JP7341916B2 - Use of thiaoxo compounds to lower apoC3 - Google Patents

Description

Application of Article 30, Paragraph 2 of the Patent Act Exhibit A: Distributed documents related to Disclosure 1 Exhibit B: Presentation content related to Disclosure 2 Exhibit C: Summary related to Disclosure 3 Exhibit D: Slides related to Disclosure 4 Exhibit E: Related to Disclosure 5 Website Exhibit F: Website regarding disclosure 4

The present disclosure provides a method for reducing apolipoprotein C-III (apoC-III) mRNA or protein in a subject in need thereof, comprising: a pharmaceutically effective amount of a compound of formula (I);

又はその薬学的に許容される塩若しくはエステルを対象に投与することを含み、
式中、R₁及びR₂は、水素原子又は直鎖、分岐、及び/若しくは環式C₁～C₆アルキル基から独立して選択され、但しR₁及びR₂が両方とも水素であることはない、方法に関する。このような方法、化合物、及び組成物は、肝性及び/又は血漿アポC-IIIの上昇に起因するか、関連するか、又はそれにより増悪する状態、例えば高トリグリセリド血症(HTG)、高カイロミクロン血症、脂質異常症、膵炎を処置するために、並びに心血管疾患若しくは代謝異常、又はこれらの症状の1種以上の予防及び/又は処置において、有用である。

or a pharmaceutically acceptable salt or ester thereof,
where R ₁ and R ₂ are independently selected from hydrogen atoms or linear, branched, and/or cyclic C ₁ -C ₆ alkyl groups, provided that R ₁ and R ₂ are both hydrogen; Not about the method. Such methods, compounds, and compositions are useful for treating conditions caused by, associated with, or exacerbated by elevated hepatic and/or plasma apoC-III, such as hypertriglyceridemia (HTG), It is useful for treating chylomicronemia, dyslipidemia, pancreatitis, and in the prevention and/or treatment of cardiovascular disease or metabolic disorders, or one or more of these conditions.

Dietary polyunsaturated fatty acids (PUFA), including omega-3 fatty acids, play a role in normal health and chronic diseases, including the regulation of plasma lipid levels, cardiovascular and immune function, insulin action, neurodevelopment, and visual function. It has effects on a wide variety of physiological processes that it affects.

Omega-3 fatty acids, such as (5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenoic acid (EPA) and (4Z,7Z,10Z,13Z,16Z,19Z) -Docosa-4,7,10,13,16,19-hexaenoic acid (DHA) regulates plasma lipid levels, cardiovascular and immune function, insulin action, and neurological development and visual function. Omega-3 fatty acids have been shown to have beneficial effects on risk factors for cardiovascular diseases, such as hypertension and hypertriglyceridemia (HTG), and on the activity of the coagulation factor VII phospholipid complex.

WO2010/128401 shows that 2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenyloxy)butanoic acid has an advantageous lipid profile compared to the control. , inhibit the development of atherosclerosis in the arteries, reduce total cholesterol, and increase HDL cholesterol. These results indicate that 2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenyloxy)butanoic acid and its derivatives are effective against inflammation and hyperlipidemic conditions. have demonstrated that they may be useful in the prevention or treatment of various conditions such as obesity, fatty liver disease, atherosclerosis, peripheral insulin resistance, and/or diabetic conditions. Further uses of 2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenyloxy)butanoic acid and its derivatives for treating various diseases or conditions is disclosed in WO2012/059818.

More specifically, WO2012/059818 identifies elevated apoB, primary hypercholesterolemia (heterozygous familial and nonfamilial), and primary dyslipoproteinemia (Fredrickson A method of treating or preventing at least one disease or condition selected from type III) is described, the method comprising administering to a subject a pharmaceutically effective amount of a compound of formula (I). However, although it has already been established that pathways associated with apoB and apoE (dysβlipoproteinemia) are positively influenced by compounds of formula (I), two clinical studies in different patient populations The data surprisingly revealed that a further apolipoprotein, apoC-III, was also strongly reduced by compounds of formula (I).

ApoC-III is a glycoprotein produced primarily by the liver, and its function is thought to include promoting the assembly and secretion of triglyceride-rich VLDL particles from hepatocytes under lipid-rich conditions. (Sundaram M et al., J Lipid Research, vol. 51, 2010). In plasma, apoC-III is highly associated with very low density lipoproteins (VLDL), high density lipoproteins (HDL) and chylomicrons. Increased apoC-III levels induce the development of hypertriglyceridemia. The mechanism by which apoC-III expression increases plasma triglycerides is partially mediated by inhibition of lipoprotein lipase and hepatic lipase; thus slowing the catabolism of triglyceride-rich particles. ApoC-III is also thought to inhibit hepatic uptake of triglyceride-rich particles. The clinical importance of apoC-III demonstrates that carriers of rare mutations that disrupt apoC-III function have both lower TG levels and reduced risk of coronary/ischemic cardiovascular disease It has been established by research (N Engl J Med. July 3, 2014; 371(1):22-31, Loss-of-function mutations in APOC3, triglycerides, and coronary disease).

The long-chain omega-3 fatty acids, EPA and DHA, have already gained validation in the treatment of HTG. ApoC-III has recently been identified as a central regulator of triglyceride levels and also as a genetically valid target for the prevention of coronary cardiovascular disease, and therefore omega-3 in various forms and compositions. The effect of fatty acids on plasma apoC-III levels has been studied. By way of example, US2014/0221486 requires a subject on statin therapy to have a baseline fasting triglyceride of about 200 mg/dl to about 499 mg/dl, or a subject with a baseline fasting triglyceride of at least about 500 mg/dl. ApoC-III levels of any of the following are claimed: by administering to a subject a pharmaceutical composition comprising from about 1 g to about 4 g per day of ethyl eicosapentaenoate. US2013/0177643 provides a method for reducing serum or plasma apoC-III levels comprising: an amount of at least about 50% (a/a) of EPA, substantially in the free acid form; DHA in an amount of at least about 15% (a/a); DPA, in substantially free acid form, in an amount of at least about 1% (a/a); -III is claimed in an amount and for a period of time sufficient to reduce it from pre-treatment levels. Yet another example is a method of reducing a lipid parameter level in a subject from a baseline parameter level, wherein the lipid parameter is selected from the group consisting of apoC-III, and comprising administering to the subject a composition comprising a fatty acid. At least 50% by weight of the fatty acids include omega-3 fatty acids, salts, esters, or derivatives thereof, and the omega-3 fatty acids include eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid DHA. The ratio of EPA (DHA:EPA) is less than 1:10 and the ratio of DHA to DPA (DHA:DPA) is less than 2:1, as can be found in US2014/0094520 claiming a method .

Effective reduction of hepatic/plasma apoC-III using orally delivered omega-3/omega-3 derivatives may be attractive for selected patient populations if clinically meaningful reductions can be achieved. provide treatment options. Although it has not yet been determined how much apoC-III reduction is "clinically meaningful," studies in subjects with loss-of-function apoC-III mutations have shown that apoC-III is 46% lower than non-carriers. C-III levels shown to be associated with 40% lower risk of coronary cardiovascular disease (CHD) (N Engl J Med. 2014 Jul 3;371(1):22- 31, Loss-of-function mutations in APOC3, triglycerides, and coronary disease). In addition to reduced apoC-III concentrations, carriers also had 39% lower TG concentrations than noncarriers. As loss-of-function forms correspond to lifelong effects, therefore, treatments aimed at apoC-III reduction over a shorter period of time may be relevant to loss-of-function mutations if beneficial effects against CHD can be achieved. It is thought that the aim should be to achieve apoC-III reduction close to (or higher than) that of Compounds that reduce apoC-III more potently since the apoC-III results achieved with naturally occurring omega-3 lipids are relatively modest (see Example 26). may provide not only better triglyceride lowering but also better cardioprotection.

The present disclosure provides a method for reducing apolipoprotein C-III (apoC-III) mRNA or protein in a subject in need thereof, comprising: a pharmaceutically effective amount of a compound of formula (I);

又はその薬学的に許容される塩若しくはエステルを対象に投与することを含み、
式中、R₁及びR₂は、水素原子又は直鎖、分岐、及び/若しくは環式C₁～C₂アルキル基から独立して選択され、但しR₁及びR₂が両方とも水素であることはない、方法に関する。

or a pharmaceutically acceptable salt or ester thereof,
where R ₁ and R ₂ are independently selected from hydrogen atoms or linear, branched, and/or cyclic C ₁ -C ₂ alkyl groups, provided that R ₁ and R ₂ are both hydrogen; Not about the method.

A number of metabolic diseases or conditions are closely associated with increased risk of cardiovascular events. Such diseases or conditions include type I and type II diabetes mellitus, metabolic syndrome, dyslipidemic conditions such as hypercholesterolemia, hyperlipidemia, mixed dyslipidemia, hypertriglyceridemia, and hyperchylomicronemia. and various familial dyslipidemias.

In at least one embodiment, the disease or condition is any of hypertriglyceridemia (HTG), hyperchylomicronemia, dyslipidemia, and pancreatitis, and a cardiovascular disease or metabolic disorder, or one of these conditions. selected from those in prevention and/or treatment of more than one species.

The present disclosure also includes a method of reducing apoC-III in a subject in need thereof, the method comprising administering a pharmaceutically effective amount of 2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8 ,11,14,17-pentaen-1-yloxy)butanoic acid:

又はその薬学的に許容される塩若しくはエステルを対象に投与することを含む。

or a pharmaceutically acceptable salt or ester thereof to the subject.

FIG. 3 discloses relative hepatic apoC-III gene expression for compounds of formula (I), control, and reference compounds.

Certain aspects of the disclosure are described in more detail below. The terms and definitions used in this application and apparent herein are intended to represent the meaning within this disclosure.

The singular forms "a," "an," and "the" include plural references unless the context dictates otherwise.

The terms "approximately" and "about" mean approximately the same as the stated number or value. As used herein, the terms "approximately" and "about" are generally understood to encompass ±5% of a particular amount, frequency, or value.

The terms "treat," "treating," and "treatment" include any therapeutic application that can benefit a human or non-human mammal. Both human and veterinary treatments are within the scope of this disclosure. Treatment may be responsive to an existing condition or prophylactic, ie, prophylactic.

As used herein, the terms "administer," "administration," and "administering" mean (1) either by a health instructor or a person authorized by the physician, or under the direction of the physician; (2) providing, administering, dosing and/or prescribing a compound or composition according to the present disclosure; and (2) administering a compound or composition according to the present disclosure by a human patient or person or non-human mammal. It means that something is taken in, ingested, or consumed.

The term "pharmaceutically effective amount" means an amount of a compound of the present disclosure sufficient to achieve the desired pharmacological and/or therapeutic effect, i.e., an amount effective for its intended purpose. means. While the needs of individual subjects/patients may vary, determination of optimal ranges for effective amounts of compounds of the present disclosure is within the skill of the art. In general, dosing regimens for the treatment of diseases and/or conditions using the compounds disclosed herein will depend on various factors such as subject/patient type, age, weight, sex, diet, and/or medical condition. can be determined.

The term "pharmaceutical composition" means a compound according to the present disclosure in any form suitable for medical use.

Compounds of formula (I) may exist in various stereoisomeric forms, including enantiomers, diastereomers, or mixtures thereof. It will be understood that the present invention encompasses all optical isomers of the compounds of formula (I) and mixtures thereof. Therefore, compounds of formula (I) that exist as diastereomers, racemates and/or enantiomers are within the scope of this disclosure.

The present disclosure provides a method for reducing apolipoprotein C-III (apoC-III) mRNA or protein in a subject in need thereof, comprising: a pharmaceutically effective amount of a compound of formula (I);

又はその薬学的に許容される塩若しくはエステルを対象に投与することを含み、
式中、R₁及びR₂は、水素原子又は直鎖、分岐、及び/若しくは環式C₁～C₆アルキル基から独立して選択され、但しR₁及びR₂が両方とも水素であることはない、方法に関する。

or a pharmaceutically acceptable salt or ester thereof,
where R ₁ and R ₂ are independently selected from hydrogen atoms or linear, branched, and/or cyclic C ₁ -C ₆ alkyl groups, provided that R ₁ and R ₂ are both hydrogen; Not about the method.

In at least one embodiment, the present disclosure provides a pharmaceutically effective amount of a compound of formula (I) for reducing apolipoprotein C-III (apoC-III) mRNA or protein in a subject in need thereof:

又はその薬学的に許容される塩若しくはエステルの使用であって、
式中、R₁及びR₂は、水素原子又は直鎖、分岐、及び/若しくは環式C₁～C₆アルキル基から独立して選択され、但しR₁及びR₂が両方とも水素であることはない、使用に関する。

or the use of a pharmaceutically acceptable salt or ester thereof,
where R ₁ and R ₂ are independently selected from hydrogen atoms or linear, branched, and/or cyclic C ₁ -C ₆ alkyl groups, provided that R ₁ and R ₂ are both hydrogen; Not related to use.

In at least one embodiment, R ₁ and R ₂ are selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl.

In at least one embodiment, R ₁ and R ₂ are selected from hydrogen, methyl, and ethyl.

In at least one embodiment, one of R ₁ and R ₂ is a hydrogen atom and the other of R ₁ and R ₂ is selected from a C ₁ -C ₃ alkyl group. In one embodiment, one of R ₁ and R ₂ is a hydrogen atom and the other of R ₁ and R ₂ is selected from a methyl group or an ethyl group.

In at least one embodiment, the compound exists in its various stereoisomers, such as enantiomers (R or S), diastereomers, or mixtures thereof.

In at least one embodiment, the compound exists in racemic form.

