent the mean ± standard error.

C. DHA-H and DHA levels in HEK293T cells in the presence (C1) or absence (C2) of culture medium. The levels of DHA-H (• ) and DHA (o) in the culture medium (% of initial levels at time 0), on the ordinate axis, versus incubation time (h), on the abscissa axis. The concentration of the lipid in the culture medium is 30 pM and the culture plates are incubated up to 72 h. In the presence of cell culture (C1), the levels of DHA in the medium decreased significantly at 48 and 72 h, as a consequence of the uptake of DHA by the cells, while the levels of DHA-H remained unchanged up to 72 h. In the absence of cell culture (C2), the levels of both DHA and DHA-H remained constant over time. Bars represent mean ± standard error, and statistical analysis was performed by one-way ANOVA and Tukey's multiple assessment test: * p < 0.05 when compared to control.

DESCRIPTION OF THE INVENTION

The present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof:

COOH -CHOH-(CH2)a-(CH=CH-CH2)b-(CH2)c-CH3

(I)

as a prodrug:

- of a compound of formula (II) or of a pharmaceutically acceptable salt or ester thereof:

COOH -(CH2)a-(CH=CH-CH2V(CH2)c-CH3

(II)

or

- of a compound of formula (III) or of a pharmaceutically acceptable ester salt thereof:

COOH -(CH2)a-(CH=CH-CH2)m-(CH2)3-(CH=CH-CH2Wmr(CH2)c-CH3

(III)

where a is an integer between 1 and 7; b is an integer between 2 and 7; c is an integer between 0 and 7; m is an integer between 0 and ( b - 1); and where a +3 b + c +3 is an even integer.

For the purposes of the present invention, when a specific formula or composition is not indicated, the values of a , b , c and m are applicable to all the formulas and compositions described in this document.

For the purposes of the present invention, the term "prodrug" refers to a compound that, when administered to a subject, is transformed, through a metabolic process, into a second compound that is the one with biological activity.

On the other hand, the term "subject" refers, for the purposes of the present invention, to a human or an animal.

The term "pharmaceutically acceptable" means, for the purposes of this invention, that which is authorized or authorizable by a regulatory agency of the federal government or a state government or listed in the European, United States or other generally recognized pharmacopoeia for use in animals. , and more particularly in humans.

Thus, the term "pharmaceutically acceptable salt" refers to a salt of a compound that possesses the desired pharmacological activity of the parent compound from which it is derived. Preferably, the pharmaceutically acceptable salt is the sodium salt.

Thus, in one embodiment of the present invention the pharmaceutically acceptable salt of the compound of formula (I) is a sodium salt.

For purposes of the present invention, the term "ester" refers to any compound in which the hydroxyl group belonging to a carboxylic acid residue has been replaced by an alkoxide group. In a preferred embodiment of the invention, the ester is a methyl or ethyl ester. More preferably the ester is an ethyl ester.

For the purposes of the present invention, the term "stereoisomer" refers to those compounds that have the same chemical formula and the same sequence of atoms, but have a different three-dimensional orientation in space, and includes the R and S stereoisomers (which also use the nomenclature (+) and (-)) resulting from the presence of a chiral carbon, as well as the E and Z stereoisomers (which also use the cis/trans nomenclature) resulting from the arrangement of the substituents of the carbons that They constitute a double bond. Thus, since the prodrugs of formula (I) comprise a chiral carbon (alpha carbon to the carboxylic group), the invention also includes the two R and S stereoisomers, as well as any mixture of both, with respect to the configuration of said chiral carbon. On the other hand, given that both the prodrugs of formula (I) and their metabolites of formula (II) or (III) comprise C=C double bonds, the invention also includes all the E and Z stereoisomers for each of their double bonds. . In a preferred embodiment, all the double bonds of the prodrug of formula (I), of the compound of formula (II) and of the compound of formula (III) have an all-cis configuration. Thus, if the prodrug of formula (I) has a certain cis/trans (or E/Z) stereochemical configuration of its doubles bonds, the metabolite of formula (II) or of formula (III) will also have said configuration for the double bonds it contains.

Thus, according to the metabolism scheme of Figure 1A, the compounds of formula (I) are polyunsaturated alpha-hydroxy fatty acids with an even number of carbon atoms ( a+3b+c+3 is an even integer). . Said fatty acids are prodrugs of the corresponding polyunsaturated fatty acids with a number of carbon atoms n-1 with respect to the precursor of formula (I) and which, therefore, have an odd number of carbon atoms. Therefore, the present invention refers to the pharmaceutical, nutraceutical and cosmetic use of lipids that give rise to lipid species that are necessary, but not abundant in the human diet. These odd-chain metabolites may have either formula (II) or formula (III), depending on whether or not hydrogenation of one of the double bonds occurs during the metabolism of the compound of formula (I). Thus, in the case in which a decarboxylation occurs, but the hydrogenation of one of the double bonds of the compound of formula (I) does not occur, the compound derived from the prodrug of formula (I) will be a compound of formula (II ). While, in the case in which the hydrogenation of one of the double bonds and a decarboxylation of the compound of formula (I) occurs, the compound derived from the prodrug of formula (I) will be a compound of formula (III), in the that the hydrogenated double bond can be in a different position depending on the value of m.

Therefore, the HPA, according to the invention, is a compound of formula (III), in which m=0, if HPA is the metabolite of a prodrug of formula (I) in which a=1, b= 6, c=0, which is an omega-3 polyunsaturated alpha-hydroxy fatty acid with 22 carbon atoms and 6 conjugated double bonds (DHA-H). Furthermore, HPA can be a compound of formula (II), for cases in which HPA is the metabolite of a prodrug of formula (I), in which a=4, b=5 and c=0, which is an acid alpha-hydroxylated polyunsaturated omega-3 fatty acid with 22 carbon atoms and 5 double bonds (2-hydroxy-docosapentaenoic acid).

An embodiment of the present invention relates to the use of the compound of formula (I), as a prodrug of a compound of formula (III), in which a=1, b=6, c=0 and m=0.

Preferably, the present invention relates to the use of 2-hydroxydocosahexaenoic acid (DHA-H) or, in particular, its sodium salt, as a prodrug of 1HPA, and its pharmaceutically acceptable salts.

Therefore, a highly preferred embodiment refers to the use of the compound of formula (I) as a prodrug of a compound of formula (III) in which a=1, b=6 and c=0; and m=0, in where said compound of formula (III) is HPA or a pharmaceutically acceptable salt thereof and in which the compound of formula (I) or pharmaceutically acceptable salt is DHA-H.

A more preferred embodiment of the invention refers, therefore, to the use of the sodium salt of the prodrug of formula (I) DHA-H as a prodrug of HPA.

In a preferred embodiment of said highly preferred embodiment, the pharmaceutically acceptable salt of DHA-H is the sodium salt.

A highly preferred embodiment of the invention refers to the use of a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof:

COOH -CHOH-(CH2)a-(CH=CH-CH2MCH2)c-CH3

(I)

as a prodrug:

of a compound of formula (III) or of a pharmaceutically acceptable salt or ester thereof:

COOH -(CH2)a-(CH=CH-CH2)m-(CH2)3-(CH=CH-CH2)rb-í-m;-(CH2)c-CH3

(III)

where a =1, b=6, c =0 and m=0.

An even more preferred embodiment of said highly preferred embodiment of the invention refers to the use of the sodium salt of a compound of formula (I):

COOH -CHOH-(CH2)a-(CH=CH-CH2)b-(CH2)c-CH3

(I)

as a prodrug of a compound of formula (III):

COOH -(CH2)a-(CH=CH-CH2)m-(CH2)3-(CH=CH-CH2)rb-í-mr(CH2)c-CH3

(III)

where a=1, b=6, c=0 and m=0.

Thus, the present invention shows that 2-hydroxypolyunsaturated fatty acids are prodrugs of other polyunsaturated fatty acids, as said prodrugs undergo a decarboxylation process and, optionally, a hydrogenation process of one of their double bonds.

As an example of the action of these prodrugs, Figure 1A shows a diagram of the metabolism by α-oxidation of DHA-H at the cellular level, giving rise to HPA. According to this pathway, the DHA-H prodrug is a 2-hydroxy polyunsaturated fatty acid, which is converted to HPA through a sequence of metabolic steps: (1) activation of DHA-H by conjugation with coenzyme A; (2) cleavage mediated by 2-hydroxyphytanoyl-CoA lyase, yielding an aldehyde with an odd number of carbon atoms; (3) action of aldehyde dehydrogenase on the aldehyde to transform it into an acid (HPA).

Example 1 also describes the method for obtaining a compound of formula (II) or formula (III), or its salts described in the present invention, represented by the synthesis of HPA and its sodium salt. On the other hand, Australian patent application 2019226257 describes the method for obtaining the prodrugs of formula (I) and their salts in its Example 1.

To describe the metabolic conversion of a prodrug of formula (I), represented by the fatty acid DHA-H, into a compound of formula (II) or a compound of formula (III), in this case HPA, cultures of HEK293T cells ( Human Embryonic Kidney Cells 293T). On the other hand, the present description provides support for the action of the prodrugs of formula (I), represented by the sodium salt of DHA-H (sodium salt of 2-hydroxydocosahexaenoic acid), as well as the effect of its metabolites of formula ( II) or formula (III), represented by the compound HPA (heneicosapentaenoic acid).

Treatment with the sodium salt of the prodrug DHA-H as a representative compound of a prodrug of formula (I), gives rise to high cellular levels of HPA, compared to the levels of the prodrug, not only in cell cultures (figure 1B), but also in mice (Figure 2A). In Figure 1B, the intracellular levels of DHA-H and HPA in HEK293T cells under treatment with the sodium salt of DHA-H are shown. Accumulation of both compounds is evident as a function of treatment concentration or incubation time, but HPA levels are significantly higher than that of the prodrug after 24 hours of incubation and 30 pM of treatment. The increase in HPA levels is inhibited in the presence of concomitant treatment with oxythiamine (partial inhibition at 1 mM and almost total inhibition at 10 mM), a competitive antagonist of 2-hydroxyphytanoyl-CoA lyase (see Figure 1A). In this sense, it should also be noted that the endogenous levels of DHA (the non-hydroxylated native form of docosahexaenoic acid) are not altered by this treatment with the sodium salt of DHA-H (figure 1C). Thus, it can be concluded that the administration of DHA-H, or its sodium salt in this case, does not alter the endogenous levels of DHA (docosahexaenoic acid), nor of other cellular fatty acids studied, but that the Treatment with DHA-H leads to an increase exclusively in HPA, suggesting that the therapeutic effect obtained through treatment with DHA-H, and in particular with its sodium salt, must be mediated by HPA and not by a modulation of the levels of other fatty acids of endogenous origin.

When the prodrug DHA-H, in particular its sodium salt, is administered in healthy mice and in transgenic models of Alzheimer's disease, a significant accumulation of HPA occurs in the brain, without the presence of the prodrug (DHA-H) being detected. H), nor changes in the endogenous levels of DHA (figure 2A). The increase in brain levels of HPA is also related to many lipid changes in the brain of these animals (figure 2B); being the levels of phosphatidylethanolamine and polyunsaturated fatty acids with five unsaturations or more, those that increase the most and, in particular, those long-chain and polyunsaturated phosphatidylethanolamines (see table 4 in the examples). This trend can be explained by the direct incorporation (or after further cellular processing) of HPA into brain phosphatidylethanolamine species. An increase in the levels of phosphatidylethanolamine and polyunsaturated acyclic chains could be related to changes in the structures of the membranes towards a liquid-disordered tendency, which seems to have neuroprotective effects against the pathology.

On the other hand, HPA levels at the brain level in Alzheimer's model mice have a statistically significant inverse relationship with behavioral parameters in a spatial and associative memory evaluation test (radial maze test) (Figure 2C). These results suggest that moderate increases in brain HPA levels are significantly related to an improvement in spatial cognition, which is one of the most affected cognitive abilities in Alzheimer's disease.

Similarly, studies of these compounds in xenographic tumors of U-118 MG cells (grade IV human glioblastoma multiforme cell line), inserted subcutaneously in healthy immunocompromised animals (NUDE), showed that treatment with DHA sodium salt -H gives rise to high levels of HPA in implanted tumors, with no apparent presence of the parent molecule (DHA-H) and no changes in endogenous levels of DHA (native non-hydroxylated form) (Figure 3A). The results demonstrated that HPA levels in xenographic tumors have a statistically significant inverse linear relationship with tumor size (FIG. 3B). In the absence of the parent molecule DHA-H in the target organ, these evidences suggest that the presence of HPA in the target organ has a therapeutic effect in vivo.

Likewise, the levels of HPA generated from the prodrug DHA-H in U-118 MG cells in culture were studied, in the presence or absence of oxythiamine (competitive inhibitor of α-oxidation) (figure 4A). The results showed that the addition of the sodium salt of DHA-H to a culture of U-118 MG cells gives rise to a significant increase in the levels of HPA. This increase is inhibited in the presence of simultaneous treatment with 1 or 10 mM oxythiamine, demonstrating that the transformation of DHA-H into HPA is mediated by α-oxidation. DHA-H sodium salt treatment on cultured U-118 MG cells had no effect on endogenous DHA levels (native non-hydroxylated form). On the same cells in culture, viability assays were carried out with the sodium salt of DHA-H in the presence or absence of 1 mM oxythiamine (FIG. 4B). First, it was found that 1 mM oxythiamine has no effect on cell viability. On the other hand, the addition of the sodium salt of DHA-H (150 pM, 48 h) has a significant anti-proliferative effect on the U118-MG cells. However, this effect is partially (statistically significantly) reversed in the presence of 1 mM oxythiamine. This concentration of oxythiamine is sufficient to completely inhibit the increase in HPA levels from DHA-H (see Figure 4A). Thus, these results show that the anti-proliferative effect mediated by DHA-H on U-118 MG cells is mediated, at least in part, by HPA, since the inhibition of the formation of this compound from DHA-H, translates into a lower anti-proliferative effect of DHA-H (figure 4B).

