Title of Invention	NEW a-SUBSTITUTED DHA COMPOUNDS, COMPOSITIONS AND PROCESSES FOR ITS MANUFACTURE AND USE
Abstract	Compounds of formula (I); wherein - R1 and R2 are the same or different and may be selected from the group consisting of a hydrogen atom, a hydroxy group, an alkyl group, a halogen atom, an alkoxy group, an acyloxy group, an acyl group, an alkenyl group, an alkynyl group, an aryl group, an alkylthio group, an alkoxycarbonyl group, an alkylsulfmyl group, an alkylsulfonyl group, an amino group, and an alkylamino group; and - X represents a carboxylic acid group, a carboxylate group, or a carboxamide group; or any pharmaceutically acceptable salt, solvate, complex or pro-drug thereof, with the provisos that the compound of formula (I) is not (all-Z)-4,7,10,13,16,19-docosahexaenoic acid (DHA), alpha-methyl DHA, alpha-methyl DHA methyl ester, alpha-methyl DHA ethyl ester or alpha-hydroxy DHA ethyl ester, are disclosed. A fatty acid composition and a pharmaceutical composition comprising such compounds are also disclosed. The use of such compounds as medicaments, in particular for the treatment of diabetes type 2, is also disclosed.

Title of Invention

NEW a-SUBSTITUTED DHA COMPOUNDS, COMPOSITIONS AND PROCESSES FOR ITS MANUFACTURE AND USE

Abstract

Compounds of formula (I); wherein - R1 and R2 are the same or different and may be selected from the group consisting of a hydrogen atom, a hydroxy group, an alkyl group, a halogen atom, an alkoxy group, an acyloxy group, an acyl group, an alkenyl group, an alkynyl group, an aryl group, an alkylthio group, an alkoxycarbonyl group, an alkylsulfmyl group, an alkylsulfonyl group, an amino group, and an alkylamino group; and - X represents a carboxylic acid group, a carboxylate group, or a carboxamide group; or any pharmaceutically acceptable salt, solvate, complex or pro-drug thereof, with the provisos that the compound of formula (I) is not (all-Z)-4,7,10,13,16,19-docosahexaenoic acid (DHA), alpha-methyl DHA, alpha-methyl DHA methyl ester, alpha-methyl DHA ethyl ester or alpha-hydroxy DHA ethyl ester, are disclosed. A fatty acid composition and a pharmaceutical composition comprising such compounds are also disclosed. The use of such compounds as medicaments, in particular for the treatment of diabetes type 2, is also disclosed.