When the compound of formula (I) is a salt of a counterion having at least one asymmetric center or an ester of an alcohol having at least one asymmetric center, the compound has more than one stereocenter. It is possible. In these situations, compounds of the present disclosure may exist as diastereomers. Thus, in at least one embodiment, a compound of the present disclosure exists as at least one diastereomer.

In at least one embodiment, the compound of the present disclosure is 2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yloxy)butanoic acid .

In at least one embodiment, a compound of the present disclosure has the formula:

で表されるそのS及び/又はR体で存在する。

It exists in its S and/or R form, represented by

In at least one embodiment, the disease or condition is any of hypertriglyceridemia (HTG), hyperchylomicronemia, dyslipidemia, and pancreatitis, and a cardiovascular disease or metabolic disorder, or one of these conditions. selected from those in prevention and/or treatment of more than one species. In one embodiment, the disease or condition is selected from any of hyperchylomicronemia, pancreatitis, and cardiovascular disease or metabolic disorders, or in the prevention and/or treatment of one or more of these conditions. . In one embodiment, the disease or condition is selected from either hyperchylomicronemia and pancreatitis.

Compounds of formula (I) may be prepared, for example, as described in PCT Application No. WO2010/128401 filed May 7, 2010 and based on Examples 1-23 below.

Examples 1-23 are illustrative and one skilled in the art will understand how to apply these general methods to arrive at other compounds within the scope of formula (I). Probably. Compounds of the present disclosure can be in the form of pharmaceutically acceptable salts or esters. For example, compounds of formula (I) may be in the form of phospholipids, glycerides or esters such as C ₁ -C ₆ -alkyl esters. In at least one embodiment, the ester is selected from glycerides or C ₁ -C ₆ -alkyl esters. In at least one embodiment, the esters include triglycerides, 1,2-diglycerides, 1,3-diglycerides, 1-monoglycerides, 2-monoglycerides, methyl esters, ethyl esters, propyl esters, isopropyl esters, n-butyl esters, and tert. - selected from butyl esters. In at least one embodiment, the compound of formula (I) is present as a methyl ester, ethyl ester, isopropyl ester, n-butyl ester or tert-butyl ester, for example as a methyl ester or ethyl ester. In vitro digestion studies in biorelevant media have demonstrated that the esters represented by formula (I) (ie, ethyl and butyl esters) are rapidly hydrolyzed in the gastrointestinal tract.

Salts suitable for the present disclosure include salts of NH ⁴⁺ ; metal ions such as Li ⁺ , Na ⁺ , K ⁺ , Mg ²⁺ , or Ca ²⁺ ; tert-butylammonium, (3S,5S,7S)-adamantane; Protonated primary amines such as -1-ammonium, 1,3-dihydroxy-2-(hydroxymethyl)propan-2-ammonium, protonated aminopyridines (e.g. pyridine-2-ammonium); diethylammonium, 2, Protonated secondary amines such as 3,4,5,6-pentahydroxy-N-methylhexane-1-ammonium, N-ethylnaphthalene-1-ammonium, protonated secondary amines such as 4-methylmorpholin-4-ium, etc. Protonation of tertiary amines, protonated quaternary amines such as 2-hydroxy-N,N,N-trimethylethane-1-aminium, and amino((4-amino-4-carboxybutyl)amino)methaniminium) These include, but are not limited to, protonated heterocycles such as guanidine or 1H-imidazol-3-ium. Further examples of suitable salts include salts of diprotonated diamines such as ethane-1,2-diammonium or piperazine-1,4-dium. Other salts according to the present disclosure may include protonated chitosan.

In at least one embodiment, the salt is selected from sodium salts, calcium salts, and choline salts.

The present disclosure provides a method of reducing apoC-III in a subject in need thereof, the method comprising administering to the subject a pharmaceutically effective amount of a compound of formula (I). The subject may be a human or non-human mammal. The compounds disclosed herein can be administered as a medicament, such as in a pharmaceutical composition.

In at least one embodiment, the present disclosure provides a baseline fasting dose of about 200 mg/dl to about 499 mg/dl during statin therapy by administering to a subject a pharmaceutically effective amount of a compound of formula (I). The present invention relates to a method of reducing apoC-III levels in a subject having triglycerides. In another embodiment, the present disclosure provides for the manufacture of a medicament for reducing apoC-III levels in a subject on statin therapy and having a baseline fasting triglyceride of about 200 mg/dl to about 499 mg/dl. Concerning the use of a pharmaceutically effective amount of a compound of formula (I). ApoC-III levels may be reduced by at least about 20%, at least about 25%, at least about 30%, or at least about 35%.

In at least one embodiment, the present disclosure provides methods for treating a subject with a baseline fasting triglyceride of about 200 mg/dl to about 499 mg/dl by administering to the subject a pharmaceutically effective amount of a compound of formula (I). Concerning methods of reducing apoC-III levels. In another embodiment, the present disclosure provides for the manufacture of a medicament for reducing apoC-III levels in a subject having a baseline fasting triglyceride of about 200 mg/dl to about 499 mg/dl. Concerning the use of compounds of formula (I). ApoC-III levels may be reduced by at least about 20%, at least about 25%, at least about 30%, or at least about 35%.

In at least one embodiment, the present disclosure provides for treating a subject with a baseline fasting triglyceride of greater than 500 mg/dl on statin therapy by administering to the subject a pharmaceutically effective amount of a compound of formula (I). Concerning methods of reducing apoC-III levels. In another embodiment, the present disclosure provides for the use of a pharmaceutically effective amount of Concerning the use of compounds of formula (I). ApoC-III levels may be reduced by at least about 25%, at least about 30%, at least about 35% or at least about 40%.

In at least one embodiment, the present disclosure provides a method for reducing apoC-III levels in a subject with a baseline fasting triglyceride of greater than 500 mg/dl by administering to the subject a pharmaceutically effective amount of a compound of formula (I). Related to methods for reducing In another embodiment, the present disclosure provides a pharmaceutically effective amount of Concerning the use of compounds. ApoC-III levels may be reduced by at least about 25%, at least about 30%, at least about 35% or at least about 40%.

The present disclosure also provides a method for reducing apoptotic cholesterol in a subject with a baseline fasting LDL-cholesterol of at least 2.5 mmol/L (about 97 mg/dl) by administering to the subject a pharmaceutically effective amount of a compound of formula (I). It also concerns how to reduce the -III level. In another embodiment, the present disclosure provides a method for reducing apoC-III levels in a subject with a baseline fasting LDL-cholesterol of at least 2.5 mmol/L (about 97 mg/dl). the use of a therapeutically effective amount of a compound of formula (I). ApoC-III levels may be reduced by at least about 25%, at least about 30%, at least about 35% or at least about 40%.

In at least one embodiment, the present disclosure provides a method of reducing apoC-III in a subject in need thereof, the method comprising: administering a pharmaceutically effective amount of a dyslipidemic agent, such as a statin and a compound of formula (I). 2. A method comprising administering to a patient.

The compositions disclosed herein may include at least one compound of formula (I) and optionally at least one non-active pharmaceutical ingredient, ie, excipient. Inactive ingredients are used to solubilize, suspend, thicken, dilute, and emulsify the active ingredients so that the active ingredients are safe, convenient, and/or otherwise acceptable for use. may be stabilized, preserved, protected, colored, flavored, and/or adapted into an applicable and effective preparation. Examples of excipients include solvents, carriers, diluents, binders, fillers, sweeteners, fragrances, pH adjusters, viscosity modifiers, antioxidants, bulking agents, water retention agents, disintegrants, and dissolution retarders. agents, absorption enhancers, wetting agents, absorbents, lubricants, colorants, dispersants, and preservatives. Excipients may have more than one role or function or be classified into more than one group; classifications are merely descriptive and are not intended to be limiting. In some embodiments, for example, the at least one excipient is corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, ethanol, glycerin, sorbitol, It may be selected from fatty substances such as polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethyl cellulose, and hard fats or suitable mixtures thereof. In some embodiments, the compositions disclosed herein include at least one compound of formula (I) and at least one pharmaceutically acceptable antioxidant, e.g., alpha-tocopherol, beta-tocopherol. , gamma-tocopherol, and delta-tocopherol, or mixtures thereof, BHA, such as 2-tert-butyl-4-hydroxyanisole and 3-tert-butyl-4-hydroxyanisole, or mixtures thereof, and BHT ( 3,5-di-tert-butyl-4-hydroxytoluene), or mixtures thereof.

The compositions disclosed herein may be formulated in oral dosage forms, such as tablets or soft or hard gelatin capsules. The dosage form can be any shape suitable for oral administration, such as spherical, oval, ellipsoidal, cuboidal, regular and/or irregular shapes. Compounds according to the present disclosure may be formulated using conventional formulation techniques known in the art. In some embodiments, the composition can be in the form of a gelatin capsule or tablet.

Suitable daily dosages of compounds of formula (I) may range from about 5 mg to about 2 g. For example, in some embodiments, the daily dose ranges from about 50 mg to about 1 g, about 100 mg to about 1 g, about 50 mg to about 800 mg, about 100 mg to about 800 mg, about 100 mg to about 600 mg. In at least one embodiment, the daily dose ranges from about 200 mg to about 600 mg. The compounds may be administered, for example, once, twice, or three times per day. In at least one embodiment, the compound of formula (I) is administered in an amount ranging from about 200 mg to about 800 mg per dose. In at least one embodiment, the compound of formula (I) is administered once per day.

We have determined that compounds of formula (I) such as 2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yloxy)butanoic acid , was found to have significantly good medicinal activity. Surprisingly, the compounds of formula (I) disclosed herein exhibit improved biological activity for reducing apoC-III compared to naturally occurring omega-3 fatty acids such as EPA and DHA. show.

In some embodiments, for example, the compound of formula (I) is capable of reducing the median level of apoC-III in plasma or liver by at least 25-30% relative to baseline, i.e. can be reduced to a greater degree than that achieved using the EPA/DHA/DPA combination. Compounds of formula (I) have been shown to reduce hepatic apoC-III mRNA (and thus probably also reduce hepatic production/secretion) in preclinical models, thus reducing hepatic uptake of apoB particles. The addition of lipid-lowering agents, such as statins or PCSK-9 inhibitors, which reduce apoC-III through an increase in apoC-III, can be expected to exert an additional plasma apoC-III lowering effect.

[Example]
The present disclosure may be further illustrated by the following non-limiting examples, in which standard techniques known to those skilled in the art and techniques similar to those described in these examples are used. , may be used where appropriate. It will be appreciated that those skilled in the art will come up with additional embodiments that are consistent with the disclosure provided herein.

Unless otherwise specified, reactions were carried out under anhydrous conditions using HPLC grade solvents at room temperature, typically in the range 18-25°C. Evaporation was carried out by rotary evaporation in vacuo. Column chromatography was performed on silica gel using the flash method. Nuclear magnetic resonance (NMR) shift values were recorded on a Bruker Avance DPX200 or 300 or AVII400 instrument, and multiple peaks were described as follows: s, singlet; d, doublet; dd, doublet. doublet; t, triplet; q, quadruplet; p, quintuplet; m, multiplet; br, wide. Mass spectra were recorded using a Gl956A mass spectrometer (electrospray, 3000 V) switched to positive and negative ionization mode. Yields reported are exemplary and do not necessarily represent the maximum yields achievable.

[Example 1]
Preparation of tert-butyl 2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yloxy)butanoate:

Tetrabutylammonium chloride (0.55 g, 1.98 mmol) was dissolved in (5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-ol (3.50 g, 1.98 mmol) in toluene (35 mL). g, 12.1 mmol) at room temperature under nitrogen. Aqueous sodium hydroxide solution (50% (w/w), 11.7 mL) was added at room temperature with vigorous stirring, followed by the addition of t-butyl 2-bromobutyrate (5.41 g, 24.3 mmol). The resulting mixture was heated to 50° C. and additional t-butyl 2-bromobutyrate was added after 1.5 hours (2.70 g, 12.1 mmol), after 3.5 hours (2.70 g, 12.1 mmol) and after 4.5 hours (2.70 g, 12.1 mmol). g, 12.1 mmol) and stirred for a total of 12 hours. After cooling to room temperature, ice water (25 mL) was added and the resulting two phases were separated. The organic phase was washed with a mixture of NaOH (5%) and brine, dried (MgSO ₄ ), filtered and concentrated. The residue was purified by flash chromatography on silica gel using increasingly polar mixtures of heptane and ethyl acetate (100:0 to 95:5) as eluent. Concentration of the appropriate fractions gave 1.87 g (36% yield) of the title compound as an oil. ¹ H NMR (300 MHz, CDCI3): δ 0.85-1.10 (m, 6H), 1.35-1.54 (m, 11H), 1.53-1.87 (m, 4H), 1.96-2.26 (m, 4H), 2.70-3.02 (m, 8H), 3.31 (dt, 1H), 3.51-3.67 (m, 2H), 5.10-5.58 (m, 10H).

[Example 2]
Preparation of 2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenyloxy)butanoic acid (Compound A):

tert-Butyl 2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yloxy)butanoate (19.6 g, 45.5 mmol) in dichloromethane (200 mL). Dissolved and placed under nitrogen. Trifluoroacetic acid (50 mL) was added and the reaction mixture was stirred at room temperature for 1 hour. Water was added and the aqueous phase was extracted twice with dichloromethane. The combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ), filtered, and concentrated. The residue was flash chromatographed on silica gel using increasingly polar mixtures of heptane, ethyl acetate and formic acid (90:10:1 to 80:20:1) as eluent. Concentration of the appropriate fractions gave 12.1 g (71% yield) of the title compound as an oil. ¹ H-NMR (300 MHz, CDCl ₃ ): δ 0.90-1.00 (m, 6H), 1.50 (m, 2H), 1.70 (m, 2H), 1.80 (m, 2H), 2.10 (m, 4H), 2.80-2.90 (m, 8H), 3.50 (m, 1H), 3.60 (m, 1H), 3.75 (t, 1H), 5.30-5.50 (m, 10H); MS (electrospray): 373.2 [MH] ^- .