The administration of the prodrugs of formula (I), ie the use of the compounds of formula (I) as prodrugs, allows a time-regulated administration of their odd-chain metabolites. This makes it possible to avoid possible adverse effects when a prolonged administration is required, or in larger amounts, due to the patient's situation or the disease being treated, of the odd-chain metabolite, which is the compound that carries out the therapeutic action. Specifically, odd-chain fatty acids are metabolized by p-oxidation, giving rise to propionyl-CoA. Unlike even chain fatty acids, whose metabolism ends in the production of acetyl-CoA which, in turn, is metabolized via the Krebs cycle. Propionyl-CoA can be converted to propionic acid, which can cause metabolic acidosis if it accumulates. Propionyl-CoA can be metabolically transformed into succinyl-CoA (which is metabolized via the Krebs cycle), in a process dependent on biotin and vitamin B12. This process is not a common fatty acid metabolic pathway, because in the mammalian body, the vast majority of fatty acids are even-chain fatty acids. Consequently, this metabolic pathway selectively affects odd-chain polyunsaturated fatty acids, such as the metabolites of formula (II) and formula (III), and can become saturated if intracellular concentrations exist. too high levels of these odd-chain metabolites or specific pathological situations involving biotin or vitamin B12 deficiency, leading to propionic acidosis.

Thus, if in general, the use of the compounds of formula (II) and (III), and their pharmaceutically or nutraceutically acceptable salts, is beneficial for the organism as has been shown in the examples of the present application. The action of these compounds of formula (II) and (III), through the administration of their corresponding prodrug of formula (I), allows avoiding adverse effects derived from their metabolism and accumulation, when a prolonged administration or high doses are required, by administering in a controlled manner, as a result of their metabolism, said compounds of formula (II) and (III). In this way, the prodrugs having formula (I) provide a way of administering the metabolites of formula (II) or formula (III) with less risk of the appearance of adverse side effects and providing a therapeutically effective amount of said metabolites in a manner sustained over time, as the prodrug having formula (I), once administered, is metabolized.

In this application, the anti-proliferative effect of HPA on a culture of U-118 MG cells has been studied, in comparison with the administration of the prodrug DHA-H and the native form of DHA. These experiments showed that, under the same experimental conditions, the administration of HPA drastically decreases the viability of the U118-MG cell culture against the effect of DHA-H or DHA (FIG. 5A). Even though it has already been widely demonstrated that DHA-H, and specifically through the administration of its sodium salt, is a prodrug of HPA, the anti-proliferative effect of DHA-H is less than that assumed by the administration of HPA per se. (see figure 5A). To explain this effect, one must look at the existing intracellular levels of HPA after stimulating the culture with the same concentration of DHA-H or HPA (FIG. 5B). Interestingly, administration of HPA under the same experimental conditions as DHA-H results in HPA levels an order of magnitude higher than those caused by DHA-H. Then, the administration of the same concentration in culture of DHA-H and HPA, under the same conditions, give rise to different intracellular levels of HPA. This effect must be due to the structural differences between DHA-H and HPA. In fact, in the present work, we have shown that the uptake of the alpha-hydroxylated form of DHA (DHA-H) is impeded compared to that of the non-hydroxylated analog (figure 5C). If DHA-H uptake is impaired compared to non-hydroxy fatty acids, then the different intracellular levels of HPA observed after stimulation in U118-MG with DHA-H and HPA must be due to the different uptake of these compounds by the cells from the extracellular medium.

On the other hand, the anti-proliferative effect on U-118 MG is much higher for HPA with respect to DHA-H and DHA (see Figure 5A). When compared to DHA-H, this effect can be explained by differences in intracellular levels of HPA, induced by DHA-H and HPA (see Figure 5B). However, the non-hydroxylated form of DHA should be taken up from the extracellular medium with an efficiency similar to that of HPA (or any non-hydroxylated polyunsaturated fatty acid). Consequently, the intracellular levels of DHA and HPA should not be too different in U-118 MG after treatment with DHA and HPA, respectively, under the same conditions. If we assume that DHA and HPA (structural analogs) have a similar anti-proliferative effect on U-118 MG, then the differences in cell viability observed between these two compounds should be explained, at least in part, by the toxic effect of HPA on U-118MG. A toxic effect that would be selective for HPA, and would not appear with DHA. Then, this effect could be explained by toxicity selectively mediated by odd-chain fatty acids, giving rise to propionic acidosis. This toxicity is a consequence, in part, of the ease of uptake of HPA from the extracellular medium by the cells. In this sense, the slower uptake of the DHA-H prodrug compared to non-hydroxylated fatty acids could be useful in avoiding excessively high intracellular concentrations of HPA and, consequently, a possible accumulation of propionic acid.

Thus, depending on the metabolic condition, the administration regimen and the condition to be treated, it may be convenient to use HPA or another metabolite of formula (II) or formula (III), or of a pharmaceutically acceptable salo ester of The same or a controlled administration over time may be convenient, through the use of the prodrug of formula (I), or a pharmaceutically acceptable salt or ester thereof, such as the sodium salt of DHA-H.

Therefore, one embodiment of the invention relates to the prodrug of formula (I), or a pharmaceutically acceptable salt or ester thereof:

COOH -CHOH-(CH2)3-(CH=CH-CH2MCH2) ^c -CH3

(I)

wherein said prodrug is a prodrug:

- of a compound of formula (II) or of a pharmaceutically acceptable salt or ester thereof:

COOH -(CH2)a-(CH=CH-CH2)b-(CH2)c-CH3

(II)

or

- of a compound of formula (III) or of a pharmaceutically acceptable salt or ester thereof:

COOH -(CH2)a-(CH=CH-CH2)m-(CH2)3-(CH=CH-CH2)rb-í-m;-(CH2)c-CH3

(III)

where a is an integer between 1 and 7; b is an integer between 2 and 7; c is an integer between 0 and 7; m is an integer between 0 and ( b - 1); and a +3 b + c +3 is an even integer; for use as a medicine; in particular, for use in the induction of neuroregeneration or for use in the prevention and/or treatment of a disease or condition selected from the group consisting of: a neurological or neurodegenerative disease; a cancer; an inflammatory disease; and a metabolic disease.

In the same way, the present invention relates to the use of a prodrug of formula (I), or a pharmaceutically acceptable salt or ester thereof:

COOH -CHOH-(CH2)a-(CH=CH-CH2)b-(CH2)c-CH3

(I)

wherein said prodrug is a prodrug:

- of a compound of formula (II) or of a pharmaceutically acceptable salt or ester thereof:

COOH -(CH2)a-(CH=CH-CH2)b-(CH2)c-CH3

(II)

or

- of a compound of formula (III) or of a pharmaceutically acceptable salt or ester thereof:

COOH -(CH2)a-(CH=CH-CH2)m-(CH2)3-(CH=CH-CH2)rb-í-mr(CH2)c-CH3

(III)

where a is an integer between 1 and 7; b is an integer between 2 and 7; c is an integer between 0 and 7; m is an integer between 0 and ( b - 1); and a +3 b + c +3 is an even integer; in the manufacture of a drug for the prevention and/or treatment of a disease or condition selected from the group consisting of: a disease neurological or neurodegenerative; a cancer; an inflammatory disease; and a metabolic disease, or for the induction of neuroregeneration.

The present invention also relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt or ester thereof, in the manufacture of a medicament for providing a patient with a compound of formula (II) or a salt or ester pharmaceutically acceptable thereof; or a compound of formula (III) or a pharmaceutically acceptable salt or ester thereof; for the prevention and/or treatment of a disease or condition selected from the group consisting of: a neurological or neurodegenerative disease; a cancer; an inflammatory disease; and a metabolic disease, or for the induction of neuroregeneration.

Additionally, part of the invention is the use of a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof, in the preparation of a drug as a prodrug of a compound of formula (II) or a pharmaceutically acceptable salt or ester of the same; or a compound of formula (III) or a pharmaceutically acceptable salt or ester thereof; for the prevention and/or treatment of a disease or condition selected from the group consisting of: a neurological or neurodegenerative disease; a cancer; an inflammatory disease; and a metabolic disease, or for the induction of neuroregeneration.

The present invention further relates to a method for obtaining/preparing/manufacturing a compound of formula (II) or a pharmaceutically acceptable salt or ester thereof; or a compound of formula (III) or a pharmaceutically acceptable salt or ester thereof; wherein said method comprises providing a compound of formula (I), or a pharmaceutically acceptable salt or ester thereof, as prodrugs of said compound of formula (II) or a pharmaceutically acceptable salt or ester thereof; or of said compound of formula (III) or a pharmaceutically acceptable salt or ester thereof.

Additionally, the present invention refers to a method of prevention and/or treatment of a neurological or neurodegenerative disease; a cancer; an inflammatory disease; and a metabolic disease, in a subject in need thereof, wherein said method comprises administering to said subject an effective amount of a prodrug:

- of a compound of formula (II) or of a pharmaceutically acceptable salt or ester thereof:

COOH -(CH2)a-(CH=CH-CH2MCH2)c-CH3

(II)

or

- of a compound of formula (III) or of a pharmaceutically acceptable salt or ester thereof:

COOH -(CH2)a-(CH=CH-CH2)m-(CH2)3-(CH=CH-CH2)rb-í-m;-(CH2)c-CH3

(III)

wherein said prodrug has formula (I):

COOH -CHOH-(CH2)a-(CH=CH-CH2)b-(CH2)c-CH3

(I)

or a pharmaceutically acceptable salt or ester thereof, wherein a is an integer between 1 and 7; b is an integer between 2 and 7; c is an integer between 0 and 7; m is an integer between 0 and ( b - 1); and a +3 b + c +3 is an even integer.

Another embodiment relates to a method of inducing neuroregeneration in a subject in need thereof, wherein said method comprises administering to said subject an effective amount of a prodrug of formula (I), or a pharmaceutically acceptable salt or ester thereof:

COOH -CHOH-(CH2)a-(CH=CH-CH2)b-(CH2)c-CH3

(I)

wherein said prodrug is a prodrug:

- of a compound of formula (II) or of a pharmaceutically acceptable salt or ester thereof:

COOH -(CH2) a -(CH=CH-CH2) b -(CH2) c -CH3

(II)

or

- of a compound of formula (III) or of a pharmaceutically acceptable salt or ester thereof:

COOH -(CH2)a-(CH=CH-CH2)m-(CH2)3-(CH=CH-CH2)rb-í-mr(CH2)c-CH3

(III)

where a is an integer between 1 and 7; b is an integer between 2 and 7; c is an integer between 0 and 7; m is an integer between 0 and ( b - 1); and a +3 b + c +3 is an even integer.

Additionally, the present invention relates to a method of administering an effective amount of a compound of formula (II), or a pharmaceutically acceptable salt or ester thereof; or of a compound of formula (III), or a pharmaceutically acceptable salt or ester thereof; for the prevention and/or treatment of a disease or condition selected from the group consisting of: a neurological or neurodegenerative disease; a cancer; an inflammatory disease; and a metabolic disease, or for the induction of neuroregeneration; wherein said compound of formula (II), or a pharmaceutically acceptable salt or ester thereof; or a compound of formula (III), or a pharmaceutically acceptable salt or ester thereof; is administered as the prodrug of formula (I), or a pharmaceutically acceptable salt or ester thereof.

The invention further relates to a method for the prevention and/or treatment of a disease or condition selected from the group consisting of: a neurological or neurodegenerative disease; a cancer; an inflammatory disease; and a metabolic disease, or for the induction of neuroregeneration; wherein said method comprises administering an effective amount of a prodrug of a compound of formula (II) or a pharmaceutically acceptable salt or ester thereof; or a compound of formula (III) or a pharmaceutically acceptable salt or ester thereof; wherein said prodrug has formula (I) or a pharmaceutically acceptable salt or ester thereof.

Additionally, the present invention relates to a method for the prevention and/or treatment of a disease or condition selected from the group consisting of: a neurological or neurodegenerative disease; a cancer; an inflammatory disease; and a metabolic disease, or for the induction of neuroregeneration; wherein said method comprises administering an effective amount, to a patient in need thereof, of a compound of formula (I), or a pharmaceutically acceptable salt or ester thereof:

COOH -CHOH-(CH2)a-(CH=CH-CH2V(CH2)c-CH3

(I)

wherein the compound of formula (I) is metabolized in the body of said patient to produce a therapeutically effective amount of a metabolite:

- which has formula (II):

COOH - ( CH2)a- ( CH=CH-CH2)b- ( CH2)c-CH3

(II)

or

- which has formula (III):

COOH -(CH ² ) ^a -(CH=CH-CH ² ) ^m -(CH ² ) ³ -(CH=CH-CH ² ) ^{rb -í-m;} -(CH ² ) ^c -CH ³

(III)

where a is an integer between 1 and 7; b is an integer between 2 and 7; c is an integer between 0 and 7; m is an integer between 0 and ( b - 1); and a +3 b + c +3 is an even integer, in which said metabolite is responsible for the prevention and/or treatment of said diseases or conditions and for the induction of neuroregeneration in the patient. Preferably, when an effective amount of a compound of formula (I) is administered, the metabolite having formula (II) or having formula (III) is present in the body of said patient.

In a preferred embodiment, said compound of formula (I) is metabolized in more than 10%, in more than 40%, more than 50%, and up to 99% in a metabolite of formula (II) or formula ( III) when administered.

Another embodiment relates to a method for the prevention and/or treatment of a disease or condition selected from the group consisting of: a neurological or neurodegenerative disease; a cancer; an inflammatory disease; and a metabolic disease, and for the induction of neuroregeneration; wherein said method comprises administering to a patient a prodrug with the structure of formula (I):

COOH -CHOH-(CH2)a-(CH=CH-CH2)b-(CH2)c-CH3

(I)

wherein said prodrug is converted in vivo to release an active compound in cells of said patient; where said active compound has a structure:

- of formula (II):

COOH -(CH2)a-(CH=CH-CH2)b-(CH2)c-CH3

(II)

or

- of formula (III):

COOH -(CH2)a-(CH=CH-CH2)m-(CH2)3-(CH=CH-CH2)rb-í-mr(CH2)c-CH3

(III)

where a is an integer between 1 and 7; b is an integer between 2 and 7; c is an integer between 0 and 7; m is an integer between 0 and ( b - 1); and a +3 b + c +3 is an even integer,

Preferably said conversion is a chemical or physiological process. For the purposes of the present invention, the term "chemical process" refers to the conversion of the prodrug in vivo to release the active compound through a chemical reaction, in which the prodrug is a reactant and the active compound is a reaction product. For the purposes of the present invention, the term "physiological process" refers to a conversion due to an event or process that occurs naturally in an organism, for example, with enzyme activity.