Full Text	FIELD OF THE INVENTION The present invention relates to compounds of the general formula (I): and their use as medicaments, in particular for the treatment of diabetes mellitus, type 2, and pre-stages thereof. It also relates to a pharmaceutical composition comprising compounds of formula (I), as well as to a fatty acid composition comprising compounds of formula (I). BACKGROUND AND PRIOR ART OF THE INVENTION The increasing incidence of type 2 diabetes mellitus worldwide poses an immense public health and medical challenge for the implementation of successful preventive and treatment strategies. The concurrent rise in overweight and obesity, which is tightly correlated to type 2 diabetes, interferes with diabetes treatment and increases the likelihood of hypertension, dyslipidemia, and atherosclerosis related diseases. The pathophysiologic condition precluding the development of type 2 diabetes is related to reduced effects of insulin on peripheral tissues, called insulin resistance. These tissues are mainly muscle, fat and liver. Muscle tissue is the main tissue concerned by insulin resistance in type 2 diabetes. The syndrome characterized by insulin resistance, hypertension, dyslipidemia and a systemic proinflammatory state, is referred to as metabolic syndrome. The prevalence of metabolic syndrome in the adult population in developed countries is 22-39% (Meighs 2003). Currently the most promising approach to mitigate and deter the metabolic syndrome is lifestyle intervention with weight reduction, decreased consumption of saturated fat, increased physical activity in combination with appropriate pharmacotherapy. Healthy diets that avoid excess energy intake encompass substitution of mono and polyunsaturated fatty acids in exchange for saturated fat. In particular the long-chain omega-3 fatty acids from fatty fish, namely eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have proven beneficial in prevention of type 2 diabetes. EPA and DHA have effects on diverse physiological processes impacting normal health and chronic disease, such as the regulation of plasma lipid levels, cardiovascular and immune function, insulin action and neural development and visual function. Firm evidence exist for their beneficial role in the prevention and management of coronary heart disease, dyslipidemias, type 2 diabetes, insulin resistance, and hypertension (Simonopoulos 1999; Geleijnse 2002; Stprlien 1998). Recent studies suggest that omega-3 fatty acids serve as important mediators of gene expression, working via nuclear receptors like the peroxisome proliferator- activated receptors (PPARs) controlling the expression of the genes involved in the lipid and glucose metabolism and adipogenesis (Jump 2002). PPARs are nuclear fatty acid receptors that have been implicated to play an important role in obesity-related metabolic diseases such as hyperlipidemia, insulin resistance, and coronary heart disease. The three subtypes, a, y? and 8, have distinct expression pattern and evolved to sense components of different lipoproteins and regulate lipid homeostasis based on the need of a specific tissue. PP ARa potentiates fatty acid catabolism in the liver and is the molecular target of the lipid-Iowering fibrates. PPARy on the other hand is essential for adipocyte differentiation and mediates the activity of the insulin- sensitizing thiazolidinedions (the glitazones) through mechanisms not fully understood. (Chih-Hao 2003; Yki-Jarvinen 2004) Recently, pharmaceuticals acting as ligands to the PPARy receptor have been introduced as treatment of type 2 diabetes (Yki-Jarvinen 2004). These compounds called thiazolidinediones or glitazones are drugs that reverse insulin resistance which is the pathophysiologic basis for development of the metabolic syndrome and type 2 diabetes. These compounds, of which rosiglitazone and pioglitazone have been launched as pharmaceuticals, lower fasting and postprandial glucose concentrations (which is being manifest as a pathologic glucose tolerance test), plasma insulin as well as free fatty acid concentrations. In this respect the glitazones act as insulin sensitizers. However, these improvements are generally accompanied by weight gain and an increase in the subcutaneous adipose-tissue mass (Adams 1997). The use of thiazolidinediones is not only associated with weight gain but a subgroup of patients also have fluid retention and plasma volume expansion, leading to peripheral oedema. The increase in body weight and oedema has been associated with an increase in the incidence of heart failure, which is the reason why the Food and Drug Administration has included a warning in the prescription information for rosiglitazone (provided by Avandia) and pioglitazone (provided by Takeda). These adverse effects restrict the use of the glitazones especially in patients with coronary heart conditions. Clearly there is a potential for new drugs with positive effects on insulin resistance but with weight reduction activity and no fluid retention tendency. The effect of the poly-unsaturated fatty acids (PUFAs) on PPARs are not only a result of fatty acid structure and affinity to the receptor. Factors contributing to the composition of the intracellular non-esterified fatty acids (NEFA) levels are also important. This NEFA pool is affected by the concentration of exogenous fatty acids entering the cell and the amount of endogenous synthesised fatty acids, their removal via incorporation into lipids as well as their oxidation pathways. (Pawar 2003). Although omega-3 fatty acids are weak agonists of PPARs, when compared with pharmacological agonists like the thioglitazones, these fatty acids have demonstrated improvement in glucose uptake and insulin sensitivity (Storlien 1987). It has been reported that adipocytes were more insulin sensitive and transported more glucose when the polyunsaturated to saturated fatty acid ratio in the diet was increased (Field 1990). Collectively, these data indicate that the 20- and 22-carbon fatty acids, namely EPA and DHA could play a preventive role in the development of insulin resistance. Due to their limited stability in vivo and their lack of biological specificity, PUFAs have not achieved widespread use as therapeutic agents. Chemical modifications of the n-3 polyunsaturated fatty acids have been performed by several research groups in order to change or increase their metabolic effects. For example, the hypolipidemic effects of EPA was potentiated by introducing methyl or ethyl in a- or p-position of EPA. (Vaagenes 1999). The compounds also reduced plasma free fatty acid while EPA EE had no effect. In a recent work published by L. Larsen (Larsen 2005) the authors show that the a-methyl derivatives of EPA and DHA increased the activation of the nuclear receptor PP ARa and thereby the expression of L-FABP compared to EPA/DHA. EPA with an ethyl group in the a-position activated PP ARa with equal strength as a- methyl EPA. The authors suggest that delayed catabolism of these a-methyl FA may contribute to their increased effects due to decreased P-oxidation in mitochondria leading to peroxisomal oxidation. Alpha-methyl EPA has been shown to be a stronger inhibitor of platelet aggregation than EPAs both in vitro (Larsen 1998) and in vivo (Willumsen 1998). Patent Abstract of Japan, publication number 05-00974 discloses DHA substituted in alpha-position with an OH-group, however only as an intermediate. No examination as to possible pharmaceutical effects of this compound is disclosed. Laxdale Limited has also described the use of alpha substituted derivatives of EPA in the treatment of psychiatric or central nervous disorders (US6689812). R= HI CH3, CH2CH3 (A) a-methyl EPA None of these modified fatty acids have, however, shown satisfactory pharmaceutical activity, and none of them has reached the pharmaceutical market. OBJECTIVES OF THE PRESENT INVENTION The principal object of the present invention is to provide new DHA-derivative having therapeutic activity. Another object of the present invention is to develop a process for the preparation of new DHA-derivative having therapeutic activity. Yet another object of the present invention is to provide a pharmaceutical composition of new DHA-derivative having therapeutic activity. Still another object of the present invention is to provide a fatty acid composition of new DHA-derivative having therapeutic activity. Still another object of the present invention is to use new DHA-derivative for prevention and/ or treatment of diabetes, obesity, preventing body weight gain, amyloidos-related disease, prophylaxis of multiple risk factors or cardiovascular diseases STATEMENT OF INVENTION Accordingly, the present invention provides a compound of formula (I): wherein - R1 and R2 are the same or different and may be selected from the group consisting of a hydrogen atom, a hydroxy group, an alkyl group, a halogen atom, an alkoxy group, an acyloxy group, an acyl group, an alkenyl group, an alkynyl group, an aryl group, an alkylthio group, an alkoxycarbonyl group, an alkylsulfmyl group, an alkylsuifonyl group, an amino group, and an alkylamino group; and - X represents a carboxylic acid group, a carboxylate group, or a carboxamide group, or any pharmaceutically acceptable salt, solvate, complex or pro-drug thereof; with the provisos that: ■ the compound of formula (I) is not (all-Z)-4,7,10,13,16,19- docosahexaenoic acid (DHA), alpha-methyl DHA, alpha-methyl DHA methyl ester, alpha-methyl DHA ethyl ester or alpha-hydroxy DHA ethyl ester; a process for the manufacture of a compound of formula (I); a pharmaceutical composition a compound of formula (I); A fatty acid composition of a compound of formula (I); Use of a compound of formula (I) for the manufacture of a medicament for controlling body weight reduction and/or for preventing body weight gain, use of a compound of formula (I) for the manufacture of a medicament for the treatment and/or the prevention of obesity or an overweight condition, use of a compound of formula (I) for the manufacture of a medicament for the prevention and/or treatment of diabetes in an animal, use of a compound of formula (I) for the manufacture of a medicament for the treatment and/or prevention of amyloidos- related diseases, use of a compound of formula (I) for the manufacture of a medicament for the treatment or prophylaxis of multiple R1sk factors for cardiovascular diseases, preferably for the treatment of elevated blood lipids, use of a compound of formula (I) for the manufacture of a medicament for prevention of stroke, cerebral or transient ischaemic attacks related to atherosclerosis of several arteR1es; and a method for controlling body weight reduction and/or for preventing body weight gain, wherein a pharmaceutically effective amount of a compound of formula (I) to a human or an animal, a method for the treatment and/or the prevention of obesity or an overweight condition, wherein a pharmaceutically effective amount of a compound of formula (I) is administered to a human or an animal, a method for the prevention and/or treatment of diabetes, wherein a pharmaceutically effective amount of a compound of formula (I) is administered to a human or an animal, a method for the treatment and/or prevention of amyloidos-related diseases, wherein a pharmaceutically effective amount of a compound of formula (I) is administered to a human or an animal, a method for the treatment or prophylaxis of multiple R1sk factors for cardiovascular diseases, wherein a pharmaceutically effective amount of a compound of formula (I) is administered to a human or an animal, a method for the prevention of stroke, cerebral or transient ischaemic attacks related to atherosclerosis of several arteR1es, wherein a pharmaceutically effective amount of a compound of formula (I) is administered to a human or an animal. BR1EF DESCR1PTION OF THE ACCOMPANYING DRAWINGS Fig. 1 is a schematic overview of the free fatty acid pool theory. Fig. 2 shows an overview of the models and methods used in the present invention for demonstrating effects on the metabolic syndrome and type 2 diabetes Fig. 3 depicts the free fatty acid concentrations of different compounds according to the invention in liver tissue from animals given these compounds in a concentration of 1.5% of total fat content. Fig. 4 depicts the intracellular concentrations of DHA in liver tissue from animals given different compounds according to the invention in a concentration of 1.5% of total fat content. Fig. 5 depicts the binding affinities for the PPARy receptor of different compounds according to the invention. Fig. 6 depicts the binding affinities to the nuclear receptor PP ARa of different compounds according to the invention. Fig. 7 depicts the binding affinities to the nuclear receptor RXRa of different compounds according to the invention. Fig. 8 depicts the release of luciferase from transfected cells treated with different compounds according to the invention. Fig. 9 shows the study design of the expeR1ment of block 4. Fig. 10 shows the change of body weight duR1ng 2 weeks of diet intervention after 8 weeks of HP diet. Fig. 11 shows the results from luciferase activity, i.e. endogenous PP ARy- activity). Fig, 12 shows the endogenous luciferase activity in differenc compounds according to the invention compared to DHA. Fig. 13 shows a typical blood glucose elimination curve before and after animals with insulin resistance are given a compound with insulin resistance reducing effect. Figs. 14, 15 and 16 show different effects of DHA deR1vatives according to the invention on metabolic syndrome and insulin resistance. DETAILED DESCR1PTION OF THE INVENTION The present invention is in relation to a compound of formula (I): - R] and R2 are the same or different and may be selected from the group consisting of a hydrogen atom, a hydroxy group, an alkyl group, a halogen atom, an alkoxy group, an acyloxy group, an acyl group, an alkenyl group, an alkynyl group, an aryl group, an alkylthio group, an alkoxycarbonyl group, an alkylsulfmyl group, an alkylsulfonyl group, an amino group, and an aikylamino group; and - X represents a carboxylic acid group, a carboxylate group, or a carboxamide group, or any pharmaceutically acceptable salt, solvate, complex or pro-drug thereof; with the provisos that: ■ the compound of formula (I) is not (all-Z)-4,7,10,13,16,19- docosahexaenoic acid (DHA), alpha-methyl DHA, alpha-methyl DHA methyl ester, alpha-methyl DHA ethyl ester or alpha-hydroxy DHA ethyl ester. In another embodiment of the present invention wherein said alkyl group is selected from a group compR1sing of methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-buthyl, sec. -butyl, n-hexyl, and benzyl. In yet another embodiment of the present invention, wherein said halogen atom is selected from a group compR1sing of fluoR1ne, chloR1ne, bromine, and iodine. In still another embodiment of the present invention, wherein said alkoxy group is selected from a group compR1sing of methoxy, ethoxy, propoxy, isopropoxy, sec- butoxy, phenoxy, benzyloxy, OCH2CF3, and OCH2CH2OCH3. In still another embodiment of the present invention, wherein said alkenyl group is selected from a group compR1sing of allyl, 2-butenyl, and 3-hexenyl. In still another embodiment of the present invention, wherein said alkynyl group is selected from a group compR1sing of propargyl, 2-butynyl, and 3-hexynyl. In still another embodiment of the present invention, wherein said aryl group is a phenyl group. In still another embodiment of the present invention, wherein said alkylthio group is selected from a group compR1sing of methylthio, ethylthio, isopropylthio, andphenylthio. In still another embodiment of the present invention, wherein said alkoxycarbonyl group is selected from a group compR1sing of methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and butoxycarbonyl. In still another embodiment of the present invention, wherein said alkylsulfinyl group is selected from a group compR1sing of methanesulfinyl, ethanesulfinyl, and isopropanesulfinyl. In still another embodiment of the present invention, wherein said aikylsulfonyl group is selected from a group compR1sing of methanesulfonyl, ethanesulfonyl, and isopropanesulf onyl. In still another embodiment of the present invention, wherein said alkylamino group is selected from a group compR1sing of methylamino, dimethylamino, ethylarnino, and diethylamino. In still another embodiment of the present invention, wherein said carboxylate group is selected from a group compR1sing of ethyl carboxylate, methyl carboxylate, n-propyl carboxylate, isopropyl carboxylate, n-butyl carboxylate, sec-butyl carboxylate, and n- hexyl carboxylate. In still another embodiment of the present invention, wherein said carboxamide group is selected from a group compR1sing of pR1mary carboxamide, N-methyl carboxamide, N,N-dimethyl carboxamide, N-ethyl carboxamide, and N,N-diethyl carboxamide. In still another embodiment of the present invention, wherein R1 and R2 are selected from the group consisting of a hydrogen atom, a hydroxy group, an alkyl group, a halogen atom, an alkoxy group, an alkylthio group, an alkylsulfmyl group, an aikylsulfonyl group, an amino group, and an alkylamino group. In still another embodiment of the present invention, wherein R1 and R2 are selected from a group compR1sing of a hydrogen atom, a hydroxy group, a C1-C7 alkyl group, a halogen atom, a C1-C7 alkoxy group, a C1-C7 alkyltio group, a C1-C7 alkylsulfmyl group, a C1-C7 alkylsulfonyl group, an amino group, and a Ci -C7 alkylamino group. In still another embodiment of the present invention, wherein said C1-C7 alkyl group is methyl, ethyl, or benzyl; said halogen atom is fluoR1ne or iodine: said C1-C7 alkoxy group is methoxy or ethoxy; said C1-C7 alkylthio group is methylthio, ethylthio or phenylthio; said C1-C7 alkylsulfmyl group is ethanesulfmyl; said C1-C7 alkylsulfonyl group is ethanesulfonyl; said C1-C7 alkylamino group is ethylamino or diethylamino; and X represents a an ethylcarboxylate or a carboxamide group. In still another embodiment of the present invention, wherein R1 and R2 are selected from the group consisting of a hydrogen atom, a C2-C7 alkyl group, a halogen atom, a CrC7 alkoxy group, a C1-C7 alkyltio group, a C1-C7 alkylsulfmyl group, a CrC7 alkylsulfonyl group, an amino group, and a C1-C7 alkylamino group; and X represents a carboxylate. In still another embodiment of the present invention, wherein said C2-C7 alkyl group is ethyl, or benzyl; said halogen atom is fluoR1ne or iodine: said C1-C7 alkoxy group is methoxy or ethoxy; said C1-C7 alkylthio group is methylthio, ethylthio or phenylthio; said C1-C7 alkylsulfmyl group is ethanesulfmyl; said C1-C7 alkylsulfonyl group is ethanesulfonyl; said C1-C7 alkylamino group is ethylamino or diethylamino; and X represents a an ethylcarboxylate. In still another embodiment of the present invention, wherein R1 and R2 are different. In still another embodiment of the present invention, wherein said compound is in racemic form. In still another embodiment of the present invention, wherein said compound is in the form of its R stereoisomer. In still another embodiment of the present invention, wherein said compound is in the form of its S stereoisomer. In still another embodiment of the present invention, wherein one Of R] and R2 represents a C2-C7 alkyl group, and the other one represents a hydrogen atom. In still another embodiment of the present invention, wherein said alkyl group is ethyl. In still another embodiment of the present invention, wherein said compound is in racemic form. In still another embodiment of the present invention, wherein said compound is in the form of its R stereoisomer. In still another embodiment of the present invention, wherein said compound is in the form of its S stereoisomer. In still another embodiment of the present invention, wherein said alkyl group is benzyl. In still another embodiment of the present invention, wherein one of R1 and R2 represents an alkoxy group, and the other one represents a hydrogen atom. In still another embodiment of the present invention, wherein said alkoxy group is ethoxy or methoxy. In still another embodiment of the present invention, wherein one of R1 and R2 represents a halogen atom, and the other one represents a hydrogen atom. In still another embodiment of the present invention, wherein said halogen atom is fluoR1ne or iodine. In still another embodiment of the present invention, wherein one of R1 and R2 represents a alkylthio group, and the other one represents a hydrogen atom. In still another embodiment of the present invention, wherein said alkylthiogroup is ethylthio. In still another embodiment of the present invention, wherein said alkylthiogroup is methylthio or phenylthio. In still another embodiment of the present invention, wherein one of R1 and R2 represents an alkylsulfonyl group, and the other one represents a hydrogen atom. In still another embodiment of the present invention, wherein said alkylsulfonyl group is ethanesulfonyl. In still another embodiment of the present invention, wherein one of R1 and R2 represents an amino group, and the other one represents a hydrogen atom. In still another embodiment of the present invention, wherein one of R1 and R2 represents an alkyl-amino group, and the other one represents a hydrogen atom. In still another embodiment of the present invention, wherein said alkyl-amino group is ethyl-amino or diethyl-amino. In still another embodiment of the present invention, wherein R1 and R2 represent Ci- C7- alkyl groups. In still another embodiment of the present invention, wherein said alkyl groups are methyl groups. In still another embodiment of the present invention, wherein said alkyl groups are ethyl groups. In still another embodiment of the present invention, wherein X is ethyl carboxylate. In still another embodiment of the present invention, in the form, of a phospholipid, a tR1-, di- or monoglyceR1de, or in the form of a free acid. In still another embodiment of the present invention, wherein said compound is for use as a medicament. The present invention also relates to a process for the manufacture of a compound of formula (I). In another embodiment of the present invention, wherein said compound is prepared from (all-Z)-4, 7, 10, 13, 16, 19-docosahexaenoic acid (DHA). In yet another embodiment of the present invention, wherein said DHA is prepared from a vegetable, a microbial and/or an animal source. In still another embodiment of the present invention, wherein said DHA is prepared from a maR1ne oil. In still another embodiment of the present invention, wherein said maR1ne oil is fish oil. The present invention also relates to a pharmaceutical composition compR1sing a compound of formula (I) as an active ingredient. In still another embodiment of the present invention, wherein said composition further compR1sing a pharmaceutically acceptable carR1er. In still another embodiment of the present invention, wherein said composition is formulated for oral administration. In still another embodiment of the present invention, wherein said formulation is in the form of a capsule or a sachet. In still another embodiment of the present invention, wherein said formulation is formulated to provide a daily dosage ranging from 10 mg to 10 g of said compound. In still another embodiment of the present invention, wherein said formulation is formulated to provide a daily dosage ranging from 100 mg to 1 g of said compound. The present invention also relates to a fatty acid composition compR1sing a compound of formula (I). In still another embodiment of the present invention, wherein at least 60% by weight of the fatty acid composition is compR1sed of said compound. In still another embodiment of the present invention, wherein at least 90% by weight of the fatty acid composition is compR1sed of said compound. In still another embodiment of the present invention, wherein said composition further compR1sing fatty acids selected from (all-Z)-5,8,l 1,14,17-eicosapentaenoic acid (EPA), (all-Z)-4,7,10,13,16,19-docosahexaenoic acid (DHA), (all-Z)- 6,9,12,15,18- heneicosapentaenoic acid (HPA), and/or (all-Z)-7.10,13.16,19- docosapentaenoic acid (DPA). In still another embodiment of the present invention, wherein said fatty acids are present in the form of deR1vatives. In still another embodiment of the present invention, wherein said composition further compR1sing a pharmaceutically acceptable antioxidant. In still another embodiment of the present invention, wherein said antioxidant is tocopherol. In still another embodiment of the present invention, wherein said composition is for use as a medicament. The present invention is in relation to use of a compound of formula (I) for the manufacture of a medicament for controlling body weight reduction and/or for preventing body weight gain. The present invention is in relation to use of a compound of formula (I) for the manufacture of a medicament for the treatment and/or the prevention of obesity or an overweight condition. The present invention is in relation to use of a compound of formula (I) for the manufacture of a medicament for the prevention and/or treatment of diabetes in an animal. In another embodiment of the present invention, wherein the diabetes is type 2 diabetes. The present invention is in relation to use of a compound of formula (I) for the manufacture of a medicament for the treatment and/or prevention of amyloidos- related diseases. The present invention is in relation to use of a compound of formula (I) for the treatment or prophylaxis of multiple R1sk factors for cardiovascular diseases, preferably for the treatment of elevated blood lipids. The present invention is in relation to use of a compound of formula (I) for the manufacture of a medicament for prevention of stroke, cerebral or transient ischaemic attacks related to atherosclerosis of several arteR1es. The present invention relates to a method for controlling body weight reduction and/or for preventing body weight gain, wherein a pharmaceutically effective amount of a compound of formula (I) is administered to a human or an animal. The present invention relates to a method for the treatment and/or the prevention of obesity or an overweight condition, wherein a pharmaceutically effective amount of a compound of formula (I) is administered to a human or an animal. The present invention relates to a method for the prevention and/or treatment of diabetes, wherein a pharmaceutically effective amount of a compound of formula (I) is administered to a human or an animal. In another embodiment of the present invention, wherein the diabetes is type 2 diabetes. The present invention relates to a method for the treatment and/or prevention of amyloidos-related diseases, wherein a pharmaceutically effective amount of a compound of formula (I) is administered to a human or an animal. The present invention relates to a method for the treatment or prophylaxis of multiple R1sk factors for cardiovascular diseases, wherein a pharmaceutically effective amount of a compound of formula (I) is administered to a human or an animal. The present invention relates to a method for the prevention of stroke, cerebral or transient ischaemic attacks related to atherosclerosis of several arteR1es, wherein a pharmaceutically effective amount of a compound of formula (I) is administered to a human or an animal. In another embodiment of the present invention, wherein the compound of formula (I) is administered orally to a human or an animal. The aim of the present invention is to provide new DHA-deR1vatives having therapeutical activity. Based on the present invention a number of aspects are presented in the appended claims. Some of these aspects are: 1. Novel compounds, i.e. certain a-substituted polyunsaturated fatty acid deR1vatives. 2. The novel compounds for use as a medicament and for use in therapy. 3. A fatty acid composition or a pharmaceutical composition compR1sing the novel compounds. 4. A fatty acid composition compR1sing the novel compounds for use as a medicament and for use in therapy. 5. Use of the novel compounds for the production of a medicament for the prevention and/or treatment of diabetes in humans or an animal. 6. Use of the novel compounds for the production of a medicament for the treatment and/or the prevention of obesity or an overweight condition. 7. Use of the novel compounds for the production of a medicament for controlling body weight reduction and/or for preventing body weight gain. 8. Use of the novel compounds for the production of a medicament for the treatment and/or prevention of amyloidos-related diseases. 9. Use of the novel compounds for the production of a medicament for the treatment or prophylaxis of multiple R1sk factors or cardiovascular diseases. 10. Use of the novel compounds for the production of a medicament for the prevention of stroke, cerebral or transient ischaemic attacks related to atherosclerosis of several arteR1es. 11. A method for specific treatment of a diabetic condition, preferably type 2 diabetes. 12. A method for controlling body weight reduction, for preventing body weight gain and/or for the treatment and/or the prevention of obesity or an overweight condition. 13. A method for the treatment and/or prevention of amyloidos-related diseases. 14. A method for the treatment or prophylaxis of multiple R1sk factors for cardiovascular diseases. 15. A method for the prevention of stroke, cerebral or transient ischaemic attacks related to atherosclerosis of several arteR1es. 16. Processes for prepaR1ng novel fatty acid analogous according to the invention. The present invention relates to a compound of formula (I): wherein - R1 and R2 are the same or different and may be selected from the group consisting of a hydrogen atom, a hydroxy group, an alkyl group, a halogen atom, an alkoxy group, an acyloxy group, an acyl group, an alkenyl group, an alkynyl group, an aryl group, an alkylthio group, an alkoxycarbonyl group, an alkylsulfmyl group, an alkylsulfonyl group, an amino group, and an alkylamino group; and - X represents a carboxylic acid group, a carboxylate group, or a carboxamide group, or any pharmaceutically acceptable salt, solvate, complex or pro-drug thereof, with the provisos that: ■ the compound of formula (I) is not (all-Z)-4,7, 10,13,16,19- docosahexaenoic acid (DHA), alpha-methyl DHA, alpha-methyl DHA methyl ester, alpha-methyl DHA ethyl ester, or alpha-hydroxy DHA ethyl ester. The provisos correspond to the following cases: ' when R1 is a hydrogen atom, then R2 is not a hydrogen atom; ? when R2 is a hydrogen atom, then R1 is not a hydrogen atom; ? when R1 is a methyl group, then R2 is not a hydrogen atom, and X is not a carboxylic acid group, a methylcarboxylate, or an ethylcarboxylate; ? when R2 is a methyl group, then R] is not a hydrogen atom, and X is not a 5 carboxylic acid group, a methylcarboxylate, or an ethylcarboxylate; ? when R1 is a hydroxy group, then R2 is not a hydrogen atom, and X is not an ethylcarboxylat; and ? when R2 is a hydroxy group, then R\ is not a hydrogen atom, and X is not an ethylcarboxylat. 0 In a compound according to the invention, said alkyl group may be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, n- hexyl, and benzyl; said halogen atom may be selected from the group consisting of fluoR1ne, chloR1ne, bromine, and iodine; said alkoxy group may be selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, sec.-butoxy, phenoxy, 5 benzyloxy, OCH2CF3, and OCH2CH2OCH3; said acyloxy group may be selected from acetoxy, propionoxy, and butyroxy; said alkenyl group may be selected from the group consisting of allyl, 2-butenyl, and 3-hexenyl; said alkynyl group may be selected from the group consisting of propargyl, 2-butynyl, and 3-hexynyl; said aryl group is a phenyl group; said alkylthio group may be selected from the group O consisting of methylthio, ethylthio, isopropylthio, and phenylthio; said alkoxycarbonyl group may be selected from the group consisting of methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and butoxy car bony 1; said alkylsulfinyl group may be selected from the group consisting of methanesulfmyl, ethanesulfinyl, and isopropanesulfmyl; said alkylsulfonyl group may be selected from 5 the group consisting of methanesulfonyl, ethanesulfonyl, and isopropanesulfonyl; said alkylamino group may be selected from the group consisting of methylamino, dimethylamino, ethylamino, and diethylamino; said carboxylate group may be selected from the group consisting of ethyl carboxylate, methyl carboxylate, n-propyl carboxylate, isopropyl carboxylate, n-butyl carboxylate, sec-butyl carboxylate, and O n-hexyl carboxylate; said carboxamide group may be selected from the group consisting of pR1mary carboxamide, N-methyl carboxamide, N,N-dimethyl carboxamide, N-ethyl carboxamide, and N,N-diethyl carboxamide. In one embodiment of the invention, R1 and R2 are selected from the group consisting of a hydrogen atom, a hydroxy group, an alkyl group, a halogen atom, an 5 alkoxy group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group, an amino group, and an alkylamino group. In another embodiment of the invention, R1 and R2 are selected from the group consisting of a hydrogen atom, a hydroxy group, a C1-C7 alkyl group, a halogen atom, a C1-C7 alkoxy group, a C1-C7 alkyltio group, a C1-C7 alkylsulfmyl group, a C1-C7 alkylsulfonyl group, an amino group, and a Ci -C? alkylamino group. Then, said C1-C7 alkyl group may be methyl, ethyl, or benzyl; said halogen atom may be fluoR1ne or iodine; said C1-C7 alkoxy group may be methoxy or ethoxy; said C1-C7 alkylthio group may be methylthio, ethylthio or phenylthio; said C1-C7 alkylsulfmyl group may be ethanesulfmyl; said C1-C7 alkylsulfonyl group may be ethanesulfonyl; said C1-C7 alkylamino group may be ethylamino or diethylamino; and X may represent an ethylcarboxylate or a carboxamide group. In another embodiment of the invention, R1 and R2 are selected from the group consisting of a hydrogen atom, a C2-C7 alkyl group, a halogen atom, a C1-C7 alkoxy group, a C1-C7 alkyltio group, a C1-C7 alkylsulfmyl group, a CrC7 alkylsulfonyl group, an amino group, and a C1-C7 alkylamino group; and X represents a carboxylate. Then, said C2-C7 alkyl group may be ethyl, or benzyl; said halogen atom may be fluoR1ne or iodine: said C1-C7 alkoxy group may be methoxy or ethoxy; said C1-C7 alkylthio group may be methylthio, ethylthio or phenylthio; said C1-C7 alkylsulfmyl group may be ethanesulfmyl; said C1-C7 alkylsulfonyl group may be ethanesulfonyl; said C1-C7 alkylamino group may be ethylamino or diethylamino; and X represents a an ethylcarboxylate. In the compound according to formula (I) of the present invention, R1 and R2 may be the same or different. When they are different, the compounds of formula (I) are capable of existing in stereoisomeR1c forms. It will be understood that the invention encompasses all optical isomers of the compounds of formula (I) and mixtures thereof including racemates. Therefore, the present invention includes, where R1 is different from R2, compounds of formula (I) that are racemic or enantiomeR1cally pure, either as the (S) or (R) enantiomer. Therefore, the present invention includes, where R1 is different from R2, compounds of formula (I) that are racemic or enantiomeR1c pure, either as the (S) or (R) stereoisomer. Within the scope of the invention are enantiomers of the compounds of the formula (I), as hereinbefore defined. Moreover, the enantiomers of the DHA deR1vatives according to the invention might be in the form of a carboxylic acid, or a pharmaceutically acceptable salt thereof, any ester, anhydR1de or amide (pR1mary, secondary, tertiary). The acid deR1vative might be in the form of a phospholipid or a tR1- di- or monoglyceR1de. In one embodiment of a compound of formula (I) according to the invention, one of R] and R2 represents a C2-C7 alkyl group, e.g. ethyl or benzyl, and the other one represents a hydrogen atom. Preferably, the alkylgroup is ethyl. In another embodiment of a compound of formula (I) according to the invention, one of R1 and R2 represents an alkoxy group, e.g. ethoxy or methoxy, and the other one represents a hydrogen atom. In another embodiment of a compound of formula (I) according to the invention, one OfR] and R2 represents a halogen atom, e.g. fluoR1ne or iodine, and the other one represents a hydrogen atom. In another embodiment of a compound of formula (I) according to the invention, one of R1 and R2 represents an alkylthio group, e.g. ethylthio, methylthio or phenylthio, and the other one represents a hydrogen atom. Preferably, the alkylthiogroup is ethylthio. In another embodiment of a compound of formula (I) according to the invention, one of R1 and R2 represents an alkylsulfonyl group, e.g. ethylsulfonyl, and the other one represents a hydrogen atom. In another embodiment of a compound of formula (I) according to the invention, one of R] and R2 represents an amino group, and the other one represents a hydrogen atom. In another embodiment of a compound of formula (I) according to the invention, one of R1 and R2 represents an alkyl-amino group, e.g. ethyl-amino or diethyl-amino, and the other one represents a hydrogen atom. In a further embodiment of a compound of formula (I) according to the invention, R1 and R2 are the same and represent Ci-C7-alkyl groups, preferably methyl groups or ethyl groups. In preferred embodiments of the compound of formula (I), X is a carboxylate, e.g. ethyl carboxylate. The compound according to the invention may exist in the form of a phospholipid, a tR1- , di- or monoglyceR1de, or in the form of a free acid. The alpha-substituted DHA- deR1vatives according to the invention have very surpR1singly shown excellent results with regard to pharmaceutical activity. In particular, the fatty acid deR1vatives according to the present invention possess a huge potential to be used in the treatment and/or prevention of diabetes and pre-stages thereof. Another aspect of the present invention relates to a compound of formula (I) for use as a medicament. The invention also relates to a process for the manufacture of a compound of formula (I). For example, a compound of formula (I) may be prepared from (all-Z)- 4,7,10,13,16,19-docosahexaenoic acid (DHA). The DHA may e.g. oR1ginate from a vegetable, a microbial and/or an animal source, such as a maR1ne fish oil. Another important advantage with compounds of formula (I) is that the fatty acid analogues can be prepared directly from (all-Z)-4,7,10,13,16,19-docosahexaenoic acid (DHA). In a preferred embodiment of the invention, the fatty acid analogues of formula (I) are prepared from DHA, wherein said DHA is obtained from at least one of vegetable, microbial and animal oR1gins, or combinations thereof. The invention includes therefore deR1vatives prepared from DHA-containing oil from microbial oR1gin. Suitable, said DHA is produced from a maR1ne oil, such as a fish oil. Another aspect of the present invention relates to a pharmaceutical composifion compR1sing a compound of formula (I) as an active ingredient. The pharmaceutical composition may further compR1se a pharmaceutically acceptable carR1er. Suitably, a pharmaceutical composition according to the invention is formulated for oral administration, e.g. in the form of a capsule or a sachet. A suitable daily dosage of a compound of formula (I) according to the present invention is 10 mg to 10 g, in particular 100 mg to 1 g of said compound. In addition, the present invention relates to a fatty acid composition compR1sing a compound of formula (I). At least 60%, or at least 90% by weight of the fatty acid composition may be compR1sed of said compound. The fatty acid composition may further compR1se (all-Z)-5,8,l 1,14,17-eicosapentaenoic acid (EPA), (all-Z)- 4,7,10,13,16,19-docosahexaenoic acid (DHA), (all-Z)-6,9,12,15,18- heneicosapentaenoic acid (HPA), and/or (all-Z)-7,10,13,16,19-docosapentaenoic acid (DPA). The fatty acids may be present in the form of deR1vatives. A fatty acid composition according to the present invention may further compR1se a pharmaceutically acceptable antioxidant, e.g. tocopherol. Within the scope of the present invention is also a fatty acid composition descR1bed above, for use as a medicament. In a further aspect, the present invention relates to the use of a compound according to formula (I) for the manufacture of a medicament for controlling body weight reduction and/or for preventing body weight gain; for the manufacture of a medicament for the treatment and/or the prevention of obesity or an overweight condition; for the manufacture of a medicament for the prevention and/or treatment of diabetes in an animal, in particular type 2 diabetes; for the manufacture of a medicament for the treatment and/or prevention of amyloidos-related diseases; for the manufacture of a medicament for the treatment or prophylaxis of multiple R1sk factors for cardiovascular diseases, preferably for the treatment of elevated blood lipids for the manufacture of a medicament for prevention of stroke, cerebral or transient ischaemic attacks related to atherosclerosis of several arteR1es. In addition, the present invention relates to a method for controlling body weight reduction and/or for preventing body weight gain; a method for the treatment and/or the prevention of obesity or an overweight condition; a method for the prevention and/or treatment of diabetes, in particular type 2 diabetes; a method for the treatment and/or prevention of amyloidos-related diseases; a method for the treatment or prophylaxis of multiple R1sk factors for cardiovascular diseases; a method for the prevention of stroke, cerebral or transient ischaemic attacks related to atherosclerosis of several arteR1es, wherein a pharmaceutically effective amount of a compound of formula (I) is administered to a human or an animal. Suitably, the compound of formula (I) is administered orally to a human or an animal. In the research work leading to the present invention, novel DHA-deR1vatives were prepared, which showed excellent pharmaceutical activity. Fatty acids enter cells passively or trough G-protein coupled transporter systems, such as fatty acid transport proteins. Well inside the cells they are temporaR1ly bound by binding proteins (Fatty acid binding proteins, FABP), which play an important role in directing fatty acids to vaR1ous intracellular compartments for metabolism and gene expression (Pawar & Jump 2003). (Fig. 1 liver cell). EsteR1fication of fatty acids into tR1glyceR1des, polar lipids, and cholesterol esters and their beta-oxidation (mitochondR1al and peroxisomal) requires conversion of fatty acids to acyl CoA thioesters. Other pathways, like microsomal NADPH- dependent mono-oxidation and eikosanoids synthesis, utilise non-esteR1fied fatty acids as substrates. All these reactions are likely to influence cellular levels of free fatty acids (non-esterfified) and thereby the amount and type of fatty acids which could be used as ligands to nuclear receptors. Because PPARs are known to bind non-esteR1fied fatty acids it is reasonable to expect that the composition of the free fatty acid pool is an important determinant in the control of PPAR activity. The composition of the free fatty acid pool is affected by the concentration of exogenous fatty acids enteR1ng the cells, and their rate of removal via pathways listed above. Since short and medium chain fatty acids are effectively recruited to these pathways, in practice only the long-chain polyunsaturated fatty acids will be available for liganding to nuclear receptors. In addition, fatty acid structure may also be an important determinant. Even if a seR1es of mono and polyunsaturated fatty acids demonstrated affinity to the PP ARa receptor, EPA and DHA demonstrated the highest binding capacity in expeR1ments with rat liver cells (Pawar & Jump 2003). Searching for fatty acid candidates available for genetic modification of proteins by interaction with nuclear receptors like the PPARs, it is important to veR1fy that the respective fatty acids will be enR1ched in the free fatty acid pool. DHA which enter cells are rapidly converted to fatty acyl-CoA thioesters and incorporated into phospholipids and due to this, the intracellular DHA level is relatively low. These DHA-CoA are also substrate for P-oxidation pR1maR1ly in the peroxisomes that lead to retroconvertion of DHA to EPA, see Fig. 1. Because of the 5 rapid incorporation into neutral lipids and the oxidation pathway DHA will not stay long in the free fatty acid pool. Due to this the effect of DHA on gene expression is probably limited. The present invention aims at achieving an accumulation of fatty acid deR1vatives in the free fatty acid pool, rather than incorporation into phosholipids. The 0 present inventors have surpR1singly found that the introduction of at least one substituent in the a-position of DHA will lead to a slower oxidation rate in addition to less incorporation into neutral lipids. This will lead to an increased effect on gene expression, since the DHA deR1vatives will accumulate in the tissue particular within liver, muscle, and adipose cells and tR1gger local nuclear receptor activity to a greater 5 extent than DHA. The different substituents according to the invention will give vaR1able affinities of the deR1vatives to fatty acids binding receptors. It is also possible that changes in affinity to fatty acids binding proteins lead to changes in the biological activity of these a-substituted DHA deR1vatives of formula (I). Altogether theses O changes lead to an increased therapeutic effect of the DHA deR1vatives according to the invention compared to DHA. EPA (all-Z)-5,8,l 1,14,17-eicosapentaenoic acid) has earlier been alkylated in a- and p-position to inhibit mitochondR1al p-oxidation. DHA is not oxidised in the mitochondR1a, but rather incorporated into phospholipids. In the peroxisomes though 5 some DHA is retroconverted to EPA. A substituent in the a-position of EPA and DHA will due to this affect different metabolic pathways. It has earlier been shown that a-methyl EPA and P-methyl EPA is incorporated into phospholipids and tR1glyceR1ds while a-ethyl EPA is not (Larsen 1998), In this study the deR1vatives were tested as substrates and/or inhibitors of enzymes involved in the eicosanoid cascade. O Since most of the substrates for these enzymes are fatty acids liberated from phospholipids it was desired that the deR1vatives were incorporated into phospholipids. In contrast to this, as mentioned before, we want deR1vatives that will not incorporate into lipids, but rather accumulate in the NEFA pool. Througout this descR1ption, the abbreviation "PRB-x", where x is an integer, 5 will be used when descR1bing specific compounds according to the invention. Below, the structural formulas and tR1vial names for each of these compounds are listed: t PRB-5 a,a di-methyl docosahexaenoic acid ethyl ester PRB-6 a-tlomethyl docosahexaenoic acid ethyl ester PRB-7 a-tioethyl docosahexaenoic acid ethyl ester PRE-8 a,a di-ethyl docosahexaenoic acid ethyl ester PRB-9 a-benzyl docosahexaenoic acid ethyl ester PRB-1 Oa-ethanesulfinyl docosahexaenoic acid ethyl ester PRB-11 a-tiophenyl docosahexaenoic acid ethyl ester PRB-12a-hydroxy docosahexaenoic acid ethyl ester PRB-13a-methyl docosahexaenoic acid PRB-14 a-methoxy docosahexaenoic acid ethyf ester PRB-15 a-iodo docosaiiexaenoic acid ethyl ester PRB-17a--amJno docosahexanolc acid ethyl ester PRB-18 (4R,5S)-3-docosahexaenoyl-4-methyl-5-phenyl-oxa2olidin-2-one PRB-19 (4R,5S)-3-[{S)-a"ethyldocosahexaenoy!]-4-nnethyl-5-phenyl-oxazolidin-2-one PRB-20 (S)-(+)-a-6thy! docosahexanoic acid ethyl ester PRB-21 (4S,5R)-3-clocosahexaenoyl- 4-methyl-5-phenyl-oxazofidin-2-one PRB-22(4S,5R)-3-[(R)-a-ethyldocosahexaenoyl]-4-methyl-5-pheny[-oxazolidin-2-one V PRB-23 (R)-(-)-a-ethyl docosahexanoic add ethyl ester PRB-24 2-(1,3-Dioxo-1,3-dihycfro-isoindol-2-y[)-docos ahexaenoic acid ethyl ester PRB-25a-ethyl-amino docosahexanoic acid ethyl ester I I PRB-26a-diethyl-amino docosahexanoic acid ethyl ester PRB-I corresponds to a compound of formula (I) in which KI or K2 is memyi, ana ihe other one is hydrogen, and X is ethyl carboxylate. PRB-2 corresponds to a compound of formula (I) in which R1 or R2 is ethyl, and the other one is hydrogen, and X is ethyl carboxylate. PRB-3 corresponds to a compound of formula (I) in which R1 or R2 is ethoxy, and the other one is hydrogen, and X is ethyl carboxylate. PRB-4 corresponds to a compound of formula (I) in which R1 or R2 is fluoR1ne, and the other one is hydrogen, and X is ethyl carboxylate. PRB-5 corresponds to a compound of formula (I) in which R1 and R2 is methyl, and X is ethyl carboxylate. PRB-6 corresponds to a compound of formula (I) in which R] or R2 is methylthio, and X is ethyl carboxylate. PRB-7 corresponds to a compound of formula (I) in which R1 or R2 is ethylthio, and the other one is hydrogen, and X is ethyl carboxylate. PRB-8 corresponds to a compound of formula (I) in which R1 and R2 is ethyl, and the other one is hydrogen, and X is ethyl carboxylate. PRB-9 corresponds to a compound of formula (I) in which R1 or R2 is benzyl, and the other one is hydrogen, and X is ethyl carboxylate. PRB-IO corresponds to a compound of formula (I) in which R1 or R2 is ethanesulfmyl, and the other one is hydrogen, and X is ethyl carboxylate. PRB-11 corresponds to a compound of formula (I) in which R1 or R2 is phenylthio, and the other one is hydrogen, and X is ethyl carboxylate. PRE- 12 corresponds to a compound of formula (I) in which R1 or R2 is hydroxy, and the other one is hydrogen, and X is ethyl carboxylate. PRB-13 corresponds to a compound of formula (I) in which R] or R2 is methyl, and the other one is hydrogen, and X is pR1mary carboxamide. PRB- 14 corresponds to a compound of formula (I) in which R1 or R2 is methoxy, and the other one is hydrogen, and X is ethyl carboxylate. PRB-15 corresponds to a compound of formula (I) in which R\ or R2 is iodine, and the other one is hydrogen, and X is ethyl carboxylate. PRB-17 corresponds to a compound of formula (I) in which R1 or R2 is amino, and the other one is hydrogen, and X is ethyl carboxylate. PRB-20 corresponds to the (S) stereoisomer of a compound of formula (I) in which R1 or R2 is ethyl, and the other one is hydrogen, and X is ethyl carboxylate. PRB-23 corresponds to the (R) stereoisomer of a compound of formula (I) in which R1 or R2 is ethyl, and the other one is hydrogen, and X is ethyl carboxylate. PRB-24 corresponds to a compound of formula (I) in which R1 or R2 is N- phtalimide, and the other one is hydrogen, and X is ethyl carboxylate. PRB-25 corresponds to a compound of formula (I) in which R1 or R2 is ethyl- amino, and the other one is hydrogen, and X is pR1mary carboxamide. PRB-26 corresponds to a compound of formula (I) in which R1 or R2 is diethyl-amino, and the other one is hydrogen, and X is ethyl carboxylate. PRB-2 is the most preferred compound according to the present invention. Other preferred compounds according to the invention are PRB-5, PRB-7, and PRB- 8. It is to be understood that the present invention encompasses any possible pharmaceutically acceptable salts, solvates, complexes or prodrugs of the compounds of formula (I). "Prodrugs" are entities which may or may not possess pharmacological activity as such, but may be administered (such as orally or parenterally) and thereafter subjected to bioactivation (for example metabolized) in the body to form the agent of the present invention which is pharmacologically active. Where X is a carboxylic acid, the present invention also includes salts of the carboxylic acids. Suitable pharmaceutically acceptable salts of carboxy groups includes metal salts, such as for example aluminium, alkali metal salts such as lithium, sodium or potassium, alkaline metal salts such as calcium or magnesium and ammonium or substituted ammonium salts. A "therapeutically effective amount" refers to the amount of the therapeutic agent which is effective to achieve its intended purpose. While individual patient needs may vary, determination of optimal ranges for effective amounts of each nitR1c oxide adduct is within the skill of the art. Generally the dosage regimen for treating a condition with the compounds and/or compositions of this invention is selected in accordance with a vaR1ety of factors, including the type, age, weight, sex, diet and medical condition of the patient. By "a medicament" is meant a compound according to formula (I), in any form suitable to be used for a medical purpose, e.g. in the form of a medicinal product, a pharmaceutical preparation or product, a dietary product, a food stuff or a food supplement. In the context of the present specification, the term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be constructed accordingly. Treatment includes any therapeutic application that can benefit a human or non-human animal. The treatment of mammals is particularly preferred. Both human and veteR1nary treatments are within the scope of the present invention. Treatment may be in respect of an existing condition or it may be prophylactic. It may be of an adult, a juvenile, an infant, a foetus, or a part of any of the aforesaid (e.g. an organ, tissue, cell, or nucleic acid molecule). By "chronic treatment" is meant treatment that continues for some weeks or years. "A therapeutically or a pharmaceutically active amount" relates to an amount that will lead to the desired pharmacological and/or therapeutic effects. A compound according to the present invention may for example be included in a food stuff, a food supplement, a nutR1tional supplement, or a dietary product. Alpha-substituted DHA deR1vatives and EPA (or DHA for that matter) can be bound together and combined on tR1glyceR1de form by an esteR1fication process between a mixture of alpha-deR1vatives, EPA and glycerol catalysed by Novozym 435 (a commercially available lipase from Candida antarctica on immobilised form). The compounds of formula (I) have activity as pharmaceuticals, in particular as tR1ggers of nuclear receptor activity. Thus, the present invention also relates to compounds of formula (I), pharmaceutically acceptable salts, solvates, complexes or pro-drugs thereof, as hereinbefore defined, for use as a medicament and/or for use in therapy. Preferably, the novel compounds, or pharmaceutically acceptable salts, solvates, complexes or pro-drugs thereof, of the invention may be used: - for the prevention and/or treatment of diabetes mellitus in humans or animals; for controlling body weight reduction and/or for preventing body weight gain; - for the prevention and/or treatment of obesity or an overweight condition in humans or in an animal; - for the treatment and/or prevention of amyloidos-related diseases; - for the treatment or prophylaxis of multiple R1sk factors for cardiovascular diseases; - for the prevention of stroke, cerebral or transient ischaemic attacks related to atherosclerosis of several arteR1es. - for the treatment of TBC or HIV. There are two major forms of diabetes mellitus. One is type 1 diabetes, which is known as insulin-dependent diabetes mellitus (IDDM), and the other one is type 2 diabetes, which is also known as non-insulin-dependent diabetes mellitus (NIDDM). Type 2 diabetes is related to obesity/overweight and lack of exercise, often of gradual onset, usually in aduhs, and caused by reduced insulin sensitivity, so called peR1ferral insulin resistance. This leads to a compensatory increase in insulin production. This stage before developing full fetched type 2 diabetes is called the metabolic syndrome and characteR1zed by hypeR1nsulinemia, insulin resistance, obesity, glucose intolerance, hypertension, abnormal blood lipids, hypercoagulopathia, dyslipidemia and inflammation, often leading to atherosclerosis of the arteR1es. Later when insulin production seizes, type 2 diabetes mellitus develops. In a preferred embodiment, the compounds according to formula (I) may used for the treatment of type 2 diabetes. The compounds according to formula (I) may also be used for the treatment of other types of diabetes selected from the group consisting of metabolic syndrome, secondary diabetes, such as pancreatic, extrapancreatic/endocR1ne or drug-induced diabetes, or exceptional forms of diabetes, such as lipoatrophic, myatonic or a disease caused by disturbance of the insulin receptors. The invention also includes treatment of type 2 diabetes. Suitably, compounds of formula (I), as hereinbefore defined, may activate nuclear receptors, preferably PPAR (peroxisome proliferator-activated receptor) a and/or y. The compounds of formula (I) may also be used for the treatment and/or prevention of obesity. Obesity is usually linked to an increased insulin resistance and obese people run a high R1sk of developing type 2 diabetes which is a major R1sk factor for development of cardiovascular diseases. Obesity is a chronic disease that afflict an increasing proportion of the population in Western societies and is associated, not only with a social stigma, but also with decreasing life span and numerous problems, for instance diabetes mellitus, insulin resistance and hypertension. The present invention thus fulfils a long-felt need for a drug that will reduce total body weight, or the amount of adipose tissue, of preferably obese humans, towards their ideal body weight without significant adverse side effects. The compounds according to formula (I) may also be used for the prevention and/or treatment of amyloidos-related diseases. Amyloidos-related conditions or diseases associated with deposition of amyloid, preferably as a consequence of fibR1l or plaque formation, includes Alzheimer's disease or dementia, Parkinson's disease, amyotropic lateral sclerosis, the spongiform encephalopathies, such as Creutzfeld- Jacob disease, cystic fibrosis, pR1mary or secondary renal amyloidoses, IgA nephropathy, and amyloid depostion in arteR1es, myocardium and neutral tissue. These diseases can be sporadic, inheR1ted or even related to infections such as TBC or HIV, and are often manifested only late in life even if inheR1ted forms may appear much earlier. Each disease is associated with a particular protein or aggregates of these proteins are thought to be the direct oR1gin of the pathological conditions associated with the disease. The treatment of a amyloidos-related disease can be made either acutely or chronically. The compounds of formula (I) may also be used for the treatment due to reduction of amyloid aggregates, prevention of misfolding of proteins that may lead to formation of so called fibR1ls or plaque, treatment due to decreasing of the production of precursor protein such as Ap-protein (amyloid beta protein), and prevention and/or treatment due to inhibiting or slow down the formation of protein fibR1ls, aggregates, or plaque. Prevention of fibR1l accumulation, or formation, by administeR1ng compounds of formula (I), as hereinbefore defined, is also included herein. In one embodiment, the novel compounds, pharmaceutically acceptable salts, solvates, complexes or pro-drugs thereof, as hereinbefore defined, are used for the treatment of TBC (tuberculosis) or HIV (human immunodeficiency virus). Further, the compounds of formula (I) may be administered to patients with symptoms of atherosclerosis of arteR1es supplying the brain, for instance a stroke or transient ischaemic attack, in order to reduce the R1sk of a further, possible fatal, attack. The compounds of formula (I) may also be used for the treatment of elevated blood lipids in humans. Additionally, the compounds of formula (I), as hereinbefore defined, are valuable for the treatment and prophylaxis of multiple R1sk factors known for cardiovascular diseases, such as hypertension, hypertR1glyceR1demia and high coagulation factor VII phospholipid complex activity. Preferably, the compounds of formula (I) is used for the treatment of elevated blood lipids in humans. The compounds of formula (I) and pharmaceutically acceptable salts, solvates, prodrugs or complexes thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the compounds of formula (I) (the active ingredient) are in association with a pharmaceutically acceptable adjuvant, diluent or carR1er. The present invention thus also provides a pharmaceutical composition compR1sing a therapeutically effective amount of the compound of formula (I) of the present invention and a pharmaceutically acceptable carR1er, diluent or excipients (including combinations thereof). This is a composition that compR1ses or consists of a therapeutically effective amount of a pharmaceutically active agent. It preferably includes a pharmaceutically acceptable carR1er, diluent or excipients (including combinations thereof). Acceptable carR1ers or diluents for therapeutic use are well known in the pharmaceutical art. The choice of pharmaceutical carR1er, excipient or diluent can be selected with regard to the intended route of administration and standard pharmaceutical practice. The pharmaceutical compositions may compR1se as - or in addition to - the carR1er, excipient or diluent any suitable binder(s), lubR1cant(s), suspending agent(s), coating agent(s), solubilising agent(s). Pharmaceutical compositions within the scope of the present invention may include one or more of the following: preserving agents, solubilising agents, stabilising agents, s wetting agents, emulsifiers, sweeteners, colourants, flavouR1ng agents, odourants, salts compounds of the present invention may themselves be provided in the form of a pharmaceutically acceptable salt), buffers, coating agents, antioxidants, suspending agents, adjuvants, excipients and diluents. A pharmaceutical composition according to the invention is preferably formulated for oral administration to a human or an animal. The pharmaceutical composition may also be formulated for administration through any other route where the active ingredients may be efficiently absorbed and utilized, e.g. intravenously, subcutaneously, intramuscularly, intranasally, rectally, vaginally or topically. In a specific embodiment of the invention, the pharmaceutical composition is shaped in form of a capsule, which could also be microcapsules generating a powder or a sachet. The capsule may be flavoured. This embodiment also includes a capsule wherein both the capsule and the encapsulated fatty acid composition according to the invention is flavoured. By flavouR1ng the capsule it becomes more attractive to the user. For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired a kd the disorder indicated. The pharmaceutical composition may be formulated to provide a daily dosage of 10 mg to 10 g. Preferably, the pharmaceutical composition is formulated to provide a daily dosage between 50 mg and 5 g of said composition. Most preferably, the pharmaceutical composition is formulated to provide a daily dosage between 100 mg and 1 g of said composition. By a daily dosage is meant the dosage per 24 hours. The dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. Typically, a physician will determine the actual dosage which will be most suitable for an individual subject. The specific dose level and frequency of dosage for any particular patient may be vaR1ed and will depend upon a vaR1ety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the seveR1ty of the particular condition, and the individual undergoing therapy. The agent and/or the pharmaceutical composition of the present invention may be administered in accordance with a regimen of from 1 to 10 times per day, such as once or twice per day. For oral and parenteral administration to human patients, the daily dosage level of the agent may be in single or divided doses. A further aspect of the present invention relates to a fatty acid composition compR1sing compounds of formula (I). A fatty acid composition compR1sing compounds of formula (I) increases the natural biological effects of DHA that are a result of regulation of gene expression, and the deR1vatives according to the present invention will accumulate in the free fatty acid pool. The fatty acid composition may compR1se in the range of 60 to 100 % by weight of the compounds of formula (I), all percentages by weight being based on the total weight of the fatty acid composition. In a preferred embodiment of the invention, at least 80% by weight of the fatty acid composition is compR1sed of compounds of formula (I). More preferably, the compounds of formula (1) constitute at least 90% by weight of the fatty acid composifion. Most preferably, the compounds of formula (I) constitutes more than 95% by weight of the fatty acid composition. The fatty acid composition may further compR1se at least one of the fatty acids (all-Z)-5,8,11,14,17-eicosapentaenoic acid (EPA), (all-Z)-4,7,10,13,16,19- docosahexaenoic acid (DHA), (all-Z)-6,9, 12,15, 18-heneicosapentaenoic acid (HPA), and (all-Z)-7,10,13,16,19-docosapentaenoic acid (DPAn-3), (all-Z)-8,l 1,14,17- eicosatetraenoic acid (ETAn-3), or combinations thereof. Further, the fatty acid composition may compR1se (all-Z)-4,7, 10,13,16-Docosapentaenoic acid (DPAn-6) and/or (all-Z)-5,8,l 1,14-eicosatetraenoic acid (ARA), or deR1vatives thereof The fatty acid composition may also compR1se at least these fatty acids, or combinations thereof, in the form of deR1vatives. The deR1vatives are suitably substituted in the same way as the DHA deR1vatives of formula (I), as hereinbefore defined. The fatty acid composition according to the invention may compR1se (all-Z omega-3)-6, 9, 12, 15, 18-heneicosapentaenoic acid (HPA), or deR1vatives thereof, in an amount of at least 1% by weight, or in an amount of 1 to 4% by weight. Further, the fatty acid composition according to the invention may compR1se omega-3 fatty acids other than EPA and DHA that have 20, 21, or 22 carbon atoms, or deR1vatives thereof, in an amount of at least 1.5% by weight, or in an amount of at least 3% by weight. In specific embodiments of the invention, the fatty acid composition is a pharmaceutical composition, a nutR1tional composition or a dietary composition. The fatty acid composition may further compR1se an effective amount of a pharmaceutically acceptable antioxidant. Preferably, the antioxidant is tocopherol or a mixture of tocopherlos. In a preferred embodiment the fatty acid composition further compR1ses tocopherol, or a mixture of tocopherols, in an amount of up to 4 mg per g of the total weight of the fatty acid composition. Preferably, the fatty acid composition compR1ses an amount of 0.2 to 0.4 mg per g of tocopherols, based on the total weight of the composition. Another aspect of the invention provides a fatty acid composition, or any pharmaceutically acceptable salt, solvate, pro-drug or complex thereof, compR1sing compounds of formula (I), as hereinbefore defined, for use as a medicament and/or in therapy. Such a fatty acid composition may be used to prevent and/or treat the same conditions as outlined for the compounds of formula (I) above. When the fatty acid composition is used as a medicament, it will be administered in a therapeutically or a pharmaceutically active amount. In a preferred embodiment, the fatty acid composition is administered orally to a human or an animal. The present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, pro-drug or complex thereof, as hereinbefore defined, for the manufacture of a medicament for controlling body weight reduction and/or for preventing body weight gain; for the manufacture of a medicament for the treatment and/or the prevention of obesity or an overweight condition; for the manufacture of a medicament for the prevention and/or treatment of diabetes in a human or animal; for the manufacture of a medicament for the treatment and/or prevention of amyloidos-related diseases; for the manufacture of a medicament for the treatment and prophylaxis of multiple R1sk factors known for cardiovascular diseases, such as hypertension, hypertR1glyceR1demia and high coagulation factor VII phospholipid complex activity; for the manufacture of a medicament for the treatment of TBC or HIV; for the manufacture of a medicament for prevention of stroke, cerebral or transient ischaemic attacks related to atherosclerosis of several arteR1es; for the manufactuR1ng of a medicament for loweR1ng tR1glyceR1des in the blood of mammals and/or evelating the HDL cholesterol levels in the serum of a human patients; or for the manufactuR1ng of a medicament for the treatment and/or prevention of the multi metabolic syndrome termed "metabolic syndrome". All these embodiments also include the use of a fatty acid composition, as hereinbefore defined, compR1sing compounds of formula (I) for the manufacture of medicaments as outlined above. The present invention further relates to the use of alpha-hydroxy-DHA for the manufacture of medicaments as outlined above. The present invention also relates to a method for controlling body weight reduction and for preventing body weight gain, wherein a fatty acid composition compR1sing at least a compound of formula (I), as hereinbefore defined, is administered to a human or an animal. Further, the invention relates to a method for the treatment and/or the prevention of obesity or an overweight condition, wherein a fatty acid composition compR1sing at least a compound of formula (I), as hereinbefore defined, is administered to a human or an animal. In a preferred embodiment of the invention, the present invention relates to a method for the prevenfion and/or treatment of diabetes mellitus, wherein a fatty acid composifion compR1sing at least a compound of formula (I), as hereinbefore defined, is administered to a human or an animal. Preferably, diabetes mellitus is a type 2 diabetes. Other aspects of the present invention relate to; -a method for the treatment and/or prevention of amyloidos-related diseases; -a method for the treatment or prophylaxis of multiple R1sk factors for cardiovascular diseases; -a method for prevention of stroke, cerebral or transient ischaemic attacks related to atherosclerosis of several arteR1es; wherein a fatty acid composition compR1sing at least a compound of formula (I), as hereinbefore defined, is administered to a human or an animal. The fatty acid deR1vatives of formula (I) may be prepared most effectively from DHA. If the start mateR1al is not pure DHA (i.e. not 100% DHA) the final fatty acid composition will contain a mixture of DHA deR1vatives, as hereinbefore defined, and an amount of other fatty acids than DHA, wherein these fatty acids are substituted in the same way as the novel fatty acid analogous of formula (I). Such embodiments are also included herein. In another embodiment of the invention, the compounds of formula (I) are prepared from (all-Z)-4,7, 10,13, 16,19-docosahexaenoic acid (DHA), wherein said DHA is obtained from a vegetable, a microbial and/or an animal source, or combinations thereof. Preferably, said DHA is obtained from a maR1ne oil, such as a fish oil. The fatty acids in the composition may also be obtained from a vegetable, a microbial or an animal source, or combinations thereof. Thus, the invention also includes a fatty acid composition prepared from a microbial oil. The present invention provides processes for prepaR1ng novel fatty acid analogous of formula (I), as hereinbefore defined. DHA is produced from biological sources like maR1ne, microbial or vegetable fats. All possible raw mateR1als are mixtures of fatty acids on tR1glyceR1de form where DHA constitutes only a fraction of the fatty acids. Typical DHA concentrations are 40% in microbial fats and 10-25% in maR1ne fats. DHA-containing vegetable fats are duR1ng development and fats with high DHA concentrations are expected in the future. The first process step will always be conversion of the tR1glyceR1des to free fatty acids or monoesters. Preferable esters are methyl or ethyl esters, but other esters are possible. In this way the fatty acids bound together three by three on tR1glyceR1des are separated from each other and thereby making separation possible. Several methods of separating DHA from other fatty acids are available, the most common ones being short path distillation separating the fatty acids by volatility, and urea precipitation separating the fatty acids by degree of unsaturation. Other methods reported are silver nitrate complexation also separating the fatty acids on degree on unsaturation, esteR1fication reactions catalysed by fatty acid selective lipases in combination with short path distillation and countercurrent extraction with supercR1tical carbon dioxide. The most important challenges connected to production of pure DHA is to separate it from the other C20-22 highly unsaturated fatty acids present in all available sources. These fatty acids have properties so similar to DHA that none of the methods mentioned above provide sufficient degree of separation. For some microbial high DHA fats, which have very low levels of C20-22 highly unsaturated fatty acids, short path distillation alone or in combination of other methods mentioned may provide more that 90% puR1ty. Most DHA containing fats also contain considerable amounts of C20-22 highly unsaturated fatty acids, e.g. EPA (20:5n-3), n-3DPA (22:5n-3), HPA (21 :5n-3) and others. The only available method for separating DHA from such fatty acids is preparative High Performance Liquid Chromatography, the stationary phase being silica gel or silver nitrate impregnated silica gel, the mobile phase being selected organic solvents or supercR1tical carbon dioxide. With this method DHA with more than 97% puR1ty is available. However, it has to be noted that the production costs increases strongly with concentration, as an example is production cost for 97% DHA more 5 times higher than for 90% DHA. DHA having a puR1ty of 90, 95 eller 97% contains small amounts of other fatty acids. As an example, DHA having a puR1ty of 97% contains n-3DPA (22:5n-3), but also long chain fatty acids, e.g. EPA (20:5n-3), HPA (21:5n-3), and others. However, the other fatty acids will react in a way similar to DHA and provide alpha-substituted deR1vatives. Organic synthesis may provide a puR1fication method since DHA and n-6DP A (and 22:5n-6 which normally is present in very low concentrations) are the only known fatty acids that can provide gamma-lactones by cyclisation with the first double bond. Lactonisation followed by puR1fication and hydrolysis back to DHA may be a possibility, but it is expected that this pathway is even more expensive than HPLC. In one embodiment, the compounds of formula (I) where R1 (or R2) is a hydrogen are prepared through the following processes (Scheme 1). Suitably adapted, these processes can alsoe be used for prepaR1ng compounds represented by the general formula (I) where both R1 and R2 are e.g. a C1-C7 alkyl group, a benzyl, a halogen, a benzyl, an alkenyl, or an alkynyl. Compounds represented by the general formula (I) where R1 is a hydrogen and R2 denotes a C1-C7 alkyl group, a benzyl, a halogen, a benzyl, an alkenyl, an alkynyl are prepared by reacting a DHA ester with a strong non-nucleophilic base like lithium diisopropylamine or potassium/sodium hexamethyldisilazideane in a solvent such as tetrahydrofuran, diethylether at temperatures of —60 to —78 ^C, to provide the ester enolate (process 1). This ester enolate is reacted with an electrophilic reagent like an alkylhalide exemplified by ethyliodine, benzylcloR1de, an acyl halide exemplified by acetyl chloR1de, benzoyl bromide, a carboxylic anhydR1de exemplified by acetic anhydR1de or a electrophilic halogenation reagent exemplified by N-fluorobenzene sulfonimide (NFSI), etc. to provide the monosubstitued deR1vative (process 2). The ester is further hydrolysed in a solvent like ethanol or methanol to the carboxylic acid deR1vative by addition of a base like lithium/sodium hydroxide in water at temperatures between 15-40 °C. Claisen condensation of the DHA EE occurs duR1ng the treatment of DHA EE with a strong base. This condensation product might possess interesting biologically activity. Thus, in one embodiment of the invention the condensation (intermediate) product mentioned above, as well as the use of this product for treatment and/or prevention of diseases according to the present invention, are disclosed. In a further embodiment, compounds represented by the general formula (I) are synthesised through following processes (Scheme 2). (Scheme 2) Compounds represented by the general formula (I) where R1 is a hydrogen and R2 denotes a hydroxy, an alkoxy group, an acyloxy are prepared by reacting a DHA ester with a strong non-nucleophilic base like lithium diisopropylamine or potassium/sodium hexamethyldisilazideane in a