[Example 3]
(4S,5R)-3-((S)-2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenyloxy)butanoyl)-4-methyl -5-phenyloxazolidin-2-one and (4S,5R)-3-((R)-2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17- Preparation of pentaenyloxy)butanoyl)-4-methyl-5-phenyloxazolidin-2-one:

DMAP (1.10 g, 8.90 mmol) and DCC (1.90 g, 9.30 mmol) were dissolved in 2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14 ,17-pentaenyloxy)butanoic acid (3.20 g, 8.50 mmol) and maintained at 0° C. under nitrogen. The resulting mixture was stirred at 0°C for 20 minutes. (4S,5R)-4-Methyl-5-phenyloxazolidin-2-one (1.50 g, 8.50 mmol) was added and the resulting cloudy mixture was stirred at ambient temperature for 5 days. The mixture was filtered and concentrated under reduced pressure to obtain a crude product containing the desired product as a mixture of two diastereomers. The residue was purified by flash chromatography on silica gel using 15% ethyl acetate in heptane as eluent. The two diastereomers were separated and the appropriate fractions were concentrated. (4S,5R)-3-((S)-2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenyloxy)butanoyl)-4-methyl -5-phenyloxazolidin-2-one eluted first, yielding 1.1 g (40% yield) as an oil. (4S,5R)-3-((R)-2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenyloxy)butanoyl)-4-methyl 0.95 g (34% yield) of -5-phenyloxazolidin-2-one was obtained as an oil.

(4S,5R)-3-((S)-2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenyloxy)butanoyl)-4-methyl -5-Phenyloxazolidin-2-one (E1): ¹ H-NMR (300 MHz, CDCl ₃ ): δ 0.90 (d, 3H), 1.00 (t, 3H), 1.07 (t, 3H), 1.45-1.57 (m, 2H), 1.62-1.76 (m, 3H), 1.85-1.95 (m, 1H), 2.05-2.15 (m, 4H), 2.87 (m, 8H), 3.39 (m, 1H), 3.57 (m , 1H), 4.85-4.92 (m, 2H), 5.30-5.45 (m, 10H), 5.75 (d, 1H), 7.32 (m, 2H), 7.43 (m, 3H).

(4S,5R)-3-((R)-2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenyloxy)butanoyl)-4-methyl -5-Phenyloxazolidin-2-one (E2): ¹ H-NMR (300 MHz, CDCl ₃ ): δ 0.98 (d, 3H), 0.99 (t, 3H), 1.08 (t, 3H), 1.40-1.52 (m, 2H), 1.55-1.75 (m, 3H), 1.80-1.90 (m, 1H), 2.05-2.15 (m, 4H), 2.84 (m, 8H), 3.39 (m, 1H), 3.56 (m , 1H), 4.79 (quintet, 1H), 4.97 (dd, 1H), 5.30-5.45 (m, 10H), 5.71 (d, 1H), 7.33 (m, 2H), 7.43 (m, 3H).

[Example 4]
Preparation of (S)-2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenyloxy)butanoic acid:

Hydrogen peroxide (35% in water, 0.75 mL, 8.54 mmol) and lithium hydroxide monohydrate (0.18 g, 4.27 mmol) were dissolved in (4S,5R)-3- in tetrahydrofuran (12 mL) and water (4 mL). ((S)-2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenyloxy)butanoyl)-4-methyl-5-phenyloxazolidine-2- (1.10 g, 2.13 mmol) and maintained at 0° C. under nitrogen. The reaction mixture was stirred at 0°C for 30 minutes. 10% Na ₂ SO ₃ (aq) (30 mL) was added, the pH was adjusted to ~2 using 2M HCl, and the mixture was extracted twice with heptane (30 mL). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered, and concentrated. The residue was flash chromatographed on silica gel using increasingly polar mixtures of heptane and ethyl acetate (98:8 to 1:1) as eluent. Concentration of the appropriate fractions gave 0.48 g (60% yield) of the title compound as an oil. ¹ H-NMR (300 MHz, CDCl ₃ ): δ 0.90-1.00 (m, 6H), 1.48 (m, 2H), 1.65 (m, 2H), 1.85 (m, 2H), 2.10(m, 4H), 2.80-2.90 (m, 8H), 3.55 (m, 1H), 3.60 (m, 1H), 3.88 (t, 1H), 5.35-5.45 (m, 10H); MS (electrospray): 373.3 [MH] ^- ; [α] _D -37° (c=0.104, ethanol).

[Example 5]
Preparation of (R)-2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenyloxy)butanoic acid:

Hydrogen peroxide (35% in water, 0.65 mL, 7.37 mmol) and lithium hydroxide monohydrate (0.15 g, 3.69 mmol) were dissolved in (4S,5R)-3- in tetrahydrofuran (12 mL) and water (4 mL). ((R)-2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenyloxy)butanoyl)-4-methyl-5-phenyloxazolidine-2- (0.95 g, 1.84 mmol) and maintained at 0° C. under nitrogen. The reaction mixture was stirred at 0°C for 30 minutes. 10% Na ₂ SO ₃ (aq) (30 mL) was added, the pH was adjusted to 2 using 2M HCl, and the mixture was extracted twice with heptane (30 mL). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered, and concentrated. The residue was flash chromatographed on silica gel using increasingly polar mixtures of heptane and ethyl acetate (98:8 to 50:50) as eluent. Concentration of the appropriate fractions gave 0.19 g (29% yield) of the title compound as an oil. ¹ H-NMR (300 MHz, CDCl ₃ ): δ 0.90-1.00 (m, 6H), 1.48 (m, 2H), 1.65 (m, 2H), 1.85 (m, 2H), 2.10 (m, 4H), 2.80-2.90 (m, 8H), 3.55 (m, 1H), 3.60 (m, 1H), 3.88 (t, 1H), 5.35-5.45 (m, 10H); MS (electrospray): 373.3 [MH] ^- ; [α] _D -31° (c=0.088, ethanol).

[Example 6]
Preparation of tert-butyl 2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenyloxy)propanoate:

(5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-ol (1.00 g, 3.47 mmol), tetrabutylammonium chloride (0.24 g, 0.87 mmol) and t A mixture of -butyl 2-bromopropionate (3.62 g, 17.3 mmol) was dissolved in toluene (36 mL) and placed under nitrogen. An aqueous solution of sodium hydroxide (50%, 8 mL) was added slowly with vigorous stirring and the resulting mixture was stirred at ambient temperature for 20 hours. Water was added and the mixture was extracted three times with ether. The combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ), filtered, and concentrated. The residue was purified by flash chromatography on silica gel using 2% ethyl acetate in heptane as eluent. Concentration of the appropriate fractions gave 1.40 g (90% yield) of the title compound as an oil. ¹ H-NMR (300 MHz, CDCl ₃ ): δ 0.95 (t, 3H), 1.41 (d, 3H), 1.48 (s, 9H), 1.48-1.66 (m, 4H), 2.05 (m, 4H), 2.83 (m, 8H), 3.35 (m, 1H), 3.55 (m, 1H), 3.79 (q, 1H), 5.32-5.44 (m, 10H).

[Example 7]
Preparation of 2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenyloxy)propanoic acid:

Trifluoroacetic acid (2 mL) was mixed with 2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenyloxy)propanoate (1.40 g) in dichloromethane (10 mL). 3.36 mmol) and maintained under nitrogen, the reaction mixture was stirred at room temperature for 3 hours. Diethyl ether (50 mL) was added and the organic phase was washed with water (30 mL), dried (Na ₂ SO ₄ ) and concentrated. The residue was flash chromatographed on silica gel using increasingly polar mixtures of heptane, ethyl acetate and formic acid (95:5:0.25 to 80:20:1) as eluent. Concentration of the appropriate fractions gave 0.67 g of slightly impure product. This material was dissolved in heptane (15 mL), washed three times with water (5 mL), dried (Na ₂ SO ₄ ), filtered, and concentrated to give 0.50 g (41% yield) of the title as an oil. The compound was obtained. ¹ H-NMR (300 MHz, CDCl ₃ ): δ 0.99 (t, 3H), 1.40-1.48 (m, 5H), 1.67 (m, 2H), 2.09 (m, 4H), 2.80-2.60 (m, 8H) ), 3.53 (m, 2H), 4.01 (q, 1H), 5.31-5.47 (m, 10H); MS (electrospray): 359.2 [MH] ^- .

[Example 8]
Preparation of tert-butyl 2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenyloxy)-2-methylpropanoate:

(5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-ol (0.83g, 3.14mmol), tetrabutylammonium chloride (0.24g, 0.85mmol) and t A mixture of -butyl 2-bromoisobutyrate (3.50 g, 15.7 mmol) was dissolved in toluene (15 mL) and placed under nitrogen. Aqueous sodium hydroxide solution (50%, 5 mL) was added at room temperature with vigorous stirring. The resulting mixture was heated to 60°C and stirred for 6 hours. The mixture was cooled, water was added and extracted three times with ether. The combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ), filtered, and concentrated. The residue was purified by flash chromatography on silica gel using a gradient of 5-10% ethyl acetate in heptane as eluent. Concentration of the appropriate fractions gave 0.60 g (44% yield) of the title compound as an oil. MS (electrospray): 453.3[M+Na] ⁺ .

[Example 9]
Preparation of 2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenyloxy)-2-methylpropanoic acid:

Trifluoroacetic acid (5 mL) was dissolved in tert-butyl 2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenyloxy)-2 in dichloromethane (20 mL). -Methyl propanoate (600 mg, 1.39 mmol) under nitrogen and the reaction mixture was stirred at room temperature for 2 hours. Water was added and the aqueous phase was extracted twice with dichloromethane. The combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ), filtered, and concentrated. The residue was purified by flash chromatography on silica gel using a mixture of heptane, ethyl acetate and formic acid (80:20:1) as eluent. The appropriate fractions were concentrated and the residue (135 mg) was further purified by flash chromatography on silica gel using a 5-10% gradient of a mixture of ethyl acetate and formic acid in heptane (95:5) as eluent. Purified. Concentration of the appropriate fractions gave 80 mg of slightly impure product. This material was dissolved in heptane (5 mL), washed twice with water (5 mL), dried (Na ₂ SO ₄ ), filtered, and concentrated to give 40 mg (8% yield) of the title compound as an oil. I got it. ¹ H-NMR (300 MHz, CDCl ₃ ): δ 0.99 (t, 3H), 1.47 (s, 6H), 1.64 (m, 2H), 2.07 (m, 4H), 2.81-2.88 (m, 8H), 3.46 (t, 2H), 5.29-5.44 (m, 10H); MS (electrospray): 373.3 [MH] ^- .

[Example 10]
Preparation of tert-butyl 2-ethyl-2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yloxy)butanoate:

tert-Butyl 2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yloxy)butanoate (480 mg, 1.11 mmol) was dissolved in dry tetrahydrofuran (10 mL). was added dropwise over 30 minutes to a solution of lithium diisopropylamine (LDA) (2.0 M, 750 μL, 1.50 mmol) in the solution and maintained at −70° C. under nitrogen. The reaction mixture was stirred for 30 minutes. Ethyl iodide (312 mg, 2.00 mmol) was added in one portion and the resulting mixture was warmed to ambient temperature for 1 hour. The reaction mixture was stirred at ambient temperature for 17 hours. The mixture was poured into saturated NH ₄ Cl (aq) (50 mL) and extracted with heptane (2 x 50 mL). The combined organic phases were washed successively with brine (50 mL), 0.25 M HCl (50 mL), and brine (50 mL), dried (MgSO ₄ ), filtered, and concentrated. The residue was purified by flash chromatography on silica gel using increasingly polar mixtures of heptane and ethyl acetate (100:0 to 95:5) as eluent. Concentration of the appropriate fractions gave 343 mg (67% yield) of the title compound as an oil. ¹ H NMR (300 MHz, CDCI ₃ ): δ 0.84 (t, 6H), 0.99 (td, 3H), 1.35-1.55 (m, 11 H), 1.54-1.69 (m, 2H), 1.68-1.87 (m MS (electrospray): 401.3 [M-1] ^- .

[Example 11]
Preparation of 2-ethyl-2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yloxy)butanoic acid:

Formic acid (5 ml) and tert-butyl 2-ethyl-2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yloxy)butanoate (250 mg, 0.55 mmol) was stirred vigorously at room temperature under nitrogen for 4.5 hours. Formic acid was removed in vacuo. The residue was purified by flash chromatography on silica gel using increasingly polar mixtures of heptane and ethyl acetate (100:0 to 80:20) as eluent. Concentration of the appropriate fractions gave 163 mg (74% yield) of the title compound as an oil. ¹ H NMR (300 MHz, CDCl ₃ ): δ 0.86 (t, 6H), 0.99 (t, 3H), 1.36-1.57 (m, 2H), 1.68 (dd, 2H), 1.73-1.98 (m, 4H) , 2.11 (tt, 4H), 2.70-3.01 (m, 8H), 3.39 (t, 2H), 5.20-5.56 (m, 10H). MS (electrospray): 481.4 [M+Na] ⁺ .