The present invention also relates to a pharmaceutical composition comprising at least one prodrug of formula (I), or a pharmaceutically acceptable salt or ester thereof:

COOH -CHOH-(CH2)a-(CH=CH-CH2)b-(CH2)c-CH3

(I)

wherein said prodrug is a prodrug:

- of a compound of formula (II) or of a pharmaceutically acceptable salt or ester thereof:

COOH -(CH2)a-(CH=CH-CH2)b-(CH2)c-CH3

(II)

or

- of a compound of formula (III) or of a pharmaceutically acceptable salt or ester thereof:

COOH -(CH2)a-(CH=CH-CH2)m-(CH2)3-(CH=CH-CH2)rb-í-m;-(CH2)c-CH3

(III)

where a is an integer between 1 and 7; b is an integer between 2 and 7; c is an integer between 0 and 7; m is an integer between 0 and (b - 1); and a+3b+c+3 is an even integer; and at least one pharmaceutically acceptable excipient; for use as a medicine; in particular for use in the induction of neuroregeneration and for use in the prevention and/or treatment of a disease or condition selected from the group consisting of: a neurological or neurodegenerative disease; a cancer; an inflammatory disease; and a metabolic disease.

Additionally, the invention relates to the use of a pharmaceutical composition comprising at least one prodrug of formula (I), or a pharmaceutically acceptable salt or ester thereof:

COOH -CHOH-(CH ² ) ^a -(CH=CH-CH ² ) ^b -(CH ² ) ^c -CH ³

(I)

wherein said prodrug is a prodrug:

- of a compound of formula (II) or of a pharmaceutically acceptable salt or ester thereof:

COOH -(CH2)a-(CH=CH-CH2)b-(CH2)c-CH3

(II)

or

- of a compound of formula (III) or of a pharmaceutically acceptable salt or ester thereof:

COOH -(CH2)a-(CH=CH-CH2)m-(CH2)3-(CH=CH-CH2)rb-í-m;-(CH2)c-CH3

(III)

where a is an integer between 1 and 7; b is an integer between 2 and 7; c is an integer between 0 and 7; m is an integer between 0 and (b - 1); ); and a+3b+c+3 is an even integer; and at least one pharmaceutically acceptable excipient; in the manufacture of a drug for the prevention and/or treatment of a disease or condition selected from the group consisting of: a neurological or neurodegenerative disease; a cancer; an inflammatory disease and a metabolic disease; or for the induction of neuroregeneration.

Alternatively, the invention relates to a method of prevention and/or treatment of a neurological or neurodegenerative disease; a cancer; an inflammatory disease; and a metabolic disease, in a subject in need thereof, wherein said method comprises administering to said subject an effective amount of a pharmaceutical composition having at least one prodrug of formula (I), or a pharmaceutically acceptable salt or ester thereof:

COOH -CHOH-(CH2)a-(CH=CH-CH2)b-(CH2)c-CH3

(I)

wherein said prodrug is a prodrug:

- of a compound of formula (II) or of a pharmaceutically acceptable salt or ester thereof:

COOH -(CH2)a-(CH=CH-CH2)b-(CH2)c-CH3

(II)

or

- of a compound of formula (III) or of a pharmaceutically acceptable salt or ester thereof:

COOH -(CH2)a-(CH=CH-CH2)m-(CH2)3-(CH=CH-CH2)rb-í-m;-(CH2)c-CH3

(III)

where a is an integer between 1 and 7; b is an integer between 2 and 7; c is an integer between 0 and 7; and m is an integer between 0 and ( b - 1); and a +3 b + c +3 is an even integer; and at least one pharmaceutically acceptable excipient.

The invention also relates to a method of inducing neuroregeneration in a subject in need thereof, wherein said method comprises administering to said subject an effective amount of a pharmaceutical composition comprising at least one prodrug of formula (I), or a pharmaceutically acceptable ester salt thereof:

COOH -CHOH-(CH2)a-(CH=CH-CH2)b-(CH2)c-CH3

(I)

wherein said prodrug is a prodrug:

- of a compound of formula (II) or of a pharmaceutically acceptable salt or ester thereof:

COOH -(CH2) a -(CH=CH-CH2) b -(CH2) c -CH3

(II)

or

- of a compound of formula (III) or of a pharmaceutically acceptable salt or ester thereof:

COOH -(CH2)a-(CH=CH-CH2)m-(CH2)3-(CH=CH-CH2)rb-í-mr(CH2)c-CH3

(III)

where a is an integer between 1 and 7; b is an integer between 2 and 7; c is an integer between 0 and 7; and m is an integer between 0 and ( b - 1); and a +3 b + c +3 is an even integer; and at least one pharmaceutically acceptable excipient.

In a highly preferred embodiment, the prodrug of formula (I) or the sodium salt thereof:

COOH -CHOH-(CH2)a-(CH=CH-CH2)b-(CH2)c-CH3

(I)

is a prodrug of a compound of formula (III) or a pharmaceutically acceptable salt thereof:

COOH -(CH2)a-(CH=CH-CH2)m-(CH2)3-(CH=CH-CH2)rib-í-mr(CH2)c-CH3

(III)

where a =1, b=6, c =0 and m=0.

The present invention also relates to a pharmaceutically acceptable salt or ester of a compound of formula (II) or of a compound of formula (III):

COOH -(CH2)a-(CH=CH-CH2)b-(CH2)c-CH3

(II)

COOH -(CH2)a-(CH=CH-CH2)m-(CH2)3-(CH=CH-CH2)rb-í-mr(CH2)c-CH3

(III)

where a is an integer between 1 and 7; b is an integer between 2 and 7; c is an integer between 0 and 7; m is an integer between 0 and ( b - 1); and a +3 b + c +3 is an even integer.

Additionally, the present invention relates to a pharmaceutically acceptable salt or ester of a compound of formula (II), or to a compound of formula (III:

COOH -(CH2) a -(CH=CH-CH2) b -(CH2) c -CH3

(II)

COOH -(CH2)a-(CH=CH-CH2)m-(CH2)3-(CH=CH-CH2)rb-í-mr(CH2)c-CH3

(III)

where a is an integer between 1 and 7; b is an integer between 2 and 7; c is an integer between 0 and 7; m is an integer between 0 and ( b - 1); and a +3 b + c +3 is an even integer; for use as a medicine; in particular, for use in the induction of neuroregeneration; or for use in the prevention and/or treatment of a disease or condition selected from the group consisting of: a neurological or neurodegenerative disease; a cancer; an inflammatory disease and a metabolic disease.

In a preferred embodiment, said salt or ester of a compound of formula (II) or formula (III), for use as a medicine or in the aforementioned indications; is administered as the prodrug of formula (I), or a pharmaceutically acceptable salt or ester thereof.

In particular, the present invention relates to a compound of formula (II), or a compound of formula (III), or a pharmaceutically acceptable salt or ester of any of them:

COOH -(CH2)a-(CH=CH-CH2MCH2)c-CH3

(II)

COOH -(CH2)a-(CH=CH-CH2)m-(CH2)3-(CH=CH-CH2)rb-í-m;-(CH2)c-CH3

(III)

where a is an integer between 1 and 7; b is an integer between 2 and 7; c is an integer between 0 and 7; m is an integer between 0 and ( b - 1); and a +3 b + c +3 is an even integer; for use in the induction of neuroregeneration, and in the prevention and/or treatment of a neurodegenerative disease, in particular a neurodegenerative disease selected from the group consisting of: Alzheimer's disease; Parkinson's disease; senile dementia; multiple sclerosis and amyotrophic lateral sclerosis; hippocampal sclerosis and other types of epilepsy; focal sclerosis; adrenoleukodystrophy and other types of leukodystrophy; vascular dementia; headache, including migraine; central nervous system trauma; sleep disorders; Vertigo; pain; cerebrovascular accidents; the Depression; the anxiety; neuropathic pain, other neurodegenerative disorders of the peripheral nervous system such as Guillan-Barré syndrome, diabetic neuropathy, Wallerian degeneration, Levy body dementia, fronto-temporal dementia, Huntington's disease, multiple system atrophy, progressive supranuclear palsy and corticobasal degeneration, and the disorders due to substance use or addictive behaviors.

In a preferred embodiment, said compound of formula (II), or a pharmaceutically acceptable salt or ester thereof for use; or said compound of formula (III), or a pharmaceutically acceptable salt or ester thereof for use, in the aforementioned indications; is administered as the prodrug of formula (I), or a pharmaceutically acceptable salt or ester thereof.

Preferably a =4, b =5 and c =0 and the compound for use is a compound of formula (II), or a pharmaceutically acceptable salt or ester thereof.

Also preferably, a =1, b =6, c =0 and m =0, and the compound for use is a compound of formula (III), or a pharmaceutically acceptable salt or ester thereof.

The present invention also relates to the use of a pharmaceutically acceptable salt or ester of a compound of formula (II), or of a compound of formula (III):

COOH -(CH2)a-(CH=CH-CH2)b-(CH2)c-CH3

(II)

COOH -(CH2)a-(CH=CH-CH2)m-(CH2)3-(CH=CH-CH2)rb-í-m;-(CH2)c-CH3

(III)

where a is an integer between 1 and 7; b is an integer between 2 and 7; c is an integer between 0 and 7; m is an integer between 0 and ( b - 1); and a +3 b + c +3 is an even integer; in the manufacture of a drug for the prevention and/or treatment of a disease or condition selected from the group consisting of: a neurological or neurodegenerative disease; a cancer; an inflammatory disease and a metabolic disease; or for the induction of neuroregeneration.

In particular, the present invention relates to the use of a compound of formula (II), or a compound of formula (III), or a pharmaceutically acceptable salt or ester of any of them:

COOH -(CH2)a-(CH=CH-CH2)b-(CH2)c-CH3

(II)

COOH -(CH2)a-(CH=CH-CH2)m-(CH2)3-(CH=CH-CH2)rb-í-mr(CH2)c-CH3

(III)

where a is an integer between 1 and 7; b is an integer between 2 and 7; c is an integer between 0 and 7; m is an integer between 0 and ( b - 1); and a +3 b + c +3 is an even integer; in the manufacture of a medicament for the induction of neuroregeneration, and for the prevention and/or treatment of a neurodegenerative disease, in particular a neurodegenerative disease selected from the group consisting of: Alzheimer's disease; Parkinson's disease; senile dementia; multiple sclerosis and amyotrophic lateral sclerosis; hippocampal sclerosis and other types of epilepsy; focal sclerosis; adrenoleukodystrophy and other types of leukodystrophy; vascular dementia; headache, including migraine; central nervous system trauma; sleep disorders; Vertigo; pain; cerebrovascular accidents; the Depression; the anxiety; neuropathic pain, other neurodegenerative disorders of the peripheral nervous system such as Guillan-Barré syndrome, diabetic neuropathy, Wallerian degeneration, Levy body dementia, fronto-temporal dementia, Huntington's disease, multiple system atrophy, progressive supranuclear palsy and cortico-basal degeneration disorders due to substance use or addictive behaviors.

Preferably, a =4, b=5 and c =0 and the compound is a compound of formula (II), or a pharmaceutically acceptable salt or ester thereof.

Also preferably, a =1, b =6, c =0 and m=0, and the compound is a compound of formula (III), or a pharmaceutically acceptable salt or ester thereof.

Also part of the present invention is a method of prevention and/or treatment of a neurological or neurodegenerative disease; a cancer; an inflammatory disease; and a metabolic disease, in a subject in need thereof, wherein said method comprises administering to said subject an effective amount of a pharmaceutically acceptable salt or ester of a compound of formula (II) or of a compound of formula (III):

COOH -(CH2)a-(CH=CH-CH2)b-(CH2)c-CH3

(II)

COOH -(CH2)a-(CH=CH-CH2)m-(CH2)3-(CH=CH-CH2)rb-í-mr(CH2)c-CH3

(III)

where a is an integer between 1 and 7; b is an integer between 2 and 7; c is an integer between 0 and 7; m is an integer between 0 and ( b - 1); and a +3 b + c +3 is an even integer.

In particular, the present invention relates to a method of prevention and/or treatment of a neurodegenerative disease, in particular a neurodegenerative disease selected from the group consisting of: Alzheimer's disease; Parkinson's disease; senile dementia; multiple sclerosis and amyotrophic lateral sclerosis; hippocampal sclerosis and other types of epilepsy; focal sclerosis; adrenoleukodystrophy and other types of leukodystrophy; vascular dementia; headache, including migraine; central nervous system trauma; sleep disorders; Vertigo; pain; cerebrovascular accidents; the Depression; the anxiety; neuropathic pain, other neurodegenerative disorders of the peripheral nervous system such as Guillan-Barré syndrome, diabetic neuropathy, Wallerian degeneration, Levy body dementia, fronto-temporal dementia, Huntington's disease, multiple system atrophy, progressive supranuclear palsy and corticobasal degeneration, and the disorders due to the consumption of addictive substances or behaviors, in a subject in need thereof, wherein said method comprises administering to said subject an effective amount of a compound of formula (II), or of a compound of formula (III), or a salt or pharmaceutically acceptable ester of any of the same:

COOH -(CH2) a -(CH=CH-CH2) b -(CH2) c -CH3

(II)

COOH -(CH2)a-(CH=CH-CH2)m-(CH2)3-(CH=CH-CH2WmHCH2)c-CH3

(III)

where a is an integer between 1 and 7; b is an integer between 2 and 7; c is an integer between 0 and 7; m is an integer between 0 and (b - 1); and a+3b+c+3 is an even integer.

The invention also relates to a method of inducing neuroregeneration in a subject in need thereof, wherein said method comprises administering to said subject an effective amount of a compound of formula (II), or of a compound of formula (III), or of a pharmaceutically acceptable salt or ester of any of the following:

COOH -(CH2)a-(CH=CH-CH2)b-(CH2)c-CH3

(II)

COOH -(CH2)a-(CH=CH-CH2)m-(CH2)3-(CH=CH-CH2)rb-í-mr(CH2)c-CH3

(III)

where a is an integer between 1 and 7; b is an integer between 2 and 7; c is an integer between 0 and 7; m is an integer between 0 and (b - 1); and a+3b+c+3 is an even integer.