solvent such as tetrahydrofuran, diethylether at temperatures of -60 to -78 ^Cs to provide the ester enolate (process 4). This ester enolate is reacted with an oxygen source like dimethyldioxirane, 2- (phenylsulfonyl)-3-phenyloxaziR1dine, molecular oxygen with different additives like tR1methylphosphite or different catalysts like a Ni(II) complex to provide alpha- hydroxy DHA ester(process 5). Reaction of the secondary alcohol with a base like sodiumhydR1de in a solvent like THF or DMF generates an alkoxide that is reacted with different electrophilic reagents as alkyliodide for example; methyl iodide, ethyl iodide, benzylbromide or an acyl halide, for example; acetyl chloR1de, benzoyl bromide (process 6). The ester is hydrolysed in a solvent like ethanol or methanol to the carboxylic acid deR1vative by addition of a base like lithium/sodium hydroxide in water at temperatures between 15-40 °C (process 7). The hydroxy-DHA ester is a useful intermediate for the introduction of other functional groups in the a-position according to the invention. The hydroxyl function can be activated by conversion to a halide or tosylate pR1or to reaction with different nucleophiles like ammonia, amines, thiols, etc. The Mitsunobu reaction is also useful for the conversion of a hydroxylgroup into other functional groups. (Mitsunobu, O, Synthesis, 1981, 1). Compounds represented by the general formula (I), as hereinbefore defined, can also be synthesised by combinations of the different processes previously descR1bed. The present invention includes the processes mentioned above. The invention further provides a process for the preparation of a pharmaceutical composition of the invention, with compR1ses mixing of at least a compound of formula (I), or a pharmaceutically acceptable salt, solvate, complex or pro-drug thereof, as hereinbefore defined, with a pharmaceutically acceptable adjuvant, diluent or a carR1er. The enantiomeR1c pure compounds can be prepared by resolving a racemic compound of formula (I), as hereinbefore defined. The resolution of a compound of formula (I) may be carR1ed out using known resolution procedures, for example by reacting the compound of formula (I) with an enantiomeR1cally pure auxiliary to provide a mixture of diastereomers that can be separated by chromatography. Thereafter the two enantiomers of compound (I) may be regenerated from the separated diastereomers by conventional means, such as hydrolysis. There is also a possibility to use stochiometR1c chiral auxiliaR1es to effect an asymmetR1cintroduction of the substituents, as hereinbefore defined, in the a-position of DHA. The use of chiral oxazolidin-2-ones has proved to be a particularly effective methodology. The enolates deR1ved from chiral iV-acyloxazolidines can be quenched with a vaR1ety of electrophiles in a highly stereoregulated manner (Ager, Prakash, Schaadl996). The technology of the instant Application is further elaborated with the help of following examples. However, the examples should not be construed to limit the scope of the invention. Examples In the examples the structures were veR1fied by Mass Spectrometry (MS). It should be pointed out that the fatty acid deR1vatives may also be produced from low and medium DHA- containing starting mateR1al (i.e. about 40-60 w% DHA). Synthesis protocols Preparation of g-methyl DHA EE TPRB-I) Butyllithium (228 ml, 0.37 mol, 1.6 M in hexane) was added drop wise to a stirred solution of diisopropylamine (59.5 ml, 0.42 mol) in dry THF (800 ml) under N2 at 0 ^C. The resulting solution was stirred at 0 ^C for 30 min., cooled to -78 ^C and stirred an additional 30 min. before drop wise addition of DHA EE (100 g, 0.28 mol) in dry THF (500 ml) duR1ng 2 h. The dark-green solution was stirred at -78 °C for 30 min. before Mel (28 ml, 0.45mol) was added. The solution was allowed to reach -20 ^C duR1ng 1.5 h, then poured into water (1.5 1) and extracted with heptane (2 x 800 ml). The combined organic phases were washed with 1 M HCl (11), dR1ed (Na2S04), filtered and evaporated in vacuo. The product was puR1fied by dry flash chromatography on silica gel eluting with heptane/ EtOAc (99:1) to give 50 g (48%) of the titled compound as a slightly yellow oil; ^H-NMR (200MHz, CDCI3) 8 1.02 (t, J 7.5 Hz, 3H), 1.20 (d, J6.8 Hz, 3H), 1.29 (t, J 7.1 Hz, 3H), 2.0-2.6 (m, 5H), 2.8-3.0 (m, lOH), 4.17 (t, J 7.1 Hz, 2H), 5.3- 5.5 (m, 12H); MS (electrospray); 393 [M+Na]. Preparation of a-ethyl DHA EE (TRB-2) Butyllithium (440 ml, 0.67 mol, 1.6 M in hexane) was added drop wise to a stirred solution of diisopropylamine (111 ml, 0.78 mol) in dry THF (750 ml) under N2 at 0 ^C. The resuhing solution was stirred at -78 °C for 45 min. before dropwise addition of DHA EE (200 g, 0.56 mol) in dry THF (1.6 1). The addition of the ester was complete in 4 hours. The dark-green solution was stirred at -78 ^C for 30 min. before EtI (65 ml, 0.81 mol) was added. The solution was allowed to reach -40 ^C before an additional amount of EtI (5 ml, 0.06 mol) was added, and finally reach -15 °C (duR1ng 3 hours from -78 ^C) before the mixture was poured into water and extracted with hexane (2x). The combined organic phases were washed with 1 M HCl, water. dR1ed (Na2S04), filtered and evaporated in vacuo. The product was puR1fied by flash chromatography on silica gel eluting with heptane/EtOAc (99:1 followed by 50:1) to give 42.2 g (20%) of the titled compound as a yellow oil; 'H-NMR (200 MHz; CDCI3) 5 0.8-1.0 (m, 6H), 1.2-1.4 (m, 4H), 1.5-1.7 (m, 2H), 2.12 (m, 2H), 2.3-2.5 (m, 2H), 2.8-3.0 (m, lOH), 4.18 (t, J7.1 Hz, 2H)3 5.3-5.6 (m, 12H); MS (electrospray); 407 [M+Na]. Preparation of a-ethoxv-DHA ethvlester (PRB-3) To a suspension of 60 % NaH (84.1 mg, 2.1 mmol) in THF, 5 mL, at -78°C under N2-atmosphere was added drop wise a solution of a-hydroxy-DHA ethyl ester (PRB-12) (372 mg, 1.00 mmol) in THF, 5 mL, the resulting mixture was stirred at - 78^C for 20 minutes before ethyl iodide (0.24 mL, 3.01 mmol) was added drop wise. The reaction mixture was gradually warmed to room temperature over night. Saturated aqueous NH4CI, 15 mL, was added and the mixture was extracted with diethyl ether, 25 mL x 2, the organic phase was washed with bR1ne, 25 mL, dR1ed (Na2S04) filtered, evaporated in vacuo and subjected to flash chromatography on silica gel eluting with heptane/EtOAc (95:5) to yield 68 mg (17 %) of the product as a yellow liquid. ^H NMR (200 MHz, CDCI3) 5 0.94 (t, J=7.5 Hz, 3H), 1.16-1.29 (m, 6H), 2.05 (quint, J=7.2 Hz, 2H), 2.50 (m, 2H), 2.76-2.84 (m, lOH), 3.33-3.48 (m, IH), 3.53- 3.71 (m, IH), 3.83 (dd, J=6.8 Hz, J=6.2 Hz, IH), 4.18 (q, J=I. \ Hz, 2H), 5.31-5.45 (m, 12 H) ^^C NMR (50 MHz, CDCI3) 8 14.2, 15.1, 20.5, 25.5, 25.6, 25.7, 31.0, 60.8, 66.0, 78.7, 124.1, 127.0, 127.8, 127.9, 128.0 (2 signals), 128.2 (2 signals), 128.5, 130.7, 132.0, 172.5 (3 signals hidden) MS (electrospray); 423 [M+Na]^ Preparation of g-fluoro DHA EE fPRB-4) LDA (2.1 ml, 4.2 mol, 2 M in THF/heptane/ ethylbenzene) in dry THF (10 ml) under N2 at -78 V was drop wise added DHA EE (1 g, 2.8 mmol) in dry THF (30 ml) duR1ng 15 min. NFSi (1.06 g, 3.4 mmol) was then added. The solution was allowed to reach RT and stirred for 70 hours. The mixture was poured into water and extracted with hexane (2x). The combined organic phases were washed with 1 M HCl, water, dR1ed (Na2S04), filtered and evaporated in vacuo; MS (electrospray); 397 [M+Na], Preparation of a,a-dimethvl DHA EE (PRB-5) Butyllithium (100 ml, 0.17 mol, 1.6 M in hexane) was added drop wise to a stirred solution of diisopropylamine (28 ml, 0.20 mol) in dry THF (100 ml) under N2 at 0 ^C. The resulting solution was stirred at 0 ^C for 30 min., cooled to -78 ^C and drop wise added a solution of DHA EE (50 g, 0.14 mol) in dry THF (200 ml). The resulting dark-green solution was stirred at -78 °C for 30 min. before Mel (17 ml, 0.28 mol) was added. The solution was allowed to reach -10 ^C, then poured into water and extracted with hexane (2x). The combined organic phases were washed with 1 M HCl, dR1ed (Na2S04), filtered and evaporated in vacuo. The procedure was repeated, but the crude product of a-methyl DHA EE was used instead of DHA EE. The product was puR1fied by dry flash chromatography on silica gel eluting with heptane/EtO Ac (99:1 followed by 98:2) to give- 31.6 g (59%) of the titled compound as a slightly yellow oil; ^H-NMR (200 MHz; CDCI3) 8 1.01 (t, J7.5 Hz, 3H), 1.21 (s, 6H), 1.28 (t, J 7.1 Hz, 3H), 2.08 (m, 2H), 2.34 (d, J 6.8 Hz, 2H), 2.8-3.0 (m, lOH), 4.15 (q, J7.5 Hzs 2H), 5.3-5.6 (m, 12H); '^C-NMR (50 MHz; CDCI3) 5 14.7, 21.0, 25.3, 26.0, 26.1, 38.3, 42.8, 60.7, 125.8, 127.4, 128.3, 128.5, 128.6, 128.7, 129.0, 130.7, 132.4, 177.9; MS (electrospray); 385 [M+H]. Preparation of g-thiomethyl DHA (PRB-6) a-Iodo DHA EE (0.5 g, 1.04 mmol) dissolved in 20 mL THF at O^C under N2. MeSNa (80 mg, 1.14 mmol) was added the reaction and the mixture was allowed to stir for a few minutes before it was diluted with heptane. The organic phase was washed with water (2x) dR1ed (Na2S04) and evaporated in vacuo. The desired product was was isolated by flash chromatography Heptan/EtOAc (30:1) to give a-thiomethyl DHA EE as a pale yellow oil. The a-thiomethyl DHA EE was dissolved in 10 mL EtOH and 10 mL THF. The solution was added LiOH (0.39 g, 9.2 mmol) dissolved in 5 mL water. The reaction mixture was allowed to stir overnight at RT, before diluting with water and heptane. The organic fraction was extracted with IM LiOH (2x) and the combined aqueous phases was acidified with 5M HCl and extracted with diethyl ether (2x). The combined organic phases was washed with bR1ne, water, dR1ed (Na2S04) and evaporated in vacuo to give 183 mg (47 %) of the title compound as a pale yellow oil; 'H-NMR (200MHZ, CDCI3) 5 0.98 (t, J 6.6Hz, 3H), 1.95-2.65 (m, 7H), 2.72- 3.05 (m, lOH), 3.12-3.43 (m, IH), 5.20-5.70 (m, 12H), 10.65 (br s, IH); ^^H-NMR (50MHz, CDCI3) 8 14.7, 21.0, 25.9, 26.0, 26.2, 28.8, 125.4, 127.4, 128,1, 128.3, 128.4, 128.7, 128.9, 129.0, 131.6, 132.4, 177.0. Preparation of g-thioethvl DHA EE nPRB-7) a-Iodo DHA EE (11 g, 23 mmol) dissolved in 100 mL THF under N2 at O^C. EtSNa (2.1 g, 25 mmol) was added the solution and was allowed to stir for 1 hour at 0°C. The reaction was quenched with IM HCl and diluted with Heptan. The organic phase was washed with water (2x), dR1ed (Na2S04) and evaporated in vacuo. The desired product was isolated by flash chromatography Heptan/EtOAc (30:1) to give 7.3 g (76 %) of the title compound as a pale yellow oil; 'H-NMR (200MHz, CDCI3) 8 1.1-1.3 (m, 9H), 2.05 (m, 2H), 2.3-2.7 (m, 4H), 2.7-2.9 (m, lOH), 3.25 (m, IH), 4.17 (q, J7.1 Hz, 2H), 5.3-5.5 (m, 12H); MS (electrospray): 439 [M+Na]. Preparation of a,a-diethvl DHA EE (PRB-8) Butyllithium (38.6 ml, 0.62 mol, 1.6 M in hexane) was added drop wise to a stirred solution of diisopropylamine (9.1 ml, 0.65 mol) in dry THF (200 ml) under N2 at O^C. The resulting solution was stirred at O^C for 30 min., cooled to -78^C and drop wise added a solution of DHA EE (20.0 g, 0.56 mol) in dry THF (100 ml). The resulting dark-green solution was stirred at -78°C for 30 min., before EtI (6.8 ml, 0.84 mol) was added. The solution was allowed to reach -lO^C, then poured into water and extracted with hexane (2x). The combined organic phases were washed with 1 M HCl, dR1ed (Na2S04), filtered and evaporated in vacuo. The procedure was repeated, but the crude product of a-ethyl DHA EE was used instead of DHA EE. The reaction mixture after addition of EtI was allowed to reach ambient temperature and was stirred over night. The product was puR1fied by dry flash chromatography on silica gel eluting with heptane/EtOAc (99:1 followed by 98:2) to give 10.0 g (43%) of the titled compound as a slightly yellow oil; H-NMR (200 MHz; CDCI3) 8 0.83 (t, J 7.4 Hz, 6H), 0.94 (t, J 5.8 Hz, 3H), 1.28 (t, J 7.1 Hz, 3H), 1.63 (q, J 7.4 Hzs 4H), 2.10 (m, 2H), 2.34 (d, J 6.9 Hz, 2H), 2.8-3.0 (m, lOH), 4.15 (q, J7.5 Hz, 2H), 5.3-5.6 (m, 12H); ^^C-NMR (50 MHz; CDCI3) 6 8.9, 14.7, 21.0, 23.1, 25.9, 26.0, 26.2, 27.4, 31.2, 50.1, 60.6, 125.5, 127.4, 128.3, 128.6, 128.9, 130.5, 132.4, 177.1; MS (electrospray); 413.3 [M+H], 435.3 [M+Na]. Preparation of a-benzvl DHA EE (PRB-9) To a stirred solution of diisopropyl amine (0.91 mL, 6.46 mmol) in dry THF (20 mL) under inert atmosphere held at OV was added drop wise n-BuLi (1.6 M in hexanes, 3.86 mL, 6.18 mmol). The mixture was stirred at 0°C for 30 minutes, given - 78^ and stirred at this temperature for five minutes. DHA EE (2.0 g, 5.62 mmol) in dry THF (10 mL) was added drop wise and the mixture was stirred at -78°C for 20 minutes, then benzyl bromide (0.80 mL, 6.74 mmol) was added. The resuking solution was allowed to reach 0^C over three hours, portioned between water (100 mL) and heptane (100 mL). The aqueous layer was extracted with heptane (50 mL) and the combined organic layer was washed with IM HCl and dR1ed (Na2S04). Concentration under reduced pressure and puR1fication by flash chromatography (Heptane : EtOAc 99: 1) afforded 1.05 g (42%) of the title compound as a colorless oil; 'H-NMR (200 MHz, CDCI3): 5 0.99 (t, 3H), 1.18 (t, 3H), 2.08-2.16 (m, 2H), 2.35-2.42 (m, 2H), 2.74-2.98 (m, 13H), 4.09 (q, 4H), 5.38-5.50 (m, lOH), 7.19-7.36 (m, 5H); '^C-NMR (50 MHz, CDCI3): 5 14.61, 14.71, 20.99, 25.98, 26.07, 30.07, 38.32, 48.02, 60.88, 126.75, 126.83, 127.46, 128.31, 128.45, 128.53, 128.58, 128.86, 128.77, 129.01, 129.35, 130.55, 132.46, 138.89, 175.39. MS (electrospray): 447.3 [M+H], 469.3 [M+Na]. Preparation of g-ethanesulfmvl DHA EE fPRB-10) To a solution of a-thioethyl DHA EE (0.5 g, 1.3 mmol) in 15 mL CHCI3 held at -20 ^C under inert atmosphere was added a solution of MCPBA (0.22 g, 1.3 mmol) in 10 mL CHCI3. The reaction mixture was stirred for 2h at this temperature, filtered and washed with a saturated aqueous solution OfNaHCOs. The aqueous phase was extracted twice with CHCI3 and the combined organic phase was washed with water and bR1ne, dR1ed with Na2S04, filtered and concentrated. The product was isolated from residual mateR1al after flash chromatography using hexane: EtOAc 8:2 to afford 0.35 g (70%) of the title compound. ^HNMR (200 MHz, CDCI3): 8 0.99 (t, 3H), 1.27-1.45 (m, 6H), 2.09 (m, 2H), 2.79-2.94 (m, 14H), 3.55 (m, IH), 4.25 (q, 2H), 5.37-5.59 (m, 12H). '^C NMR (50 MHZ5 CDCI3): 5 7.97, 14.58, 14.68, 20.95, 23.68, 25.17, 25.93, 26.04, 44.20, 45.15, 62.30, 64.08, 123.91, 124.47, 127.41, 127.86, 128.26, 128.40, 128.44, 128.72, 128.72, 128.96, 129.12, 132.42, 132.47, 174.55. MS (electrospray): 455.3 [M+Na]. Preparation of a-thiophenvI-DHA ethvlester (PRB-ll) To a solution of a-iodo-DHA ethylester (PRB-15) (3.40 g, 7.05 mmol) in acetone, 20 mL, a solution of sodium phenyl sulfide (1.039 g, 7.86.mmol) in acetone, 110 mL, was added drop wise. The resulting mixture was stirred at ambient temperature for 1 Vz hrs, evaporated in vacuo and subjected to flash chromatography on silica gel eluting with heptane/EtOAc 200:1 - 95:5 to yield 2.35 g (72 %) of the product as a yellow liquid. 'H NMR (200 MHz, CDCI3) 8 0.97 (t, J=7.5 Hz, 3H), 1.18 (t, J=7.1 Hz, 3H)5 2.09 (quint, J=7.1 Hz, 2H), 2.54-2.66 (m, 2H), 2.83-2.86 (m, 10 H), 3.67 (dd, J=6.8 Hz, J=8.3 Hz, 1 H), 4.12 (q, J=7.1 Hz, 2H), 5.24-5.49 (m, 12 H), 7.28-7.33 (m, 3H), 7.46- 7.50 (m, 2H) '^C NMR (50 MHz, CDCI3) 8 14.0, 14.2, 20.5, 25.5, 25.6, 25.7, 29.4, 50.6, 61.1, 125.1, 127.0, 127.7, 127.9, 128.0, 128.3, 128.42, 128.45, 128.9, 131.2, 132.0, 133.0, 133.2, 174.1 (5 signals hidden) MS (electrospray); 465 [M+H]^ 487 [M+Na]^ HRMS (EI) calculated for C30H40O2S: 464.2749, found: 464.2741 Preparation of g-hydroxv-DHA ethvlester (PRB-12) To a solution of diisopropyl amine (19.76 mL, 140 mmol) in dry THF, 40 mL, under Na-atmosphere at -78°C was added drop wise 1.6 M BuLi in hexane (87.5 mL, 140 mmol). The resulting mixture was stirred at -78°C for 15 minutes before a solution of DHA ethylester (24.99 g, 70.1 mmol) in THF, 80 mL, was added drop wise. The resulting dark green reaction mixture was stirred for 1 hour at -78^C before tR1ethylphosphite (12.2 mL, 70.1 mmol) was added drop wise and then O2 was bubbled through the reaction mixture over night while the reaction mixture was kept at -78^C for 5 hrs and then slowly warmed to room temperature. Saturated aqueous NaHCOa, 100 mL, was added and the mixture was extracted with diethyl ether, 200 niL x 2. The organic phase was dR1ed (Na2S04), filtered and evaporated in vacuo and subjected to flash chromatography on silica gel eluting with heptane/EtOAc 99:1 - 95:5 to yield 4.52 g (17 %) of the product as a yellow liquid. ^H NMR (200 MHz, CDCI3) 8 0.92 (t, J=7.5 Hz, 3H), 1.24 (t, J=7.1 Hz, 3H), 5 2.02 (quint, J=7.1 Hz, 2H), 2.44-2.54 (m, 2H), 2.74-2.87 (m, 10 H), 4.13-4.24 (m, 3H), 5.25-5.94 (m, 12H) ^^C NMR (50 MHz, CDCI3) 8 14.0, 14.1, 20.4, 25.4, 25.5, 25.6, 32.0, 61.5, 69.9, 123.3, 126.9, 127.7, 127.9, 128.08, 128.1, 128.2, 128.4, 131.3, 131.8, 174.4 (4 signals hidden) 10 MS (electrospray); 395 [MH-Na]^ HRMS (ES) calculated for C24H3603Na: 395.2556, found: 395.2543 Preparation of g-methvl-DHA amide (PRB-13) A solution of a-methyl-DHA (PRB-I FA) (3.13 g, 9.1 mmol) and oxalyl chloR1de (8.0 mL, 94.5 mmol) in toluene, 90 mL, was added DMF, 0.1 mL, and the resulting mixture was stirred at ambient temperature under N2-atmosphere for 15 ^A 20 hours. The mixture was then evaporated in vacuo and the residue was dissolved in THE, 100 mL, cooled to O^C and aqueous NH3 (20 mL) was added drop wise. The ice-bath was removed and the mixture was stirred at ambient temperature for 4 hours, water, 50 mL, was added and the aqueous phase was extracted with diethyl ether, 2x100 mL. The organic phase was washed with saturated aqueous NH4CI, 50 mL, dR1ed (Na2S04), filtered and evaporated in vacuo and subjected to flash chromatography on silica gel eluting with CH2CI2/2M NH3 in MeOH 97.5:2.5 to yield 2.51 g (80 %) of the product as a yellow liquid. U NMR (200 MHz, CDCI3) 5 0.91 (t, J=7.5 Hz, 3H), 1.10 (d, J=9.8 Hz, 3H), 1.94-2.11 (m, 3H), 2.19-2.35 (m, 2H), 2.76-2.77 (m, 10 H), 5.18-5.45 (m, 12 H), 6.03 30 (s, IH), 6.72 (s, IH) ^^C NMR (50 MHz, CDCI3) 5 14.6, 17.6, 20.8, 25.8, 25.9, 32.0, 41.0, 127.3, 128.1, 128.4, 128.6, 128.8, 130.1, 132.2, 179.6 (8 signals hidden) MS (electrospray); 342 [M+H]^, 364 [M+Na]^ HRMS (EI) calculated for C23H35NO: 341.2719, found: 341.2707 Preparation of q-methoxy-DHA ethvlester (PRB-14) To a suspension of 60 % NaH (61.1 mg, 1.53 nimol) in THF, 5 mL, at -78°C under N2-atmosphere was added drop wise a solution of a-hydroxy-DHA ethyl ester (PRB-12) (373 mg, 1.00 mmol) in THF, 5 mL, the resulting mixture was stirred at - TS^'C for 20 minutes before methyl iodide (0.13 mL, 2.09 mmol) was added drop wise. The reaction mixture was gradually warmed to room temperature for 5 hrs. Saturated aqueous NH4CI, 15 mL, was added and the mixture was extracted with diethyl ether, 25 mL x 2, the organic phase was washed with bR1ne, 25 mL, dR1ed (Na2S04) filtered, evaporated in vacuo and subjected to flash chromatography on silica gel eluting with heptane/EtOAc 99:1 - 4:1 to yield 136 mg (35 %) of the product as a yellow liquid. 'H NMR (200 MHz, CDCI3) 8 0.92 (t, J=7.5 Hz, 3H), 1.24 (t, J=7.1 Hz, 3H), 2.03 (quint, J=7.3 Hz, 2 H), 2.48 (t, J=5.7 Hz, 2H), 2.73-2.82 (m, 10 H), 3.34 (s, 3H), 3.74 (t, J=6.2Hz, IH), 4.17 (q, J-7.1 Hz, 2 H), 5.24-5.43 (m, 12H) ^^C NMR (50 MHz, CDC13) 8 14.1, 20.4, 25.4, 25.5, 25.7, 30.6, 57.9, 60.9, 80.8, 123,7, 126.9, 127.71, 127.73, 127.92, 127.94, 128.07, 128.1, 128.2, 128.4, 130.7, 131.8, 171.9 (3 signals hidden) MS (electrospray); 409 [M+Na]^ ' HRMS (ES) calculated for CssHsgOsNa: 409.2713, found: 409.2711 Preparation of g-iodo DHA EE (PRB-15) Diisopropylamine ( 20 mL, 140 mmol) was dissolved in 150 mL THF under N2 at - 20°C. n-BuLi (88mL, 140 mmol, 1.6 M) was added drop wise to the mixture before the solution was cooled to -78^C. DHA EE (50 g, 140 mmol) in 250 mL THF was added dropwise to the solution and the reaction mixture was stirred for 30 min at RT. The resulting mixture was added dropwise to a solution of I2 (42.8 g, 169 mmol) in 400 mL THF under N2 at -78^C. The reaction was quenched with IM HCl and diluted with Heptan. The organic phase was washed with 10% Na2S203 (2x), dR1ed (Na2S04), filtered and evaporated in vacuo. The desired product was isolated by fiash chromatography Heptan/EtOAc (100:1) to give 11.0 g (16 %) of the title compound as a pale yellow oil; MS (Electrospray): 505 [M+Na]. Preparation of g-iodo-DHA ethvlester (PRB-15) To a solution of diisopropyl amine (42 mL, 298 mmol) in dry THF, 150 niL, under N2-atmosphere at -78 °C was added drop wise 1.6 M BuLi in hexane (158 mL, 253 mmol). The resulting mixture was stirred at -78°C for 35 minutes before a solution of DHA ethylester (75.05 g, 210 mmol) in THF, 300 mL, was added drop wise. The resulting dark green reaction mixture was stirred for 30 minutes at -78°C before a solution of I2 (91.06 g, 359 mmol) in THF, 200 mL was added drop wise. The reaction mixture was stirred at -78^C for 20 minutes before it was quenched with water, 200 mL, and extracted with heptane, 300 mL. The organic phase was washed with 1 M HCl, 150 mL, and water, 200 mL, dR1ed (Na2S04), filtered and evaporated in vacuo. The resulting crude product was subjected to flash chromatography on silica gel eluting with heptane/EtOAc (100:1) yielding 26.14 g (26%) of the product as a yellow liquid. 'H NMR (200 MHz, CDCI3) 5 0.94 (t, J=7.5 Hz, 3H), 1.24 (t, J=7.1 Hz, 3H), 2.04 (quint, J=7A Hzs 2H), 2.69-2.84 (m, 12 H), 4.17 (q, J=7.1 Hz, 2H), 4.22 (t, j=7.9 Hz, IH), 5.24-5.49 (m, 12 H) '^C NMR (50 MHz, CDCI3) 5 13.7, 14.2, 25.5, 26.0 (2 signals), 25.8, 34.0, 61.7, 126.1, 127.0, 127.4, 127.8, 127.9, 128.0, 128.2, 128.5, 128.5, 131.6, 131.9, 170.9 (4 signals hidden) MS (electrospray); 505 [M+Na]"" Preparation of a-amino-DHA etvlester (PRB-17) A solution of a-phtalimide-DHA ethylester (313.5 mg, 0.62 mmol) in EtOH, 5 mL, was added hydrazine hydrate (46 \|il, 0.95 mmol) and the resulting mixture was refluxed under N2-atmosphere for 15 'A hrs followed by evaporation in vacuo and flash chromatography on silica gel eluting with CH2Cl2:7M NH3 in MeOH (99:1- 95:1) to yield 149 mg (64 %) of the product as a yellow liquid. 'HNMR (200 MHz, CDCI3) 5 0.91 (t, J-7.5 Hz, 3H), 1.22 (t, J=7.1 Hz, 3H), 1.72 (bs, 2H), 2.02 (quint., J=7.2 Hz , 2H), 2.39-2.46 (m, 2H), 2.73-2.82 (m, 10 H), 3.47 (bs, IH), 4.13 (q, 2H)5 5.23-5.56 (m, 12 H) ^^C NMR (50 MHz5 CDCI3) 8 14.1, 20.4, 25.4, 25.5, 25.6, 54.1, 60.8, 124.4, 126.9, 127.7 (2 signals), 127.9, 128.2, 128.3, 128.4, 131.4, 131.9, 189.3 (6 signals hidden) MS (electrospray); 372 [M+H]"^ Preparation of (S)-r+)-a-ethvl DHA EE (PRB-20): Synthesis of intermediate PRB-18: DHA (3.00g, 18.3 mmol) was dissolved in dry CH2CI2 (120 mL) held at O^C under inert atmosphere and added DMAP (2.45 g, 20.1 mmol) and DCC (3.96 g, 19.2 mmol). The mixture was stirred at O^C for 20 minutes, added (4R,5S)-(+)-4-methyl-5- phenyl-2-oxazolidinone (3.24 g, 18.3 mmol) and stirred at ambient temperature for 20 hours. Filtration and puR1fication by flash chromatography (heptane : EtOAc 6:1) afforded 3.00 g (34%) of intermediate PRB-18 as a colorless oil. 'H-NMR (200 MHz5 CDCI3): 8 0.93-1.05 (t+d, 6H), 2.11 (m, 2H), 2.51 (m, 2H), 2.80-3.00 (m, lOH), 3.05 (m, 2H), 4.77 (m, IH), 5.34-5.68 (m,12H), 5.70 (d, IH), 7.28.7.32 (m,2H), 131-1 Al(m,3H). Synthesis of intermediate PRB-19: PRB-18 (1.80 g, 3.70 mmol) in dry THF (10 mL) was added drop wise to a solution of LiHMDS (IM in THF, 4.00 mL, 4,00 mmol) in dry THF (15 mL) held at - 78V under inert atmosphere. The mixture was stirred at -78^ for 30 minutes, added EtI (0.89 mL, 11.1 mmol) and slowly given OV over one hour. The mixture was then stirred at OV for 18 hours and portioned between saturated NH4CI (50 mL) and diethyl ether (50 mL). The aqueous layer was extracted with diethyl ether (50 mL) and the combined organic layer was washed with 0.1 M HCl (50 mL) and bR1ne (50 mL). Drying (Na2S04) and puR1fication by flash chromatography (heptane : EtOAc 95:5) afforded 0.52 g (27 %) of intermediate PRB- 19 as a colorless oil. 'H-NMR (200 MHz, CDCI3): 5 0.88-1.01 (m ,9H), 1.64-1.78 (m, 2H), 2.08 (m, 2H), 2.31 (m, IH), 2.48 (m, IH), 2.87 (m, lOH), 3.87 (m, IH), 4.75 (m, IH), 5.32 (m, 12H), 5.63 (d, J7.1 Hz, IH), 7.32 (m, 2H), 7.42 (m, 3H). '^C-NMR (50 MHz, CDCI3): 5 7.26, 11.75, 14.67, 14.98, 20.95, 25.57, 25.93, 26.04, 29.93, 44.59, 55.31, 79.10, 125.21, 126.01, 127.17, 127.42, 128.27, 128.50, 128.55, 128.67, 128.95, 129.09, 130.35, 132.42, 133.80, 153.18, 176.25. MS (electrospray): 538.2 [M+Na] PRB-19 (0.25 g, 0.485 mmol) was dissolved in abs EtOH (5 mL) and given 0°C under inert atmosphere. NaOEt (IM in EtOH, 0.54 mL, 0.54 mmol) was added and the mixture was stirred at 0°C for 30 minutes and portioned between water and heptane. The aqueous layer was extracted with heptane and the combined organic layer was washed with 0.1 M HCl and dR1ed. PuR1fication by flash chromatography afforded 0.025 g (13 %) of the title compound PRB-20 as a colorless oil. 'H-NMR (200 MHz; CDCI3) 8 0.8-1.0 (m, 6H), 1.2-1.4 (m, 4H), 1.5-1.7 (m. 2H), 2.12 (m, 2H), 2.3-2.5 (m, 2H), 2.8-3.0 (m, 10H)5 4.18 (t, 2H), 5.3-5.6 (m, 12H). MS (electrospray); 407 [M+Na]. [a]D+1.7° (c=1.5, ethanol). Preparation of flO-f-Va-ethvl DHA EE (PRB-23); Synthesis of intermediate PRB-21: DHA (l.OOg, 3.05 mmol) was dissolved in dry CH2CI2 (20 mL) held at O^C under inert atmosphere and added DMA? (0.41 g, 3.35 mmol) and DCC (0.66g, 3.20 mmol). The mixture was stirred at O^C for 20 minutes, added (4S,5R)-(-)-4-methyl-5- phenyl-2-oxazolidinone (0.54 g, 3.05 mmol) and stirred at ambient temperature for 20 hours. Filtration and puR1fication by flash chromatography (heptane : EtOAc 6:1) afforded 1.08 g (73%) of intermediate PRB-21 as a colorless oil. 'H-NMR (200 MHz, CDCI3): 5 0.93-1.05 (t+d, 6H), 2.11 (m, 2H)3 2.51 (m, 2H)5 2.80-3.00 (m, lOH), 3.05 (m, 2H)5 4.77 (m, IH)5 5.34-5.68 (m,12H), 5.70 (d, IH), 7.28.7.32 (m,2H), 131-1 Al(m,3H). Synthesis of intermediate PRB-22: PRB-21 (3.25g, 6.67 mmol) in dry THF (15 mL) was added drop wise to a solution of LiHMDS (IM in THF, 7.34 mL, 7,34 mmol) in dry THF (35 mL) held at 78^C under inert atmosphere. The mixture was stirred at -78^C for 30 minutes, added EtI (1.6 mL, 20.0 mmol) and slowly given O^C over one hour. The mixture was then stirred at O^C for 18 hours and portioned between saturated NH4CI (50 mL) and diethyl ether (50 mL). The aqueous layer was extracted with diethyl ether (50 mL) and the combined organic layer was washed with 0.1 M HCl (50 mL) and bR1ne (50 mL). Drying (Na2S04) and puR1fication by flash chromatography (heptane : EtOAc 95:5) afforded 1.50 g (44 %) of intermediate PRB-22 as a colorless oil. 'H-NMR (200 MHz, CDCI3): 5 0.88-1.01 (m ,9H), 1.64-1.78 (m, 2H), 2.08 (m, 2H), 2.31 (m, IH), 2.48 (m, IH), 2.87 (m, lOH), 3.87 (m, IH), 4.75 (m, IH), 5.32 (m, 12H), 5.63 (d, J7.1 Hz, IH), 7.32 (m, 2H), 7.42 (m, 3H). '^C-NMR (50 MHz, CDCI3): 5 7.26, 11.75, 14.67, 14.98, 20.95, 25.57, 25.93, 26.04, 29.93, 44.59, 55.31, 79.10, 125.21, 126.01, 127.17, 127.42, 128.27, 128.50, 128.55, 128.67, 128.95, 129.09, 130.35, 132.42, 133.80, 153.18, 176.25. MS (electrospray): 538.2 [M+Na] PRB-22 (0.25 g, 0.485 mmol) was dissolved in abs EtOH (5 mL) and given 0"C under inert atmosphere. NaOEt (IM in EtOH, 0.54 mL, 0.54 mmol) was added and the mixture was stirred at O^C for 30 minutes and portioned between water and heptane. The aqueous layer was extracted with heptane and the combined organic layer was washed with 0.1 M HCl and dR1ed. PuR1fication by flash chromatography afforded 0.025 g (13 %) of the title compound PRB-23 as a colorless oil. 'H-NMR (200 MHz; CDCI3) 5 0.8-1.0 (m, 6H), 1.2-1.4 (m, 4H), 1.5-1.7 (m, 2H), 2.12 (m, 2H), 2.3-2.5 (m, 2H), 2.8-3.0 (m, lOH), 4.18 (t, 2H)3 5.3-5.6 (m, 12H); MS (electrospray); 407 [M+Na]. [a]D -\3° (c=1.00, ethanol). Preparation of a-phtalimide-DHA ethvlester (PRB-24) A mixture of the a-hydroxy-DHA ethyl ester (PRB-12) (373.5 mg, 1.00 mmol), phtalimide (178 mg, 1.21 mmol) and tR1phenyl phosphine (313.9 mg, 1.20 mmol) in THF, 10 mL, was cooled to 0°C under Na-atmosphere before diisopropyl azodicarboxylate (0.24 mL, 1.24 mmol) was added drop wise. The ice-bath was removed and the reaction mixture was stirred at ambient temperature for 18 hrs, whereupon it was evaporated in vacuo and subjected to flash chromatography on silica gel eluting with heptane/EtOAc (99:1-95:1) to yield 323 mg (64 %) of the product as a yellow liquid. 'H NMR (200 MHz, CDCb) 5 0.95 (t, J=7.5 Hz, 3H), 1.22 (t, J=7.1 Hz, 3H), 2.05 (m, 2H), 2.72-2.84 (m, 1 IH), 3.02-3.22 (IH)5 4.20 (q, J=7.1 Hz, 2H), 4.87 (dd, J=I 1 Hz, J=4.9 Hz5 IH), 5.17-5.40 (m, 12H)5 7.68-7.75 (m, 2H)5 7.79-7.85 (m, 2H) '^C NMR (50 MHzs CDCI3) 8 14.0, 14.1, 20.4, 25.4, 25.4, 25.5, 27.0, 51.8, 61.7, 123.8, 124.3, 126.9, 127.5, 127.7, 127.9, 127.9, 128.1, 128.1, 128.3, 128.4, 131.6, 131.8, 131.8, 134.0, 167.3, 168.7 (2 signals hidden) MS (electrospray); 502 [M+H]^ 524[M+Na]^ Preparation of a-ethvlamino-DHA etylester (PRB-25) and a-diethylamino-BHA etvlester (PRB-26) A mixture of the a-amino-DHA ethylester (PRB-17) (746.5 mg, 2.01 mmol), LiOH-H2O (171.6 mg, 4.09 mmol) and molsieve 4A (599 mg) in DMF5 4 mL, was added ethylbromide (3.0 ml, 40.2 mmol) and the resulting mixture was stirred at ambient temperature for 71 hrs. The mixture was diluted with diethyl ether, 100 mL, and filtered. The organic phase was washed with 1 M NaOHs 20 mL, and bR1ne, 20 mL, dR1ed (Na2S04), filtered and evaporated in vacuo and subjected to flash chromatography on silica gel eluting with heptaneiEtOAc (95:5) - CH2Cl2:2M NH3 in MeOH (99:1) to yield 458 nig (53 %) of PRB-26 as a yellow liquid and 152 mg (19%) of PRB-25 as a yellow liquid. PRB-26: ^HNMR (200 MHz, CDCI3) 5 0.89 (t, J=7.5 Hz, 3H), 1.03 (t, 3H), 1.24 (t, J=L \ Hz, 6H), 2.05 (quint, J=7.1 Hz, 2H), 2.52 (m, 4H), 2.76-2.85 (m, 12 H), 3.35 (t, IH), 4.13 (q, J=7.1 Hz, 2 H), 5.28-5.44 (m, 12 H) ^^C NMR (75 MHz, CDCI3) 5 14.1, 14.3, 14.4, 20.5, 22.6, 25.5, 25.6, 25,7, 31.9, 44.4, 60.1, 62,9, 127.0, 127.8, 128.05, 128.13, 128.17, 128.22, 128.5, 132.0, 173.3 (5 signals hidden) Examples An overview of the models and methods used in the present invention for demonstrating effects on the metabolic syndrome and type 2 diabetes are presented in Fig. 2: Five blocks of expeR1ments have been performed in order to elucidate the effects of DHA deR1vatives for reduction of insulin resistance and/or alleviating the metabolic syndrome. The invention shall not be limited to the shown embodiments and examples. Example!. Analysis of intracellular free fatty acids (non-esteR1fied fatty acids) in liver cells (block 1 in Fig. 2) Background In the first block of expeR1ments (see Fig. 2) liver tissue from animals fed PRB-1, 2,5, and 7 was analysed with respect to free unesteR1fied fatty acids. The animals were recruited from the fifth block of expeR1ments (pharmacodynamic effects of DHA deR1vatives in an animal model of metabolic syndrome). The animals had been given DHA (15% of fat content of the diet) or the DHA-deR1vatives (1, 5% of the fat content in their diet) for 8 weeks and were supposed to be in a steady-state situation with stable levels of DHA and the DHA-deR1vatives intracellulaR1ly. Liver tissue was chosen due to the fact that the metabolisation rate is very high in liver. Method The liver samples were homogenized in cold PBS buffer, and extracted immediately with chloroform: methanol (2:1) containing 0.2mM butylated hydroxytoluene (BHT) using cis-10-heptadecenoic acid as internal standard. The organic phases were dR1ed under nitrogen, re-dissolved in acetonitR1le with 0.1% acetic acid and 10\|xM BHT for RP-HPLC MS/MS analysis. Total protein content was measured using Bio-Rad method after homogenization. Agilent 1100 system was used for reverse phase column (Supelco Ascentis Cis column, 25cm x 4.6mm, i.d. 5\|xm) separation of DHA and its PRB deR1vatives within 22min. The flow phase was iso-gradient acetonitR1le-HaO (87+13, v/v) containing 0.1% acetic acid. The column oven temperature was set at 35°C. The column elute was identified and quantified in the negative electrospray ionisation applying multiple reaction monitoR1ng mode by tR1ple tandem quadrapole mass/mass (ABI Qtrap-4000). The parent-daughter ion pairs were 327.3/327.3 (DHA)3 341.3/341.3 (PRB-I), 355.3/355.3 (PRB-2 and PRB-5), 387.3 /387.3 (PRB-7), 267.2/267.2 (LS. FA 17:1) respectively under unit resolufion. The signal collection dwell time was all 100 msec except for FA 17:1 which was set at 200msec. Accurate veR1fication of isomeR1c PRB compounds was done by combination of the retention time and characteR1stic mass/charge ratio. The quadratic regression standard curve was used for quantification after internal standard calibration. Results Concentration of the different DHA-deR1vatives and the concentrations of DHA was given as \|ig per g of total amount of protein in the liver cells. Fig, 3 depicts the concentrations of the different PRBs from animals given PRB-I, 2, 5 and 7 in a concentration of 1.5% of total fat content in the high fat diet. The highest intracellular concentration of the PRBs was obtained for PRB-2. Also PRB-5 was enR1ched intracellulaR1ly, although not to the same extent as PRB-2. This finding is unexpected. Fig. 4 depicts the intracellular concentrations of DHA in liver tissue from animals given the different PRBs. DHA reached a significantly higher level in the animals given PRB- 7 compared to the other three DHA-deR1vatives. Animals given PRB-2 had the lowest concentration of DHA. It seems that PRB-7 is to some extent converted back to DHA. PRB-2 reached the highest intracellular concentration. This means that PRB-2 will be more available as a ligand to nuclear receptors, a pattern which could be translated into therapeutic effects in handling of blood glucose and blood lipids. Example 2 Computer based affinity testing (block 2 in Fig. 2) Background Nuclear receptors have been sequenced and the amino acid sequence is known for the PPARs and other relevant receptors engaged in the genetic control of glucose and fat. X-ray crystallography and NMR spectroscopy of the PPAR receptors are available and computeR1sed affinity testing of fatty acids liganding to the receptors can be used to estimate binding kinetics. The binding geometR1es, often called binding modes or poses, include both positioning of the ligand relative to the receptor and the conformational state of the ligand and the receptor. Effective ligand docking can therefore be analysed. Affinity of the ligand to the receptor is defined by two different parameters: docking of the ligand (DHA deR1vative) into the binding site of the receptor and electrostatic bonding between certain amino acids of the receptor and the carboxyl group or side chains in the head of the fatty acid. (KrumR1ne). As previously known, the PP ARa receptor is more promiscuous compared to PPARy, meaning that PP ARa will accept more fatty acids as ligands compared to PPARy. However, since patients with metabolic syndrome or type 2 diabetes are usually obese or overweight and have pathologic blood lipids, mainly elevated tR1glyceR1des and low High-Density Cholesterol (HDL-chol) activation of the PP ARa receptor is important. An ideal drug for treatment of metabolic syndrome or type 2 diabetes should act as ligand to both these receptors, preferably with the highest affinity to the PPARy receptor. Method Ranking of the different DHA-deR1vatives according to their binding affinity was calculated and given as lowest binding affinity (LBA) and average binding affinity (ABE). A total of 15 DHA deR1vatives (PRB-I through PRE-15) were tested with the computeR1zed docking method. Some of the deR1vatives, such as PRB-I, PRB-2, PRB- 7, PRB-9, PRB-IO, PRB-11, PRB-12, PRB-13, PRB-14 and PRB-15, are presented as r and s enantiomeres and in this case both were tested. The PPARy ligands rosiglitazone and pioglitazone, both in the r and s form, were also tested for compaR1son. These compounds are registered pharmaceuticals for treatment of diabetes. Results The results are shown in Table 1, presenting the parameters Lowest binding energy of single confirmation (LBE), average binding energy (ABE) of the correctly posed confirmation and fraction of correctly posed confirmation of the ICM-saved 20 lowest energy confirmation (Abound) of the compounds tested. Affinity to the RXRa was tested in the same setting. The RXRa receptor interacts with the PPAR receptor forming a heterodimer by liganding of a fatty acid. Fig. 5 depicts the binding affinities for the PPARy receptor, which is mainly engaged in the transcR1ption of proteins engaged in handling of blood glucose. Clearly PRB-2 both in the r and the s stereoisomer forms had a good affinity to the PPARy receptor. PRB-5 scored somewhat poorer while PRB-8 had the highest ABE score. These findings are highly unsuspected and could be translated into a more effective transcR1ption of the respective PPARy activated gene responsible for handling of blood glucose. Fig. 6 depicts the binding affinities to the nuclear receptor PPARa which is mainly responsible for metabolisation of fat, blood lipids, fat tissue biology and weight control. Several DHA-deR1vatives had high binding affinity but.PRBS had the highest score. This is also highly unsuspected. Fig. 7 depicts the binding affinities to the nuclear receptor RXRa. The physiologic consequence of binding to the RXRa receptor has not been firmly established. It is known that RXR binds to the PPAR receptors thereby forming a heterodimer which then, subsequently, initiates transcR1ption of the defined gene. ND- Not docked, c = the double bonds in all-cis form. r= R enantioisomer, s= S enantioisomer. ROSI= Rosiglitazone, PIO= Pioglitazone. Several of the PRBs have a high LBE and ABE score for the PPARa and PPARy receptors even compared to the mother compound DHA but also to the PPARy ligands rosiglitazone and pioglitazone, both in the r and s form. This is an interesting observation indicating that several of the PRBs could be promising competitors to the established anti-diabetics rosiglitazone and pioglitazone. Ethyl deR1vativates in alfa position of the same fatty acids, both the r and the s form, did not improve affinity. This was especially true for the PPARy receptor. As mentioned previously the PPARa receptor is more promiscuous binding a long seR1es of fatty acids. In conclusion, many of the DHA-deR1vatives tested demonstrated interesting affinities to the PP ARa and PP ARy receptors with binding affinities better than rosiglitazone and pioglitazone. Example 3 Affinity testing in transfected cells (block 3 in Fig. 2) Background Release of luciferase is correlated to transcR1ption of genes. Binding of a ligand to a nuclear receptor such as PP ARy induces transcR1ption of the respective gene thereby releasing luciferase. This technique therefore provides a measure of ligand affinity to the receptor as well as activation of the responsible gene. Method Transient transfection of COS-I cells was performed in 6-well plates as descR1bed by Graham and van der Eb (Graham). For full length PPAR transfection studies, each well received 5 \|ag reporter construct, 2.5 \|xg pSV-P-galactosidase as an internal control, 0.4 \|xg pSG5-PPARy2. The cells were harvested after 72 h, and the luciferase activity was measured according to the protocol (Promega). The luciferase activity was normalised against P-galactosidase activity. The adipocytes were transfected at Dl 1 of differentiation using 16 \|J,1 LipofectaminPlus reagent, 4 \|j,l Lipofectamine (Life Technologies Inc.), 0.2 ^g pSGS-PPARy, and 100 ng pTK Renilla luciferase as control of transfection afficiency. Three hours after transfection, cells were cultured in serum containing medium and incubated for 48 hours in the same medium containing appropR1ate agents. The luciferase activities were measured as recommended by the manufacturer (Dual Luciferase assay, Promega). All transfections were performed in tR1plicate. Fatty acids (BRL or DHA) and PRBs (stock solutions) were solubilized to 0.1 M final concentration in DMSO. Then, Fatty solubilized to lOmM in DMSO and stored in 1.5 ml tubes (homoplymer, plastic tubes) flushed with argon and stored at - 20^C. 10 \|LIM of PRBs or fatty acids and DMSO (control) was added to the media 5h after transfection. Transfected cells were maintained for 24h before lysis by reporter lysis buffer. Binding of PRBs or fatty acids to the LBD of PPAR activates GAL4 binding to UAS, which in turn stimulates the tk promoter to dR1ve luciferase expression. Luciferase activity was measured using a luminometer (TD-20/20 luminometer; Turner Designs, Sunnycvale, CA) and normalized against protein content. Results Fig. 8 depicts the release of luciferase from transfected cells treated with different PRBs. The results indicate that PRB- 1,2,6,7 and 14 have a significantly higher release of luciferase compared to PRB-3,5,9,10,11,12, and 16. Example 4 Affinity testing in adipose prone animals with metabolic syndrome (block 4 in Fig. 2) Background An animal model of the metabolic syndrome using the adipose prone mice of the C57BL/6J strain was used to test affinity of PRB-2,5, and 8 compared to 97% DHA and the antidiabetic compound rosiglitazone to PPARy, by measuR1ng the release of luciferase from adipose celles taken from these animals. The animals (n^S in each group) were fed high fat diet (fat constituting 60% of total caloR1es, the same diet as used in Block 5) for 8 weeks. Thereafter they were given the PRBs in a dose of 1.5% of the fat content of the diet for another two weeks. The rosiglitazone group was given an amount of 100 mg/KG diet. The control groups continued with either only high fat diet or standard chow. Fig. 9 shows the study design. Method After sacR1fice adipose tissue (epididymal and subcutaneous) was cleared from other structures and cut into millimeter-size pieces. Fat tissue was R1nsed in 0,9% NaCl and digested in 5 mL of Krebs-R1nger solution containing Hepes, fatty-acid free bovine serum albumin, 20OnM of adenosin, 2 nM of glucose, and 260 U/mL of collagenase for 1,5 h at 37 degrees C in a shaking water bath. After collagensae digestion, adipocytes were separated from tissue debR1s by filteR1ng. Cells were then washed in Krebs-R1nger solution containing Hepes, fatty-acid free bovine serum albumin, 20OnM of adenosin, 2 nM of glucose and kept in a shaking water bath at 37 degrees for a maximum of 30 min until electroporation. Isolated pR1mary adipocytes were transfected by electroporation to measure the specific PPAR gamma response element (PPRE) activity. In this case we incorporated a plasmid encoding firefly luciferase cDNA under control of a PPRE from the acyl-CoA-oxidase gene. The cells were also co-transfected with a plasmid containing cDNA for Renilla luciferase controlled by a constitutively active promoter. The PPRE inducible firefly luciferase activity was normalised according to Renilla luciferase, thus correcting for potential differences in the amount of transfected cells. To measure luciferase signal we used the Dual-Luciferase® Reporter assay System (Promega,USA). Pooled epidydimal fat tissue was enough to isolate adipocytes for running duplicates. Each of groups was sacR1ficed in two separated days, and 4 independent transfections for each dietetic group were obtained. Results DuR1ng first 8 weeks of feeding with HF diet (33,7% of fat, w/w), there was a gradual increase of body weight in compaR1son to control mice fed with chow diet (4,5% w/w). DuR1ng last 2 weeks of feeding with expeR1mental diets high fat diet animals and animals given high fat diet in combination with Rosiglitazon continued gaining weight, approximately with the same rate as before. In case of PRB-8 and PRB-5 enR1ched HF diet the weight gain was reduced. However, in case of PRB-2 and DHA (5% w/w) the diet completely stopped the weight gain and even led to reduction of body weight (Fig. 10). Food consumption was recorded occasionally (4x). There were no differences between the HF and the intervention groups. In case of high fat in combination with Rosiglitazon, the endogenous activity of PPARy was approximately 2-fold higher than in all the others diet groups (Fig. 11). Furthermore, these fat cells became more sensitive to additional in vitro stimulation with 5uM Rosiglitazon (5, 12- fold stimulation) in compaR1son to i.e. HF diet itself (1, 5-fold stimulation). This rosiglitazon - sensitizing effect was also recorded in the PRB-2 and the PRB-5 diet group (2, 6-fold stimulation). Data from this study clearly demonstrates activity on the nuclear PPAR receptors, in particular with the effects on weight which was most prominent for the groups given PRB-2. Even animals given PRB-5 and PRB-8 did not increase in weight as did the high fat diet group. Interestingly animals given rosiglitazone increaed in weight to the same extent as animals given only the high fat diet. This clearly demonstrates the negative effects of giving only a PPARy ligand, like the glitazones, with the R1sk of weight increase even if insulin resistance is reduced. However, when it comes to PPARy activation measured as luciferase activity in this expeR1ment, rosiglitazone scores higher compared to any of the PRBs. Within the PRB groups PRB-2 and PRB-5 had a higher score compared to PRB-8 and DHA only (Fig. 12). Example 5 Pharmacodynamic effects of DHA deR1vatives in an animal model of metabolic syndrome (block 5 in Fig. 2) Background An animal model of the metabolic syndrome using the adipose prone mice of the C57BL/6J strain was used to document effects on typical laboratory and pathological anatomical features common for the metabolic syndrome. When given a high fat diet containing about 60% of fat, the animals are getting obese developing high insulin plasma levels, pathological glucose tolerance test, elevated serum tR1glyceR1des and non-esteR1fied fatty acids, and fat liver. Example 5a Effect of DHA deR1vatives in adipose prone mice duR1ng 4 months of dietary interventions Method All expeR1ments were performed on male C57BL/6 mice, either a substrain C57BL/N (supplier: Charles R1ver, Germany, n = 160, expeR1ments A-C, see below), or a substrain C57BL/6J (supplier: the Jackson laboratory, Bar Harbor, ME, USA, n = 32, expeR1ment D). Total numbers of animals used were higher (n = 170 and 36, respectively), because of culling. In the latter case, animals were bred for several generations ( Animals weree fed 3 types of expeR1mental diets: (i) Chow diet (ssniff RM-H from SSNIFF Spezialdieten Gmbh, Soest, Germany; see also http://ssniff.de) with protein, fat and carbohydrate forming 33, 9, and 58 energy %, respectively (ii) High-fat diet prepared in the laboratory (cHF diet) with protein, fat and carbohydrate forming 15, 59, and 26 energy %, respectively, and well characteR1zed fatty acid composition (with most of the lipids coming from com oil; see Ruzickova 2004) (iii) cHF diets in which 0.15, 0.5, and 1.5 % of fat (specifically the corn oil constituent) was replaced by vaR1ous PRB-compounds, namely PRBl, PRB2, PRB5, PRB7, and PRB8, or by DHA. AU these compounds were in the form of ethyl esters, provided by Pronova Biocare a.s. in sealed containers. Chemical composition of the PRB-compounds was unknown to the laboratory performing the expeR1ments (Institute of Physiology, Academy of Sciences Prague, Czech Republic). After arR1val, the PRB-compounds were stored in a refR1gerator in oR1ginal containers. The containers were opened just before preparation of the expeR1mental diets. Diets were kept in plastic bags flushed by nitrogen and stored at -70V in small aliquots sufficient for feeding animals for one week. Fresh ratios were given in 2-day intervals or daily. Outline of the study The study was based on 4 individual expeR1ments. In each of the expeR1ments, different PRB-compounds (or DHA, respectively) admixed to cHF diet in three different concentrations (0.15, 0.5, and 1.5 % of the fat content) were tested. In each expeR1ment, a subgroup of plain cHF diet-fed mice was included and served as a control. Mice were caged in groups of 4 and fed standard chow diet until 3 mo of age, when animals (n = 8-13) were randomly assigned to the different test diets. After 2 mo on this new diet (at 5 mo of age), animals were fasted overnight and in the morning, intrapeR1toneal Glucose Tolerance Test (GTT) was performed. Animals were sacR1ficed after 4 months on the expeR1mental diets, at 7 mo of age, and the end- point analysis were performed. Study parameters. The parameters in the study were: Body weight gain (grams), area under the curve (AUC) from intrapeR1toneal glucose tolerance tests (mMol x 180 min), plasma insulin (ng/ml), serum tR1glyceR1des (TAGss mmol/1), and non-esteR1fied fatty acids (NEFA5 mmol/1). Fig. 13 shows a typical blood glucose elimination curve before and after animals with insulin resistance are given a compound with insulin resistance reducing effect. Reduction of the area under the curve means that blood glucose is eliminated more effectively due to reduced insulin resistance. Results The results are shown in the following tables 2, 3 and 4. (* = significant differencies compared to cHF diets (P Table 2 shows the effects in animals given 1.5% concentration of the PRB test compounds compared to animals given standard chow (STD), composite high fat diet (cHF) or 97% DHA. Body weight gain was significantly reduced in animals given PRB-2 compared to animals given high fat diet (cHF). Food intake was somewhat lower in this group. The most pronounced reduction in AUC from glucose tolerance tests was seen in the same group and even in animals given PRB-I .Plasma insulin was significantly lower in the PRB-2 group compared to the cHF controls even if the PRB-I and PRB-5 treated animals showed some effect on this parameter too. The PRB-2 group showed the biggest reduction in tR1glyceR1des (TAGs) and non-esteR1fied fatty acids (NEFA). Table 3 shows the effects in animals given a lower concentration, 0.5%, of the PRB test compounds compared to animals given standard chow (STD), composite high fat diet (cHF) or 97%» DHA. Body weight gain was somewhat lower in animals given PRB-2 and PRB-5. AUC from the glucose tolerance test as well as plasma insulin, however, was significantly lower only in the PRB-2 group. Table 4 shows the rsults from the lowest PRB concentration given, 0.15%. Here, the differences were small. Weight gain was somewhat lower in the PRB-I and PRB-2 groups while AUC was significantly lower only in the PRB-2 group. Plasma insulin was lower in PRB-1, 2 and 7. In conclusion, testing of PBR-1, 2,5, and 7 duR1ng 4 months in adipose prone animals with insulin resistance and metabolic syndrome demonstrated a clear and unsuspected effect of the PRBs tested, in particular the DHA- deR1vative PBR-2, on insulin resistance and symptoms of the metabolic syndrome such as weight reduction, reduced AUC in the intrapeR1toneal glucose tolerance test, lower insulin/plasma levels as well as reduced tR1glyceR1de and non-esteR1fied free fatty acids. Effects were observed in the dose of 1.5% as well as in the 0.5% group. Some effects were even noticed in the lowest concentration group of 0.15%. Testing of the PRB-8 compound was started later, therefore only data from 2 months intervention in three dose groups (1.5%, 0.5% and 0,15%) are given. In the group given 1.5%, body weight (BW) was 28.0 ±0.7 grams compared to controls 29.6±0.9, AUC 1031 ±104 compared to 1074±91. These differences are small but the trend is interesting. There were no differences between intervention and controls.for the lower doses of 0.5% and 0.15%). The data regarding PRB-8 data from 2 months medication showing a trend towards weight reduction and AUC. Example 5b Effect of DHA deR1vatives on established metabolic syndrome and insulin resistance Method In another expeR1ment, PRB-2, PRB-5, and PRB-7 were tested in the same breed of animals. In this expeR1ment, animals were initially fed high fat diet (the same as in the previous expeR1ment 5 a) for 8 weeks developing insulin resistance and the metabolic syndrome, and then given the PRBs. The start dose was to substitute 15%) of the fat content with the PRBs but the animals did not tolerate this dose. After a peR1od of another two weeks the animals were given 1.5%) of PRB-2, 5%) andl.5%> of PRB-5, and 1.5%and0.5%ofPRB-7. Results Weight reduction was very good in the animals given PRB-2. Even the animals given PRB-5 showed some weight reduction but in the higher dose of 5%>. TR1glyceR1des were reduced with all deR1vatives tested compared to the control animals fed composite High Fat diet. Reduction of non-esteR1fied fatty acids was most pronounced with PRB-2 and PRB-5, however in different doses. (See Fig. 14) Blood cholesterol was reduced in animals given PRB-2 and PRB-5. Blood glucose was not affected due to the fact that these animals are in a pre-diabetic state with normal glucose due to a high insulin production. However, more importantly, plasma insulin was significantly reduced in the PRB-2 group in a much lower concentration compared to the second best DHA-deR1vative PRB-5. Even PRB-7 showed some effects on the insulin concentration. (See Fig. 15). PRB-2 showed a statistically significant reduction of the AUC blood glucose at all time points of the curve compared to the baseline values. This means that blood glucose was more effectively removed after treatment of 1,5% of PRB-2. PBR-5 and PBR-7 showed some effect but not to the same extent. (See Fig. 16). These effects are highly unsuspected and very relevant for a positive effect in metabolic syndrome and type 2 diabetes. These patients are almost exclusively overweight or obese and a weight reductive effect of a drug is highly positive. The mostly used remedies used for treatment of type 2 diabetes today, the thiazolidinedions, which are potent PPARy ligands thereby reducing insulin resistance, often result in weight increase which is highly negative for these subset of patients (Yki-Jarvinen 2004). Reduction of serum tR1glyceR1des is another very important effect that was demonstrated in the expeR1ments. Patients with metabolic syndrome and type 2 diabetes usually have elevated tR1glyceR1des. The tR1glyceR1de loweR1ng effects of the DHA-deR1vatives is a positive finding and again PRB-2 demonstrated the most potent effect with the lowest dose given. The very positive effects on plasma insulin and glucose tolerance test are very promising and highly unsuspected. Taken together the effects obtained with the DHA-deR1vatives in particular PRB-2 are very promising forming a good basis for development of an antidiabetic drug. Example 5c Testing of DHA deR1vatives on liver fat Method Tissue samples from animals in the expeR1ments with DHA deR1vatives was histologically analysed. After paraffmation, tissue samples from liver, adipose tissue, skeletal muscle, pancreas, and kidney were stained with eosin-hematoxylin. Results There were no pathological findings in the tissues examined with exception from liver. Control animals fed high fat diet had developed fat liver (liver steatosis). Fat droplets in the liver can easily be distinguished from normal liver cells. Animals treated with PRB-I, 5, and 7 had low degree of fat liver. However, animals treated with 1.5% of PRB-2 had completely normal liver cells with no trace of steatosis. This is an extremely important finding and very relevant for treatment of patients with insulin resistance, obesity and type 2 diabetes. Liver steatosis is a common finding in these patients which is usually related to an overload of fatty acids and tR1glyceR1des, biological markers present in the development of insulin resistance and the metabolic syndrome. DHA-deR1vatives reduce liver steatosis, and PRB-2 was the most efficient compound showing this effect. Discussion and conclusions The present application clearly identifies a new group of compounds which are activating nuclear receptors, especially PP ARy and PP ARa, thereby offeR1ng a seR1es of therapeutic effects in the treatment of insulin resistance, the metabolic syndrome, type 2 diabetes, cardiovascular disease and other atherosclerotic related diseases. Members of this group are DHA deR1vatives with side chains of different kind in the alfa position of the molecule. A large number of alfa-substituted DHA deR1vatives have been tested and compared with controls as well as pure DHA and EPA. Several of the compounds tested have demonstrated interesting biological effects very relevant for a potential anti-diabetic drug. Interestingly, and not conceivable on beforehand, alfa-ethyl DHA ethyl ester (PRB-2) was significantly more effective in the battery of tests used to demonstrate effects related to insulin resistance and thereby diseases mainly caused by this pathophysiologic condition such as the metabolic syndrome, type 2 diabetes, cardiovascular disease and other atherosclerotic related diseases. Alfa-ethyl DHA ethyl ester was enR1ched in liver tissue from animals given the different DHA deR1vatives tested (Block 1) indicating that this compound was not utilised for synthesis of tR1glyceR1des, eikosanoids or other metabolic intermediates. Indirectly this would mean that alfa-ethyl DHA would be available for liganding to nuclear receptors like the PPARs. In testing of affinity to PPAR y and PP ARa using computeR1zed docking technology a large number of the DHA-deR1vatives showed affinities to both receptors, not least PPAR y which probably is the most important nuclear receptor engaged in the activation of genes responsible for metabolisation of blood glucose. In particular alfa-ethyl DHA (PRB-2) as well as alfa-diethyl DHA (PBR-8) possessed excellent affinity to these nuclear receptors. Compared to alfa-diethyl DHA alfa-ethyl DHA has two stereoisomers, the r and the s form. Using the docking technology both stereoisomers possessed about the same affinity to PPAR y and PP ARa meaning that neither the r or the s form should have advantages compared to the racemic form. In fact the racemic form may have advantages over each one of the stereoisomers. When affinity was tested in transfected cells carrying the nuclear receptor and the subsequent DNA response element, several of the PRBs demonstrated good affinity measured as release of luciferase. Alfa-ethyl DHA (PRB-2) together with PRB-6,7 and 14 demonstrated the best effects. Five of the DHA deR1vatives have been extensively tested in the C57BL/6 mouse model developing insulin resistance and the metabolic syndrome when fed high fat diet. Alfa-ethyl DHA (PRB-2) has been tested in three individual expeR1ments while PRB- 1,5, and 7 were tested in two and alfa-diethyl DHA (PRB-8) was tested in one expeR1ment. All deR1vatives demonstrated significant biological effects. However, alfa-ethyl DHA (PRB-2) showed the most promising effects with a consistent reduction in body weight, AUC from intrapeR1toneal glucose tolerance testing, plasma insulin as well as serum tR1glyceR1des and non-esteR1fied fatty acids. The effects were obtained on the doses 1.5% and 0.5%. The lowest tested dose 0.15% did not perform convincingly. Alfa-ethyl DHA (PRB-2) in a dose of 1.5% has also demonstrated a normalisation of fat liver, an important pathological finding in patients and animals with insulin resistance and metabolic syndrome. CompaR1ng with pure DHA, alfa-ethyl DHA (PRB-2) seems to be 10-30 times as potent as DHA. All in all these findings and the potency compared to the mother molecule DHA are not predictable and highly unexpected. Since alfa-ethyl DHA (PRB-2) seems to work by simultaneous liganding to the nuclear receptors PP ARa and PPARy the compound would not only possess therapeutic interesting effects on glucose and lipid metabolism, not least in patients with insulin resistance, metabolic syndrome and type 2 diabetes but also have weight reduction as well as a general anti-inflammatory effect. Directly or through positive intervention on R1sk factors alfa-ethyl DHA (PRB-2) would have a preventive effect on the development of cardiovascular disease such as myocardial infarction and cerebral stroke as well as having a preventive effect on cardio-vascular mortality. Pharmaceuticals acting as PPARy ligands are already on the market but even if these compounds are having positive effects on glucose metabolism, they are hampered by adverse effects such as elevated tR1glyceR1des, weight increase and oedema. The alfa- substituted DHA deR1vatives presented in this application are having a combined PPARy and PP ARa effect which is probably both relevant and advantageous for patients with insulin resistance, metabolic syndrome and type 2 diabetes. Furthermore, these combinative actions should have important effects also on blood lipids, inflammatory events, atherosclerosis, and thereby cardiovascular disease. The invention shall not be limited to the shown embodiments and examples. References Simonopoulos AP. Essential fatty acids in health and chronic disease. Am J Clin Nutr 1999;70(Suppl):560S-569S Geleijnse JM, Giltay EJ, Grobbee DE, et al. Blood pressure response to fish oil supplementation: metaregression analysis of randomized tR1als. J Hypertension 2002;20:1493-1499 Storlien LH, Hulbert AJ, and Else PL. Polyunsaturated fatty acids, membrane function and metabolic diseases such as diabetes and obesity. Curr Opin Clin Nutr Metab Care 1998;] -.559-563 Jump DB. The biochemistry of n-3 polyunsaturated fatty acids. J Biol Chem 2002;277 - 8755-8758 Pawar A and Jump D. Unsaturated fatty acid regulation of peroxisomes proliferator- activated receptor alfa activity in rat pR1mary hepatocytes. J Biol Chem 2003;278:35931-35939 Meigs JB, Wilson PWF, Nathan DM, et al. Prevalence and characteR1stics of the metabolic syndrome in the San Antonio Heart and Framingham offspR1ng studies. Diabetes 2003 ;52:2160-2167 Storlien LH, KraegenWE, Chisholm DJ, et al. Fish oil prevents insulin resistance induced by high fat feeding in rats. Science 1987;237:885-888 Field CJ, Ryan EA, Thomson ABR, et al. Diet fat composition alters membrane phospholipid composition, insulin binding and glucose metabolism in adipocytes from control and diabetic animals. J Biol Chemistry 1990 ;265 : 11143 - 11150 Yki-Jarvinen, H. Thiazolidinediones. NEJM 2004;351:1106-1118 Adams M, Montague CT5 PR1ns JB, et al. Activators of peroxisomes proliferator-activated receptor gamma have depot-specific effects on human preadipocyte differentiation. J Clin Invest 1997,100:3149-3153 Ruzickovaj, Rossmeisl M, Prazak T, et al. Omega-3 PUFA of maR1ne oR1gin limit diet-induced obesity in mice by reducing cellulaR1ty of adipose tissue, Lipids 2004; 39: 1177-1185 Vaagenes H, Madsen L, Dyr0y E, et al. The hypolipidaemic effect of EPA is potentiated by 2- and 3-methylation. Biochim Pharmacol 1999;58:1133-1143 Larsen L, Granslund L,Holmeide AK, et al. Sulfur-substituted and a-methylated fatty acids as peroxisome proliferator-activated receptor activators. Lipids 2005;40:49-57 Larsen L, Horvik K, Sorensen HIN, et al. Polyunsaturated thia- and oxa-fatty acids: incorporation into cell-lipids and their effects on arachidonic acid- and eikosanoids synthesis. Biochim et Biophys Acta 1997,1348:346-354 Larsen, et.al Biochemical Pharmacology 1998; 55, 405 Chih-Hao L, Olson P, and Evans RM. Lipid metabolism, metabolic diseases, and peroxisome proliferator-activated receptors. EndocR1nology 2003;144:2201-2207 Willumsen N, Waagenes H, Holmsen H, et al. On the effect of 2-deuteR1um- and 2-methyl-eicosapentaenoic acid deR1vatives on tR1glyceR1des, peroxisomal beta-oxidation and platelet aggregation in rats. Biochim Biophys Acta 1998;1369:193-203 Mitsunobu O, Synthesis 1981 ;1 Ager DJ, Prakash I, and Schaad DR. 1,2-amino alcohols and their heterocyclic deR1vatives as chiral auxiliaR1es in asymmetR1c synthesis Chem Rev 1996;96:835-876 We claim: 1) A compound of formula (I): wherein - R1 and R2 are the same or different and may be selected from the group consisting of a hydrogen atom, a hydroxy group, an alkyl group, a halogen atom, an alkoxy group, an acyloxy group, an acyl group, an alkenyl group, an alkynyl group, an aryl group, an alkylthio group, an alkoxycarbonyl group, an alkylsulfinyl group, an alkylsulfonyl group, an amino group, and an alkylamino group; and - X represents a carboxylic acid group, a carboxylate group, or a carboxamide group, or any pharmaceutically acceptable salt, solvate, complex or pro-drug thereof; with the provisos that: ■ the compound of formula (I) is not (all-Z)-4,7,10,13,16,19- docosahexaenoic acid (DHA), alpha-methyl DHA, alpha-methyl DHA methyl ester, alpha-methyl DHA ethyl ester or alpha-hydroxy DHA ethyl ester. 2) The compound as claimed in claim 1, wherein said alkyl group is selected from a group compR1sing of methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-buthyl, sec. -butyl, n-hexyl, and benzyl. 3) The compound as claimed in claim 1, wherein said halogen atom is selected from a group compR1sing of fluoR1ne, chloR1ne, bromine, and iodine. 4) The compound as claimed in claim 1, wherein said alkoxy group is selected from a group compR1sing of methoxy, ethoxy, propoxy, isopropoxy, sec- butoxy, phenoxy, benzyloxy, OCH2CF3, and OCH2CH2OCH3. 5) The compound as claimed in claim 1, wherein said alkenyl group is selected from a group compR1sing of allyl, 2-butenyl, and 3-hexenyl. 6) The compound as claimed in claim 1, wherein said alkynyl group is selected from a group compR1sing of propargyl, 2-butynyl, and 3-hexynyl. 7) The compound as claimed in claim 1, wherein said aryl group is a phenyl group. The compound as claimed in claim 1, wherein said aikylthio group is selected from a group compR1sing of methylthio, ethylthio, isopropylthio, andphenylthio. The compound as claimed in claim 1, wherein said alkoxycarbonyl group is selected from a group compR1sing of methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and butoxycarbonyl. I The compound as claimed in claim 1, wherein said alkylsulfinyl group is selected from a group compR1sing of methanesulfmyl, ethanesulfmyl, and isopropanesulfinyl. The compound as claimed in claim 1, wherein said alkylsulfonyl group is selected from a group compR1sing of methanesulfonyl, ethanesulfonyl, and isopropanesulf onyl. The compound as claimed in claim 1, wherein said alkylamino group is selected from a group compR1sing of methylamino, dimethylamino, ethylarnino, and diethylamino. The compound as claimed in claim 1, wherein said carboxylate group is selected from a group compR1sing of ethyl carboxylate, methyl carboxylate, n-propyl carboxylate, isopropyl carboxylate, n-butyl carboxylate, sec-butyl carboxylate, and n-hexyl carboxylate. The compound as claimed in claim 1, wherein said carboxamide group is selected from a group compR1sing of pR1mary carboxamide, N-methyl carboxamide, N,N-dimethyl carboxamide, N-ethyl carboxamide, and N,N-diethyl carboxamide. The compound as claimed in claim 1, wherein R1 and R2 are selected from the group consisting of a hydrogen atom, a hydroxy group, an alkyl group, a halogen atom, an alkoxy group, an aikylthio group, an alkylsulfmyl group, an alkylsulfonyl group, an amino group, and an alkylamino group. The compound as claimed in claim 1, wherein R1 and R2 are selected from a group compR1sing of a hydrogen atom, a hydroxy group, a C1-C7 alkyl group, a halogen atom, a C1-C7 alkoxy group, a C1-C7 alkyltio group, a C1-C7 alkylsulfmyl group, a C1-C7 alkylsulfonyl group, an amino group, and a C] - C? alkylamino group. The compound as claimed in claim 1, wherein said C1-C7 alkyl group is methyl, ethyl, or benzyl; said halogen atom is fluoR1ne or iodine: said C1-C7 alkoxy group is methoxy or ethoxy; said C1-C7alkylthio group is methylthio, ethylthio or phenylthio; said C1-C7 alkylsulfmyl group is ethanesulfmyl; said C1-C7 alkylsulfonyl group is ethanesulfonyl; said C1-C7 alkylamino group is ethylamino or diethylamino; and X represents a an ethylcarboxylate or a carboxamide group. ) The compound as claimed in claim 1, wherein R1 and R2 are selected from the group consisting of a hydrogen atom, a C2-C7 alkyl group, a halogen atom, a Ci- C7 alkoxy group, a C1-C7 alkyltio group, a CpCy alkylsulfmyl group, a C1-C7 alkylsulfonyl group, an amino group, and a C1-C7 alkylamino group; and X represents a carboxylate. ► The compound as claimed in claim 18, wherein said C2-C7 alkyl group is ethyl, or benzyl; said halogen atom is fluoR1ne or iodine: said C1-C7 alkoxy group is methoxy or ethoxy; said C1-C7 alkylthio group is methylthio, ethylthio or phenylthio; said C1-C7 alkylsulfmyl group is ethanesulfmyl; said C1-C7 alkylsulfonyl group is ethanesulfonyl; said C1-C7 alkylamino group is ethylamino or diethylamino; and X represents a an ethylcarboxylate. The compound as claimed in claim 1, wherein R1 and R2 are different. The compound as claimed in claim 20, wherein said compound is in racemic form. The compound as claimed in claim 20, wherein said compound is in the form of its R stereoisomer. The compound as claimed in claim 20, wherein said compound is in the form of its S stereoisomer. The compound as claimed in claim 1, wherein one Of R1 and R2 represents a C2-C7 alkyl group, and the other one represents a hydrogen atom. The compound as claimed in claim 24, wherein said alkyl group is ethyl. The compound as claimed in claim 25, wherein said compound is in racemic form. The compound as claimed in claim 25, wherein said compound is in the form of its R stereoisomer. The compound as claimed in claim 25, wherein said compound is in the form of its S stereoisomer. The compound as claimed in claim 24, wherein said alkyl group is benzyl. The compound as claimed In claim 1, wherein one of R1 and R2 represents an alkoxy group, and the other one represents a hydrogen atom. The compound as claimed in claim 30, wherein said alkoxy group is ethoxy or methoxy. The compound as claimed in claim 1, wherein one of R1 and R2 represents a halogen atom, and the other one represents a hydrogen atom. The compound as claimed in claim 32, wherein said halogen atom is fluoR1ne or iodine. The compound as claimed in claim 1, wherein one of R1 and R2 represents a alkylthio group, and the other one represents a hydrogen atom. The compound as claimed in claim 34, wherein said alkylthiogroup is ethylthio. The compound as claimed in claim 34, wherein said alkylthiogroup is methylthio or phenylthio. The compound as claimed in claim 1, wherein one of R1 and R2 represents an alkylsulfonyl group, and the other one represents a hydrogen atom. The compound as claimed in claim 1, wherein said alkylsulfonyl group is ethanesulfonyl. The compound as claimed in claim 1, wherein one of R1 and R2 represents an amino group, and the other one represents a hydrogen atom. The compound as claimed in claim 1, wherein one of R1 and R2 represents an alkyl-amino group, and the other one represents a hydrogen atom. The compound as claimed in claim 40, wherein said alkyl-amino group is ethyl-amino or diethyl-amino. The compound as claimed in claim 1, wherein R1 and R2 represent C1-C7- alkyl groups. The compound as claimed in claim 42, wherein said alkyl groups are methyl groups. The compound as claimed in claim 42, wherein said alkyl groups are ethyl groups. The compound as claimed in claims 20 to 44, wherein X is ethyl carboxylate. The compound as claimed in claims 1 to 45, in the form, of a phospholipid, a tR1-, di- or monoglyceR1de, or in the form of a free acid. The compound as claimed in claims 1 to 46, wherein said compound is for use as a medicament. A process for the manufacture of a compound as claimed in claims 1 to 46. The process as claimed in claim 48, wherein said compound is prepared from (all-Z)-4, 7, 10, 13, 16, 19-docosahexaenoic acid (DHA). The process as claimed in claim 49, wherein said DHA is prepared from a vegetable, a microbial and/or an animal source. The process as claimed in claim 50, wherein said DHA is prepared from a maR1ne oil. The process as claimed in claim 51, wherein said maR1ne oil is fish oil. A pharmaceutical composition compR1sing a compound as claimed in claims 1 to 46 as an active ingredient. The pharmaceutical composition as claimed in claim 53, wherein said composition further compR1sing a pharmaceutically acceptable carR1er. The pharmaceutical composition as claimed in claim 54, wherein said composition is formulated for oral administration. The pharmaceutical composition as claimed claim 55, wherein said formulation is in the form of a capsule or a sachet. The pharmaceutical composition as claimed in claims 53 to 56, wherein said formulation is formulated to provide a daily dosage ranging from 10 mg to 10 g of said compound. The pharmaceutical composition as claimed in claim 57, wherein said formulation is formulated to provide a daily dosage ranging from 100 mg to 1 g of said compound, A fatty acid composition compR1sing a compound according to any one of the claims 1 to 46. The fatty acid composition as claimed in claim 59, wherein at least 60% by weight of the fatty acid composition is compR1sed of said compound. The fatty acid composition according to claim 60, wherein at least 90% by weight of the fatty acid composition is compR1sed of said compound. The fatty acid composition as claimed in claims 59 to 61, wherein said composition further compR1sing fatty acids selected from (all-Z)-5,8,l 1,14,17-eicosapentaenoic acid (EPA), (all-Z)-4,7,10,13,16,19-docosahexaenoic acid (DHA), (all-Z)- 6,9,12,15,18-heneicosapentaenoic acid (HPA), and/or (all-Z)-7.10,13.16,19- docosapentaenoic acid (DPA). The fatty acid composition as claimed in claim 62, wherein said fatty acids are present in the form of deR1vatives. The fatty acid composition as claimed in claims 59 to 63, wherein said composition further compR1sing a pharmaceutically acceptable antioxidant. The fatty acid composition as claimed in claim 64, wherein said antioxidant is tocopherol. The fatty acid composition as claimed in claims 59 to 65, wherein said composition is for use as a medicament. Use of a compound as claimed in claims 1 to 46 for the manufacture of a medicament for controlling body weight reduction and/or for preventing body weight gain. Use of a compound as claimed in claims 1 to 46 for the manufacture of a medicament for the treatment and/or the prevention of obesity or an overweight condition. Use of a compound as claimed in claims 1 to 46 for the manufacture of a medicament for the prevention and/or treatment of diabetes in an animal. Use of a compound as claimed in claim 69, wherein the diabetes is type 2 diabetes. Use of a compound as claimed claims 1 to 46 for the manufacture of a medicament for the treatment and/or prevention of amyloidos- related diseases. Use of a compound as claimed in claims 1 to 46 for the manufacture of a medicament for the treatment or prophylaxis of multiple R1sk factors for cardiovascular diseases, preferably for the treatment of elevated blood lipids. Use of a compound as claimed in claims 1 to 46 for the manufacture of a medicament for prevention of stroke, cerebral or transient ischaemic attacks related to atherosclerosis of several arteR1es. A method for controlling body weight reduction and/or for preventing body weight gain, wherein a pharmaceutically effective amount of a compound according to any one of the claims 1 to 46 is administered to a human or an animal. A method for the treatment and/or the prevention of obesity or an overweight condition, wherein a pharmaceutically effective amount of a compound of formula (I) according to any one of the claims 1 to 46 is administered to a human or an animal. A method for the prevention and/or treatment of diabetes, wherein a pharmaceutically effective amount of a compound of formula (I) according to any one of the claims 1 to 46 is administered to a human or an animal. The method as claimed in claim 76, wherein the diabetes is type 2 diabetes. A method for the treatment and/or prevention of amyloidos-related diseases, wherein a pharmaceutically effective amount of a compound of formula (I) according to any one of claims 1 to 46 is administered to a human or an animal. A method for the treatment or prophylaxis of multiple R1sk factors for cardiovascular diseases, wherein a pharmaceutically effective amount of a compound of formula (I) according to any one of the claims 1 to 46 is administered to a human or an animal. A method for the prevention of stroke, cerebral or transient ischaemic attacks related to atherosclerosis of several arteR1es, wherein a pharmaceutically effective amount of a compound of formula (I) according to any one of the claims 1 to 47is administered to a human or an animal. The method as claimed in claims 74 to 80, wherein the compound of formula (I) is administered orally to a human or an animal. A compound of formula (I), a process to prepare the compound of formula (I), use of the compound and method of treatment as substantially herein descR1bed with the help of accompanying drawings and examples.