[Example 12]
Preparation of ethyl 2-(((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yl)oxy)butanoate:

Dicyclohexylmethanediimine (DCC) (304 mg, 1.47 mmol) and N,N-dimethylpyridin-4-amine (DMAP) (10 mg, 0.067 mmol) were dissolved in 2-(((5Z ,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yl)oxy)butanoic acid (501.3 mg, 1.335 mmol) was added to a stirred solution of nitrogen at 0 °C. Added under atmosphere. After stirring the mixture for 5 minutes, ethanol (EtOH) (0.16 mL, 2.67 mmol) was added. The resulting mixture was stirred at room temperature for 20 hours. The reaction mixture was purified by flash chromatography on silica gel using increasing mixtures of heptane and ethyl acetate (100:0 to 99:1) as eluent. Concentration of the appropriate fractions gave 473 mg (88% yield) of the title compound as an oil. ¹ H NMR (300 MHz, chloroform-d) δ 0.95 (2 xt, 6H), 1.37-1.48 (m, 2H), 1.54-1.79 (m, 4H), 2.01-2.10 (m, 4H), 2.77-2.84 (m, 8H), 3.27-3.34 (m, 1H), 3.53-3.60 (m, 1H), 3.69-3.73 (dd, 1H), 4.13-4.24 (m, 2H), 5.25-5.33 (m, 10H) , MS (electrospray); 425.3 [M+Na] ⁺ ; HRMS (electrospray): Observed value 425.3021 [M+Na] ⁺ , Calculated value for [C ₂₆ H ₄₂ O ₃ +Na] ⁺ 425.3031.

[Example 13]
Preparation of isopropyl 2-(((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yl)oxy)butanoate

DCC (310 mg, 1.47 mmol) and DMAP (9 mg, 0.067 mmol) were mixed with 2-(((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17) in DCM (4 mL). -Pentaen-1-yl)oxy)butanoic acid (501 mg, 1.335 mmol) was added to a stirred solution at 0° C. under nitrogen atmosphere. After the mixture was stirred for 5 minutes, isopropanol (iPrOH) (0.16 mL, 2.67 mmol) was added. The resulting mixture was stirred at room temperature for 20 hours. The mixture was filtered and concentrated in vacuo. The residue was added to heptane (50 mL), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using 1% ethyl acetate in heptane as eluent. Concentration of the appropriate fractions gave 496 mg (89% yield) of the title compound as an oil. ¹ H NMR (300 MHz, CDCl ₃ ): δ 0.97 (2 xt, 6H), 1.25 (m, 6H), 1.42-1.50 (m, 2H), 1.61-1.70 (m, 2H), 1.70-1.77 (m , 2H), 2.05-2.12 (m, 4H), 2.79-2.86 (m, 8H), 3.29-3.34 (m, 1H), 3.54-3.59 (m, 1H), 3.67-3.71 (m, 1H), 5.06 -5.10 (m, 1H), 5.31-5.42 (m, 10 H); MS (electrospray): 439.3 [M+Na] ⁺ .

[Example 14]
Preparation of methyl 2-(((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yl)oxy)butanoate:

Sulfuric acid (0.049 ml, 0.918 mmol) was dissolved in 2-(((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yl) in methanol (20 ml). A solution of oxy)butanoic acid (385 mg, 1.028 mmol) was added at room temperature under _N2 atmosphere and the resulting mixture was stirred at room temperature overnight. MS (electrospray): 389.3[M+1] ⁺ .

[Example 15]
Preparation of butyl 2-(((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yl)oxy)butanoate:

Sulfuric acid (0.049 ml, 0.918 mmol) was dissolved in 2-(((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17) in butan-1-ol (400 mL, 4.37 mol). -pentaen-1-yl)oxy)butanoic acid (33 g, 88 mmol) at room temperature under _N2 atmosphere and the reaction mixture was stirred for 120 h. Heptane (400 mL) and ethyl acetate (400 mL) were added and the solution was washed with saturated aqueous NaHCO ₃ (3 x 300 mL) and water (2 x 300 mL). The combined aqueous phases were extracted with heptane/ether (1:1) (2 x 300 mL). The combined organic phases were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by flash chromatography using increasing mixtures of heptane and ethyl acetate (99:1 to 96:4) as eluent. Concentration of the appropriate fractions gave 26.3 g (67% yield) of the title compound as an oil. ¹ H NMR (400 MHz, CDCl3) δ 0.93-1.02 (m, 9H), 1.36-1.51 (m, 4H), 1.60-1.70 (m, 4H), 1.72-1.84 (m, 2H), 2.05-2.16 ( m,4H), 2.78-2.92 (m, 8H), 3.28-3.39 (m, 1H), 3.54-3.65 (m, 1H), 3.70-3.82 (m, 1H), 4.08-4.24 (m, 2H), 5.27-5.48 (m, 10H), MS (electrospray): 453.2 [M+Na] ⁺ .

[Example 16]
Preparation of 2,3-dihydroxypropyl 2-(((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yl)oxy)butanoate:

Step a) (2,2-dimethyl-1,3-dioxolan-4-yl)methyl 2-(((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaene Preparation of -1-yl)oxy)butanoate

2-(((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yl)oxy)butanoic acid (25 g, 66.7 mmol) and DMAP (8.15 g, 66.7 mmol) was added to a solution of 2,2-dimethyl-1,3-dioxolane-4-methanol (7.54 mL, 60.7 mmol) in chloroform (150 mL) under nitrogen atmosphere. A solution of DCC (13.77 g, 66.7 mmol) in chloroform (65 mL) was then added dropwise at ambient temperature. The mixture was stirred overnight and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using increasingly polar mixtures of 10% ethyl acetate in heptane as eluent. Concentration of the appropriate fractions gave 19.6 g (66% yield) of the title product as an oil. ¹ H NMR (300 MHz, CDCl3) δ 0.99 (t, 6H), 1.37-1.40 (m, 3H), 1.41-1.53 (m, 5H), 1.59-1.71 (m, 2H), 1.72-1.85 (m, 2H), 2.05-2.14 (m, 4H), 2.74-2.95 (m, 8H), 3.31-3.38 (m, 1H), 3.57-3.65 (m, 1H), 3.72-3.86 (m, 2H), 4.07- 4.12 (m, 1H), 4.15-4.27 (m, 2H), 4.29-4.40 (m, 1H), 5.23-5.50 (m, 10H). MS (electrospray): 511.3 [M+Na] ⁺ .

Step b) Preparation of 2,3-dihydroxypropyl 2-(((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yl)oxy)butanoate

(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 2-(((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14, To a solution of 17-pentaen-1-yl)oxy)butanoate (27.5 g, 56.3 mmol) was added aqueous HCl (37% (w/w), 28 mL, 341 mmol) at room temperature under nitrogen, and the mixture was stirred for 60 min. Stir for a minute. The mixture was then carefully poured into saturated aqueous NaHCO ₃ (500 mL) and extracted with EtOAc (2×300 mL). The organic phase was washed with 1M HCl (200 mL), brine (200 mL), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using heptane and ethyl acetate (50:50) as eluent. Concentration of the appropriate fractions gave 19 g of the title product as an oil. The product contains approximately 10% of the isomeric 1,3-dihydroxypropan-2-yl 2-(((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaene -1-yl)oxy)butanoate was contaminated. This material was further purified by preparative HPLC after mixing with another batch of 1.35 grams. A 17:83 homogeneous mixture of water/acetonitrile (9:1) to acetonitrile (100%) was used as the eluent. Concentration of the appropriate fractions gave 11.3 g (38% yield) of the title product as an oil. ¹ H NMR (300 MHz, CDCl3) δ 0.97-1.03 (m, 6H), 1.41-1.51 (m, 2H), 1.59-1.69 (m, 2H), 1.72-1.87 (m, 2H), 2.05-2.14 ( m, 5H), 2.56 (s, 1H), 2.73-2.94 (m, 8H), 3.33-3.40 (m, 1H), 3.55-3.68 (m, 2H), 3.69-3.77 (m, 1H), 3.79- 3.85 (m, 1H), 3.93-4.03 (m, 1H), 4.15-4.37 (m, 2H), 5.25-5.51 (m, 10H). MS (electrospray): 471.3 [M+Na] ⁺ .

[Example 17]
Preparation of 1,3-dihydroxypropan-2-yl 2-(((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yl)oxy)butanoate

Step a) Preparation of oxiran-2-ylmethyl 2-(((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yl)oxy)butanoate

2-(((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yl)oxy)butanoic acid (800 mg, 2.14 mmol) in dry DCM (7 mL) ), glycidol (0.17 mL, 2.56 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC*HCl) (491 mg, 2.56 mmol) and 4-dimethylaminopyridine (DMAP) (313 mg, 2.56 mmol) was stirred at room temperature under _N2 atmosphere. The reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel using increasingly polar mixtures of heptane and ethyl acetate (99:1 to 95:5) as eluent. Concentration of the appropriate fractions gave 527 mg (57% yield) of the title product as an oil. ¹ H NMR (400 MHz, CDCl3) δ 0.94-0.98 (m, 6H), 1.40-1.44 (m, 2H), 1.57-1.64 (m, 2H), 1.70-1.82 (m, 2H), 2.02-2.12 ( m, 4H), 2.63 (bs, 1H), 2.78-2.84 (m, 9H), 3.20 (bs, 1H), 3.30-3.35 (m, 1H), 3.55-3.61 (m, 1H), 3.77-3.80 ( m, 1H), 3.94-4.01 (m, 1H), 4.42-4.48 (m, 1H), 5.36-5.26 (m, 10H). MS (electrospray): 453.3 [M+Na] ⁺ .

Step b) 2-((2-(((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yl)oxy)butanoyl)oxy)propane-1 Preparation of ,3-diylbis(2,2,2-trifluoroacetate)

Trifluoroacetic anhydride (TFAA) (0.55 mL, 3.96 mmol) in dry DCM (3 mL) was dissolved in oxiran-2-ylmethyl 2-(((5Z,8Z,11Z,14Z,17Z )-icosa-5,8,11,14,17-pentaen-1-yl)oxy)butanoate (286 mg, 0.66 mmol) in portions at -20 °C under _N2 atmosphere. Added. After removing the cooling bath and stirring the mixture for 19 hours at ambient temperature, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in toluene (6 mL) and passed through a pad of silica (6.5 g), eluting with toluene (150 mL). Concentration in vacuo gave 357 mg (84% yield) of the title compound as an oil. ¹ H NMR (400 MHz, CDCl3) δ 0.95 (2xt, 6H), 1.38-1.45 (m, 2H), 1.57-1.63 (m, 2H), 1.66-1.78 (m, 2H), 2.09-2.02 (m, 4H), 2.78-2.84 (m, 8H), 3.27-3.33 (m, 1H), 3.51-3.56 (m, 1H), 3.77 (dd, 1H), 4.30-4.53 (m, 2H), 4.60-4.69 ( m, 2H), 5.17-5.43 (m, 10H), 5.43-5.55 (m, 1H). MS (electrospray): 661.1 [M+Na] ⁺ .

Step c) 1,3-dihydroxypropan-2-yl 2-(((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yl)oxy)butanoate preparation of

A solution of pyridine (0.4 mL, 4.95 mmol) and methanol (0.3 mL, 7.41 mmol) in pentane/DCM (2:1) (4.5 mL) was mixed with 2- ((2-(((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yl)oxy)butanoyl)oxy)propane-1,3-diylbis( 2,2,2-trifluoroacetate) (354 mg, 0.552 mmol) was cooled to −20° C. and added dropwise under N ₂ atmosphere. The cooling bath was removed and the mixture was stirred for 3 hours at room temperature before being concentrated in vacuo. The residue was purified by flash chromatography on silica gel using increasingly polar mixtures of heptane and ethyl acetate (95:5 to 90:10 to 80:20 to 50:50) as eluent. Concentration of the appropriate fractions gave 223 mg of the title product as a crude oil. Purification by preparative HPLC gave 58 mg (22% yield) of the title compound as an oil. ¹ H NMR (400 MHz, CDCl3) δ 0.95 (t, 3H), 0.96 (t, 3H), 1.38-1.45 (m, 2H), 1.54-1.64 (m, 2H), 1.67-1.84 (m, 2H) , 2.01-2.09 (m, 4H), 2.45 (bs, 2H), 2.83-2.77 (m, 8H), 3.36-3.30 (m, 1H), 3.60-3.55 (m, 1H), 3.84-3.78 (m, 5H), 4.98-4.93 (m, 1H), 5.65-5.09 (m, 10H). MS (electrospray): 471.1 [M+Na] ⁺ .

[Example 18]
3-Hydroxypropane-1,2-diylbis(2-(((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yl)oxy)butanoate) preparation

Step a) Preparation of tert-butyl((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)dimethylsilane

tert-Butyl-chlorodimethylsilane (14.41 g, 91 mmol) was mixed with (2,2-dimethyl-1,3-dioxolan-4-yl)methanol (10 g, 76 mmol) and imidazole (7.73 g, 114 mmol) at ambient temperature and under nitrogen atmosphere. The mixture was stirred for 1.5 hours, poured into water (200 mL) and extracted with tert-butyl methyl ether (2 x 150 mL). The phases were separated and the organic layer was washed with water (100 mL), brine (100 mL), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using 3% ethyl acetate in heptane as eluent. Concentration of the appropriate fractions gave 18 g (97% yield) of the title compound as an oil. 1H NMR (300 MHz, CDCl3) δ 0.02-0.05 (m, 6H), 0.85-0.89 (m, 9H), 1.31-1.35 (m, 3H), 1.35-1.40 (m, 3H), 3.50-3.60 (m MS (electrospray): 229.2 [M+ Na] ⁺ .