Preferably, a=4, b=5 and c=0 and the compound is a compound of formula (II), or a pharmaceutically acceptable salt or ester thereof.

Also preferably, a=1, b=6, c=0 and m=0, and the compound is a compound of formula (III), or a pharmaceutically acceptable salt or ester thereof.

The present invention also relates to a pharmaceutical composition comprising at least one first compound selected from the group consisting of:

- a pharmaceutically acceptable salt or ester of a compound of formula (II):

COOH-(CH2)a-(CH=CH-CH2)b-(CH2)c-CH3

(II)

Y

- a pharmaceutically acceptable salt or ester of a compound of formula (III):

COOH -(CH2)a-(CH=CH-CH2)m-(CH2)3-(CH=CH-CH2)rb-í-mr(CH2)c-CH3

(III)

where a is an integer between 1 and 7; b is an integer between 2 and 7; c is an integer between 0 and 7; m is an integer between 0 and (b - 1); and a+3b+c+3 is an even integer; and at least one pharmaceutically acceptable excipient.

In a preferred embodiment of the invention, said pharmaceutical composition is characterized in that it also comprises a second compound of formula (I), or a pharmaceutically acceptable salt or ester thereof:

COOH -CHOH-(CH2)a-(CH=CH-CH2)b-(CH2)c-CH3

(I)

where a , b and c have the same values as for the first compound.

Another embodiment refers to a pharmaceutical composition comprising at least one first compound selected from the group consisting of:

- a compound of formula (II) or a pharmaceutically acceptable salt or ester thereof:

COOH-(CH2) a -(CH=CH-CH2) b -(CH2) c -CH3

(II)

Y

- a compound of formula (III) or a pharmaceutically acceptable salt or ester thereof:

COOH -(CH2)a-(CH=CH-CH2)m-(CH2)3-(CH=CH-CH2)rb-í-mr(CH2)c-CH3

(III)

characterized in that it further comprises a second compound of formula (I), or a pharmaceutically acceptable salt or ester thereof:

COOH -CHOH-(CH2) a -(CH=CH-CH2) b -(CH2) c -CH3

(I)

where a is an integer between 1 and 7; b is an integer between 2 and 7; c is an integer between 0 and 7; m is an integer between 0 and (b - 1); and a+3b+c+3 is an even integer; and at least one pharmaceutically acceptable excipient.

One embodiment of the present invention relates to a pharmaceutical composition comprising at least one first compound selected from the group consisting of:

-- a pharmaceutically acceptable salt or ester of a compound of formula (II):

COOH-(CH2)a-(CH=CH-CH2)b-(CH2)c-CH3

(II)

Y

- a pharmaceutically acceptable salt or ester of a compound of formula (III):

COOH -(CH2)a-(CH=CH-CH2)m-(CH2)3-(CH=CH-CH2)rb-í-m;-(CH2)c-CH3

(III)

where a is an integer between 1 and 7; b is an integer between 2 and 7; c is an integer between 0 and 7; m is an integer between 0 and (b - 1); and a+3b+c+3 is an even integer; and at least one pharmaceutically acceptable excipient, for use as a medicine; in particular for use in the induction of neuroregeneration and for use in the prevention and/or treatment of a disease or condition selected from the group consisting of: a neurological or neurodegenerative disease; a cancer; an inflammatory disease; and a metabolic disease.

In a preferred embodiment of said composition for use as a medicine or in the aforementioned indications; the pharmaceutically acceptable salt or ester of a compound of formula (II) or of formula (III) is administered as a prodrug of formula (I), or a pharmaceutically acceptable salt or ester thereof.

In a preferred embodiment of the invention, said pharmaceutical composition for use is characterized in that it also comprises a second compound of formula (I), or a pharmaceutically acceptable salt or ester thereof:

COOH -CHOH-(CH2)a-(CH=CH-CH2)b-(CH2)c-CH3

(I)

where a , b and c have the same values as for the first compound.

In particular, the present invention relates to a pharmaceutical composition comprising at least one first compound selected from the group consisting of:

- a compound of formula (II) or a pharmaceutically acceptable salt or ester thereof:

COOH-(CH2)a-(CH=CH-CH2)b-(CH2)c-CH3

(II)

Y

- a compound of formula (III) or a pharmaceutically acceptable salt or ester thereof:

COOH -(CH2)a-(CH=CH-CH2)m-(CH2)3-(CH=CH-CH2)rb-í-mr(CH2)c-CH3

(III)

where a is an integer between 1 and 7; b is an integer between 2 and 7; c is an integer between 0 and 7; m is an integer between 0 and (b - 1); and a+3b+c+3 is an even integer; and at least one pharmaceutically acceptable excipient, for use in inducing neuroregeneration; and for use in the prevention and/or treatment of a neurodegenerative disease selected from the group consisting of: : Alzheimer's disease; Parkinson's disease; senile dementia; multiple sclerosis and amyotrophic lateral sclerosis; hippocampal sclerosis and other types of epilepsy; focal sclerosis; adrenoleukodystrophy and other types of leukodystrophy; vascular dementia; headache, including migraine; central nervous system trauma; sleep disorders; Vertigo; pain; cerebrovascular accidents; the Depression; the anxiety; neuropathic pain, other neurodegenerative disorders of the peripheral nervous system such as Guillan-Barré syndrome, diabetic neuropathy, Wallerian degeneration, Levy body dementia, fronto-temporal dementia, Huntington's disease, multiple system atrophy, progressive supranuclear palsy and cortico-basal degeneration disorders due to substance use or addictive behaviors.

In a preferred embodiment of said composition for use in the aforementioned indications; the compound of formula (II) or formula (III), or a pharmaceutically acceptable salt or ester thereof, is administered as a prodrug of formula (I), or a pharmaceutically acceptable salt or ester thereof.

Preferably, the composition comprises a compound of formula (II) or a pharmaceutically acceptable salt or ester thereof, in which a=4, b=5 and c=0.

Also preferably, the composition comprises a compound of formula (III) or a pharmaceutically acceptable salt or ester thereof, in which a=1, b=6, c=0 and m=0.

Another embodiment of the present invention relates to a pharmaceutical composition comprising at least one first compound selected from the group consisting of:

- a compound of formula (II) or a pharmaceutically acceptable salt or ester thereof:

COOH-(CH2)a-(CH=CH-CH2)b-(CH2)c-CH3

(II)

Y

- a compound of formula (III) or a pharmaceutically acceptable salt or ester thereof:

COOH -(CH2)a-(CH=CH-CH2)m-(CH2)3-(CH=CH-CH2)rb-í-mr(CH2)c-CH3

(III)

characterized in that it further comprises a second compound of formula (I), or a pharmaceutically acceptable salt or ester thereof:

COOH -CHOH-(CH2)a-(CH=CH-CH2MCH2)c-CH3

(I)

where a is an integer between 1 and 7; b is an integer between 2 and 7; c is an integer between 0 and 7; m is an integer between 0 and (b - 1); and a+3b+c+3 is an even integer; and at least one pharmaceutically acceptable excipient, for use as a medicine; in particular for use in the induction of neuroregeneration and for use in the prevention and/or treatment of a disease or condition selected from the group consisting of: a neurological or neurodegenerative disease; a cancer; an inflammatory disease; and a metabolic disease.

One embodiment of the invention relates to the use of a pharmaceutical composition comprising at least one first compound selected from the group consisting of:

- a pharmaceutically acceptable salt or ester of a compound of formula (II):

COOH-(CH2)a-(CH=CH-CH2)b-(CH2)c-CH3

(II)

Y

- a pharmaceutically acceptable salt or ester of a compound of formula (III):

COOH -(CH2)a-(CH=CH-CH2)m-(CH2)3-(CH=CH-CH2)rb-í-mr(CH2)c-CH3

(III)

where a is an integer between 1 and 7; b is an integer between 2 and 7; c is an integer between 0 and 7; m is an integer between 0 and (b - 1); and a+3b+c+3 is an even integer; and at least one pharmaceutically acceptable excipient; in the manufacture of a drug for the prevention and/or treatment of a disease or condition selected from the group consisting of: a neurological or neurodegenerative disease; a cancer; an inflammatory disease and a metabolic disease; or for the induction of neuroregeneration.

In particular, the invention relates to the use of a pharmaceutical composition comprising at least one first compound selected from the group consisting of:

- a compound of formula (II) or a pharmaceutically acceptable salt or ester thereof: COOH-(CH2)a-(CH=CH-CH2)b-(CH2)c-CH3

(II)

Y

- a compound of formula (III) or a pharmaceutically acceptable salt or ester thereof:

COOH -(CH2)a-(CH=CH-CH2)m-(CH2)3-(CH=CH-CH2Wmr(CH2)c-CH3

(III)

where a is an integer between 1 and 7; b is an integer between 2 and 7; c is an integer between 0 and 7; m is an integer between 0 and (b - 1); and a+3b+c+3 is an even integer; and at least one pharmaceutically acceptable excipient; in the preparation of a medicament for the induction of neuroregeneration, or of a medicament for the prevention and/or treatment of a neurodegenerative disease selected from the group consisting of: Alzheimer's disease; Parkinson's disease; senile dementia; multiple sclerosis and amyotrophic lateral sclerosis; hippocampal sclerosis and other types of epilepsy; focal sclerosis; adrenoleukodystrophy and other types of leukodystrophy; vascular dementia; headache, including migraine; central nervous system trauma; sleep disorders; Vertigo; pain; cerebrovascular accidents; the Depression; the anxiety; neuropathic pain, other neurodegenerative disorders of the peripheral nervous system such as Guillan-Barré syndrome, diabetic neuropathy, Wallerian degeneration, Levy body dementia, fronto-temporal dementia, Huntington's disease, multiple system atrophy, progressive supranuclear palsy and cortico-basal degeneration disorders due to substance use or addictive behaviors.

Preferably, the composition comprises a compound of formula (II) or a pharmaceutically acceptable salt or ester thereof, in which a=4, b=5 and c=0.

Also preferably, the composition comprises a compound of formula (III) or a pharmaceutically acceptable salt or ester thereof, in which a=1, b=6, c=0 and m=0.

Another embodiment relates to a method of prevention and/or treatment of a neurological or neurodegenerative disease; a cancer; an inflammatory disease; and a metabolic disease, in a subject in need thereof, wherein said method comprises administering to said subject an effective amount of a pharmaceutical composition comprising at least one first compound selected from the group consisting of:

-- a pharmaceutically acceptable salt or ester of a compound of formula (II):

COOH-(CH2)a-(CH=CH-CH2)b-(CH2)c-CH3

(II)

Y

- a pharmaceutically acceptable salt or ester of a compound of formula (III):

COOH -(CH2)a-(CH=CH-CH2)m-(CH2)3-(CH=CH-CH2)rb-í-m;-(CH2)c-CH3

(III)

where a is an integer between 1 and 7; b is an integer between 2 and 7; c is an integer between 0 and 7; m is an integer between 0 and (b - 1); and a+3b+c+3 is an even integer; and at least one pharmaceutically acceptable excipient.

In particular, the invention relates to a method of prevention and/or treatment of a neurodegenerative disease selected from the group consisting of: Alzheimer's disease; Parkinson's disease; senile dementia; multiple sclerosis and amyotrophic lateral sclerosis; hippocampal sclerosis and other types of epilepsy; focal sclerosis; adrenoleukodystrophy and other types of leukodystrophy; vascular dementia; headache, including migraine; central nervous system trauma; sleep disorders; Vertigo; pain; cerebrovascular accidents; the Depression; the anxiety; neuropathic pain, other neurodegenerative disorders of the peripheral nervous system such as Guillan-Barré syndrome, diabetic neuropathy, Wallerian degeneration, Levy body dementia, fronto-temporal dementia, Huntington's disease, multiple system atrophy, progressive supranuclear palsy and cortico-basal degeneration disorders due to substance use or addictive behaviors, in a subject in need thereof, wherein said method comprises administering to said subject an effective amount of a pharmaceutical composition comprising at least one first compound selected from the group consisting of:

- a compound of formula (II) or a pharmaceutically acceptable salt or ester thereof:

COOH-(CH2)a-(CH=CH-CH2)b-(CH2)c-CH3

(II)

Y

- a compound of formula (III) or a pharmaceutically acceptable salt or ester thereof:

COOH -(CH2)a-(CH=CH-CH2)m-(CH2)3-(CH=CH-CH2)rb-í-mr(CH2)c-CH3

(III)

where a is an integer between 1 and 7; b is an integer between 2 and 7; c is an integer between 0 and 7; m is an integer between 0 and (b - 1); and a+3b+c+3 is an even integer; and at least one pharmaceutically acceptable excipient.

Preferably, the composition comprises a compound of formula (II) or a pharmaceutically acceptable salt or ester thereof, in which a=4, b=5 and c=0.

Also preferably, the composition comprises a compound of formula (III) or a pharmaceutically acceptable salt or ester thereof, in which a=1, b=6, c=0 and m=0.

Another embodiment relates to a method of inducing neuroregeneration in a subject in need thereof, wherein said method comprises administering to said subject an effective amount of a pharmaceutical composition comprising at least one first compound selected from the group consisting of:

-- a compound of formula (II), or a pharmaceutically acceptable salt or ester thereof:

COOH-(CH2)a-(CH=CH-CH2)b-(CH2)e-CH3

(II)

Y

- a compound of formula (III), or a pharmaceutically acceptable salt or ester thereof:

COOH -(CH2)a-(CH=CH-CH2)m-(CH2)3-(CH=CH-CH2)rb-í-mr(CH2)c-CH3

(III)

where a is an integer between 1 and 7; b is an integer between 2 and 7; c is an integer between 0 and 7; m is an integer between 0 and (b - 1); and a+3b+c+3 is an even integer; and at least one pharmaceutically acceptable excipient; wherein said composition for use optionally further comprises a second compound of formula (I), or a pharmaceutically acceptable salt or ester thereof:

COOH -CHOH-(CH2)a-(CH=CH-CH2)b-(CH2)c-CH3

(I)

where a , b and c have the same values as for the first compound.

The embodiments indicated below refer to the embodiments of compounds, uses, methods and compositions described above. In the event that a value of m is defined, the preferred embodiment refers to any previous embodiment of the invention that comprises a compound of formula (III) and its corresponding prodrug of formula (I), while, if the value of m is not mentioned, the preferred embodiment refers to any previous embodiment of the invention comprising a compound of formula (II) and its corresponding prodrug of formula (I).