Full Text

FIELD OF THE INVENTION
The present invention relates to compounds of the general formula (I):

and their use as medicaments, in particular for the treatment of diabetes mellitus, type 2, and pre-stages thereof. It also relates to a pharmaceutical composition comprising compounds of formula (I), as well as to a fatty acid composition comprising compounds of formula (I).
BACKGROUND AND PRIOR ART OF THE INVENTION The increasing incidence of type 2 diabetes mellitus worldwide poses an immense public health and medical challenge for the implementation of successful preventive and treatment strategies. The concurrent rise in overweight and obesity, which is tightly correlated to type 2 diabetes, interferes with diabetes treatment and increases the likelihood of hypertension, dyslipidemia, and atherosclerosis related diseases. The pathophysiologic condition precluding the development of type 2 diabetes is related to reduced effects of insulin on peripheral tissues, called insulin resistance. These tissues are mainly muscle, fat and liver. Muscle tissue is the main tissue concerned by insulin resistance in type 2 diabetes. The syndrome characterized by insulin resistance, hypertension, dyslipidemia and a systemic proinflammatory state, is referred to as metabolic syndrome. The prevalence of metabolic syndrome in the adult population in developed countries is 22-39% (Meighs 2003).
Currently the most promising approach to mitigate and deter the metabolic syndrome is lifestyle intervention with weight reduction, decreased consumption of saturated fat, increased physical activity in combination with appropriate pharmacotherapy. Healthy diets that avoid excess energy intake encompass substitution of mono and polyunsaturated fatty acids in exchange for saturated fat. In particular the long-chain omega-3 fatty acids from fatty fish, namely eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have proven beneficial in prevention of type 2 diabetes. EPA and DHA have effects on diverse physiological processes impacting normal health and chronic disease, such as the regulation of plasma lipid levels, cardiovascular and

immune function, insulin action and neural development and visual function. Firm evidence exist for their beneficial role in the prevention and management of coronary heart disease, dyslipidemias, type 2 diabetes, insulin resistance, and hypertension (Simonopoulos 1999; Geleijnse 2002; Stprlien 1998).
Recent studies suggest that omega-3 fatty acids serve as important mediators of gene expression, working via nuclear receptors like the peroxisome proliferator- activated receptors (PPARs) controlling the expression of the genes involved in the lipid and glucose metabolism and adipogenesis (Jump 2002). PPARs are nuclear fatty acid receptors that have been implicated to play an important role in obesity-related metabolic diseases such as hyperlipidemia, insulin resistance, and coronary heart disease.
The three subtypes, a, y? and 8, have distinct expression pattern and evolved to sense components of different lipoproteins and regulate lipid homeostasis based on the need of a specific tissue. PP ARa potentiates fatty acid catabolism in the liver and is the molecular target of the lipid-Iowering fibrates. PPARy on the other hand is essential for adipocyte differentiation and mediates the activity of the insulin- sensitizing thiazolidinedions (the glitazones) through mechanisms not fully understood. (Chih-Hao 2003; Yki-Jarvinen 2004)
Recently, pharmaceuticals acting as ligands to the PPARy receptor have been introduced as treatment of type 2 diabetes (Yki-Jarvinen 2004). These compounds called thiazolidinediones or glitazones are drugs that reverse insulin resistance which is the pathophysiologic basis for development of the metabolic syndrome and type 2 diabetes. These compounds, of which rosiglitazone and pioglitazone have been launched as pharmaceuticals, lower fasting and postprandial glucose concentrations (which is being manifest as a pathologic glucose tolerance test), plasma insulin as well as free fatty acid concentrations. In this respect the glitazones act as insulin sensitizers. However, these improvements are generally accompanied by weight gain and an increase in the subcutaneous adipose-tissue mass (Adams 1997). The use of thiazolidinediones is not only associated with weight gain but a subgroup of patients also have fluid retention and plasma volume expansion, leading to peripheral oedema. The increase in body weight and oedema has been associated with an increase in the incidence of heart failure, which is the reason why the Food and Drug Administration has included a warning in the prescription information for rosiglitazone (provided by