Step b) Preparation of 3-((tert-butyldimethylsilyl)oxy)propane-1,2-diol

FeCl ₃ x6H ₂ O (30 g, 11.9 mmol) was added and the mixture was stirred overnight. The mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using increasingly polar mixtures of heptane and ethyl acetate (50:50 to 25:75) as eluent. Concentration of the appropriate fractions gave 760 mg (9% yield) of the title compound as an oil. ¹ H NMR (300 MHz, CDCl3) δ 0.09-0.12 (m, 6H). 0.91- 0.95 (m, 9H), 2.11-2.17 (m, 1H), 2.60 (d, 1H), 3.57- 3.85 (m, 5H). MS (electrospray): 229.2 [M+Na] ⁺ .

Step c) 3-((tert-butyldimethylsilyl)oxy)propane-1,2-diylbis(2-(((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17 -Pentaen-1-yl)oxy)butanoate)

₂ -((( 5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yl)oxy)butanoic acid (3.47g, 9.3mmol), DMAP (1.13g, 9.3mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (DCI) (1.776g, 9.26mmol) and dry DCM (60ml) were added. After stirring the mixture overnight, the reaction mixture was diluted with diethyl ether (200 mL). The mixture was washed with 1M HCl (100 mL) and brine (100 mL), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using 3% ethyl acetate in heptane as eluent. Concentration of the appropriate fractions gave 2.26 g (56% yield) of the title compound as an oil. ¹ H NMR (300 MHz, CDCl3) δ 0.08 (s, 6H), 0.90 (d, 9H), 0.95-1.03 (m, 12H), 1.40-1.52 (m, 4H), 1.58-1.69 (m, 4H) , 1.70-1.83 (m, 4H), 2.04-2.15 (m, 8H), 2.77-2.92 (m, 16H), 3.27-3.37 (m, 2H), 3.57-3.67 (m, 2H), 3.72-3.80 ( m, 4H), 4.14-4.32 (m, 1H), 4.41-4.56 (m, 1H), 5.09-5.22 (m, 1H), 5.23-5.49 (m, 20H). MS (electrospray): 941.6 [M +Na] ⁺ .

Step d) 3-Hydroxypropane-1,2-diylbis(2-(((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yl)oxy) butanoate) preparation

3-((tert-butyldimethylsilyl)oxy)propane-1,2-diylbis(2-(((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11, To a solution of 14,17-pentaen-1-yl)oxy)butanoate (2.26 g, 2.46 mmol) was added aqueous HCl (37% (w/w, 2 mL)) and the mixture was stirred for 3 h under nitrogen atmosphere. After stirring at ambient temperature, it was concentrated in vacuo. The residue was purified by flash chromatography on silica gel using 15% ethyl acetate in heptane as eluent. Concentration of the appropriate fractions gave an oil. 0.83 g (42% yield) of the title compound was obtained. ¹ H NMR (300 MHz, CDCl3) δ 0.96-1.03 (m, 12H), 1.40-1.53 (m, 4H), 1.58-1.68 (m, 4H), 1.70-1.85 (m, 4H), 1.87-2.01 (m, 1H), 2.05-2.15 (m, 8H), 2.75-2.95 (m, 16H), 3.28-3.41 (m, 2H), 3.56- 3.65 (m, 2H), 3.73-3.85 (m, 4H), 4.24-4.37 (m, 1H), 4.42-4.53 (m, 1H), 5.14-5.23 (m, 1H), 5.26-5.51 (m, 20H) ). MS (electrospray): 827.5 [M+Na] ⁺ .

[Example 19]
2-Hydroxypropane-1,3-diylbis(2-(((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yl)oxy)butanoate) Preparation:

Step a) 2-oxopropane-1,3-diylbis(2-(((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yl)oxy) butanoate)

2-(((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yl)oxy)butanoic acid (5.0 g, 13.4 mmol) and DMAP (1.63 g , 13.4 mmol) was added to a solution of 1,3-dihydroxyacetone dimer (1.145 g, 6.36 mmol) in chloroform (25 mL) under nitrogen atmosphere. A solution of DCC (2.75 g, 13.35 mmol) in chloroform (10 mL) was then added dropwise at ambient temperature. The mixture was stirred overnight at room temperature and then concentrated in vacuo. The residue was purified by flash chromatography on silica gel using increasingly polar mixtures of heptane and ethyl acetate (90:10 to 88:12) as eluent. Concentration of the appropriate fractions gave 2.4 g (47% yield) of the title compound as an oil. ¹ H NMR (300 MHz, CDCl3) δ 0.97-1.06 (m, 12H). 1.38-1.53 (m, 4H), 1.57-1.73 (m, 4H), 1.73-1.96 (m, 4H), 2.03-2.17 ( m, 8H), 2.76-2.92 (m, 16H), 3.35-3.42 (m, 2H), 3.63-3.70 (m, 2H), 3.89 (dd, 2H), 4.75-4.93 (m, 4H), 5.27- 5.49 (m, 20H). MS (electrospray): 827.5 [M+Na] ⁺ .

Step b) 2-hydroxypropane-1,3-diylbis(2-(((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yl)oxy) butanoate)

NaBH ₄ (0.336 g, 8.87 mmol) was dissolved in 2-oxopropane-1,3-diylbis(2-(((5Z,8Z,11Z,14Z,17Z)-icosa) in THF (55 mL) and water (4 mL). -5,8,11,14,17-pentaen-1-yl)oxy)butanoate) (3.24 g, 4.03 mmol) at 0° C. carefully. The mixture was stirred at 0°C for 15 minutes. Then acetic acid (1 mL) was carefully added followed by ethyl acetate (100 mL). The mixture was washed with water (100 mL), saturated aqueous NaHCO ₃ (100 mL) and brine, then dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was combined with another batch of material and then purified by flash chromatography on silica gel using 15% ethyl acetate in heptane as eluent. Concentration of the appropriate fractions gave 1.62 g (50% yield) of the title compound as an oil. ¹ H NMR (300 MHz, CDCl3) δ 0.97-1.03 (m, 12H), 1.41-1.52 (m, 4H), 1.58-1.69 (m, 6H), 1.71-1.87 (m, 4H), 2.05-2.14 ( m, 8H), 2.38-2.42 (m, 1H), 2.78-2.92 (m, 16H), 3.32-3.39 (m, 2H), 3.57-3.64 (m, 2H), 3.80-3.84 (m, 2H), 4.05-4.34 (m, 5H), 5.26-5.49 (m, 20H). MS (electrospray): 827.5 [M+Na] ⁺ .

[Example 20]
Preparation of propane-1,2,3-tolyltris(2-(((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yl)oxy)butanoate)

2-(((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yl)oxy)butanoic acid (4.0g, 10.7mmol), 4-dimethylamino Pyridine (1.305 g, 10.7 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.047 g, 10.7 mmol) and dry DCM (30 ml) were dissolved in glycerol (0.173 ml) in DMF (10 ml). , 2.373 mmol) at room temperature under _N2 atmosphere. After stirring the mixture overnight, the reaction mixture was diluted with diethyl ether (250 mL). The mixture was washed with 1M aqueous HCl (100 mL) and brine (100 mL), then dried (Na ₂ SO ₄ ), filtered and evaporated in vacuo. The residue was purified by flash chromatography on silica gel using 5% ethyl acetate in heptane as eluent. Concentration of the appropriate fractions gave 2.1 g (73% yield) of the title compound as an oil. ¹ H NMR (300 MHz, CDCl3) δ 0.91-1.05 (m, 18H), 1.40-1.52 (m, 6H), 1.57-1.69 (m, 6H), 1.69-1.86 (m, 6H), 2.01-2.17 ( m, 12H), 2.69-2.96 (m, 24H), 3.27-3.38 (m, 3H), 3.53-3.67 (m, 3H), 3.73-3.81 (m, 3H), 4.17-4.27 (m, 2H), 4.37-4.54 (m, 2H), 5.28-5.47 (m, 30H). MS (electrospray): 1183.8 [M+Na] ⁺ .

[Example 21]
Preparation of calcium 2-(((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yl)oxy)butanoate

2-(((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yl)oxy)butanoic acid (1.87 g, 4.99 mmol, 93%), Mixed with _CaCO3 (0.25g, 2.50mmol). Water (1 ml) was added and the mixture was stirred with a mechanical stirrer for 1 hour at RT. _CO2 is generated. A thick, homogeneous paste was formed. Acetone (7ml) was added while stirring. Solid substances separate. The solid material was filtered, dried over nitrogen, sealed, and stored in the refrigerator at 4°C. Yield: 1.86 grams (95%). Although the solid was not further characterized by analytical or spectroscopic methods, several experiments were performed that indicated that a calcium salt was formed:
- Solid substances melt below 100°C on a hot plate. No sharp melting point was measured.
- This material does not release _CO2 upon addition of acid, but "dissolves" and precipitates as an oil.

[Example 22]
Preparation of sodium 2-(((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yl)oxy)butanoate

2-(((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yl)oxy)butanoic acid (1.87 g, 4.99 mmol, 93%), Mixed with _NaHCO3 (0.420g, 5.00mmol). Water (1 ml) was added and the mixture was stirred at RT for 1 h with a mechanical stirrer. _CO2 evolved and a thick homogeneous paste was formed. Ethanol (7 ml) was added to the reaction flask while stirring. The sodium salt formed from 2-(((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yl)oxy)butanoic acid was dissolved in ethanol (7 ml). is included in the solution upon addition of . A small amount of unreacted _NaHCO3 was filtered off and the solution was evaporated to dryness. The crude slightly viscous oil was evaporated twice with 96% ethanol to remove traces of water.

[Example 23]
2-Hydroxy-N,N,N-trimethylethane-1-aminium 2-(((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yl) Preparation of oxy)butanoate

Choline hydroxide in water (327.7 μL) was pipetted into a scintillation vial along with approximately 2.5 mL MTBE and 7.5 mL n-heptane. 2-(((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yl)oxy)butanoic acid (500 mg, 95.8%) in a nitrogen chamber. Transferred into a vial. Approximately 1.0 mL of water was slowly added to the vial while stirring in a nitrogen chamber. The vial was then sealed. The reaction mixture was stirred for approximately 30 minutes. The formed 2-(((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yl)oxy)butanoic acid choline salt was filtered on a Buchner funnel. It was a rigid gel-like substance. The wet material on the filter was washed three times using 1 mL of MTBET. The washed material appeared to be a rigid gel-like solid.

[Example 24]
Preclinical studies Evaluation of apoC-III regulation in a mouse model of dyslipidemia (APOE*3 Leiden transgenic mice)
APOE*3Leiden transgenic mice express a mutant form of human apolipoprotein E3 (APOE3), APOE*3Leiden, in addition to human apolipoprotein C1 (APOC1). APOE*3 Leiden transgenic mice exhibit elevated plasma cholesterol and triglyceride levels that are primarily restricted to the VLDL/LDL-sized lipoprotein fraction (Van den Maagdenberg AMJM et al., Transgenic mice carrying the apolipoprotein E3-Leiden gene exhibit hyperlipoproteinemia , J Biol Chem 1993;268:10540-10545). In contrast to normal wild-type mice, APOE*3 Leiden transgenic mice are highly responsive to diet and antihyperlipidemic drugs that affect plasma VLDL and chylomicron levels (Van Vlijmen B et al. , Diet-induced hyperlipoproteinemia and atherosclerosis in apolipoprotein E3-Leiden transgenic mice, J Clin Invest 1994;93:1403-1410; Groot PHE et al., Quantitative assessment of aortic atherosclerosis in apoE3Leiden transgenic mice and its relationship to serum cholesterol exposure,Arterioscler Thromb Vasc Biol 1996;16:926-933). Consequently, this model is suitable for evaluating the effects of antihyperlipidemia drugs.

In this study, female APOE*3 Leiden transgenic mice were fed a semi-synthetic Western-type diet (WTD; 15% cocoa butter, 40% sucrose and 0.25% cholesterol; all w/w). After 4 weeks using this diet, plasma cholesterol levels reached moderately elevated levels of approximately 12-15 mmol/l. The mice were then subdivided into groups of 10 mice matched for plasma cholesterol, triglycerides, and body weight (t=0). The test substance was mixed with WTD and administered orally at 0.3 mmol/kg body weight/day. After 4 weeks, all animals were sacrificed and serum and tissues were collected.

Liver tissues were stored at -80°C in RNA later (Qiagen). Tissues were homogenized in RLT buffer with dithiothreitol (Qiagen) and RNA isolated using the RNeasy kit (Qiagen) according to the manufacturer's procedures. The quality of the isolated RNA was tested using a Bioanalyser (Agilent) and showed a RIN (RNA integrity number) value between 8.1 and 9.5, indicating high quality. cDNA was synthesized with the "RNA to cDNA" kit (Applied Biosystems). Gene expression was measured using low density array (LDA, specific for mouse RNA (Applied Biosystems)). Each sample was measured in triplicate and the results are presented as the average value compared to the control (WTD without addition). Fold changes in gene expression were calculated by the comparative Ct method using Rplp0 as the housekeeping gene and the mean value of the control samples as the standard.

The results shown in Figure 1 confirm that mice fed Compound A (Example 2) have significantly reduced apoC-III expression than mice fed standard WTD (P< 0.05, Student's T-test). The effect of compound A is stronger than that of reference compound 12, and the EPA derivative prepared based on Example 20 of WO2010/008299 has the following structure:

In addition, the ability of both compounds to reduce plasma TG was determined. Both compounds reduced TG levels by 69% compared to control. This confirms that there is no direct correlation between the observed apoC-III reduction and TG lowering effect.

[Example 25]
Clinical Studies The apoC-III reducing properties of Compound A were demonstrated in two 12-week studies and one 4-week study in patients with dyslipidemia. All three studies demonstrated clinically and statistically significant apoC-III reduction using Compound A treatment.