In one embodiment, either the compound of formula (I), or its metabolite of formula (II) or of formula (III), or all of them, is a salt. More preferably, the salt is a sodium salt.

In a preferred embodiment a is an integer between 1 and 7; b is an integer between 2 and 7; c is 0; m is an integer between 0 and (b - 1); and a+3b+c+3 is an even integer.

In another preferred embodiment , a is an integer between 1 and 7; b is an integer between 2 and 7; c is 3; m is an integer between 0 and (b - 1); and a+3b+c+3 is an even integer.

In an even more preferred embodiment of the present invention:

a=6, b=2, c=3 and m is 0 or 1; or

a=6, b=3, c=0 and m is selected from 0, 1 or 2, and even more preferably m is 0 or 1; or a=3, b=3, c=3 and m is selected from 0, 1 or 2, and even more preferably m is 0 or 1; or a=2, b=4, c=3 and m is selected from 0, 1, 2, or 3, and even more preferably m is 0 or 1; or a=2, b=5, c=0 and m is selected from 0, 1, 2, 3 or 4, and even more preferably m is 0 or 1; or

a=1, b=6, c=0 and m=0.

In a preferred embodiment of said even more preferred embodiment of the present invention, a=6, b=2, c=3 and m is 0 or 1.

In another preferred embodiment of said even more preferred embodiment of the present invention, a=6, b=3, c=0 and m is selected from 0, 1 or 2; and even more preferably m is 0 or 1.

In another preferred embodiment of said even more preferred embodiment of the present invention, a=3, b=3, c=3 and m is selected from 0, 1 or 2; and even more preferably m is 0 or 1.

In another preferred embodiment of said even more preferred embodiment of the present invention, a=2, b=4, c=3 and m is selected from 0, 1, 2, or 3; and even more preferably m is 0 or 1.

In another preferred embodiment of said even more preferred embodiment of the present invention, a =2, b =5, c =0 and m is selected from 0, 1, 2, 3 or 4; and even more preferably m is 0 or 1.

In another preferred embodiment of said even more preferred embodiment of the present invention, a=1, b=6, c=0 and m=0.

In a more preferred embodiment of said preferred, more preferred and even more preferred embodiments, m is 0.

In an even more preferred embodiment of said preferred, more preferred and still more preferred embodiments, the salt is a sodium salt.

In a preferred embodiment a is an integer between 1 and 7; b is an integer between 2 and 7; c is 0; and a+3b+c+3 is an even integer.

In another preferred embodiment , a is an integer between 1 and 7; b is an integer between 2 and 7; c is 3; and a+3b+c+3 is an even integer.

In an even more preferred embodiment of the present invention:

a=6, b=2, c=3; or

a=5, b=2 and c=3; or

a=6, b=3, c=0; or

a=5, b=3 and c=0; or

a=3, b=3, c=3; or

a=2, b=3 and c=3; or

a=2, b=4, c=3; or

a=1, b=4 and c=3;

a=2, b=5, c=0; or

a=1, b=5 and c=0; or

a=4, b=5 and c=0.

In a preferred embodiment of said even more preferred embodiment of the present invention, a=6, b=2 and c=3.

In another preferred embodiment of said even more preferred embodiment of the present invention, a=6, b=3 and c=0.

In another preferred embodiment of said even more preferred embodiment of the present invention, a=3, b=3 and c=3.

In another preferred embodiment of said even more preferred embodiment of the present invention, a=2, b=4 and c=3.

In another preferred embodiment of said even more preferred embodiment of the present invention, a=2, b=5 and c=0.

In another preferred embodiment of said even more preferred embodiment of the present invention, a=4, b=5 and c=0.

In an even more preferred embodiment of said preferred, more preferred and still more preferred embodiments, the salt is a sodium salt.

In a highly preferred embodiment, the prodrug of formula (I) or the sodium salt thereof:

COOH -CHOH-(CH2)a-(CH=CH-CH2V(CH2)c-CH3

(I)

is a prodrug of a compound of formula (III):

COOH -(CH2)a-(CH=CH-CH2MCH2)3-(CH=CH-CH2Wmr(CH2)c-CH3

(III)

where a=1, b=6, c=0 and m=0.

In an even more preferred embodiment of said preferred, more preferred and even more preferred embodiments, the pharmaceutically acceptable salt of any of the compounds of formula (II) or of any of the compounds of formula (III), or of all the compounds of formula (II) and of formula (III), is a sodium salt.

In another even more preferred embodiment of said preferred, more preferred and even more preferred embodiments, the ester is a methyl ester or an ethyl ester.

In yet another more preferred embodiment of said preferred, more preferred and even more preferred embodiments, the compound is a stereoisomer with all double bonds in the cis configuration.

The pharmaceutical compositions of the present invention may comprise yet another therapeutically active agent.

For the purposes of the present invention, the term "therapeutically active agent" refers to that substance, compound or ingredient that causes a biological effect when administered to a subject, said biological effect being an effect that allows the treatment or prevention of a disease. or pathological condition, or that produces an improvement in the general state of health of said subject.

Among the active agents are compounds for the treatment of neurodegenerative diseases, anticancer agents, metabolism regulating compounds, cardiovascular agents, and obesity and overweight regulating agents.

Among the chemotherapeutic agents that can be found in the composition with HPA can be selected from the group consisting of: temozolomide, cyclophosphamide; melphalan, Docetaxel, paclitaxel, carboplatin, cisplatin, oxaliplatin, methotrexate, pemetrexed, azathiopyrene, capecitabine, fluoracil, mercaptopurine, gemcitabine, bleomycin, actinomycin, vincristine, vinblastine, vinorelbine, retinoic acid, daunorubicin, doxorubicin, irinotecan, and topotecan.

In a preferred embodiment of the invention, said excipient is albumin, for example: ovalbumin, lactalbumin, native or recombinant albumin of human, bovine, murine, or rabbit origin, more preferably, human serum albumin or bovine serum albumin.

The person skilled in the art will be able to select one or more pharmaceutically acceptable vehicles or excipients that are known in the state of the art, such that the pharmaceutical compositions are suitable for administration to both a human subject and an animal subject.

The effective amount, or therapeutically effective amount, for the purposes of the present invention, is understood as that which provides a therapeutic effect without providing unacceptable toxic effects in the patient. The effective amount or dose of the drug depends on the compound and the condition or disease being treated and on, for example, the age, weight and clinical condition of the patient being treated, the form of administration, the patient's medical history, the severity of the disease and the potency of the administered compound.

For the purposes of the present invention, neurological diseases are all those diseases that affect the nervous system (central and peripheral). Within said group are neurodegenerative diseases which, for the purposes of the present invention, are a heterogeneous group of disorders characterized by progressive degeneration of the structure and function of the central nervous system or the peripheral nervous system.

Preferably, said neurodegenerative disease is selected from the group consisting of: Alzheimer's disease; Parkinson's disease; senile dementia; multiple sclerosis and amyotrophic lateral sclerosis; hippocampal sclerosis and other types of epilepsy; focal sclerosis; adrenoleukodystrophy and other types of leukodystrophy; vascular dementia; headache, including migraine; central nervous system trauma; sleep disorders; Vertigo; pain; cerebrovascular accidents; the Depression; the anxiety; neuropathic pain, other neurodegenerative disorders of the peripheral nervous system such as Guillan-Barré syndrome, diabetic neuropathy, Wallerian degeneration, Levy body dementia, fronto-temporal dementia, Huntington's disease, multiple system atrophy, progressive supranuclear palsy and cortico-basal degeneration disorders due to substance use or addictive behaviors.

Preferably, the neurodegenerative disease is selected from the group consisting of spinal cord injury and pain of neurological origin.

Preferably, the cancer is selected from the group consisting of lung cancer, brain cancer, breast cancer, leukemia, liver cancer, and pancreatic cancer.

Preferably, the inflammatory disease is selected from the group consisting of: cardiovascular inflammation; inflammation caused by tumors; inflammation of rheumatoid origin; inflammation caused by infection; respiratory inflammation; acute and chronic inflammation; inflammatory wholeness hyperalgesia; and edema and inflammation caused by trauma or burns.

Preferably, the metabolic disease is selected from the group consisting of obesity, overweight, hypercholesterolemia, hypertriglyceridemia, diabetes, and insulin resistance.

In this regard, the fact that lipids, when they integrate the cell membrane, can control cell signaling means that they can also regulate the physiological state of the cells and, therefore, the general state of health.

On the other hand, for the purposes of the present invention, neurodegenerative processes are a heterogeneous group of disorders that are characterized by the progressive degeneration of the structure and function of the central nervous system or the peripheral nervous system. These neurodegenerative processes include the induction of neuroregeneration, the prevention and/or treatment of spinal cord injuries and/or the prevention and/or treatment of pain.

Some of these neurodegenerative processes involve a significant decrease in the cognitive capacity of patients or motor alterations. Neurodegenerative processes, neurological and neuropsychiatric disorders have a common base of neuronal degeneration or alterations of its components, such as lipids (for example, myelin) or membrane proteins (for example, adrenergic receptors, serotonergic receptors, etc.). Preferably, these pathologies of the central nervous system include: Alzheimer's disease, 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, headaches including migraine, central nervous system trauma, sleep disorders, vertigo, pain, stroke, depression, neuropathic pain, other neurodegenerative disorders of the peripheral nervous system such as Guillan-Barré syndrome, diabetic neuropathy, Wallerian degeneration, Levy body dementia, fronto-temporal dementia, Huntington's disease, multiple system atrophy, progressive supranuclear palsy, cortico-basal degeneration, anxiety, addictions, etc.

In particular, neurodegenerative diseases select from the group consisting of:

Inflammatory diseases of the central nervous system such as bacterial meningitis, nonbacterial meningitis, acute necrotizing hemorrhagic encephalopathy, other encephalitis, myelitis and encephalomyelitis, cerebral ventriculitis not otherwise specified NOS, intracranial and intraspinal abscess and granuloma, extradural and subdural abscess, phlebitis, Intracranial thrombophlebitis in spinal cord injury and sequelae of inflammatory diseases of the central nervous system.

Systemic atrophies mainly affecting the central nervous system such as Huntington's chorea, Huntington's dementia, hereditary ataxia; spinal muscular atrophy and related syndromes such as Werdnig-Hoffman; systemic atrophies mainly affecting the central nervous system, post-polio syndrome; motor neuron diseases such as amyotrophic lateral sclerosis and progressive bulbar palsy.

Extrapyramidal and movement disorders such as Parkinson's disease, Secondary Parkinsonism, Neuroleptic malignant syndrome, Drug-induced secondary Parkinsonism Postencephalitic Parkinsonism, Vascular Parkinsonism, Basal nuclei degenerative diseases, Hallervorden-Spatz, Progressive supranuclear ophthalmoplegia, Striatonigral degeneration, dystonia essential tremor, drug-induced tremor, myclonia, drug-induced chorea, drug-induced tics, tics of organic origin, drug-induced movement disorders, akathisia, restless leg syndrome, stiff-man syndrome, and benign attacks of shivering.

Other degenerative diseases of the nervous system such as Alzheimer's disease, early or late onset Alzheimer's, fronto temporal dementia such as Pick's disease, degeneration of the nervous system due to alcohol, Alpers' disease, Leigh's disease, Lewy body dementia, mild cognitive impairment, corticobasal degeneration, primary degenerative dementia includes Alzheimer's dementia, senile and presenile forms.

Demyelinating diseases of the central nervous system such as multiple sclerosis of the spinal cord, brainstem, disseminated, generalized, or not otherwise specified (NOS); acute disseminated demyelination, diffuse sclerosis of the central nervous system;

Episodic and paroxysmal disorders such as epilepsy and recurrent epileptic seizures, idiopathic epilepsy and epileptic seizures, grand mal seizures, nonspecific atonic or clonic epilepsy, Lennox-Gastaut syndrome, epileptic spasms, epilepsy of unspecified type, migraine, headache, ischemic attacks transient cerebral and related syndromes, sleep disorders and vertigo.

Nerve, root and nerve plexus disorders such as trigeminal nerve disorders, facial nerve disorders, cranial nerve disorders, nerve root and plexus disorders, upper or lower extremity mononeuropathies and Wallerian degeneration.

Polyneuropathies and other disorders of the peripheral nervous system, including hereditary and idiopathic neuropathy such as Roussy-Levy Syndrome, Refsum disease; inflammatory polyneuropathy; polyneuropathy sequelae such as Guillan-Barré sequelae, serum neuropathy; other polyneuropathies such as neuropathy due to drugs, alcoholic, toxic agent, radiation; sequelae of inflammatory and toxic polyeneuropathies.

Muscle and neuromuscular junction diseases such as myasthenia gravis and other myoneural disorders, muscle and neuromuscular junction disorders.

Cerebral palsy and other paralytic syndromes, including hemiplegia, paraplegia, tetraplegia.

Other nervous system disorders such as complex regional pain syndrome, autonomic nervous system disorders, peripheral autonomic neuropathy, hydrocephalus, brain cysts, Riley-Day syndrome, multisystem autonomic nervous system degeneration, hippocampal sclerosis, mesial sclerosis, diabetic neuropathy or Wolfram Syndrome, adrenoleukodystrophy, leukodystrophy and spinal cord injury.

Mental and behavioral disorders due to physiological conditions such as vascular dementia, dementia unspecified; behavioral disorders related to the consumption of psychoactive substances; schizophrenia, schizotypal disorder, delusional disorder, and other non-mood psychotic disorders; mood (affective) disorders such as manic episode, bipolar disorder, major depressive disorder, cyclothymic disorder, dysthymic disorder; anxiety disorder, dissociative, stress-related and other non-psychotic somatoform mental disorders; behavioral syndromes associated with physiological disorders and physical factors such as eating disorders, sleep disorders; personality disorder, impulse disorder, pathological gambling; intellectual disability; speech disorders, writing, learning disorder.