Avandia) and pioglitazone (provided by Takeda). These adverse effects restrict the use of the glitazones especially in patients with coronary heart conditions. Clearly there is a potential for new drugs with positive effects on insulin resistance but with weight reduction activity and no fluid retention tendency.
The effect of the poly-unsaturated fatty acids (PUFAs) on PPARs are not only a result of fatty acid structure and affinity to the receptor. Factors contributing to the composition of the intracellular non-esterified fatty acids (NEFA) levels are also important. This NEFA pool is affected by the concentration of exogenous fatty acids entering the cell and the amount of endogenous synthesised fatty acids, their removal via incorporation into lipids as well as their oxidation pathways. (Pawar 2003).
Although omega-3 fatty acids are weak agonists of PPARs, when compared with pharmacological agonists like the thioglitazones, these fatty acids have demonstrated improvement in glucose uptake and insulin sensitivity (Storlien 1987). It has been reported that adipocytes were more insulin sensitive and transported more glucose when the polyunsaturated to saturated fatty acid ratio in the diet was increased (Field 1990). Collectively, these data indicate that the 20- and 22-carbon fatty acids, namely EPA and DHA could play a preventive role in the development of insulin resistance. Due to their limited stability in vivo and their lack of biological specificity, PUFAs have not achieved widespread use as therapeutic agents. Chemical modifications of the n-3 polyunsaturated fatty acids have been performed by several research groups in order to change or increase their metabolic effects.
For example, the hypolipidemic effects of EPA was potentiated by introducing methyl or ethyl in a- or p-position of EPA. (Vaagenes 1999). The compounds also reduced plasma free fatty acid while EPA EE had no effect. In a recent work published by L. Larsen (Larsen 2005) the authors show that the a-methyl derivatives of EPA and DHA increased the activation of the nuclear receptor PP ARa and thereby the expression of L-FABP compared to EPA/DHA. EPA with an ethyl group in the a-position activated PP ARa with equal strength as a- methyl EPA. The authors suggest that delayed catabolism of these a-methyl FA may contribute to their increased effects due to decreased P-oxidation in mitochondria leading to peroxisomal oxidation. Alpha-methyl EPA has been shown to be a stronger inhibitor of platelet aggregation than EPAs both in vitro (Larsen 1998) and in vivo (Willumsen 1998).

Patent Abstract of Japan, publication number 05-00974 discloses DHA substituted in alpha-position with an OH-group, however only as an intermediate. No examination as to possible pharmaceutical effects of this compound is disclosed.
Laxdale Limited has also described the use of alpha substituted derivatives of EPA in the treatment of psychiatric or central nervous disorders (US6689812).

R= HI CH3, CH2CH3
(A) a-methyl EPA None of these modified fatty acids have, however, shown satisfactory pharmaceutical
activity, and none of them has reached the pharmaceutical market.
OBJECTIVES OF THE PRESENT INVENTION
The principal object of the present invention is to provide new DHA-derivative having
therapeutic activity.
Another object of the present invention is to develop a process for the preparation of
new DHA-derivative having therapeutic activity.
Yet another object of the present invention is to provide a pharmaceutical composition
of new DHA-derivative having therapeutic activity.
Still another object of the present invention is to provide a fatty acid composition of
new DHA-derivative having therapeutic activity.
Still another object of the present invention is to use new DHA-derivative for
prevention and/ or treatment of diabetes, obesity, preventing body weight gain,
amyloidos-related disease, prophylaxis of multiple risk factors or cardiovascular
diseases
STATEMENT OF INVENTION
Accordingly, the present invention provides a compound of formula (I):

wherein
- R1 and R2 are the same or different and may be selected from the group consisting of a
hydrogen atom, a hydroxy group, an alkyl group, a halogen atom, an alkoxy group, an acyloxy group, an acyl group, an alkenyl group, an alkynyl group, an aryl group, an alkylthio group, an alkoxycarbonyl group, an alkylsulfmyl group, an alkylsuifonyl group, an amino group, and an alkylamino group; and
- X represents a carboxylic acid group, a carboxylate group, or a carboxamide group, or
any pharmaceutically acceptable salt, solvate, complex or pro-drug thereof; with the
provisos that:
■ the compound of formula (I) is not (all-Z)-4,7,10,13,16,19- docosahexaenoic acid (DHA), alpha-methyl DHA, alpha-methyl DHA methyl ester, alpha-methyl DHA ethyl ester or alpha-hydroxy DHA ethyl ester; a process for the manufacture of a compound of formula (I); a pharmaceutical composition a compound of formula (I); A fatty acid composition of a compound of formula (I); Use of a compound of formula (I) for the manufacture of a medicament for controlling body weight reduction and/or for preventing body weight gain, use of a compound of formula (I) for the manufacture of a medicament for the treatment and/or the prevention of obesity or an overweight condition, use of a compound of formula (I) for the manufacture of a medicament for the prevention and/or treatment of diabetes in an animal, use of a compound of formula (I) for the manufacture of a medicament for the treatment and/or prevention of amyloidos- related diseases, use of a compound of formula (I) for the manufacture of a medicament for the treatment or prophylaxis of multiple R1sk factors for cardiovascular diseases, preferably for the treatment of elevated blood lipids, use of a compound of formula (I) for the manufacture of a medicament for prevention of stroke, cerebral or transient ischaemic attacks related to atherosclerosis of several arteR1es; and a method for controlling body weight reduction and/or for preventing body weight gain, wherein a pharmaceutically effective amount of a compound of formula (I) to a human or an animal, a method for the treatment and/or the prevention of obesity or an overweight condition, wherein a pharmaceutically effective amount of a compound of formula (I) is administered to a human or an animal, a method for the prevention and/or treatment of diabetes, wherein a pharmaceutically effective amount of a compound of formula (I) is administered to a human or an animal, a method for the treatment and/or prevention

of amyloidos-related diseases, wherein a pharmaceutically effective amount of a
compound of formula (I) is administered to a human or an animal, a method for the
treatment or prophylaxis of multiple R1sk factors for cardiovascular diseases, wherein a
pharmaceutically effective amount of a compound of formula (I) is administered to a
human or an animal, a method for the prevention of stroke, cerebral or transient
ischaemic attacks related to atherosclerosis of several arteR1es, wherein a
pharmaceutically effective amount of a compound of formula (I) is administered to a
human or an animal.
BR1EF DESCR1PTION OF THE ACCOMPANYING DRAWINGS
Fig. 1 is a schematic overview of the free fatty acid pool theory.
Fig. 2 shows an overview of the models and methods used in the present invention for
demonstrating effects on the metabolic syndrome and type 2 diabetes
Fig. 3 depicts the free fatty acid concentrations of different compounds according to the
invention in liver tissue from animals given these compounds in a concentration of
1.5% of total fat content.
Fig. 4 depicts the intracellular concentrations of DHA in liver tissue from animals
given different compounds according to the invention in a concentration of 1.5% of
total fat content.
Fig. 5 depicts the binding affinities for the PPARy receptor of different compounds
according to the invention.
Fig. 6 depicts the binding affinities to the nuclear receptor PP ARa of different
compounds according to the invention.
Fig. 7 depicts the binding affinities to the nuclear receptor RXRa of different
compounds according to the invention.
Fig. 8 depicts the release of luciferase from transfected cells treated with different
compounds according to the invention.
Fig. 9 shows the study design of the expeR1ment of block 4.
Fig. 10 shows the change of body weight duR1ng 2 weeks of diet intervention after 8
weeks of HP diet.
Fig. 11 shows the results from luciferase activity, i.e. endogenous PP ARy- activity).
Fig, 12 shows the endogenous luciferase activity in differenc compounds according to
the invention compared to DHA.

Fig. 13 shows a typical blood glucose elimination curve before and after animals with insulin resistance are given a compound with insulin resistance reducing effect. Figs. 14, 15 and 16 show different effects of DHA deR1vatives according to the invention on metabolic syndrome and insulin resistance. DETAILED DESCR1PTION OF THE INVENTION The present invention is in relation to a compound of formula (I):

- R] and R2 are the same or different and may be selected from the group consisting of a
hydrogen atom, a hydroxy group, an alkyl group, a halogen atom, an alkoxy group, an
acyloxy group, an acyl group, an alkenyl group, an alkynyl group, an aryl group, an
alkylthio group, an alkoxycarbonyl group, an alkylsulfmyl group, an alkylsulfonyl
group, an amino group, and an aikylamino group; and
- X represents a carboxylic acid group, a carboxylate group, or a carboxamide group, or
any pharmaceutically acceptable salt, solvate, complex or pro-drug thereof; with the
provisos that:
■ the compound of formula (I) is not (all-Z)-4,7,10,13,16,19- docosahexaenoic acid
(DHA), alpha-methyl DHA, alpha-methyl DHA methyl ester, alpha-methyl DHA ethyl
ester or alpha-hydroxy DHA ethyl ester.
In another embodiment of the present invention wherein said alkyl group is selected
from a group compR1sing of methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-buthyl, sec.
-butyl, n-hexyl, and benzyl.
In yet another embodiment of the present invention, wherein said halogen atom is
selected from a group compR1sing of fluoR1ne, chloR1ne, bromine, and iodine.
In still another embodiment of the present invention, wherein said alkoxy group is
selected from a group compR1sing of methoxy, ethoxy, propoxy, isopropoxy, sec-
butoxy, phenoxy, benzyloxy, OCH2CF3, and OCH2CH2OCH3.
In still another embodiment of the present invention, wherein said alkenyl group is
selected from a group compR1sing of allyl, 2-butenyl, and 3-hexenyl.

In still another embodiment of the present invention, wherein said alkynyl group is
selected from a group compR1sing of propargyl, 2-butynyl, and 3-hexynyl.
In still another embodiment of the present invention, wherein said aryl group is a
phenyl group.
In still another embodiment of the present invention, wherein said alkylthio group is
selected from a group compR1sing of methylthio, ethylthio, isopropylthio,
andphenylthio.
In still another embodiment of the present invention, wherein said alkoxycarbonyl
group is selected from a group compR1sing of methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, and butoxycarbonyl.
In still another embodiment of the present invention, wherein said alkylsulfinyl group is
selected from a group compR1sing of methanesulfinyl, ethanesulfinyl, and
isopropanesulfinyl.
In still another embodiment of the present invention, wherein said aikylsulfonyl group
is selected from a group compR1sing of methanesulfonyl, ethanesulfonyl, and
isopropanesulf onyl.
In still another embodiment of the present invention, wherein said alkylamino group is
selected from a group compR1sing of methylamino, dimethylamino, ethylarnino, and
diethylamino.
In still another embodiment of the present invention, wherein said carboxylate group is
selected from a group compR1sing of ethyl carboxylate, methyl carboxylate, n-propyl
carboxylate, isopropyl carboxylate, n-butyl carboxylate, sec-butyl carboxylate, and n-
hexyl carboxylate.
In still another embodiment of the present invention, wherein said carboxamide group
is selected from a group compR1sing of pR1mary carboxamide, N-methyl carboxamide,
N,N-dimethyl carboxamide, N-ethyl carboxamide, and N,N-diethyl carboxamide.
In still another embodiment of the present invention, wherein R1 and R2 are selected
from the group consisting of a hydrogen atom, a hydroxy group, an alkyl group, a
halogen atom, an alkoxy group, an alkylthio group, an alkylsulfmyl group, an
aikylsulfonyl group, an amino group, and an alkylamino group.
In still another embodiment of the present invention, wherein R1 and R2 are selected
from a group compR1sing of a hydrogen atom, a hydroxy group, a C1-C7 alkyl group, a

halogen atom, a C1-C7 alkoxy group, a C1-C7 alkyltio group, a C1-C7 alkylsulfmyl
group, a C1-C7 alkylsulfonyl group, an amino group, and a Ci -C7 alkylamino group.
In still another embodiment of the present invention, wherein said C1-C7 alkyl group is
methyl, ethyl, or benzyl; said halogen atom is fluoR1ne or iodine: said C1-C7 alkoxy
group is methoxy or ethoxy; said C1-C7 alkylthio group is methylthio, ethylthio or
phenylthio; said C1-C7 alkylsulfmyl group is ethanesulfmyl; said C1-C7 alkylsulfonyl
group is ethanesulfonyl; said C1-C7 alkylamino group is ethylamino or diethylamino;
and X represents a an ethylcarboxylate or a carboxamide group.
In still another embodiment of the present invention, wherein R1 and R2 are selected
from the group consisting of a hydrogen atom, a C2-C7 alkyl group, a halogen atom, a
CrC7 alkoxy group, a C1-C7 alkyltio group, a C1-C7 alkylsulfmyl group, a CrC7
alkylsulfonyl group, an amino group, and a C1-C7 alkylamino group; and X represents a
carboxylate.
In still another embodiment of the present invention, wherein said C2-C7 alkyl group is
ethyl, or benzyl; said halogen atom is fluoR1ne or iodine: said C1-C7 alkoxy group is
methoxy or ethoxy; said C1-C7 alkylthio group is methylthio, ethylthio or phenylthio;
said C1-C7 alkylsulfmyl group is ethanesulfmyl; said C1-C7 alkylsulfonyl group is
ethanesulfonyl; said C1-C7 alkylamino group is ethylamino or diethylamino; and X
represents a an ethylcarboxylate.
In still another embodiment of the present invention, wherein R1 and R2 are different.
In still another embodiment of the present invention, wherein said compound is in
racemic form.
In still another embodiment of the present invention, wherein said compound is in the
form of its R stereoisomer.
In still another embodiment of the present invention, wherein said compound is in the
form of its S stereoisomer.
In still another embodiment of the present invention, wherein one Of R] and R2
represents a C2-C7 alkyl group, and the other one represents a hydrogen atom.
In still another embodiment of the present invention, wherein said alkyl group is ethyl.
In still another embodiment of the present invention, wherein said compound is in
racemic form.
In still another embodiment of the present invention, wherein said compound is in the
form of its R stereoisomer.

In still another embodiment of the present invention, wherein said compound is in the
form of its S stereoisomer.
In still another embodiment of the present invention, wherein said alkyl group is
benzyl.
In still another embodiment of the present invention, wherein one of R1 and R2
represents an alkoxy group, and the other one represents a hydrogen atom.
In still another embodiment of the present invention, wherein said alkoxy group is
ethoxy or methoxy.
In still another embodiment of the present invention, wherein one of R1 and R2
represents a halogen atom, and the other one represents a hydrogen atom.
In still another embodiment of the present invention, wherein said halogen atom is
fluoR1ne or iodine.
In still another embodiment of the present invention, wherein one of R1 and R2
represents a alkylthio group, and the other one represents a hydrogen atom.
In still another embodiment of the present invention, wherein said alkylthiogroup is
ethylthio.
In still another embodiment of the present invention, wherein said alkylthiogroup is
methylthio or phenylthio.
In still another embodiment of the present invention, wherein one of R1 and R2
represents an alkylsulfonyl group, and the other one represents a hydrogen atom.
In still another embodiment of the present invention, wherein said alkylsulfonyl group
is ethanesulfonyl.
In still another embodiment of the present invention, wherein one of R1 and R2
represents an amino group, and the other one represents a hydrogen atom.
In still another embodiment of the present invention, wherein one of R1 and R2
represents an alkyl-amino group, and the other one represents a hydrogen atom.
In still another embodiment of the present invention, wherein said alkyl-amino group is
ethyl-amino or diethyl-amino.
In still another embodiment of the present invention, wherein R1 and R2 represent Ci-
C7- alkyl groups.
In still another embodiment of the present invention, wherein said alkyl groups are
methyl groups.

In still another embodiment of the present invention, wherein said alkyl groups are
ethyl groups.
In still another embodiment of the present invention, wherein X is ethyl carboxylate.
In still another embodiment of the present invention, in the form, of a phospholipid, a
tR1-, di- or monoglyceR1de, or in the form of a free acid.
In still another embodiment of the present invention, wherein said compound is for use
as a medicament.
The present invention also relates to a process for the manufacture of a compound of
formula (I).
In another embodiment of the present invention, wherein said compound is prepared
from (all-Z)-4, 7, 10, 13, 16, 19-docosahexaenoic acid (DHA).
In yet another embodiment of the present invention, wherein said DHA is prepared
from a vegetable, a microbial and/or an animal source.
In still another embodiment of the present invention, wherein said DHA is prepared
from a maR1ne oil.
In still another embodiment of the present invention, wherein said maR1ne oil is fish oil.
The present invention also relates to a pharmaceutical composition compR1sing a
compound of formula (I) as an active ingredient.
In still another embodiment of the present invention, wherein said composition further
compR1sing a pharmaceutically acceptable carR1er.
In still another embodiment of the present invention, wherein said composition is
formulated for oral administration.
In still another embodiment of the present invention, wherein said formulation is in the
form of a capsule or a sachet.
In still another embodiment of the present invention, wherein said formulation is
formulated to provide a daily dosage ranging from 10 mg to 10 g of said compound.
In still another embodiment of the present invention, wherein said formulation is
formulated to provide a daily dosage ranging from 100 mg to 1 g of said compound.
The present invention also relates to a fatty acid composition compR1sing a compound
of formula (I).
In still another embodiment of the present invention, wherein at least 60% by weight of
the fatty acid composition is compR1sed of said compound.

In still another embodiment of the present invention, wherein at least 90% by weight of
the fatty acid composition is compR1sed of said compound.
In still another embodiment of the present invention, wherein said composition further
compR1sing fatty acids selected from (all-Z)-5,8,l 1,14,17-eicosapentaenoic acid (EPA),
(all-Z)-4,7,10,13,16,19-docosahexaenoic acid (DHA), (all-Z)- 6,9,12,15,18-
heneicosapentaenoic acid (HPA), and/or (all-Z)-7.10,13.16,19- docosapentaenoic acid
(DPA).
In still another embodiment of the present invention, wherein said fatty acids are
present in the form of deR1vatives.
In still another embodiment of the present invention, wherein said composition further
compR1sing a pharmaceutically acceptable antioxidant.
In still another embodiment of the present invention, wherein said antioxidant is
tocopherol.
In still another embodiment of the present invention, wherein said composition is for
use as a medicament.
The present invention is in relation to use of a compound of formula (I) for the
manufacture of a medicament for controlling body weight reduction and/or for
preventing body weight gain.
The present invention is in relation to use of a compound of formula (I) for the
manufacture of a medicament for the treatment and/or the prevention of obesity or an
overweight condition.
The present invention is in relation to use of a compound of formula (I) for the
manufacture of a medicament for the prevention and/or treatment of diabetes in an
animal.
In another embodiment of the present invention, wherein the diabetes is type 2 diabetes.
The present invention is in relation to use of a compound of formula (I) for the
manufacture of a medicament for the treatment and/or prevention of amyloidos- related
diseases.
The present invention is in relation to use of a compound of formula (I) for the
treatment or prophylaxis of multiple R1sk factors for cardiovascular diseases, preferably
for the treatment of elevated blood lipids.

The present invention is in relation to use of a compound of formula (I) for the
manufacture of a medicament for prevention of stroke, cerebral or transient ischaemic
attacks related to atherosclerosis of several arteR1es.
The present invention relates to a method for controlling body weight reduction and/or
for preventing body weight gain, wherein a pharmaceutically effective amount of a
compound of formula (I) is administered to a human or an animal.
The present invention relates to a method for the treatment and/or the prevention of
obesity or an overweight condition, wherein a pharmaceutically effective amount of a
compound of formula (I) is administered to a human or an animal.
The present invention relates to a method for the prevention and/or treatment of
diabetes, wherein a pharmaceutically effective amount of a compound of formula (I) is
administered to a human or an animal.
In another embodiment of the present invention, wherein the diabetes is type 2 diabetes.
The present invention relates to a method for the treatment and/or prevention of
amyloidos-related diseases, wherein a pharmaceutically effective amount of a
compound of formula (I) is administered to a human or an animal.
The present invention relates to a method for the treatment or prophylaxis of multiple
R1sk factors for cardiovascular diseases, wherein a pharmaceutically effective amount of
a compound of formula (I) is administered to a human or an animal.
The present invention relates to a method for the prevention of stroke, cerebral or
transient ischaemic attacks related to atherosclerosis of several arteR1es, wherein a
pharmaceutically effective amount of a compound of formula (I) is administered to a
human or an animal.
In another embodiment of the present invention, wherein the compound of formula (I)
is administered orally to a human or an animal.
The aim of the present invention is to provide new DHA-deR1vatives having
therapeutical activity.
Based on the present invention a number of aspects are presented in the appended
claims. Some of these aspects are:
1. Novel compounds, i.e. certain a-substituted polyunsaturated fatty acid deR1vatives.
2. The novel compounds for use as a medicament and for use in therapy.
3. A fatty acid composition or a pharmaceutical composition compR1sing the novel compounds.

4. A fatty acid composition compR1sing the novel compounds for use as a medicament and for use in therapy.
5. Use of the novel compounds for the production of a medicament for the prevention and/or treatment of diabetes in humans or an animal.
6. Use of the novel compounds for the production of a medicament for the treatment and/or the prevention of obesity or an overweight condition.
7. Use of the novel compounds for the production of a medicament for controlling body weight reduction and/or for preventing body weight gain.
8. Use of the novel compounds for the production of a medicament for the treatment and/or prevention of amyloidos-related diseases.
9. Use of the novel compounds for the production of a medicament for the treatment or
prophylaxis of multiple R1sk factors or cardiovascular diseases.
10. Use of the novel compounds for the production of a medicament for the prevention of stroke, cerebral or transient ischaemic attacks related to atherosclerosis of several arteR1es.
11. A method for specific treatment of a diabetic condition, preferably type 2 diabetes.
12. A method for controlling body weight reduction, for preventing body weight gain and/or for the treatment and/or the prevention of obesity or an overweight condition.
13. A method for the treatment and/or prevention of amyloidos-related diseases.
14. A method for the treatment or prophylaxis of multiple R1sk factors for
cardiovascular diseases.
15. A method for the prevention of stroke, cerebral or transient ischaemic attacks related to atherosclerosis of several arteR1es.
16. Processes for prepaR1ng novel fatty acid analogous according to the invention. The present invention relates to a compound of formula (I):

wherein
- R1 and R2 are the same or different and may be selected from the group consisting of a
hydrogen atom, a hydroxy group, an alkyl group, a halogen atom, an alkoxy group, an

acyloxy group, an acyl group, an alkenyl group, an alkynyl group, an aryl group, an alkylthio group, an alkoxycarbonyl group, an alkylsulfmyl group, an alkylsulfonyl group, an amino group, and an alkylamino group; and
- X represents a carboxylic acid group, a carboxylate group, or a carboxamide group, or any pharmaceutically acceptable salt, solvate, complex or pro-drug thereof, with the provisos that:
■ the compound of formula (I) is not (all-Z)-4,7, 10,13,16,19- docosahexaenoic acid
(DHA), alpha-methyl DHA, alpha-methyl DHA methyl ester, alpha-methyl DHA ethyl
ester, or alpha-hydroxy DHA ethyl ester. The provisos correspond to the following
cases:
' when R1 is a hydrogen atom, then R2 is not a hydrogen atom;
? when R2 is a hydrogen atom, then R1 is not a hydrogen atom;
? when R1 is a methyl group, then R2 is not a hydrogen atom, and X is not a carboxylic acid group, a methylcarboxylate, or an ethylcarboxylate;

? when R2 is a methyl group, then R] is not a hydrogen atom, and X is not a 5 carboxylic acid group, a methylcarboxylate, or an ethylcarboxylate;
? when R1 is a hydroxy group, then R2 is not a hydrogen atom, and X is not an ethylcarboxylat; and
? when R2 is a hydroxy group, then R\ is not a hydrogen atom, and X is not an ethylcarboxylat. 0 In a compound according to the invention, said alkyl group may be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, n- hexyl, and benzyl; said halogen atom may be selected from the group consisting of fluoR1ne, chloR1ne, bromine, and iodine; said alkoxy group may be selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, sec.-butoxy, phenoxy, 5 benzyloxy, OCH2CF3, and OCH2CH2OCH3; said acyloxy group may be selected from acetoxy, propionoxy, and butyroxy; said alkenyl group may be selected from the group consisting of allyl, 2-butenyl, and 3-hexenyl; said alkynyl group may be selected from the group consisting of propargyl, 2-butynyl, and 3-hexynyl; said aryl group is a phenyl group; said alkylthio group may be selected from the group O consisting of methylthio, ethylthio, isopropylthio, and phenylthio; said alkoxycarbonyl group may be selected from the group consisting of methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and butoxy car bony 1; said alkylsulfinyl group may be selected from the group consisting of methanesulfmyl, ethanesulfinyl, and isopropanesulfmyl; said

alkylsulfonyl group may be selected from 5 the group consisting of methanesulfonyl, ethanesulfonyl, and isopropanesulfonyl; said alkylamino group may be selected from the group consisting of methylamino, dimethylamino, ethylamino, and diethylamino; said carboxylate group may be selected from the group consisting of ethyl carboxylate, methyl carboxylate, n-propyl carboxylate, isopropyl carboxylate, n-butyl carboxylate, sec-butyl carboxylate, and O n-hexyl carboxylate; said carboxamide group may be selected from the group consisting of pR1mary carboxamide, N-methyl carboxamide, N,N-dimethyl carboxamide, N-ethyl carboxamide, and N,N-diethyl carboxamide. In one embodiment of the invention, R1 and R2 are selected from the group consisting of a hydrogen atom, a hydroxy group, an alkyl group, a halogen atom, an 5 alkoxy group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group, an amino group, and an alkylamino group.
In another embodiment of the invention, R1 and R2 are selected from the group consisting of a hydrogen atom, a hydroxy group, a C1-C7 alkyl group, a halogen atom, a C1-C7 alkoxy group, a C1-C7 alkyltio group, a C1-C7 alkylsulfmyl group, a C1-C7 alkylsulfonyl group, an amino group, and a Ci -C? alkylamino group. Then, said C1-C7 alkyl group may be methyl, ethyl, or benzyl; said halogen atom may be fluoR1ne or iodine; said C1-C7 alkoxy group may be methoxy or ethoxy; said C1-C7 alkylthio group may be methylthio, ethylthio or phenylthio; said C1-C7 alkylsulfmyl group may be ethanesulfmyl; said C1-C7 alkylsulfonyl group may be ethanesulfonyl; said C1-C7 alkylamino group may be ethylamino or diethylamino; and X may represent an ethylcarboxylate or a carboxamide group.
In another embodiment of the invention, R1 and R2 are selected from the group consisting of a hydrogen atom, a C2-C7 alkyl group, a halogen atom, a C1-C7 alkoxy group, a C1-C7 alkyltio group, a C1-C7 alkylsulfmyl group, a CrC7 alkylsulfonyl group, an amino group, and a C1-C7 alkylamino group; and X represents a carboxylate. Then, said C2-C7 alkyl group may be ethyl, or benzyl; said halogen atom may be fluoR1ne or iodine: said C1-C7 alkoxy group may be methoxy or ethoxy; said C1-C7 alkylthio group may be methylthio, ethylthio or phenylthio; said C1-C7 alkylsulfmyl group may be ethanesulfmyl; said C1-C7 alkylsulfonyl group may be ethanesulfonyl; said C1-C7 alkylamino group may be ethylamino or diethylamino; and X represents a an ethylcarboxylate.

In the compound according to formula (I) of the present invention, R1 and R2 may be
the same or different. When they are different, the compounds of formula (I) are
capable of existing in stereoisomeR1c forms. It will be understood that the invention
encompasses all optical isomers of the compounds of formula (I) and mixtures thereof
including racemates.
Therefore, the present invention includes, where R1 is different from R2, compounds of
formula (I) that are racemic or enantiomeR1cally pure, either as the (S) or (R)
enantiomer. Therefore, the present invention includes, where R1 is different from R2,
compounds of formula (I) that are racemic or enantiomeR1c pure, either as the (S) or (R)
stereoisomer.
Within the scope of the invention are enantiomers of the compounds of the formula (I),
as hereinbefore defined. Moreover, the enantiomers of the DHA deR1vatives according
to the invention might be in the form of a carboxylic acid, or a pharmaceutically
acceptable salt thereof, any ester, anhydR1de or amide (pR1mary, secondary, tertiary).
The acid deR1vative might be in the form of a phospholipid or a tR1- di- or
monoglyceR1de.
In one embodiment of a compound of formula (I) according to the invention, one of R]
and R2 represents a C2-C7 alkyl group, e.g. ethyl or benzyl, and the other one represents
a hydrogen atom. Preferably, the alkylgroup is ethyl.
In another embodiment of a compound of formula (I) according to the invention, one of
R1 and R2 represents an alkoxy group, e.g. ethoxy or methoxy, and the other one
represents a hydrogen atom.
In another embodiment of a compound of formula (I) according to the invention, one
OfR] and R2 represents a halogen atom, e.g. fluoR1ne or iodine, and the other one
represents a hydrogen atom. In another embodiment of a compound of formula (I)
according to the invention, one of R1 and R2 represents an alkylthio group, e.g.
ethylthio, methylthio or phenylthio, and the other one represents a hydrogen atom.
Preferably, the alkylthiogroup is ethylthio.
In another embodiment of a compound of formula (I) according to the invention, one of
R1 and R2 represents an alkylsulfonyl group, e.g. ethylsulfonyl, and the other one
represents a hydrogen atom.
In another embodiment of a compound of formula (I) according to the invention, one of
R] and R2 represents an amino group, and the other one represents a hydrogen atom. In

another embodiment of a compound of formula (I) according to the invention, one of
R1 and R2 represents an alkyl-amino group, e.g. ethyl-amino or diethyl-amino, and the
other one represents a hydrogen atom.
In a further embodiment of a compound of formula (I) according to the invention, R1
and R2 are the same and represent Ci-C7-alkyl groups, preferably methyl groups or
ethyl groups.
In preferred embodiments of the compound of formula (I), X is a carboxylate, e.g. ethyl
carboxylate.
The compound according to the invention may exist in the form of a phospholipid, a tR1-
, di- or monoglyceR1de, or in the form of a free acid. The alpha-substituted DHA-
deR1vatives according to the invention have very surpR1singly shown excellent results
with regard to pharmaceutical activity. In particular, the fatty acid deR1vatives according
to the present invention possess a huge potential to be used in the treatment and/or
prevention of diabetes and pre-stages thereof. Another aspect of the present invention
relates to a compound of formula (I) for use as a medicament.
The invention also relates to a process for the manufacture of a compound of formula
(I). For example, a compound of formula (I) may be prepared from (all-Z)-
4,7,10,13,16,19-docosahexaenoic acid (DHA). The DHA may e.g. oR1ginate from a
vegetable, a microbial and/or an animal source, such as a maR1ne fish oil. Another
important advantage with compounds of formula (I) is that the fatty acid analogues can
be prepared directly from (all-Z)-4,7,10,13,16,19-docosahexaenoic acid (DHA).
In a preferred embodiment of the invention, the fatty acid analogues of formula (I) are
prepared from DHA, wherein said DHA is obtained from at least one of vegetable,
microbial and animal oR1gins, or combinations thereof. The invention includes therefore
deR1vatives prepared from DHA-containing oil from microbial oR1gin. Suitable, said
DHA is produced from a maR1ne oil, such as a fish oil.
Another aspect of the present invention relates to a pharmaceutical composifion
compR1sing a compound of formula (I) as an active ingredient. The pharmaceutical
composition may further compR1se a pharmaceutically acceptable carR1er. Suitably, a
pharmaceutical composition according to the invention is formulated for oral
administration, e.g. in the form of a capsule or a sachet. A suitable daily dosage of a
compound of formula (I) according to the present invention is 10 mg to 10 g, in
particular 100 mg to 1 g of said compound.

In addition, the present invention relates to a fatty acid composition compR1sing a
compound of formula (I). At least 60%, or at least 90% by weight of the fatty acid
composition may be compR1sed of said compound. The fatty acid composition may
further compR1se (all-Z)-5,8,l 1,14,17-eicosapentaenoic acid (EPA), (all-Z)-
4,7,10,13,16,19-docosahexaenoic acid (DHA), (all-Z)-6,9,12,15,18-
heneicosapentaenoic acid (HPA), and/or (all-Z)-7,10,13,16,19-docosapentaenoic acid (DPA). The fatty acids may be present in the form of deR1vatives. A fatty acid composition according to the present invention may further compR1se a pharmaceutically acceptable antioxidant, e.g. tocopherol. Within the scope of the present invention is also a fatty acid composition descR1bed above, for use as a medicament. In a further aspect, the present invention relates to the use of a compound according to formula (I) for the manufacture of a medicament for controlling body weight reduction and/or for preventing body weight gain; for the manufacture of a medicament for the treatment and/or the prevention of obesity or an overweight condition; for the manufacture of a medicament for the prevention and/or treatment of diabetes in an animal, in particular type 2 diabetes; for the manufacture of a medicament for the treatment and/or prevention of amyloidos-related diseases; for the manufacture of a medicament for the treatment or prophylaxis of multiple R1sk factors for cardiovascular diseases, preferably for the treatment of elevated blood lipids for the manufacture of a medicament for prevention of stroke, cerebral or transient ischaemic attacks related to atherosclerosis of several arteR1es.
In addition, the present invention relates to a method for controlling body weight reduction and/or for preventing body weight gain; a method for the treatment and/or the prevention of obesity or an overweight condition; a method for the prevention and/or treatment of diabetes, in particular type 2 diabetes; a method for the treatment and/or prevention of amyloidos-related diseases; a method for the treatment or prophylaxis of multiple R1sk factors for cardiovascular diseases; a method for the prevention of stroke, cerebral or transient ischaemic attacks related to atherosclerosis of several arteR1es, wherein a pharmaceutically effective amount of a compound of formula (I) is administered to a human or an animal. Suitably, the compound of formula (I) is administered orally to a human or an animal.
In the research work leading to the present invention, novel DHA-deR1vatives were prepared, which showed excellent pharmaceutical activity. Fatty acids enter cells

passively or trough G-protein coupled transporter systems, such as fatty acid transport proteins. Well inside the cells they are temporaR1ly bound by binding proteins (Fatty acid binding proteins, FABP), which play an important role in directing fatty acids to vaR1ous intracellular compartments for metabolism and gene expression (Pawar & Jump 2003). (Fig. 1 liver cell).
EsteR1fication of fatty acids into tR1glyceR1des, polar lipids, and cholesterol esters and their beta-oxidation (mitochondR1al and peroxisomal) requires conversion of fatty acids to acyl CoA thioesters. Other pathways, like microsomal NADPH- dependent mono-oxidation and eikosanoids synthesis, utilise non-esteR1fied fatty acids as substrates. All these reactions are likely to influence cellular levels of free fatty acids (non-esterfified) and thereby the amount and type of fatty acids which could be used as ligands to nuclear receptors. Because PPARs are known to bind non-esteR1fied fatty acids it is reasonable to expect that the composition of the free fatty acid pool is an important determinant in the control of PPAR activity.
The composition of the free fatty acid pool is affected by the concentration of exogenous fatty acids enteR1ng the cells, and their rate of removal via pathways listed above. Since short and medium chain fatty acids are effectively recruited to these pathways, in practice only the long-chain polyunsaturated fatty acids will be available for liganding to nuclear receptors. In addition, fatty acid structure may also be an important determinant. Even if a seR1es of mono and polyunsaturated fatty acids demonstrated affinity to the PP ARa receptor, EPA and DHA demonstrated the highest binding capacity in expeR1ments with rat liver cells (Pawar & Jump 2003). Searching for fatty acid candidates available for genetic modification of proteins by interaction with nuclear receptors like the PPARs, it is important to veR1fy that the respective fatty acids will be enR1ched in the free fatty acid pool. DHA which enter cells are rapidly converted to fatty acyl-CoA thioesters and incorporated into phospholipids and due to this, the intracellular DHA level is relatively low. These DHA-CoA are also substrate for P-oxidation pR1maR1ly in the peroxisomes that lead to retroconvertion of DHA to EPA, see Fig. 1. Because of the 5 rapid incorporation into neutral lipids and the oxidation pathway DHA will not stay long in the free fatty acid pool. Due to this the effect of DHA on gene expression is probably limited.