[Example 25A]
Population with Severe Hypertriglyceridemia This study investigated patients with fasting plasma triglyceride levels greater than 500 mg/dL. The first goal of this study was to evaluate the efficacy of 600 mg once daily (QD) oral administration of Compound A (Example 2) by examining the rate of change from baseline in triglycerides (TG) after 12 weeks of treatment. The objective was to evaluate the One of the secondary goals was to evaluate the effect of Compound A on plasma levels of apoC-III.

This Phase II, multicenter, proof-of-concept study will include a 6-8 week screening period (including a 4- or 6-week dietary and lifestyle stabilization/drug washout period and a 2-week TG eligibility period). , and a 12-week double-blind, randomized, parallel group, placebo-controlled treatment period.

After confirmation of eligibility of fasting TG values, eligible subjects entered a 12-week, randomized, double-blind treatment period. At Visit 4 (Week 0), subjects were randomized in a 1:1 ratio to one of the following treatment groups: Compound A 600 mg QD or Placebo QD.

Approximately 43 subjects per treatment group (approximately 86 subjects total) were randomized in this study. Stratification was performed by baseline TG level (≤700 mg/dL or >700 mg/dL), statin use at randomization, and gender.

The study population was men and women between the ages of 18 and 79 years (women of childbearing potential were required to take suitable measures to avoid pregnancy). Subjects on stabilized lipid-lowering statin therapy and those not on non-statin lipid-lowering therapy were eligible for enrollment in this study. Subjects must have mean fasting TG levels of ≧500 mg/dL and ≦1500 mg/dL from Visit 2 and Visit 3 values or Visit 3 and Visit 3.1 values prior to randomization It was said that

The Inclusive Analysis (ITT) population consists of all randomized subjects who received at least one dose of the study product, had a baseline efficacy measurement, and had at least one post-randomization efficacy measurement. It consisted of objects. The ITT population was the primary analysis population. All efficacy analyzes were performed on the ITT population.

Summary statistics (n, mean, standard deviation [SD], median, minimum and maximum), percent change or amount of change from baseline for baseline and post-baseline measurements were analyzed. All efficacy variables are presented by treatment group and visit.

The first efficacy analysis used an analysis of covariance (ANCOVA) model with treatment, gender, and use of statin therapy at randomization as factors, and with baseline TG levels as a covariate. carried out. Least squares means, standard errors, and two-sided 95% confidence intervals (CI) were obtained for each treatment group and for Compound A vs. placebo.

For analysis of secondary efficacy variables, we used an ANCOVA model with treatment, gender, and use of statin therapy at randomization as factors, and baseline values for each efficacy variable as covariates. did.

The population recruited for the current study included men (69.0%) and women (31.0%) with a mean age of 52.5 years. Approximately 21% of subjects in both treatment groups received statin treatment throughout the study. All other non-statin lipid-altering therapies were discontinued at screening. The average compliance rates for studying drug therapy during this study were 96.5% for the placebo group and 99.9% for the Compound A 600 mg group.

In the ITT population, the mean least squares (LS) change in apoC-III was -38.0% (-47.5, -28.5) versus baseline and -34.7% (-46.5, -22.8) versus placebo. Met.

[Example 25B]
Populations with mixed dyslipidemia This study included patients with fasting plasma TG levels between 200 and 499 mg/dL and non-high-density lipoprotein cholesterol (non-HDL-C) above 130 mg/dL who were not taking statins. We surveyed patients who had already undergone the treatment. The first goal of this study was to evaluate the efficacy of 600 mg QD of Compound A (Example 2) orally by examining the percent change from baseline in triglyceride non-HDL-C after 12 weeks of treatment. there were. One of the secondary goals was to evaluate the effect of Compound A on plasma levels of apoC-III.

This Phase II, multicenter, proof-of-concept study will include a 6-8 week screening period (4 or 6 weeks of dietary and lifestyle stabilization/drug washout period and 2 weeks of TG and non-HDL-C eligibility). The study consisted of a 12-week, double-blind, randomized, parallel-group, placebo-controlled treatment period.

After confirmation of eligibility of fasting TG and non-HDL-C values, eligible subjects entered a 12-week, randomized, double-blind treatment period. At Visit 4 (Week 0), subjects were randomized in a 1:1 ratio to one of the following treatment groups: Compound A 600 mg QD or Placebo QD.

The study population was men and women between the ages of 18 and 79 years (women of childbearing potential were required to take suitable measures to avoid pregnancy). Subjects on stabilized lipid-lowering statin therapy and those not on non-statin lipid-lowering therapy were eligible for enrollment in this study. Subjects had a mean fasting TG level between 200 and 499 mg/dL and a non-active TG level of >130 mg/dL from Visit 2 and Visit 3 values or Visit 3 and Visit 3.1 values prior to randomization. Required to have HDL-C values.

The Inclusive Analysis (ITT) population consists of all randomized subjects who received at least one dose of the study product, had a baseline efficacy measurement, and had at least one post-randomization efficacy measurement. It consisted of objects. The ITT population was the primary analysis population. All efficacy analyzes were performed on the ITT population.

Summary statistics (n, mean, standard deviation [SD], median, minimum and maximum), percent change or amount of change from baseline for baseline and post-baseline measurements were analyzed. All efficacy variables are presented by treatment group and visit.

The first efficacy analysis was performed using an ANCOVA model with randomization as a factor and baseline non-HDL-C value as a covariate. Least squares means, standard errors, and two-sided 95% CIs were obtained for each treatment group and for Compound A vs. placebo.

The first efficacy analysis was based on the 12-week completer population.

The population recruited for the current study included men (58.4%) and women (46.1%) with a mean age of 58.3 years. All subjects were required to be on statin treatment (with or without ezetimibe) during the study. All other non-statin lipid-altering therapies were discontinued at screening. The average compliance rates for studying drug therapy during this study were 97.2% for the placebo group and 95.3% for the Compound A group.

The baseline mean non-HDL-C level of the study population was 165.9 mg/dL; the baseline median TG level was 262.0 mg/dL.

In the 12-week completer population, the mean LS change in apoC-III was -32.5% (-38.4, -26.6) versus baseline and -20.8% (-28.8, -12.7) versus placebo. there were.

Example 25A describes a study in patients with very high triglycerides (TG 500-2000 mg/dl). Example 25B describes a study in statin stabilized patients with mixed dyslipidemia and persistent hypertriglyceridemia (TG 200-499 mg/dl). Studies included in each section have comparable patient populations and are similar in design.

Example 25C Population with Hypercholesterolemia This study investigated subjects with fasting LDL-C of at least 2.5 mmol (approximately 97 mg/dl). The purpose of this study was to determine the pharmacodynamic and lipid-lowering effects of Compound A (Example 2) after 4 weeks of treatment in male hypercholesterolemic subjects who discontinued stabilizing statin therapy. .

The study population consisted of men aged 18 to 65 years of any ethnic origin with a BMI between 18.0 and 35.0 kg/ ^m2 .

The Phase Ib study consisted of a 4- to 5-week screening period and a 4-week double-blind, randomized, placebo-controlled treatment period.

All subjects had to have been on lipid-lowering statin therapy for at least 3 months prior to the first screening visit and on a stabilizing statin for at least 4 weeks prior to the first screening visit. .

Statin treatment was discontinued at the first screening visit and remained discontinued during the entire screening period. Following discontinuation of statin therapy for at least 21 days, subjects must have an LDL-C of at least 2.5 mmol/l (approximately 97 mmol/l) at the second screening visit and at the first screening visit prior to randomization. Must have had an LDL-C increase of at least 20% between the examination and the second screening visit.

After confirmation of eligibility of fasting LDL-C values, eligible subjects entered a 4-week, double-blind, randomized, placebo-controlled treatment period. Subjects were randomly assigned in a 3:1 ratio to one of the following treatment groups: Compound A 600 mg QD (N=18) or Placebo QD (N=6).

Blood lipids were measured at the end of the screening period and after 4 weeks of treatment. Exploratory pharmacodynamic measurements included LDL-C, VLDL-C, TC, TG, HDL-C, non-HDL-C, and apoB. The influence of Compound A on apoC-III was also determined.

Summary statistics regarding baseline are obtained as mean values using coefficients of variation. Mean changes from baseline with 95% confidence intervals are presented by treatment group for all efficacy variables analyzed.

Analyzes were performed using an analysis of covariance (ANCOVA) model with baseline included as a covariate for the amount of change from baseline.

The population recruited for the current study included Caucasian males (100%) with a mean age of 55 years, mean weight of 85 kg, and mean BMI of 27.9 kg/ ^m2 .

The average percent change in apoC-III after treatment with Compound A was -42% versus baseline. This change was statistically significant.

[Example 26]
Comparative reduction in apoC-III achieved with EPA/DHA versus Compound A
(a) Effect of EPA/DHA formulation for Compound A on plasma apoC-III and other lipid parameters in subjects with severe HTG
MARINE exam:
In a double-blind, randomized, placebo-controlled study, the administration of eicosapentaenoic acid ethyl ester (>96% by weight concentrate) (Vascepa) in 229 subjects with fasting plasma TG between 500 and 2000 mg/dl. The effect on apoC-III was investigated. Vascepa 4 g/day for 12 weeks reduced median apoC-III levels from 25.6 mg/dl to 19.7 mg/dl, corresponding to a median change of -10.1% from baseline [Journal of Clinical Lipidology 2014;8(3):313-314, Icosapent Ethyl(eicosapentaenoic acid ethyl ester): Effects on Apolipoprotein C-III in patients from the MARINE and ANCHOR studies.] (Table 1).

EVOLVE exam:
In a double-blind, randomized, placebo-controlled study, a combination of EPA and DHA as free fatty acids (55 wt% EPA and 20 wt% The effect of % DHA) (Epanova) on apoC-III was investigated. Epanova at 4 g/day for 12 weeks resulted in a -15% median change in apoC-III from baseline [Circulation 2012;126:A19030, Abstract 19030:Apolipoprotein C-III is Significantly Reduced by Prescription Omega-3 Free Fatty Acids (Epanova) in Patients with Severe Hypertriglyceridemia and Changes Correlate with Increases in LDL-C: A Sub-analysis of the EVOLVE trial] (Table 1).

(b) Effect of EPA/DHA formulation for Compound A on plasma apoC-III and other lipid parameters in statin-stabilized subjects with mixed dyslipidemia and persistent hypertriglyceridemia.
ANCHOR exam:
In a double-blind, randomized, placebo-controlled study, in 702 statin-stabilized patients with mixed dyslipidemia and persistent hypertriglyceridemia with fasting plasma TG between 200 and 499 mg/dl; The effect of eicosapentaenoic acid ethyl ester (Vascepa) on apoC-III was investigated. Vascepa 4 g/day for 12 weeks reduced median apoC-III levels from 15.2 mg/dl to 13.7 mg/dl, corresponding to a median change of -9.4% from baseline [Journal of Clinical Lipidology Published in 2015, http://dx.doi.org/10.1016/j.jacl.2014.11.009, Effects of icosapent ethyl on lipoprotein particle concentration and size in persistent statin-treated patients with high triglycerides(ANCHOR study)]( Table 2).

ESPRIT exam:
In a double-blind, randomized, placebo-controlled study, in 647 statin-stabilized patients with mixed dyslipidemia and persistent hypertriglyceridemia with fasting plasma TG between 200 and 499 mg/dl; The effect of the combination of EPA and DHA as free fatty acids (Epanova) on apoC-III was investigated. Epanova at 4 g/day for 12 weeks resulted in a mean apoC-III change from baseline of -13.1% [JACC 2013;61: E1468, A highly bioavailable omega-3 fatty acid reduces non-high density lipoprotein cholesterol in high-risk patients treated with a statin and residual hypertriglyceridemia (ESPRIT trial)] (Table 2).

COMBOS exam:
In a double-blind, randomized study, EPA and DHA The effect of a combination of ethyl esters (46.5% wt. EPA EE and 37.5 wt.% DHA EE) (Lovaza) on apoC-III was investigated. Lovaza 4 g/day per week resulted in a median apoC-III change of -7.8% from baseline [Clinical Therapeutics 2007;29(7):1354-1367, Efficacy and tolerability of adding prescription Omega-3 fatty acids 4 g/d to simvastatin 40 mg/d in hypertriglyceridemic patients: An 8-week, randomized, double-blind, placebo-controlled study] (Table 2).

Summary of Comparative Reductions in Plasma Apoc A convincing benchmark is provided to compare the effectiveness of Compound A versus EPA/DHA in lowering C-III. There are two notable differences between naturally occurring omega-3 fatty acids and Compound A.

The first factor is the superior efficacy of Compound A, which achieved median apoC-III reductions of 35 and 41%, respectively, in patient populations with mixed dyslipidemia and severe HTG. This compares to apoC-III reductions of only 7.8-15% in EPA/DHA studies.