Certain neurodegenerative diseases can lead to processes in which blindness, hearing problems, disorientation, changes in mood, etc. develop. An example of a well-characterized neurodegenerative disorder is Alzheimer's disease, in which the formation of plaques has been observed, formed mainly by the p-amyloid peptide that comes from altered protein processing, followed by an accumulation on the outside of the cells. On the other hand, neurofilament tangles of hyperphosphorylated tau protein appear inside the cell. This process has been associated with alterations in cholesterol metabolism and the consequent alteration in the levels of certain membrane lipids, such as docosahexaenoic acid. On the other hand, several neurodegenerative pathologies, such as Parkinson's disease, Alzheimer's disease, senile dementia (or Lewy bodies), have been related to the pathological accumulation of fibrillar aggregates of protein a-synuclein, which give rise to to a significant alteration in the metabolism of cellular triglycerides. In fact, the development of these and other neurodegenerative diseases is related to alterations in serum or cellular levels of lipids, such as cholesterol, triglycerides, sphingomyelin, phosphatidylethanolamine, etc. This again suggests that lipids play a crucial role in the proper functioning of neurons, glial cells, nerves, cerebrum, cerebellum, and spinal cord, which is logical considering the high abundance of lipids in the system. central nervous

Alzheimer's disease (AD) is a neurodegenerative disease that to date does not have an effective therapy or treatment whose pathophysiology is still largely unknown. Multiple drugs and therapies have been designed and developed in the last decade with the aim of stopping or slowing down the neurodegenerative process characteristic of this disease. However, no treatment is yet known to have successfully completed a phase III clinical trial in humans. Most therapies have been inspired by the amyloid cascade hypothesis, which is currently in question due to the almost complete failure of clinical trials of anti-amyloid/tau therapies.

On the other hand, different types of sclerosis and other neurodegenerative processes are related to "demyelination", the net result of which is the loss of lipids in the of the neuronal axons, with the consequent alterations in the process of propagation of electrical signals that this entails. Myelin is a lipid layer that surrounds the axons of many neurons and is formed by a succession of spiral folds of the plasma membrane of glial cells (Schwann cells and oligodendrocytes, peripherally and centrally, respectively). For all these reasons, it has been shown that lipids play an important role in the development of neurodegenerative diseases. Moreover, it has been proven that natural polyunsaturated fatty acids have a moderate preventive effect on the development of neurodegenerative processes. In fact, the most abundant lipid in the central nervous system is docosahexaenoic acid (DHA), whose abundance is altered in many neurodegenerative processes, such as Alzheimer's disease.

Metabolic diseases form a set of pathologies characterized by the accumulation or deficiency of certain molecules. A typical example is the accumulation of glucose, cholesterol and/or triglycerides above normal levels. The increase in the levels of glucose, cholesterol and/or triglycerides, both at the systemic level (eg, increased plasma levels) and at the cellular level (eg, in cell membranes) is associated with alterations in cell signaling that lead to dysfunctions at various levels, and that are normally due to errors in the activity of certain enzymes or the control of said proteins. Among the most important metabolic disorders are hypercholesterolemia (high cholesterol levels) and hypertriglyceridemia (high triglyceride levels). These diseases have high incidence, morbidity and mortality rates, so their treatment is a first-order need. Other important metabolic disorders are diabetes and insulin resistance, characterized by problems in the control of glucose levels. These metabolic disorders are involved in the appearance of other pathological processes, such as cancer, hypertension, obesity, arteriosclerosis, etc.

Another pathological process related to the previously described metabolic disorders has been identified and which could constitute per se a new metabolic disorder, which is the metabolic syndrome.

Cancer is a type of hyperproliferative disease that occurs in various organs. There are multiple types of cancer among which are, for example, pancreatic cancer, bile duct carcinoma, neuroblastoma, colon cancer, breast cancer, myeloma, gastric cancer, liver cancer, glioblastoma, ovarian cancer, colorectal cancer, non-Hodgkin's lymphoma, lung cancer, prostate cancer, small cell lung cancer, large cell lung cancer, kidney cancer, esophageal cancer, lung cancer stomach, cervical cancer or lymphoma tumors. The lipid modification of the cell membrane can be used as a strategy for the prevention or treatment of multiple types of cancer.

Obesity is caused by an alteration between the balance of intake and energy expenditure that is due, in part, to alterations in the mechanisms that regulate these processes. On the other hand, this pathology is characterized by hyperplasia (increase in the number of cells) or hypertrophy (increase in size) of the adipose tissue cells, the adipocytes. Numerous studies show that fatty acids, both free and those that are part of other molecules, can influence a series of parameters related to energy homeostasis, such as body fat mass, lipid metabolism, thermogenesis or food intake. , among others.

Another embodiment of the invention relates to a nutraceutical composition comprising at least one first compound selected from the group consisting of:

- a compound of formula (II), or a nutraceuticalally acceptable salt or ester thereof:

COOH-(CH2MCH=CH-CH2MCH2) ^c -CH3

(II)

Y

- a compound of formula (III), or a nutraceuticalally acceptable salt or ester thereof:

COOH -(CH2)a-(CH=CH-CH2MCH2)3-(CH=CH-CH2Wmr(CH2)c-CH3

(III)

where a is an integer between 1 and 7; b is an integer between 2 and 7; c is an integer between 0 and 7; m is an integer between 0 and (b - 1); and a+3b+c+3 is an even integer; and at least one nutraceutical acceptable excipient.

The present invention also relates to a nutraceutical composition comprising at least one first compound selected from the group consisting of:

- a nutraceuticalally acceptable salt or ester of a compound of formula (II):

COOH-(CH2)a-(CH=CH-CH2)b-(CH2)c-CH3

(II)

Y

- a nutraceuticalally acceptable salt or ester of a compound of formula (III:

COOH -(CH2)a-(CH=CH-CH2)m-(CH2)3-(CH=CH-CH2)rb-í-m;-(CH2)c-CH3

(III)

where a is an integer between 1 and 7; b is an integer between 2 and 7; c is an integer between 0 and 7; m is an integer between 0 and (b - 1); and a+3b+c+3 is an even integer; and at least one nutraceutical acceptable excipient.

The term "nutraceutical acceptable" refers, for the purposes of the present invention, to everything that is used in nutraceutical products.

For the purposes of the present invention, the term "nutraceutical" or "nutraceutical composition" refers to a dietary supplement, to be taken by itself, or in combination with other foods, and that produces a beneficial effect on the health of the subject that consumes it. eat, especially in disease prevention.

Another aspect of the invention relates to a nutraceutical composition comprising at least one first compound selected from the group consisting of:

- a compound of formula (II) or a nutraceuticalally acceptable salt or ester thereof:

COOH-(CH2)a-(CH=CH-CH2)b-(CH2)c-CH3

(II)

Y

- a compound of formula (III) or a nutraceuticalally acceptable salt or ester thereof:

COOH -(CH2)a-(CH=CH-CH2)m-(CH2)3-(CH=CH-CH2)rb-í-mr(CH2)c-CH3

(III)

characterized in that it further comprises a second compound of formula (I), or a nutraceuticalally acceptable salt or ester thereof:

COOH -CHOH-(CH2)a-(CH=CH-CH2)b-(CH2)c-CH3

(I)

where a is an integer between 1 and 7; b is an integer between 2 and 7; c is an integer between 0 and 7; m is an integer between 0 and (b - 1); and a+3b+c+3 is an even integer; and at least one nutraceutical acceptable excipient.

Another embodiment refers to the use of a nutraceutical composition comprising at least one first compound selected from the group consisting of:

- a compound of formula (II), or a nutraceuticalally acceptable salt or ester thereof: COOH-(CH2)a-(CH=CH-CH2)b-(CH2)c-CH3

(II)

Y

- a compound of formula (III), or a nutraceuticalally acceptable salt or ester thereof:

COOH -(CH2)a-(CH=CH-CH2)m-(CH2)3-(CH=CH-CH2Wmr(CH2)c-CH3

(III)

where a is an integer between 1 and 7; b is an integer between 2 and 7; c is an integer between 0 and 7; m is an integer between 0 and (b - 1); and a+3b+c+3 is an even integer; and at least one nutraceutical acceptable excipient; for the prevention of a neurological or neurodegenerative disease; a cancer; an inflammatory disease and a metabolic disease; or for the induction of neuroregeneration.

In one embodiment, the use of said nutraceutical composition is preferably for the induction of neuroregeneration, and for the prevention of a neurodegenerative disease selected from the group consisting of: Alzheimer's disease; Parkinson's disease; senile dementia; multiple sclerosis and amyotrophic lateral sclerosis; hippocampal sclerosis and other types of epilepsy; focal sclerosis; adrenoleukodystrophy and other types of leukodystrophy; vascular dementia; headache, including migraine; central nervous system trauma; sleep disorders; Vertigo; pain; cerebrovascular accidents; the Depression; the anxiety; neuropathic pain; other neurodegenerative disorders of the peripheral nervous system such as Guillan-Barré syndrome; diabetic neuropathy; Wallerian degeneration; Levy body dementia; fronto-temporal dementia; Huntington's disease, multiple system atrophy; progressive supranuclear palsy; cortico-basal degeneration and disorders due to substance use or addictive behaviors.

More preferably, the composition comprises a compound of formula (II) or a pharmaceutically acceptable salt or ester thereof, wherein a=4, b=5 and c=0.

Also more preferably, the composition comprises a compound of formula (III) or a pharmaceutically acceptable salt or ester thereof, wherein a=1, b=6, c=0 and m=0.

Another embodiment refers to a nutraceutical composition comprising at least one first compound selected from the group consisting of:

- a nutraceuticalally acceptable salt or ester of a compound of formula (II):

COOH-(CH2)a-(CH=CH-CH2)b-(CH2)c-CH3

(II)

Y

- a nutraceuticalally acceptable salt or ester of a compound of formula (III:

COOH -(CH2)a-(CH=CH-CH2)m-(CH2)3-(CH=CH-CH2Wmr(CH2)c-CH3

(III)

where a is an integer between 1 and 7; b is an integer between 2 and 7; c is an integer between 0 and 7; m is an integer between 0 and (b - 1); and a+3b+c+3 is an even integer; and at least one nutraceutical acceptable excipient; for the prevention of a neurological or neurodegenerative disease; a cancer; an inflammatory disease and a metabolic disease; or for the induction of neuroregeneration.

In a preferred embodiment a is an integer between 1 and 7; b is an integer between 2 and 7; c is 0; m is an integer between 0 and (b - 1); and a+3b+c+3 is an even integer.

In another preferred embodiment , a is an integer between 1 and 7; b is an integer between 2 and 7; c is 3; m is an integer between 0 and (b - 1); and a+3b+c+3 is an even integer.

In an even more preferred embodiment of the present invention:

a=6, b=2, c=3 and m is 0 or 1; or

a=6, b=3, c=0 and m is selected from 0, 1 or 2, and even more preferably m is 0 or 1; or a=3, b=3, c=3 and m is selected from 0, 1 or 2, and even more preferably m is 0 or 1; or a=2, b=4, c=3 and m is selected from 0, 1, 2, or 3, and even more preferably m is 0 or 1; or a=2, b=5, c=0 and m is selected from 0, 1, 2, 3 or 4, and even more preferably m is 0 or 1; or

a=1, b=6, c=0 and m=0.

In a preferred embodiment of said even more preferred embodiment of the present invention, a=6, b=2, c=3 and m is 0 or 1.

In another preferred embodiment of said even more preferred embodiment of the present invention, a=6, b=3, c=0 and m is selected from 0, 1 or 2 and even more preferably m is 0 or 1.

In another preferred embodiment of said even more preferred embodiment of the present invention, a=3, b=3, c=3 and m is selected from 0, 1 or 2 and even more preferably m is 0 or 1.

In another preferred embodiment of said even more preferred embodiment of the present invention, a=2, b=4, c=3 and m is selected from 0, 1, 2, or 3 and even more preferably m is 0 or 1.

In another preferred embodiment of said even more preferred embodiment of the present invention, a=2, b=5, c=0 and m is selected from 0, 1,2, 3 or 4 and even more preferably m is 0 or 1.

In another preferred embodiment of said even more preferred embodiment of the present invention, a=1, b=6, c=0 and m=0.

In a more preferred embodiment of said preferred, more preferred and even more preferred embodiments, m is 0.

More preferably, the nutraceutical acceptable salt of any of the compounds of formula (II) or of any of the compounds of formula (III), or of any of the compounds of formula (I), or of all the compounds of formula (II ), of formula (III) and of formula (I), is a sodium salt.

In another more preferred embodiment, the ester is a methyl ester or an ethyl ester.

In yet another more preferred embodiment, the compound is a stereoisomer with all double bonds in the cis configuration.

In one embodiment of the invention, the compositions described in the present application comprise a compound of formula (I) together with a compound of formula (II), or a compound of formula (III), in a concentration between 0.01% to 99.99% w/w, preferably the composition comprises 10% to 80% w/w, or even more preferably in a concentration between 20% and 50% w/w.

In another embodiment of the invention, the compositions described in this application comprise a prodrug of formula (I) together with a compound of formula (II), or a compound of formula (III), wherein said combination is in a ratio in the range between 0.01:100 to 100:0.01, preferably 1:5 to 5:1 and even more preferably 1:2 to 2:1.

In an additional aspect, the pharmaceutical or nutraceutical compositions of the invention can be presented in vials, ampoules, powders, capsules, tablets, sachets, solutions, syrups, ointments, creams, emulsions, gels, patches, controlled release formulations, suppositories, ovules , etc. The formulations are useful to be administered among others by oral, sublingual, gastroenteric, rectal, parenteral (intravenous, intraarterial, intramuscular and subcutaneous), respiratory, topical (ophthalmic, otic, transdermal) routes. The route of administration can be determined in a simple manner by those skilled in the art.

It is known in the literature that stable formulations with high contents of omega 3 fatty acids, as excipients or adjuvants can contain medium chain triglycerides, which are triglycerides whose glycerol molecule is linked to linear chain saturated fatty acids with 6-12 carbon atoms. and they can be present in an amount of between 10% and 30%, typically from 22% to 28%, for example, about 25.5% by weight with respect to the weight of the total composition. Another ingredient known to stabilize these formulations is any enzyme that belongs to the superoxide dismutase (SOD) family. These enzymes belong to the class of oxidoreductases and transform superoxide into less harmful molecules such as oxygen and hydrogen peroxide. In certain embodiments, the compositions of the invention comprise SOD in an amount between 0.2% and 2%, typically from 0.5% to 1.6%, for example, about 1.1% by weight of the total composition. .