The present invention aims at achieving an accumulation of fatty acid deR1vatives in the free fatty acid pool, rather than incorporation into phosholipids. The 0 present inventors have surpR1singly found that the introduction of at least one substituent in the a-position of DHA will lead to a slower oxidation rate in addition to less incorporation into neutral lipids. This will lead to an increased effect on gene expression, since the DHA deR1vatives will accumulate in the tissue particular within liver, muscle, and adipose cells and tR1gger local nuclear receptor activity to a greater 5 extent than DHA. The different substituents according to the invention will give vaR1able affinities of the deR1vatives to fatty acids binding receptors. It is also possible that changes in affinity to fatty acids binding proteins lead to changes in the biological activity of these a-substituted DHA deR1vatives of formula (I). Altogether theses O changes lead to an increased therapeutic effect of the DHA deR1vatives according to the invention compared to DHA.
EPA (all-Z)-5,8,l 1,14,17-eicosapentaenoic acid) has earlier been alkylated in a- and p-position to inhibit mitochondR1al p-oxidation. DHA is not oxidised in the mitochondR1a, but rather incorporated into phospholipids. In the peroxisomes though 5 some DHA is retroconverted to EPA. A substituent in the a-position of EPA and DHA will due to this affect different metabolic pathways. It has earlier been shown that a-methyl EPA and P-methyl EPA is incorporated into phospholipids and tR1glyceR1ds while a-ethyl EPA is not (Larsen 1998), In this study the deR1vatives were tested as substrates and/or inhibitors of enzymes involved in the eicosanoid cascade. O Since most of the substrates for these enzymes are fatty acids liberated from phospholipids it was desired that the deR1vatives were incorporated into phospholipids. In contrast to this, as mentioned before, we want deR1vatives that will not incorporate into lipids, but rather accumulate in the NEFA pool.
Througout this descR1ption, the abbreviation "PRB-x", where x is an integer, 5 will be used when descR1bing specific compounds according to the invention. Below, the structural formulas and tR1vial names for each of these compounds are listed:

t
PRB-5 a,a di-methyl docosahexaenoic acid ethyl ester

PRB-6 a-tlomethyl docosahexaenoic acid ethyl ester

PRB-7 a-tioethyl docosahexaenoic acid ethyl ester

PRE-8 a,a di-ethyl docosahexaenoic acid ethyl ester

PRB-9 a-benzyl docosahexaenoic acid ethyl ester

PRB-1 Oa-ethanesulfinyl docosahexaenoic acid ethyl ester

PRB-11 a-tiophenyl docosahexaenoic acid ethyl ester

PRB-12a-hydroxy docosahexaenoic acid ethyl ester

PRB-13a-methyl docosahexaenoic acid

PRB-14 a-methoxy docosahexaenoic acid ethyf ester

PRB-15 a-iodo docosaiiexaenoic acid ethyl ester

PRB-17a--amJno docosahexanolc acid ethyl ester

PRB-18 (4R,5S)-3-docosahexaenoyl-4-methyl-5-phenyl-oxa2olidin-2-one

PRB-19 (4R,5S)-3-[{S)-a"ethyldocosahexaenoy!]-4-nnethyl-5-phenyl-oxazolidin-2-one

PRB-20 (S)-(+)-a-6thy! docosahexanoic acid ethyl ester

PRB-21 (4S,5R)-3-clocosahexaenoyl-
4-methyl-5-phenyl-oxazofidin-2-one

PRB-22(4S,5R)-3-[(R)-a-ethyldocosahexaenoyl]-4-methyl-5-pheny[-oxazolidin-2-one
V

PRB-23 (R)-(-)-a-ethyl docosahexanoic add ethyl ester

PRB-24
2-(1,3-Dioxo-1,3-dihycfro-isoindol-2-y[)-docos
ahexaenoic acid ethyl ester

PRB-25a-ethyl-amino
docosahexanoic acid ethyl
ester
I I
PRB-26a-diethyl-amino docosahexanoic acid ethyl ester

PRB-I corresponds to a compound of formula (I) in which KI or K2 is memyi, ana ihe
other one is hydrogen, and X is ethyl carboxylate.
PRB-2 corresponds to a compound of formula (I) in which R1 or R2 is ethyl, and the
other one is hydrogen, and X is ethyl carboxylate. PRB-3 corresponds to a compound
of formula (I) in which R1 or R2 is ethoxy, and the other one is hydrogen, and X is ethyl
carboxylate.
PRB-4 corresponds to a compound of formula (I) in which R1 or R2 is fluoR1ne, and the
other one is hydrogen, and X is ethyl carboxylate.
PRB-5 corresponds to a compound of formula (I) in which R1 and R2 is methyl, and X
is ethyl carboxylate.
PRB-6 corresponds to a compound of formula (I) in which R] or R2 is methylthio, and
X is ethyl carboxylate.
PRB-7 corresponds to a compound of formula (I) in which R1 or R2 is ethylthio, and the
other one is hydrogen, and X is ethyl carboxylate. PRB-8 corresponds to a compound
of formula (I) in which R1 and R2 is ethyl, and the other one is hydrogen, and X is ethyl
carboxylate.
PRB-9 corresponds to a compound of formula (I) in which R1 or R2 is benzyl, and the
other one is hydrogen, and X is ethyl carboxylate.
PRB-IO corresponds to a compound of formula (I) in which R1 or R2 is ethanesulfmyl,
and the other one is hydrogen, and X is ethyl carboxylate.
PRB-11 corresponds to a compound of formula (I) in which R1 or R2 is phenylthio, and
the other one is hydrogen, and X is ethyl carboxylate.
PRE- 12 corresponds to a compound of formula (I) in which R1 or R2 is hydroxy, and
the other one is hydrogen, and X is ethyl carboxylate. PRB-13 corresponds to a
compound of formula (I) in which R] or R2 is methyl, and the other one is hydrogen,
and X is pR1mary carboxamide.
PRB- 14 corresponds to a compound of formula (I) in which R1 or R2 is methoxy, and
the other one is hydrogen, and X is ethyl carboxylate.
PRB-15 corresponds to a compound of formula (I) in which R\ or R2 is iodine, and the
other one is hydrogen, and X is ethyl carboxylate.
PRB-17 corresponds to a compound of formula (I) in which R1 or R2 is amino, and the
other one is hydrogen, and X is ethyl carboxylate.

PRB-20 corresponds to the (S) stereoisomer of a compound of formula (I) in which R1
or R2 is ethyl, and the other one is hydrogen, and X is ethyl carboxylate. PRB-23
corresponds to the (R) stereoisomer of a compound of formula (I) in which R1 or R2 is
ethyl, and the other one is hydrogen, and X is ethyl carboxylate.
PRB-24 corresponds to a compound of formula (I) in which R1 or R2 is N- phtalimide,
and the other one is hydrogen, and X is ethyl carboxylate.
PRB-25 corresponds to a compound of formula (I) in which R1 or R2 is ethyl- amino,
and the other one is hydrogen, and X is pR1mary carboxamide. PRB-26 corresponds to a
compound of formula (I) in which R1 or R2 is diethyl-amino, and the other one is
hydrogen, and X is ethyl carboxylate.
PRB-2 is the most preferred compound according to the present invention. Other
preferred compounds according to the invention are PRB-5, PRB-7, and PRB- 8.
It is to be understood that the present invention encompasses any possible
pharmaceutically acceptable salts, solvates, complexes or prodrugs of the compounds
of formula (I).
"Prodrugs" are entities which may or may not possess pharmacological activity as such,
but may be administered (such as orally or parenterally) and thereafter subjected to
bioactivation (for example metabolized) in the body to form the agent of the present
invention which is pharmacologically active.
Where X is a carboxylic acid, the present invention also includes salts of the carboxylic
acids. Suitable pharmaceutically acceptable salts of carboxy groups includes metal
salts, such as for example aluminium, alkali metal salts such as lithium, sodium or
potassium, alkaline metal salts such as calcium or magnesium and ammonium or
substituted ammonium salts.
A "therapeutically effective amount" refers to the amount of the therapeutic agent
which is effective to achieve its intended purpose. While individual patient needs may
vary, determination of optimal ranges for effective amounts of each nitR1c oxide adduct
is within the skill of the art. Generally the dosage regimen for treating a condition with
the compounds and/or compositions of this invention is selected in accordance with a
vaR1ety of factors, including the type, age, weight, sex, diet and medical condition of the
patient.
By "a medicament" is meant a compound according to formula (I), in any form suitable
to be used for a medical purpose, e.g. in the form of a medicinal product, a

pharmaceutical preparation or product, a dietary product, a food stuff or a food
supplement.
In the context of the present specification, the term "therapy" also includes
"prophylaxis" unless there are specific indications to the contrary. The terms
"therapeutic" and "therapeutically" should be constructed accordingly.
Treatment includes any therapeutic application that can benefit a human or non-human
animal. The treatment of mammals is particularly preferred. Both human and veteR1nary
treatments are within the scope of the present invention. Treatment may be in respect of
an existing condition or it may be prophylactic. It may be of an adult, a juvenile, an
infant, a foetus, or a part of any of the aforesaid (e.g. an organ, tissue, cell, or nucleic
acid molecule). By "chronic treatment" is meant treatment that continues for some
weeks or years.
"A therapeutically or a pharmaceutically active amount" relates to an amount that will
lead to the desired pharmacological and/or therapeutic effects. A compound according
to the present invention may for example be included in a food stuff, a food
supplement, a nutR1tional supplement, or a dietary product.
Alpha-substituted DHA deR1vatives and EPA (or DHA for that matter) can be bound
together and combined on tR1glyceR1de form by an esteR1fication process between a
mixture of alpha-deR1vatives, EPA and glycerol catalysed by Novozym 435 (a
commercially available lipase from Candida antarctica on immobilised form).
The compounds of formula (I) have activity as pharmaceuticals, in particular as tR1ggers
of nuclear receptor activity. Thus, the present invention also relates to compounds of
formula (I), pharmaceutically acceptable salts, solvates, complexes or pro-drugs
thereof, as hereinbefore defined, for use as a medicament and/or for use in therapy.
Preferably, the novel compounds, or pharmaceutically acceptable salts, solvates,
complexes or pro-drugs thereof, of the invention may be used: - for the prevention
and/or treatment of diabetes mellitus in humans or animals; for controlling body weight
reduction and/or for preventing body weight gain;
- for the prevention and/or treatment of obesity or an overweight condition in humans or in an animal;
- for the treatment and/or prevention of amyloidos-related diseases; - for the treatment or prophylaxis of multiple R1sk factors for cardiovascular diseases;

- for the prevention of stroke, cerebral or transient ischaemic attacks related to
atherosclerosis of several arteR1es.
- for the treatment of TBC or HIV.
There are two major forms of diabetes mellitus. One is type 1 diabetes, which is known as insulin-dependent diabetes mellitus (IDDM), and the other one is type 2 diabetes, which is also known as non-insulin-dependent diabetes mellitus (NIDDM). Type 2 diabetes is related to obesity/overweight and lack of exercise, often of gradual onset, usually in aduhs, and caused by reduced insulin sensitivity, so called peR1ferral insulin resistance. This leads to a compensatory increase in insulin production. This stage before developing full fetched type 2 diabetes is called the metabolic syndrome and characteR1zed by hypeR1nsulinemia, insulin resistance, obesity, glucose intolerance, hypertension, abnormal blood lipids, hypercoagulopathia, dyslipidemia and inflammation, often leading to atherosclerosis of the arteR1es. Later when insulin production seizes, type 2 diabetes mellitus develops.
In a preferred embodiment, the compounds according to formula (I) may used for the treatment of type 2 diabetes. The compounds according to formula (I) may also be used for the treatment of other types of diabetes selected from the group consisting of metabolic syndrome, secondary diabetes, such as pancreatic, extrapancreatic/endocR1ne or drug-induced diabetes, or exceptional forms of diabetes, such as lipoatrophic, myatonic or a disease caused by disturbance of the insulin receptors. The invention also includes treatment of type 2 diabetes. Suitably, compounds of formula (I), as hereinbefore defined, may activate nuclear receptors, preferably PPAR (peroxisome proliferator-activated receptor) a and/or y.
The compounds of formula (I) may also be used for the treatment and/or prevention of obesity. Obesity is usually linked to an increased insulin resistance and obese people run a high R1sk of developing type 2 diabetes which is a major R1sk factor for development of cardiovascular diseases. Obesity is a chronic disease that afflict an increasing proportion of the population in Western societies and is associated, not only with a social stigma, but also with decreasing life span and numerous problems, for instance diabetes mellitus, insulin resistance and hypertension. The present invention thus fulfils a long-felt need for a drug that will reduce total body weight, or the amount of adipose tissue, of preferably obese humans, towards their ideal body weight without significant adverse side effects.

The compounds according to formula (I) may also be used for the prevention and/or treatment of amyloidos-related diseases. Amyloidos-related conditions or diseases associated with deposition of amyloid, preferably as a consequence of fibR1l or plaque formation, includes Alzheimer's disease or dementia, Parkinson's disease, amyotropic lateral sclerosis, the spongiform encephalopathies, such as Creutzfeld- Jacob disease, cystic fibrosis, pR1mary or secondary renal amyloidoses, IgA nephropathy, and amyloid depostion in arteR1es, myocardium and neutral tissue. These diseases can be sporadic, inheR1ted or even related to infections such as TBC or HIV, and are often manifested only late in life even if inheR1ted forms may appear much earlier. Each disease is associated with a particular protein or aggregates of these proteins are thought to be the direct oR1gin of the pathological conditions associated with the disease. The treatment of a amyloidos-related disease can be made either acutely or chronically. The compounds of formula (I) may also be used for the treatment due to reduction of amyloid aggregates, prevention of misfolding of proteins that may lead to formation of so called fibR1ls or plaque, treatment due to decreasing of the production of precursor protein such as Ap-protein (amyloid beta protein), and prevention and/or treatment due to inhibiting or slow down the formation of protein fibR1ls, aggregates, or plaque. Prevention of fibR1l accumulation, or formation, by administeR1ng compounds of formula (I), as hereinbefore defined, is also included herein. In one embodiment, the novel compounds, pharmaceutically acceptable salts, solvates, complexes or pro-drugs thereof, as hereinbefore defined, are used for the treatment of TBC (tuberculosis) or HIV (human immunodeficiency virus).
Further, the compounds of formula (I) may be administered to patients with symptoms of atherosclerosis of arteR1es supplying the brain, for instance a stroke or transient ischaemic attack, in order to reduce the R1sk of a further, possible fatal, attack. The compounds of formula (I) may also be used for the treatment of elevated blood lipids in humans. Additionally, the compounds of formula (I), as hereinbefore defined, are valuable for the treatment and prophylaxis of multiple R1sk factors known for cardiovascular diseases, such as hypertension, hypertR1glyceR1demia and high coagulation factor VII phospholipid complex activity. Preferably, the compounds of formula (I) is used for the treatment of elevated blood lipids in humans. The compounds of formula (I) and pharmaceutically acceptable salts, solvates, prodrugs or complexes thereof may be used on their own but will generally be

administered in the form of a pharmaceutical composition in which the compounds of formula (I) (the active ingredient) are in association with a pharmaceutically acceptable adjuvant, diluent or carR1er.
The present invention thus also provides a pharmaceutical composition compR1sing a therapeutically effective amount of the compound of formula (I) of the present invention and a pharmaceutically acceptable carR1er, diluent or excipients (including combinations thereof).
This is a composition that compR1ses or consists of a therapeutically effective amount of a pharmaceutically active agent. It preferably includes a pharmaceutically acceptable carR1er, diluent or excipients (including combinations thereof). Acceptable carR1ers or diluents for therapeutic use are well known in the pharmaceutical art. The choice of pharmaceutical carR1er, excipient or diluent can be selected with regard to the intended route of administration and standard pharmaceutical practice. The pharmaceutical compositions may compR1se as - or in addition to - the carR1er, excipient or diluent any suitable binder(s), lubR1cant(s), suspending agent(s), coating agent(s), solubilising agent(s).
Pharmaceutical compositions within the scope of the present invention may include one or more of the following: preserving agents, solubilising agents, stabilising agents, s wetting agents, emulsifiers, sweeteners, colourants, flavouR1ng agents, odourants, salts compounds of the present invention may themselves be provided in the form of a pharmaceutically acceptable salt), buffers, coating agents, antioxidants, suspending agents, adjuvants, excipients and diluents.
A pharmaceutical composition according to the invention is preferably formulated for oral administration to a human or an animal. The pharmaceutical composition may also be formulated for administration through any other route where the active ingredients may be efficiently absorbed and utilized, e.g. intravenously, subcutaneously, intramuscularly, intranasally, rectally, vaginally or topically.
In a specific embodiment of the invention, the pharmaceutical composition is shaped in form of a capsule, which could also be microcapsules generating a powder or a sachet. The capsule may be flavoured. This embodiment also includes a capsule wherein both the capsule and the encapsulated fatty acid composition according to the invention is flavoured. By flavouR1ng the capsule it becomes more attractive to the user. For the above-mentioned therapeutic uses the dosage administered will, of course, vary with

the compound employed, the mode of administration, the treatment desired a kd the disorder indicated.
The pharmaceutical composition may be formulated to provide a daily dosage of 10 mg to 10 g. Preferably, the pharmaceutical composition is formulated to provide a daily dosage between 50 mg and 5 g of said composition. Most preferably, the pharmaceutical composition is formulated to provide a daily dosage between 100 mg and 1 g of said composition. By a daily dosage is meant the dosage per 24 hours. The dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. Typically, a physician will determine the actual dosage which will be most suitable for an individual subject. The specific dose level and frequency of dosage for any particular patient may be vaR1ed and will depend upon a vaR1ety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the seveR1ty of the particular condition, and the individual undergoing therapy. The agent and/or the pharmaceutical composition of the present invention may be administered in accordance with a regimen of from 1 to 10 times per day, such as once or twice per day. For oral and parenteral administration to human patients, the daily dosage level of the agent may be in single or divided doses. A further aspect of the present invention relates to a fatty acid composition compR1sing compounds of formula (I). A fatty acid composition compR1sing compounds of formula (I) increases the natural biological effects of DHA that are a result of regulation of gene expression, and the deR1vatives according to the present invention will accumulate in the free fatty acid pool.
The fatty acid composition may compR1se in the range of 60 to 100 % by weight of the compounds of formula (I), all percentages by weight being based on the total weight of the fatty acid composition. In a preferred embodiment of the invention, at least 80% by weight of the fatty acid composition is compR1sed of compounds of formula (I). More preferably, the compounds of formula (1) constitute at least 90% by weight of the fatty acid composifion. Most preferably, the compounds of formula (I) constitutes more than 95% by weight of the fatty acid composition.
The fatty acid composition may further compR1se at least one of the fatty acids (all-Z)-5,8,11,14,17-eicosapentaenoic acid (EPA), (all-Z)-4,7,10,13,16,19- docosahexaenoic

acid (DHA), (all-Z)-6,9, 12,15, 18-heneicosapentaenoic acid (HPA), and (all-Z)-7,10,13,16,19-docosapentaenoic acid (DPAn-3), (all-Z)-8,l 1,14,17- eicosatetraenoic acid (ETAn-3), or combinations thereof. Further, the fatty acid composition may compR1se (all-Z)-4,7, 10,13,16-Docosapentaenoic acid (DPAn-6) and/or (all-Z)-5,8,l 1,14-eicosatetraenoic acid (ARA), or deR1vatives thereof The fatty acid composition may also compR1se at least these fatty acids, or combinations thereof, in the form of deR1vatives. The deR1vatives are suitably substituted in the same way as the DHA deR1vatives of formula (I), as hereinbefore defined. The fatty acid composition according to the invention may compR1se (all-Z omega-3)-6, 9, 12, 15, 18-heneicosapentaenoic acid (HPA), or deR1vatives thereof, in an amount of at least 1% by weight, or in an amount of 1 to 4% by weight.
Further, the fatty acid composition according to the invention may compR1se omega-3 fatty acids other than EPA and DHA that have 20, 21, or 22 carbon atoms, or deR1vatives thereof, in an amount of at least 1.5% by weight, or in an amount of at least 3% by weight.
In specific embodiments of the invention, the fatty acid composition is a pharmaceutical composition, a nutR1tional composition or a dietary composition. The fatty acid composition may further compR1se an effective amount of a pharmaceutically acceptable antioxidant. Preferably, the antioxidant is tocopherol or a mixture of tocopherlos. In a preferred embodiment the fatty acid composition further compR1ses tocopherol, or a mixture of tocopherols, in an amount of up to 4 mg per g of the total weight of the fatty acid composition. Preferably, the fatty acid composition compR1ses an amount of 0.2 to 0.4 mg per g of tocopherols, based on the total weight of the composition.
Another aspect of the invention provides a fatty acid composition, or any pharmaceutically acceptable salt, solvate, pro-drug or complex thereof, compR1sing compounds of formula (I), as hereinbefore defined, for use as a medicament and/or in therapy. Such a fatty acid composition may be used to prevent and/or treat the same conditions as outlined for the compounds of formula (I) above. When the fatty acid composition is used as a medicament, it will be administered in a therapeutically or a pharmaceutically active amount.
In a preferred embodiment, the fatty acid composition is administered orally to a human or an animal. The present invention also provides the use of a compound of formula (I),

or a pharmaceutically acceptable salt, solvate, pro-drug or complex thereof, as hereinbefore defined, for the manufacture of a medicament for controlling body weight reduction and/or for preventing body weight gain; for the manufacture of a medicament for the treatment and/or the prevention of obesity or an overweight condition; for the manufacture of a medicament for the prevention and/or treatment of diabetes in a human or animal; for the manufacture of a medicament for the treatment and/or prevention of amyloidos-related diseases; for the manufacture of a medicament for the treatment and prophylaxis of multiple R1sk factors known for cardiovascular diseases, such as hypertension, hypertR1glyceR1demia and high coagulation factor VII phospholipid complex activity; for the manufacture of a medicament for the treatment of TBC or HIV; for the manufacture of a medicament for prevention of stroke, cerebral or transient ischaemic attacks related to atherosclerosis of several arteR1es; for the manufactuR1ng of a medicament for loweR1ng tR1glyceR1des in the blood of mammals and/or evelating the HDL cholesterol levels in the serum of a human patients; or for the manufactuR1ng of a medicament for the treatment and/or prevention of the multi metabolic syndrome termed "metabolic syndrome". All these embodiments also include the use of a fatty acid composition, as hereinbefore defined, compR1sing compounds of formula (I) for the manufacture of medicaments as outlined above. The present invention further relates to the use of alpha-hydroxy-DHA for the manufacture of medicaments as outlined above.
The present invention also relates to a method for controlling body weight reduction and for preventing body weight gain, wherein a fatty acid composition compR1sing at least a compound of formula (I), as hereinbefore defined, is administered to a human or an animal.
Further, the invention relates to a method for the treatment and/or the prevention of obesity or an overweight condition, wherein a fatty acid composition compR1sing at least a compound of formula (I), as hereinbefore defined, is administered to a human or an animal.
In a preferred embodiment of the invention, the present invention relates to a method for the prevenfion and/or treatment of diabetes mellitus, wherein a fatty acid composifion compR1sing at least a compound of formula (I), as hereinbefore defined, is administered to a human or an animal. Preferably, diabetes mellitus is a type 2 diabetes. Other aspects of the present invention relate to;

-a method for the treatment and/or prevention of amyloidos-related diseases;
-a method for the treatment or prophylaxis of multiple R1sk factors for cardiovascular
diseases;
-a method for prevention of stroke, cerebral or transient ischaemic attacks related to
atherosclerosis of several arteR1es; wherein a fatty acid composition compR1sing at least
a compound of formula (I), as hereinbefore defined, is administered to a human or an
animal.
The fatty acid deR1vatives of formula (I) may be prepared most effectively from DHA.
If the start mateR1al is not pure DHA (i.e. not 100% DHA) the final fatty acid
composition will contain a mixture of DHA deR1vatives, as hereinbefore defined, and an
amount of other fatty acids than DHA, wherein these fatty acids are substituted in the
same way as the novel fatty acid analogous of formula (I). Such embodiments are also
included herein.
In another embodiment of the invention, the compounds of formula (I) are prepared
from (all-Z)-4,7, 10,13, 16,19-docosahexaenoic acid (DHA), wherein said DHA is
obtained from a vegetable, a microbial and/or an animal source, or combinations
thereof. Preferably, said DHA is obtained from a maR1ne oil, such as a fish oil.
The fatty acids in the composition may also be obtained from a vegetable, a microbial
or an animal source, or combinations thereof. Thus, the invention also includes a fatty
acid composition prepared from a microbial oil.
The present invention provides processes for prepaR1ng novel fatty acid analogous of
formula (I), as hereinbefore defined.
DHA is produced from biological sources like maR1ne, microbial or vegetable fats. All
possible raw mateR1als are mixtures of fatty acids on tR1glyceR1de form where DHA
constitutes only a fraction of the fatty acids. Typical DHA concentrations are 40% in
microbial fats and 10-25% in maR1ne fats. DHA-containing vegetable fats are
duR1ng development and fats with high DHA concentrations are expected in the future.
The first process step will always be conversion of the tR1glyceR1des to free fatty acids
or monoesters. Preferable esters are methyl or ethyl esters, but other esters are possible.
In this way the fatty acids bound together three by three on tR1glyceR1des are separated
from each other and thereby making separation possible. Several methods of separating
DHA from other fatty acids are available, the most common ones being short path
distillation separating the fatty acids by volatility, and urea precipitation separating the

fatty acids by degree of unsaturation. Other methods reported are silver nitrate complexation also separating the fatty acids on degree on unsaturation, esteR1fication reactions catalysed by fatty acid selective lipases in combination with short path distillation and countercurrent extraction with supercR1tical carbon dioxide. The most important challenges connected to production of pure DHA is to separate it from the other C20-22 highly unsaturated fatty acids present in all available sources. These fatty acids have properties so similar to DHA that none of the methods mentioned above provide sufficient degree of separation. For some microbial high DHA fats, which have very low levels of C20-22 highly unsaturated fatty acids, short path distillation alone or in combination of other methods mentioned may provide more that 90% puR1ty.
Most DHA containing fats also contain considerable amounts of C20-22 highly unsaturated fatty acids, e.g. EPA (20:5n-3), n-3DPA (22:5n-3), HPA (21 :5n-3) and others. The only available method for separating DHA from such fatty acids is preparative High Performance Liquid Chromatography, the stationary phase being silica gel or silver nitrate impregnated silica gel, the mobile phase being selected organic solvents or supercR1tical carbon dioxide. With this method DHA with more than 97% puR1ty is available. However, it has to be noted that the production costs increases strongly with concentration, as an example is production cost for 97% DHA more 5 times higher than for 90% DHA.
DHA having a puR1ty of 90, 95 eller 97% contains small amounts of other fatty acids. As an example, DHA having a puR1ty of 97% contains n-3DPA (22:5n-3), but also long chain fatty acids, e.g. EPA (20:5n-3), HPA (21:5n-3), and others. However, the other fatty acids will react in a way similar to DHA and provide alpha-substituted deR1vatives. Organic synthesis may provide a puR1fication method since DHA and n-6DP A (and 22:5n-6 which normally is present in very low concentrations) are the only known fatty acids that can provide gamma-lactones by cyclisation with the first double bond. Lactonisation followed by puR1fication and hydrolysis back to DHA may be a possibility, but it is expected that this pathway is even more expensive than HPLC. In one embodiment, the compounds of formula (I) where R1 (or R2) is a hydrogen are prepared through the following processes (Scheme 1). Suitably adapted, these processes can alsoe be used for prepaR1ng compounds represented by the general formula (I)

where both R1 and R2 are e.g. a C1-C7 alkyl group, a benzyl, a halogen, a benzyl, an alkenyl, or an alkynyl.
Compounds represented by the general formula (I) where R1 is a hydrogen and R2 denotes a C1-C7 alkyl group, a benzyl, a halogen, a benzyl, an alkenyl, an alkynyl are prepared by reacting a DHA ester with a strong non-nucleophilic base like lithium diisopropylamine or potassium/sodium hexamethyldisilazideane in a solvent such as tetrahydrofuran, diethylether at temperatures of —60 to —78 ^C, to provide the ester enolate (process 1).

This ester enolate is reacted with an electrophilic reagent like an alkylhalide exemplified by ethyliodine, benzylcloR1de, an acyl halide exemplified by acetyl chloR1de, benzoyl bromide, a carboxylic anhydR1de exemplified by acetic anhydR1de or a electrophilic halogenation reagent exemplified by N-fluorobenzene sulfonimide (NFSI), etc. to provide the monosubstitued deR1vative (process 2). The ester is further hydrolysed in a solvent like ethanol or methanol to the carboxylic acid deR1vative by addition of a base like lithium/sodium hydroxide in water at temperatures between 15-40 °C.
Claisen condensation of the DHA EE occurs duR1ng the treatment of DHA EE with a strong base. This condensation product might possess interesting biologically activity.

Thus, in one embodiment of the invention the condensation (intermediate) product mentioned above, as well as the use of this product for treatment and/or prevention of diseases according to the present invention, are disclosed.
In a further embodiment, compounds represented by the general formula (I) are synthesised through following processes (Scheme 2). (Scheme 2)

Compounds represented by the general formula (I) where R1 is a hydrogen and R2 denotes a hydroxy, an alkoxy group, an acyloxy are prepared by reacting a DHA ester with a strong non-nucleophilic base like lithium diisopropylamine or potassium/sodium hexamethyldisilazideane in a solvent such as tetrahydrofuran, diethylether at temperatures of -60 to -78 ^Cs to provide the ester enolate (process 4). This ester enolate is reacted with an oxygen source like dimethyldioxirane, 2- (phenylsulfonyl)-3-phenyloxaziR1dine, molecular oxygen with different additives like tR1methylphosphite or different catalysts like a Ni(II) complex to provide alpha- hydroxy DHA ester(process 5). Reaction of the secondary alcohol with a base like sodiumhydR1de in a solvent like THF or DMF generates an alkoxide that is reacted with different electrophilic reagents as alkyliodide for example; methyl iodide, ethyl iodide, benzylbromide or an acyl

halide, for example; acetyl chloR1de, benzoyl bromide (process 6). The ester is hydrolysed in a solvent like ethanol or methanol to the carboxylic acid deR1vative by addition of a base like lithium/sodium hydroxide in water at temperatures between 15-40 °C (process 7).
The hydroxy-DHA ester is a useful intermediate for the introduction of other functional groups in the a-position according to the invention. The hydroxyl function can be activated by conversion to a halide or tosylate pR1or to reaction with different nucleophiles like ammonia, amines, thiols, etc. The Mitsunobu reaction is also useful for the conversion of a hydroxylgroup into other functional groups. (Mitsunobu, O, Synthesis, 1981, 1).
Compounds represented by the general formula (I), as hereinbefore defined, can also be synthesised by combinations of the different processes previously descR1bed. The present invention includes the processes mentioned above. The invention further provides a process for the preparation of a pharmaceutical composition of the invention, with compR1ses mixing of at least a compound of formula (I), or a pharmaceutically acceptable salt, solvate, complex or pro-drug thereof, as hereinbefore defined, with a pharmaceutically acceptable adjuvant, diluent or a carR1er. The enantiomeR1c pure compounds can be prepared by resolving a racemic compound of formula (I), as hereinbefore defined. The resolution of a compound of formula (I) may be carR1ed out using known resolution procedures, for example by reacting the compound of formula (I) with an enantiomeR1cally pure auxiliary to provide a mixture of diastereomers that can be separated by chromatography. Thereafter the two enantiomers of compound (I) may be regenerated from the separated diastereomers by conventional means, such as hydrolysis.
There is also a possibility to use stochiometR1c chiral auxiliaR1es to effect an asymmetR1cintroduction of the substituents, as hereinbefore defined, in the a-position of DHA. The use of chiral oxazolidin-2-ones has proved to be a particularly effective methodology. The enolates deR1ved from chiral iV-acyloxazolidines can be quenched with a vaR1ety of electrophiles in a highly stereoregulated manner (Ager, Prakash, Schaadl996).