又はその薬学的に許容される塩若しくはエステルを対象に投与することを含み、
式中、R₁及びR₂は、水素原子又は直鎖、分岐、及び/若しくは環式C₁～C₆アルキル基から独立して選択され、但しR₁及びR₂が両方とも水素であることはない、方法。
（付記２）
前記化合物が、エナンチオマー、ジアステレオマー、又はこれらの混合物の形態で存在する、付記1に記載の方法。
（付記３）
R₁及びR₂が、水素原子、メチル基、エチル基、n-プロピル基及びイソプロピル基から選択される、付記1に記載の方法。
（付記４）
R₁及びR₂が、水素原子、メチル基、及びエチル基から選択される、付記1に記載の方法。
（付記５）
R₁及びR₂の一方が水素原子であり、R₁及びR₂の他方がC₁～C₃アルキル基から選択される、付記1に記載の方法。
（付記６）
R₁及びR₂の一方が水素原子であり、R₁及びR₂の他方がメチル基又はエチル基から選択される、付記1に記載の方法。
（付記７）
前記エステルが、グリセリド、及びC₁～C₆アルキルエステルから選択される、付記1に記載の方法。
（付記８）
前記エステルが、トリグリセリド、1,2-ジグリセリド、1,3-ジグリセリド、1-モノグリセリド、及び2-モノグリセリドから選択される、付記1に記載の方法。
（付記９）
前記エステルが、メチルエステル、エチルエステル、イソプロピルエステル、n-ブチルエステル、及びtert-ブチルエステルから選択される、付記1に記載の方法。
（付記１０）
前記エステルが、メチルエステル及びエチルエステルから選択される、付記1に記載の方法。
（付記１１）
前記化合物が、そのR体で存在する、付記2に記載の方法。
（付記１２）
前記化合物が、そのS体で存在する、付記2に記載の方法。
（付記１３）
前記化合物が、ラセミ体で存在する、付記2に記載の方法。
（付記１４）
R₁が水素であり、R₂がエチルであり、前記式が

である、付記1に記載の方法。
（付記１５）
前記化合物が、式:

で表されるそのS及び/又はR体で存在する、付記14に記載の方法。
（付記１６）
式(I)の化合物の薬学的有効量が、1用量当たり約5mg～約2gの範囲である、付記1に記載の方法。
（付記１７）
式(I)の化合物の薬学的有効量が、1用量当たり約200mg～約800mgの範囲である、付記1に記載の方法。
（付記１８）
式(I)の化合物の薬学的有効量が、約600mgである、付記1に記載の方法。
（付記１９）
前記対象が、ヒトである、付記1に記載の方法。
（付記２０）
前記化合物を、1日1回投与する、付記1に記載の方法。
（付記２１）
前記化合物が、経口投与用の医薬組成物として製剤されている、付記1に記載の方法。（付記２２）
前記医薬組成物が、ゼラチンカプセル剤又は錠剤の形態である、付記21に記載の方法。（付記２３）
前記医薬組成物が、少なくとも1種の結合剤、賦形剤、希釈剤、又はこれらの任意の組合せを更に含む、付記22に記載の方法。
（付記２４）
前記医薬組成物が、抗酸化剤を更に含む、付記22に記載の方法。
（付記２５）
前記抗酸化剤が、トコフェロール、BHA、及びBHT、又はこれらの混合物から選択される、付記24に記載の方法。
（付記２６）
必要とする対象においてアポC-IIIを低減する方法であって、薬学的有効量の2-((5Z,8Z,11Z,14Z,17Z)-イコサ-5,8,11,14,17-ペンタエン-1-イルオキシ)ブタン酸:

又はその薬学的に許容される塩若しくはエステルを対象に投与することを含む、方法。
（付記２７）
2-((5Z,8Z,11Z,14Z,17Z)-イコサ-5,8,11,14,17-ペンタエン-1-イルオキシ)ブタン酸の薬学的有効量が、1用量当たり約200mg～約800mgの範囲である、付記26に記載の方法。
（付記２８）
2-((5Z,8Z,11Z,14Z,17Z)-イコサ-5,8,11,14,17-ペンタエン-1-イルオキシ)ブタン酸を、1日1回投与する、付記27に記載の方法。
（付記２９）
薬学的有効量の式(I)の化合物

又はその薬学的に許容される塩若しくはエステルの使用であって、
式中、R₁及びR₂が、水素原子又は直鎖、分岐、及び/若しくは環式C₁～C₆アルキル基から独立して選択され、但しR₁及びR₂が両方とも水素であることはなく、
必要とする対象においてアポリポタンパク質C-III(アポC-III)mRNA又はタンパク質を低減するための医薬の製造における、使用。
（付記３０）
前記化合物が、エナンチオマー、ジアステレオマー、又はこれらの混合物の形態で存在する、付記29に記載の使用。
（付記３１）
R₁及びR₂が、水素原子、メチル基、エチル基、n-プロピル基及びイソプロピル基から選択される、付記29に記載の使用。
（付記３２）
R₁及びR₂が、水素原子、メチル基、及びエチル基から選択される、付記29に記載の使用。
（付記３３）
R₁及びR₂の一方が水素原子であり、R₁及びR₂の他方はC₁～C₃アルキル基から選択される、付記29に記載の使用。
（付記３４）
R₁及びR₂の一方が水素原子であり、R₁及びR₂の他方がメチル基又はエチル基から選択される、付記29に記載の使用。
（付記３５）
前記エステルが、グリセリド、及びC₁～C₆アルキルエステルから選択される、付記29に記載の使用。
（付記３６）
前記エステルが、トリグリセリド、1,2-ジグリセリド、1,3-ジグリセリド、1-モノグリセリド、及び2-モノグリセリドから選択される、付記29に記載の使用。
（付記３７）
前記エステルが、メチルエステル、エチルエステル、イソプロピルエステル、n-ブチルエステル、及びtert-ブチルエステルから選択される、付記29に記載の使用。
（付記３８）
前記エステルが、メチルエステル及びエチルエステルから選択される、付記29に記載の使用。
（付記３９）
前記化合物が、そのR体で存在する、付記30に記載の使用。
（付記４０）
前記化合物が、そのS体で存在する、付記30に記載の使用。
（付記４１）
前記化合物が、ラセミ体で存在する、付記30に記載の使用。
（付記４２）
R₁が水素であり、R₂がエチルであり、前記式が

である、付記29に記載の使用。
（付記４３）
前記化合物が、式:

で表されるそのS及び/又はR体で存在する、付記42に記載の使用。
（付記４４）
式(I)の化合物の薬学的有効量が、1用量当たり約5mg～約2gの範囲である、付記29に記載の使用。
（付記４５）
式(I)の化合物の薬学的有効量が、1用量当たり約200mg～約800mgの範囲である、付記29に記載の使用。
（付記４６）
式(I)の化合物の薬学的有効量が、約600mgである、付記29に記載の使用。
（付記４７）
前記対象が、ヒトである、付記29に記載の使用。
（付記４８）
前記化合物を、1日1回投与する、付記29に記載の使用。
（付記４９）
前記化合物が、経口投与用の医薬組成物として製剤化される、付記29に記載の使用。
（付記５０）
前記医薬組成物が、ゼラチンカプセル剤又は錠剤の形態である、付記49に記載の使用。（付記５１）
前記医薬組成物が、少なくとも1種の結合剤、賦形剤、希釈剤、又はこれらの任意の組合せを更に含む、付記50に記載の使用。
（付記５２）
前記医薬組成物が、抗酸化剤を更に含む、付記50に記載の使用。
（付記５３）
前記抗酸化剤が、トコフェロール、BHA、及びBHT、又はこれらの混合物から選択される、付記52に記載の使用。
（付記５４）
薬学的有効量の2-((5Z,8Z,11Z,14Z,17Z)-イコサ-5,8,11,14,17-ペンタエン-1-イルオキシ)ブタン酸:

又はその薬学的に許容される塩若しくはエステルの使用であって、必要とする対象においてアポC-IIIを低減するための医薬の製造における、使用。
（付記５５）
2-((5Z,8Z,11Z,14Z,17Z)-イコサ-5,8,11,14,17-ペンタエン-1-イルオキシ)ブタン酸の薬学的有効量が、1用量当たり約200mg～約800mgの範囲である、付記54に記載の使用。
（付記５６）
2-((5Z,8Z,11Z,14Z,17Z)-イコサ-5,8,11,14,17-ペンタエン-1-イルオキシ)ブタン酸を、1日1回投与する、付記55に記載の使用。
（付記５７）
前記対象が、スタチン療法中であり、約200mg/dl～約499mg/dlのベースラインの空腹時トリグリセリドを有する、付記1に記載の方法。
（付記５８）
前記対象が、約200mg/dl～約499mg/dlのベースラインの空腹時トリグリセリドを有する、付記1に記載の方法。
（付記５９）
アポC-IIIレベルが、少なくとも約20%低減される、付記57又は58に記載の方法。
（付記６０）
アポC-IIIレベルが、少なくとも約35%低減される、付記57又は58に記載の方法。
（付記６１）
前記対象が、スタチン療法中であり、500mg/dl超のベースラインの空腹時トリグリセリドを有する、付記1に記載の方法。
（付記６２）
前記対象が、500mg/dl超のベースラインの空腹時トリグリセリドを有する、付記1に記載の方法。
（付記６３）
アポC-IIIレベルが、少なくとも約25%低減される、付記61又は62に記載の方法。
（付記６４）
アポC-IIIレベルが、少なくとも約40%低減される、付記61又は62に記載の方法。
（付記６５）
前記対象が、少なくとも2.5mmol/L(約97mg/dl)の空腹時LDL-コレステロールを有する、付記1に記載の方法。
（付記６６）
アポC-IIIレベルが、少なくとも約25%低減される、付記65に記載の方法。
（付記６７）
アポC-IIIレベルが、少なくとも約40%低減される、付記65に記載の方法。
（付記６８）
必要とする対象においてアポC-IIIを低減する方法であって、薬学的有効量の脂質異常症薬剤及び式(I)の化合物:

又はその薬学的に許容される塩若しくはエステルを対象に投与することを含み、
式中、R₁及びR₂は、水素原子又は直鎖、分岐、及び/若しくは環式C₁～C₆アルキル基から独立して選択され、但しR₁及びR₂が両方とも水素であることはない、方法。
（付記６９）
前記脂質異常症薬剤が、スタチンである、付記68に記載の方法。
（付記７０）
前記対象が、スタチン療法中であり、約200mg/dl～約499mg/dlのベースラインの空腹時トリグリセリドを有する、付記29に記載の使用。
（付記７１）
前記対象が、約200mg/dl～約499mg/dlのベースラインの空腹時トリグリセリドを有する、付記29に記載の使用。
（付記７２）
アポC-IIIレベルが、少なくとも約20%低減される、付記70又は71に記載の使用。
（付記７３）
アポC-IIIレベルが、少なくとも約35%低減される、付記70又は71に記載の使用。
（付記７４）
前記対象が、スタチン療法中であり、500mg/dl超のベースラインの空腹時トリグリセリドを有する、付記29に記載の使用。
（付記７５）
前記対象が、500mg/dl超のベースラインの空腹時トリグリセリドを有する、付記29に記載の使用。
（付記７６）
アポC-IIIレベルが、少なくとも約25%低減される、付記74及び75に記載の使用。
（付記７７）
アポC-IIIレベルが、少なくとも約40%低減される、付記74及び75に記載の使用。
（付記７８）
前記対象が、少なくとも2.5mmol/L(約97mg/dl)の空腹時LDL-コレステロールを有する、付記29に記載の使用。
（付記７９）
アポC-IIIレベルが、少なくとも約25%低減される、付記78に記載の使用。
（付記８０）
アポC-IIIレベルが、少なくとも約40%低減される、付記78に記載の使用。
（付記８１）
前記必要とする対象が、重度の高トリグリセリド血症、混合型脂質異常症、及び高コレステロール血症から選択される疾患又は状態を有する、付記1に記載の方法。
（付記８２）
前記必要とする対象が、重度の高トリグリセリド血症、混合型脂質異常症、及び高コレステロール血症から選択される疾患又は状態を有する、付記29に記載の使用。 The second differentiating factor is the lower dose of Compound A required (600 mg QD) versus the 4 g dose in the EPA/DHA study. On a gram-to-gram basis, this difference is even greater for Compound A, clearly demonstrating the efficacy of Compound A molecules relative to EPA/DHA in reducing plasma apoC-III. As mentioned above, preclinical models suggest that apoC-III reduction is independent of TG reduction (Figure 1).
(Additional note)
(Additional note 1)
A method of reducing apolipoprotein C-III (apoC-III) mRNA or protein in a subject in need thereof, the method comprising: a pharmaceutically effective amount of a compound of formula (I):

or a pharmaceutically acceptable salt or ester thereof,
where R ₁ and R ₂ are independently selected from hydrogen atoms or linear, branched, and/or cyclic C ₁ -C ₆ alkyl groups, provided that R ₁ and R ₂ are both hydrogen; No way.
(Additional note 2)
1. The method according to claim 1, wherein the compound is present in the form of enantiomers, diastereomers, or mixtures thereof.
(Additional note 3)
The method according to appendix 1, wherein R ₁ and R ₂ are selected from a hydrogen atom, a methyl group, an ethyl group, an n-propyl group and an isopropyl group.
(Additional note 4)
The method according to appendix 1, wherein R ₁ and R ₂ are selected from a hydrogen atom, a methyl group, and an ethyl group.
(Appendix 5)
The method according to appendix 1, wherein one of R ₁ and R ₂ is a hydrogen atom and the other of R ₁ and R ₂ is selected from a C ₁ to C ₃ alkyl group.
(Appendix 6)
The method according to supplementary note 1, wherein one of R ₁ and R ₂ is a hydrogen atom, and the other of R ₁ and R ₂ is selected from a methyl group or an ethyl group.
(Appendix 7)
1. The method of claim 1, wherein the ester is selected from glycerides and C ₁ -C ₆ alkyl esters.
(Appendix 8)
1. The method of claim 1, wherein the ester is selected from triglycerides, 1,2-diglycerides, 1,3-diglycerides, 1-monoglycerides, and 2-monoglycerides.
(Appendix 9)
1. The method according to claim 1, wherein the ester is selected from methyl ester, ethyl ester, isopropyl ester, n-butyl ester, and tert-butyl ester.
(Appendix 10)
1. The method according to claim 1, wherein the ester is selected from methyl ester and ethyl ester.
(Appendix 11)
2. The method according to appendix 2, wherein the compound is present in its R form.
(Appendix 12)
The method according to appendix 2, wherein the compound is present in its S form.
(Appendix 13)
The method according to appendix 2, wherein the compound is present in racemic form.
(Appendix 14)
R ₁ is hydrogen, R ₂ is ethyl, and the above formula is