The compositions of the present invention may be in the form of a gastro-resistant composition to prevent degradation of its components by the low pH of the gastric environment.

In certain embodiments, the composition of the invention further includes one or more additional components, such as flavors, fillers, and thickeners such as anhydrous colloidal silica and glyceryl monostearate.

EXAMPLES

The examples described below are for illustrative purposes and are not intended to limit the scope of the present invention.

Example 1: Fatty acids, reagents and organic solvents

DHA (docosahexaenoic acid sodium salt; C22:6 n-3) and DHA-H (2-hydroxy-drocosahexaenoic acid sodium salt; 2OH-C22:6 n-3) were obtained from Lipopharma Therapeutics (Spain). Margaric acid (C17:0) was purchased from Sigma-Aldrich and heneicosapentaenoic acid (HPA; C21:5 n-3) was purchased from Cayman Chemicals (Michigan, USA). D(+)-Glucose (cell culture tested), sodium pyruvate, L-Gln (culture cell tested), acetyl chloride, and N,O-bis(trimethylsilyl)acetamide, sodium chloride, sodium phosphate, EDTA (ethylenediaminetetraacetic acid), and tris-base were purchased from Sigma-Aldrich. In contrast, chloroform, ethanol, methanol, hydrochloric acid, and hexane were obtained from Scharlab (Spain). Heparin (5000 units/ml) was purchased from Hospira Invicta SA (Spain), ketamine (Anesketin 100 mg/ml) from Eurovet Anima1Health BV (The Netherlands), xylazine (Xilagesic 20 mg/ml) from Laboratorios Calier SA ( Spain), and oxythiamine hydrochloride from Santa Cruz Biotechnology (Germany).

For the production of this compound, it is possible to start from DHA-H, both in vitro and in vivo (as a prodrug of HPA). The chemical synthesis of HPA is disclosed in the state of the art (Larsen et al., 1997, Lipids 32(7), 707-714. doi: 10.1007/s11745-997-0090-4). the reactions were carried out in the absence of light and under a nitrogen atmosphere. The synthesis is carried out from (5Z, 8Z, 11Z, 14Z,17Z)-eicosa-5, 8, 11, 14, 17-pentaenoic acid (1), according to reaction scheme 1. For the tests carried out in the In this application, the HPA produced by Cayma Chemical, reference 10670, was used.

Scheme 1.

Reagents and conditions: a)(COCl) ² /PhH 1.5h rt., b)CH ² N ² /ether 20 min. 0°C, c)AgOBz(cat.), Et3N/THF/H2O

The synthesis of the HPA sodium salt of the present invention has been carried out from the compound designated with the number 5 when R is CH3-CH2-(CH=CH-CH2)5-CH2CH2-, which corresponds to HPA (C ²¹ ). The salt is obtained under an acid-base reaction, a liquid-liquid extraction is performed with MTBE/HCl and the pH is adjusted with NaOMe to obtain the HPA sodium salt in good yields.

Example 2: Compositions

Some examples of compositions that do not limit the scope of the invention are described in general below.

Table 1. Example formulation for topical use:

Table 2. Example oral formulation:

Table 3. Example soft capsule oral formulation:

Example 3: Cellular Assays

To describe the metabolic conversion of DHA-H into HPA, HEK293T cell cultures ( Human Embryonic Kidney Cells 293T) were used, which is an embryonic, non-tumor cell line widely used in studies of human metabolism under physiological conditions.

HEK293T cells were grown in Dulbecco's Modified Eagle Medium (DMEM; Biowest, France), supplemented with 10% FBS (Fetal Bovine Serum; Gibco, Thermo-Fisher), 2 mM L-Gln, 25 mM D( +)-glucose, 1mM sodium pyruvate and penicillin/streptomycin. Mouse neuroblastoma N2a cells were maintained in a 1:1 (v:v) mixture of DMEM and Opti-Mem (Gibco, Thermo-Fisher), supplemented with 5% FBS and penicillin/streptomycin. Both cell lines were incubated in an atmosphere of 5% CO2 at 37°C.

HEK293T cells were incubated with DHA-H and DHA at 10, 30, and 100 pM for 24 hours, and at 30 pM for 6, 48, and 72 hours. N2a cells were incubated with DHA-H at 30 pM for 6, 24, 48, and 72 hours, and HEK293T cells were also incubated with oxythiamine (water-soluble) in the presence of DHA-H under the same conditions, at final concentrations. of 1 and 10 mM oxythiamine. HEK293T cells were separated from the plates by means of pipettes with cold phosphate buffered saline (PBS), while N2a cells were harvested by trypsinization (3-5min, 37°C). Cells were recovered by centrifugation (1000 xg, 10 min at 4°C) and washed twice with cold PBS before being frozen at -80°C.

To analyze the levels of DHA-H and DHA in cell culture medium, 90 mm diameter dishes were filled with 11 mL of complete cell culture medium containing 30 pM DHA-H or DHA in the presence or absence of HEK293T cells. coated (5,105 cells/plate). Plates were incubated as described above and 1 ml aliquots were collected from plates at 0, 6, 24, 48 and 72 hours. Aliquots of cell culture medium were immediately centrifuged at 1000 xg for 10 min at 4°C to remove any cell suspension, and cell-free aliquots were stored at -20°C.

The U-118 MG cell line was purchased from the European Collection of Cell Cultures (ECACC) through Sigma-Aldrich Co (St Louis, MO) and grown in RPMI (Roswell Park Memorial Institute) culture medium supplemented with a 10 %

FBS (Gibco, Thermo-Fisher), in an atmosphere of 5% CO ² at 37°C. U-118 MG cells were treated with 150 pM DHA-H, 150 pM DHA, and 150 pM HPA for 48 hours, at presence or absence of oxythymine (1 or 10 mM). Cell survival was analyzed in a Bürker chamber using trypan blue vital exclusion staining (Scharlab).

DHA-H treatment results in high cellular levels of HPA, compared to prodrug levels in cell culture (FIG. 1B). In Figure 1B, the intracellular levels of DHA-H and HPA in HEK293T cells under DHA-H treatment are shown. The increase in HPA levels is inhibited in the presence of concomitant treatment with oxythiamine (partial inhibition at 1 mM and almost total inhibition at 10 mM), a competitive antagonist of 2-hydroxyphytanoyl-CoA lyase (see Figure 1A). In this sense, it has also been possible to verify that the endogenous levels of DHA (the native non-hydroxylated form) are not altered by this treatment with DHA-H (figure 1C).

Example 4: In vivo tests.

The 5xFAD model of Alzheimer's disease is a double transgenic PS1/APP mouse harboring five human mutations associated with familial AD (lineage Tg6799): Swedish (K670N/M671L), Florida 151(I716V) and London (V717I) in APP ; and the clinical mutations M146L and L286V in human PS1. Both transgenes are expressed under the control of the Thy-1 promoter and mice show cognitive decline from 4 months of age (Oackley et al., 2006, Neurosci 26(40), 10129-10140. doi: 10.1523/jneurosci .1202-06.2006). 5xFAD transgenic and wild type (WT) animals were obtained from Jackson Laboratories (USA) and were maintained on a B6/SJL genetic background by crossing heterozygous transgenic mice with B6/SJL WT (F1) breeders. The animals were housed at a controlled temperature of 22 °C (±2 °C) and 70% humidity, in a 12h-12h light-dark cycle, with free access to a standard laboratory diet (Panlab A03, Barcelona, Spain).

WT and 5xFAD transgenic male mice received DHA-H (or DHA) orally, dissolved in 5% ethanol, at daily doses of 5, 20, 50, and 200 mg/kg, or vehicle alone. These treatments were started when the mice reached 3 months of age (dosed 5 days/week) and continued until 7 months of age. During the last month of treatment, all animals were kept on a hypocaloric diet to perform selected behavioral spatial learning and memory tests (armed radial maze). A total of 46 animals were used for this study: WT treated with vehicle (n=3), WT treated with DHA-H (20 mg/kg, n=3; and 200 mg/kg, n=3), WT treated with DHA(20mg/kg, n=3); 5xFAD(n=5) treated with DHA-H (5 mg/kg, n=6; 20 mg/kg, n=5; 50 mg/kg, n=6; and 200 mg/kg, n=7), and 5xFAD (20 mg/kg, n=5) treated with DHA. After behavioral testing, mice were maintained on a normal diet (and treatment) for a a further week, after which they were anesthetized with an intraperitoneal injection of ketamine/xylazine (100/10mg/kg) and intracardially perfused with 50 ml of heparinized saline. The brains of the animals were immediately removed and dissected along the midline on a cold surface. After the cerebellum was removed, each free half of the cerebellum was frozen in liquid nitrogen and stored at -80 °C.

NUDE (Swiss) Crl:NU (Ico)-Foxn1nu mice (8-12 weeks old, 30-35 g, Charles River Laboratories, Paris, France) were kept in a thermostatic cabinet (28°C, EHRET, Labor- U-Pharmatechnik) with a flow of sterile air at a relative humidity of 40-60% and with 12-hour dark/light cycles. Their diet consisted of a standard diet with feed (Labdiet 22% rat-mouse breeding, Sodispan) ad libitum. To cause xenographic tumors, 7.5*106 U-118 MG cells were inoculated subcutaneously on both sides of the dorsal flank of the animal, and after one week the tumors became visible with a volume of about 100 mm3. Animals were randomly divided into groups with similar mean tumor volume and received daily oral treatments for 42 days: vehicle and DHA-H (200 mg/kg). Tumor volumes (v) were calculated as v = A2 * L/2, where A is the width of the tumor and L is its length. After completion of treatment, mice were sacrificed by cervical dislocation and xenographic tumors were dissected and frozen in liquid nitrogen at -80°C.

All protocols used were approved by the Bioethics Committee of the University of the Balearic Islands, and comply with national and international guidelines on animal welfare.

In the use of healthy and transgenic mice models of Alzheimer's disease (5xFAD), it was found that there was a significant accumulation of HPA at the brain level, while the mother molecule (DHA-H) could not be detected, nor changes in the endogenous levels of DHA (native non-hydroxylated form) ( figure 2A ). On the other hand, changes in the levels of several lipids (figure 2B) were measured when mice were treated with DHA-H: B1 -phosphatidylethanolamine (PE), B2 - polyunsaturated lipids with 5 or more unsaturations (PI), B3 -lipids saturated, B4 - phosphatidylcholine (PC), B5 - phosphatidylinositol (PI), B6 - phosphatidylserine (PS), B7 - cholesterol, B8 - sphingomyelin (including dihydro-sphingomyelin) and B9 - ceramides (including hexosyl- and lactosyl-ceramide). The results are presented in table 4: Table 4. Characterization of diacyl-PE species in the brain of 5xFAD mice treated with DHA-H.

diacyl-PE W T 5xFAD 5xFAD DHA-H

subspecies M ed ia1 SEM1 M ed ia1 SEM1 % change 2 M ed ia1 SEM1 % change 2

32:0 112 3 105 3 -6.3 ± 3.0 NS 134 3 19.6 ± 3.0 * *

Chains 32:1 168 4 205 39 22.2 ± 22.9 NS 240 13 42.5 ± 7.7 NS Short 34:1 2197 148 1817 71 -17.3 ± 3.2 NS 3030 188 37.9 ± 8.5 * * 34:2 326 25 372 71 17 23.5 ± 5.4 NS Subtotal 2803 154 2500 85 -10.7 ± 3.0 NS 3805 216 35.7 ± 7.7 * *

36:1 3862 477 3332 185 -13.7 ± 4.8 NS 5426 204 40.5 ± 5.3 * *

36:2 3108 195 2584 98 -16.9 ± 3.2 NS 4319 210 39.0 ± 6.8 * *

36:3 274 30 254 27 -7.2 ± 9.9 NS 303 22 10.4 ± 8.2 NS

36:4 3184 454 3416 465 7.3 ± 14.6 NS 5390 352 69.3 ± 11.0 *

Chains 36:5 201 16 318 69 58.8 ± 34.6 NS 295 11 46.9 ± 5.5 * Means 38:1 588 12 441 50 -24.9 ± 8.5 NS 713 53 21.4 ± 9.0 * 38:2 547 18 389 5 ± 9130 * 57 8.5 ± 10.4 NS

38:4 16804 2171 16670 1969 -0.8 ± 11.7 NS 24716 1072 47.1 ± 6.4 *

38: 5 2799 135 2903 143 3.7 ± 5.1 NS 4579 90 63.6 ± 3.2 * * * 38: 6 13444 2330 12244 821 -8.9 ± 6.1 NS 16532 1412 23.0 ± 10.5 NS 38: 7 244 30 340 100 38.9 ± 40.8 NS 425 19 73.7 ± 7.6 NS subtotal 45054 5749 42891 3716 -4.8 ± 8.2 NS 63290 3171 40.4 ± 7.0 * 40: 1 174 13 106 17 -38.9 ± 9.7 NS 160 23 -8.0 ± 13.0 NS Chains 40: 3 2768 369 2764 315 -0.2 11.4 NS 4121 257 48.9 ± 9.3 NS Long 40:5 26517 3064 26194 2062 -1.2 ± 7.8 NS 38945 2170 46.9 ± 8.2 *

40:6 3289 896 3901 785 18.6 ± 23.9 NS 6089 286 85.2 ± 8.7 *

Subtot

32747 4196 32964 3137 0.7 ± 9.6 NS 49314 2633 50.5 8.0 * al

Total 80605 10036 78356 6833 -2.8 ± 8.5 NS 116411 10334 44.4 ± 7.4 * 1Measurement of diacyl-phosphatidylethanolamine (PE) subspecies (mean ± standard error -SEM-) is shown as pmol lipid/mg protein

The relative change in 5xFAD or 5xFAD DHA-H treated brains relative to mean WT value is shown as mean ± standard error (SEM). Statistical analysis was performed using ANOVA and the Tukey multiple comparison test: NS: not significant, * p<0.05, ** p<0.01 and *** p<0.001, with respect to the 5xFAD control.

The animals under treatment with DHA-H present a statistically significant increase in the levels of PE, PI and polyunsaturated lipids, with respect to the animals that only receive vehicle. The most significant changes are an increase in the levels of phosphatidylethanolamine (PE) and in the levels of polyunsaturated lipid species (5 unsaturations or more). A more detailed study of the levels of phosphatidylethanolamine shows that the long-chain and polyunsaturated species of PE are the ones that increase the most.