The technology of the instant Application is further elaborated with the help of
following examples. However, the examples should not be construed to limit the
scope of the invention.
Examples
In the examples the structures were veR1fied by Mass Spectrometry (MS). It should be
pointed out that the fatty acid deR1vatives may also be produced from low and medium
DHA- containing starting mateR1al (i.e. about 40-60 w% DHA).
Synthesis protocols
Preparation of g-methyl DHA EE TPRB-I)
Butyllithium (228 ml, 0.37 mol, 1.6 M in hexane) was added drop wise to a stirred
solution of diisopropylamine (59.5 ml, 0.42 mol) in dry THF (800 ml) under N2 at 0 *^C.
The resulting solution was stirred at 0 ^C for 30 min., cooled to -78 ^C and stirred an
additional 30 min. before drop wise addition of DHA EE (100 g, 0.28 mol) in dry THF
(500 ml) duR1ng 2 h. The dark-green solution was stirred at -78 °C for 30 min. before
Mel (28 ml, 0.45mol) was added. The solution was allowed to reach -20 ^C duR1ng 1.5
h, then poured into water (1.5 1) and extracted with heptane (2 x 800 ml). The
combined organic phases were washed with 1 M HCl (11), dR1ed (Na2S04), filtered and
evaporated in vacuo. The product was puR1fied by dry flash chromatography on silica
gel eluting with heptane/ EtOAc (99:1) to give 50 g (48%) of the titled compound as a
slightly yellow oil;
^H-NMR (200MHz, CDCI3) 8 1.02 (t, J 7.5 Hz, 3H), 1.20 (d, J6.8 Hz, 3H), 1.29 (t, J 7.1
Hz, 3H), 2.0-2.6 (m, 5H), 2.8-3.0 (m, lOH), 4.17 (t, J 7.1 Hz, 2H), 5.3- 5.5 (m, 12H);
MS (electrospray); 393 [M+Na].
Preparation of a-ethyl DHA EE (TRB-2)
Butyllithium (440 ml, 0.67 mol, 1.6 M in hexane) was added drop wise to a stirred
solution of diisopropylamine (111 ml, 0.78 mol) in dry THF (750 ml) under N2 at 0 ^C.
The resuhing solution was stirred at -78 °C for 45 min. before dropwise addition of
DHA EE (200 g, 0.56 mol) in dry THF (1.6 1). The addition of the ester was complete
in 4 hours. The dark-green solution was stirred at -78 ^C for 30 min. before EtI (65 ml,
0.81 mol) was added. The solution was allowed to reach -40 ^C before an additional
amount of EtI (5 ml, 0.06 mol) was added, and finally reach -15
°C (duR1ng 3 hours from -78 ^C) before the mixture was poured into water and extracted
with hexane (2x). The combined organic phases were washed with 1 M HCl, water.

dR1ed (Na2S04), filtered and evaporated in vacuo. The product was puR1fied by flash
chromatography on silica gel eluting with heptane/EtOAc (99:1 followed by 50:1) to
give 42.2 g (20%) of the titled compound as a yellow oil;
'H-NMR (200 MHz; CDCI3) 5 0.8-1.0 (m, 6H), 1.2-1.4 (m, 4H), 1.5-1.7 (m, 2H), 2.12
(m, 2H), 2.3-2.5 (m, 2H), 2.8-3.0 (m, lOH), 4.18 (t, J7.1 Hz, 2H)3 5.3-5.6 (m, 12H);
MS (electrospray); 407 [M+Na].
Preparation of a-ethoxv-DHA ethvlester (PRB-3)

To a suspension of 60 % NaH (84.1 mg, 2.1 mmol) in THF, 5 mL, at -78°C under N2-atmosphere was added drop wise a solution of a-hydroxy-DHA ethyl ester (PRB-12) (372 mg, 1.00 mmol) in THF, 5 mL, the resulting mixture was stirred at - 78^C for 20 minutes before ethyl iodide (0.24 mL, 3.01 mmol) was added drop wise. The reaction mixture was gradually warmed to room temperature over night. Saturated aqueous NH4CI, 15 mL, was added and the mixture was extracted with diethyl ether, 25 mL x 2, the organic phase was washed with bR1ne, 25 mL, dR1ed (Na2S04) filtered, evaporated in vacuo and subjected to flash chromatography on silica gel eluting with heptane/EtOAc (95:5) to yield 68 mg (17 %) of the product as a yellow liquid.
^H NMR (200 MHz, CDCI3) 5 0.94 (t, J=7.5 Hz, 3H), 1.16-1.29 (m, 6H), 2.05 (quint, J=7.2 Hz, 2H), 2.50 (m, 2H), 2.76-2.84 (m, lOH), 3.33-3.48 (m, IH), 3.53- 3.71 (m, IH), 3.83 (dd, J=6.8 Hz, J=6.2 Hz, IH), 4.18 (q, J=I. \ Hz, 2H), 5.31-5.45 (m, 12 H) ^^C NMR (50 MHz, CDCI3) 8 14.2, 15.1, 20.5, 25.5, 25.6, 25.7, 31.0, 60.8, 66.0, 78.7, 124.1, 127.0, 127.8, 127.9, 128.0 (2 signals), 128.2 (2 signals), 128.5, 130.7, 132.0, 172.5 (3 signals hidden) MS (electrospray); 423 [M+Na]^
Preparation of g-fluoro DHA EE fPRB-4)
LDA (2.1 ml, 4.2 mol, 2 M in THF/heptane/ ethylbenzene) in dry THF (10 ml) under N2 at -78 V was drop wise added DHA EE (1 g, 2.8 mmol) in dry THF (30 ml) duR1ng 15 min. NFSi (1.06 g, 3.4 mmol) was then added. The solution was allowed to reach

RT and stirred for 70 hours. The mixture was poured into water and extracted with hexane (2x). The combined organic phases were washed with 1 M HCl, water, dR1ed (Na2S04), filtered and evaporated in vacuo; MS (electrospray); 397 [M+Na], Preparation of a,a-dimethvl DHA EE (PRB-5)
Butyllithium (100 ml, 0.17 mol, 1.6 M in hexane) was added drop wise to a stirred solution of diisopropylamine (28 ml, 0.20 mol) in dry THF (100 ml) under N2 at 0 ^C. The resulting solution was stirred at 0 ^C for 30 min., cooled to -78 ^C and drop wise added a solution of DHA EE (50 g, 0.14 mol) in dry THF (200 ml). The resulting dark-green solution was stirred at -78 °C for 30 min. before Mel (17 ml, 0.28 mol) was added. The solution was allowed to reach -10 ^C, then poured into water and extracted with hexane (2x). The combined organic phases were washed with 1 M HCl, dR1ed (Na2S04), filtered and evaporated in vacuo.
The procedure was repeated, but the crude product of a-methyl DHA EE was used instead of DHA EE. The product was puR1fied by dry flash chromatography on silica gel eluting with heptane/EtO Ac (99:1 followed by 98:2) to give- 31.6 g (59%) of the titled compound as a slightly yellow oil;
^H-NMR (200 MHz; CDCI3) 8 1.01 (t, J7.5 Hz, 3H), 1.21 (s, 6H), 1.28 (t, J 7.1 Hz, 3H), 2.08 (m, 2H), 2.34 (d, J 6.8 Hz, 2H), 2.8-3.0 (m, lOH), 4.15 (q, J7.5 Hzs 2H), 5.3-5.6 (m, 12H);
'^C-NMR (50 MHz; CDCI3) 5 14.7, 21.0, 25.3, 26.0, 26.1, 38.3, 42.8, 60.7, 125.8, 127.4, 128.3, 128.5, 128.6, 128.7, 129.0, 130.7, 132.4, 177.9; MS (electrospray); 385 [M+H]. Preparation of g-thiomethyl DHA (PRB-6)
a-Iodo DHA EE (0.5 g, 1.04 mmol) dissolved in 20 mL THF at O^C under N2. MeSNa (80 mg, 1.14 mmol) was added the reaction and the mixture was allowed to stir for a few minutes before it was diluted with heptane. The organic phase was washed with water (2x) dR1ed (Na2S04) and evaporated in vacuo. The desired product was was isolated by flash chromatography Heptan/EtOAc (30:1) to give a-thiomethyl DHA EE as a pale yellow oil. The a-thiomethyl DHA EE was dissolved in 10 mL EtOH and 10 mL THF. The solution was added LiOH (0.39 g, 9.2 mmol) dissolved in 5 mL water. The reaction mixture was allowed to stir overnight at RT, before diluting with water and heptane. The organic fraction was extracted with IM LiOH (2x) and the combined aqueous phases was acidified with 5M HCl and extracted with diethyl ether (2x). The

combined organic phases was washed with bR1ne, water, dR1ed (Na2S04) and evaporated
in vacuo to give 183 mg (47 %) of the title compound as a pale yellow oil;
'H-NMR (200MHZ, CDCI3) 5 0.98 (t, J 6.6Hz, 3H), 1.95-2.65 (m, 7H), 2.72- 3.05 (m,
lOH), 3.12-3.43 (m, IH), 5.20-5.70 (m, 12H), 10.65 (br s, IH);
^^H-NMR (50MHz, CDCI3) 8 14.7, 21.0, 25.9, 26.0, 26.2, 28.8, 125.4, 127.4, 128,1,
128.3, 128.4, 128.7, 128.9, 129.0, 131.6, 132.4, 177.0.
Preparation of g-thioethvl DHA EE nPRB-7)
a-Iodo DHA EE (11 g, 23 mmol) dissolved in 100 mL THF under N2 at O^C. EtSNa
(2.1 g, 25 mmol) was added the solution and was allowed to stir for 1 hour at 0°C. The
reaction was quenched with IM HCl and diluted with Heptan. The organic phase was
washed with water (2x), dR1ed (Na2S04) and evaporated in vacuo. The desired product
was isolated by flash chromatography Heptan/EtOAc (30:1) to give 7.3 g (76 %) of the
title compound as a pale yellow oil;
'H-NMR (200MHz, CDCI3) 8 1.1-1.3 (m, 9H), 2.05 (m, 2H), 2.3-2.7 (m, 4H), 2.7-2.9
(m, lOH), 3.25 (m, IH), 4.17 (q, J7.1 Hz, 2H), 5.3-5.5 (m, 12H); MS (electrospray): 439
[M+Na].
Preparation of a,a-diethvl DHA EE (PRB-8)
Butyllithium (38.6 ml, 0.62 mol, 1.6 M in hexane) was added drop wise to a stirred
solution of diisopropylamine (9.1 ml, 0.65 mol) in dry THF (200 ml) under N2 at O^C.
The resulting solution was stirred at O^C for 30 min., cooled to -78^C and drop wise
added a solution of DHA EE (20.0 g, 0.56 mol) in dry THF (100 ml). The resulting
dark-green solution was stirred at -78°C for 30 min., before EtI (6.8 ml, 0.84 mol) was
added. The solution was allowed to reach -lO^C, then poured into water and extracted
with hexane (2x). The combined organic phases were washed with 1 M HCl, dR1ed
(Na2S04), filtered and evaporated in vacuo.
The procedure was repeated, but the crude product of a-ethyl DHA EE was used
instead of DHA EE. The reaction mixture after addition of EtI was allowed to reach
ambient temperature and was stirred over night. The product was puR1fied by dry flash
chromatography on silica gel eluting with heptane/EtOAc (99:1 followed by 98:2) to
give 10.0 g (43%) of the titled compound as a slightly yellow oil;
*H-NMR (200 MHz; CDCI3) 8 0.83 (t, J 7.4 Hz, 6H), 0.94 (t, J 5.8 Hz, 3H), 1.28 (t, J
7.1 Hz, 3H), 1.63 (q, J 7.4 Hzs 4H), 2.10 (m, 2H), 2.34 (d, J 6.9 Hz, 2H), 2.8-3.0 (m,
lOH), 4.15 (q, J7.5 Hz, 2H), 5.3-5.6 (m, 12H);

^^C-NMR (50 MHz; CDCI3) 6 8.9, 14.7, 21.0, 23.1, 25.9, 26.0, 26.2, 27.4, 31.2, 50.1,
60.6, 125.5, 127.4, 128.3, 128.6, 128.9, 130.5, 132.4, 177.1;
MS (electrospray); 413.3 [M+H], 435.3 [M+Na].
Preparation of a-benzvl DHA EE (PRB-9)
To a stirred solution of diisopropyl amine (0.91 mL, 6.46 mmol) in dry THF (20 mL)
under inert atmosphere held at OV was added drop wise n-BuLi (1.6 M in hexanes,
3.86 mL, 6.18 mmol). The mixture was stirred at 0°C for 30 minutes, given - 78^ and
stirred at this temperature for five minutes. DHA EE (2.0 g, 5.62 mmol) in dry THF (10
mL) was added drop wise and the mixture was stirred at -78°C for 20 minutes, then
benzyl bromide (0.80 mL, 6.74 mmol) was added. The resuking solution was allowed
to reach 0*^C over three hours, portioned between water (100 mL) and heptane (100
mL). The aqueous layer was extracted with heptane (50 mL) and the combined organic
layer was washed with IM HCl and dR1ed (Na2S04). Concentration under reduced
pressure and puR1fication by flash chromatography (Heptane : EtOAc 99: 1) afforded
1.05 g (42%) of the title compound as a colorless oil;
'H-NMR (200 MHz, CDCI3): 5 0.99 (t, 3H), 1.18 (t, 3H), 2.08-2.16 (m, 2H), 2.35-2.42
(m, 2H), 2.74-2.98 (m, 13H), 4.09 (q, 4H), 5.38-5.50 (m, lOH), 7.19-7.36 (m, 5H);
'^C-NMR (50 MHz, CDCI3): 5 14.61, 14.71, 20.99, 25.98, 26.07, 30.07, 38.32, 48.02,
60.88, 126.75, 126.83, 127.46, 128.31, 128.45, 128.53, 128.58, 128.86, 128.77, 129.01,
129.35, 130.55, 132.46, 138.89, 175.39.
MS (electrospray): 447.3 [M+H], 469.3 [M+Na].
Preparation of g-ethanesulfmvl DHA EE fPRB-10)
To a solution of a-thioethyl DHA EE (0.5 g, 1.3 mmol) in 15 mL CHCI3 held at -20 ^C
under inert atmosphere was added a solution of MCPBA (0.22 g, 1.3 mmol) in 10 mL
CHCI3. The reaction mixture was stirred for 2h at this temperature, filtered and washed
with a saturated aqueous solution OfNaHCOs. The aqueous phase was extracted twice
with CHCI3 and the combined organic phase was washed with water and bR1ne, dR1ed
with Na2S04, filtered and concentrated. The product was isolated from residual
mateR1al after flash chromatography using hexane: EtOAc 8:2 to afford 0.35 g (70%) of
the title compound.
^HNMR (200 MHz, CDCI3): 8 0.99 (t, 3H), 1.27-1.45 (m, 6H), 2.09 (m, 2H), 2.79-2.94
(m, 14H), 3.55 (m, IH), 4.25 (q, 2H), 5.37-5.59 (m, 12H).

'^C NMR (50 MHZ5 CDCI3): 5 7.97, 14.58, 14.68, 20.95, 23.68, 25.17, 25.93, 26.04,
44.20, 45.15, 62.30, 64.08, 123.91, 124.47, 127.41, 127.86, 128.26, 128.40, 128.44,
128.72, 128.72, 128.96, 129.12, 132.42, 132.47, 174.55.
MS (electrospray): 455.3 [M+Na].
Preparation of a-thiophenvI-DHA ethvlester (PRB-ll)

To a solution of a-iodo-DHA ethylester (PRB-15) (3.40 g, 7.05 mmol) in acetone, 20
mL, a solution of sodium phenyl sulfide (1.039 g, 7.86.mmol) in acetone, 110 mL, was
added drop wise. The resulting mixture was stirred at ambient temperature for 1 Vz hrs,
evaporated in vacuo and subjected to flash chromatography on silica gel eluting with
heptane/EtOAc 200:1 - 95:5 to yield 2.35 g (72 %) of the product as a yellow liquid. 'H
NMR (200 MHz, CDCI3) 8 0.97 (t, J=7.5 Hz, 3H), 1.18 (t, J=7.1 Hz, 3H)5
2.09 (quint, J=7.1 Hz, 2H), 2.54-2.66 (m, 2H), 2.83-2.86 (m, 10 H), 3.67 (dd, J=6.8 Hz,
J=8.3 Hz, 1 H), 4.12 (q, J=7.1 Hz, 2H), 5.24-5.49 (m, 12 H), 7.28-7.33 (m, 3H), 7.46-
7.50 (m, 2H)
'^C NMR (50 MHz, CDCI3) 8 14.0, 14.2, 20.5, 25.5, 25.6, 25.7, 29.4, 50.6, 61.1, 125.1,
127.0, 127.7, 127.9, 128.0, 128.3, 128.42, 128.45, 128.9, 131.2, 132.0, 133.0, 133.2,
174.1 (5 signals hidden)
MS (electrospray); 465 [M+H]^ 487 [M+Na]^
HRMS (EI) calculated for C30H40O2S: 464.2749, found: 464.2741
Preparation of g-hydroxv-DHA ethvlester (PRB-12)

To a solution of diisopropyl amine (19.76 mL, 140 mmol) in dry THF, 40 mL, under Na-atmosphere at -78°C was added drop wise 1.6 M BuLi in hexane (87.5 mL, 140

mmol). The resulting mixture was stirred at -78°C for 15 minutes before a solution of DHA ethylester (24.99 g, 70.1 mmol) in THF, 80 mL, was added drop wise. The resulting dark green reaction mixture was stirred for 1 hour at -78^C before tR1ethylphosphite (12.2 mL, 70.1 mmol) was added drop wise and then O2 was bubbled through the reaction mixture over night while the reaction mixture was kept at -78^C for 5 hrs and then slowly warmed to room temperature. Saturated aqueous NaHCOa, 100 mL, was added and the mixture was extracted with diethyl ether, 200 niL x 2. The organic phase was dR1ed (Na2S04), filtered and evaporated in vacuo and subjected to flash chromatography on silica gel eluting with heptane/EtOAc 99:1 - 95:5 to yield 4.52 g (17 %) of the product as a yellow liquid.
^H NMR (200 MHz, CDCI3) 8 0.92 (t, J=7.5 Hz, 3H), 1.24 (t, J=7.1 Hz, 3H), 5 2.02 (quint, J=7.1 Hz, 2H), 2.44-2.54 (m, 2H), 2.74-2.87 (m, 10 H), 4.13-4.24 (m, 3H), 5.25-5.94 (m, 12H)
^^C NMR (50 MHz, CDCI3) 8 14.0, 14.1, 20.4, 25.4, 25.5, 25.6, 32.0, 61.5, 69.9, 123.3, 126.9, 127.7, 127.9, 128.08, 128.1, 128.2, 128.4, 131.3, 131.8, 174.4 (4 signals hidden) 10 MS (electrospray); 395 [MH-Na]^ HRMS (ES) calculated for C24H3603Na: 395.2556, found: 395.2543

Preparation of g-methvl-DHA amide (PRB-13)

A solution of a-methyl-DHA (PRB-I FA) (3.13 g, 9.1 mmol) and oxalyl chloR1de (8.0
mL, 94.5 mmol) in toluene, 90 mL, was added DMF, 0.1 mL, and the resulting mixture
was stirred at ambient temperature under N2-atmosphere for 15 ^A 20 hours. The
mixture was then evaporated in vacuo and the residue was dissolved in THE, 100 mL,
cooled to O^C and aqueous NH3 (20 mL) was added drop wise. The ice-bath was
removed and the mixture was stirred at ambient temperature for 4 hours, water, 50 mL,
was added and the aqueous phase was extracted with diethyl ether, 2x100 mL. The
organic phase was washed with saturated aqueous NH4CI, 50 mL, dR1ed (Na2S04),
filtered and evaporated in vacuo and subjected to flash chromatography on silica gel
eluting with CH2CI2/2M NH3 in MeOH 97.5:2.5 to yield 2.51 g (80 %) of the product
as a yellow liquid.
*U NMR (200 MHz, CDCI3) 5 0.91 (t, J=7.5 Hz, 3H), 1.10 (d, J=9.8 Hz, 3H), 1.94-2.11
(m, 3H), 2.19-2.35 (m, 2H), 2.76-2.77 (m, 10 H), 5.18-5.45 (m, 12 H), 6.03
30 (s, IH), 6.72 (s, IH)
^^C NMR (50 MHz, CDCI3) 5 14.6, 17.6, 20.8, 25.8, 25.9, 32.0, 41.0, 127.3, 128.1,
128.4, 128.6, 128.8, 130.1, 132.2, 179.6 (8 signals hidden) MS (electrospray); 342
[M+H]^, 364 [M+Na]^ HRMS (EI) calculated for C23H35NO: 341.2719, found:
341.2707
Preparation of q-methoxy-DHA ethvlester (PRB-14)

To a suspension of 60 % NaH (61.1 mg, 1.53 nimol) in THF, 5 mL, at -78°C under N2-atmosphere was added drop wise a solution of a-hydroxy-DHA ethyl ester (PRB-12)

(373 mg, 1.00 mmol) in THF, 5 mL, the resulting mixture was stirred at - TS^'C for 20
minutes before methyl iodide (0.13 mL, 2.09 mmol) was added drop wise. The reaction
mixture was gradually warmed to room temperature for 5 hrs. Saturated aqueous
NH4CI, 15 mL, was added and the mixture was extracted with diethyl ether, 25 mL x 2,
the organic phase was washed with bR1ne, 25 mL, dR1ed (Na2S04) filtered, evaporated in
vacuo and subjected to flash chromatography on silica gel eluting with heptane/EtOAc
99:1 - 4:1 to yield 136 mg (35 %) of the product as a yellow liquid.
'H NMR (200 MHz, CDCI3) 8 0.92 (t, J=7.5 Hz, 3H), 1.24 (t, J=7.1 Hz, 3H), 2.03
(quint, J=7.3 Hz, 2 H), 2.48 (t, J=5.7 Hz, 2H), 2.73-2.82 (m, 10 H), 3.34 (s, 3H), 3.74
(t, J=6.2Hz, IH), 4.17 (q, J-7.1 Hz, 2 H), 5.24-5.43 (m, 12H)
^^C NMR (50 MHz, CDC13) 8 14.1, 20.4, 25.4, 25.5, 25.7, 30.6, 57.9, 60.9, 80.8, 123,7,
126.9, 127.71, 127.73, 127.92, 127.94, 128.07, 128.1, 128.2, 128.4, 130.7, 131.8, 171.9
(3 signals hidden)
MS (electrospray); 409 [M+Na]^ ' HRMS (ES) calculated for CssHsgOsNa: 409.2713,
found: 409.2711
Preparation of g-iodo DHA EE (PRB-15)
Diisopropylamine ( 20 mL, 140 mmol) was dissolved in 150 mL THF under N2 at -
20°C. n-BuLi (88mL, 140 mmol, 1.6 M) was added drop wise to the mixture before the
solution was cooled to -78^C. DHA EE (50 g, 140 mmol) in 250 mL THF was added
dropwise to the solution and the reaction mixture was stirred for 30 min at RT. The
resulting mixture was added dropwise to a solution of I2 (42.8 g, 169 mmol) in 400 mL
THF under N2 at -78^C. The reaction was quenched with IM HCl and diluted with
Heptan. The organic phase was washed with 10% Na2S203 (2x), dR1ed (Na2S04),
filtered and evaporated in vacuo. The desired product was isolated by fiash
chromatography Heptan/EtOAc (100:1) to give 11.0 g (16 %) of the title compound as
a pale yellow oil; MS (Electrospray): 505 [M+Na].
Preparation of g-iodo-DHA ethvlester (PRB-15)

To a solution of diisopropyl amine (42 mL, 298 mmol) in dry THF, 150 niL, under N2-atmosphere at -78 °C was added drop wise 1.6 M BuLi in hexane (158 mL, 253 mmol).

The resulting mixture was stirred at -78°C for 35 minutes before a solution of DHA
ethylester (75.05 g, 210 mmol) in THF, 300 mL, was added drop wise. The resulting
dark green reaction mixture was stirred for 30 minutes at -78°C before a solution of I2
(91.06 g, 359 mmol) in THF, 200 mL was added drop wise. The reaction mixture was
stirred at -78^C for 20 minutes before it was quenched with water, 200 mL, and
extracted with heptane, 300 mL. The organic phase was washed with 1 M HCl, 150
mL, and water, 200 mL, dR1ed (Na2S04), filtered and evaporated in vacuo. The resulting
crude product was subjected to flash chromatography on silica gel eluting with
heptane/EtOAc (100:1) yielding 26.14 g (26%) of the product as a yellow liquid.
'H NMR (200 MHz, CDCI3) 5 0.94 (t, J=7.5 Hz, 3H), 1.24 (t, J=7.1 Hz, 3H), 2.04
(quint, J=7A Hzs 2H), 2.69-2.84 (m, 12 H), 4.17 (q, J=7.1 Hz, 2H), 4.22 (t, j=7.9 Hz,
IH), 5.24-5.49 (m, 12 H)
'^C NMR (50 MHz, CDCI3) 5 13.7, 14.2, 25.5, 26.0 (2 signals), 25.8, 34.0, 61.7, 126.1,
127.0, 127.4, 127.8, 127.9, 128.0, 128.2, 128.5, 128.5, 131.6, 131.9, 170.9 (4 signals
hidden)
MS (electrospray); 505 [M+Na]""
Preparation of a-amino-DHA etvlester (PRB-17)

A solution of a-phtalimide-DHA ethylester (313.5 mg, 0.62 mmol) in EtOH, 5 mL, was added hydrazine hydrate (46 |il, 0.95 mmol) and the resulting mixture was refluxed under N2-atmosphere for 15 'A hrs followed by evaporation in vacuo and flash chromatography on silica gel eluting with CH2Cl2:7M NH3 in MeOH (99:1- 95:1) to yield 149 mg (64 %) of the product as a yellow liquid.
'HNMR (200 MHz, CDCI3) 5 0.91 (t, J-7.5 Hz, 3H), 1.22 (t, J=7.1 Hz, 3H), 1.72 (bs, 2H), 2.02 (quint., J=7.2 Hz , 2H), 2.39-2.46 (m, 2H), 2.73-2.82 (m, 10 H), 3.47 (bs, IH), 4.13 (q, 2H)5 5.23-5.56 (m, 12 H)

^^C NMR (50 MHz5 CDCI3) 8 14.1, 20.4, 25.4, 25.5, 25.6, 54.1, 60.8, 124.4, 126.9,
127.7 (2 signals), 127.9, 128.2, 128.3, 128.4, 131.4, 131.9, 189.3 (6 signals hidden) MS
(electrospray); 372 [M+H]"^
Preparation of (S)-r+)-a-ethvl DHA EE (PRB-20):
Synthesis of intermediate PRB-18:

DHA (3.00g, 18.3 mmol) was dissolved in dry CH2CI2 (120 mL) held at O^C under inert atmosphere and added DMAP (2.45 g, 20.1 mmol) and DCC (3.96 g, 19.2 mmol). The mixture was stirred at O^C for 20 minutes, added (4R,5S)-(+)-4-methyl-5- phenyl-2-oxazolidinone (3.24 g, 18.3 mmol) and stirred at ambient temperature for 20 hours. Filtration and puR1fication by flash chromatography (heptane : EtOAc 6:1) afforded 3.00 g (34%) of intermediate PRB-18 as a colorless oil.
'H-NMR (200 MHz5 CDCI3): 8 0.93-1.05 (t+d, 6H), 2.11 (m, 2H), 2.51 (m, 2H), 2.80-3.00 (m, lOH), 3.05 (m, 2H), 4.77 (m, IH), 5.34-5.68 (m,12H), 5.70 (d, IH), 7.28.7.32 (m,2H), 131-1 Al(m,3H). Synthesis of intermediate PRB-19:

PRB-18 (1.80 g, 3.70 mmol) in dry THF (10 mL) was added drop wise to a solution of LiHMDS (IM in THF, 4.00 mL, 4,00 mmol) in dry THF (15 mL) held at - 78V under inert atmosphere. The mixture was stirred at -78^ for 30 minutes, added EtI (0.89 mL, 11.1 mmol) and slowly given OV over one hour. The mixture was then stirred at OV for 18 hours and portioned between saturated NH4CI (50 mL) and diethyl ether (50

mL). The aqueous layer was extracted with diethyl ether (50 mL) and the combined organic layer was washed with 0.1 M HCl (50 mL) and bR1ne (50 mL). Drying (Na2S04) and puR1fication by flash chromatography (heptane : EtOAc 95:5) afforded 0.52 g (27 %) of intermediate PRB- 19 as a colorless oil.
'H-NMR (200 MHz, CDCI3): 5 0.88-1.01 (m ,9H), 1.64-1.78 (m, 2H), 2.08 (m, 2H), 2.31 (m, IH), 2.48 (m, IH), 2.87 (m, lOH), 3.87 (m, IH), 4.75 (m, IH), 5.32 (m, 12H), 5.63 (d, J7.1 Hz, IH), 7.32 (m, 2H), 7.42 (m, 3H). '^C-NMR (50 MHz, CDCI3): 5 7.26, 11.75, 14.67, 14.98, 20.95, 25.57, 25.93, 26.04, 29.93, 44.59, 55.31, 79.10, 125.21, 126.01, 127.17, 127.42, 128.27, 128.50, 128.55, 128.67, 128.95, 129.09, 130.35, 132.42, 133.80, 153.18, 176.25. MS (electrospray): 538.2 [M+Na]

PRB-19 (0.25 g, 0.485 mmol) was dissolved in abs EtOH (5 mL) and given 0°C under inert atmosphere. NaOEt (IM in EtOH, 0.54 mL, 0.54 mmol) was added and the mixture was stirred at 0°C for 30 minutes and portioned between water and heptane. The aqueous layer was extracted with heptane and the combined organic layer was washed with 0.1 M HCl and dR1ed. PuR1fication by flash chromatography afforded 0.025 g (13 %) of the title compound PRB-20 as a colorless oil.
'H-NMR (200 MHz; CDCI3) 8 0.8-1.0 (m, 6H), 1.2-1.4 (m, 4H), 1.5-1.7 (m. 2H), 2.12 (m, 2H), 2.3-2.5 (m, 2H), 2.8-3.0 (m, 10H)5 4.18 (t, 2H), 5.3-5.6 (m, 12H). MS (electrospray); 407 [M+Na]. [a]D+1.7° (c=1.5, ethanol).

Preparation of flO-f-Va-ethvl DHA EE (PRB-23);
Synthesis of intermediate PRB-21:

DHA (l.OOg, 3.05 mmol) was dissolved in dry CH2CI2 (20 mL) held at O^C under inert atmosphere and added DMA? (0.41 g, 3.35 mmol) and DCC (0.66g, 3.20 mmol). The mixture was stirred at O^C for 20 minutes, added (4S,5R)-(-)-4-methyl-5- phenyl-2-oxazolidinone (0.54 g, 3.05 mmol) and stirred at ambient temperature for 20 hours. Filtration and puR1fication by flash chromatography (heptane : EtOAc 6:1) afforded 1.08 g (73%) of intermediate PRB-21 as a colorless oil.
'H-NMR (200 MHz, CDCI3): 5 0.93-1.05 (t+d, 6H), 2.11 (m, 2H)3 2.51 (m, 2H)5 2.80-3.00 (m, lOH), 3.05 (m, 2H)5 4.77 (m, IH)5 5.34-5.68 (m,12H), 5.70 (d, IH), 7.28.7.32 (m,2H), 131-1 Al(m,3H). Synthesis of intermediate PRB-22:

PRB-21 (3.25g, 6.67 mmol) in dry THF (15 mL) was added drop wise to a solution of LiHMDS (IM in THF, 7.34 mL, 7,34 mmol) in dry THF (35 mL) held at 78^C under inert atmosphere. The mixture was stirred at -78^C for 30 minutes, added EtI (1.6 mL, 20.0 mmol) and slowly given O^C over one hour. The mixture was then stirred at O^C for 18 hours and portioned between saturated NH4CI (50 mL) and diethyl ether (50 mL). The aqueous layer was extracted with diethyl ether (50 mL) and the combined organic layer was washed with 0.1 M HCl (50 mL) and bR1ne (50 mL). Drying

(Na2S04) and puR1fication by flash chromatography (heptane : EtOAc 95:5) afforded
1.50 g (44 %) of intermediate PRB-22 as a colorless oil.
'H-NMR (200 MHz, CDCI3): 5 0.88-1.01 (m ,9H), 1.64-1.78 (m, 2H), 2.08 (m, 2H),
2.31 (m, IH), 2.48 (m, IH), 2.87 (m, lOH), 3.87 (m, IH), 4.75 (m, IH), 5.32 (m, 12H),
5.63 (d, J7.1 Hz, IH), 7.32 (m, 2H), 7.42 (m, 3H).
'^C-NMR (50 MHz, CDCI3): 5 7.26, 11.75, 14.67, 14.98, 20.95, 25.57, 25.93, 26.04,
29.93, 44.59, 55.31, 79.10, 125.21, 126.01, 127.17, 127.42, 128.27, 128.50, 128.55,
128.67, 128.95, 129.09, 130.35, 132.42, 133.80, 153.18, 176.25.
MS (electrospray): 538.2 [M+Na]

PRB-22 (0.25 g, 0.485 mmol) was dissolved in abs EtOH (5 mL) and given 0"C under inert atmosphere. NaOEt (IM in EtOH, 0.54 mL, 0.54 mmol) was added and the mixture was stirred at O^C for 30 minutes and portioned between water and heptane. The aqueous layer was extracted with heptane and the combined organic layer was washed with 0.1 M HCl and dR1ed. PuR1fication by flash chromatography afforded 0.025 g (13 %) of the title compound PRB-23 as a colorless oil.
'H-NMR (200 MHz; CDCI3) 5 0.8-1.0 (m, 6H), 1.2-1.4 (m, 4H), 1.5-1.7 (m, 2H), 2.12 (m, 2H), 2.3-2.5 (m, 2H), 2.8-3.0 (m, lOH), 4.18 (t, 2H)3 5.3-5.6 (m, 12H); MS (electrospray); 407 [M+Na]. [a]D -\3° (c=1.00, ethanol). Preparation of a-phtalimide-DHA ethvlester (PRB-24)

A mixture of the a-hydroxy-DHA ethyl ester (PRB-12) (373.5 mg, 1.00 mmol), phtalimide (178 mg, 1.21 mmol) and tR1phenyl phosphine (313.9 mg, 1.20 mmol) in THF, 10 mL, was cooled to 0°C under Na-atmosphere before diisopropyl

azodicarboxylate (0.24 mL, 1.24 mmol) was added drop wise. The ice-bath was
removed and the reaction mixture was stirred at ambient temperature for 18 hrs,
whereupon it was evaporated in vacuo and subjected to flash chromatography on silica
gel eluting with heptane/EtOAc (99:1-95:1) to yield 323 mg (64 %) of the product as a
yellow liquid.
'H NMR (200 MHz, CDCb) 5 0.95 (t, J=7.5 Hz, 3H), 1.22 (t, J=7.1 Hz, 3H), 2.05 (m,
2H), 2.72-2.84 (m, 1 IH), 3.02-3.22 (IH)5 4.20 (q, J=7.1 Hz, 2H), 4.87 (dd, J=I 1 Hz,
J=4.9 Hz5 IH), 5.17-5.40 (m, 12H)5 7.68-7.75 (m, 2H)5 7.79-7.85 (m, 2H)
'^C NMR (50 MHzs CDCI3) 8 14.0, 14.1, 20.4, 25.4, 25.4, 25.5, 27.0, 51.8, 61.7, 123.8,
124.3, 126.9, 127.5, 127.7, 127.9, 127.9, 128.1, 128.1, 128.3, 128.4, 131.6, 131.8,
131.8, 134.0, 167.3, 168.7 (2 signals hidden)
MS (electrospray); 502 [M+H]^ 524[M+Na]^
Preparation of a-ethvlamino-DHA etylester (PRB-25) and a-diethylamino-BHA
etvlester (PRB-26)

A mixture of the a-amino-DHA ethylester (PRB-17) (746.5 mg, 2.01 mmol), LiOH-H2O (171.6 mg, 4.09 mmol) and molsieve 4A (599 mg) in DMF5 4 mL, was added ethylbromide (3.0 ml, 40.2 mmol) and the resulting mixture was stirred at ambient temperature for 71 hrs. The mixture was diluted with diethyl ether, 100 mL, and filtered. The organic phase was washed with 1 M NaOHs 20 mL, and bR1ne, 20 mL, dR1ed (Na2S04), filtered and evaporated in vacuo and subjected to flash chromatography on silica gel eluting with heptaneiEtOAc (95:5) - CH2Cl2:2M NH3 in MeOH (99:1) to yield 458 nig (53 %) of PRB-26 as a yellow liquid and 152 mg (19%) of PRB-25 as a yellow liquid.

PRB-26:
^HNMR (200 MHz, CDCI3) 5 0.89 (t, J=7.5 Hz, 3H), 1.03 (t, 3H), 1.24 (t, J=L \ Hz,
6H), 2.05 (quint, J=7.1 Hz, 2H), 2.52 (m, 4H), 2.76-2.85 (m, 12 H), 3.35 (t, IH), 4.13
(q, J=7.1 Hz, 2 H), 5.28-5.44 (m, 12 H)
^^C NMR (75 MHz, CDCI3) 5 14.1, 14.3, 14.4, 20.5, 22.6, 25.5, 25.6, 25,7, 31.9, 44.4,
60.1, 62,9, 127.0, 127.8, 128.05, 128.13, 128.17, 128.22, 128.5, 132.0, 173.3 (5 signals
hidden)
Examples
An overview of the models and methods used in the present invention for
demonstrating effects on the metabolic syndrome and type 2 diabetes are presented in
Fig. 2: Five blocks of expeR1ments have been performed in order to elucidate the effects
of DHA deR1vatives for reduction of insulin resistance and/or alleviating the metabolic
syndrome. The invention shall not be limited to the shown embodiments and examples.
Example!. Analysis of intracellular free fatty acids (non-esteR1fied fatty acids) in
liver cells (block 1 in Fig. 2)
Background
In the first block of expeR1ments (see Fig. 2) liver tissue from animals fed PRB-1, 2,5,
and 7 was analysed with respect to free unesteR1fied fatty acids. The animals were
recruited from the fifth block of expeR1ments (pharmacodynamic effects of DHA
deR1vatives in an animal model of metabolic syndrome). The animals had been given
DHA (15% of fat content of the diet) or the DHA-deR1vatives (1, 5% of the fat content
in their diet) for 8 weeks and were supposed to be in a steady-state situation with stable
levels of DHA and the DHA-deR1vatives intracellulaR1ly. Liver tissue was chosen due to
the fact that the metabolisation rate is very high in liver.
Method
The liver samples were homogenized in cold PBS buffer, and extracted immediately
with chloroform: methanol (2:1) containing 0.2mM butylated hydroxytoluene (BHT)
using cis-10-heptadecenoic acid as internal standard. The organic phases were dR1ed
under nitrogen, re-dissolved in acetonitR1le with 0.1% acetic acid and 10|xM BHT for
RP-HPLC MS/MS analysis. Total protein content was measured using Bio-Rad method
after homogenization.
Agilent 1100 system was used for reverse phase column (Supelco Ascentis Cis column,
25cm x 4.6mm, i.d. 5|xm) separation of DHA and its PRB deR1vatives within 22min.

The flow phase was iso-gradient acetonitR1le-HaO (87+13, v/v) containing 0.1% acetic
acid. The column oven temperature was set at 35°C. The column elute was identified
and quantified in the negative electrospray ionisation applying multiple reaction
monitoR1ng mode by tR1ple tandem quadrapole mass/mass (ABI Qtrap-4000). The
parent-daughter ion pairs were 327.3/327.3 (DHA)3 341.3/341.3 (PRB-I), 355.3/355.3
(PRB-2 and PRB-5), 387.3 /387.3 (PRB-7), 267.2/267.2 (LS. FA 17:1) respectively
under unit resolufion. The signal collection dwell time was all 100 msec except for FA
17:1 which was set at 200msec. Accurate veR1fication of isomeR1c PRB compounds was
done by combination of the retention time and characteR1stic mass/charge ratio. The
quadratic regression standard curve was used for quantification after internal standard
calibration.
Results
Concentration of the different DHA-deR1vatives and the concentrations of DHA was
given as |ig per g of total amount of protein in the liver cells. Fig, 3 depicts the
concentrations of the different PRBs from animals given PRB-I, 2, 5 and 7 in a
concentration of 1.5% of total fat content in the high fat diet.
The highest intracellular concentration of the PRBs was obtained for PRB-2. Also
PRB-5 was enR1ched intracellulaR1ly, although not to the same extent as PRB-2. This
finding is unexpected.
Fig. 4 depicts the intracellular concentrations of DHA in liver tissue from animals given
the different PRBs. DHA reached a significantly higher level in the animals given PRB-
7 compared to the other three DHA-deR1vatives. Animals given PRB-2 had the lowest
concentration of DHA. It seems that PRB-7 is to some extent converted back to DHA.
PRB-2 reached the highest intracellular concentration. This means that PRB-2 will be
more available as a ligand to nuclear receptors, a pattern which could be translated into
therapeutic effects in handling of blood glucose and blood lipids.
Example 2 Computer based affinity testing (block 2 in Fig. 2)
Background
Nuclear receptors have been sequenced and the amino acid sequence is known for the
PPARs and other relevant receptors engaged in the genetic control of glucose and fat.
X-ray crystallography and NMR spectroscopy of the PPAR receptors are available and
computeR1sed affinity testing of fatty acids liganding to the receptors can be used to
estimate binding kinetics. The binding geometR1es, often called binding modes or poses,

include both positioning of the ligand relative to the receptor and the conformational
state of the ligand and the receptor. Effective ligand docking can therefore be analysed.
Affinity of the ligand to the receptor is defined by two different parameters: docking of
the ligand (DHA deR1vative) into the binding site of the receptor and electrostatic
bonding between certain amino acids of the receptor and the carboxyl group or side
chains in the head of the fatty acid. (KrumR1ne).
As previously known, the PP ARa receptor is more promiscuous compared to PPARy,
meaning that PP ARa will accept more fatty acids as ligands compared to PPARy.
However, since patients with metabolic syndrome or type 2 diabetes are usually obese
or overweight and have pathologic blood lipids, mainly elevated tR1glyceR1des and low
High-Density Cholesterol (HDL-chol) activation of the PP ARa receptor is important.
An ideal drug for treatment of metabolic syndrome or type 2 diabetes should act as
ligand to both these receptors, preferably with the highest affinity to the PPARy
receptor.
Method
Ranking of the different DHA-deR1vatives according to their binding affinity was
calculated and given as lowest binding affinity (LBA) and average binding affinity
(ABE).
A total of 15 DHA deR1vatives (PRB-I through PRE-15) were tested with the
computeR1zed docking method. Some of the deR1vatives, such as PRB-I, PRB-2, PRB-
7, PRB-9, PRB-IO, PRB-11, PRB-12, PRB-13, PRB-14 and PRB-15, are presented as r
and s enantiomeres and in this case both were tested. The PPARy ligands rosiglitazone
and pioglitazone, both in the r and s form, were also tested for compaR1son. These
compounds are registered pharmaceuticals for treatment of diabetes.
Results
The results are shown in Table 1, presenting the parameters Lowest binding energy of
single confirmation (LBE), average binding energy (ABE) of the correctly posed
confirmation and fraction of correctly posed confirmation of the ICM-saved 20 lowest
energy confirmation (Abound) of the compounds tested. Affinity to the RXRa was
tested in the same setting. The RXRa receptor interacts with the PPAR receptor
forming a heterodimer by liganding of a fatty acid.
Fig. 5 depicts the binding affinities for the PPARy receptor, which is mainly engaged in
the transcR1ption of proteins engaged in handling of blood glucose. Clearly PRB-2 both

in the r and the s stereoisomer forms had a good affinity to the PPARy receptor. PRB-5 scored somewhat poorer while PRB-8 had the highest ABE score. These findings are highly unsuspected and could be translated into a more effective transcR1ption of the respective PPARy activated gene responsible for handling of blood glucose. Fig. 6 depicts the binding affinities to the nuclear receptor PPARa which is mainly responsible for metabolisation of fat, blood lipids, fat tissue biology and weight control. Several DHA-deR1vatives had high binding affinity but.PRBS had the highest score. This is also highly unsuspected. Fig. 7 depicts the binding affinities to the nuclear receptor RXRa. The physiologic consequence of binding to the RXRa receptor has not been firmly established. It is known that RXR binds to the PPAR receptors thereby forming a heterodimer which then, subsequently, initiates transcR1ption of the defined gene.