The method described in Appendix 1.
(Appendix 15)
The compound has the formula:

The method according to appendix 14, wherein the method is present in its S and/or R form represented by
(Appendix 16)
1. The method of claim 1, wherein the pharmaceutically effective amount of the compound of formula (I) ranges from about 5 mg to about 2 g per dose.
(Appendix 17)
The method of Clause 1, wherein the pharmaceutically effective amount of the compound of formula (I) ranges from about 200 mg to about 800 mg per dose.
(Appendix 18)
1. The method of claim 1, wherein the pharmaceutically effective amount of the compound of formula (I) is about 600 mg.
(Appendix 19)
The method according to supplementary note 1, wherein the subject is a human.
(Additional note 20)
1. The method according to appendix 1, wherein the compound is administered once a day.
(Additional note 21)
1. The method of claim 1, wherein said compound is formulated as a pharmaceutical composition for oral administration. (Additional note 22)
22. The method according to appendix 21, wherein the pharmaceutical composition is in the form of a gelatin capsule or tablet. (Additional note 23)
23. The method of clause 22, wherein the pharmaceutical composition further comprises at least one binder, excipient, diluent, or any combination thereof.
(Additional note 24)
23. The method of claim 22, wherein the pharmaceutical composition further comprises an antioxidant.
(Additional note 25)
25. The method of claim 24, wherein the antioxidant is selected from tocopherols, BHA, and BHT, or mixtures thereof.
(Additional note 26)
A method for reducing apoC-III in a subject in need thereof, the method comprising: -1-yloxy)butanoic acid:

or a pharmaceutically acceptable salt or ester thereof to a subject.
(Additional note 27)
The pharmaceutically effective amount of 2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yloxy)butanoic acid is about 200 mg to about 800 mg per dose. The method described in Appendix 26, which is within the scope of
(Additional note 28)
The method according to appendix 27, wherein 2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yloxy)butanoic acid is administered once a day. .
(Additional note 29)
a pharmaceutically effective amount of a compound of formula (I);

or the use of a pharmaceutically acceptable salt or ester thereof,
where R ₁ and R ₂ are independently selected from hydrogen atoms or linear, branched, and/or cyclic C ₁ -C ₆ alkyl groups, provided that R ₁ and R ₂ are both hydrogen; Not,
Use in the manufacture of a medicament for reducing apolipoprotein C-III (apoC-III) mRNA or protein in a subject in need thereof.
(Additional note 30)
The use according to claim 29, wherein said compound is present in the form of enantiomers, diastereomers or mixtures thereof.
(Appendix 31)
The use according to appendix 29, wherein R ₁ and R ₂ are selected from a hydrogen atom, a methyl group, an ethyl group, an n-propyl group and an isopropyl group.
(Appendix 32)
The use according to appendix 29, wherein R ₁ and R ₂ are selected from a hydrogen atom, a methyl group, and an ethyl group.
(Appendix 33)
The use according to claim 29, wherein one of R ₁ and R ₂ is a hydrogen atom and the other of R ₁ and R ₂ is selected from a C ₁ -C ₃ alkyl group.
(Appendix 34)
The use according to appendix 29, wherein one of R ₁ and R ₂ is a hydrogen atom and the other of R ₁ and R ₂ is selected from a methyl group or an ethyl group.
(Appendix 35)
The use according to claim 29, wherein the ester is selected from glycerides and C ₁ -C ₆ alkyl esters.
(Appendix 36)
Use according to clause 29, wherein the ester is selected from triglycerides, 1,2-diglycerides, 1,3-diglycerides, 1-monoglycerides and 2-monoglycerides.
(Additional note 37)
The use according to claim 29, wherein the ester is selected from methyl ester, ethyl ester, isopropyl ester, n-butyl ester and tert-butyl ester.
(Appendix 38)
Use according to clause 29, wherein said ester is selected from methyl ester and ethyl ester.
(Appendix 39)
The use according to appendix 30, wherein said compound is present in its R form.
(Additional note 40)
The use according to appendix 30, wherein said compound is present in its S-configuration.
(Appendix 41)
The use according to appendix 30, wherein said compound is present in racemic form.
(Additional note 42)
R ₁ is hydrogen, R ₂ is ethyl, and the above formula is

, the use described in Appendix 29.
(Appendix 43)
The compound has the formula:

The use according to appendix 42, present in its S and/or R form represented by
(Appendix 44)
The use according to clause 29, wherein the pharmaceutically effective amount of the compound of formula (I) ranges from about 5 mg to about 2 g per dose.
(Additional note 45)
The use according to clause 29, wherein the pharmaceutically effective amount of the compound of formula (I) ranges from about 200 mg to about 800 mg per dose.
(Appendix 46)
The use according to clause 29, wherein the pharmaceutically effective amount of the compound of formula (I) is about 600 mg.
(Additional note 47)
The use according to appendix 29, wherein the subject is a human.
(Additional note 48)
The use according to clause 29, wherein said compound is administered once a day.
(Additional note 49)
The use according to clause 29, wherein said compound is formulated as a pharmaceutical composition for oral administration.
(Additional note 50)
The use according to clause 49, wherein the pharmaceutical composition is in the form of a gelatin capsule or tablet. (Appendix 51)
The use according to clause 50, wherein the pharmaceutical composition further comprises at least one binder, excipient, diluent, or any combination thereof.
(Appendix 52)
The use according to clause 50, wherein the pharmaceutical composition further comprises an antioxidant.
(Appendix 53)
53. The use according to claim 52, wherein the antioxidant is selected from tocopherols, BHA, and BHT, or mixtures thereof.
(Appendix 54)
Pharmaceutically effective amount of 2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yloxy)butanoic acid:

or a pharmaceutically acceptable salt or ester thereof, in the manufacture of a medicament for reducing apoC-III in a subject in need thereof.
(Appendix 55)
The pharmaceutically effective amount of 2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yloxy)butanoic acid is about 200 mg to about 800 mg per dose. The uses described in Appendix 54, which are within the scope of
(Appendix 56)
2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yloxy)butanoic acid is administered once a day, the use according to appendix 55. .
(Appendix 57)
The method of Clause 1, wherein the subject is on statin therapy and has a baseline fasting triglyceride of about 200 mg/dl to about 499 mg/dl.
(Appendix 58)
The method of Clause 1, wherein the subject has a baseline fasting triglyceride of about 200 mg/dl to about 499 mg/dl.
(Appendix 59)
59. The method of claim 57 or 58, wherein apoC-III levels are reduced by at least about 20%.
(Additional note 60)
59. The method of claim 57 or 58, wherein apoC-III levels are reduced by at least about 35%.
(Additional note 61)
The method of Clause 1, wherein the subject is on statin therapy and has a baseline fasting triglyceride of greater than 500 mg/dl.
(Appendix 62)
The method of Clause 1, wherein the subject has a baseline fasting triglyceride of greater than 500 mg/dl.
(Additional note 63)
63. The method of clause 61 or 62, wherein apoC-III levels are reduced by at least about 25%.
(Additional note 64)
63. The method of claim 61 or 62, wherein apoC-III levels are reduced by at least about 40%.
(Appendix 65)
1. The method of clause 1, wherein the subject has a fasting LDL-cholesterol of at least 2.5 mmol/L (about 97 mg/dl).
(Appendix 66)
66. The method of claim 65, wherein apoC-III levels are reduced by at least about 25%.
(Appendix 67)
66. The method of claim 65, wherein apoC-III levels are reduced by at least about 40%.
(Appendix 68)
A method of reducing apoC-III in a subject in need thereof, comprising: a pharmaceutically effective amount of a dyslipidemic agent and a compound of formula (I):

or a pharmaceutically acceptable salt or ester thereof,
where R ₁ and R ₂ are independently selected from hydrogen atoms or linear, branched, and/or cyclic C ₁ -C ₆ alkyl groups, provided that R ₁ and R ₂ are both hydrogen; No way.
(Appendix 69)
69. The method according to appendix 68, wherein the dyslipidemia drug is a statin.
(Additional note 70)
The use of Clause 29, wherein the subject is on statin therapy and has a baseline fasting triglyceride of about 200 mg/dl to about 499 mg/dl.
(Additional note 71)
The use of Clause 29, wherein the subject has a baseline fasting triglyceride of about 200 mg/dl to about 499 mg/dl.
(Additional note 72)
The use according to Clause 70 or 71, wherein apoC-III levels are reduced by at least about 20%.
(Additional note 73)
The use according to Clause 70 or 71, wherein apoC-III levels are reduced by at least about 35%.
(Additional note 74)
The use according to clause 29, wherein said subject is on statin therapy and has a baseline fasting triglyceride of greater than 500 mg/dl.
(Additional note 75)
The use according to clause 29, wherein said subject has a baseline fasting triglyceride of greater than 500 mg/dl.
(Additional note 76)
The use according to Clauses 74 and 75, wherein apoC-III levels are reduced by at least about 25%.
(Appendix 77)
The use according to Clauses 74 and 75, wherein apoC-III levels are reduced by at least about 40%.
(Appendix 78)
The use according to clause 29, wherein the subject has a fasting LDL-cholesterol of at least 2.5 mmol/L (about 97 mg/dl).
(Additional note 79)
The use according to clause 78, wherein apoC-III levels are reduced by at least about 25%.
(Additional note 80)
The use according to clause 78, wherein apoC-III levels are reduced by at least about 40%.
(Additional note 81)
1. The method of claim 1, wherein the subject in need thereof has a disease or condition selected from severe hypertriglyceridemia, mixed dyslipidemia, and hypercholesterolemia.
(Additional note 82)
The use according to appendix 29, wherein the subject in need thereof has a disease or condition selected from severe hypertriglyceridemia, mixed dyslipidemia, and hypercholesterolemia.

Claims (16)

A pharmaceutical composition for reducing apolipoprotein C-III (apoC-III) mRNA or apoC-III in a subject in need thereof, comprising: a pharmaceutically effective amount of a compound of formula (I):

or a pharmaceutically acceptable salt or ester thereof,
where R ₁ and R ₂ are independently selected from hydrogen atoms or linear, branched, and/or cyclic C ₁ -C ₆ alkyl groups, provided that R ₁ and R ₂ are both hydrogen; Not,
the pharmaceutically effective amount is 600 mg per dose;
A pharmaceutical composition in which the subject in need thereof has severe hypertriglyceridemia and has a fasting plasma triglyceride level greater than 500 mg/dl. 2. A pharmaceutical composition according to claim 1, wherein the compound is present in the form of enantiomers, diastereomers, or mixtures thereof. The pharmaceutical composition according to claim 1, wherein one of R ₁ and R ₂ is a hydrogen atom and the other of R ₁ and R ₂ is selected from a C ₁ to C ₃ alkyl group. A pharmaceutical composition according to claim 1, wherein the ester is selected from glycerides and C ₁ -C ₆ alkyl esters. Pharmaceutical composition according to claim 1, wherein the ester is selected from methyl ester and ethyl ester. R ₁ is hydrogen, R ₂ is ethyl, and the above formula is

The pharmaceutical composition according to claim 1, which is. The compound has the formula:

7. The pharmaceutical composition according to claim 6, which is present in its S and/or R form. 2. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition further comprises at least one binder, excipient, diluent, or any combination thereof. 2. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition further comprises an antioxidant. A pharmaceutical composition for reducing apoC-III in a subject in need thereof, comprising a pharmaceutically effective amount of 2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14). ,17-pentaen-1-yloxy)butanoic acid:

or a pharmaceutically acceptable salt or ester thereof,
the pharmaceutically effective amount is 600 mg per dose;
A pharmaceutical composition in which the subject in need thereof has severe hypertriglyceridemia and has a fasting plasma triglyceride level greater than 500 mg/dl. a pharmaceutically effective amount of a compound of formula (I);

or a pharmaceutically acceptable salt or ester thereof, in the manufacture of a medicament for reducing apolipoprotein C-III (apoC-III) mRNA or apoC-III in a subject in need thereof, comprising:
where R ₁ and R ₂ are independently selected from hydrogen atoms or linear, branched, and/or cyclic C ₁ -C ₆ alkyl groups, provided that R ₁ and R ₂ are both hydrogen; Not,
the pharmaceutically effective amount is 600 mg per dose;
Use where the subject in need has severe hypertriglyceridemia and fasting plasma triglyceride levels greater than 500 mg/dl. R ₁ is hydrogen, R ₂ is ethyl, and the above formula is

12. The use according to claim 11. The compound has the formula:

13. The use according to claim 12, present in its S and/or R form. 2. The pharmaceutical composition of claim 1, wherein the subject is on statin therapy. A pharmaceutical composition for reducing apoC-III in a subject in need thereof, comprising a pharmaceutically effective amount of a dyslipidemic agent and a compound of formula (I):

or a pharmaceutically acceptable salt or ester thereof,
where R ₁ and R ₂ are independently selected from hydrogen atoms or linear, branched, and/or cyclic C ₁ -C ₆ alkyl groups, provided that R ₁ and R ₂ are both hydrogen; Not,
the pharmaceutically effective amount is 600 mg per dose;
A pharmaceutical composition in which the subject in need thereof has severe hypertriglyceridemia and has a fasting plasma triglyceride level greater than 500 mg/dl. 16. The pharmaceutical composition according to claim 15, wherein the dyslipidemia drug is a statin.

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