Radial arm maze test.

The spatial behavior test was performed as previously described, with some modifications (Fiol-Deroque et al., 2013, Biogerontology 14(6), 763-775. doi: 10.1007/s10522-013-9461-4). All animals were isolated and subjected to caloric restriction until reaching 80-85% of normal body weight, and were kept under these conditions one week before starting the trial and until the end of it. After food restriction and 3 days before the start of the tests, the animals were trained twice daily in the eight-arm radial maze test (LE766/8, Panlab SL, Spain) for 3 days. Each mouse was placed in the center of the maze and allowed to search for the reward, a 45-mg food pellet (Dustless Precision Pellets, Bio-Serv, USA), placed on the end of each arm. Each session ended when the animal managed to find all eight baited arms or failed to complete all arms in 10 minutes. The movement of each animal was recorded with a digital video tracking system (LE 8300 with Sedacomv1.3 software, Panlab, SL, Spain) and after training, the experimental paradigm began. In all experimental sessions (1 session per day), only four arms were primed compared to the training protocol, and each session ended when the animals managed to find all four arms primed or failed after 10 min. Performance was evaluated taking into account: (1) the time to perform the test; (2) the number of working memory errors ( WME, re-entry into a previously visited primed arm); (3) the number of reference memory errors ( RME, entry into an unprimed arm); and (4) the total number of errors (WME+RME). The test was repeated 5 days/week for 3 weeks. Once the test was finished, the animals were fed ad libitum for an extra week before sacrifice.

In this sense, it can be seen that HPA levels at the brain level in Alzheimer's model mice have a statistically significant inverse relationship with behavioral parameters in a spatial and associative memory evaluation test (radial maze test) (Fig. 2 C). These results suggest that moderate increases in brain HPA levels are significantly related to improved spatial cognition.

Example 5: Extraction of lipids and transmethylation of fatty acids

HEK293T or U-118 MG cells used in the previous examples were lysed with cold hypotonic buffer (1 mM EDTA, 20 mM Tris-HCl [pH 7.4]) by pipetting up and down. Cell lysates were subjected to pulsed ultrasound (4 cycles, 10 s/cycle, 10W) before lipid extraction. For brain analysis, tissue from each animal was homogenized in cold PBS at 1:10 (w:v) in the presence of protease inhibitors (Roche), using a blade homogenizer (Polytron PT3100). Homogenates were sonicated, aliquoted and stored at -80°C. Only one aliquot of each sample, containing about 8 mg protein/aliquot, underwent lipid extraction. Protein content before lipid extraction was determined by a modified Lowry method (Bio-rad DC Protein Assay).

Margaric acid (C17:0) was added to the lipid extracted samples as an internal standard, and the lipids were extracted with chloroform: methanol (Eggers and Schwudke, 2016). Briefly, 0.75 volumes of the aqueous phase (which already contained the biological sample) were mixed with 2 volumes of chloroform and 1 volume of methanol. This mixture was vortexed for 1 minute and centrifuged at 1000 xg for 10 minutes. The lower organic phase was collected and washed with 1 ml of PBS:methanol (1:1, v:v), and the resulting organic phase was dried under flowing argon. The film containing the extracted lipids was transmethylated by incubating the lipid mixture for 90 minutes at 100°C in 3 ml of methanol:acetyl chloride (10:1, v:v), under an argon atmosphere (Christie, 1993). The resulting Fatty Acid Methyl Esters ( FAMEs) were extracted with hexane, adding 3 mL H ² O and 1 mL hexane to the transmethylation reaction, and thoroughly vortexing the mixture. After centrifugation at room temperature (1000 xg for 10 min), the upper phase containing the FAMEs was collected and the remaining volume was washed twice with 1 ml of hexane. The hexane phases were combined, evaporated under argon flow, and resuspended in 60 μl of hexane (for analysis of cell samples, cell culture medium, and blood plasma) or 200 μl (for analysis of brain samples). To test whether a fatty acid compound is hydroxylated, isolated FAMEs were subjected to a second derivatization with trimethylsilyl (Alderson et al., 2004, J Biol Chem 279(47), 48562-48568. doi: 10.1074/jbc.M406649200) . Briefly, the FAMEs were dried under argon flow and the Lipid film was dissolved in N,O-bis(trimethylsilylyl) acetamide (0.1-5.0 mg lipids for 200-400 pl trimethylsilylation reagent), which in turn was heated in a stoppered vial to 70°C for 30 min. The solvent was evaporated and the lipid film was resuspended in hexane for analysis. When the fatty acid under study is hydroxylated, the retention time of FAME changes as a result of this second derivatization. However, if the fatty acid under study is not hydroxylated, the resulting FAME shows the same retention time regardless of the second derivatization.

The levels of HPA generated from the treatment with the prodrug DHA-H in these cells were evaluated, in the presence or absence of oxythiamine (a competitive inhibitor of oxidation) (FIG. 4A). The results showed that the addition of DHA-H to a culture of U-118 MG cells leads to a significant increase in HPA levels. This increase is inhibited in the presence of simultaneous treatment with 1 or 10 mM oxythiamine, demonstrating that the transformation of DHA-H into HPA is mediated by aoxidation. DHA-H treatment on U-118 MG cells in culture had no effect on endogenous levels of DHA (native non-hydroxylated form). On the same cells in culture, viability assays were carried out with DHA-H in the presence or absence of 1 mM oxythiamine (FIG. 4B), proving that 1 mM oxythiamine has no effect on cell viability.

On the other hand, the addition of DHA-H (150 pM, 48 h) has a significant anti-proliferative effect on U118-MG cells. However, this effect is partially (statistically significantly) reversed in the presence of 1 mM oxythiamine. At this point, it must be remembered that this concentration of oxytimaine is sufficient to completely inhibit the increase in HPA levels from DHA-H. Thus, these results show that the anti-proliferative effect mediated by DHA-H on U-118 MG cells is mediated, at least in part, by HPA, since the inhibition of the formation of this compound from DHA-H, translates into a lower anti-proliferative effect of DHA-H (figure 4B).

The anti-proliferative effect of HPA on a culture of U-118 MG cells was also studied, in comparison with the administration of the prodrug DHA-H and the native form of DHA. The anti-proliferative effect on U-118 MG is much higher for HPA with respect to DHA-H and DHA (see Figure 5A). When compared to DHA-H, this effect can be explained by differences in intracellular levels of HPA, induced by DHA-H and HPA (see Figure 5B). In fact, Figure 5C shows that the uptake of the hydroxylated form of DHA is impeded compared to that of the non-hydroxylated analog.

Claims (23)

1. A pharmaceutically acceptable salt or ester of a compound of formula (II): COOH -(CH2)a-(CH=CH-CH2MCH2)c-CH3 (II) or a pharmaceutically acceptable salt or ester of a compound of formula (III): COOH -(CH2)a-(CH=CH-CH2)m-(CH2)3-(CH=CH-CH2)rb-í-m;-(CH2)c-CH3 (III) where a is an integer between 1 and 7; b is an integer between 2 and 7; c is a integer between 0 and 7; m is an integer between 0 and (b - 1); and a+3b+c+3 is a even integer. 2. A salt or an ester of a compound of formula (II), according to claim 1, in the one where a=6, b=2, c=3; or a=6, b=3, c=0; or a=3, b=3, c=3; or a=2, b=4, c=3; or a=2, c=0; or a=4, b=5 and c=0. 3. A salt or an ester of a compound of formula (III), according to claim 1, where a=1, b=6, c=0 and m=0. 4. The salt according to any of claims 1 to 3, wherein said salt pharmaceutically acceptable is a sodium salt. 5. The salt or ester according to any of claims 1 to 4, for use as medicine. 6. The salt or ester according to any of claims 1 to 4, for use in the induction of neuroregeneration or in the prevention and/or treatment of a disease or condition selected from the group consisting of: a disease neurological or neurodegenerative; a cancer; an inflammatory disease and metabolic disease. 7. A compound of formula (II): COOH -(CH2)a-(CH=CH-CH2MCH2)c-CH3 (II) where a is an integer between 1 and 7; b is an integer between 2 and 7; c is a integer between 0 and 7; and a+3b+c+3 is an even integer; for use on induction of neuroregeneration or in the prevention and/or treatment of a disease neurodegenerative, and in which a=6, b=2 and c=3; or a=6, b=3 and

c=0; or a=3, b=3 a=2, b=4 and c=3; or a=2, b=5 and c=0. 8. A compound of formula (II I): COOH -(CH2)a-(CH=CH-CH2)m-(CH2)3-(CH=CH-CH2)rb-í-m;-(CH2)c-CH3 (III) where a is an integer between 1 and 7; b is an integer between 2 and 7; c is a integer between 0 and 7; m is an integer between 0 and (b - 1); and a+3b+c+3 is a even integer; for use in the induction of neuroregeneration or in the prevention and/or the treatment of a neurodegenerative disease, and wherein the disease Neurodegenerative is selected from the group consisting of spinal cord injury and neck pain. neuropathic origin. 9. The compound of formula (III) for use according to claim 8, wherein a=1, b=6, c=0 and m=0 10. A pharmaceutical or nutraceutical composition comprising at least one first compound selected from the group consisting of: - a pharmaceutically or nutraceutically acceptable salt or ester of a compound of formula (II): COOH-(CH2)a-(CH=CH-CH2)b-(CH2)c-CH3 (II) Y - a pharmaceutically or nutraceutically acceptable salt or ester of a compound of formula (III): COOH -(CH2)a-(CH=CH-CH2)m-(CH2)3-(CH=CH-CH2)rb-í-m;-(CH2)c-CH3 (III) where a is an integer between 1 and 7; b is an integer between 2 and 7; c is an integer between 0 and 7; m is an integer between 0 and (b - 1); and a+3b+c+3 is an even integer; and at least one pharmaceutically or nutraceutically acceptable excipient. 11. The pharmaceutical or nutraceutical composition according to claim 10, wherein the first compound is: a compound of formula (III) wherein a=1, b=6, c=0, m=0; or a compound of formula (II) in which a=6, b=2, c=3; or a=6, b=3, c=0; or a=3, b=3, c=3; or a=2, b=4, c=3; or a=2, b=5, c=0; or a=4, b=5 and c=0. 12. Pharmaceutical or nutraceutical composition according to any of claims 10 or 11, characterized in that it also comprises a second compound of formula (I), or a pharmaceutically acceptable salt or ester thereof: COOH -CHOH-(CH2)a-(CH=CH-CH2)b-(CH2)c-CH3 (I) wherein a , b and c have the same values as for the first compound of formula (II) or of formula (III). 13. Pharmaceutical or nutraceutical composition according to claim 12, in which the pharmaceutically acceptable salt of any of the compounds of formula (II) or of any of the compounds of formula (III), or of any of the compounds of formula (I), or of all the compounds of formula (II), of formula (III) and of formula (I), is a sodium salt. 14. Pharmaceutical composition according to any of claims 10 to 13, for use as a medicine. 15. Pharmaceutical composition according to any of claims 10 to 13, for use in the induction of neuroregeneration or in the prevention and/or treatment of a disease or condition selected from the group consisting of: a neurological disease or neurodegenerative; a cancer; an inflammatory disease; and a metabolic disease. 16. Nutraceutical composition according to any of claims 10 to 13 for use in the prevention of a disease or condition selected from the group that consists of: a neurological or neurodegenerative disease; a cancer; an inflammatory disease; and a metabolic disease; or in the induction of neuroregeneration. 17. A pharmaceutical composition comprising at least one first compound selected from the group consisting of: - a compound of formula (II): COOH-(CH2M CH=CH-CH2M CH2)c-CH3 (II) Y - a compound of formula (III): COOH -(CH2MCH=CH-CH2MCH2MCH=CH-CH2)b-í-mHCH2)c-CH3 (III) where a is an integer between 1 and 7; b is an integer between 2 and 7; c is an integer between 0 and 7; m is an integer between 0 and (b - 1); and a+3b+c+3 is an even integer; and at least one pharmaceutically acceptable excipient; for use in the induction of neuroregeneration or in the prevention and/or treatment of a neurodegenerative disease. 18. The pharmaceutical composition for use according to claim 17, wherein the first compound is a compound of formula (II) wherein a=6, b=2, ^c =3; or a=6, b=3, c=0; or a=3, b=3, c=3; or a=2, b=4, c=3; or a=2, b=5, c=0; or a=4, b=5 and c=0, or a compound of formula (III) in which a=1, b=6, ^c =0 and m=0. 19. A pharmaceutical or nutraceutical composition comprising at least one first compound selected from the group consisting of: - a compound of formula (II): COOH-(CH2MCH=CH-CH2MCH2) ^c -CH3 (II) Y - a compound of formula (III): COOH -(CH2)a-(CH=CH-CH2)m-(CH2)3-(CH=CH-CH2)rb-í-m;-(CH2)c-CH3 (III) characterized in that it further comprises a second compound of formula (I), or a pharmaceutically or nutraceutically acceptable salt or ester thereof: COOH -CHOH-(CH2MCH=CH-CH2MCH2) ^c -CH3 (I) where a is an integer between 1 and 7; b is an integer between 2 and 7; c is an integer between 0 and 7; m is an integer between 0 and (b - 1); and a+3b+c+3 is an even integer; and at least one pharmaceutically or nutraceutically acceptable excipient. 20. Pharmaceutical or nutraceutical composition according to claim 19, in which a=6, b=2, c=3; or a=6, b=3, c=0; or a=3, b=3, c=3; or a=2, b=4, c=3; or a=2, b=5, c=0; or a=4, b=5 and c=0, or a compound of formula (111) in which a=1, b=6, c=0 and m=0. 21. Pharmaceutical composition according to any of claims 19 or 20, for use as a medicine. 22. Pharmaceutical composition according to any of claims 19 or 20, for use in the induction of neuroregeneration or in the prevention and/or treatment of a disease or condition selected from the group consisting of: a neurological disease or neurodegenerative; a cancer; an inflammatory disease; and a metabolic disease. 23. Nutraceutical composition according to any of claims 19 or 20, for use in the prevention of a disease or condition selected from the group consisting of: a neurological or neurodegenerative disease; a cancer; an inflammatory disease; and a metabolic disease; or in the induction of neuroregeneration.