ND- Not docked, c = the double bonds in all-cis form. r= R enantioisomer, s= S
enantioisomer. ROSI= Rosiglitazone, PIO= Pioglitazone.
Several of the PRBs have a high LBE and ABE score for the PPARa and
PPARy receptors even compared to the mother compound DHA but also to the PPARy
ligands rosiglitazone and pioglitazone, both in the r and s form. This is an interesting
observation indicating that several of the PRBs could be promising competitors to the
established anti-diabetics rosiglitazone and pioglitazone. Ethyl deR1vativates in alfa
position of the same fatty acids, both the r and the s form, did not improve affinity. This
was especially true for the PPARy receptor. As mentioned previously the PPARa
receptor is more promiscuous binding a long seR1es of fatty acids.
In conclusion, many of the DHA-deR1vatives tested demonstrated interesting affinities
to the PP ARa and PP ARy receptors with binding affinities better than rosiglitazone
and pioglitazone.

Example 3
Affinity testing in transfected cells (block 3 in Fig. 2)
Background
Release of luciferase is correlated to transcR1ption of genes. Binding of a ligand to a nuclear receptor such as PP ARy induces transcR1ption of the respective gene thereby releasing luciferase. This technique therefore provides a measure of ligand affinity to the receptor as well as activation of the responsible gene. Method
Transient transfection of COS-I cells was performed in 6-well plates as descR1bed by Graham and van der Eb (Graham). For full length PPAR transfection studies, each well received 5 |ag reporter construct, 2.5 |xg pSV-P-galactosidase as an internal control, 0.4 |xg pSG5-PPARy2. The cells were harvested after 72 h, and the luciferase activity was measured according to the protocol (Promega). The luciferase activity was normalised against P-galactosidase activity. The adipocytes were transfected at Dl 1 of differentiation using 16 |J,1 LipofectaminPlus reagent, 4 |j,l Lipofectamine (Life Technologies Inc.), 0.2 ^g pSGS-PPARy, and 100 ng pTK Renilla luciferase as control of transfection afficiency. Three hours after transfection, cells were cultured in serum containing medium and incubated for 48 hours in the same medium containing appropR1ate agents. The luciferase activities were measured as recommended by the manufacturer (Dual Luciferase assay, Promega). All transfections were performed in tR1plicate.
Fatty acids (BRL or DHA) and PRBs (stock solutions) were solubilized to 0.1 M final concentration in DMSO. Then, Fatty solubilized to lOmM in DMSO and stored in 1.5 ml tubes (homoplymer, plastic tubes) flushed with argon and stored at - 20^C. 10 |LIM of PRBs or fatty acids and DMSO (control) was added to the media 5h after transfection. Transfected cells were maintained for 24h before lysis by reporter lysis buffer. Binding of PRBs or fatty acids to the LBD of PPAR activates GAL4 binding to UAS, which in turn stimulates the tk promoter to dR1ve luciferase expression. Luciferase activity was measured using a luminometer (TD-20/20 luminometer; Turner Designs, Sunnycvale, CA) and normalized against protein content. Results

Fig. 8 depicts the release of luciferase from transfected cells treated with different
PRBs. The results indicate that PRB- 1,2,6,7 and 14 have a significantly higher release
of luciferase compared to PRB-3,5,9,10,11,12, and 16.
Example 4
Affinity testing in adipose prone animals with metabolic syndrome (block 4 in Fig.
2) Background
An animal model of the metabolic syndrome using the adipose prone mice of the C57BL/6J strain was used to test affinity of PRB-2,5, and 8 compared to 97% DHA and the antidiabetic compound rosiglitazone to PPARy, by measuR1ng the release of luciferase from adipose celles taken from these animals. The animals (n^S in each group) were fed high fat diet (fat constituting 60% of total caloR1es, the same diet as used in Block 5) for 8 weeks. Thereafter they were given the PRBs in a dose of 1.5% of the fat content of the diet for another two weeks. The rosiglitazone group was given an amount of 100 mg/KG diet. The control groups continued with either only high fat diet or standard chow. Fig. 9 shows the study design. Method
After sacR1fice adipose tissue (epididymal and subcutaneous) was cleared from other structures and cut into millimeter-size pieces. Fat tissue was R1nsed in 0,9% NaCl and digested in 5 mL of Krebs-R1nger solution containing Hepes, fatty-acid free bovine serum albumin, 20OnM of adenosin, 2 nM of glucose, and 260 U/mL of collagenase for 1,5 h at 37 degrees C in a shaking water bath. After collagensae digestion, adipocytes were separated from tissue debR1s by filteR1ng. Cells were then washed in Krebs-R1nger solution containing Hepes, fatty-acid free bovine serum albumin, 20OnM of adenosin, 2 nM of glucose and kept in a shaking water bath at 37 degrees for a maximum of 30 min until electroporation.
Isolated pR1mary adipocytes were transfected by electroporation to measure the specific PPAR gamma response element (PPRE) activity. In this case we incorporated a plasmid encoding firefly luciferase cDNA under control of a PPRE from the acyl-CoA-oxidase gene. The cells were also co-transfected with a plasmid containing cDNA for Renilla luciferase controlled by a constitutively active promoter. The PPRE inducible firefly luciferase activity was normalised according to Renilla luciferase, thus correcting for potential differences in the amount of transfected cells. To measure

luciferase signal we used the Dual-Luciferase® Reporter assay System (Promega,USA).
Pooled epidydimal fat tissue was enough to isolate adipocytes for running duplicates. Each of groups was sacR1ficed in two separated days, and 4 independent transfections for each dietetic group were obtained. Results
DuR1ng first 8 weeks of feeding with HF diet (33,7% of fat, w/w), there was a gradual increase of body weight in compaR1son to control mice fed with chow diet (4,5% w/w). DuR1ng last 2 weeks of feeding with expeR1mental diets high fat diet animals and animals given high fat diet in combination with Rosiglitazon continued gaining weight, approximately with the same rate as before. In case of PRB-8 and PRB-5 enR1ched HF diet the weight gain was reduced. However, in case of PRB-2 and DHA (5% w/w) the diet completely stopped the weight gain and even led to reduction of body weight (Fig. 10). Food consumption was recorded occasionally (4x). There were no differences between the HF and the intervention groups.
In case of high fat in combination with Rosiglitazon, the endogenous activity of PPARy was approximately 2-fold higher than in all the others diet groups (Fig. 11). Furthermore, these fat cells became more sensitive to additional in vitro stimulation with 5uM Rosiglitazon (5, 12- fold stimulation) in compaR1son to i.e. HF diet itself (1, 5-fold stimulation). This rosiglitazon - sensitizing effect was also recorded in the PRB-2 and the PRB-5 diet group (2, 6-fold stimulation).
Data from this study clearly demonstrates activity on the nuclear PPAR receptors, in particular with the effects on weight which was most prominent for the groups given PRB-2. Even animals given PRB-5 and PRB-8 did not increase in weight as did the high fat diet group. Interestingly animals given rosiglitazone increaed in weight to the same extent as animals given only the high fat diet. This clearly demonstrates the negative effects of giving only a PPARy ligand, like the glitazones, with the R1sk of weight increase even if insulin resistance is reduced. However, when it comes to PPARy activation measured as luciferase activity in this expeR1ment, rosiglitazone scores higher compared to any of the PRBs. Within the PRB groups PRB-2 and PRB-5 had a higher score compared to PRB-8 and DHA only (Fig. 12).

Example 5
Pharmacodynamic effects of DHA deR1vatives in an animal model of metabolic
syndrome (block 5 in Fig. 2)
Background
An animal model of the metabolic syndrome using the adipose prone mice of the C57BL/6J strain was used to document effects on typical laboratory and pathological anatomical features common for the metabolic syndrome. When given a high fat diet containing about 60% of fat, the animals are getting obese developing high insulin plasma levels, pathological glucose tolerance test, elevated serum tR1glyceR1des and non-esteR1fied fatty acids, and fat liver. Example 5a
Effect of DHA deR1vatives in adipose prone mice duR1ng 4 months of dietary interventions Method
All expeR1ments were performed on male C57BL/6 mice, either a substrain C57BL/N (supplier: Charles R1ver, Germany, n = 160, expeR1ments A-C, see below), or a substrain C57BL/6J (supplier: the Jackson laboratory, Bar Harbor, ME, USA, n = 32, expeR1ment D). Total numbers of animals used were higher (n = 170 and 36, respectively), because of culling. In the latter case, animals were bred for several generations (
Animals weree fed 3 types of expeR1mental diets:
(i) Chow diet (ssniff RM-H from SSNIFF Spezialdieten Gmbh, Soest, Germany; see
also http://ssniff.de) with protein, fat and carbohydrate forming 33, 9, and 58 energy %,
respectively
(ii) High-fat diet prepared in the laboratory (cHF diet) with protein, fat and
carbohydrate forming 15, 59, and 26 energy %, respectively, and well characteR1zed
fatty acid composition (with most of the lipids coming from com oil; see Ruzickova
2004) (iii) cHF diets in which 0.15, 0.5, and 1.5 % of fat (specifically the corn oil
constituent) was replaced by vaR1ous PRB-compounds, namely PRBl, PRB2, PRB5,
PRB7, and PRB8, or by DHA. AU these compounds were in the form of ethyl esters,
provided by Pronova Biocare a.s. in sealed containers. Chemical composition of the
PRB-compounds was unknown to the laboratory performing the expeR1ments (Institute
of Physiology, Academy of Sciences Prague, Czech Republic).
After arR1val, the PRB-compounds were stored in a refR1gerator in oR1ginal containers.
The containers were opened just before preparation of the expeR1mental diets. Diets
were kept in plastic bags flushed by nitrogen and stored at -70V in small aliquots
sufficient for feeding animals for one week. Fresh ratios were given in 2-day intervals
or daily.
Outline of the study
The study was based on 4 individual expeR1ments. In each of the expeR1ments, different
PRB-compounds (or DHA, respectively) admixed to cHF diet in three different
concentrations (0.15, 0.5, and 1.5 % of the fat content) were tested. In each expeR1ment,
a subgroup of plain cHF diet-fed mice was included and served as a control. Mice were
caged in groups of 4 and fed standard chow diet until 3 mo of age, when animals (n =
8-13) were randomly assigned to the different test diets. After 2 mo on this new diet (at
5 mo of age), animals were fasted overnight and in the morning, intrapeR1toneal
Glucose Tolerance Test (GTT) was performed. Animals were sacR1ficed after 4 months
on the expeR1mental diets, at 7 mo of age, and the end- point analysis were performed.
Study parameters.
The parameters in the study were: Body weight gain (grams), area under the curve
(AUC) from intrapeR1toneal glucose tolerance tests (mMol x 180 min), plasma insulin
(ng/ml), serum tR1glyceR1des (TAGss mmol/1), and non-esteR1fied fatty acids (NEFA5
mmol/1).

Fig. 13 shows a typical blood glucose elimination curve before and after animals with
insulin resistance are given a compound with insulin resistance reducing effect.
Reduction of the area under the curve means that blood glucose is eliminated more
effectively due to reduced insulin resistance.
Results
The results are shown in the following tables 2, 3 and 4. (* = significant differencies
compared to cHF diets (P Table 2 shows the effects in animals given 1.5% concentration of the PRB test
compounds compared to animals given standard chow (STD), composite high fat diet
(cHF) or 97% DHA. Body weight gain was significantly reduced in animals given
PRB-2 compared to animals given high fat diet (cHF). Food intake was somewhat
lower in this group. The most pronounced reduction in AUC from glucose tolerance
tests was seen in the same group and even in animals given PRB-I .Plasma insulin was
significantly lower in the PRB-2 group compared to the cHF controls even if the PRB-I
and PRB-5 treated animals showed some effect on this parameter too. The PRB-2
group showed the biggest reduction in tR1glyceR1des (TAGs) and non-esteR1fied fatty
acids (NEFA).
Table 3 shows the effects in animals given a lower concentration, 0.5%, of the PRB test
compounds compared to animals given standard chow (STD), composite high fat diet
(cHF) or 97%» DHA. Body weight gain was somewhat lower in animals given PRB-2
and PRB-5. AUC from the glucose tolerance test as well as plasma insulin, however,
was significantly lower only in the PRB-2 group.
Table 4 shows the rsults from the lowest PRB concentration given, 0.15%. Here, the
differences were small. Weight gain was somewhat lower in the PRB-I and PRB-2
groups while AUC was significantly lower only in the PRB-2 group. Plasma insulin
was lower in PRB-1, 2 and 7.

In conclusion, testing of PBR-1, 2,5, and 7 duR1ng 4 months in adipose prone animals
with insulin resistance and metabolic syndrome demonstrated a clear and unsuspected
effect of the PRBs tested, in particular the DHA- deR1vative PBR-2, on insulin
resistance and symptoms of the metabolic syndrome such as weight reduction, reduced
AUC in the intrapeR1toneal glucose tolerance test, lower insulin/plasma levels as well as
reduced tR1glyceR1de and non-esteR1fied free fatty acids. Effects were observed in the
dose of 1.5% as well as in the 0.5% group. Some effects were even noticed in the
lowest concentration group of 0.15%.
Testing of the PRB-8 compound was started later, therefore only data from 2 months
intervention in three dose groups (1.5%, 0.5% and 0,15%) are given. In the group given
1.5%, body weight (BW) was 28.0 ±0.7 grams compared to controls 29.6±0.9, AUC
1031 ±104 compared to 1074±91. These differences are small but the trend is
interesting. There were no differences between intervention and controls.for the lower
doses of 0.5% and 0.15%). The data regarding PRB-8 data from 2 months medication
showing a trend towards weight reduction and AUC.
Example 5b
Effect of DHA deR1vatives on established metabolic syndrome and insulin
resistance
Method
In another expeR1ment, PRB-2, PRB-5, and PRB-7 were tested in the same breed of
animals. In this expeR1ment, animals were initially fed high fat diet (the same as in the
previous expeR1ment 5 a) for 8 weeks developing insulin resistance and the metabolic
syndrome, and then given the PRBs. The start dose was to substitute 15%) of the fat
content with the PRBs but the animals did not tolerate this dose. After a peR1od of
another two weeks the animals were given 1.5%) of PRB-2, 5%) andl.5%> of PRB-5, and
1.5%and0.5%ofPRB-7.
Results
Weight reduction was very good in the animals given PRB-2. Even the animals given
PRB-5 showed some weight reduction but in the higher dose of 5%>. TR1glyceR1des were
reduced with all deR1vatives tested compared to the control animals fed composite High
Fat diet. Reduction of non-esteR1fied fatty acids was most pronounced with PRB-2 and
PRB-5, however in different doses. (See Fig. 14)

Blood cholesterol was reduced in animals given PRB-2 and PRB-5. Blood glucose was not affected due to the fact that these animals are in a pre-diabetic state with normal glucose due to a high insulin production. However, more importantly, plasma insulin was significantly reduced in the PRB-2 group in a much lower concentration compared to the second best DHA-deR1vative PRB-5. Even PRB-7 showed some effects on the insulin concentration. (See Fig. 15).
PRB-2 showed a statistically significant reduction of the AUC blood glucose at all time points of the curve compared to the baseline values. This means that blood glucose was more effectively removed after treatment of 1,5% of PRB-2. PBR-5 and PBR-7 showed some effect but not to the same extent. (See Fig. 16).
These effects are highly unsuspected and very relevant for a positive effect in metabolic syndrome and type 2 diabetes. These patients are almost exclusively overweight or obese and a weight reductive effect of a drug is highly positive. The mostly used remedies used for treatment of type 2 diabetes today, the thiazolidinedions, which are potent PPARy ligands thereby reducing insulin resistance, often result in weight increase which is highly negative for these subset of patients (Yki-Jarvinen 2004). Reduction of serum tR1glyceR1des is another very important effect that was demonstrated in the expeR1ments. Patients with metabolic syndrome and type 2 diabetes usually have elevated tR1glyceR1des. The tR1glyceR1de loweR1ng effects of the DHA-deR1vatives is a positive finding and again PRB-2 demonstrated the most potent effect with the lowest dose given. The very positive effects on plasma insulin and glucose tolerance test are very promising and highly unsuspected. Taken together the effects obtained with the DHA-deR1vatives in particular PRB-2 are very promising forming a good basis for development of an antidiabetic drug. Example 5c
Testing of DHA deR1vatives on liver fat Method
Tissue samples from animals in the expeR1ments with DHA deR1vatives was histologically analysed. After paraffmation, tissue samples from liver, adipose tissue, skeletal muscle, pancreas, and kidney were stained with eosin-hematoxylin.

Results
There were no pathological findings in the tissues examined with exception from liver. Control animals fed high fat diet had developed fat liver (liver steatosis). Fat droplets in the liver can easily be distinguished from normal liver cells. Animals treated with PRB-I, 5, and 7 had low degree of fat liver. However, animals treated with 1.5% of PRB-2 had completely normal liver cells with no trace of steatosis. This is an extremely important finding and very relevant for treatment of patients with insulin resistance, obesity and type 2 diabetes. Liver steatosis is a common finding in these patients which is usually related to an overload of fatty acids and tR1glyceR1des, biological markers present in the development of insulin resistance and the metabolic syndrome. DHA-deR1vatives reduce liver steatosis, and PRB-2 was the most efficient compound showing this effect. Discussion and conclusions
The present application clearly identifies a new group of compounds which are activating nuclear receptors, especially PP ARy and PP ARa, thereby offeR1ng a seR1es of therapeutic effects in the treatment of insulin resistance, the metabolic syndrome, type 2 diabetes, cardiovascular disease and other atherosclerotic related diseases. Members of this group are DHA deR1vatives with side chains of different kind in the alfa position of the molecule. A large number of alfa-substituted DHA deR1vatives have been tested and compared with controls as well as pure DHA and EPA. Several of the compounds tested have demonstrated interesting biological effects very relevant for a potential anti-diabetic drug.
Interestingly, and not conceivable on beforehand, alfa-ethyl DHA ethyl ester (PRB-2) was significantly more effective in the battery of tests used to demonstrate effects related to insulin resistance and thereby diseases mainly caused by this pathophysiologic condition such as the metabolic syndrome, type 2 diabetes, cardiovascular disease and other atherosclerotic related diseases. Alfa-ethyl DHA ethyl ester was enR1ched in liver tissue from animals given the different DHA deR1vatives tested (Block 1) indicating that this compound was not utilised for synthesis of tR1glyceR1des, eikosanoids or other metabolic intermediates. Indirectly this would mean that alfa-ethyl DHA would be available for liganding to nuclear receptors like the PPARs.

In testing of affinity to PPAR y and PP ARa using computeR1zed docking technology a large number of the DHA-deR1vatives showed affinities to both receptors, not least PPAR y which probably is the most important nuclear receptor engaged in the activation of genes responsible for metabolisation of blood glucose. In particular alfa-ethyl DHA (PRB-2) as well as alfa-diethyl DHA (PBR-8) possessed excellent affinity to these nuclear receptors. Compared to alfa-diethyl DHA alfa-ethyl DHA has two stereoisomers, the r and the s form. Using the docking technology both stereoisomers possessed about the same affinity to PPAR y and PP ARa meaning that neither the r or the s form should have advantages compared to the racemic form. In fact the racemic form may have advantages over each one of the stereoisomers. When affinity was tested in transfected cells carrying the nuclear receptor and the subsequent DNA response element, several of the PRBs demonstrated good affinity measured as release of luciferase. Alfa-ethyl DHA (PRB-2) together with PRB-6,7 and 14 demonstrated the best effects.
Five of the DHA deR1vatives have been extensively tested in the C57BL/6 mouse model developing insulin resistance and the metabolic syndrome when fed high fat diet. Alfa-ethyl DHA (PRB-2) has been tested in three individual expeR1ments while PRB- 1,5, and 7 were tested in two and alfa-diethyl DHA (PRB-8) was tested in one expeR1ment. All deR1vatives demonstrated significant biological effects. However, alfa-ethyl DHA (PRB-2) showed the most promising effects with a consistent reduction in body weight, AUC from intrapeR1toneal glucose tolerance testing, plasma insulin as well as serum tR1glyceR1des and non-esteR1fied fatty acids. The effects were obtained on the doses 1.5% and 0.5%. The lowest tested dose 0.15% did not perform convincingly. Alfa-ethyl DHA (PRB-2) in a dose of 1.5% has also demonstrated a normalisation of fat liver, an important pathological finding in patients and animals with insulin resistance and metabolic syndrome.
CompaR1ng with pure DHA, alfa-ethyl DHA (PRB-2) seems to be 10-30 times as potent as DHA. All in all these findings and the potency compared to the mother molecule DHA are not predictable and highly unexpected.
Since alfa-ethyl DHA (PRB-2) seems to work by simultaneous liganding to the nuclear receptors PP ARa and PPARy the compound would not only possess therapeutic interesting effects on glucose and lipid metabolism, not least in patients with insulin resistance, metabolic syndrome and type 2 diabetes but also have weight reduction as

well as a general anti-inflammatory effect. Directly or through positive intervention on
R1sk factors alfa-ethyl DHA (PRB-2) would have a preventive effect on the
development of cardiovascular disease such as myocardial infarction and cerebral
stroke as well as having a preventive effect on cardio-vascular mortality.
Pharmaceuticals acting as PPARy ligands are already on the market but even if these
compounds are having positive effects on glucose metabolism, they are hampered by
adverse effects such as elevated tR1glyceR1des, weight increase and oedema. The alfa-
substituted DHA deR1vatives presented in this application are having a combined
PPARy and PP ARa effect which is probably both relevant and advantageous for
patients with insulin resistance, metabolic syndrome and type 2 diabetes. Furthermore,
these combinative actions should have important effects also on blood lipids,
inflammatory events, atherosclerosis, and thereby cardiovascular disease.
The invention shall not be limited to the shown embodiments and examples.
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Field CJ, Ryan EA, Thomson ABR, et al. Diet fat composition alters membrane phospholipid composition, insulin binding and glucose metabolism in adipocytes from control and diabetic animals. J Biol Chemistry 1990 ;265 : 11143 - 11150 Yki-Jarvinen, H. Thiazolidinediones. NEJM 2004;351:1106-1118 Adams M, Montague CT5 PR1ns JB, et al. Activators of peroxisomes proliferator-activated receptor gamma have depot-specific effects on human preadipocyte differentiation. J Clin Invest 1997,100:3149-3153
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Vaagenes H, Madsen L, Dyr0y E, et al. The hypolipidaemic effect of EPA is potentiated by 2- and 3-methylation. Biochim Pharmacol 1999;58:1133-1143 Larsen L, Granslund L,Holmeide AK, et al. Sulfur-substituted and a-methylated fatty acids as peroxisome proliferator-activated receptor activators. Lipids 2005;40:49-57 Larsen L, Horvik K, Sorensen HIN, et al. Polyunsaturated thia- and oxa-fatty acids: incorporation into cell-lipids and their effects on arachidonic acid- and eikosanoids synthesis. Biochim et Biophys Acta 1997,1348:346-354 Larsen, et.al Biochemical Pharmacology 1998; 55, 405
Chih-Hao L, Olson P, and Evans RM. Lipid metabolism, metabolic diseases, and peroxisome proliferator-activated receptors. EndocR1nology 2003;144:2201-2207 Willumsen N, Waagenes H, Holmsen H, et al. On the effect of 2-deuteR1um- and 2-methyl-eicosapentaenoic acid deR1vatives on tR1glyceR1des, peroxisomal beta-oxidation and platelet aggregation in rats. Biochim Biophys Acta 1998;1369:193-203 Mitsunobu O, Synthesis 1981 ;1
Ager DJ, Prakash I, and Schaad DR. 1,2-amino alcohols and their heterocyclic deR1vatives as chiral auxiliaR1es in asymmetR1c synthesis Chem Rev 1996;96:835-876

We claim:
1) A compound of formula (I):

wherein
- R1 and R2 are the same or different and may be selected from the group consisting of a
hydrogen atom, a hydroxy group, an alkyl group, a halogen atom, an alkoxy group, an acyloxy group, an acyl group, an alkenyl group, an alkynyl group, an aryl group, an alkylthio group, an alkoxycarbonyl group, an alkylsulfinyl group, an alkylsulfonyl group, an amino group, and an alkylamino group; and
- X represents a carboxylic acid group, a carboxylate group, or a carboxamide group, or
any pharmaceutically acceptable salt, solvate, complex or pro-drug thereof; with the
provisos that:
■ the compound of formula (I) is not (all-Z)-4,7,10,13,16,19- docosahexaenoic acid (DHA), alpha-methyl DHA, alpha-methyl DHA methyl ester, alpha-methyl DHA ethyl ester or alpha-hydroxy DHA ethyl ester.
2) The compound as claimed in claim 1, wherein said alkyl group is selected from
a group compR1sing of methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-buthyl,
sec. -butyl, n-hexyl, and benzyl.
3) The compound as claimed in claim 1, wherein said halogen atom is selected
from a group compR1sing of fluoR1ne, chloR1ne, bromine, and iodine.
4) The compound as claimed in claim 1, wherein said alkoxy group is selected
from a group compR1sing of methoxy, ethoxy, propoxy, isopropoxy, sec-
butoxy, phenoxy, benzyloxy, OCH2CF3, and OCH2CH2OCH3.
5) The compound as claimed in claim 1, wherein said alkenyl group is selected from a group compR1sing of allyl, 2-butenyl, and 3-hexenyl.
6) The compound as claimed in claim 1, wherein said alkynyl group is selected from a group compR1sing of propargyl, 2-butynyl, and 3-hexynyl.
7) The compound as claimed in claim 1, wherein said aryl group is a phenyl group.

The compound as claimed in claim 1, wherein said aikylthio group is selected from a group compR1sing of methylthio, ethylthio, isopropylthio, andphenylthio. The compound as claimed in claim 1, wherein said alkoxycarbonyl group is selected from a group compR1sing of methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and butoxycarbonyl. I The compound as claimed in claim 1, wherein said alkylsulfinyl group is selected from a group compR1sing of methanesulfmyl, ethanesulfmyl, and isopropanesulfinyl.
The compound as claimed in claim 1, wherein said alkylsulfonyl group is selected from a group compR1sing of methanesulfonyl, ethanesulfonyl, and isopropanesulf onyl.
The compound as claimed in claim 1, wherein said alkylamino group is selected from a group compR1sing of methylamino, dimethylamino, ethylarnino, and diethylamino.
The compound as claimed in claim 1, wherein said carboxylate group is selected from a group compR1sing of ethyl carboxylate, methyl carboxylate, n-propyl carboxylate, isopropyl carboxylate, n-butyl carboxylate, sec-butyl carboxylate, and n-hexyl carboxylate.
The compound as claimed in claim 1, wherein said carboxamide group is selected from a group compR1sing of pR1mary carboxamide, N-methyl carboxamide, N,N-dimethyl carboxamide, N-ethyl carboxamide, and N,N-diethyl carboxamide.
The compound as claimed in claim 1, wherein R1 and R2 are selected from the group consisting of a hydrogen atom, a hydroxy group, an alkyl group, a halogen atom, an alkoxy group, an aikylthio group, an alkylsulfmyl group, an alkylsulfonyl group, an amino group, and an alkylamino group. The compound as claimed in claim 1, wherein R1 and R2 are selected from a group compR1sing of a hydrogen atom, a hydroxy group, a C1-C7 alkyl group, a halogen atom, a C1-C7 alkoxy group, a C1-C7 alkyltio group, a C1-C7 alkylsulfmyl group, a C1-C7 alkylsulfonyl group, an amino group, and a C] - C? alkylamino group.
The compound as claimed in claim 1, wherein said C1-C7 alkyl group is methyl, ethyl, or benzyl; said halogen atom is fluoR1ne or iodine: said C1-C7 alkoxy

group is methoxy or ethoxy; said C1-C7alkylthio group is methylthio, ethylthio
or phenylthio; said C1-C7 alkylsulfmyl group is ethanesulfmyl; said C1-C7
alkylsulfonyl group is ethanesulfonyl; said C1-C7 alkylamino group is
ethylamino or diethylamino; and X represents a an ethylcarboxylate or a
carboxamide group. ) The compound as claimed in claim 1, wherein R1 and R2 are selected from the
group consisting of a hydrogen atom, a C2-C7 alkyl group, a halogen atom, a Ci-
C7 alkoxy group, a C1-C7 alkyltio group, a CpCy alkylsulfmyl group, a C1-C7
alkylsulfonyl group, an amino group, and a C1-C7 alkylamino group; and X
represents a carboxylate. ► The compound as claimed in claim 18, wherein said C2-C7 alkyl group is ethyl,
or benzyl; said halogen atom is fluoR1ne or iodine: said C1-C7 alkoxy group is
methoxy or ethoxy; said C1-C7 alkylthio group is methylthio, ethylthio or
phenylthio; said C1-C7 alkylsulfmyl group is ethanesulfmyl; said C1-C7
alkylsulfonyl group is ethanesulfonyl; said C1-C7 alkylamino group is
ethylamino or diethylamino; and X represents a an ethylcarboxylate.
The compound as claimed in claim 1, wherein R1 and R2 are different.
The compound as claimed in claim 20, wherein said compound is in racemic
form.
The compound as claimed in claim 20, wherein said compound is in the form of
its R stereoisomer.
The compound as claimed in claim 20, wherein said compound is in the form
of its S stereoisomer.
The compound as claimed in claim 1, wherein one Of R1 and R2 represents a
C2-C7 alkyl group, and the other one represents a hydrogen atom.
The compound as claimed in claim 24, wherein said alkyl group is ethyl.
The compound as claimed in claim 25, wherein said compound is in racemic
form.
The compound as claimed in claim 25, wherein said compound is in the form of
its R stereoisomer.
The compound as claimed in claim 25, wherein said compound is in the form of
its S stereoisomer.
The compound as claimed in claim 24, wherein said alkyl group is benzyl.

The compound as claimed In claim 1, wherein one of R1 and R2 represents an alkoxy group, and the other one represents a hydrogen atom. The compound as claimed in claim 30, wherein said alkoxy group is ethoxy or methoxy.
The compound as claimed in claim 1, wherein one of R1 and R2 represents a halogen atom, and the other one represents a hydrogen atom. The compound as claimed in claim 32, wherein said halogen atom is fluoR1ne or iodine.
The compound as claimed in claim 1, wherein one of R1 and R2 represents a alkylthio group, and the other one represents a hydrogen atom. The compound as claimed in claim 34, wherein said alkylthiogroup is ethylthio. The compound as claimed in claim 34, wherein said alkylthiogroup is methylthio or phenylthio.
The compound as claimed in claim 1, wherein one of R1 and R2 represents an alkylsulfonyl group, and the other one represents a hydrogen atom. The compound as claimed in claim 1, wherein said alkylsulfonyl group is ethanesulfonyl.
The compound as claimed in claim 1, wherein one of R1 and R2 represents an amino group, and the other one represents a hydrogen atom. The compound as claimed in claim 1, wherein one of R1 and R2 represents an alkyl-amino group, and the other one represents a hydrogen atom. The compound as claimed in claim 40, wherein said alkyl-amino group is ethyl-amino or diethyl-amino.
The compound as claimed in claim 1, wherein R1 and R2 represent C1-C7- alkyl groups.
The compound as claimed in claim 42, wherein said alkyl groups are methyl groups.
The compound as claimed in claim 42, wherein said alkyl groups are ethyl groups.
The compound as claimed in claims 20 to 44, wherein X is ethyl carboxylate. The compound as claimed in claims 1 to 45, in the form, of a phospholipid, a tR1-, di- or monoglyceR1de, or in the form of a free acid.

The compound as claimed in claims 1 to 46, wherein said compound is for use as a medicament.
A process for the manufacture of a compound as claimed in claims 1 to 46. The process as claimed in claim 48, wherein said compound is prepared from (all-Z)-4, 7, 10, 13, 16, 19-docosahexaenoic acid (DHA). The process as claimed in claim 49, wherein said DHA is prepared from a vegetable, a microbial and/or an animal source.
The process as claimed in claim 50, wherein said DHA is prepared from a maR1ne oil.
The process as claimed in claim 51, wherein said maR1ne oil is fish oil. A pharmaceutical composition compR1sing a compound as claimed in claims 1 to 46 as an active ingredient.
The pharmaceutical composition as claimed in claim 53, wherein said composition further compR1sing a pharmaceutically acceptable carR1er. The pharmaceutical composition as claimed in claim 54, wherein said composition is formulated for oral administration.
The pharmaceutical composition as claimed claim 55, wherein said formulation is in the form of a capsule or a sachet.
The pharmaceutical composition as claimed in claims 53 to 56, wherein said formulation is formulated to provide a daily dosage ranging from 10 mg to 10 g of said compound.
The pharmaceutical composition as claimed in claim 57, wherein said formulation is formulated to provide a daily dosage ranging from 100 mg to 1 g of said compound,
A fatty acid composition compR1sing a compound according to any one of the claims 1 to 46.
The fatty acid composition as claimed in claim 59, wherein at least 60% by weight of the fatty acid composition is compR1sed of said compound. The fatty acid composition according to claim 60, wherein at least 90% by weight of the fatty acid composition is compR1sed of said compound. The fatty acid composition as claimed in claims 59 to 61, wherein said composition further compR1sing fatty acids selected from (all-Z)-5,8,l 1,14,17-eicosapentaenoic acid (EPA), (all-Z)-4,7,10,13,16,19-docosahexaenoic acid

(DHA), (all-Z)- 6,9,12,15,18-heneicosapentaenoic acid (HPA), and/or (all-Z)-7.10,13.16,19- docosapentaenoic acid (DPA).
The fatty acid composition as claimed in claim 62, wherein said fatty acids are present in the form of deR1vatives.
The fatty acid composition as claimed in claims 59 to 63, wherein said composition further compR1sing a pharmaceutically acceptable antioxidant. The fatty acid composition as claimed in claim 64, wherein said antioxidant is tocopherol.
The fatty acid composition as claimed in claims 59 to 65, wherein said composition is for use as a medicament.
Use of a compound as claimed in claims 1 to 46 for the manufacture of a medicament for controlling body weight reduction and/or for preventing body weight gain.
Use of a compound as claimed in claims 1 to 46 for the manufacture of a medicament for the treatment and/or the prevention of obesity or an overweight condition.
Use of a compound as claimed in claims 1 to 46 for the manufacture of a medicament for the prevention and/or treatment of diabetes in an animal. Use of a compound as claimed in claim 69, wherein the diabetes is type 2 diabetes.
Use of a compound as claimed claims 1 to 46 for the manufacture of a medicament for the treatment and/or prevention of amyloidos- related diseases. Use of a compound as claimed in claims 1 to 46 for the manufacture of a medicament for the treatment or prophylaxis of multiple R1sk factors for cardiovascular diseases, preferably for the treatment of elevated blood lipids. Use of a compound as claimed in claims 1 to 46 for the manufacture of a medicament for prevention of stroke, cerebral or transient ischaemic attacks related to atherosclerosis of several arteR1es.
A method for controlling body weight reduction and/or for preventing body weight gain, wherein a pharmaceutically effective amount of a compound according to any one of the claims 1 to 46 is administered to a human or an animal.

A method for the treatment and/or the prevention of obesity or an overweight condition, wherein a pharmaceutically effective amount of a compound of formula (I) according to any one of the claims 1 to 46 is administered to a human or an animal.
A method for the prevention and/or treatment of diabetes, wherein a pharmaceutically effective amount of a compound of formula (I) according to any one of the claims 1 to 46 is administered to a human or an animal. The method as claimed in claim 76, wherein the diabetes is type 2 diabetes. A method for the treatment and/or prevention of amyloidos-related diseases, wherein a pharmaceutically effective amount of a compound of formula (I) according to any one of claims 1 to 46 is administered to a human or an animal. A method for the treatment or prophylaxis of multiple R1sk factors for cardiovascular diseases, wherein a pharmaceutically effective amount of a compound of formula (I) according to any one of the claims 1 to 46 is administered to a human or an animal.
A method for the prevention of stroke, cerebral or transient ischaemic attacks related to atherosclerosis of several arteR1es, wherein a pharmaceutically effective amount of a compound of formula (I) according to any one of the claims 1 to 47is administered to a human or an animal.
The method as claimed in claims 74 to 80, wherein the compound of formula (I) is administered orally to a human or an animal.
A compound of formula (I), a process to prepare the compound of formula (I), use of the compound and method of treatment as substantially herein descR1bed with the help of accompanying drawings and examples.

Documents:

http://ipindiaonline.gov.in/patentsearch/GrantedSearch/viewdoc.aspx?id=ZsJOnBZDVb9ILJzQIy5tpg==&loc=egcICQiyoj82NGgGrC5ChA==

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Patent Number

278877

Indian Patent Application Number

4959/CHENP/2007

PG Journal Number

01/2017

Publication Date

06-Jan-2017

Grant Date

02-Jan-2017

Date of Filing

05-Nov-2007

Name of Patentee

PRONOVA BIOPHARMA NORGE AS

Applicant Address

P.O. BOX 420, N-1327 LYSAKER, NORWAY

Inventors:

#	Inventor's Name	Inventor's Address
1	BRYHN, MORTEN	STORGATEN 43, N-3060 SVELVIK, NORWAY
2	HOLMEIDE, ANNE, KRISTIN	ORIONVEIEN 12, N-0489 OSLO, NORWAY
3	KOPECKY, JAN	ROZSIRENA 23, 182 00 PRAHA 8, CZECH REPUBLIC

PCT International Classification Number

C11C 3/00

PCT International Application Number

PCT/IB2006/001155

PCT International Filing date

2006-05-04

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	0501044-2	2005-05-04	U.S.A.
2	60/677,350	2005-05-04	U.S.A.
3	0501045-9	2005-05-04	U.S.A.
4	60/677,351	2005-05-04	U.S.A.